| 研究生: |
葉慧容 Yeh, Hui-Jung |
|---|---|
| 論文名稱: |
二異氰酸甲苯之暴露與生物指標關係之探討 Investigation of the relationship between the exposure to toluene diisocyanate (TDI) and biomarker |
| 指導教授: |
張火炎
Chang, Ho-Yuan |
| 學位類別: |
博士 Doctor |
| 系所名稱: |
醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences |
| 論文出版年: | 2007 |
| 畢業學年度: | 95 |
| 語文別: | 中文 |
| 論文頁數: | 131 |
| 中文關鍵詞: | 二胺基甲苯 、生物偵測 、暴露評估 、二異氰酸甲苯 、皮膚吸收 、動力學 、微波輔助加熱 、半衰期 |
| 外文關鍵詞: | toluene diamine, biological monitoring, exposure assessment, Toluene diisocyante, kinetic, half-life, dermal absorption |
| 相關次數: | 點閱:105 下載:2 |
| 分享至: |
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二異氰酸甲苯 (toluene diisocyanate,TDI) 在工業上主要作為製造聚氨基甲酸乙酯 (polyurethane, PU) 等產品製造。文獻上TDI可以引起職業性氣喘及過敏性肺炎等。針對TDI相關工廠之職業衛生研究目前有三項待研究改進:(1)代表TDI相關工廠勞工暴露實態 (exposure profile);(2)TDI經皮吸收;(3)改善TDI生物偵測分析效率。
本研究以實際職場研究為起點,系統性調查全國TDI相關工廠作業勞工TDI暴露實態、除呼吸外之皮膚暴露及其與製程之關係,並進一步以動物模式探討TDI皮膚暴露後是否經由皮膚吸收,並以尿中代謝物二胺基甲苯 (toluene diamine, TDA) 作為TDI內在暴露評估指標,建立TDI皮膚暴露劑量與效應關係。另又因在分析尿中TDA前,尿液樣本需在強酸、100℃下經16小時以上加熱水解,非常費時,在經濟、儀器可近性及節省時間考量下,以微波輔助加熱 (microwave assisted heating, MAH) 方式進行尿液樣本水解之可行性研究。
職場研究結果發現TDI濃度隨產品別有顯著差異,其中以泡綿業濃度最高,再者2,4-與2,6-TDI濃度比例不同於原料中兩種異構物之比例且非為定值。空氣中2,4-TDI濃度約有1/3樣本數超過法令容許濃度標準,我國在2003年以前只規定2,4-TDI作業環境空氣容許濃度標準,而2,6-TDI亦對人體有健康危害,對於2,6-TDI未有規範,故有增訂其容許濃度之必要,且由製程發現液態TDI在混料、注入或發泡時而污染勞工皮膚,勞工可能因皮膚暴露而增加健康風險。以大鼠動物模式進行TDI液體皮膚暴露發現,能在尿中檢測出TDA,顯示TDI的確可經皮吸收,且TDI暴露與TDA內在劑量呈正比關係。而尿中2,6-與2,4-TDA為first-order kinetic排除方式,半衰期約為20小時,惟在高劑量組似乎排除速率較慢。為節省上述TDA分析時間,使用MAH進行尿液樣本前處理水解,傳統加熱 (16小時) 與微波加熱之2,4-及2,6-TDA釋出量、回收率並無顯著差異,但MAH時間只需20分鐘即可達CH之效率,運用MAH進行TDI暴露之尿中TDA生物偵測樣品前處理方法是可行的。
Toluene diisocyanates (TDIs) are widely used in the production of polyurethane (PU). TDIs have been documented to cause occupational asthma. Up to the present time, three issues, however, are still waiting for further investigation with respect to TDI-related occupational health: (1) to determine the general exposure scenario among various TDI-related industries; (2) to develop a method accelerating the urine analysis in biological monitoring of TDIs exposure; and (3) to affirm skin absorption of TDIs.
In summary, the objectives of this study were to determine the nationwide 2,4- and 2,6-TDIs exposure profile on an industry-specific basis by a systematic survey. The results showed a significant difference in TDIs concentrations among three industries and PU foam with the highest TDIs concentration. Moreover, the TDIs could easily expose workers to TDIs via skin contact during the manufacturing processes e.g. charging and foaming. The findings hypothesized that TDIs skin exposure could results in skin absorption, but warrant a more thorough study to affirm. A rat model was used to evaluate the skin absorption to explore the dose-response pattern and determine the kinetic characteristics of U-TDAs during skin exposure. We confirmed that skin absorption of TDIs through skin contact and there is a clear dose-response fashion. U-TDAs concentrations via skin exposure reveal the first-order elimination kinetics and the apparent half-lives are about 20 hr. An attempt is made to apply microwave-assisted heating (MAH) to reduce the duration in analysis. The hydrolysis efficiency obtained from MAH procedure is significantly greater than that from conventional one. Hydrolysis by MAH required only 20 minutes, 48 times faster than with conventional heating. The use of the MAH method in hydrolysis was demonstrated to be a reproducible, timesaving and efficient technique in measuring the concentration of urinary TDAs. This method could be applied for analysis of U-TDAs in occupational health.
1.王家劑:高化學性危害工業勞工暴露調查研究-甲醛、氫氟酸、二異氰酸甲苯等之暴露。行政院勞工委員會勞工安全衛生研究所,IOSH89-A110。
2.高名人等著:異氰酸鹽作業勞工呼吸健康初步調查研究,勞工安全衛生季刊,9(1),37-50。2001年。
3.郭育良等著:職業病概論。華杏出版股份有限公司,台北。2000年。
4.陳美蓮、毛義方、汪禧年:二異氰酸甲苯採樣分析技術研究。行政院勞工委員會勞工安全衛生研究所,1998。
5.黃嵩立、郭育良、蔡朋枝:異氰酸鹽作業勞工職業流行病學調查研究。行政院勞工委員會勞工安全衛生研究所,1998。
6.熊映美:泡綿作業勞工之健康影響因素調查。行政院勞工委員會勞工安全衛生研究所,1998。
7.蔡春進:勞工作業環境有害物TDI蒸氣與氣膠同步個人採樣技術研究。行政院勞工委員會勞工安全衛生研究所,IOSH90-A101。
8.賴耿陽:聚尿脂樹脂PU原理與實用。復漢出版社,台北。1999年。
9.Abu-Samra A, Morris J.S, koirtyohann. Wet ashing of some biological samples in a microwave oven. Anal Chem 47 (8): 475-7 (1975).
10.Adams WGF. Long-term effect on the health of men engaged in the manufacture of toluene diisocyanate. Br J Ind Med 32: 72-78 (1975).
11.American Conference of Governmental Industrial Hygienists: 2006 TLV( and BEI( Threshold Limit Values for Chemical Substances and Physical Agents. ISBN: 1-882417-40-2, Cincinnati. (2006).
12.ASTM Standard Method D5932-96, (1996).
13.Baur X. Occupational asthma due to isocyanates. Lung 174: 23-30 (1996).
14.Bello D, et al. Skin exposure to isocyanates: reason for concern. Environ Health Perspect 15: 328-335 (2007).
15.Bello D, Smith TJ, Woskie SR, Streicher RP, Boeniger MF, Redlich CA, Liu Y. An FTIR investigation of isocyanate skin absorption using in vitro guinea pig skin. J Environ Monit 8: 523-529 (2006).
16.Bernstein JA. Overview of diisocyanate occupational asthma. Toxicology 111: 181-189 (1996).
17.Bishop RW, Ayers TA, Esposito GG. A gas chromatogramphic procedure for the determineation of airborne MDI and TDI. Am Ind Hyg J 44(3): 151-155 (1983).
18.Brorson T, Skarping G, Sangö C. Biological monitoring of isocyanates and related amines Ⅳ 2,4 and 2,6- toluenediamine in hydrolysed plasma and urine after test-chamber exposure of humans to 2,4- and 2,6- toluene diisocyanate. Int Arch Occup Environ Health 63: 253-259 (1991).
19.Carbonnelle P, Boukortt S, Lison D. Determination of toluenediamines in urine of workers occupationally exposed to isocyanates by high-performance liquid chromatography. Analyst 121: 663-669 (1996).
20.Carroll KB, Secombe CJ, Pepys J. Asthma due to nonoccupational exposure to toluene (tolylene) di-isocyanate. Clin Allergy 6(2): 99-104 (1976).
21.Chang HY, Chou TC, Wang PY, Shih TS. Biological monitoring of carbon disulphide: kinetics of urinar 2-thiothiazolidine-4-carboxylic acid (TTCA) in exposed workers. Toxicol Ind Health 18: 1-14 (2002).
22.Creely KS, Hughson GW, Cocker J, Jones K. Assessing isocyanate exposures in polyurethane industry sectors using biological and air monitoring methods. Ann Occup Hyg 50(6): 609-621 (2006).
23.Dalene M, Skarping G, Lind P. Workers exposure to thermal degradation products of TDI- and MDI-based polyurethane: biomonitoring of 2,4-TDA,2,6-TDA,and 4,4'-MDA in hydrolyzed urine and plasma. Am Ind Hyg Assoc J 58: 587-591 (1997).
24.Deschamps F, Prevost A, Lavaud F, Kochman S. Mechanisms of occupational asthma induced by isocyanates. Ann Occup Hyg 42: 33-36 (1998).
25.Developments in Microwave Chemistry, Evalueserve 2005.
26.Dietemann-Molard A, Kopferschmitt-Kubler MC, Meyer PD, Tomb R, Pauli G. Allergic asthma due to domestic use of insulating polyurethane foam. Lancet 338 (8772): 953 (1991).
27.England E, et al. Comparison of sampling method for monomer and polyisocyanates of 1,6-hexamethylene diisocyanate during spray finishing operations. Appl Occup Environ Hyg 15: 472-8 (2000).
28.EPA., Pesticide Assessment Guidelines, subdivision U- Applicator Exposure Monitoring, U.S. EPA , Washington, D.C. (1987).
29.Eriefalt I, Persson CG. Increased sensitivity to toluene diisocyanate (TDI) in airways previously exposed to low doses of TDI. Clin Exp Allergy 22(9): 854-862 (1992).
30.Frisch FC. Polyurethane technology. Ed., Bruim PF., Interscience Publishers, New York, p1 (1979).
31.Gntel Oertel. Polyurethane handbook. Hanser Publisher, Munich Vienna, New York, (1982).
32.Health and Safety Executive. MDHS 25/2, methods for the determination of hazardous substances: organic isocyanate in air. Sheffield, U.K.: Occupational Medicine and Hygiene Laboratory, Health and safety Executive, (1994).
33.Hepbun C. Polyurethane eastomers. Applied Science, London. (1982).
34.Herrick CA, Xu L, Wisnewski AV, Das J, Redlich CA, Bottomly K. A novel mouse model of diisocyanate-induced asthma showing allergic-type inflammation in the lung after inhaled antigen challenge. J Allergy Clin Immunol 109(5): 873-878 (2002).
35.Hornung RW, Reed LD. Estimation of average concentration in the presence of nondetectable values. Appl Occup Environ Hyg 5: 41-51 (1990).
36.International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risk to Humans: Some Chemical Used in Plastics and Elastomers: ISBN 92 832 1239 0 IARC Press, Lyon, Vol. 39, pp. 287-723 (1986).
37.International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risk to Humans: Some Chemical Used in Plastics and Elastomers: ISBN 92 832 1239 0 IARC Press, Lyon, Vol. 39, pp. 287-723 (1986).
38.IRIS: Integrated Risk Information System (IRIS). Micromedex, CO, USA, (2000).
39.John RM, Joseph D. A strategy for assessing and managing occupational exposure: AIHA press, 1(998).
40.Kääriä K, et al. Exposure to 2,4- and 2,6-toluene diisocyanate (TDI) during production of flexible foam: determination of airborne TDI and urinary 2,4- and 2,6-toluenediamine (TDA). Analyst 126: 1025-31 (2001).
41.Kanerva L, Estlander T, Jolanki R, Keskinen H. Asthma from diisocyanates is not mediated through a type IV, patch-testpositive mechanism. Contact Dermatitis 44: 246-263 (2001).
42.Karol MH, hauth BA, Riley EJ, Magreni CM. Dermal contact with toluene diisocyanate (TDI) produces respiratory tract hypersensitivity in guinea pigs. Toxicol Appl Pharmacol 58(2): 221-230 (1981).
43.Kennedy AL, Brown WE. Isocyanate and lung disease: experimental approach to molecular mechanicsm. Occup Med 7: 301-329 (1992).
44.Kingston HM, Haswell ST. Microwave enhanced chemistry. Washington, DC; J. Am Chem Soc 119: 772 (1997).
45.Krone CA, Klingner TD. Isocyanates, polyurethane and childhood asthma. Pediatr Allergy Immunol 16(5): 368-379 (2005).
46.Leibold E, Hoffmann H, Hidebrand B. MDI: study of absorption after single dermal and intradermal administration in rats. Manchester, UK: international Isocyanate Institute (1999).
47.Lesage J, et al. Workers’ exposure to isocyanates. Am Ind Hyg Assoc J 53: 146-53 (1992).
48.Levine SP, et al. Critical review of method of sampling,analysis,and monitoring for TDI and MDI. Am Ind Hyg Assoc J 56: 581-589 (1995).
49.Lind P, Dalene M, Skarping G, Hagmar L. Toxicokinetics of 2,4- and 2,6-toluene- diamine in hydrolysed urine and plasma after occupational exposure to 2,4- and 2,6-toluene diisocyanate. Occup Environ Med 53: 94-99 (1996).
50.Lind P, Dalene M, Tinnerberg H. Biomarkers in hydrolysed urine, plasma and erythrocytes among workers exposed to thermal degradation products from toluene diisocyanate foam. Analyst 22: 51-56 (1997).
51.Liu Y, et al. Qualitative assessment of isocyanate skin exposure in auto body shops: a pilot study. Am J Ind Med 37: 265-274 (2003).
52.Maitre A, Berode M, Perdrix A, Romazini S, Savolarinen H. Biological monitoring of occupational exposure to toluene diisocyanate. Int Arch Occup Environ Health 65: 97-100 (1993).
53.Mapp CE, Corona PC, De Marzo N, Fabbri L. Persistent asthma due to isocyanates: a follow - up study of subjects with occupational asthma due to toluene diisocyanate (TDI). Am Rev Respir Dis 137: 1326-1329 (1988).
54.Neas ED, Collins MJ. Introduction to microwave sample preparation. American Chemical Society: Washington DC, Chap. 2, 7-32 (1988).
55.NIOSH ALERT:Asthma and Death from diisocyanate exposure. DHHS(NIOSH) Publication No.96-111 (1996).
56.NIOSH: Current intelligence bulletin 53:toluene diisocyanate(TDI) and toluene- diamine(TDA); evidence of carcinogenicity. Cincinnati, U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health, DHHS(NIOSH) Publication, No.90-101 (1989).
57.Nomiyama T, Nakashima H, Chen LL, Tanaka S. N,N-dimethylformamide: significance of dermal absorption and adjustment method for urinary N-methylformamide concentration as a biological exposure item. Int Arch Occup Environ Health 74: 224-228 (2001).
58.Occupational Safety and Health Administration (OSHA): “OSHA Method 47: Diisocyanates.” OSHA Analytical Laboratory, Organic Methods Development Branch, Salt Lake City, UT, 1989.
59.Occupational Safety and Health Administration (OSHA). Sampling for surface contamination. In: OSHA Technical Manual, Section II, Chapter 2. Salt Lake City, Utah: OSHA Technical Center, p 1-16 (1999).
60.Ott MG, Diller WF, Jolly AT. Respiratory Effects of Toluene Diisocyanate in the Workplace: A Discussion of Exposure-Response Relationships. Crit Rev Toxicol 33: 1-60 (2003).
61.Paul F. WoolRICH. Toxicology, industrial hygiene and medical control of TDI, MDI, and PMPPI. Am Ind Hyg Assoc J 43: 89-97 (1982).
62.Persson P, Dalene M, Skarping G, Adamsson M, Hagmar L. Biological monitoring of occupational exposure to toluene diisocyanate: measurement of toluenediamine in hydrolysed urine and plasma by gas chromatography -mass spectrometry. Br J Ind Med 50: 1111-1118 (1993).
63.Peters JM, Murphy RL. Hazards to health: do it yourself polyurethane foam. Am Rev Respir Dis 104(3): 432-433 (1971).
64.Potter DW, Wederbrand KS. Total IgE production in BALB/c mice after dermal exposure to chemical. Fundam Appl Toxicol 26: 127-135 (1995).
65.Rando RJ, et al. Isomeric composition of airborne TDI in the polyurethane foam industry. Am Ind Hyg Assoc J 45: 199-203 (1984).
66.Rattray NJ, et al., Induction of respiratory hypersensitivity to diphenylmethane- 4,4-diisocyanate (MDI) in guinea pigs. Influence of route exposure. Toxicology 88: 15-30 (1994).
67.Rosenberg C, Savolaine H. Detection of urinary amine metabolites in toluene diisocyanate. J Chromatgr 323: 429-33 (1985).
68.Rosenberg C, Savolaine H. Determination of occupational exposure to toluene diisocyanate by biological monitoring. J Chromatgr 367: 385-92 (1985).
69.Roy JR, Halet GP. Dichotomous sampling of vapor and aerosol of methylene-bis-(phenylisocyanate) [MDI] with an annular diffusional denuder. Am Ind Hyg Assoc J 55: 716-21 (1994).
70.Rudzinski WE, et al. A comparison of solid sampler methods for the determination of Hexamethylene based. Am Ind Hyg Assoc J 62: 246-50 (2001).
71.Saetta M, Maestrelli P, Di Stefano A, et al., Effect of cessation of exposure to toluene diisocyanate (TDI) on bronchial mucosa of subjects with TDI-induced asthma. Am Rev Respir Dis 145: 169-174 (1992).
72.Saikai T, Morita Y, Roh J, Kim H, Kim Y. Improvement in the GC-MS method for determining urinary toluene-diamine and its application to the biological monitoring of workers exposed to toluene-diisocyanate. Int Arch Occup Environ Health 78: 459–466 (2005).
73.Schollenberger CS. Polyurethane technology. Ed., Bruim PF., Interscience Publishers, New York, p197 (1979).
74.Sheu F, Shyu YT. Determination of benzyl isothiocyanate in papaya fruit by Solid Phase Extraction and Gas Chromatography. J Food Drug Analysis 4: 327-334 (1996).
75.Skarping G, Brorson T, Sangö C. Biological monitoring of isocyanates and related amines Ⅲ test chamber exposure of humans to toluene diisocyanate, Int Arch Occup Environ Health 63: 83-88 (1991).
76.Streicher RP, et al. Determination of airborne isocyanate exposure: considerations in method selection. Am Ind Hyg Assoc J 61: 544-556 (2001).
77.Strid J, Hourihane J, Kimber I, Callard R, Strobel S. Epicutaneous exposure to peanut protein prevents oral tolerance and enhances allergic sensitization. Clin Exp Allergy 35(6): 757-766 (2005).
78.Timchalk C, Smith FA, Bartels MJ. Route-dependent comparative metabolism of [14C] toluene 2,4-diisocyanate and [14C]toluene 2,4-diamine in Fischer 344 rats. Toxicol Appl Pharmacol 124(2): 181-190 (1994).
79.Tinnerberg H, Dalene M, Skarping G. Air and biological monitoring of toluene diisocyanate in a flexible foam plant. Am Ind Hyg Assoc J 1997; 58: 229-235.
80.Tsai CJ, et al. Sampling time effect on 2,4-tolune diisocyanate concentration by using different samplers. Sep Sci Tech 41: 1799-1812 (2006).
81.Vandenplas O, Cartier A, Lesage J. Occupational asthma caused by a prepolymer but not the monomer of toluene diiisocyanate(TDI). J Allergy Clin Immunol 89(11): 1183-1188 (1992).
82.Vera Fiserova-Bergerova. Modeling of inhalation exposure to vapors uptake, distribution, and elimination. CRC Press: Boca Raton, Florida, US, (1983).
83.Walters K, et al. The National Toxicology Program’s. Lewis Publishers. (1992).
84.Wang JD, Huang PH, Lin JM. Occupational asthma due to toluene diisocyanate among Velcro-like tape manufacturers. Am J Ind Med 4: 73-78 (1998).
85.Weill H, et al. Respiratory and immunologic evaluation of isocyanate exposure in new manufacturing plant. NIOSH Publication, No. 81-125, NIOSH Technical Report,Washington DC, U.S. Government Printing Office (1981).
86.Yeh HJ, Lin WC, Sheu SC, Shih TS, Chen LH, Chang HY. Microwave-assisted acid hydrolysis of toluene diamine conjugates in urine samples form biomarkers in toluene diisocyanate analysis. Talanta 72: 1527-1532 (2007).
87.Yeh HJ, Shih TS, Tsai PJ, Chang HY. Toluene diisocyanate concentration investigation among TDI-related factories in Taiwan and their relations to the type of industry. J Exp Anal Environ Epidemiol 12: 157-164 (2002).
88.Zlotorzynski A. The application of microwave radiation to analytical and enviromental chemistry. Crit Rev Anal Chem 25: 43-76 (1995).