臺灣博碩士論文加值系統

摘要
醇醚類化合物具有良好的親水性與親酯性及常溫下揮發性低等特性，因此工業界廣泛將其使用在塗料、印刷、油漆等行業作為有機溶劑的混合劑。由動物實驗顯示乙二醇醚類化合物對人體會產生生殖毒害、發育障礙等危害，因此近年來各國均以毒性相對較低之丙二醇醚醚類化合物取代乙二醇醚類化合物之使用。長久以來，皮膚吸收一直為職業衛生或職業病預防工作所忽視，而丙二醇醚類化合物為經皮吸收物質之一，對皮膚之滲透性極高，本研究擬以較不具侵入性的膠帶撕貼法進行該物質的皮膚暴露評估探究。
膠帶撕貼法由於具有省時、成本低廉、操作簡單的特性，廣泛被運用於生醫材料及化妝品領域作為藥物動力學及皮膚滲透吸收之評估方法。本實驗中以膠帶撕貼法將膠帶貼於受測者皮膚部位，藉皮表危害物被膠帶移除，以測得角質層危害物含量，藉以評估受測者皮膚暴情形。研究中將對膠帶撕貼法採樣之相關影響因子，包括：皮膚溫度、貼膚部位、皮膚保水度及皮膚細緻度等進行評估，以確認膠帶撕貼法未來運用於職場丙二醇醚類化合物皮膚暴露評估之適用性。
本實驗針對12位自願受測者，於室溫下進行手指、手掌至手臂等七個貼膚部位測試，以4cm ´ 2.5cm膠帶在皮膚表面丙二醇單甲基醚醋酸酯添加量分別為0.5L、1L、2L、4L (0.485、0.97、1.94、3.88mg)時進行同部位連續三次貼膚測試評估，實驗結果顯示在10cm2貼敷面積下2l (0.194 mg/sample)具有最佳移除率，於0.194mg/cm2 皮表濃度下，手部一次貼膚樣品之平均回收率為69.25% (CV=1.95 %)，同部位連續三次貼總移除率達87.06%。而於皮表貼膚採樣10分鐘時危害物在皮表的滲透吸附可達到穩定平衡狀態。部位一、二、三次貼膚樣品相對於總移除率之比率分別為90.2%：8.6%：1.2%。而本實驗結果結果顯示10分鐘為PGMEA最適化採樣時間，此時滲透吸附達平衡穩定狀態，從不同部位一次貼之移除率不受人體體脂肪(BMI)與皮表油脂多寡之影響，但受皮表溫度及皮膚表面細緻度影響。初步結果顯示，以膠帶撕貼法運用於丙二醇醚類化合物皮膚暴露評估具相當可行性。

關鍵字：丙二醇醚類化合物、膠帶撕貼法、皮膚暴露

Abstract
Glycol ethers are frequently used as solvents, detergents and emulsifiers in industrial and consumer products. Because of their toxic potential, the ethylene glycol ethers are increasingly being substituted by propylene glycol ethers, wich do not show toxic properties such as tetratogenicity, haemolysis and testicular atrophy,but for which less information is published.Exposure of formulators and users to propylene glycol ethers, and among them mainly propylene glycol ethers, can occur via respiratory and dermal uptake of the vapour,or via dermal uptake of liquid after direct contact.
A simple, non-invasive dermal sampling technique, which employed the tape stripping of the stratum corneum, was developed for the measuring of dermal exposure to propylene glycol mono-methyl ether acetate (PGMEA). Samples were subsequently extracted and a gas chromatographic method was performed for quantitative analysis.
Including 12 human volunteers were exposed to an a priori determined amount of PGMEA at different sites on both hands and arms. Dermal surface exposure PGMEA to 0.5L、1L、2L、4L (0.485、0.97、1.94、3.88mg) in in the same site (3 con-secutive tape strippings). The results from 10cm2 area showed that with 2µL (0.194mg/sample) of neat PGMEA spiked, the best removal efficiency with less variations can be obtained because of the spreading area capacity and chemical volatility. It was also found that the first tape stripping will removed 69.25 % (CV=1.95%) of the amount spiked , and the total removal efficiency for 3 consecutive tape strippings at the same site was 87.06%. The 1st strip , the 2nd strip and the 3rd strip samples versus to total recovery were 90.2: 8.6:1.2 respectively.
The steady state for PGMEA evaporation and adsorption by skin will be 10 min after exposure. Besides, human BMI and skin oiliness were found to have no correlations with the removal of PGMEA from the first tape stripping. However, significant differences were observed between females and males, probably due to the differences in surface temperature and roughness of the skin. The results indicate that this tape stripping technique can be used to quantify the dermal exposure to PGEs in the future.

Keywords: Propylene glycol monomethyl ether acetate (PGMEA);
tape stripping; dermal exposure

摘要 I
Abstract III
誌謝 V
目錄 VII
圖目錄 XI
表目錄 XII

第一章 序論 1
1-1 研究背景 1
1-2 研究目的 4
第二章 文獻回顧 5
2-1 丙二醇醚類化合物介紹 5
2-1-1 丙二醇醚類化合物之基本特性 5
2-1-2 PGEs 法規容許濃度標準 7
2-1-3 PGEs代謝與健康效應 8
2-1-3-1 動物實驗結果 10
2-1-3-2 人體實驗結果 11
2-1-4 PGEs化合物偵測方法 13
2-1-5 PGEs皮膚暴露 14
2-2 皮膚構造介紹 18
2-2-1 皮膚基本構造 18
2-2-1-1 表皮 19
2-2-1-2 真皮 21
2-2-1-3皮下組織 21
2-2-2 經皮吸收 21
2-2-3皮膚藥動試驗法 22
2-2-4皮膚的功能 22
2-2-4-1 防禦功能 23
2-2-4-2 生理恆定 24
2-2-5 皮膚吸收的定義 25
2-3 皮膚障壁功能指標 26
2-3-1經皮水分散失 27
2-3-2皮膚含水量 28
2-3-3皮膚修復功能 28
2-4 皮膚採樣方法 28
2-4-1螢光法 (UV Fluorescence) 31
2-4-2擦拭法 (Wet wipe) 31
2-4-3洗手法 (Hand wash) 32
2-4-4貼膚法 (Patch) 32
2-4-5膠帶貼布法 (Tape stripping; TS) 32
2-5 皮膚種類與來源 35
2-6 研究限制 36
第三章 材料與方法 37
3-1 設備及材料 37
3-2 研究架構 38
3-2-1 最適化採樣方法 38
3-2-2 採樣影響因子評估 40
3-3 研究對象 40
3-4 分析方法 41
3-4-1 分析條件 42
3-4-2 檢量線 44
3-4-3 最低偵測極限 45
3-4-4 品管分析 45
3-5 實驗室分析之品保品管 46
3-5-1 檢量線配置 46
3-5-2 脫附效率 47
3-5-3 精密度(Precision) 50
3-5-4 QC Check 50
3-5-5 最低偵測極限 50
3-5-6 試劑空白 51
3-6 皮膚採樣 51
3-7 統計分析方法 52
第四章 結果與討論 53
4-1 建立Tape-stripping最適化採樣方法 53
4-1-1 最適化採樣時間 53
4-1-2 最佳萃取時間 54
4-1-3 樣品存放穩定性 55
4-2影響皮膚暴露變異因子之探討 56
4-2-1 個體因素 57
4-2-1-1 不同部位之影響 57
4-2-1-2 不同部位對應個體差異之影響 58
4-2-1-3 不同材質比較 60
4-3 不同材質移除比例 61
第五章 結論 64
參考文獻 66

圖目錄
圖2-1 丙二醇單甲醚之合成 9
圖2-2 丙二醇單甲醚醋酸酯體內代謝圖 9
圖2-3 α-PGME人體代謝途徑圖 12
圖2-4 β-PGME之人體代謝途徑圖 12
圖2-5 皮膚構造圖 19
圖2-6 角質層結構圖 20
圖2-7 表皮層結構 20
圖2-8 穿透角質層之路徑 26
圖2-9 身體各部位之吸收倍率(以手臂內側為1時) 30
圖2-10 膠帶撕貼法示意圖 35
圖3-1 研究架構圖 39
圖3-2 PGME/PGMEA/DPGME三物質共存之圖譜 43
圖3-3 PGMEA單一物質皮膚暴露之圖譜 43
圖3-4 三物質GC-MS定性之圖譜 44
圖3-5 PGMEA之檢量線 44
圖3-6 研究對象採樣部位圖 48
圖3-7 Tape-stripping採樣過程 49
圖4-1 最適化採樣時間 54
圖4-2 最佳萃取時間 55

表目錄
表1-1 常見醇醚類化合物之簡稱 2
表2-1 丙二醇迷類化合物基本物化特性 6
表2-2 醇醚類化合物所應用之領域 7
表2-3 我國及世界國家之E、P系列醇醚類化合物容許濃度標準 8
表2-4 PGEs之生物檢體採樣分析方法彙整表 13
表2-5 PGEs之內在劑量生物偵測方法彙整表 15
表2-6 影響皮膚吸收滲透之因子 30
表2-7 皮表危害物優暴露評估缺點比較 31
表2-8 運用不同的膠帶進行tape stripping 34
表3-1 PGMEA之最低偵測極限 45
表3-2 儀器穩定性品管分析表 45
表4-1 PGMEA不同的萃取時間下其脫附的變化量 55
表4-2 不同的變化量下其樣品存放穩定性 56
表4-3 不同變化量對應不同部位移除率之比較 58
表4-4 不同部位之一次貼於不同個體之差異 59
表4-5 不同材質PGMEA之移除率比較 60
表4-6 於玻璃平板移除率 61
表4-7 於人皮皮表層移除率 62
表4-8於人工敷料移除率 62
表4-9玻璃平板、人皮、人工敷料三次貼之總移除率 63

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學位論文
蔡靜宜，2002，「職業暴露DMF之皮膚吸收與生物偵測」。國立成功大學環境醫學研究所。台南。
江伯榮，2003，「芝麻油以浸泡方式經皮膚吸收對大白鼠體內氧化性壓力的影響」。國立成功大學醫學院。台南。
周子傑，2005，「二硫化碳暴露對皮膚疾病與皮膚障壁估能損失之探討」。國立成功大學環境醫學研究所。台南。
陳恕誼，2005，「利用體外釋出、皮膚層撕法及皮膚藥物動力學比較未用Tretinoin製劑」。國立成功大學臨床藥學研究所。台南。
梁若寒，2005，「職業環境中乙二醇乙醚醋酸脂之呼吸暨皮膚暴露評估與生物偵測之探討」。國立成功大學環境醫學研究所。台南。
林雅崙，2006，「泥水業員工皮膚鉻暴露與經皮水份喪失值對鉻暴露生物指標之影響」。長榮大學職業安全衛生研究所。台南。
周瑞淑，2006，「勞工甲苯暴露及健康危害之探討」。國立台灣大學公共衛生學院環境衛生研究所。台北。
宋宥慶，2008，「驅蟲劑工廠中對二氯苯與呼吸及皮膚暴露評估之相關與生物偵測之探討」。國立成功大學環境醫學研究所。台南。
吳信賢，2008，「利用數值模型定量尿素經皮吸收之滲透係數」。國立中興大學化學工程學系。台中。
沈書弘，2008，「以空氣、皮膚、尿液及血液採樣測定評估泥水業勞工六價鉻暴露」。長榮大學職業安全衛生研究所。台南。
劉宇翔，2009，「噪音與有機溶劑暴露對飛機檢修人員皮膚屏障功能之影響」。中國醫藥大學。台中。
郭佳慧，2010，「固相微萃取技術應用於空氣中丙二醇單甲基醚醋酸酯採樣分析之評估」。弘光科技大學職業安全暨防災研究所。台中。

(三)研究報告
林佳谷、石東生，1993，「乙二醇醚溶劑使用管理之探討」。行政院勞工委員會勞工安全衛生研究所 No. 82。台北。
陳承裕、石東生，1993，「餐飲業清潔劑有機溶劑成分調查」行政院勞工委員會勞工安全衛生研究所No. 88。台北。
林佳谷、葉文裕等人，1994，「乙二醇醚溶劑使用現況調查-作業環境濃度偵測」。行政院勞工委員會勞工安全衛生研究所No. 83。台北。
(四)網站資料、書籍
1.竹內米久司、稻津教久，2009，「無孔不入經皮毒 ：防禦疾病，從保護皮膚開始! 」。
2.丙二醇化合物採樣分析方法參考資料，1996，行政院勞委會勞工安全衛生研究所。台北。(http://www.iosh.gov.tw/)
3.ACGIH(American Conference of Governmental Industrial Hygienists). Threshold limit values for chemical ubstances and physical agents andbiological indices. Cincinnati, OH: ACGIH,2005( http://www.acgih.org/About/)
4.NIOSH Research Report, “Development and validation of Methods For Sampling and Analysis of Workplace Toxec Substances”, U.S. Department of Health and Human Services, Publ. (NIOSH) 80-133 (1980)( http://www.niosh.com.my/)
5.MAK http://www.mak.com/
6.OSHA (Occupational Safety and Health Administration)
7.SRI http://www.sri.com/
8.OECD, “The principles of creatiot centers on of high-quality Servicee companies: Management Reform Cenntres on IT.(2004a) ( http://www.oecd.org/)
9.IRAC, http://www.irac-online.org/