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a I I I I t I I I I I I 1 W I 1 AN EPIDEMIOLOGICAL INVESTIGATION OF RISK FACTORS FOR LUNG CANCER IN GUANGZHOU, CHINA Du Yine-xiu*, Cha Qing*, Chen Xiao-wei*, Chen Yong-zhong* Huang Lan-fang**, Feng Zhen-zhi** and Wu Xia-fen** * Department of Hygiene, Guangzhou Medical College, Guangzhou, China ** The Municipal Health & Antiepidemic Station of Guangzhou, Guangzhou, China Abstract Lung cancer is one of the five leading tumors in the city of Guangzhou and has been increasing steadily in both males and females since the 1970s. In this report, more than 6,000 cases of lung cancer deaths, accumulated over the past nine years, were analyzed. Significant differences were found between males and females with respect to lung cancer risk factors. In a case-control study, 849 cases (571 males and 278 females) and a conditional logistic regression analysis of 120 nonsmokers (28 males, 92 females) were studied on the relative contributions of smoking, occupational exposure and indoor air pollution as risk factors for the rising incidence of lung cancer. The conclusions were as follows: In females, indoor air pollution, derived primarily from burning coal, is a highly significant risk factor for lung cancer. In males, however, cigarette smoking and occupational exposure play a more important role. Diet, especially vegetable intake, afforded positive protection for lung cancer. Estrogen changes are suggested to be significantly involved in the increased incidence of female adenocarcinoma. Introduction Statistics published by the National Bureau of Public Health in China show that the overall population death rate in the sixteen largest cities from 1982 to 1988 remained relatively constant at 565/100,000 (regression coefficient b=0.001, p> 0.05), while the mortality rate attributable to all forms of cancer has steadily increased from 100/100,000 in 1982 to 125/100,000 in 1988 (b=0.0117, p<0.05). Of particular note is the change in the lung cancer death rate, having increased from 25/100,000 in 1982 to 32/100,000 in 1988 (b=0.0151, p<0.001), which accounts for 25-26% of all cancer-related deaths. Lung cancer deaths in the city of Guangzhou rank as the third highest in the nation, behind the cities of Chungking and Shanghai. Since the early 1970s, lung cancer has been the foremost cause of death among the leading tumor-induced deaths. In 1989, the world standardized mortality rate (per 100,000) for the five leading tumors ranked, respectively, as follows: lung cancer (39.79), liver cancer (24.12), stomach cancer (9.67), nasopharynx cancer (6.07) and esophageal cancer (5.00), with lung cancer deaths amounting to almost the total of those originating from the liver, the stomach, and the nasopharynx. ' Cigarette smoking, occupational exposure, and air pollution (indoor and outdoor) are generally believed to be the three major risk factors for lung cancer. The relative importance of each of these N I factors, however, is known to vary with sex as well as with region and location. For example, in the city pC)p of Guangzhou, the ratio of the incidence of lung cancer in males and females is approximately 2.1:1; ~ however, cigarette smoking is much more prevalent among males (43 % of males, age 15 and above, are OVo ` smokers) compared to females (only 4%).(1) Forty percent (40%) of female lung cancer deaths were ~ ! V W I

I found to be never smokers, suggesting that, in females, factors other than smoking must exist and contribute significantly to lung cancer deaths. In an occupational analysis involving 5546 cases of lung cancer deaths, it was found that the percentage attributable to occupational exposure is small and can account for no more than 15 % of the cases in both males and females.(2) In an earlier investigation, Du et al.(3) concluded that in the various city districts of Guangzhou in which significantly different lung cancer death rates exist (ranging from a low of 20/100,000 to a high of 48/100,000), lung cancer incidence was correlated with the severity of atmospheric pollution. These findings show that even within the same city, the incidence of lung cancer can be influenced by the complex interaction of numerous known and unknown factors. Our previous studies have also revealed an association between indoor air pollution and the incidence of female lung cancer deaths.(4) Similar results have been obtained in other cities in China. In a case-control study on the prevalence of female lung cancer in the city of Shanghai, Gao, etal.(5) suggested that indoor air pollution and the related use of rapeseed oil in cooking may significantly contribute to the recent pronounced increase in lung cancer cases. Similarly, in a case-control study in Harbin, Dai eta l.(6) observed that the risk for adenocarcinoma was correlated with lower I3-carotene consumption and the use of coal for heating. Risk was also related to the generation of smoky conditions during heating. In the same study, it was reported that the frequency of squamous cell carcinoma was significantly associated with smoking, a history of bronchitis, and a prevailing smoky environment during heating. In Xuanwei county, Yunnan Province (documented to have the highest national female lung cancer mortality of 121/100,000 based on statistics published in 1973-1975), He et al.(7) reported in a case-control study that extremely high lung cancer mortality was caused by indoor air pollution and by "smoky" coal combustion. Substantial differences exist regarding the nature of indoor air pollution between a still developing country such as China and developed countries. Since cooking in industrialized nations primarily uses electricity or gas and seldom involves deep or stir frying over high heat, insignificant levels of respirable particulate matter and B(a)P are generated during cooking. Consequently, cooking is not considered a significant source of indoor air pollution. On the other hand, there are substantial particulates liberated from carpets, walls, ceilings and other types of indoor decorations, which would constitute the bulk of indoor air pollutants in families of developed countries and which are rarely encountered in China. In China, families in rural villages use wood and straw for cooking and heating, while in cities, coal is the primary fuel source for cooking. Cities in northern China are additionally dependent on burning coal for heating. These social habits, coupled with China's population density and, hence, small-size living area, have compounded the severity of indoor air pollution. Although many of the published case-control epidemiologic studies investigating the relationship between indoor air pollution and the incidence of female lung cancer have suggested a causal relationship, it is important to emphasize that such information is merely a clue and must be complemented by laboratory investigations in order to definitively demonstrate the biological plausibility of a causal relationship. For example, the notion that indoor coal burning is a major factor for female lung cancer would require studies showing that: 1) coal consumption indoors can generate significant levels of potentially carcinogenic substances and 2) such materials are also found to be present in exposed subjects at concentrations sufficiently high for cancer to be induced. In addition, because the development of lung cancer is likely to involve multiple factors and has a relatively long latency, and since factors being 2 I I I 1 I I• I I I i I I I I

I I I I I ~ I I I I I I I I investigated may be causal as well as consequential, due consideration must be given to confounding in connection with attempting to elucidate the effects of a single agent (or event) on the development of lung cancer. For example, the real impact of indoor air pollution on female lung cancer should be addressed in the context of confounding due to occupational exposure and cigarette smoking. Because the cell-types in male and female lung cancer are distinctly different, with squamous cell carcinoma being most predominant in males and adenocarcinoma prevailing in females, and because numerous studies have already concluded that unique lung cancer cell-types are caused by different carcinogenic factors, it is of interest to determine the cell-type in lung cancer cases that are attributed to indoor air pollutants. In this report, we have systematically analyzed the risk factors for female lung cancer deaths and have compared the associated risk factors between males and females. Materials and Methods Because of the long latency of lung cancer, and since the three factors (air pollution, occupational exposure, and cigarette smoking) being investigated in relation to lung cancer deaths may have complex interactive effects, a broad database, collected over a long period of time, is required for reaching meaningful conclusions. 1. Case History. In Guangzhou (population 2,000,000), there are four districts with 63 local police stations. Each station has a complete registry, containing information on age, sex, occupation, residence, and time/cause of death. In 1976, we began a detailed analysis of the registry, concentrating on cases in which death was caused by cancers of the lung, liver, nasopharynx, stomach, and esophagus. The annual crude and age- adjusted death rate, as well as the wotld age-adjusted death rate, was calculated yearly in order to ascertain the trend of deaths attributed to the five cancers. Beginning in 1980, every case of death from lung cancer was further analyzed using a standardized questionnaire containing 31 questions. Information was obtained retrospectively from relatives and verified by comparison with hospital records. The questionnaires were administered by trained medical personnel, and the data were entered into a computer. Because all deaths in China, including time and cause, must be reported to the local police station, and the report must agree with information provided to cremation centers, the data generated were considered to be highly reliable and accurate. 2. Analysis of Outdoor and Indoor Air Pollutants. ~ The city of Guangzhou, with an area of 55 square kilometers, can be divided into the four districts of Liwan, Yuexiu, Dongshan, and Haizhu. Atmospheric pollution status was systematically ' monitored by the Guangzhou Health and Antiepidemic Station(8), by the Guangzhou Environmental Monitoring Center(9), and by International Atmospheric Pollution Centers(8) established and managed by the World Health Organization. The information collected over the past two decades was used to ~ calculate the Air Pollution Index according to the following equations(10): p W i V ~ 00 3- N cc V N I

1 n Ci API = E where: Ci -- Measured concentration of pollutants Si -- Permissible level of pollutants To assess the effects of indoor air pollution, two investigations were conducted in 1984 and 1985 as follows: Five families were randomly selected in each of the four districts. Samples were obtained over a 5-day period at each of the four seasons during the year. Daily samples were collected as follows: SO2 and NOx samples were obtained every 2 hours from 7 a.m. to 7 p.m. for a total of 7 samples per day; TSP and B(a)P were determined daily. To compare the levels of indoor and outdoor pollution, samples of SO2, NOx, TSP and B(a)P were also collected in the immediate outdoor vicinity of the selected families.(11) The levels of indoor and outdoor radioactivity in Guangzhou were measured by Wu(11) as follows: ten families were randomly selected in each of the four districts in July of 1984 and in February of 1985. Radon, thoron, and their daughters were measured. To determine whether the measurements may be affected by the construction material and by the type of cooking fuel used, houses constructed with different materials and homes using either coal or liquified petroleum for cooking were used. The major source of indoor pollution came from cooking. This is especially evident when burning coal was used. Thus, a comparative study was conducted in 1986-1987 in which total suspended particulate (TSP), TSP-B(a)P, sedimentary dust (SD), SD-B(a)P and B(a)P in the urine of housewives were determined. To avoid contamination from industrial sources, only families located far from factories and highways were used. The age of housewives ranged from 40-70. They were nonsmokers and had been working at home for at least 1 year. 3. Occupation Analysis. The majority of the participants were males with steady, well-defined jobs. To be eligible, a person must have worked in the same job for a minimum of 10 years. To determine the true risk potential of the different occupations, Hench's method was used to calculate the Standard Mortality Rate (SMR) and the Population Attributable Risk (PAR). The relationship between lung cancer deaths and occupation was ranked as "None," "Probable." and "Obvious." Such a ranking system permits a systematic comparison of the relative contribution of occupation on the incidence of lung cancer deaths. 4. Active Smoking. Smoking history includes age at which smoking began, number of cigarettes smoked per day, number of years smoked, and the type of tobacco consumed. A smoking index was obtained by multiplying the number of cigarettes smoked per day by the number of years smoked. In addition to case-control studies, we further analyzed whether smoking is a confounding factor for the effects of occupational exposure. Since it was not possible to obtain the rate of smoking for every case in each occupation, the effects of smoking on the standard mortality rate (generated from occupational exposure) were determined by rank correlation. 4 N 0 ~ ~ V Co N tD V rn I 11 I I t M l I I I I I I I I

I I I I I S 1 I I I I The effect of smoking on lung cancer cell-type was also investigated by correlating the smoking status and the smoking index. 5. Case-Control Studies. (a) Effects of Smoking and Coal Fume Exposure. In 1985, there were 849 lung cancer deaths (571 males and 298 females). They were matched for sex, age ( t 2 years), and residence with nonlung cancer-related deaths. They were analyzed according to Mantel-Haenszel and by the stratification method, from which the relative risks associated with smoking status and contact with smoke from burning coal were obtained. (b) Effects of Other Risk Factors: Study Involving Nonsmokers. In the 849 lung cancer death cases, 120 cases (28 males and 92 females) were never-smokers. To investigate the effects of risk factors other than smoking, a separate case-control study, matched 1:2 for sex, age, and residence, was performed using two groups of controls. The first group consisted of 120 cases of never smokers who died from nonrespiratory illnesses. The second group consisted of never smokers whose deaths were caused by tumors outside of the respiratory system. Items investigated include: X1-history of respiratory disease; X2-consumption of fresh vegetables; X3-history of contact with toxic substances prior to death; X4-ETS exposure; X5-indoor air pollution; X6-size of living quarters; X7-size of kitchen; X8-cooking fuel; X9-participation in cooking; X10-family history of cancer. The contribution of each of these items was analyzed using conditional logistic regression. 6. Factors Affecting the Distribution of Lung Cancer Cell Tvnes In this study, we examined the influence of active and passive smoking, air pollution (indoor and outdoor), and occupational exposures on lung cancer cell types in both males and females. Eight cell- types of lung cancer were identified. These include squamous cell, small cell, adeno, large cell, epi- adeno, carcinoid, bronchial gland, and others. Over 80% of the total cases can be classified into squamous cell carcinoma and adenocarcinoma. The occurrence of these cell types shows a significant difference between males and females. Results 1. Deaths Attributed to Five Leading Cancers in Guangzhou From 1976 to 1989 Table 1 shows the results of the regression analysis of deaths due to the five leading tumors. In the case of lung cancer, a significant increase was observed in both males and females (p<0.01). Little change was found in liver and stomach cancers (p>0.05). Deaths due to nasopharynx and esophageal cancers show a decline (p<0.05) in the same period. O ~ ~ v 00 ~ v N I

2. Analysis of Lung Cancer Death Records. Between 1980 and 1989, 6,812 cases of lung cancer deaths, with 4,615 males and 2,197 females (sex ratio of 2.1:1), were recorded. For the present study, the following death cases were excluded: 1) those not involving primary lung cancer and 2) those residing for less than 10 years in Guangzhou. A total of 5,546 cases (3,760 males and 1,786 females) were included in the analysis (sex ratio 2.1:1). The youngest subject was 25 years old and the oldest was 98 years of age. The average death age was 64 in males and 65 in females. There were more cases of death due to cancer of the right lung, and the majority of these cases had central rather than peripheral foci. Metastasis was observed in 60% of the cases. 3. Atmospheric Pollution Between 1972 and 1990, 3 large-scale samplings of atmospheric pollutants were conducted. The results were transformed into an Atmospheric Pollution Index (API), which measured the concentrations of S02 and TSP. The TSP were further checked for their mutagenic activity using the Ames test (TA98, S9-) as described by Li et al.(12) Results in Table 2 show that atmospheric pollution was most severe in Liwan and was also correlated with the greatest incidence of lung cancer deaths. Likewise, TSP in Liwan demonstrated the most pronounced mutagenic activity (Table 2. 4. Indoor Air Pollution An investigation into indoor air pollution over a two year period shows that the level of pollutants is higher indoors than outdoors (Table 3, due to the fact that most of the factories are located in the outskirts of the city and because of the infrequent automobile use in Guangzhou in the year 1984-1985. Three daily peaks (7:00 a.m., 11:00 a.m., and 7:00 p.m.) in the levels of SO2 and NOx were observed. The levels were higher in winter and spring (when the windows were usually closed) than in summer and autumn (when the windows were open), suggesting that the major source of indoor air pollution came from cooking (Table 4. In Guangzhou, the traditional use of wood for cooking in the 1950s was replaced by coal in the 1960s, Beginning in 1980, some of the families began using liquefied petroleum. In 1992, about 50% of the families used gas for cooking. Table 5 compares the levels of indoor air pollutants and B(a)P in the urine of housewives among families using burning coal and those using gas. The levels are significantly higher in coal-buming families. The presence of B(a)P in the urine suggests that the amounts generated during cooking are readily taken up by the body. Table 6 illustrates the levels of radon and thoron (and their daughters) inside and outside of the home. The levels are correlated with the type of construction materials Table 7 and cooking fuel used (Table 8. Specifically, houses constructed with green and red bricks emit more radon and thoron than houses constructed with concrete. Moreover, thoron and radon levels were further elevated by the presence of burning coal, although never exceeding the National Standards (GB 4792-84). -6- i 1 11 I I R I I I I I I I ^ 1

a I I I I I I I I I I 5. The Effects of Occupational Exposure In the 5,546 cases of lung cancer, 6,167 personal occupation files were found. Approximately 600 people spent 10 years in 2 or more different professions. Occupation distribution is illustrated in Table 9 and Table 10. About 15 % of the cases may have exposure to job-related pollutants. To correlate occupational exposure and incidence of lung cancer deaths, a Standardized Mortality Ratio (SMR) was calculated for 434 cases of lung cancer deaths in the year, 1982 (Table 11). The Population Attributable Risks (PAR) for the 12 occupations are shown in Table 12. Chemists have the highest SMR in males, whereas homemakers have the highest SMR in females. Homemakers also have the highest PAR. 6. Active Smoking About 93% and 59% of the 3,755 and 1,784 cases of male and female lung cancer deaths, respectively, had a smoking history record. 95.3%, 2.8%, 1.4% and 0.5% of the smokers smoked cigarettes, water pipes, pipes, and cigars, respectively. The smoking history in the 5,539 cases of male/female lung cancer deaths is illustrated in Table 13. About 70% of the smokers began smoking before age 20. Cigarette consumption is higher in males (25 per day) than in females (20 per day). The smoking index is also higher in males (670) compared to females (630). The longer duration of smoking in females is probably due to their longer life expectancy. Using a rank correlation method, the contribution of smoking as a confounding factor on "Occupation-SMR" was studied and is illustrated in Table 14. In subjects with identical occupation, female "Occupation-SMR" was not affected by smoking, whereas in males, smoking did significantly influence "Occupation-SMR". Cigarette sales (packs/person/year) in Guangzhou between the years 1961-1974 were correlated with lung cancer death rates between the years 1976-1989. The coefficient of correlation (r) was 0.86 (p<0.01) in males and 0.71 (p>0.05) in females, showing that cigarette consumption is more closely associated with male lung cancer deaths. 7. Case-Control Studies The 849 (571 males and 278 females) lung cancer deaths in 1985 were further analyzed in two case-control studies. In the first study, in addition to evaluating the relative risks associated with cigarette smoke and contact with burning coal, the estimated annual death rate, the attributable death rate, and attributable risk were also evaluated and are listed in Table 15. The effect of cigarette smoke on lung cancer is much less important in females than males. By ] contrast, indoor air pollution is a highly significant risk factor for female lung cancer deaths but had no ' effect in males. The estimated death rate in males attributable to cigarette smoking is 31 % higher than the standardized death rate (68.5 compared to 52.2), while that attributable to contact with burning coal N ~ is much lower (38%, 19.9/52.2). In the case of females, the corresponding percentages are 49% p~p _L ti co 7_ y ~ M tc 1

i (12.3/24.7) and 77.7% (19.2/24.7), further showing that smoking is a more important risk factor for males, while contact with burning coal is a highly significant risk factor for females. ~ i In the second study, conditional logistic regression analysis was performed on the 120 cases of nonsmokers (28 males and 92 females) matched 1:2 with controls. ~ When lung cancer cases were matched with nonrespiratory cancer, we obtained results that are described by the following equations: ~ Males: logit Pi= ai + 0.045X3 11 Females: logit Pi= ai - 0.663X2 + 0.129X5 - 0.217X7 When lung cancers were matched with deaths not involving the respiratory system, the observed results were shown to fit the following equations: Males: logit Pi= ai - 1.330X2 + 0.0481X3 Females: Logit Pi = ai - 0.796X2 + 0.032X3 + 0.216X5 - 0.548X7 These results suggest that the consumption of fresh vegetables (X2) was a protective factor for lung cancer, whereas contact with toxic substances (X3) increases the risk for lung cancer. It is worth noting that in nonsmoking females, indoor air pollution (X5) and size of kitchen (X7) are risk factors for lung cancer, whereas ETS exposure (X4), respiratory disease history (Xl), familial history of cancer (X10), living conditions (X6), use of cooking fuel (X8), and participation in cooking (X9) had no effect whatsoever on female lung cancer deaths. The exclusion of X8 and X9 in the regression equations suggest that cooking fuel use and the degree of cooking participation may have been quite similar between the lung cancer cases and the matched controls. In the case of nonsmoking males, the major risk factors were contact with toxic substances and occupational exposure. 8. Factors Affecting the Distribution of Lung Cancer Cell Types (a) Effects of Gender, 1,093 of the 5,546 lung cancer death cases (804 males and 289 females) contain information on lung cancer cell type (19.7%). In males, the most common cell type is squamous cell carcinoma (58%) followed by adenocarcinoma (24%). In females, the converse was observed, with 48% adenocarcinoma and 29% squamous cell carcinoma (Table 16 . (b) Contribution of Cigarette Smoking. These results are shown in Table 16. In addition, the relationship between smoking index and lung cancer cell types was also studied (Table 17 . A significant difference between the ratio of the various lung cancer cell types was shown to exist between smokers and nonsmokers (males, X2=15.74, p<0.01; females, X2=8.55, p<0.05). In males, the smoking index is proportional to the percentage of squamous cell carcinoma (p <0.01) and inversely proportional to the percentage of adenocarcinoma (p<0.0001). The smoking index did not affect the lung cancer cell type in females (p>0.05). In both males and females, the incidence of squamous cell carcinoma is higher in smokers than in nonsmokers, whereas the frequency of adenocarcinoma is lower in smokers than in -8- I I I I

t I I I I nonsmokers. These results suggest that smoking may be correlated with an increased incidence of squamous cell carcinoma. (c) Occupational Exposure and Lung Cancer Cell TjMe. These results are shown in Table 18. In males, occupations requiring significant exposure to toxic substances showed a greater proportion of squamous cell carcinoma lung cancer than adenocarcinoma. No difference was observed between the two cell types in occupations lacking such exposures. Such effects were not observed in females. (d) The Relationship between Lung Cancer Cell Type and Indoor (coal fume exposure) or Outdoor (houses surrounded with pollution sources) Air Pollution. These results are shown in Table 19. No difference in cell types was observed between the "exposed" and "nonexposed" groups in both males and females, except that an increasing trend of squamous cell carcinoma was noted in females exposed to coal fumes (p<0.05). Table 20 provides a comparison and a summary of the lung cancer associated risk factors in males and females. Discussion I 1 I I Our studies clearly show that major differences exist between males and females with respect to risk factors for lung cancer. In males, cigarette smoking and occupational exposure are important considerations, whereas in females, indoor air pollution appears to be most significant. A similar conclusion has been reached in numerous epidemiological investigations carried out in China. Although these studies have provided important leads with respect to factors that could play a significant role in the etiology of lung cancer, it is necessary to emphasize that the epidemiological clues must be supplemented with laboratory investigations in order to unequivocally confirm their biological plausibility and to further show that they are at least mechanistically compatible with the pathogenesis of lung cancer. 1. Cigarette Smoking Cigarette smoking is widely accepted as a major risk factor for lung cancer in males. In our studies, 93% of the males have a history of smoking. The calculated relative risk (RR) of smoking for male lung cancer was 3.54(95% CI=2.44-5.11) (p<0.001). In females, the RR was 1.93 (95% CI =1.30-2.87)(p < 0.01). Numerous studies have focussed on the chemical composition of mainstream and sidestream tobacco smoke.(13) Among the 108 chemicals that have been identified, 2-naphthylamine and 4- aminobiphenyl are considered by IARC (International Agency for Research on Cancer) to be human carcinogens.(14) Benzo(a)pyrene, N-nitrosodimethylamine, formaldehyde, and acetamide are suggested to be probable carcinogens, while 1,3-butadiene, nitrosonornicotine, N-nitrosopyrrolidine and indino(1,2,3-cd)pyrene are listed as possible carcinogens. Benzo(a)pyrene has been studied most extensively. A number of studies have shown the concentrations of benzo(a)pyrene to be elevated in the urine of smokers. N O 00 ~ V 9- 00 N CO 00 s I

As a pro-carcinogen, benzo(a)pyrene is actively metabolized to phenols, quinones, and dihydrodiols by microsotttal enzymes. While no carcinogenic effects have been associated with phenols and quinones, some of the dihydrodiols have been demonstrated to be highly reactive with DNA. We have treated human fetal tracheal epithelial cells (HFTE) with four different dihydrodiols (i.e., anti- BPDE, syn-BPDE, 3-hydroxy-BP, and 9-hydro-BP) and found that cells exposed to anti-BPDE are accompanied by an increase in micronuclei content, an induction of unscheduled DNA synthesis, and point mutations in codon 12 of the H-ras gene.(15, 16) These results are similar to the findings of Kapitulnik et al.,(17) showing that anti-BPDE was capable of inducing lung tumors in mice. Mutations in codon 12 of the H-ras gene have been similarly established in squamous cell carcinoma and adenocarcinoma of the lung. Squamous cell carcinoma and adenocarcinoma constitute 58 % and 23 % of lung cancer in males, whereas in females, the most commonly observed lung cancer is adenocarcinoma (48 %), with squamous cell carcinoma constituting only 29 %. Insofar as the incidence of squamous cell carcinoma is concerned, the 59% and 36% observed in male and female smokers are significantly higher than that observed in nonsmokers (40% in males and 22% in females, p<0.01), suggesting that cigarette smoking is mainly associated with an increased incidence of squamous cell carcinoma. In addition, we observed that the ratio of squamous cell carcinoma to adenocarcinoma in male smokers and nonsmokers is 2.57:1 and 1.14:1, respectively. In females, the ratio of squamous cell carcinoma to adenocarcinoma is 0.89:1 in smokers and 0.39:1 in nonsmokers. Thus, no significant difference can be observed in the incidence of squamous cell carcinoma to adenocarcinoma in nonsmokers (p>0.05), further supporting the role of cigarette smoking in inducing an increase in the incidence of squamous cell carcinoma. In female nonsmokers, 56% of the lung cancer is of the adenocarcinoma type. The incidence of squamous cell carcinoma in smoking females (36%) is slightly higher than the average 29% observed in the general female population, but is still lower than the observed 40% adenocarcinoma in nonsmoking females, suggesting that other factors must account for the high incidence of adenocarcinoma and that the same factor(s) must also somehow counteract the effects of cigarette smoking in inducing squamous cell carcinoma. Analysis of cell types in 1,048 cases of lung cancer deaths show that in males, squamous cell carcinoma is the most prevalent, followed by adenocarcinoma. In females, adenocarcinoma is more prevalent than squamous cell carcinoma. 2. Air Pollution Unlike other tumors, lung cancer is mainly caused by inhalation of carcinogenic substances. In our studies, areas with the highest air pollution index have the most cases of lung cancer deaths, clearly pointing to atmospheric pollution being associated with lung cancer deaths. A similar conclusion was reached by Yu et al.(18) in their studies on mutagenicity of size-fractionated air particles. It is necessary to point out that, although the magnitude of air pollution in an urban setting can be influenced by factors such as population density; the degree of industrialization and development; the source of energy; the quality and quantity of traffic; the geographical location of city and its design; etc., the major source of atmospheric pollution in Chinese cities comes from coal burning in connection with home heating and cooking. Because females stay indoors longer than males, indoor air pollution has been established as a major risk factor for female lung cancer deaths. Such a conclusion has been reached by numerous studies carried out in different parts of China. -10- a I I I I I