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研究生:李梅菁
研究生(外文):Mei-Ching Li
論文名稱:1.奈米氧化鋅微粒毒性研究2.奈米碳球毒性研究
論文名稱(外文):Part Ι: Toxicity study of zinc oxide nanoparticles Part Ⅱ: Toxicity study of carbon nanocapsules
指導教授:鄭尊仁鄭尊仁引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
畢業學年度:96
語文別:中文
論文頁數:82
中文關鍵詞:Part Ι:奈米氧化鋅呼吸暴露肺泡灌洗液發炎指標 Part Ⅱ: 奈米碳球氣管灌注水溶性微粒肺泡灌洗液發炎指標
外文關鍵詞:Part Ι:Zinc oxide nanoparticlesInhalation exposureBronchoalveolar lavageLung inflammation and injury Part Ⅱ:Carbon nanocapsulesIntratracheal instillationBronchoalveolar lavageInflammation markers
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Part Ι:
奈米氧化鋅用途廣泛,可以被應用在塗料、油漆、橡膠輪胎工業、化妝品等產品上,但相關的毒理研究並不多。因此我們利用全身性呼吸暴露的方式,將奈米氧化鋅微粒暴露於健康大鼠,觀察其肺部及系統性的毒性效應。
本實驗利用呼吸暴露的方式,於實驗動物進行奈米氧化鋅微粒的暴露,我們以奈米微粒產生系統產生粒徑約為30 nm的奈米氧化鋅微粒,產生微粒的同時以微粒粒徑濃度分佈自動監測儀(SMPS+CPC)進行微粒粒徑及濃度的監測,分別進行了低暴露組(5 hrs)以及高暴露組(10 hrs)的暴露,並以在相同暴露條件下,未填入鋅粉於爐管內空燒的實驗(暴露5hrs)為對照組,每組暴露6隻大鼠,共計18隻。暴露後24小時進行犧牲,並採集周邊血液樣本,測試血液中血球數目(CBC/DC)及細胞激素的濃度(IL-6、TNF-α),同時採集其肺泡灌洗液(BALF)進行肺部發炎及傷害指標的分析,包括總細胞數、血球分類計數、乳酸脫氫酵素(LDH)及總蛋白質(Total protein)。
實驗結果顯示奈米產生器可穩定產生奈米粒徑的氧化鋅微粒,低暴露組(5 hrs)所產生的奈米氧化鋅微粒,中數粒徑(count median diameter, CMD)為34.0 nm,數目濃度約為5.3 × 105 #/cm3;高暴露組(10 hrs)的中數粒徑為24.7 nm,數目濃度約為4.1 × 106 #/cm3。
動物實驗結果發現大鼠暴露於低暴露組及高暴露組的奈米氧化鋅微粒後,在肺泡灌洗液中的嗜中性球百分比(Neutrophils)及乳酸脫氫酵素(LDH)相較於對照組有顯著增加,而且呈現劑量反應關係(p<0.05)。另外,暴露於高暴露組的奈米氧化鋅微粒後,還發現周邊血液中的白血球數目(WBC)、血小板數目(PLT)以及細胞激素(IL-6)相較於對照組有顯著增加(p<0.05)。
本研究發現,奈米氧化鋅微粒會誘使健康大鼠發生急性肺部發炎與傷害反應,同時有系統性發炎產生,顯示奈米氧化鋅微粒可能具有急性毒性效應,值得進一步關注,不過真正機制需要未來研究加以探討。
Part Ⅱ:
奈米碳球(carbon nanocapsules, CNC)為新興材料,目前國內已成功開發可大量生產並純化奈米碳球的方法,但是其毒性並不清楚。一旦經由呼吸將微粒吸入可能會造成健康危害。所以我們將大鼠暴露於奈米碳球,觀察其肺部及系統性毒性。
本實驗利用氣管灌注的方式,對實驗動物進行奈米碳球的暴露,包括三種奈米碳球(水溶性:CNC-(OH)n、CNC-(COOH)n及非水溶性:純CNC),兩種劑量(1與5 mg/kg),並以生理食鹽水(PBS)為對照組,每一個組別各需要6隻大鼠。實驗動物於微粒灌注後24小時進行犧牲,並採集周邊血液樣本,測試血液中血球數目(CBC/DC)及氧化壓力(oxidative stress),同時採集其肺泡灌洗液(BALF)進行肺部發炎及傷害指標的分析,包括總細胞數、血球分類計數、乳酸脫氫酵素(lactate dehydrogenase, LDH)及總蛋白質(Total protein)。
實驗發現大鼠暴露於高劑量的水溶性奈米碳球微粒(CNC-(OH)n及CNC-(COOH)n)後,在肺泡灌洗液中的總細胞及嗜中性球數目相較於控制組有顯著增加(p<0.05),但是總蛋白質及乳酸脫氫酵素(LDH),及周邊血液血球及分類計數和氧化壓力皆沒有明顯變化。至於純CNC暴露後,各項指標皆沒有顯著差異。
研究顯示經過表面處理的奈米碳球(水溶性),在較高劑量時可能造成肺部發炎反應,真正機轉有待進ㄧ步評估。
目錄 I
Part Ι 1
摘要 2
Abstract 4
第一章 目的 5
第二章 文獻探討 6
2-1 奈米材料的應用及特性 6
2-2 奈米氧化鋅的特性及應用 6
2-3 奈米微粒毒理研究 7
2-4 奈米微粒與肺部毒性 8
2-5 奈米微粒其他相關毒理研究 10
2-6 奈米氧化鋅相關毒理研究 10
2-7 肺部發炎及發炎反應指標 11
2-8 系統性發炎及發炎反應指標 12
2-9 氣管灌注與呼吸暴露方式比較 12
2-10 奈米微粒產生方法 13
2-10-1 噴霧法 (Atomization) 13
2-10-2 爐管氣流反應器 (Furnace flow reactors) 13
第三章 材料與方法 14
3-1 奈米微粒產生與監測 14
3-1-1 奈米氧化鋅微粒的產生 14
3-1-2 監測系統 14
3-2 實驗動物 14
3-3 實驗設計 15
3-4 全身性呼吸暴露模式(whole-body inhalation exposure) 15
3-5 系統性發炎反應指標分析 15
3-6 肺泡灌洗液發炎損傷指標分析 16
3-7 統計方法分析 16
3-8 實驗架構 17
第四章 結果 18
4-1 奈米氧化鋅微粒的暴露 18
4-2 動物實驗 19
第五章 討論 21
5-1 奈米產生器以及微粒的產生及暴露 21
5-2 呼吸暴露奈米氧化鋅微粒所引起之毒性效應 22
第六章 結論 26
第七章 未來改進與展望 27
參考文獻: 42
PartⅡ 46
摘要 47
Abstract 48
第一章 目的 49
第二章 文獻探討 50
2-1 奈米材料的應用及特性 50
2-2 奈米碳球簡介 50
2-2-1 奈米碳球及其特性 50
2-2-2 奈米碳球的來源及應用 51
2-2-3 奈米碳球官能化方法 52
2-3 奈米微粒毒理研究 53
2-4 奈米微粒與肺部毒性 53
2-5 奈米微粒其他相關毒理研究 53
2-6 奈米碳球相關毒理研究 53
2-7 肺部發炎及發炎反應指標 53
2-8 反應性含氧物種與氧化壓力 54
第三章 材料與方法 55
3-1 微粒 55
3-2 實驗動物 55
3-3 實驗設計 55
3-4 氣管內灌注暴露模式 56
3-5 周邊血液血球與氧化壓力測試 56
3-6 肺泡灌洗液發炎損傷指標分析 56
3-7 實驗架構 57
第四章 結果 58
第五章 討論 59
第六章 結論 61
參考文獻: 68
附錄 70
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PartⅡ:
Driscoll KE, Costa DL, Hatch G, Henderson R, Oberdorster G, Salem H, Schlesinger RB. Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: uses and limitations. Toxicol Sci. 2000;55:24-35.
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Elder A, Gelein R, Azadniv M , Frampton M, Finkelstein J, Oberdorster G. Systemic effects of inhaled ultrafine particles in two compromised, aged rat strains. Inhal Toxicol. 2004;16:461-71.
Nel A, Xia T, Mädler L, Li N. Toxic potential of materials at the nanolevel. Science 2006;311: 622-7.
Oberdorster G. Pulmonary effects of inhaled ultrafine particles. Int Arch Occup Environ Health. 2001;74:1-8.
Sayes CM, Wahi R, Kurian PA, Liu Y, West JL, Ausman KD, Warheit DB, Colvin VL. Correlating nanoscale titania structure with toxicity: A cytotoxicity and inflammatory response study with human dermal fibroblasts and human lung epithelial cells. Toxicol Sci. 2006;92(1):174-85.
Seaton A, Donaldson K. Nanoscience, nanotoxicology, and the need to think small. Lancet 2005;365:923-4.
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Warheit DB, Webb TR, Sayes CM, Colvin VL, Reed KL. Pulmonary instillation studies with nanoscale TiO2 rods and dots in rats: Toxicity is not dependent upon particle size and surface area. Toxicol Sci. 2006;91:227-36.
Warheit DB, Brock WJ, Lee KP, Webb TR, Reed KL.Comparative pulmonary toxicity inhalation and instillation studies with different TiO2 particle formulations: impact of surface treatments on particle toxicity. Toxicol Sci. 2005;88:514-24.
Warheit DB, Laurence BR, Reed KL, Roach DH, Reynolds GAM, Webb TR. Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats. Toxicol Sci. 2004;77:117-25.
工業技術研究院:奈米碳球
http://www.itri.org.tw/chi/rnd/advanced_rnd/materials_chem/XD92-05.jsp
黃贛麟:奈米碳球科學與應用,化工資訊與商情,2006;34:54-6。
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