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研究生：	林育群 Lin, Yu-Qun
論文名稱：	建立唾液中二甲基甲醯胺職業暴露之生物指標分析方法 Development of an analytical method to determine salivary biomarkers of the occupational exposure to N,N-dimethylformamide
指導教授：	張火炎 Chang, Ho-Yuan
學位類別：	碩士 Master
系所名稱：	醫學院 - 環境醫學研究所 Department of Environmental and Occupational Health
論文出版年：	2003
畢業學年度：	91
語文別：	中文
論文頁數：	87
中文關鍵詞：	現場驗證、生物指標、唾液、生物暴露指標、方法開發
外文關鍵詞：	BEI, method development, field validation, Biomarker, saliva
相關次數：	點閱：121 下載：2
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目的：二甲基甲醯胺（N, N-dimethylformamide；DMF）是工業界常用的溶劑之一。目前對於DMF所常用的生物暴露指標為工作日下班前尿中的N-methylformamide（NMF）。但尿液並非能隨時收集且有涉及個人隱私權的問題，本研究擬開發唾液中DMF和NMF的分析方法，作為推估勞工暴露DMF之替代性生物暴露指標物之可適用性。
方法：本研究採用的分析儀器為氣相層析儀 / 熱敏感偵測器（GC / TSD），目前唾液分析採用的前處理方法為取1mL唾液樣本，經離心（5000 rpm，10 min）後，加入0.5 mL的甲醇於0.5 mL之上清液後上機分析並評估以唾液基質所建立的檢量線、偵測下限、精密度、濃度儲存穩定度之品保及品管內容；現場驗證則進行包括跟暴露與實際DMF暴露之52位勞工空氣DMF、工作前、後尿液和唾液的採集和分析，評估空氣暴露和體內各生物偵測指標物間的相關性，探討以唾液中之DMF與NMF作為DMF暴露生物指標之可行性。
結果與結論：
1.本研究所開發的唾液中DMF和NMF之分析方法可通用於唾液0.09~ 75.6mg/L和0.10~80.0mg/L之濃度範圍的定量，而其中0.04mg/L、0.03 mg/L為DMF和NMF之方法偵測下限，且職業性DMF暴露者之唾液中DMF與NMF之濃度值皆低於此偵測下限。足以涵蓋職業暴露DMF之勞工唾液中DMF、NMF之濃度範圍，並且在DMF和NMF分別為0.95mg/L、14.18 mg/L、28.35mg/L和1mg/L、15mg/L、30mg/L的濃度值之精密度誤差皆小於7.5﹪，說明本方法可以應用於職業暴露DMF之唾液中DMF、NMF量測。

2.本分析方法發現，DMF、NMF分別在7.09mg/L、14.18mg/L、28.35mg/L和 7.5mg/L、15mg/L、30mg/L之濃度值的唾液樣本如密封儲存於-20℃冰箱內，在儲存四天內的回收率皆大於80％，所以建議應於採樣完畢後四天內完成分析，已確定唾液中DMF和NMF濃度回收率達至80％以上。
3. 本研究發現唾液中DMF濃度值皆顯著大於NMF濃度值，其與文獻中尿中NMF濃度值恆大於DMF濃度值之情形有所不同，推測原因可能是唾液中DMF、NMF產生的機制和尿中不同所產生的情形，詳細機制，尚待進一步研究探討。
4.以現行法規空氣中DMF暴露容許濃度值10ppm，及尿中NMF現行建議BEI值15mg/L（ACGIH, 2001）和尿中DMF值為1.9 mg/L（Chang et al., 2003）為分界點，發現高低暴露者之唾液中DMF與NMF濃度值有顯著差異，顯示以唾液中DMF或NMF濃度值確實可以判別DMF職業族群之空氣中DMF暴露濃度是否高於法規容許暴露值。
5.根據空氣中DMF與尿中NMF分別與唾液中DMF、NMF之線性迴歸方程式推估DMF空氣濃度恕限值為10ppm及尿中NMF BEI值為15mg/L值之唾液生物暴露指標分別為5.91~6.53mg/L與4.85 ~5.70mg/L。

Objective: N,N-dimethylformamide (DMF) has been extensively used as a solvent in many industries. Urinary N,N-methylformamide (NMF) is commonly used as a biomarker of occupational exposure DMF. The constraint of sampling timing availability and the concern of personal privacy, however, warrant a need to develop other possible biomarkers like saliva to more efficiently evaluate the internal dose of occupational exposure to DMF.
Methods: Gas chromatography / thermal sensitive detector (GC / TSD) was used in instrumental analysis. One ml of mixed saliva was collected from healthy unexposed subjects and then was centrifuged at 5000 rpm for 10 min. After centrifugation, 0.5 ml methanol was added to supernatant (0.5 ml). The following items of quality assurance and quality control in laboratory tests were examined: correlation coefficient of the linearity of calibration, method limit of detection (MLOD), precision, and storage stability across fives weeks. The field validation was performed by a six-healthy-volunteer semi-actual exposure field study and actual occupational settings including fifty-two workers directly exposed to DMF from four DMF-related factories. Time-weighted average airborne samples and urine samples at both pre- and post-shifts were collected and analyzed and they were correlated with salivary DMF and NMF for the evaluation of the applicability of salivary biomarkers.
Results and Conclusions:
1.The applicable range of DMF and NMF concentration in saliva were 0.09~ 75.6 mg/L and 0.10~80.0 mg/L and their corresponding MLOD were 0.04mg/L and 0.03mg/L, respectively. The coefficient of variance (CV%) for precision was below 7.5%. Judged by the applicable range, MLOD, and relative small CV%, we concluded that DMF and NMF in saliva could be used as complementary biomarkers of occupational exposure to DMF.
2.In the storage stability tests at -20℃, we found the recovery rates for the saliva spiked with DMF at 7.09, 14.18, and 28.35 mg/L and with NMF at 7.50, 15.00, and 30.00 mg/L were above 80% within four days. In order to avoid sample loss, we hereby suggested that the analysis for the salivary samples should be achieved within four days right after the completeness of sample collection for the samples stored in a -20℃ refrigerator.
3.We found that the levels of salivary DMF were consistently greater than that of NMF, which was different from the observed in urinary samples. One of the possible explanations could be the generation process of DMF and NMF in saliva is different from that in urine. The exact mechanism, however, warrants a further study.
4.We grouped salivary concentrations of DMF and NMF into two categories according to the following cut points: whether their airborne DMF concentrations were greater than the current permissible exposure limit (PEL = 10ppm); urinary NMF were greater than the current biological exposure index (BEI = 15mg/L); and urinary DMF were greater than 1.9mg/L (Chang et al., 2003). We found the salivary DMF and NMF were significantly different between two groups by all cut points, suggesting the salivary DMF and NMF could be appropriate biomarkers to differentiate the exposure over/below the allowable exposure limits.
5.According to the linear regression equations derived from the results, the estimates of the biological exposure indices for salivary DMF and NMF at post-shift were 5.91~6.53mg/L and 4.85~ 5.70 mg /L, respectively, given the workers’ exposure to DMF at 10ppm for eight hours or their urinary NMF were 15 mg/L at post-shift.

中文摘要........................................................................................................................1
目錄.......................................................................................................................5
圖目錄............................................................................................................................8
表目錄..........................................................................................................................10

第一章 序論................................................................................................................11
　　1-1 研究背景....................................................................................................11
　　1-2 研究意義和重要性....................................................................................14
　　1-3 研究目的....................................................................................................15
　　1-4 研究架構....................................................................................................16

第二章 文獻探討......................................................................................................17
　　2-1 DMF 之物化特性和其應用.......................................................................17
　　2-2 DMF 的代謝和其健康效應.......................................................................17
　　　　2-2-1 DMF 之代謝（圖二） ......................................................................17
　　　　2-2-2 DMF 之健康效應..............................................................................20
　　2-3 DMF 之皮膚吸收研究探討.......................................................................21
　　2-4 DMF 之生物偵測.......................................................................................21
　　2-5 唾液組成和其分泌控制............................................................................23
　　　　2-5-1 唾液的組成成分...............................................................................23
　　　　2-5-2 唾液分泌的控制...............................................................................24
　　2-6 唾液的形成機制........................................................................................24
　　2-7 影響唾液分泌速度和組成之因素............................................................27
　　2-8 唾液於生物偵測上之應用........................................................................30
　　2-9 目前唾液之分析方法................................................................................33
　　　　2-9-1 免疫分析方法...................................................................................33
　　　　2-9-2 層析之分析方法...............................................................................33

第三章 材料與方法....................................................................................................35
　　3-1 實驗室之方法開發....................................................................................35
　　　　3-1-1 唾液之收集.......................................................................................35
　　　　3-1-2 前處理方法測試...............................................................................35
　　　　3-1-3 儀器分析條件之測試.......................................................................35
　　　　3-1-4 檢量線之測試...................................................................................36
　　　　3-1-5 回收率之測試...................................................................................36
　　　　3-1-6 精密度之測試...................................................................................37
　　　　3-1-7 方法偵測下限之測試.......................................................................37
　　　　3-1-8 濃度儲存穩定性分析測試...............................................................37
　　3-2 職場中作業環境測定和生物偵測之採樣................................................38
　　　　3-2-1 研究對象之選取...............................................................................38
　　　　3-2-2 採樣方法...........................................................................................40
　　　　3-2-3 化學藥品...........................................................................................42
　　　　3-2-4 分析儀器...........................................................................................43
　　　　3-2-5 分析方法...........................................................................................43
　　　　　　3-2-5-1 空氣樣本分析方法.................................................................43
　　　　　　　　3-2-5-1-1 空氣樣本之前處理.....................................................43
　　　　　　　　3-2-5-1-2 空氣樣本分析條件.....................................................44
　　　　　　3-2-5-2 尿液樣本分析方法.................................................................44
　　　　　　　　3-2-5-2-1 尿液樣本前處理方法.................................................44
　　　　　　　　3-2-5-2-2 尿液樣本之分析條件.................................................45
　　　　　　3-2-5-3 唾液樣本分析方法.................................................................45
　　　　　　　　3-2-5-3-1 唾液樣本之前處理方法.............................................45
　　　　　　　　3-2-5-3-2 唾液樣本之分析條件.................................................45
　　3-3 實驗室分析之品保品管控制....................................................................48
　　　　3-3-1 檢量線配置........................................................................................48
　　　　　　3-3-1-1 空氣部分.................................................................................48
　　　　　　3-3-1-2 尿液部分.................................................................................48
　　　　　　3-3-1-3 唾液部分.................................................................................49
　　　　3-3-2 脫附效率............................................................................................49
　　　　　　3-3-2-1 空氣部分.................................................................................49
　　　　3-3-3 精密度測試........................................................................................50
　　　　3-3-4 QC 測試.............................................................................................50
　　　　3-3-5 方法偵測下限....................................................................................50
　　　　3-3-6 試劑空白............................................................................................51
　　　　3-3-7 介質空白............................................................................................51
　　3-4 統計分析方法............................................................................................52

第四章 結果與討論....................................................................................................53
　　4-1 唾液中DMF 與NMF 前處理與實驗室方法開發部份...........................53
　　　　4-1-1 前處理和分析條件之測試...............................................................53
　　　　4-1-2 檢量線之建立...................................................................................55
　　　　4-1-3 回收率之測試...................................................................................58
　　　　4-1-4 精密度測試.......................................................................................59
　　　　4-1-5 方法偵測下限測試...........................................................................60
　　　　4-1-6 濃度儲存穩定性分析.......................................................................60
　　4-2 工廠採樣結果探討....................................................................................64
　　　　4-2-1 跟暴露結果分析之探討...................................................................64
　　　　　　4-2-1-1 空氣中DMF 濃度值............................................................64
　　　　　　4-2-1-2 尿液中DMF 和NMF 濃度值.............................................64
　　　　　　4-2-1-3 唾液中DMF 和NMF 濃度值.............................................65
　　　　4-2-2 五家工廠分析資料之探討...............................................................69
　　　　　　4-2-2-1 空氣中DMF 暴露濃度值....................................................69
　　　　　　4-2-2-2 尿液中DMF、NMF 濃度值...............................................69
　　　　　　4-2-2-3 唾液中DMF、NMF 濃度值...............................................72
　　　　　　4-2-2-4 唾液中DMF、NMF 濃度於空氣中DMF 和尿液DMF
　　　　　　　　　　、NMF 濃度高低組別之差異............................................75
　　　　　　4-2-2-5 唾液中DMF、NMF 濃度值和尿中DMF、NMF生物指標
　　　　　　　　　　、空氣中DMF 暴露之線性迴歸...................................76

第五章 結論與建議....................................................................................................78
參考文獻......................................................................................................................80
                                    

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