簡易檢索 / 詳目顯示

回結果列表
研究生： 朱祐民
Chu, You-Ming
論文名稱： 應用跟暴露方式探討人造皮工廠暴露環境下N,N-dimethylformamide(DMF)不同暴露途徑之生物偵測
The application of semi-actual exposure method in the investigation of the effects of biological monitoring due to the different routes of occupational exposure to N,N-dimethylformamide (DMF) in a synthetic leather industry
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： 71
中文關鍵詞： 生物偵測 、動力學 、皮膚吸收 、跟暴露 、時間活動模式 、二甲基甲醯胺
外文關鍵詞： kinetics, biological monitoring, time-activity pattern (TAP), dermal exposure, semi-actual exposure approach, dimethylformamide (DMF)
相關次數： 點閱：117  下載：3 
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報

    • 　　毒性化學物質於職場中進入人體大多以呼吸吸收及皮膚吸收為主，而近年來工作場所呼吸暴露的防護越趨完善，因此若只考慮呼吸吸收的量可能會對有害物進入體內的真實暴露量造成低估。本研究的目的是擬探討皮膚暴露及呼吸暴露兩種暴露途徑其對於二甲基甲醯胺(DMF)吸收的貢獻量及兩種途徑所計算之體內N-methylformamide (NMF)的排除動力學。本次研究是以跟暴露方式進行，暴露現場為台灣某人造皮革製造工廠，選定六位健康志願者，在一整天的工作時間內全程亦步亦趨的跟隨六位作業現場中實際DMF暴露員工，以模擬現場作業員工的暴露情形，並收取受試者的生物採樣資料，藉由受試者配合度高的特性，可以得到較精確的採樣資料，有利進行生物偵測的計算。本次研究分為兩個部分，第一個部分為讓受試者戴上裝有標準濾毒罐且均無洩漏之防毒面罩，以徹底阻絕其呼吸暴露，藉以評估控制呼吸暴露情形下，僅有皮膚的暴露方式之尿中DMF生物暴露指標情形，第二部分模式為無任何防護具的作業方式下，計算呼吸與皮膚兩種途徑下之尿中DMF生物暴露指標情形。藉比較兩次不同情形下尿中DMF生物指標情形的差異來計算單純皮膚暴露的貢獻量，再藉由36小時全程連續尿液的量測以評估不同暴露途徑出尿中的DMF排除動力學情形是否不同，並藉此計算出不同途徑的半衰期。空氣DMF之暴露測定是應用DMF即時偵測器及參與人員之時間活動模式計算而得，皮膚DMF之測定為包含每位受試者隻手掌、手背、手前臂及背後第7頸椎分別於暴露前、暴露中及暴露後，並採用橫斷式及累積式兩種方式進行測定。生物偵測則是收集每位受試者暴露前、中、後之尿液，以及暴露後連續完整36小時之尿液，測定尿中DMF與NMF之濃度值。我們發現結合即時空氣偵測器與時間活動模式，推估本研究個人氣態DMF僅皮膚暴露日時均量之暴露值為8.10(2.75) ppm (幾何平均(幾何標準差))，而皮膚+呼吸暴露則為9.52(3.47)ppm，暴露前到暴露中的的全裸露手部暴露濃度為51.85（2.26）μg/cm2，利用累積性的採樣方式所採到的暴露前到暴露後的全裸露手部皮膚暴露濃度為75.20（1.62）ug/cm2，利用橫斷性的採樣方式所採到的暴露前到暴露後的全裸露手部皮膚暴露濃度為56.90（1.70）ug/cm2，顯示出利用橫斷式之測定方法可能會造成皮膚暴露之低估。計算暴露結束後36小時尿液中NMF濃度曲線下面積，Area under curve簡稱AUC，以計算兩種不同暴露途徑之間吸收量的差異，發現呼吸吸收與皮膚吸收兩種暴露途徑其貢獻量各佔47％及53％，顯示真實職場中DMF皮膚蒸氣吸收可能較呼吸途徑之暴露更為重要，在正常的暴露狀態下（呼吸＋皮膚）其尿中NMF的半衰期為6.36小時，若將呼吸吸收途徑阻隔後在只有皮膚吸收的暴露下半衰期為7.49小時，顯示皮膚暴露之尿中NMF排除之半衰期的確較呼吸暴露為長。本研究建議職業暴露DMF之作業員工除呼吸暴露外，應加強防護皮膚途徑之暴露。

    　　The major routes of chemical exposure for the subjects in the occupational environment are through respiratory tract and through dermal tract. However, continuous improvement exerted in the respiratory protection these days in the occupational setting has substantially reduced the absorbed amount via respiratory route. Dermal exposure, thus, has become increasingly important with respect to the protection of the workers from the chemical hazards. The purposes of this study were to determine the relative contribution of dimethylformamide (DMF) exposure via dermal route and via respiratory route, respectively, and to determine the separate kinetic behaviors of skin vapor exposure and skin vapor plus respiratory exposure, respectively, by using a semi-actual exposure approach in a synthetic leather factory. Six healthy volunteers were designated to closely follow the actual DMF-exposed employees across a whole work shift for two exposure scenarios: with (skin vapor exposure only) and without (skin vapor plus respiratory exposure) wearing respiratory protection equipment. Their airborne and dermal exposures to DMF were determined on the individual basis. Airborne exposure assessment was conducted by integrating real-time DMF monitoring and time-activity pattern (TAP) for each individual. Dermal exposure assessment was performed by using taped method by both cross-sectional and cumulative measures on the palm and dorsal palm of both hands, both forearms and 7th cervical neck at pre-, during- and post-shifts, respectively. Biological monitoring was achieved to collect each participant’s urine at pre-, during- and post-shifts, respectively. Moreover, 36-hr consecutive urine samples were collected since the termination of the exposure to elaborate the kinetics. Urinary DMF and N-methylformamide (NMF) were determined as biological exposure markers for DMF exposure. We found the time-weighted average of airborne DMF concentrations among all participants by the integration of real-time monitor and TAP were 8.10 (2.75) and 9.52 (3.47) ppm (GM(GSD)), respectively, for skin vapor exposure only and skin vapor plus respiratory exposure. The dermal exposure concentrations for whole hand (forearm plus hand) for both hands among all participants were 51.85 (2.26) μg/cm2 and 75.20 (1.62) μg/cm2, respectively, for cross-sectional basis and for cumulative basis, indicating the estimates based on cross-sectional measure probably result in the underestimation of the actually dermal exposure to DMF vapor. Area under curve (AUC) of urinary NMF throughout 36 hrs showed 47% and 53% of excretory NMF contributed to respiratory exposure and dermal exposure, respectively, indicating that the absorbed dose of DMF via dermal vapor exposure was even greater than that via respiratory exposure. The excretory kinetics of urinary NMF also showed that the half-life estimate for skin vapor plus respiratory exposure (6.36 hrs) was shorter than that for skin vapor exposure only (7.49 hrs), suggesting the longer half-life for the DMF exposure via dermal route. We suggested that skin exposure protection should be enhanced for those who occupationally exposed to DMF in addition to the respiratory protection.

    1.序論………………………………………………………………P 12. 2.研究目的…………………………………………………………P 16 3.文獻探討…………………………………………………………P 16 　3-1. DMF的物化特性及毒性……………………………………P 16 　3-2. DMF的代謝途徑……………………………………………P 16 　3-3. DMF的現場濃度採樣（皮膚、空氣）……………………P.17 　3-4. 時間-活動模式(Time-Activity Pattern) …………………P.20 　3-5. DMF的生物偵測……………………………………………P.22 　3-6. DMF的皮膚吸收……………………………………………P.24 4. 材料與方法 ……………………………………………………P.23 　　4-1-1. 採樣材料……………………………………………P.23 　　4-1-2. 分析儀器……………………………………………P.23 　　4-1-3. 使用藥品……………………………………………P.23 　4-2. 採樣方法…………………………………………………P.24 　　4-2-1. 現場分區域濃度測定………………………………P.24 　4-3. 跟暴露研究設計…………………………………………P.33 　4-4. 皮膚採樣…………………………………………………P.33 　4-5. 生物偵測…………………………………………………P.34 　4-6. 空白採樣…………………………………………………P.35 　4-7. 採樣的品保品管…………………………………………P.35 　4-8. 總採樣樣本數……………………………………………P.36 　4-9. 氣態DMF濃度之分析…………………………………….P.36 　　4-9-1. 即時偵測器…………………………………………P.36 　　4-9-2. 校正方法……………………………………………P.37 　　4-9-3. 校正步驟……………………………………………P.37 　4-10. 皮膚貼布濃度分析………………………………………P.37 　　4-10-1. 分析條件……………………………………………P.38 　4-11. 尿液濃度分析……………………………………………P.38 　　4-11-1. 分析條件……………………………………………P.38 　4-12. 尿中檢量線配置…………………………………………P.38 　4-13. 員工暴露實際時程………………………………………P.39 　4-14. 資料分析及統計…………………………………………P.40 5.結果與討論………………………………………………………P.41 　5-1. 研究對象……………………………………………………P.41 　5-2. 個人空氣中DMF之暴露……………………………………P.41 　5-3. 氣態DMF的皮膚暴露………………………………………P.42 　5-4. 尿中NMF與DMF的濃度變化…………………………………P.43 　5-5. 尿中NMF和DMF與空氣中DMF之相關性……………………P.44 　5-6. 尿中NMF之動力學探討……………………………………P.44 　5-7. 兩種暴露途徑之蒸氣DMF吸收之曲線相符（curve-fitting） 　　　　與半衰期之推估…………………………………………P.45 6. 結論……………………………………………………………… P.46 7. 參考文獻………………………………………………………… P.48 圖表目錄 表1、人體試驗者之基本資料……………………………………………P.54 表2、受試人體之上、下午和一天平均之DMF TWA濃度值之比較…..P.55 表3、空氣中DMF上下午與全天濃度於9/27與9/30兩天之統計比較.P.56 表4、勞工於9/27工作前、中、後皮膚暴露DMF的濃度分布情形…..P.57 表5、勞工於9/30工作前、中、後皮膚暴露DMF的濃度分布情形…..P.58 表6、勞工工作前、中、後皮膚暴露DMF的濃度分布情形…………….P.59 表7、受試人體於工作前、中、後之個人尿中DMF和NMF濃度值…P.60 表8、勞工於工作前、中、後尿中DMF濃度分布情形………………...P.62 表9、勞工於工作前、中、後尿中NMF濃度分布情形………………....P.63 表10、尿中DMF和NMF與空氣中DMF濃度之相關性……………....P.64 表11、尿中NMF代謝曲線之AUC……………………………………....P.65 表12、尿中NMF 24小時收集之動力學曲線……………………….…...P.66 表13、表四到表六代號所代表之涵義……………………………………P.67 圖1 某人造皮工廠之生產示意圖……………………………………….P.69 圖2 利用MIRAN即時偵測器與TAP所描繪之6位受試者DMF-TWA兩天（9/27,9/30）分時濃度圖……………………………………………… P.70 圖3. DMF體內代謝途徑………………………………………………….P.71

    1. Angerer J, Goen T, Kramer A, Kafferlein HU. N-methylcarbamoyl adducts at the N-terminal valine of globin in workers exposed to N,N-dimethylformamide. Archives of Toxicology. 1998;72(5):309-13.

    2. Brooke I, Cocker J, Delic JI, Payne M, Jones K, Gregg NC, et al. Dermal uptake of solvents from the vapour phase: an experimental study in humans. Annals of Occupational Hygiene 1998;42(8):531-40.

    3. Cai SX, Huang MY, Xi LQ, Li YL, Qu JB, Kawai T, et al. Occupational dimethylformamide exposure. 3. Health effects of dimethylformamide after occupational exposure at low concentrations. International Archives of Occupational & Environmental Health 1992;63(7):461-8.

    4. Chang. H-Y, Shin. T-S, Cheng. C-C, Tsai C-Y, Lai. J-S, Wang. V-S. The effects of co-exposure to methyl ethyl ketone on the biological monitoring of occupational exposure to N,N-dimethylformamide. International Archives of Occupational & Environmental Health 2001.(In press)

    5. Cherrie JW, Robertson A. Biologically relevant assessment of dermal exposure. Annals of Occupational Hygiene 1995;39(3):387-92.

    6. Farrant RD, Salman SR, Lindon JC, Cupid BC, Nicholson JK. Deuterium NMR spectroscopy of biofluids for the identification of drug metabolites: application to N,N-dimethylformamide. Journal of Pharmaceutical & Biomedical Analysis. 1993;11(8):687-92.

    7. Franz TJ. Percutaneous absorption on the relevance of in vitro data. Journal of Investigative Dermatology 1975;64(3):190-5.

    8. Gescher A. Metabolism of N,N-dimethylformamide: Key to the Understanding of its Toxicity. Chemical Research in Toxicology. 1993;6(3):245-251.

    9. Guidelines for Exposure Assessment, Federal Register, 57:22888-22938, 1992

    10. Han DH, Pearson PG, Baillie TA, Dayal R, Tsang LH, Gescher A. Chemical synthesis and cytotoxic properties of N-alkylcarbamic acid thioesters, metabolites of hepatotoxic formamides. Chemical Research in Toxicology 1990;3(2):118-24.

    11. Hundley SG, Lieder PH, Valentine R, Malley LA, Kennedy GL, Jr. Dimethylformamide pharmacokinetics following inhalation exposures to rats and mice. Drug & Chemical Toxicology. 1993;16(1):21-52 sW.

    12. Hundley SG, McCooey KT, Lieder PH, Hurtt ME, Kennedy GL, Jr. Dimethylformamide pharmacokinetics following inhalation exposure in monkeys. Drug & Chemical Toxicology. 1993;16(1):53-79.

    13. Jenkins PL, Phillips TJ, Mulberg EJ, Hui SP. Activity Patterns of Californians : Use of And Proximity to Indoor Pollutant Sources. Atmospheric Environment 1992;26A:2141-2148.

    14. Kafferlein HU, Angerer J. Simultaneous determination of two human urinary metabolites of N,N-dimethylformamide using gas chromatography-thermionic sensitive detection with mass spectrometric confirmation. Journal of Chromatography. B, Biomedical Sciences & Applications. 1999;734(2):285-98.

    15. Kafferlein HU, Goen T, Muller J, Wrbitzky R, Angerer J. Biological monitoring of workers exposed to N,N-dimethylformamide in the synthetic fibre industry. International Archives of Occupational & Environmental Health. 2000;73(2):113-20.

    16. Katsouyanni K. Health effects of air pollution in southern Europe: are there interacting factors? Environmental Health Perspectives. 1995;103(Suppl 2):23-7.

    17. Kawai T, Yasugi T, Mizunuma K, Watanabe T, Cai SX, Huang MY, et al. Occupational dimethylformamide exposure. 2. Monomethylformamide excretion in urine after occupational dimethylformamide exposure. International Archives of Occupational & Environmental Health 1992;63(7):455-60.

    18. Kimmerle G, Eben A. Metabolism studies of N,N-dimethylformamide. II. Studies in persons. Int Arch Arbeitsmed. 1975;34:127-136.

    19. Kimmerle G, Eben A. Metabolism studies of N,N-dimethylformamide. I. Studies in rats and dogs. Int Arch Arbeitsmed. 1975;34:109-126.

    20. Kraeling ME, Reddy G, Bronaugh RL. Percutaneous absorption of trinitrobenzene: animal models for human skin. Journal of Applied Toxicology. 1998;18(6):387-92.

    21. Lebowitz MD. Exposure assessment needs in studies of acute health effects. The Science of the Total Environment 1995;168:109-117.

    22. Leech JA, Wilby K, McMullen E. Environmental tobacco smoke exposure patterns: a subanalysis of the Canadian Human Time-Activity Pattern Survey. Canadian Journal of Public Health. Revue Canadienne de Sante Publique. 1999;90(4):244-9.

    23. Liu L JS, Koutrakis P, Suh H H, Mulik J D, Burton R M. Use of Personal Measurements for Ozone Exposure Assessment : A Pilot Study. Environmental Health Perspectives. 1993;101:318-324.

    24. Lotte C, Rougier A, Wilson DR, Maibach HI. In vivo relationship between transepidermal water loss and percutaneous penetration of some organic compounds in man: effect of anatomic site. Archives of Dermatological Research. 1987;279(5):351-6.

    25. Miyauchi H, Tanaka S, Nomiyama T, Seki Y, Imamiya S, Omae K. N,N-dimethylformamide (DMF) vapor absorption through the skin in workers. Journal of Occupational Health 2001;43:92-94.

    26. Mraz J, Galova E, Nohova H, Vitkova D. Uptake, metabolism and elimination of cyclohexanone in humans. International Archives of Occupational & Environmental Health 1994;66(3):203-8.

    27. Mraz J, Jheeta P, Gescher A, Hyland R, Thummel K, Threadgill MD. Investigation of the mechanistic basis of N,N-dimethylformamide toxicity. Metabolism of N,N-dimethylformamide and its deuterated isotopomers by cytochrome P450 2E1. Chemical Research in Toxicology. 1993;6(2):197-207.

    28. Mraz J, Nohova H. Percutaneous absorption of N,N-dimethylformamide in humans. International Archives of Occupational & Environmental Health 1992;64(2):79-83.

    29. Nomiyama T, Haufroid V, Buchet JP, Miyauchi H, Tanaka S, Yamauchi T, et al. Insertion polymorphism of CYP2E1 and urinary N-methylformamide after N,N- dimethylformamide exposure in Japanese workers. International Archives of Occupational & Environmental Health. 2001;74(7):519-22.

    30. Nomiyama T, Nakashima H, Chen LL, Tanaka S, Miyauchi H, Yamauchi T, et al. N,N-dimethylformamide: significance of dermal absorption and adjustment method for urinary N-methylformamide concentration as a biological exposure item. International Archives of Occupational & Environmental Health. 2001;74(3):224-8.

    31. Nomiyama T, Nakashima H, Sano Y, Chen LL, Tanaka S, Miyauchi H, et al. Does the polymorphism of cytochrome P-450 2E1 affect the metabolism of N,N-dimethylformamide? Comparison of the half-lives of urinary N-methylformamide. Archives of Toxicology. 2001;74(12):755-9.

    32. Nomiyama T, Omae K, Ishizuka C, Yamauchi T, Kawasumi Y, Yamada K, et al. Dermal absorption of N,N-dimethylacetamide in human volunteers. International Archives of Occupational & Environmental Health 2000;73(2):121-6.

    33. Poet TS, Corley RA, Thrall KD, Edwards JA, Tanojo H, Weitz KK, et al. Assessment of the percutaneous absorption of trichloroethylene in rats and humans using MS/MS real-time breath analysis and physiologically based pharmacokinetic modeling. Toxicological Sciences 2000;56(1):61-72.

    34. Poet TS, McDougal JN. Skin absorption and human risk assessment. Chemico-Biological Interactions. 2002;140(1):19-34.

    35. Redlich CA, West AB, Fleming L, True LD, Cullen MR, Riely CA. Clinical and pathological characteristics of hepatotoxicity associated with occupational exposure to dimethylformamide. Gastroenterology 1990;99(3):748-57.

    36. Robinson JP. Time-Diary Research and human Exposure Assessment : Some Methodological Considerations. Atmospheric Environment 1988;22:2085-2092.

    37. Schneider T, Cherrie JW, Vermeulen R, Kromhout H. Dermal exposure assessment. Annals of Occupational Hygiene. 2000;44(7):493-9.

    38. Styles CB, Noujaim AA, Jugdutt BI, Sykes TR, Turner C. Omega iodo fatty acid scintigraphy--what are we measuring? European Heart Journal. 1985;6(Suppl B):103-6.

    39. Venkateswaran KS, Raghuveeran CD, Gopalan N, Agarwal GS, Kaushik MP, Vijayaraghavan R. Monitoring of haemoglobin-methyl isocyanate adduct by high-performance liquid chromatography with diode array detector. Biochemistry International 1992;28(4):745-50.

    40. Waldman JM, Bilder SM, Freeman NCG, Friedman M. A Portable Datalogger to Evaluate Recall-Based Time-Use Measures. Journal of Exposure Analysis and Environmental Epidemiology 1993;3:39-48.

    41. Wester RC, Maibach HI. Benzene percutaneous absorption: dermal exposure relative to other benzene sources. International Journal of Occupational & Environmental Health 2000;6(2):122-6.

    42. Wheeler JP, Stancliffe JD. Comparison of methods for monitoring solid particulate surface contamination in the workplace. Annals of Occupational Hygiene. 1998;42(7):477-88.

    43. Wrbitzky R, Angerer J. N,N-dimethylformamide--influence of working conditions and skin penetration on the internal exposure of workers in synthetic textile production. International Archives of Occupational & Environmental Health. 1998;71(5):309-16.

    44. Yang JS, Kim EA, Lee MY, Park IJ, Kang SK. Biological monitoring of occupational exposure to N,N-dimethylformamide--the effects of co-exposure to toluene or dermal exposure. International Archives of Occupational & Environmental Health. 2000;73(7):463-70.

    45. Yasugi T, Kawai T, Mizunuma K, Horiguchi S, Iguchi H, Ikeda M. Occupational dimethylformamide exposure. 1. Diffusive sampling of dimethylformamide vapor for determination of time-weighted average concentration in air. International Archives of Occupational & Environmental Health 1992;63(7):449-53.

    下載圖示 校內：立即公開
    校外：2003-02-14公開
    QR CODE