Tobacco Documents Online

ETIOLOGY OF LUNG CANCER IN WOMEN Au Ying-xiu Guangzhou Research Center for Lung Cancer, Guangzhou, China Studies in epidemiology have shown that there are more male smokers than female smokers, yet female lung cancer rates remain very high. For example, for the over-15 population in Guangzhou, 65% of the males, but only 5% of the females are smokers. However, the lung cancer death rate for many years has maintained a male to female ratio of 2.4:1.0, implying that in female lung cancer there may be some risk factors other than smoking. Figure 1. The increase in cancer mortality in the U.S. in the last 40 years. Figure 2. The increase of total death rate, total cancer death rate and lung cancer death rate of the 1980s in the urban population in China. Figure 3. The increase of total of the five leading cancer death rates in Guangzhou, 1973-1988.

Table 1 A Comparison of Smoking Rates with Male/Female Lung Cancer Death Rates Smoking Rate Lung Cancer Death Rate Mate Female Relative Male Female Relative Ratio Ratio Peasant Guangzhou 65,000/105 5,000/105 13.0 45/105 25/105 1.8 j Xuanwei I I Many studies have emphasized the importance of ETS as a risk factor for lung cancer. Yet case studies have revealed that more than 50% of the female lung cancer cases are nonsmokers. Leaving aside the question of whether ETS-exposure is actually associated with lung cancer, there is no apparent rationale to believe that 50% of all nonsmoking female lung cancers are exclusively due to exposure to ETS. Clearly, further investigations of all potential risk factors for female lung cancer are needed. It is common knowledge that the etiology of a disease is closely related to the mechanism of the disease development; thus, in any etiology research, the methodology should include mutual verifications from both epidemiological and experimental results. Lung cancer mortality rates have risen dramatically in recent decades. One logical explanation is that lung cancer is caused by - 2 -

environmental carcinogens, since the influence of genetic factors is usually relatively constant and rarely triggers sudden changes in a relatively short time. Since there is an apparent difference in the relative distribution of cell types between male and female lung cancers, it seems possible that different mechanisms are involved in the induction of different histological types of lung cancer. Some studies have reported the tendency of lung cancer to be clustered in families. Whether the rapid rise in lung cancer death rate is attributed to external factors or to internal considerations or, a1ternati.vel.y, to their interactions remain to be investigated. There are many cell types in lung cancer. The four most common types are: squamous cell carcinoma, adenocarcinoma, small cell carcinoma and large cell carcinoma, with squamous cell carcinoma and adenocarcinoma making up more than 80% of the total lung cancer cases. These two malignant cell types have many different biological characteristics. Squamous Cell Carcinoma Adenocarcinoma > Cell Origin From mutation of From mutation of mucous membrane cells small bronchial of main or larger cells, pulmonary bronchia; slow alveolar cells or developing glandular cells; fast developing - 3 -

Location Central type Peripheral type, invasive to pulmonary membrane Morphology ? ? Structure ? ? Microscopic ? ? Structure Biochemical Low serum cytokeratin High serum Characteristics 19 level cytokeratin 19 level, capable of endocrine secretion Proto-oncogen r Cel1 Membrane Low positive estrogen High positive Receptors receptors estrogen receptors The cell type difference in male and female cancer patients holds clinical significance. Squamous cell carcinomas are seen more frequently in males (approximately 55% of cases), and adenocarcinomas are the next most frequently seen (approximately 25% of cases) . The reverse is true with female patients: the most frequently seen are adenocarcinomas (approximately 60% of cases), the next most frequently seen are squamous cell carcinomas (approximately 25% of cases). It is apparent, then, in the investigation of female lung cancer etiology, we should focus on research of adenocarcinoma. Furthermore, as many recent reports have indicated, the ratio of lung adenocarcinoma continues to rise among lung cancers. This is one of the important reasons for the investigation of the etiology of lung cancer. - 4 -

Table 2 comparison of Lung Cancer Cell Type Between Male/Female Smokers and Non-Smokers* in Both Male and Female Cases* (M806, F289) Male Female Smoker Non-Smoker' Smoker, Non-srrDker No._ X No. : X No. X No. Y Squamous cell carcinoma 438 59.03 25 40.32 51 36.17 33 22.30 Small cell carcinoma 56 7.55 2 3.23 12 8.51 12 8.11 Adenocarcinoma 170 22.91 22 35.48 57 40.43 83 56.08 Large cell carcinoma 14 1.80 1 1.60 1 0.71 1 0.67 Others 64 8.62 12 19.36 20 14.18 19 12.84 TOTAL 743 100.0 62 100.0 141 100.0 148 100.0 Male Female Smoker Sqm (59.03) > Ade (22.91) Sqm (36.17) = Ade (40.43) * A total of 1093 (Male 804, female 189) were used. 1. Smoking and Female Lung Cancer. Smoking is generally recognized as an important risk factor for lung cancer in both men and women. However, smoking's relative significance for female lung cancer seems to be lower than that for male lung cancer. Because a large number of female lung cancer patients are nonsmokers, the OR for smoking in women is lower than the OR for men. When the cell types of smoking and nonsmoking male and female patients are compared, the results show that among male smokers, the squamous cell carcinoma rate is decidedly higher than the adenocarcinoma rate, but among female - 5 -

smokers the rates are similar; among nonsmokers, the squamous cell. carcinoma and adenocarcinoma rates are similar in men, but the adenocarcinoma rate is much higher than squamous cell carcinoma rate for women. The results clearly show that smoking may induce squamous cell carcinoma, but in women, there must be other risks for the high incidence of adenocarcinoma. 2. Exposure to ETS and Female Lung Cancer. This is a difficult subject for precise research results. First of all, lung cancer has a long latency. It usually takes more than 10 years even for active smokers to develop lung cancer. Exposure to ETS, if it is capable of inducing lung cancer, must take even longer. During such a long latency period, data and conditions of exposure such as numbers of cigarettes smoked by the smokers, the extent of contact with smokers, the shared living space, all could be unstable and variable. Moreover, in order to obtain accurate results of the effect of ETS exposure on lung cancer, in addition to ascertaining that the study subjects be truly nonsmokers, other risks or confounders such as effects of air pollution and occupational exposures must also be excluded. All these requirements are realistically difficult to achieve. Second, if the smoking-related lung cancers are of the centrally localized squamous cell carcinoma type, it follows that lung cancer associated with ETS must also be squamous cell carcinoma, and not - 6 -

the peripheral type adenocarcinoma. This, however, contradicts the reality of high incidence of adenocarcinoma in women. However, it should also be pointed out that although the relationship between ETS and lung cancer cannot be established at the present, ETS cannot be excluded as a health risk. 3. Indoor Air Pollution and Female Lung Cancer. Reports from many areas of China have clearly demonstrated a significant relationship between indoor air pollution and lung cancer in women. A major source of indoor air pollution is coal burning for cooking and heating. The following epidemiological surveys and experimental studies demonstrate that female lung cancer is likely to be related to indoor air pollution. Indoor coal burning may increase B(a)P concentration in the indoor air. Housewives in coal-burning households have significantly higher levels of urine B(a)P than housewives in liquified gas burning households. Epidemiological analyses also indicate that indoor air pollution is associated more with female lung cancer than male lung cancer. In addition to coal-burning as a source of indoor air pollution, Gao et al. also reported that there was a relationship between lung cancer and pollutants generated by certain cooking oil and cooking practices. Moreover, such a hypothesis has been substantiated by epidemiological research,and laboratory experiments. - 7 -

f Table 3 Comparison of Air Pollutants and Urine B(a)P Levels in House Wives Cooking with Coal or Propane Cooking With Coal Cooking With Liquified Gas Coal/Gas SOZ (µ/M3) 279 58 4.81 NOx (µ/M3) 76 63 1.21 CO (g/M3) 9,424 2,340 0.03 TSP (kt/M3) 332 188 1.77 SD (g/mz/month) 12 5 2.40 B(a)P ((µ/l00M3) 11.9 2.2 5.41 Radon (Bq/M3) 18.6 16.6 1.12 Thoron (Bq/M3) 42.5 28.3 1.50 Urine-B(a)P (ng/1) 4.0 2.8 1.43 -11 However, many questions remain unanswered: coal has been in use for cooking and heating and vegetable oil has been used for frying for many years; why, then, have lung cancer rates been on the rise only during the past 20 or 30 years? Environmental carcinogenic chemicals have been known to induce squamous cell carcinomas but female lung cancers are predominantly adenocarcinomas. Indoor air pollution characteristics and conditions are different for industrialized and developing countries, why have all nations experienced similar trends of higher female lung cancer and higher percentage of adenocarcinomas? - 8 -

4. History of Respiratory Disease in Female Lung Cancer. Several epidemiological studies point out that lung cancer patients often have a history of bronchitis. This is understandable in women, since in cooking, women are more likely to be exposed to smoke from burning coal and irritants generated by deep frying and stir-frying. Another question that begs our attention is that it has been reported that the disturbance of the microbial population may cause the procarcinogens in the intestine to be metabolized and activated into ultimate carcinogens, which, in turn, may induce colon cancer. Regarding lung cancer, can large doses of antibiotics used to combat chronic bronchitis result in the disturbance in the microbial population in the lung, causing the procarcinogens in the lung to be metabolically excited into , ultimate carcinogens? 5. Estrogen and Female Lung Cancer. Estrogen disturbance and female lung cancer may be a question worthy of our consideration. It has been reported that therapeutic use of estrogen for heart disease is correlated with an increase in lung cancer incidence. Some researchers cbnsider early menarche, long menstrual periods, shortened menstruation cycles and - 9 - ~

delayed menopause as some of the risk factors of female lung cancer (Gao Yu-tang, Liao Mei-lin). Others have reported, the level of estrogen receptors on the surface of adenocarcinoma cells is higher than other lung cancer cell types (Kabayashi). Still others think that female lung cancer may be related to use of oral contraceptives (Wang Sheng-yong). Physiologists have long recognized that the lung is not only an air exchange organ but also has hormone secretion functions. Further research into the relationship between estrogen disturbance and lung cancer, especially in relation to adenocarcinoma, known to have extra-cellular secretion characteristics, is urgently needed. Research aimed at examining endocrine disturbances in relation to lung cancer must proceed in parallel with investigations directed at the rapid increase of lung cancer. Without understanding the etiology of a disease, the prevention of the disease cannot proceed successfully. Thus, research into the etiology of lung cancer is the key to halt the rapid rise of lung cancer. -lo-