生命早期暴露於二氯二苯三氯乙烷(DDT)室內殘留噴灑與生殖系統癌症發生及死亡之長期影響： 以台灣全國人口為基礎之研究

Abstract

研究背景： 癌症為全球主要死亡原因之一，而臺灣多種內分泌相關癌症之發生率於過去數十年間持續上升，已成為重要公共衛生議題。內分泌干擾物（endocrine-disrupting chemicals, EDCs）可擾亂人體內分泌系統正常功能，被認為是多種荷爾蒙相關癌症的重要環境危險因子。其中，滴滴涕（dichlorodiphenyltrichloroethane, DDT）為具代表性的持久性有機污染物及內分泌干擾物，具有高度環境持久性及生物累積性。依據健康與疾病的發展起源（Developmental Origins of Health and Disease, DOHaD）假說，生命早期暴露於環境化學物質可能透過發育程式化及表觀遺傳機制，對成年後慢性疾病及癌症風險產生長期影響。然而，目前針對生命早期DDT暴露與成年後生殖系統癌症長期健康影響之流行病學證據仍相當有限。 研究目的： 1952至1957年間，臺灣為推動瘧疾根除計畫，於全臺多數地區實施以DDT為主要殺蟲劑之室內殘效噴灑（indoor residual spraying, IRS）。各鄉鎮依疫情需求累積0至5次噴灑，形成具有明顯時間與地理差異之歷史暴露情境。由於當時臺灣工業化程度尚低，其他環境化學物質暴露相對有限，加上歷史噴灑紀錄保存完整，使臺灣DDT室內殘效噴灑成為探討生命早期環境暴露長期健康影響之珍貴天然實驗。因此，本研究旨在利用此一歷史天然實驗，重建生命早期DDT暴露，並整合全國性健康資料庫，系統性評估生命早期DDT暴露與成年後生殖系統癌症發生、診斷期別及死亡之長期關聯。研究以1952至1958年出生世代為研究對象，以建立生命早期環境暴露與癌症風險之長期流行病學證據。 研究方法： 本研究包含三項互補性的流行病學研究。第一部分利用全民健康保險研究資料庫（2000–2022）建立全國性個體層級回溯性世代，探討生命早期DDT暴露與成年後生殖系統癌症發生風險；第二部分利用臺灣癌症登記資料庫（1979–2022）進行全國性生態研究，分析DDT暴露與生殖系統癌症發生率及診斷期別之關聯；第三部分整合全國死亡資料庫（1971–2022），評估歷史DDT暴露與生殖系統癌症死亡率之關聯。三項研究皆依據各鄉鎮歷史DDT室內殘效噴灑次數重建生命早期暴露程度，並分別採用Cox比例風險模式及Poisson迴歸模式估計DDT暴露與癌症風險之關聯。 結果： 研究結果顯示，生命早期DDT暴露與成年後多種生殖系統癌症具有一致的長期關聯。個體層級世代研究發現，較高DDT暴露與乳癌、子宮體癌、卵巢癌及攝護腺癌發生風險增加具有顯著關聯；癌症登記資料分析進一步延長追蹤期間，再次驗證上述結果，並發現睪丸癌亦呈現正向關聯，且部分癌症具有暴露反應趨勢。依癌症診斷期別分析，DDT暴露與局限期（Stage 0–II）癌症之關聯較進展期（Stage III–IV）更為一致。癌症死亡分析則顯示，較高DDT暴露與55歲以上乳癌死亡率增加具有一致關聯，限制分析中亦觀察到55歲以下乳癌及子宮體癌死亡率增加；相較之下，子宮頸癌死亡率呈現反向關聯，而卵巢癌及男性生殖系統癌症死亡率則未達統計顯著。整體而言，DDT暴露與癌症死亡之關聯較癌症發生率分析為少，且效應量相對較小，顯示生命早期DDT暴露主要影響癌症發生風險，而對癌症預後之影響相對有限。 結論： 本研究利用臺灣瘧疾防治歷史建立之天然實驗，結合完整歷史暴露資訊與全國性健康資料庫，提供目前少見且追蹤超過50年的生命早期DDT暴露流行病學證據。研究結果一致支持DOHaD假說，顯示生命早期暴露於內分泌干擾物可能增加成年後多種生殖系統癌症風險，其中以乳癌及子宮體癌之證據最為一致。本研究透過整合個體層級世代研究、生態研究及死亡率分析等互補性研究設計，提升研究結果之穩健性，並補充亞洲族群生命早期環境暴露與癌症風險之長期流行病學證據。研究結果亦顯示，環境化學物質健康風險評估除考量急性毒性外，亦應納入生命早期暴露及生命歷程健康效應，以作為持久性有機污染物管理、病媒防治策略及公共衛生政策制定之重要科學依據，降低環境暴露對未來世代健康所造成之長期負擔。

Background: Cancer is one of the leading causes of death worldwide, and the incidence of endocrine-related cancers has steadily increased in Taiwan over recent decades. Endocrine-disrupting chemicals (EDCs) have been recognized as important environmental risk factors for hormone-related cancers. Among them, dichlorodiphenyltrichloroethane (DDT) is a representative persistent organic pollutant with endocrine-disrupting properties. According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, exposure to environmental chemicals during early life may induce developmental programming and epigenetic alterations, thereby increasing the risk of chronic diseases and cancer in adulthood. However, epidemiological evidence on the long-term effects of early-life DDT exposure remains limited. Objects: Between 1952 and 1957, Taiwan implemented a nationwide indoor residual spraying (IRS) program using DDT for malaria eradication. The cumulative number of spray rounds varied from 0 to 5 across townships, creating substantial spatial and temporal variation in exposure. Given the relatively low level of industrialization, limited background exposure to other environmental chemicals, and well-preserved historical spraying records, this IRS campaign provides a unique historical natural experiment for investigating the long-term health effects of early-life environmental exposure. This study aimed to reconstruct early-life DDT exposure using this historical natural experiment and nationwide health databases to evaluate its associations with the incidence, stage at diagnosis, and mortality of reproductive cancers among individuals born between 1952 and 1958. Methods: This dissertation consists of three complementary epidemiological studies. The first study established a nationwide retrospective cohort using the NHIRD (2000–2022) to examine the association between early-life DDT exposure and the incidence of reproductive cancers. The second study employed a nationwide ecological design using the Taiwan Cancer Registry (1979–2022) to investigate associations between DDT exposure, cancer incidence, and stage at diagnosis. The third study integrated the Taiwan Cause of Death Database (1971–2022) to evaluate the relationship between historical DDT exposure and mortality from reproductive cancers. In all three studies, early-life exposure was reconstructed according to the cumulative number of historical IRS rounds at the township level. Cox proportional hazards models and Poisson regression models were applied to estimate the associations between DDT exposure and cancer outcomes. Results: The findings consistently demonstrated long-term associations between early-life DDT exposure and multiple reproductive cancers. Specifically, cohort analyses showed significant associations with breast, corpus uteri, ovarian, and prostate cancers. Ecological analyses further confirmed these findings, identified a positive association with testicular cancer, and demonstrated more consistent associations for localized-stage (Stage 0–II) than advanced-stage cancers (Stage III–IV). Mortality analyses revealed increased breast cancer mortality, particularly among women diagnosed at ≥55 years of age, while restriction analyses also identified elevated mortality from breast cancer diagnosed before age 55 and corpus uteri cancer. In contrast, cervical cancer mortality showed an inverse association, and no significant associations were observed for ovarian or male reproductive cancer mortality. Conclusion: This study provides rare epidemiological evidence based on more than 50 years of follow-up, demonstrating that early-life DDT exposure is associated with an increased risk of multiple reproductive cancers in adulthood, with the strongest and most consistent evidence observed for breast and corpus uteri cancers. These findings support the DOHaD hypothesis and highlight the long-term health consequences of early-life exposure to endocrine-disrupting chemicals. By integrating a historical natural experiment with nationwide health databases, this study strengthens the evidence on life-course environmental exposures and provides important implications for environmental risk assessment and public health policy.