環境細懸浮微粒(PM2.5)暴露影響與口腔癌及大腸癌癌症進展風險相關性探討

Environmental PM2.5 Exposure Effect in Association with Oral Cancer and Colorectal Cancer Carcinogenesis

古玫生(Mei-Sheng Ku)

指導教授 ： 劉貞佑

國立臺灣大學/公共衛生學院/環境與職業健康科學研究所/博士(2021年)

https://doi.org/10.6342/NTU202103871

摘要

背景
細懸浮微粒(PM2.5)是全世界目前備受關注的環境汙染物，其對於人類健康影響仍持續探討中；報導顯示較高的PM2.5與較短的平均餘命及較高死亡率風險皆有相關，除最常被認為與PM2.5有關之肺癌以外，大腸癌、乳癌、肝癌、腎臟癌及婦科相關癌症之死亡皆與PM2.5暴露有關。然而，PM2.5暴露與口腔腫瘤發生風險以及其在大腸直腸癌的多階段癌化過程所扮演的角色卻鮮少被闡述；因此，本論文的研究目的為闡述PM2.5與口腔腫瘤之相關性，考量地域異質性後探討其與口腔癌及口腔癌前病變之關係、量化PM2.5對於糞便潛血陽性的影響以及描述PM2.5在大腸癌三階段癌化進展模型中，是否增加大腸直腸癌發生以及後續自臨床症前期至臨床階段之進程風險。
材料與方法
PM2.5與口腔腫瘤
資料取自2006-2016參與全國口腔癌篩檢計畫，曾經或目前為嚼食檳榔者或抽菸者，以及PM2.5監測站之資料，共3,864,045位受試者被納入本分析中，研究期間共找到154,030位癌前病變及23,286位口腔癌個案，並蒐集年齡、性別、居住區域、使用檳榔、抽菸等個人習慣以及月平均PM2.5濃度等資訊，運用貝氏隨機效應羅吉斯迴歸模型分析PM2.5及癌前病變/口腔癌之關聯性
PM2.5與大腸直腸癌
運用全國大腸癌篩檢中多階段結果及回溯式大型世代追蹤設計，並連結22縣市月平均PM2.5 資料，以探討PM2.5對於短期發炎過程及大腸癌多階段癌化進展之影響。此研究共納入50-69歲於2004-2009年首次參與大腸直腸癌之4,628,995位個案，持續追蹤其篩檢結果直至2016年，並運用階層羅吉斯迴歸模型以及多階段馬可夫迴歸模型評估空氣汙染對糞便潛血陽性(發炎反應指標)以及大腸癌臨床症前期、臨床階段之影響。
結果
PM2.5與口腔癌前病變/口腔癌之分析中，在校正年齡、性別及嚼檳、抽菸等個人習慣後，我們發現相較於低暴露區域PM2.5 (<35 µg/m3)，較高PM2.5 (≥35 µg/m3)暴露區域有11% (aRR=1.11; 95% CI: 1.09-1.13)較高之癌前腫瘤及55% (aRR=1.55; 95% CI: 1.49-1.60)較高之口腔癌風險，隨著PM2.5劑量增加有更高之風險相關也於本研究中闡述。
於PM2.5與大腸癌之分析中，高PM2.5暴露(≥35 µg/m3)與11% (95%CI: 10%-12%)較高之糞便潛血陽性有顯著相關，運用彰化縣社區篩檢資料中更多的風險因子，更進一步驗證PM2.5與大腸癌發炎反應指標(糞便潛血陽性)有相關。另外，高PM2.5暴露增加14% (95%CI: 10%-18%)大腸癌臨床症前期之風險，也顯著增加21% (95%CI: 14%-28%) 後續癌化進展從臨床症前期至臨床期之風險；再者，運用年平均PM2.5以及一個月中超過35 µg/m3的天數等指標，皆發現較高PM2.5暴露有顯著較高腸癌癌化之風險。
結論
台灣高PM2.5暴露區域之個案有較高之口腔癌前病變或口腔癌之風險，未來可運用更精確之個人PM2.5暴露，更進一步探討PM2.5與口腔腫瘤之相關性。此外，短期及長期PM2.5暴露與大腸癌多階段進展風險皆有相關，此研究分析有助於針對暴露在高PM2.5的個案，設計更好的大腸癌初級及二級預防策略。

關鍵字

細懸浮微粒 ； 癌前病變 ； 口腔癌 ； 糞便潛血濃度 ； 大腸直腸癌 ； 多階段癌化進展 ； 世代追蹤研究

並列摘要

Background
Fine particulate matter <2.5 μm (PM2.5) is a pollutant of concern worldwide and its impact on human health has been investigated. A decrease in life expectancy and higher risk of mortality have been associated with increased PM2.5 exposure. Apart from lung cancer, the most investigated cancer risk associated with PM2.5, reduced mortality has been noted in multiple sites including colon, breast, liver, kidney, and genital cancers. However, the association between PM2.5 and oral neoplasm has barely been addressed, and the roles of ambient fine particulate matter (PM2.5) in the prevention of colorectal cancer (CRC) have been scarcely highlighted as there is short of empirical evidence regarding the influences of PM2.5 on multistep carcinogenic processes of CRC. As a result, the aims of this thesis were to elucidate the association between PM2.5 and oral neoplasm, including oral potentially malignant disorder (OPMD) and oral cancer (OC), taking into account the geographical heterogeneity, to quantify the effect of PM2.5 on elevated f-HbC (FIT-positive outcomes) and to characterize the effect of PM2.5 on the occurrence of pre-clinical detectable phase (PCDP) CRC and subsequent progression from PCDP to clinical phase (CP) through the three-state carcinogenesis model of CRC.
Materials and Methods
PM2.5 and OPMD/OC
Data for analysis were derived from nationwide OC screening program, targeting Taiwanese cigarette smokers and/or betel quid chewers, and the Taiwan Air Quality Monitoring Network between 2006 and 2016. Totally 3,864,045 smokers and/or betel quids chewers were enrolled in this study. Among them, 154,030 OPMD cases and 23,286 oral cancers were found during the study period. Information on age, gender, living area, personal oral habits, and monthly PM2.5 concentration in average were collected. We used the Bayesian random-effect logistic regression model to assess the association between PM2.5 and OPMD/OC.
PM2.5 and CRC
A retrospective cohort design with multistate outcomes was envisaged by linking monthly average PM2.5 concentrations at 22 city/county level with large-scale cohorts of cancer-screened population to study the influences of PM2.5 on short-term inflammatory process and multistep carcinogenic processes of CRC. Our study included a nationwide CRC screening cohort of 4,628,995 aged 50-69 years who attended first screen between 2004 and 2009 and continued periodical screens until 2016. We aimed to illustrate the carcinogenesis of PM2.5 related to CRC by applying both hierarchical logistical and multistate Markov regression models to estimate the effects of air pollution on fecal immunochemical test (FIT) positive (a proxy of inflammatory marker) and pre-clinical and clinical states of CRC in the nationwide cohort.
Results
In the analysis between PM2.5 and OPMD/OC, after adjusting for sex, age, and behavior of betel quid chewing and cigarette smoking, we found that subjects from areas of higher levels of PM2.5 (≥35 µg/m3) had an increased risk of OMPD/OC and OC by 11% (aRR=1.09; 95% CI: 1.09-1.13) and 55% (aRR=1.55; 95% CI: 1.49-1.60) respectively, compared to those from areas of lower PM2.5 (<35 µg/m3). Such effect was further demonstrated in a concentration-dependent manner.
For PM2.5 and CRC, we found a significant association of high PM2.5 exposure and FIT-positive by an increased risk of 11% [95% confidence interval (CI), 10-12]. A cohort with more risk factors further validated the inflammatory effect of PM2.5 for CRC in Changhua County. PM2.5 enhanced the risk of being preclinical state by 14% (95% CI, 10-18) and that of subsequent progression from pre-clinical to clinical state by 21% (95% CI, 14-28). Furthermore, the elevated risks for CRC carcinogenesis were significantly higher for people living in high PM2.5 pollution areas in terms of yearly averages and the number days above 35 µg/m3 than those living in low PM2.5 pollution areas.
Conclusion
Subjects from areas of higher PM2.5 levels were found to have greater risk of OPMD/OC in Taiwan. Future studies are warranted to investigate the effect of personal PM2.5 exposure on OPMD/OC risk. Furthermore, both short-term and long-term PM2.5 exposure were associated with multistep progression of CRC, which were useful to design precision primary and secondary prevention strategies of CRC for people who are exposed to high PM2.5 pollution.

並列關鍵字

Fine particulate matter ； oral potentially malignant disorder ； oral cancer ； fecal hemoglobin concentration ； colorectal cancer ； carcinogenesis ； cohort study

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