臺灣博碩士論文加值系統

台灣地區抽菸及嚼食檳榔盛行率相當高，根據不同研究統計抽菸人口約350萬至465萬人，嚼食檳榔人口推估可能140萬至200萬人；嚼食檳榔加上抽菸的人口超過130萬人。抽菸引起肺癌、口腔及喉部癌症；嚼食檳榔易導致口腔病變及口腔癌，不論是抽菸或嚼食檳榔，兩者均是重要的致癌因素。IARC於1985年認定「嚼食含菸草的檳榔」或「同時有抽菸與檳榔習慣」對人類有致癌性，致癌部位主要在口腔、咽及食道。IARC更於2003年特別刊物第八十五卷中，確定檳榔是第一類致癌物。
本研究之目的是利用血液淋巴球細胞之微小核及口腔黏膜細胞之微小核基因指標來探討嚼食檳榔與抽菸之單獨作用及其交互作用。本研究研究對象分成沒有抽煙沒有嚼食檳榔，沒有抽煙有嚼食檳榔，有抽煙沒有嚼食檳榔及有抽煙有嚼食檳榔等四組。
結果顯示血液淋巴球細胞之微小核基因指標以沒有抽菸及沒有嚼食檳榔組之微小核平均數最高，而沒有抽菸但有嚼食檳榔者最低，但四組間之微小核平均數未達統計上顯者差異。 抽菸與嚼食檳榔之間並無交互作用；抽菸者或嚼食檳榔者之淋巴球微小核數並無增加的情形，抽菸及嚼食檳榔與微小核平均數未具統計上相關。抽菸及嚼食檳榔的基因傷害效應未在本研究中發現，其可能原因是世代研究對象居民為北門、學甲烏腳病流行地區，這些居民在過去飲用含砷的深井水，長期暴露無機砷，且其作用大於抽菸和嚼食檳榔；或由於研究樣本太小，致使抽菸與嚼食檳榔的作用無法展現出來。
另一研究利用口腔黏膜細胞之微小核基因指標探討嚼食檳榔與抽菸之交互作用。以七鄉鎮世代癌症追蹤調查研究中的一般健康居民選取為研究對象。利用刷子刮取口腔黏膜細胞以測量微小核頻率，且將訪視資料之抽菸及嚼食檳榔情形加上分組比較。結果發現：（1）抽菸與嚼食檳榔沒有交互作用；（2）抽菸，尤其是每天抽20支以上的抽菸行為，增加微小核頻率，且微小核頻率與抽菸量呈現正向線性的劑量-效應關係；（3）嚼食檳榔顯著降低微小核之頻率，此降低效應與嚼檳榔量呈現劑量-效應關係；（4）吃荖花可能增加微小核頻率，但其效應尚未達統計上顯著意義。嚼食檳榔的致癌機轉及荖花在致癌機轉上扮演之角色值得進一步探討。
本研究結果發現嚼食檳榔並不會增加微小核頻率，即嚼檳榔不會造成染色體斷裂(clastogenic effect)的現象。此結果推論台灣雖發現嚼食檳榔者之口腔癌增加，但嚼食檳榔的致癌機轉可能並非透過對基因的傷害（genotoxicity）。
關鍵字：抽菸，嚼食檳榔，淋巴球細胞，口腔黏膜細胞，微小核頻率。

Cigarette smoking and areca quid chewing are common risk behaviors in residents of Taiwan. It is estimated that more than3.5 million Taiwanese (22.7%) are smokers, 1.4 million (8.8%) are areca quid chewers, and 1.3 million (8.3%) are both. IARC evaluation in 1985 & 2003 had found that chewing areca quid without tobacco is carcinogenic to humans(Group 1 carcinogen). Biological monitoring of the genotoxic effects of smoking and areca quid chewing, as well as establishing the interaction between the two, is important for cancer prevention in Taiwan due to the large population of individuals with these two concurring risk factors.
The objective of this study was to use the micronuclei from blood lymphocytes and exfoliated buccal mucosal cells to investigate the clastogenic effects of areca quid chewing and cigarette smoking, as well as the interaction between the two.
The study population in the lymphocytes micronuclei study was selected from residents of Pei-Man and Hsieh-Jia Towns in an arseniasis endemic area recruited for a community-cohort study. A total of 129 subjects were recruited based on the regular consumption of cigarettes and areca quid. The results found that there was no significant interaction between areca quid chewing and cigarette smoking. Neither smoking nor areca quid chewing was significantly associated with MN frequency. The MN frequency in areca quid chewers seemed to be lower than that of non-chewers among nonsmokers, while no difference was found for smokers. These findings suggest that the clastogenic effects of smoking and/or areca quid chewing cannot be demonstrated in arseniasis endemic area residents. Small sample size in this study population may lead to nonsignificant results in this study.
The study population in exfoliated buccal mucosal cells was selected from residents of seven villages recruited for a community-cohort study. A total of 141 subjects were recruited based on the regular consumption of cigarettes and areca quid. There was no significant interaction between the chewing of betel nut and cigarette smoking. Heavy smoking was positively associated with MN frequency, with areca quid chewing negatively associated. A significant positive trend was demonstrated for the relationship between MN frequency and either daily cigarette consumption or cumulative smoking pack-years. By contrast, significant negative trends were demonstrated for the analogous relationships with areca quid chewing. These results indicate that heavy smoking, but not areca quid chewing, increases MN formation. These findings suggest that the carcinogenesis of the oral cancers induced by areca quid chewing in Taiwan may be through a pathway other than genotoxicity.
Keywords: areca quid chewing, smoking, micronuclei, lymphocytes, exfoliated buccal mucosal cells

正 文 目　錄
頁次
目錄 I
表目錄 III
圖目錄 --------- V
附錄目錄 ---- VI
中文摘要 VII
英文摘要 IX
第一章　嚼食檳榔與抽菸致癌性之文獻回顧 1
第一節　檳榔與嚼食檳榔之歷史回顧 5
第二節　檳榔嚼食法、添加物及種類 8
第三節 檳榔嚼塊組成(檳榔子、荖花、紅灰、荖葉)
成分其致癌角色之探討---------------------10
第四節 世界各國暨台灣地區之檳榔嚼食率 24
第五節 檳榔嚼食國家與地區其口腔癌發生率
及死亡率之探討 28
第六節 抽菸致癌性暨嚼食檳榔與抽菸致癌性
之探討 33
第七節　參考文獻 36
第二章　以淋巴球細胞基因指標探討嚼食檳榔與
抽菸之交互作用 45
第一節　前言 48
第二節 研究方法與步驟 51
第三節 結果 53
第四節 討論 56
第五節　參考文獻 58
第三章　以頰部脫落細胞基因指標探討嚼食檳榔
與抽菸之交互作用 68
第一節　前言 71
第二節　研究方法與步驟 74
第三節　結果 77
第四節　討論 82
第五節　參考文獻 91
第四章 總結 106
附錄------------------------------------------109
表 目　錄
頁次
表一、四組研究對象基本特性的分佈 --------------61
表二：台南縣北門鄉烏腳病地區居民的人口特性與
健康行為對具微小核平均細胞數的影響--------------62
表三：台南縣北門鄉烏腳病地區居民的人口特性與
健康行為對微小核平均數的影響--------------------63
表四：抽菸及嚼食檳榔對具微小核平均細胞數的影響
表五：抽菸及嚼食檳榔對微小核平均數的影響--------------64
表六：抽菸、嚼食檳榔、抽菸*嚼食檳榔、職業別、
飲用深井水年數、曾經暴露染髮劑等及年齡對
微小核平均數的影響 -65
表七：抽菸、嚼食檳榔、職業別、飲用深井水年數、曾
經暴露染髮劑等及年齡對微小核平均數的影響 ---65
表八：抽菸、嚼食檳榔、抽菸*嚼食檳榔、職業別、飲用
深井水年數、曾經暴露染髮劑等及年齡對微小核平
均數的影響 66
表九：抽菸、嚼食檳榔、職業別、飲用深井水年數、曾經
暴露染髮劑等及年齡對微小核平均數的影響 66
表十：抽菸、嚼食檳榔、職業別、飲用深井水年數、曾經
暴露染髮劑等及年齡對微小核平均數的影響 67
Table 1. The distribution of characteristics stratified
by areca quid chewing and smoking as well as
piper betle inflorescence (IPB) use and smoking 99
Table 2. The distribution of quantity and duration of areca
quid chewing and smoking 100
Table 3. The comparison of MN frequency (‰) stratified
by personal habits 101
Table 4. Regression model of risk factors on the MN
frequency (‰) (n=141) 102
Table 5. Interaction and dose-response relationship regression model of areca quid chewing and smoking on the MN frequency (‰) (n=141) 103
Table 6. Interaction and dose-response relationship regression model of Piper betle inflorescence use and smoking on the MN frequency (‰) among areca quid chewers (n=49) 104
圖 目　錄
頁次
圖一 : 檳榔及其添加物 43
圖二 : 台灣地區1979-2002年男性口腔癌年齡標準化
發生率及死亡率 44
圖三 : 口腔黏膜細胞之微小核 105
Figure 1: Mean and 95% C.I. of MN frequency
stratified by group 98
附 錄　目　錄
頁次
附錄壹：本研究結果發表之文獻 109

1. IARC: Betel-quid and areca-nut chewing. International Agency for Research on Cancer, Lyon, Monographs. 37：141-291, 1985.
2. 楊弈馨，葛應欽：檳榔嚼塊與口腔癌流行病學研究之文獻回顧.(Review of Epidemiological Studies on Areca Quid and Oral Cancer) 第一期文獻回顧研析計畫報告書成果討論會. 國家衛生研究院. 6：1-44, 2000.
3. 葛應欽：台灣的嚼食檳榔與健康. 屏東醫療網通訊，23：28-33.
4. Tang JG, Jian XF, Gao ML, Ling TY, Zhang KH : Epidemiological
Survey of oral submucous fibrosis in Xiangtan City, Hunan Province, China. Dent Oral Epidemiol. 25: 177-180, 1997.
5. Pindborg JJ, Zheng KH, Kong CR, Lin FX : Pilot survey of oral mucosa in areca nut chewers on Hainan Island of the People’s Republic of China. Community Dent Oral Epidemiol. 12:195-196, 1984.
6. Bhonsle RB, Murti PR, Gupta PC: Tobacco habits in India. Control of Tobacco-related Cancers and Other Diseases. International Symposium, 1990 PC Gupta, JE Hammer, and PR Murti, Eds. Oxford University Press, Bombay, 1992, pp.25-46.
7. Reichart PA, Mohr U, Srisuwan S, Geerlings H, Theetranont C, Kangwanpong T : Precancerous and other oral mucosal lesions related to chewing, smoking and drinking habits in Thailand .Community Dent Oral Epidemiol . 15:152-160, 1987.
8. Thomas SJ, MacLennan R : Slaked lime and betel nut cancer in Papua New Guinea. Lancet. 340: 577-578, 1992.
9. IARC monographs on the evaluation of the carcinogenic risk of chemicals to human. IARC, Lyon, France, Vol. 38, 1986.
10. 鄭景暉，劉宗榮，韓良俊： 檳榔嚼塊的化學致癌性暨其防治: 現況與未來. 第一期文獻回顧研析計畫報告書成果討論會.
國家衛生研究院. 8：1-34, 2000.
11. Phillips JW, Morgan WF: DNA double strand breaks in mutagenesis. Environ Health Perspect. 22:214-217, 1993.
12 Natarjan AT: Mechanisms for induction of mutation and chromosomal alterations. Environ Health Perspect .101(Suppl):225-229,1993.
13. Stich HF, Rosin MP: Micronuclei in exfoliated human cells as a tool for studies in cancer risk and cancer intervention. Cancer Latt. 22:241-253,1984.
14. Stich HF, Mathew B, Sankaranarayanan R, Nair MK:Remission of precancerous lesions in the oral cavity of tobacco chewers and maintenance of the protective effect of β-carotene or vitamin A. Am J Clin Nutr. 53:298S-304S, 1991.
15. Rosin MP, Dunn BP, Stich HF: Use of intermediate endpoints in quantitating the response of precancerous lesions to chemopreventive agents. Can J Physiol Pharmacol. 65:483-487,1987.
16. Lippman SM,Peters EJ, Wargovich MJ, Stadnyk AN,Dixon DO, Dekmezian RH et al: Bronchial micronuclei as a marker of an early stage of carcinogenesis in the human tracheobronchial epithelium. Int J Cancer. 45:811-815,1990.
17. Dave BJ, Trivedi AH, Adhvaryu SG: In vitro genotoxic effects of areca nut extract and arecoline. J Cancer Res Clin Oncol. 118:283-288, 1992.
18. Stich HF, Stich W, Lam PPS:Potentiation of genotoxicity by concurrent application of compounds found in betel quid: arecoline, eugenol, quercetin, chlorogenetic acid and Mn2+. Mutat Res. 90:355-63,1981.
19. Lee CH, Lin RH, Liu SH, Lin-shiau SY: Mutual interactions among ingredients of betel quid in inducing genotoxicity on Chinese hamster ovary cells. Mutat Res 367:99-104, 1996.
20. Jeng JH, Kuo ML, Hahn LJ, Kuo MYP:Genotoxic and non-genotoxic effects of betel quid ingredients on oral mucosal fibroblasts in vitro. J Dent Res. 73:1043-1049, 1994.
21. Shirname LP, Menon MM, Bhide SV: Mutagenicity of betel quit and its ingredients using mammalian test systems. Carcinogenesis. 5:501-503,1984.
22. Shirname LP, Menon MM, Nair J, Bhide S: Correlation of mutagenicity and tumorigenicity of betel quid and its ingredients. Nutr Cancer. 5:87-91,1983.
23. Sundqvist K, Liu Y, Nair Bartsch H, Arvidson K, Graftstrom RC: Cytotoxic and genotoxic effects of areca nut related compounds in cultured human buccal epithelial cells. Cancer Res. 49:5294-5298, 1989.
24. Wang CK, Peng CH: The mutagenicity of alkaloids and N-nitrosoguvacoline from betel quid. Mutat Res. 360:165-171, 1996.
25. Chan Vs, Caldwell J: Comparative induction of unscheduled DNA synthesis in cultured rat hepatocytes by allylbenzenes and their 1’-hydroxy metabolites.Food Chem Toxicol. 30:831-836, 1992.
26. Hasheminejad G, Caldwell J: Genotoxicity of the alkenybenzenes a- and b-asarone, myristicin and elemicin as determined by the UDS assay in cultured rat hepatocytes. Food Chem Toxicol. 32:223-231, 1994.
27. Tayama S: Cytogenetic effects of piperony1 butoxide and safrole in CHO-K1 cells. Mutat Res. 368:249-260, 1996.
28. Vian L, Bichet N, Gouy D: The in vitro micronucleus test on isolated human lymphocytes. Mutat Res. 291:93-102, 1993.
29. Miller EC, Swanson AB, Phillips DH, Fletcher Tl, Liem A, Miller JA: Stuctural-activity studies of the carcinogenicities in the mouse and rat of some naturally occurring and synthetic alkenylbenzene derivatives related to safrole and estragole. Cancer Res. 43:1124-1134, 1983.
30. Nagabhushan M, Amonkar AJ, D’Souza AV, Bhide SV: Hydroxychavicol: a new anti-nitrosating phenolic compound from betel leaf. Mutagenesis. 4:200-204,1989.
31. Amonkar AJ, Nagabhushan M, D’Souza AV, Bhide SV: Hydroxychavicol: a new phenolic antimutagen from betel leaf.Food Chem Toxical. 24:132-134, 1986.
32. Padma PR, Amonkar AJ, Bhide SV:Antimutagenic effects of betel leaf extract against the mutagenicity of two tobacco-specific N-nitrosamines. Mutagenesis. 4:154-156,1989.
33. AmonKar AJ, Padma PR, Bhide SV: Protective effect of hydroxychavicol, a phenolic component of betel leaf, against the tobacco-specific carcinogens. Mutat Res. 210:249-253, 1989.
34. Lee-chen SF, Chen CL, Ho LY, Hsu PC, Chang JT, Sun CM, Chi CW, Liu TY: Role of oxidative DNA damage in hydroxychavicol-induced genotoxicity. Mutagenesis. 11:519-23, 1996.
35. Muirs CS, Kirk R: Betel, tobacco and cancer of the mouth. Br J Cancer. 14:596-608, 1960.
36. Sen S, Talukder G, Sharma A: Betel cytotoxicity. J Ethnopharmacol. 26:217-247, 1989.
37. Giri AK, Banerjee Ts, Talukder G, Sharma A: Induction of sister chromatid exchange and dominant lethal mutation by “Katha” (Catechu) in male mice. Cancer Lett. 36:189-196, 1987.
38. Bandyopadhyay TS, Chun LY, Giri AK, Swaminathan B: Genotoxicity of “Katha”-An ingredient of betel leaf preparation. Food chem. Toxicol. 24:1232-1235, 1986.
39. Nagabhushan M, Bhide S:Anti-mutagenicity of catechin against environmental mutagens. Mutagenesis. 3:293-296, 1988.
40. Stich HF, Curtis JR, Parida BB: Application of the micronucleus test to exfoliated cells of high cancer risk groups: tobacco chewers. Int J Cancer. 30:553-559, 1982.
41. Wang CK, Wu MJ: The separation of phenolics from piper betle leaf and the effect on the mutagenicity of arecoline. J Chin Agric Chem Soc. 34:638-647, 1996.
42. Sadasivan G, Rani G, Kumari CK: Chromosome-damaging effect of betel leaf. Mutat Res. 57:183-185, 1978.
43. Ames BN, Gold LS: Too many rodent carcinogens :Mitogenesis increases mutagenesis. Science. 249:970-971, 1990.
44. Cerutti PA: Prooxidant states and tumor promotion. Science. 227:375-381, 1985.
45. Ericson T, Bratt P: Interactions between peroxide and salivary glycoprotein: Protection by peroxidase. J Oral Pathol. 16:421-424, 1987.
46. Rosin MP: The influence of pH on the convertogenic activity of plant phenolics. Mutat Res.1135:109-113, 1984.
47. Liu TY, Chen CL, Chi CW: Oxidative damage to DNA induced by areca nut extract. Mutat Res. 367:25-31, 1996.
48. Nair UJ, Nair J, Friesen MD, Bartsch H, Ohshima H: Ortho- and meta-tyrosine formation from phenylalanine in human saliva as a marker of hydroxy1 radical generation during betel quid chewing. Carcinogenesis. 16:1195-5, 1995.
49. Thomas SJ, MacLenan R: Slaked lime and betel nut cancer in Papua New Guinea. Lancet. 340:577-578, 1992.
50. Lewis JG, Adams DO: Inflammation, oxidative DNA damage, and carinogenesis. Environ Health Perspect. 76:19, 1987.
51. Weitberg AB, Weitzman SA, Destrempes M, Latt SA, Stossei Tp: Stimulated human phagocytes produce cytogenetic changes in cultured mammalian cells. New Engl J Med. 308:26-30, 1983.
52. Shacter E, Beecham EJ, Covey JM, Kohn KW, Potter M:Activated neutrophils induce prolonged DNA damage in neighboring cells. Carcinogenesis. 9:2297-2300, 1988.
53. Bedi R, Jones P : Betel quid and tobacco chewing among the Bangladeshi community in the United Kingdom : usage and health issues. Oral Diseases. 3:52-54, 1997.
54. Reichart P, Schmidtberg W, Scheifele C: Betel chewer’s mucosa in elderly Cambodian women. J Oral Pathol Med. 25:367-370, 1996.
55. Ikeda N, Janda Y, Khim SP, Durward C, Axell T, Mizuno T, Fukano H, Kawai T : Prevalence study of oral mucosal lesions in a selected Cambodian population. Community Dent Oral Epidemiol. 23:49-54, 1995.
56. Ko YC, Chiang TA, Chang SJ, Hsieh SG : Prevalence of betel quid chewing habits in Taiwan and related sociodemographic factors. J Oral Pathol Med.
21: 261-64, 1992.
57. C.H. Chiou, C.D. Hung, P.S. Chiou. The prevalence of smoking and areca quid chewing in Taiwan area. J Chinese Dental Assoc. 16: 28-36, 1997.
58. Lu CT, Lan SJ, Hsieh CC, Yang MJ, Ko YC, Tsai CC, Yen YY :
Prevalence and characteristics of areca nut chewers among junior school students in Changhua county, Taiwan. Community Dent Oral Epidemiol. 21:370-73, 1993.
59. Yang MS, Su IH, Wen JK,K YC: Prevalence and related risk
factors of betel quid chewing by adolescent students in southern Taiwan. J Oral Pathol Med. 25:69-71, 1996
60. 陳至興,林清榮,張斌: 234例口腔癌的統計與分析. 中華民國耳鼻喉科醫學會雜誌.19: 20-25, 1984.
61. Parkin DM, Whelan SL, Ferlay J, Raymond L, Yong J. (Eds). Cancer Incidence in Five continents. Vol. VII. IARC Sci Publ no. 143. Lyon, International Agency for Research on Cancer. 1997.
62. 行政院衛生署.中華民國九十一年衛生統計, 2003年12月.
63. 蔡崇弘，邱清華：台灣地區口腔癌發生率研究. 中華牙誌. 9:104-115, 1990.
64. Osler M, Kirchhoff M. Smoking behavior in Danish adults from 1982 to 1992. Pubic Health. 109(4): 245-250, 1995.
65. IARC monographs on the evaluation of the carcinogenic risk of chemicals to human. Tobacco smoking, IARC, Lyon, France. Vol. 38, 1986.
66. IARC monographs on the evaluation of the carcinogenic risk of chemicals to human. Tobacco habits other than smoking; betel-quid and areca-nut chewing; and some related nitosamine, IARC, Lyon, France. Vol. 37, 1985.
67. J.M. Hopkin. Cigarette smoke-induced DNA damage and lung cancer risk. Nature. 283:388-389,1980.
68. J. Vijayalaxmi, H.J. Evans. In vivo and inviro effects of cigarette smoke on chromosomal damage and sister chromatid exchanges in human peripheral blood lymphocytes. Mut Res. 92:321-332, 1982.
69. 行政院衛生署.中華民國八十年衛生統計, 1992年.
70. La Vecchia C, Pagano R, Decarli A, Ferraroni M. Smoking in Italy, 1990-1991. Tumori. 80(3): 175-180, 1994.
71. Hill DJ. White VM. Australian adult smoking prevalence in 1992. Aust J Public Health. 19(3): 305-308, 1995.
72. Ma RH, Tsai CC, Shieh Ty. Increased Iysyl oxidase activity in fibroblasts cultured from oral submucous fibrosis associated with betel nut chewing in Taiwan. J Oral Pathol Med. 24(9): 407-412, 1995.
73. Summers RM, Williams SA, Curzon ME. The use of tobacco and betel quid(“pan”) among Bangladeshi women in West Yorkshire Community. Dent Health. 11(1): 12-16, 1994.
74. F.S. Mehta, J.J. Pindborg, P.C. Gupta, D.K. Daftary. Epidemiologic and histologic study of oral cancer and leukoplakia among 50,915 villagers in India. Cancer. 24 :832-838, 1969.
75. WHO Meeting Report. Control of oral cancer in developing countries. 62 :817-832, 1984.
76. P.A. Reichart. Oral cancer and precancer related to betel and miang chewing in Thiland: a review. J Oral Pathol Med. 24: 241-243, 1995.
77. N.W. Johnson, S. Warnakulasuiy, M. Tavassoli. Hereditary and environmental risk factors-clinical and laboratory risk markers for head and neck, especially oral cancer and precancer. Eur J Cancer Pre. 5 : 5-17, 1996.
78. P.R. Muri, R.B. Bhonsle, P.C. Gupta, D.K. Daftary, J.J. Pindborg, F.S. Mehta. Etiology of oral submucous fibrosis with special reference to the role of areca nut chewing. J Oral Pathol Med. 24 :145-152,1995.
79. C.H. Lee, Y.C. Ko, H.L. Huang, Y.Y. Chao, C.C. Tsai, T.Y. Shieh, L.M. Lin. The precancer risk of betel quid chewing, tobacco use and alcohol consumption in oral leukoplakia and oral submucous fibrosis in southern Taiwan. Br J Cancer. 10: 366-372, 2003.
80. P.C. Gupta, J.J. Pindborg, F.S. Mehta. Comparison of carcinogenicity of betel quid with and without tobacco: an epidemiological review. Ecol Dis. 1: 213-219, 1982.
81. P.C. Gupta. Betel quid and oral cancer: prospects for prevention. IARC Sci Publ. 105 :466-470, 1991.
82. IARC monographs on the evaluation of the carcinogenic risk of chemicals to human. Betel-quid and areca-nut chewing and some areca-nut related nitrosamines. IARC, Lyon, France. Volume 85, 11-18 June 2003.
83. Y.C. Ko, Y.L. Huang, C.H. Lee, M.J. Chen, L.M. Lin, C.C. Tsai. Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med. 24 :450-453, 1995.
1. 楊弈馨，葛應欽：檳榔嚼塊口腔癌流行病學研究之文獻回顧. 第一期文獻回顧研析計畫報告書成果討論會. 國家衛生研究院. 6：1-44, 2000.
2. IARC monographs on the evaluation of the carcinogenic risk of chemicals to human. Tobacco smoking, IARC, Lyon, France. Vol. 38, 1986.
3. IARC monographs on the evaluation of the carcinogenic risk of chemicals to human. Betel-quid and areca-nut chewing and some areca-nut related nitrosamines. IARC, Lyon, France. Volume 85, 11-18 June 2003.
4. IARC monographs on the evaluation of the carcinogenic risk of chemicals to human. Tobacco habits other than smoking; betel-quid and areca-nut chewing; and some related nitrosamine, IARC, Lyon, France. Vol. 37, 1985.
5. N.W. Johnson, S. Warnakulasuiy, M. Tavassoli. Hereditary and environmental risk factors-clinical and laboratory risk markers for head and neck, especially oral cancer and precancer. Eur J Cancer Pre. 5 :5-17,1996.
6. P.R. Muri, R.B. Bhonsle, P.C. Gupta, D.K. Daftary, J.J. Pindborg, F.S. Mehta. Etiology of oral submucous fibrosis with special reference to the role of areca nut chewing. J Oral Pathol Med. 24:145-152,1995.
7. A. Reichart. Oral cancer and precancer related to betel and miang chewing in Thiland: a review. J Oral Pathol Med. 24:241-243,1995.
8. WHO Meeting Report. Control of oral cancer in developing countries. 62: 817-832, 1984.
9. F.S. Mehta, J.J. Pindborg, P.C. Gupta, D.K. Daftary. Epidemiologic and histologic study of oral cancer and leukoplakia among 50,915 villagers in India. Cancer. 24 :832-838, 1969.
10. C.H. Chiou, C.D. Hung, P.S. Chiou. The prevalence of smoking and areca quid chewing in Taiwan area. J Chinese Dental Assoc. 16:28-36,1997.
11. Y.C. Ko, Y.L. Huang, C.H. Lee, M.J. Chen, L.M. Lin, C.C. Tsai. Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med. 24:450-453, 1995.
12. G. Sadasivan, G. Rani, C.K. Kumari. Chromosome-damaging effect of betel leaf. Mutat Res. 57 :183-185, 1978.
13. M. Riebe, K. Westphal. Studies on the induction of sister chromatid exchanges in Chinese hamster ovary cells by various tobacco alkaloids. Mut Res. 124: 281-285,1983.
14. J.J. Kayal, A.H. Trivedi, B.J. Dave, J. Nair, U.J. Nair, S.V. Bhide, U.C. Goswami, S.G. Adhvaryu. Incidence of micronuclei in oral mucosa of users of tobacco products singly or in various combinations. Mutagenesis. 8 :31-33,1993.
15. J.M. Hopkin. Cigarette smoke-induced DNA damage and lung cancer risk. Nature. 283: 388-390,1980.
16. J. Vijayalaxmi, H.J. Evans. In vivo and inviro effects of cigarette smoke on chromosomal damage and sister chromatid exchanges in human peripheral blood lymphocytes. Mut Res. 92:321-332,1982.
17. S.G. Adhvaryu, R.G. Bhatt, P.K. Dayal, A.H. Trivedi, B.J. Dave, R.C. Vyas, K.H. Jani. SCE frequencies in lymphocytes of tobacco/betel nut chewers and patients with oral submucous fibrosis. Br J Cancer. 53:141-143,1986.
18. S.A. Latt. Sister chromatid exchanges: a report of the gene-tox program. Mut Res. 87:17-62,1981)
19. H.F. Stich, M.P. Rosin. Micronuclei in exfoliated human cells as a tool for studies in cancer risk and cancer intervention. Cancer Lett. 22: 241-253,1984.
20. M.P. Lehucher-Michel, C. Di Giorgio, Y.A. Amara, M. Laget, A. Botta. The micronucleus assay in human exfoliated urothelial cells: effect of smoking. Mutagenesis. 10 :329-332,1995.
21. B.J. Dave, A.H. Trivedi, S.G. Adhvaryu. Role of areca nut consumption in the cause of oral cancers. A cytogenetic assessment. Cancer. 70:1017-1023, 1992.
22. H.F. Stich, W. Stich, M.P. Rosin, M.O. Vallejera. Use of the micronucleus test to monitor the effect of vitamin A, beta-carotene and canthaxanthin on the buccal mucosa of betel nut/tobacco chewers. Int J Cancer. 34: 745-750, 1984.
23. H.F. Stich, M.P. Rosin, M.O. Vallejera. Reduction with vitamin A and beta-carotene administration of proportion of micronucleated buccal mucosal cells in Asian betal nut and tobacco chewers. Lancet. 8388:1204-1206, 1984.
24. U. Nair, G. Obe, J. Nair, G.B. Maru, S.V. Bhide, R. Piepe, H. Bartsch. Evaluation of frequency of micronucleated oral mucosa cells as a marker for genotoxic damage in chewers of betel quid with or without tobacco. Mutat Res. 261:163-168, 1991.
25. S.G. Adhvaryu, B.J. Dave, A.H. Trivedi. Cytogenetic surveillance of tobacco-areca nut (mava) chewers, including patients with oral cancers and premalignant conditions. Mutat Res. 261:41-49,1991.
26. S. Bonassi, M. Neri, C. Lando, M. Ceppi, Y.P. Lin, W.P. Chang, N. Holland, M. Kirsch-Volders, E. Zeiger, M. Fenech; HUMN collaborative group. Effect of smoking habit on the frequency of micronuclei in human lymphocytes: results from the Human MicroNucleus project. Mutat Res.543:155-166,2003.
1. IARC monographs on the evaluation of the carcinogenic risk of chemicals to human. Tobacco smoking, IARC, Lyon, France. Vol. 38, 1986,
2. IARC monographs on the evaluation of the carcinogenic risk of chemicals to human. Betel-quid and areca-nut chewing and some areca-nut related nitrosamines. IARC, Lyon, France. Volume 85, 11-18 June 2003.
3. N.W. Johnson, S. Warnakulasuiy, M. Tavassoli. Hereditary and environmental risk factors-clinical and laboratory risk markers for head and neck, especially oral cancer and precancer. Eur J Cancer Pre. 5:5-17,1996.
4. P.R. Muri, R.B. Bhonsle, P.C. Gupta, D.K. Daftary, J.J. Pindborg, F.S. Mehta. Etiology of oral submucous fibrosis with special reference to the role of areca nut chewing. J Oral Pathol Med. 24:145-152,1995.
5. P.A. Reichart. Oral cancer and precancer related to betel and miang chewing in Thiland: a review. J Oral Pathol Med. 24:241-243,1995.
6. WHO Meeting Report. Control of oral cancer in developing countries. 62: 817-832,1984.
7. F.S. Mehta, J.J. Pindborg, P.C. Gupta, D.K. Daftary. Epidemiologic and histologic study of oral cancer and leukoplakia among 50,915 villagers in India. Cancer. 24: 832-838,1969.
8. C.H. Lee, Y.C. Ko, H.L. Huang, Y.Y. Chao, C.C. Tsai, T.Y. Shieh, L.M. Lin. The precancer risk of betel quid chewing, tobacco use and alcohol consumption in oral leukoplakia and oral submucous fibrosis in southern Taiwan. Br J Cancer. 10: 366-372,2003.
9. Y.C. Ko, Y.L. Huang, C.H. Lee, M.J. Chen, L.M. Lin, C.C. Tsai. Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. J Oral Pathol Med. 24 :450-453,1995.
10. P.C. Gupta, J.J. Pindborg, F.S. Mehta. Comparison of carcinogenicity of betel quid with and without tobacco: an epidemiological review. Ecol Dis. 1:213-219, 1982.
11. 楊弈馨，葛應欽：檳榔嚼塊口腔癌流行病學研究之文獻回顧. 第一期文獻回顧研析計畫報告書成果討論會. 國家衛生研究院. 6：1-44, 2000.
12. G.B. Panigrahi, A.R. Rao. Chromosome breaking ability of arecoline, a major betel-nut alkaloid, in mouse bone-marrow cells in vivo. Mut Res. 103:197-201,1982.
13. T.Y. Liu, C.L. Chen, C.W. Chi. Oxidative damage to DNA induced by areca nut extract. Mut Res. 367 :25-31,1996.
14. K. Polasa, S. Babu, I.S. Shenolikar. Dose-dependent genotoxic effect of pan masala and areca nut in the Salmonella typhimurium assay. Food Chem Toxicol. 31: 439-442,1993.
15. J.H. Jeng, M.L. Kuo, L.J. Hahn, M.Y. Kuo. Genotoxic and non-genotoxic effects of betel quid ingredients on oral mucosal fibroblasts in vitro. J Den Res. 73: 1043-1049,1994.
16. K.K. Wary, R.N. Sharan. Aqueous extract of betel-nut of north-east India induces DNA-strand breaks and enhances rate of cell proliferation in vitro. Effects of betel-nut extract in vitro. J Cancer Res Clin Oncol. 114:579-582,1988.
17. C.K. Wang, C.H. Peng. The mutagenicities of alkaloids and N-nitrosoguvacoline from betel quid. Mut Res. 360:165-171,1996.
18. L.P. Shirname, M.M. Menon, J. Nair, S.V. Bhide. Correlation of mutagenicity and tumorigenicity of betel quid and its ingredients. Nutr Cancer. 5:87-91,1983.
19. S.V. Bhide, N.M. Shivapurkar, S.V. Gothoskar, K.J. Ranadive. Carcinogenicity of betel quid ingredients: feeding mice with aqueous extract and the polyphenol fraction of betel nut. Br J Cancer. 40 :922-926,1979.
20. G. Sadasivan, G. Rani, C.K. Kumari. Chromosome-damaging effect of betel leaf. Mutat Res. 57:183-185,1978.
21. M. Riebe, K. Westphal. Studies on the induction of sister chromatid exchanges in Chinese hamster ovary cells by various tobacco alkaloids. Mut Res. 124 :281-285,1983.
22. A.H. Trivedi, S.K. Roy, R.J. Jaju, R.K. Patel, S.G. Adharyu, D.B. Balar. Urine of tobacco/areca nut chewers causes genomic damage in Chinese hamster ovary cells. Carcinogenesis. 16 :205-208,1995.
23. A.H. Trivedi, B.J. Dave, S.C. Adhvaryu. Genotoxic effects of nicotine in combination with arecoline on CHO cells. Cancer Letter. 74:105-110,1993.
24. J.J. Kayal, A.H. Trivedi, B.J. Dave, J. Nair, U.J. Nair, S.V. Bhide, U.C. Goswami, S.G. Adhvaryu. Incidence of micronuclei in oral mucosa of users of tobacco products singly or in various combinations. Mutagenesis. 8:31-33,1993.
25. Y.C. Chang, C.C. Hu, T.H. Tseng, K.W. Tai, C.K. Lii, M.Y. Chou. Synergistic effects of nicotine on arecoline-induced cytotoxicity in human buccal mucosal fibroblasts. J Oral Pathol Med. 30:458-464,2001.
26.Y.C. Chang, K.W. Tai, M.Y. Chou, T.H. Tseng. Synergistic effects of peroxynitrite on arecoline-induced cytotoxicity in human buccal mucosal fibroblasts. Toxicol Lett. 118 :61-68, 2000.
27. C.H. Chiou, C.D. Hung, P.S. Chiou. The prevalence of smoking and areca quid chewing in Taiwan area. J Chinese Dental Assoc. 16 :28-36,1997.
28.C.T. Lu, S.J. Lan, C.C. Hsieh. Prevalence and characteristics of areca nut chewers among junior high school students in Changhua county, Taiwan. Community Dent Oral Epidemiol. 21:370-373,1993.
29. Y.C. Ko, T.A. Chiang, S.J. Chang, S.F. Hsieh. Prevalence of betel quid chewing habit in Taiwan and related sociodemographic factors. J Oral Pathol Med. 21: 261-264, 1992.
30. B.H. Liu, S.F. Hsieh, S.J. Chang, Y.C. Ko. Prevalence of smoking, drinking and betel quid chewing and related factors among aborigines in Wufeng District. Kaohsiung Med Sci J. 10 :405-411,1994.
31.IARC monographs on the evaluation of the carcinogenic risk of chemicals to human. Tobacco habits other than smoking; betel-quid and areca-nut chewing; and some related nitrosamine, IARC, Lyon, France. Vol. 37, 1985.
32. J.M. Hopkin. Cigarette smoke-induced DNA damage and lung cancer risk. Nature. 283 :388-390,1980.
33. J. Vijayalaxmi, H.J. Evans. In vivo and inviro effects of cigarette smoke on chromosomal damage and sister chromatid exchanges in human peripheral blood lymphocytes. Mut Res. 92:321-332,1982.
34. S.G. Adhvaryu, R.G. Bhatt, P.K. Dayal, A.H. Trivedi, B.J. Dave, R.C. Vyas, K.H. Jani. SCE frequencies in lymphocytes of tobacco/betel nut chewers and patients with oral submucous fibrosis. Br J Cancer. 53:141-143,1986.
35. S.A. Latt. Sister chromatid exchanges: a report of the gene-tox program. Mut Res. 87 :17-62,1981.
36. H.F. Stich, M.P. Rosin. Micronuclei in exfoliated human cells as a tool for studies in cancer risk and cancer intervention. Cancer Lett. 22:241-253,1984.
37. M.P. Lehucher-Michel, C. Di Giorgio, Y.A. Amara, M. Laget, A. Botta. The micronucleus assay in human exfoliated urothelial cells: effect of smoking. Mutagenesis. 10 :329-332,1995.
38. B.J. Dave, A.H. Trivedi, S.G. Adhvaryu. Role of areca nut consumption in the cause of oral cancers. A cytogenetic assessment. Cancer. 70:1017-1023,1992.
39. H.F. Stich, W. Stich, M.P. Rosin, M.O. Vallejera. Use of the micronucleus test to monitor the effect of vitamin A, beta-carotene and canthaxanthin on the buccal mucosa of betel nut/tobacco chewers. Int J Cancer. 34:745-750,1984.
40. H.F. Stich, M.P. Rosin, M.O. Vallejera. Reduction with vitamin A and beta-carotene administration of proportion of micronucleated buccal mucosal cells in Asian betal nut and tobacco chewers. Lancet. 8388:1204-1206,1984.
41. U. Nair, G. Obe, J. Nair, G.B. Maru, S.V. Bhide, R. Piepe, H. Bartsch. Evaluation of frequency of micronucleated oral mucosa cells as a marker for genotoxic damage in chewers of betel quid with or without tobacco. Mutat Res. 261:163-168,1991.
42. S.G. Adhvaryu, B.J. Dave, A.H. Trivedi. Cytogenetic surveillance of tobacco-areca nut (mava) chewers, including patients with oral cancers and premalignant conditions. Mutat Res. 261:41-49,1991.
43. C.A. Sun, D.M. Wu, C.C. Lin, S.N. Lu, S.L. You, L.Y. Wang, M.H. Wu, C.J. Chen. Incidence and cofactors of hepatitis C virus-related hepatocellular carcinoma: a prospective study of 12,008 men in Taiwan. Am J Epidemiol. 157:674-682,2003.
44. H.F. Stich. Reducing the genotoxic damage in the oral mucosa of betel quid/tobacco chewers. Basic Life Sci. 39:381-391,1986.
45. H.F. Stich, W. Stich, B.B. Parida. Elevated frequency of micronucleated cells in the buccal mucosa of individuals at high risk for oral cancer: betel quid chewers. Cancer Lett. 17 :125-134,1982.
46. H.F. Stich, M.P. Rosin, K.D. Brunnemann. Oral lesions, genotoxicity and nitrosamines in betel quid chewers with no obvious increase in oral cancer risk. Cancer Lett. 31:15-25,1986.
47. S. Bonassi, M. Neri, C. Lando, M. Ceppi, Y.P. Lin, W.P. Chang, N. Holland, M. Kirsch-Volders, E. Zeiger, M. Fenech; HUMN collaborative group. Effect of smoking habit on the frequency of micronuclei in human lymphocytes: results from the Human MicroNucleus project. Mutat Res. 543:155-166,2003.
48. J.H. Jeng, M.C. Chang, L.J. Hahn. Role of areca nut in betel quid-associated chemical carcinogenesis: current awareness and future perspectives. Oral Oncol. 37: 477-492,2001.
49. M. Nagabhushan, A.J. Amonkar, A.V. D''Souza, S.V. Bhide. Nonmutagenicity of betel leaf and its antimutagenic action against environmental mutagens. Neoplasma. 34 :159-167,1987.
50. P.R. Padma, A.J. Amonkar, S.V. Bhide. Antimutagenic effects of betel leaf extract against the mutagenicity of two tobacco-specific N-nitrosamines. Mutagenesis. 4: 154-156,1989.
51. S.V. Bhide, P.R. Padma, A.J. Amonkar. Antimutagenic and anticarcinogenic effects of betel leaf extract against the tobacco-specific nitrosamine 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK). IARC Sci Publ. 105: 520-524,1991.
52. P.R. Padma, V.S. Lalitha, A.J. Amonkar, S.V. Bhide. Anticarcinogenic effect of betel leaf extract against tobacco carcinogens. Cancer Lett. 45:195-202,1989.
53. S.V. Bhide, M.B. Zariwala, A.J. Amonkar, M.A. Azuine. Chemopreventive efficacy of a betel leaf extract against benzo[a]pyrene-induced forestomach tumors in mice. J Ethnopharmacol. 34 :207-213,1991.
54. M. Nagabhushan, A.J. Amonkar, U.J. Nair, A.V. D''Souza, S.V. Bhide. Hydroxychavicol: a new anti-nitrosating phenolic compound from betel leaf. Mutagenesis. 4 :200-204,1989.
55. A.J. Amonkar, P.R. Padma, S.V. Bhide. Protective effect of hydroxychavicol, a phenolic component of betel leaf, against the tobacco-specific carcinogens. Mutat Res. 210: 249-253,1989.
56. A.J. Amonkar, M. Nagabhushan, A.V. D''Souza, S.V. Bhide. Hydroxychavicol: a new phenolic antimutagen from betel leaf. Food Chem Toxicol. 241321-1324. (1986)
57. D. Lei, C.P. Chan, Y.J. Wang, T.M. Wang, B.R. Lin, C.H. Huang, J.J. Lee, H.M. Chen, J.H. Jeng, M.C. Chang. Antioxidative and antiplatelet effects of aqueous inflorescence Piper betle extract. J Agric Food Chem. 51:2083-2088,2003.
58. A.R. Rao, A. Sinha, R.S. Selvan. Inhibitory action of Piper betle on the initiation of 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis in rats. Cancer Lett. 26: 207-214,1985.
59. K.W. Chang, C.S. Chang, K.S. Lai, M.J. Chou, K.B. Choo. High prevalence of human papillomavirus infection and possible association with betel quid chewing and smoking in oral epidermoid carcinomas in Taiwan. J Med Virol. 28 :57-61,1989.