隨著工業的發展及為了因應日常生活所需，近年來我們所使用的化學品種類日益增加，人體可能會藉由不同途徑暴露到這些化學品，進而產生不良的健康效應。然而，以常規的定量監測能獲取的資料數量相當有限，對於未在管制內的化學品更是無從得知其暴露情形。透過生物偵測的方式檢測人體檢體，可以釐清我們常見的暴露，藉此可作為未來化學品檢測及健康風險評估的優先項目。本研究利用超高效液相層析搭配飛行時間串聯式質譜儀(UHPLC-QTOF MS)分析新竹地區446個自2016年開始到2018年期間進行社區檢查之成人及孩童血清 (IRB編號：104-025-E及104-007-F)，後端比對資料庫鑑定化學品種類，並連結問卷蒐集的樣本資訊進行統計分析，以找出常見的化學品暴露及了解是否暴露情形與特定族群、生活或飲食習慣相關聯，最後針對篩查出之化學品，以樣本中的篩查頻率、暴露情形及生物可利用性等資訊做為排序的條件依據，建置優先化學品清單。
資料庫的比對中，共計篩查出326種化合物。其中有60%為醫療用藥，而多數的化合物其在樣本中的陽性篩查頻率(detection frequency)皆低於10%，僅有3個化合物其陽性篩查頻率大於90%，分別為人體必需胺基酸 (Phenylalanine)、治療癲癇藥物(Ethotoin)及食品添加物 (Piperine)。近年來高度關注的鄰苯二甲酸酯類(DEHP 和DBP)及全氟烷基化合物(PFOA和PFOS)其陽性篩查頻率僅接近30%。在統計分析的結果中，我們發現篩查到的化學品數量在成人及青少年、居住地(新竹縣和新竹市)和家庭年收入高低之間呈現顯著差異。另外，成人男性相較於女性有較高的風險暴露到DBP、PFOS和PFOA，而隨著攝取高油脂食物及貝類的頻率增高亦會增加DBP和PFOS的暴露風險。在優先化的排序結果中，排名前五分別為4-tert-Octylphenol、Caffeine、Piperine、trans-Calcifediol和Phenylalanine。透過敏感度分析，呈現出排序的結果以篩查頻率為主要貢獻因子(60%)，儘管篩查頻率可以真實反映出常見的暴露，但也因此稀釋了其他因子對於排序結果的重要性。
綜合以上，我們以高解析質譜儀來進行生物偵測，找出人體常見的暴露化學品，並結合問卷分析以釐清暴露特徵及相關的風險因子，最後進行化學品的優先化排序。此排序結果能提供台灣未來進行定量方法開發、制定常規檢測項目及健康風險評估的參考清單。

The number of emerging contaminants is increasing annually, and humans may be constantly exposed to these chemicals through diet, using consumer products, or contacting with environmental matrices. However, only the exposure information on a few chemicals are available from common targeted analysis. It is important to clarify highly exposed chemicals through biomonitoring.
In this study, ultra-high performance liquid chromatography coupled with quadrupole-TOF MS (UHPLC-QTOF MS) was used to analyze 446 human serum samples from Hsinchu area and acquired data at All Ions MS/MS mode (AIM) with both positive and negative ESI modes. We used libraries of tandem MS spectra to achieve chemicals identification. The identified chemicals were also compared with demographic data to explore the differences and associations among variables. Finally, we prioritized chemicals through the chemical detection frequencies, peak abundance, bioactivity data, and exposure information and provided a prioritized chemicals list in Taiwan.
A total of 326 chemicals were found and most of them were in low detection frequency (DF). The common detected ones (DF > 90%) were Phenylalanine (amino acid), Ethotoin (an anticonvulsant drug), and Piperine (food additives). In addition, the detection frequencies of PAEs (DBP and DEHP) and PFASs (PFOA and PFOS), which were highly concerned in recent years, were near to 30%. We also found that the number of detected chemicals was significantly different among groups (adults and adolescents), living area (city and county), and annual household income. Comparing with females, males had a higher risk of exposure to DBP, PFOA, and PFOS. The risk of exposure to DBP and PFOS was associated with high fatty food and shellfish consumption frequencies. Finally, the priorities in our identified chemicals were 4-tert-Octylphenol, caffeine, piperine, trans-Calcifediol, and Phenylalanine. Sensitivity analysis showed that the detection frequency was the major contribution (60%) to the ranking results. It might diminish the influences of other parameters (e.g., bioactivity and exposure information), although detection frequency was a good indicator to reflect the common exposure.
Overall, we used high-resolution mass spectrometry (HRMS) to conduct biomonitoring for identifying which were the mostly exposure to, and also connected to the demographic information to demonstrate the risk factor of exposure. This study provided a list of prioritized chemicals for further quantitative analysis and exposure assessment in Taiwan.

口試委員會審定書 #
誌謝 i
中文摘要 iii
ABSTRACT v
CONTENTS i
LIST OF FIGURES iv
LIST OF TABLES v
Chapter 1 Introduction 1
1.1 Introduction 1
1.2 High-resolution mass spectrometry (HRMS) and non-targeted analysis 1
1.3 Biomonitoring 3
1.4 Chemicals prioritization 5
1.5 Objectives 7
Chapter 2 Material and Methods 9
2.1 Reagents and materials 9
2.2 Sample collection 9
2.3 Sample preparation 10
2.4 UHPLC-QTOF MS Instrumental analysis 11
2.4.1 Chromatographic conditions 11
2.4.2 Mass spectrometry 12
2.4.3 Suspect screening data processing 13
2.5 Statistical analysis 15
2.5.1 Questionnaire variables transformation 15
2.5.2 Statistical analysis method 16
2.6 Chemical prioritization criteria 17
2.6.1 ToxPi framework 17
2.6.2 Prioritization criteria 17
2.6.3 Bioactivity and exposure information 18
2.6.4 Peak abundance calibration and transformation 19
2.7 Quality assurance and quality control (QA/QC) 20
2.7.1 Quality assurance 20
2.7.2 Quality control 20
Chapter 3 Results and Discussion 23
3.1 Quality assurance and quality control 23
3.2 General characteristics of participants 24
3.3 Detection frequencies of suspect chemicals 24
3.4 Statistical analysis and the participant''s characteristics 26
3.4.1 General characteristics and habits of the participants according to detected chemicals number 26
3.4.2 Associations between the participants'' characteristics and specific detected chemicals 28
3.5 Prioritization 29
3.5.1 Overview of prioritized results 30
3.5.2 Prioritizations in other studies 31
3.5.3 The prioritized chemicals in this study 33
3.6 Limitation 39
Chapter 4 Conclusions 41
References 43
Figures 52
Tables 62
Attachment(Ⅰ): The Questionnaire for Adults 86
Attachment(Ⅱ): The Questionnaire for Adolescents 102

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