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I R i I Our studies show that cooking fuel and household coal consumption is a significant risk for female lung cancers (RR= 2.21, 95% CI=1.16-4.21, p<0.01) but not male lung cancers (RR= 0.90, P>0.05). This is further supported by the fact that housewives have the highest SMR. Conditional regression analysis of case-control studies involving nonsmokers show that, whereas the major risk factors for lung cancer in males are occupational exposure to chemicals and a deficiency in fresh vegetable intake, indoor air pollution and the small size of the kitchen are important considerations in females. Previously the lung cancer death rate in 23 major cities in China has been correlated with the coal consumption and the city latitudes. Moreover, a positive correlation was shown to exist in females (r= 0.41-0.49, p< 0.05) and not in males (r =0. 16-0.08, p> 0.05). Since cities located at higher latitudes tend to have longer winters requiring proportionally more home heating, it is further suggested that contact with indoor air pollutants, generated from household coal consumption, is associated with female lung cancer. Many studies in China have analyzed and compared chemicals derived from burning coal with those generated from burning gas and have generally concluded that the concentrations of SO2, C02, CO, NOx, TSP, SD, radon, thoron and B(a)P are much higher in households using coal. Furthermore, the mutagenicity associated with TSP and RSP has been established by laboratory studies. Li et al. (19) have studied organic extracts prepared from inhalable particles derived from coal burning and have compared these to similar extracts derived from wood burning, using both the Ames test and the two-stage skin carcinogenesis test. The results show that inhalable particles generated from burning coal are more carcinogenic and mutagenic. Similar studies and conclusions were also reached by Liang et al.(20) and Guan et al.(21) Our studies show that TSP and SD in kitchens burning coal have concentrations of B(a)P that are significantly higher than those burning gas. Moreover, the concentrations of B(a)P in the urine of housewives are also elevated in coal-burning households, providing direct evidence that B(a)P present in indoor air can be taken up by humans present in such an indoor environment. In addition to burning coal, the concentration of B(a)P is also affected by the type of cooking methods. Investigations carried out in the same kitchens show that, whereas the base values of TSP and B(a)P in indoor air are 107 µg/m3 and 0.41 µg/100 m3, they are elevated to 219 µg/m3 and 0.65 µg/100 m3 when soup is being prepared and greatly increased to 521 µg/m3 and 2.64 µg/100 m3 as meat is stir- fried. These studies show clearly that B(a)P is significantly generated by the method as well as the type of ingredients used during food preparation. Wang et al.(22) in a matched case-control study concluded that cooking oil fumes are a risk factor for lung cancer. 3. Occupational Exnosure Occupational exposure to arsenic, chromium, nickel carbonyl, bis(chloromethyl)ether and chloromethyl methyl ether are known to induce lung cancer. Likewise, the presence of 2-naphthylamine, beryllium, isopropyl oils, mustard gas, and asbestos have been shown to increase the incidence of lung cancer. Underground haematite mining and iron and steel founding are also significant risk factors for human lung cancer. In Guangzhou, the majority of occupational exposure involves nickel, beryllium, isopropyl oil and pollutants present in mines. Very few workers are employed in industries with other potentially carcinogenic substances. In Table 10, all workers who may have potential contact with lung cancer inducing chemicals have been grouped into the category of "Obvious Occupational Contact". The size of this group is likely to be substantially larger than individuals having "significant" and "real"

contact with cancer inducing agents. Thus, lung cancer cases which are truly attributed to occupational exposure should comprise no more than 15 % of the total lung cancer cases, which is substantially below the numbers observed in most highly industrialized cities. Judging from occupational SMR, the incidence of lung cancer in blue collar workers is significantly higher than office workers and professionals, suggesting that the probability of occupational exposure to cancer inducing substances does play a part in lung cancer development. 4. Diet and Nutrition Some epidemiological and laboratory studies show retinoids to play an important role in preventing the development of lung cancer. Doll(23) proposed that the risk for developing squamous cell carcinoma in lung cancer cases is significantly increased when smoking is combined with a deficiency of vitamin A. Our case-control studies show that vegetable intake is a protective factor for lung cancer. In laboratory investigations, preliminary experiments using bronchial epithelial cells show that a deficiency of retinoids in the culture media is accompanied by squamous cell transformation simultaneous with increased B(a)P-DNA adduct formation. Both cellular and molecular changes can be readily reversed by the addition of retinoids. Since fresh vegetables and fruits are readily available in Guangzhou, vitamin A deficiency is unlikely, except in rare cases of individuals having extreme food habits. However, conflicting results were reported by O.P. Heinonen et al.(24). In a randomized, double-blind placebo-controlled study performed on 29,133 male smokers supplemented daily with alpho- tocopherol (50 mg per day) and beta-carotene (20 mg per day) for five to eight years, no reduction in the incidence of lung cancer was observed. The possibility was also raised that these supplements may actually have harmful as well as beneficial effects. Conclusion 1. Major differences exist between males and females with regard to lung cancer risk factors. In males, cigarette smoking and occupational exposure play an important role, whereas in females, indoor air pollution, derived from cooking fuel and household coal consumption, is more important. These risk factors were confirmed in case-control studies. Moreover, exposure to ETS, a history of respiratory disease, and general living conditions were not risk factors for nonsmoking females. In nonsmoking males, contact with toxic substances and occupational exposure were risk factors. intake of vegetables is a protective factor for lung cancer in both males and females. 2. In terms of the cell types associated with lung cancer deaths, a significant difference was found between males and females. In males, squamous cell carcinoma constitutes the major type, whereas in females, adenocarcinoma is by far the most frequent cell type. When the effects of cigarette smoking are excluded, the frequency of adenocarcinoma shows an increase in both males and females and is more clearly demonstrated in the latter. In smoking females, the proportion of squamous cell carcinoma is lower than that of adenocarcinoma, suggesting that some factors must exist contributing to the high incidence of adenocarcinoma. I I I I -12-

3. While epidemiological studies have provided some clues to the etiology of lung cancer, they must be complemented with laboratory studies in order to conclusively demonstrate the mechanisms underlying the pathogenesis of lung cancer. I 4. Currently available data do not provide an adequate explanation on the recent global rise in lung cancer incidence. Further studies must be conducted to further elucidate the mechanisms underlying the etiology and pathogenesis of lung cancer. V tb -13- cNp I

References 1. Huang, S.H. (1988) A survey on cigarette smoking in Guangzhou resident. Acta Academiae Medicine Guangzhou 16: 6-13. 2. Du, Y.X., et al. (1988) The occupational analysis of lung cancer deaths in Guangzhou. Acta Academiae Medicine Guangzhou 17(1): 69-74. 3. Du, Y.X., et al. (1991) Atmospheric pollution and human lung cancer. Lung Cancer Vol. 7 (supplement) P.2 4. Du, Y.X., et al. (1990) Indoor air pollution and woman lung cancer. The Fifth International Conference on Indoor Air Oualitv and Climate. Vol. 1: 59-64. 5. Gao, Y.T., et al. (1987) A case-control study of female lung cancer in Shanghai. Guangzhou Second Svmposium on Lung Cancer Research. P. 7 6. Dai, X.D., et al. (1991) The risk factors for lung cancer in women. Lung Cancer, Vol.7 (supplement) P.3. 7. He, H.Z., et al. (1991) A case-control study on risk factors of lung cancer. Lung Cancer, Vol. 7 (supplement) P.7. 8. Huang, L.F., et al (1991) Trend study of global atmospheric monitoring in Guangzhou, Guangzhou Health and Antiepidemic Station, Guangzhou, China. 9. Yan, L.Y. (1988) Application of the remote sensing technique in the study of the vegetation ecoline and air pollution in the city of Guangzhou, Environmental Monitoring Center, Guangzhou, China. 10. Du, Y.X., et al. (1979) The summation index of atmospheric quality, Information of Guangzhou Medical College 4, 10-16. 11. Wu, Z.H. (1987) The investigation of the indoor and outdoor concentration of 222Rn, 220Rn, and their daughters in Guangzhou city. Guangzhou Second Svmposium of Lung Cancer Research, P.34 12. Li, X.M., et al. (1985) Mutagenicity of total suspended particles from five large cities of China. Journal of the Institute of Health 14:23-26. 13. Eatough, D.J., et al. (1989) The chemical characterization of environmental tobacco smoke. Proceeding of the International Symposium at McGill University P. 3-39. 14. IACR Monograph on the Evaluation of Carcinogenic Risks to Humans (1987) supplement 7: 17- 74. -14- i I

15. Chen, J.K.; Jin, B.; Yi, F.;, Wu, Z.L. and Du, Y.X. (1992) Measurement of unscheduled DNA synthesis and micronuclei formation in human fetal tracheal epithelium following exposure to BaP metabolites. Manuscript in preparation. I I i I I 16. Zhan, D.J.; Chen, J.K.; Jin, B.; Yi, F.; Wu, Z.L. and Du, Y.X. (1994) Detection of point mutation of codon 12 of H-ras oncogene in human fetal bronchial epithelial cells treated with BPED by polymerase chain reaction. Manuscript in preparation. 17. Kapitulinik, J., et al, (1977) Nature (London) 266, 378. 18. Yu, S.Y., et al. (1991) Study on mutagenicity of size fractionated air particles. Chinese Journal of Preventive Medicine 25(2): 70-74. 19. Li, X.M., et al., (1989) Carcinogenicyt and organic fraction of indoor inhalable particle. Chinese J. Preventive Medicine 23(6): 358-260. 20. Liang, C.K., et al. (1987) Kuming mice skin tumor initiating activity of extracts of inhalable particles in indoor air. The Chinese J. Preventive Medicine 21(6): 316-318. 21. Guan, N.Y., et al. (1990) A study of carcinogenicity of extracts from different size particles in air. The Chinese J. Preventive Medicine 24(1): 9-12. 22. Wang, G.X., et al. (1992) Multivariate analysis of causal factors included cooking oil fume and others in matched case-control study of lung cancer. The Chinese J. of Preventive Medicine 26(2): 89-91. 23. Zhang, P.C., et al. (1990) The determination of methylated purines (06-mGua, m7Gua) in liver and lung of mice. Chinese Journal of Preventive Medicine 24(3):136-138 24. Heinonen, O. P., (1994), N. Engl. J. Med. 330:1029-1035 ~ ' ~ ~ N O tb _L -4 - 15 - tb cNp , O I V

Table 1. Trend of World Age-Adjusted Death Rate of the Five Leading Carcinomas in Guangzhou, China (1976-1989) Carcinorna Sex Regression Equation Regression Coefficient P-value Lung M y=1.472x-2870.7 1.4720 <0.001 F y=0.4199x-811.4 0.4199 <0.01 Liver M y=0.3454x-647.3 0.3454 >0.05 F y=0.0849x-158.4 0.0849 >0.05 Stomach M y=-0.0957x+200.9 -0.0957 >0.05 F y=-0.0255x+57.7 -0.0255 >0.05 Nasopharynx M y=-0.3309x+668.5 -0.3309 <0.05 F y=-0.1572x+316.7 -0.1572 <0.05 Esophagus M y=-0.3355x+676.3 -0.3355 <0.01 F y=-0.1164x+223.7 -0.1164 <0.05 Table 2. Correlation Between Atmospheric Pollution and Lung Cancer Death Rates in the Four Districts of Guangzhou Liwan Yuexiu Dongsban Haizhu Control AP Index (1972-1979) 2.49 1.68 117 1.64 0.57 AP Index (1982-1990) 0.898 0.721 0.47 - 0.246 Pollution statusa (1984) Severe/ heavy Heavy/ medium Mediutn/light Medium/light Clean Mutagenicity of TSPb 7600 6600 6100 - - LC Death Rate (1976-1987) 37.94 35.99 30.79 31.5 <20.00 a b Pollution status was monitored by remote-control aerial sensors, Mutagenicity was ascertained by Ames test and is based on the number of reverse colonies/100 m3. -16- I I I

Table 3. Average Indoor and Outdoor Levels of SOZ, NOX, TSP, and B(a)P in Guangzhou (1984-1985) I I I I SO2(kgIM3) NOX(µg/M3) TSP(fegJM3) B(a)P(µg/100M3) Indoor 190±80 70±30 210±70 1.30±0.98 Outdoor 80±20 40±10 200±30 0.50±0.26 Table 4. Daily Seasonal Changes in Indoor SOZ(µg/M3) and NOX (µg/M3) in Guangzhou, China (1984-1985)a Time (Hr) 7:00 9:00 11:00 13:00 15:00 17:00 19:00 S02 Spring 163 145 168 157 167 216 231 Summer 144 118 131 123 131 157 174 Autumn 174 141 167 135 110 179 173 Winter 251 217 262 235 231 342 420 NOX Spring 63 72 73 61 69 80 79 Summer 67 64 64 55 51 73 70 Autumn 73 67 73 60 54 73 69 Winter 106 95 96 78 80 118 153 a Twenty families were included in the survey. -17- I

Table 5. A Comparison of the Concentrations of TSP, TSP-B(a)P, SD, SD-B(a)P and Urine B(a)P Between Coal-Burning and Gas-Burning Kitchens (1986-1987) Briquette Coal- Burning Kitchen Liquefied Petroleum Gas- Burning Kitchen Totaf suspended No. ± D No. ± SD P-Value Particulate (µg/M3) 37 322±131.0 27 188.0±6.70 <0.01 TSP-B(a)P (µg/100 M3) 21 11.9±9.3 21 2.2±1.8 <0.01 Sedimentary dust(gm1M2/month) 37 11.9±8.4 24 5.4±2.9 <0.01 SD-B(a)P(p.g/M2/month) 28 11.1t8.4 12 2.2±1.7 <0.01 Housewives urine-B(a)P (ng/1) 24 4.0±1.8 20 2.8t1.5 <0.05 I di Table 6. A Comparison of Indoor and Outdoor Levels of Radon, Thoron and Their Daughters in Guangzhou (1984-1985) Radon (Bq/M3) Radon Daughter (10-8 UM3) Thoron (BqfM3) Thoron Dau hter (10-8 I/M~) Indoor 17.8t2.1 5.84f0.72 37.0±7.2 6.94t1.06 Outdoor 13.3t2.1 4.86t0.33 14.5t2.6 4.72t0.62 GB4792-84 3300.00 19.0 75.0 57.0 11 - 18 _ t ! I I I I

Table 7. Influence of Construction Materials on Indoor Radioactivity Levels I I i I I I I I I I I I Wall Floor Radon (BqlM3) Tltoron (Bq/M3) Green Brick Brick 18.6 t 4.7 47.3 t 16.2 Cement 13.8 23.5 Red Brick Brick 18.4 t 3.8 42.3 t 16.1 Cement 17.8 f 4.8 29.6 t 14.5 Table 8. A Comparison of Radioactivity Levels Between Coal-Burning and Gas-Burning Kitchens Fuel Radon (Bq/M3) Thoron (Bq/M3) Coal-burning 18.6 ± 4.1 42.5 ± 19.9 Gas-buming 16.6 ± 5.1 28.3 ± 13.3 P-value >0.05 <0.01 N 0 ~ V 00 N -19- i t

Table 9. Distribution of 5,546 Lung Cancer Deaths By Occupation in Gunagzhou, China (1980-1988) Job Male Female No. % No. % Office worker 884 21.1 129 6.5 Salesclerk 206 4.9 102 5.2 Engineer 116 2.8 6 0.3 Teacher 82 2.0 68 3.4 Waiter/Waitress 79 1.9 38 1.9 Doctor 55 1.3 33 1.7 Others 103 2.5 25 1.3 Farmer 69 1.6 40 2.0 Homemaker 37 0.9 494 25.0 Cargo Handler 400 9.5 68 3.4 Construction Worker 315 7.5 38 1.9 Machinist 299 7.1 38 1.9 Chemist 265 6.3 161 8.2 Cook 190 4.5 73 3.7 Driver 167 4.0 10 0.5 Foundry Worker 129 3.1 40 2.0 Handicrafter 121 2.9 125 6.3 Stoker 59 1.4 9 0.5 Lathe Operator 55 1.3 35 1.8 Other Worker 560 13.4 444 22.5 Total 4191 100.0 1976 100.0 -20- I I I I I I I I I I I I I I I