Tobacco Documents Online

RECENT PROGRESS IN THE EPIDEMIOLOGY OF LUNG CANCER IN HUMANS Du, Ying-xiu, Guangzhou Medical College Abstract: Lung cancer has been on the rapid rise worldwide during the last three or four decades. In China, death rate in lung cancer is the highest among all types of malignant tumors in the urban population. Smoking, indoor and outdoor air pollution, and certain occupational exposures have been recognized as the main risks [causes] of lung cancar. 'i'h 1 s hica boon confirmed by mnny Qp.idom:t.o].ogicn], research and laboratory studies. However, the significance of such risk factors [causes] may vary for different sexes or different areas. Smoking is an important risk factor of lung cancer in both men and women; however, a large number of female lung cancer patients are never-smokers, indicating potential important risk factors other than smoking. There is great debate over the association of passive smoking and lung cancer. Currently available information cannot sufficiently confirm that passive smoking is capable of lung cancer induction. The relationship of atmospheric air pollution and lung cancer has long been notedl however the relationship is complex and the investigation requires long-term data. Indoor air pollution is. an

important cause of lung cancer in women in China, but this is rarely reported outside China. At present, 11 carcinogens and 5 industrial processes have been confirmed as causes of occupational lung cancer. With further etiology research, more lung cancer causes may be discovered. To date, several observed phenomena are still without explanation. For example, why is smoking not an important factor in lung cancer in farmers? Or, what is the reason for the high incidence of adenocarcinoma in women? The answers may require research in the pathogenic mechanism of lung cancer. According to WHO report', for the past few years, stomach cancer and cardiovascular disease have decreased, while lung cancer is on rapid rise globally. There are already 35 nations where lung cancer is the number one malignant tumor in men; other nations will see lung cancer also becoming the number one malignant tumor in women. According to forecasts based on available information, AIDS and lung cancer will be the two most frequent health threats to mankind in early 21st century. In 1980, the number of new lung cancer cases of the world were estimated to be 600,500 (including 66,300 in China). If effective measures of prevention were not adopted, this number could reach 2 million in the year 2000 and 5 - 2 - ~

I million in 2025. In China, according to annual nationwide health statistics, during the seven years 1982-1988, the average annual death rate of China's 16 largest cities was 565/100,000 with little change in the seven years (b = 0.011, P> 0.05). The total cancer death rate, on the other hand, was on the rise; the average of 100/100,000 in 1982 was increased to 125/100,000 in 1988 (b = 0.0117, P < 0.05), including the lung cancer death rate which not only constitutes 25% of all cancers but also increased most rapidly, 25/100,000 in 1982, 32/100,000 in 1988 (b = 0.0151, P < 0.01). The swiftness with which lung cancer death rate has risen is not often seen in other diseases; this inevitably causes great concern. Regarding the cause of lung cancer, according to K.W. Brunner (1988)2, there is reason to believe that the global prevalence of lung cancer is caused by conditions of the modern society and the (unhealthy) lifestyles of the people. Smoking, indoor and outdoor air pollution, and certain occupational exposures are considered the three most important factors in the etiology of lung cancer. O.S. Selawry (1982)3 is of the opinion that at least 80% of lung cancer can be attributed to chemical carcinogens. Thus, research in the mechanism of carcinogenesis will be the basis to prevent lung cancer. Active Smoking and Lung Cancer - 3 -

That smoking can cause lung cancer has been confirmed. R. Doll's (1976)4 20-year retrospective study of 34,440 British male doctors found the adjusted death rate for non-smokers was 10/100,000, for non-cigarette smokers 48/100,000, for 15-24 cigarettes per day smokers 127/100,000, for over 25 cigarettes per day smokers 251/100,000. Lung cancer occurrence rate decreased by 11% of the estimated occurrence within 15 years of smoking cessation, while no change occurred for the incidence of other tumors. This research strongly suggests the close relationship of smoking and lung cancer. Many case-control studies of smoking and lung cancer relationship were also conducted in many areas of China. For example,f the Wuhan Medical College study reported a relative risk (RR) value of 5.33 for smoking and lung cancer; Liaoning Health Investigation Bureau reported a RR of 8.45; Ninjing Health and Disease Prevention Station reported a RR of 6.51 for smokers of fewer than 20 cigarettes per day, and RR as high as 17.95 for smokers of more than 21 cigarettes per day. In 1985 our study5 of 849 cases and controls of lung cancer in Guangzhou showed smoking had important significance for both men and women. The RR for men, at 95% confidence level, was 3.53 (2.44-5.11, P < 0.01) and 1.93 (1.30-2.27, P < 0.01) for women. The reason for the lower i relative risk for women was that many female lung cancer patients were non-smokers, which in turn indicated potential risk factors other than smoking existed for female lung cancer. - 4 -

Eatough (1989)6 reviewed world literature on the chemical constituents of mainstream and sidestream tobacco smoke and found that among the 108 traceable chemicals, in addition to the six that had already been designated as carcinogens by IARC (2- Naphthyalmine, 4-Aminobiphenyl, Benzo(a)pyrene, N- Nitrosodimethylamine, formaldehyde, and Acetamite), others may be potential carcinogens also. Zhan De-jing et al. (1992)7 applied a metabolite of B(a)P, Anti-BTBE, to bronchial epithelial cells of human fetus and observed not only mutation at H-ras gene 12 but it also resembled the mutation phenomenon observed in human lung cancer specimens. Kapitulnik (1977)8 induced lung tumor in mice by Anti-BTBE. Chen Jia-kuen (1991)9 applied smoke aerosol to cells of human fetus and found the cells to undergo morphological transformation. This can be accepted as laboratory evidence that smoking is associated with [can induce] lung cancer. Additionally, Wu Zhong-liang (1991)10 applied extracts from (?) tobacco and chewing tobacco to BALB/3T3 cells and found the cells to undergo mutation and the cell growth from the transformed colony to exhibit characteristics of neoplastic transformation. The findings indicate a possible carcinogenic effect of smokeless tobacco for its users. In summary, whether based on epidemiological or laboratory research, evidence exists for the association 5

[induction) of smoking and lung cancer. Smoking cessation is apparently an important measure to prevent lung cancer. Passive Smoking and Lung Cancer The relationship of environmental tobacco smoke (ETS) exposure and lung cancer is still being debated. In China, studies from Harbin Shanghai, Guangzhou and Xiuanwei all reported no association between smoking and female lung cancer. Studies from abroad have presented mixed reports. Some find no relationship between the two, others, while finding ETS an important risk in female lung cancer, disagree on cell types. Some find an association of ETS and adenocarcinoma only, which is unrelated to lung cancer of any other cell types, others find ETS a risk in squamous cell carcinoma only. Since the etiology of a disease is closely related to cell types, the latter two groups actually hold opposing views on the effect of ETS. Lung cancer is characterized by not only multiple risk factors but also long latency. The conditions of human exposure to ETS can also be complex. For these reasons, to ascertain the relationship between ETS and lung cancer, the research must include good control for a number of factors. Examples: - 6 -

t 1: The study subjects must experience "true" exposure to ETS, i.e. other than being non-smokers themselves, the study subjects' exposure to air pollutants and occupational exposure must be controlled; 2. Both the extent of the exposure to ETS and the active smoker's smoking status can be accurately measured; 3. Objective reference biological markers exist that can precisely reflect'the effects of ETS. Unfortunately, none of these can be achieved at present. Perhaps that is the reason why the association of ETS and female lung cancer cannot be confirmed. We (1992)11 conducted a case-control study of non-smoking lung cancer patients that included effects of the husbands' smoking on lung cancer of non-smoking wives, which also analyzed the relationship of active and passive smoking with lung cancer cell types. We found no association between the two. G. Pershagen et a1.1Z conducted a case-control study which surveyed 27,409 Swedish female non-smokers by correspondence method. They found when non- smoking women were married to smoking husbands the RR (3.30) of squamous carcinoma for these women increase with statistical significance (P < 0.05). But in their 20-year follow-up study, only 67 cases of lung cancer were found, including only 20 cases of squamous carcinoma and small cell carcinoma. The sample size seems - 7 -

small. In order to explain why ETS only induces adenocarcinoma of the peripheral type and not the central type squamous carcinoma which is primarily induced by active smoking, Wynder (1983)13 proposed a hypothesis. When ETS passes through the nasal cavity, the vibrissae are able to block certain particulates, with the result that gaseous phase carcinogens in the sidestream smoke are able to penetrate deep into the lung, even deeper than active smoking, and thereby induces peripheral type adenocarcinoma. This hypothesis invites discussion. Carcinogens in tobacco smoke have high vaporization temperatures: for example, 2-Naphthylamine at 306°C, 4-Aminobiphenyl at 302°C, Benzo(a)pyrene at 311°C and N- Nitrosodimethylamine at 152°C. It is difficult to imagine that they can maintain their gaseous state in the ambient environment or in the body without coagulating into particulates and enter the body as particulates.~ Recently, Trichopoulos et a1.14 evaluated effects of active and passive smoking by using the increase, squamous metaplasia, abnormality of the bronchial and alveoli basal cells as evidence of EPPL (epithelial possibly precancerous lesions). They used the EPPL value of 60 and less than 40 as standard determinant and found when non-smoking women were married to smokers their EPPL value was higher than those married to non- smokers. Based on this finding they supported the view that ETS can induce lung cancer. In the same paper, however, the EPPL value for heavy smokers could be as low as 29. Calculated by the same , standard determinant, the OR (6.0) for non-smoking women married to - 8 -

smokers when compared to those married to non-smokers is actually higher than the OR (4.4) for active smokers compared to non- smokers. In other words, passive smokers have a higher risk of lung cancer than smokers. This is indeed baffling. It can best be said that current data have not strongly proved the association of ETS and lung cancer. However, it does not mean that ETS is harmless to humans. The sidestream smoke of cigarettes contains many harmful substances which are apparently hazardous to health. Atmospheric Air Pollution and Lung Cancer Statistical data show that the 1988 death rate (/100,000) of China for large cities as (32.14) which is higher than for medium size and small cities (17.00) which is again higher than for rural areas (12.53). Two questions arise: 1. Death rate is higher for urban than for rural population. Is air pollution one of the causes? 2. There is little difference in the smoking rates of urban and rural population. Why is it that smoking does not appear as important to farmers' lung cancer? - 9 -

The atmospheric air pollution and lung cancer relationship has long been noted. P. Stocks (1959)" (1960)" reported lung cancer rates in various parts of Great Britain are closely related to local atmospheric sedimentation(?) index, smog index, population density, and atmospheric concentrations of B(a)P, beryllium, molybdenum, vanadium and arsenic. W.J. Blot (1976)16 analyzing regional lung cancer death rates in the U.S. found higher male lung cancer death rate in locations of paper, chemical, petroleum, and locomotive manufacturing industries and that the death rate is also related to atmospheric air pollution. Blot joined Z.Y. Xu (1989)19 in conducting a case-control study in Shenyang which found more male and female lung cancer patients living near smeltering plants for longer years. Wang Juen-shang et al.20 studied the relationship of lung cancer regional distribution and industrial pollution in Shanxi Province. They found lung cancer in Shanxi is characterized by focal distribution pattern(?), i.e. with industrial. city as the center, lung cancer spreads outwardly and to areas whose parameters are determined by the degree of industrialization. Lung cancer death rate is also related to atmospheric air pollution, the worse the air pollution the higher the lung cancer death rate. The direction of spread of lung cancer high-incidence areas is also related to prevailing wind direction, higher in down-wind areas than up-wind areas. For example, the spread from Taiyuan as focal center, the locations of - 10 -