臺灣博碩士論文加值系統

背景及研究目的：
　　造船作業會有焊接、切割、研磨等作業流程，過程中可能產生金屬微粒與燻煙等對人體有害物質；焊接金屬燻煙是一種複雜的混合物經由吸入及食入途徑進入體內循環系統增加體內活性氧化物的形成使體內氧化壓力提高，促使蛋白質、脂質及核酸氧化產生非酶反應，導致美拉德反應的出現，產生糖化終產物（Advanced Glycation End Products, AGEs）。
　　本研究尿液及趾甲樣本作為金屬短期及長期暴露型生物標記物，並以血液AGEs及皮膚AGEs當成短期及長期健康效應指標。進一步探討金屬暴露與AGEs效應之關係，目的包括：
一、 探討暴露燻煙微粒及金屬之短期暴露生物標記物尿中金屬與短、長期糖化終產物(AGEs)指標的相關。
二、 探討暴露燻煙微粒及金屬之長期暴露生物標記物趾甲金屬與短、長期糖化終產物(AGEs)指標的相關。

研究方法：
　　本研究採橫斷性研究設計，招募某造船廠的100位員工為研究對象。收案流程在星期一上工前佩戴個人採樣器測量受試者當天工作八小時之PM2.5的暴露濃度及進行問卷填寫，星期二進行空腹抽血、收集尿液、趾甲樣本及測量皮膚AGEs；尿液及趾甲樣本的金屬濃度以ICP-MS分析；血液中的AGEs以ELISA進行分析；皮膚AGEs以非侵入型皮膚自體螢光標定儀器(Skin autofluorescence, SAF)測量。以SPSS 22.0進行統計分析。

結果：
　　PM2.5暴露濃度暴露組(555.64±472.08 μg/m3)高於對照組(258.02±279.21 μg/m3)有顯著差異(p= 0.001)。暴露組在尿中鉻、尿中錳、尿中鐵、尿中銅及尿中鉛濃度高於對照組呈顯著差異。趾甲錳及趾甲鐵濃度亦高於對照組有顯著差異。對照組於尿中鎘及趾甲硒濃度高於暴露組出現顯著差異。校正肌酐酸及吸菸習慣等干擾因子後，尿中錳(β=0.279,p=0.006)、尿中鐵(β=0.273,p=0.007)及尿中鉛(β=0.290,p=0.005)濃度與血中AGEs呈顯著正相關。皮膚AGEs指標與尿中釩(β=-0.203,p=0.049)、尿中硒(β=-0.207,p=0.041)濃度有顯著負相關。校正吸菸習慣、職業別等干擾因子後，趾甲鋅(β=-0.209,p=0.022)濃度與血中AGEs呈顯著負相關。趾甲銅(β=0.243,p=0.017)及趾甲汞(β=0.298,p=0.003)濃度與皮膚AGEs指標呈顯著正相關；而趾甲鈷(β=-0.244,p=0.018)濃度與皮膚AGEs指標呈顯著負相關。

結論：
1. 短期尿中錳、尿中鐵及尿中鉛濃度會增加短期血中AGEs濃度。
2. 短期尿中釩及尿中硒於濃度會降低長期皮膚AGEs指標。
3. 長期趾甲鋅濃度會降低短期血中AGEs濃度。
4. 長期趾甲銅及趾甲汞濃度會增加長期皮膚AGEs指標。
5. 長期趾甲鈷濃度會降低長期皮膚AGEs指標。

Background：
Welding metal fumes are a complex mixture contains particulate and metals that workers could expose through inhalation and ingestion routes. Welding fume particulate matter and its components drive endogenous formation Advanced glycation end-products (AGEs) has not been explored.

Objectives：
Urinary and toenail metals are measured as short-term and long-term exposure biomarkers, while blood AGEs and skin AGEs are measured as short-term and long-term biological effect markers. Specific aims include:
1. To explore the relation between short-term (urinary metals) or long-term (toenail metals) biomarker of exposure and plasma Advanced Glycation End Products concentrations.
2. To explore the relation between short-term (urinary metals) or long-term (toenail metals) biomarker of exposure and skin Advanced Glycation End Products indicator.

Methods：
We conducted a cross-sectional study. Study participants consisted of 73 welders and 27 office workers. Exposure assessment was based on eight-hour measurement with a personal PM2.5 sampler of exposure to metal fume fine particle matter on Monday. On Tuesday morning, participants were instructed to fast for at least 10 hours prior to blood collection, urine collection, and collect toenail collection, Skin autofluorescence (SAF). Skin autofluorescence (SAF) was measured by a AGEs reader. Plasma AGEs was analyzed by ELISA kits. Urinary metal concentration was analyzed by ICP- MS. SPSS 22.0 was used to perform statistical analysis.

Result：
PM2.5 concentrations were significantly higher in exposed group (555.64±472.08 μg/m3) compared to that of control group (258.02±279.21 μg/m3)(p=0.001). Concentrations of urinary chromium, urinary manganese, urinary iron, urinary copper and urinary lead were higher in exposed group compared to control group. In addition, concentration of toenail manganese and toenail iron were higher in exposed group than that of control group. There were a positive association between urinary manganese (β=0.279, p=0.006), urinary iron (β=0.273, p=0.007) and urinary lead (β=0.290, p=0.005) with plasma AGEs after adjusted creatinine and smoking status, respectively. Furthermore, urinary vanadium (β=-0.203, p=0.049), and urinary selenium (β=-0.207, p=0.041) were statistically significant negative associated with skin AGEs indicator after adjusted creatinine and smoking status. toenail zinc (β=-0.209, p=0.022) was negatively associated with plasma AGEs after adjusted smoking status and work type.
Toenail copper (β=0.243, p=0.017), and toenail mercury (β=0.298, p=0.003) were positive associated with skin AGEs indicator after adjusted confounders, respectively.
of Exposure group and control group have significant differences of urinary cadmium and toenail selenium. But toenail cobalt (β=-0.244, p=0.018) was negative associated with skin AGEs indicator after adjusted confounders.

Conclusion：
1. Concentration of urinary manganese, urinary iron and urinary lead are associated with increased AGEs concentration.
2. Concentration of urinary vanadium and urinary selenium are associated with decreased skin AGEs indicator.
3. Toenail zinc is associated with decreased plasma AGEs level.
4. Toenail copper and toenail mercury are associated with increased skin AGEs indicator.
5. Toenail cobalt is associated with decreased skin AGEs indicator.

第一章 緒論........12
第一節 研究背景........12
第二節 研究動機與重要性........13
第三節 研究目的........15
第四節 研究假設........15

第二章 文獻探討........16
第一節 電焊作業材料與燻煙成份金屬介紹........16
第二節 金屬暴露對人體的健康影響........24
第三節 重金屬生物指標之選擇........33
壹 尿液重金屬相關研究........34
貳 趾甲重金屬相關研究........35
第四節 糖化終產物........36

第三章 研究方法與設計........42
第一節 研究設計與架構........42
第三節 研究對象........44
第三節 研究工具........46
第四節 實驗室品質管制........75
第五節 資料處理與統計方法........86

第四章 研究結果........89
第一節 基本人口學變項描述........89
第二節 自變項與依變項之相關矩陣........96
第三節 自變項與依變項之迴歸分析........101

第五章 討論........117
第一節 研究對象之代表性........117
第二節 尿液金屬濃度之探討........118
第三節 趾甲金屬濃度之探討........120
第四節 短期生物標記物與糖化終產物之探討........121
第五節 長期生物標記物與糖化終產物之探討........122
第五節 研究優點及限制與建議........123

第六章 結論........124

第七章 參考文獻........126

Ab Razak, N. H., Praveena, S. M., Aris, A. Z., & Hashim, Z. (2015). Drinking water studies: a review on heavy metal, application of biomarker and health risk assessment (a special focus in Malaysia). J Epidemiol Glob Health, 5(4), 297-310. doi:10.1016/j.jegh.2015.04.003
Ab Razak, N. H., Praveena, S. M., & Hashim, Z. (2015). Toenail as a biomarker of heavy metal exposure via drinking water: a systematic review. Rev Environ Health, 30(1), 1-7. doi:10.1515/reveh-2014-0063
Ammann, A. A. (2007). Inductively coupled plasma mass spectrometry (ICP MS): a versatile tool. J Mass Spectrom, 42(4), 419-427. doi:10.1002/jms.1206
Antonini, J. M. (2003). Health effects of welding. Crit Rev Toxicol, 33(1), 61-103. doi:10.1080/713611032
Antonini, J. M., Taylor, M. D., Zimmer, A. T., & Roberts, J. R. (2004). Pulmonary Responses to Welding Fumes: Role of Metal Constituents. Journal of Toxicology and Environmental Health, Part A, 67(3), 233-249. doi:10.1080/15287390490266909
Bayarsaikhan, E., Bayarsaikhan, D., Lee, J., Son, M., Oh, S., Moon, J., . . . Lee, B. (2015). Microglial AGE-albumin is critical for neuronal death in Parkinsons disease: a possible implication for theranostics. Int J Nanomedicine, 10 Spec Iss, 281-292. doi:10.2147/ijn.S95077
Berlin, J. A., Longnecker, M. P., & Greenland, S. J. E. (1993). Meta-analysis of epidemiologic dose-response data. 218-228.
Brook, R. D., Rajagopalan, S., Pope III, C. A., Brook, J. R., Bhatnagar, A., Diez-Roux, A. V., . . . Mittleman, M. A. J. C. (2010). Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. 121(21), 2331-2378.
Byun, K., Yoo, Y., Son, M., Lee, J., Jeong, G. B., Park, Y. M., . . . Lee, B. (2017). Advanced glycation end-products produced systemically and by macrophages: A common contributor to inflammation and degenerative diseases. Pharmacol Ther, 177, 44-55. doi:10.1016/j.pharmthera.2017.02.030
Castellani, R. J., Harris, P. L., Sayre, L. M., Fujii, J., Taniguchi, N., Vitek, M. P., . . . Medicine. (2001). Active glycation in neurofibrillary pathology of Alzheimer disease: Nε-(carboxymethyl) lysine and hexitol-lysine. 31(2), 175-180.
Crinnion, W. J. (2009). The benefit of pre- and post-challenge urine heavy metal testing: part 2. Altern Med Rev, 14(2), 103-108.
de Vos, L. C., Lefrandt, J. D., Dullaart, R. P. F., Zeebregts, C. J., & Smit, A. J. (2016). Advanced glycation end products: An emerging biomarker for adverse outcome in patients with peripheral artery disease. Atherosclerosis, 254, 291-299. doi:https://doi.org/10.1016/j.atherosclerosis.2016.10.012
Driscoll, T. R., Carey, R. N., Peters, S., Glass, D. C., Benke, G., Reid, A., & Fritschi, L. (2016). The Australian Work Exposures Study: Occupational Exposure to Polycyclic Aromatic Hydrocarbons. Ann Occup Hyg, 60(1), 124-131. doi:10.1093/annhyg/mev057
Fonseca-Nunes, A., Jakszyn, P., Agudo, A. J. C. e., & biomarkers, p. (2014). Iron and cancer risk—a systematic review and meta-analysis of the epidemiological evidence. 23(1), 12-31.
Garland, M., Morris, J. S., Rosner, B. A., Stampfer, M. J., Spate, V. L., Baskett, C. J., . . . Biomarkers, P. (1993). Toenail trace element levels as biomarkers: reproducibility over a 6-year period. 2(5), 493-497.
Gil, F., Hernández, A. F., Márquez, C., Femia, P., Olmedo, P., López-Guarnido, O., & Pla, A. J. S. o. t. t. e. (2011). Biomonitorization of cadmium, chromium, manganese, nickel and lead in whole blood, urine, axillary hair and saliva in an occupationally exposed population. 409(6), 1172-1180.
Goullé, J., Saussereau, E., Mahieu, L., Bouige, D., Groenwont, S., Guerbet, M., & Lacroix, C. J. J. o. a. t. (2009). Application of inductively coupled plasma mass spectrometry multielement analysis in fingernail and toenail as a biomarker of metal exposure. 33(2), 92-98.
Goulle, J. P., Saussereau, E., Mahieu, L., Bouige, D., Groenwont, S., Guerbet, M., & Lacroix, C. (2009). Application of inductively coupled plasma mass spectrometry multielement analysis in fingernail and toenail as a biomarker of metal exposure. J Anal Toxicol, 33(2), 92-98.
Grashow, R., Zhang, J., Fang, S. C., Weisskopf, M. G., Christiani, D. C., & Cavallari, J. M. (2014). Toenail metal concentration as a biomarker of occupational welding fume exposure. J Occup Environ Hyg, 11(6), 397-405. doi:10.1080/15459624.2013.875182
Hadjimarkos, D., & Shearer, T. R. J. J. o. d. r. (1973). Selenium content of human nails: a new index for epidemiologic studies of dental caries. 52(2), 389-389.
Hauser, R., Elreedy, S., Ryan, P. B., & Christiani, D. C. J. A. j. o. i. m. (1998). Urine vanadium concentrations in workers overhauling an oil‐fired boiler. 33(1), 55-60.
IARC. (2012). GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012.
Karakulak, U. N., Yilmaz, O. H., Tutkun, E., Gunduzoz, M., & Ercan Onay, E. J. A. o. N. E. (2017). Comprehensive electrocardiographic analysis of lead exposed workers: An arrhythmic risk assessment study. 22(2), e12376.
Kimura, S., Yamauchi, H., Hibino, Y., Iwamoto, M., Sera, K., Ogino, K. J. B., . . . toxicology. (2006). Evaluation of Urinary 8‐Hydroxydeoxyguanine inHealthy Japanese People. 98(5), 496-502.
Laohaudomchok, W., Lin, X., Herrick, R. F., Fang, S. C., Cavallari, J. M., Shrairman, R., . . . Weisskopf, M. G. J. N. (2011). Neuropsychological effects of low-level manganese exposure in welders. 32(2), 171-179.
Luo, J.-C. J., Hsu, K.-H., Shen, W.-S. J. J. o. O., & Medicine, E. (2009). Inflammatory responses and oxidative stress from metal fume exposure in automobile welders. 51(1), 95-103.
Lutgers, H. L., Gerrits, E. G., Graaff, R., Links, T. P., Sluiter, W. J., Gans, R. O., . . . Smit, A. J. (2009). Skin autofluorescence provides additional information to the UK Prospective Diabetes Study (UKPDS) risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus. Diabetologia, 52(5), 789-797. doi:10.1007/s00125-009-1308-9
Nagai, R., Ikeda, K., Higashi, T., Sano, H., Jinnouchi, Y., Araki, T., . . . communications, b. r. (1997). Hydroxyl radical mediates Nϵ-(Carboxymethyl) lysine formation from Amadori product. 234(1), 167-172.
Nowak, B., & Kozlowski, H. (1998). Heavy metals in human hair and teeth: the correlation with metal concentration in the environment. Biol Trace Elem Res, 62(3), 213-228. doi:10.1007/bf02783972
Nowak, B. J. S. o. t. T. E. (1998). Contents and relationship of elements in human hair for a non-industrialised population in Poland. 209(1), 59-68.
O’Doherty, M. G., Abnet, C. C., Murray, L. J., Woodside, J. V., Anderson, L. A., Brockman, J. D., . . . Control. (2010). Iron intake and markers of iron status and risk of Barrett’s esophagus and esophageal adenocarcinoma. 21(12), 2269-2279.
Omrane, F., Gargouri, I., Khadhraoui, M., Elleuch, B., & Zmirou-Navier, D. (2018). Risk assessment of occupational exposure to heavy metal mixtures: a study protocol. BMC Public Health, 18(1), 314. doi:10.1186/s12889-018-5191-5
OSHA (2002). [Shipyard Employment].
Ott, C., Jacobs, K., Haucke, E., Navarrete Santos, A., Grune, T., & Simm, A. (2014). Role of advanced glycation end products in cellular signaling. Redox Biology, 2, 411-429. doi:https://doi.org/10.1016/j.redox.2013.12.016
Pesch, B., Kendzia, B., Hauptmann, K., Van Gelder, R., Stamm, R., Hahn, J.-U., . . . health, e. (2015). Airborne exposure to inhalable hexavalent chromium in welders and other occupations: Estimates from the German MEGA database. 218(5), 500-506.
Pesch, B., Lotz, A., Koch, H. M., Marczynski, B., Casjens, S., Käfferlein, H. U., . . . Van Gelder, R. J. A. o. t. (2015). Oxidatively damaged guanosine in white blood cells and in urine of welders: associations with exposure to welding fumes and body iron stores. 89(8), 1257-1269.
Rajaobelina, K., Helmer, C., Velayoudom-Cephise, F. L., Nov, S., Farges, B., Pupier, E., . . . Rigalleau, V. (2017). Progression of skin autofluorescence of AGEs over 4 years in patients with type 1 diabetes. Diabetes Metab Res Rev, 33(7). doi:10.1002/dmrr.2917
Sheng, J., Qiu, W., Xu, B., Xu, H., & Tang, C. (2016). Monitoring of heavy metal levels in the major rivers and in residents blood in Zhenjiang City, China, and assessment of heavy metal elimination via urine and sweat in humans. Environ Sci Pollut Res Int, 23(11), 11034-11045. doi:10.1007/s11356-016-6287-z
Teissier, T., & Boulanger, E. (2019). The receptor for advanced glycation end-products (RAGE) is an important pattern recognition receptor (PRR) for inflammaging. Biogerontology. doi:10.1007/s10522-019-09808-3
Uribarri, J., del Castillo, M. D., de la Maza, M. P., Filip, R., Gugliucci, A., Luevano-Contreras, C., . . . Menini, T. J. A. i. n. (2015). Dietary advanced glycation end products and their role in health and disease. 6(4), 461-473.
Van Eupen, M. G., Schram, M. T., Colhoun, H. M., Scheijen, J. L., Stehouwer, C. D., & Schalkwijk, C. G. J. C. d. (2013). Plasma levels of advanced glycation endproducts are associated with type 1 diabetes and coronary artery calcification. 12(1), 149.
Wang, D., Du, X., & Zheng, W. (2008). Alteration of saliva and serum concentrations of manganese, copper, zinc, cadmium and lead among career welders. Toxicology Letters, 176(1), 40-47. doi:https://doi.org/10.1016/j.toxlet.2007.10.003
Yamagishi, S. I., & Matsui, T. (2018). Role of Hyperglycemia-Induced Advanced Glycation End Product (AGE) Accumulation in Atherosclerosis. Ann Vasc Dis, 11(3), 253-258. doi:10.3400/avd.ra.18-00070
Yoshinaga, J., Imai, H., Nakazawa, M., Suzuki, T., & Morita, M. (1990). Lack of significantly positive correlations between elemental concentrations in hair and in organs. Sci Total Environ, 99(1-2), 125-135.
Yoshinaga, J., Imai, H., Nakazawa, M., Suzuki, T., & Morita, M. (1990). Lack of significantly positive correlations between elemental concentrations in hair and in organs. Science of The Total Environment, 99(1), 125-135. doi:https://doi.org/10.1016/0048-9697(90)90217-I
Zimmer, A. T., & Biswas, P. (2001). Characterization of the aerosols resulting from arc welding processes. Journal of Aerosol Science, 32(8), 993-1008. doi:https://doi.org/10.1016/S0021-8502(01)00035-0
沈福銘, & 醫護科技學刊, 林. J. (2003). 台灣地區市售香菸中重金屬含量調查研究. 5(2), 119-129.
楊秀宜, 陳家揚, 李聯雄, & 年, 張. J. 勞. 民. (2012). 焊接燻煙健康危害新視界. 9, 383-393.
潘致弘, 賴錦皇, & Labor, 朱. J. J. o. (2015). 六價鉻對電鍍業勞工氧化傷害指標影響評估研究. 23, 229-241.
盧章智 (2015). [有毒金屬尿液篩檢 Urinary Toxic Metal Screening Test].