- 學位論文
氫氧化四甲基銨毒性緩解模式研究
Studies on the alleviat model of Tertramethylammonium Hydroxide Toxicity
摘要
氫氧化四甲銨(TMAH)大量地在半導體與光電等電子高科技產業製程中，作為顯影劑或除污清潔使用，每個月之使用量超過2000公噸，可能暴露之勞工人數亦逐漸增加。以往在其危害認知上，僅當成強鹼性與腐蝕性化學物質處置。但是92年及96年分別發生因TMAH噴濺2起之重大職災案例，死亡人數共3人，而引起主管機關與事業單位對TMAH溶液化學品事故的重視，並積極探討其中毒機轉與急救(解毒)方法，而韓國於2011年年底亦發生一死亡案例，顯見TMAH危害將日益受到重視。 TMAH屬於四級胺類分子具有與乙醯膽鹼受體結合之能力，並且與鈉離子及鉀離子通道之阻斷調控有關，作用範圍包括神經與神經及神經與肌肉(呼吸肌、心肌等)間之聯結控制等。之前研究已經由單離之小鼠橫膈肌收縮張力研究初步結果看到橫膈肌收縮會受到100 μM到1mM TMAH之暴露而受到抑制(藉由去極化之抑制)，驗證呼吸肌之抑制為主要之致死原因。若是更新緩衝溶液可明顯恢復。若將老鼠皮膚暴露於完全致死劑量(67.6毫克/公斤體重)以上時，利用清水沖洗暴露區域可以提高存活率，若以NACH溶液以體外塗抹並搭配清水沖洗暴露區域亦可以有效地提高存活率。前述之毒性緩解系統(模式)雖然仍有部分受測動物死亡，但進一步分析其中毒後之存活時間亦有增加。此外，TMA離子之LC/MS/MS分析技術已經由中興大學建立完成，並完成實際樣品偵測之分析驗證。結果顯示TMAH經由皮膚接觸後在短時間內即產生吸收，同時在短時間之內就由體內排出。 本研究之重點在於如何針對TMAH之理化特性與生化(毒性)作用方式，建立皮膚暴露模式探討TMAH之急毒性。運用符合工作環境中TMAH之主要暴露途徑，用於測試性TMAH經皮吸收後之心臟毒性，紀錄包括心跳、血壓以及心電圖之變化，並且監測動物血液生化值包括血液組成(RBC, WBC, Hb etc.)組成、肝腎生化值，可以進一步了解TMAH急性暴露對動物之影響。以老鼠實驗模式驗證可推展至臨床應用之非侵入式毒性緩解處理模式，避免因意外碰觸到高劑量TMAH而導致勞工中毒甚至死亡。同時並透過微透析與液相層析質譜分析技術，探討本模式對TMAH暴露在體內之吸收與流佈情形之影響，提供更進一步評估與驗證解毒效果之基礎。結果顯示在致命劑量之TMAH暴露後2-5分鐘內，受測動物之血壓及心跳皆達到最高值，隨後逐漸下降直到死亡，心電圖在較多之受測動物呈現ST波抑制之現象，顯示毒性作用與神經抑制以及心肌缺氧有關。當使用NAC溶液以體外塗抹並搭配清水沖洗暴露區域亦可以顯著而有效地降低TMAH經皮膚吸收之濃度。
並列摘要
Tetramethylammonium hydroxide (TMAH) is a corrosive alkaline solution. It had used as a developer in photolithography, and in the manufacturing process in the semiconductor and TFT-LCD industry. More than 2000 tons of TMAH were used in Taiwan each month, and many workers had potential exposure to it. There could not find any reports of mortality cases due to industrial TMAH except in Taiwan. TMA+ is recognized as a cholinergic agonist that can bind to nicotinic and muscarinic receptors in the ganglion cells, skeletal muscles, smooth muscles, and cardiac muscles. It needed further studies the toxicity, absorption, and distribution of TMAH as well as its antidotes by in vitro and in vovo experiment. Based on our previous observation, mice diaphragm was isolated and suspended in modified Krebs’ solution. The diaphragm was directly stimulated by a train of stimuli to induce twitch and titanic tensions in the presence of different concentration of TMAH. 100 μM to 1mM TMAH could induce significant diaphragm contraction, which may cause the dysfunction of respiratory muscles. In addition, this toxicity effect could be inhibited by renew the experimental buffer. The dorsal hairs of rat were shaved, and different volumes of 25％TMAH were daubed on the skin. Rat exposed to higher dose (≧67.6 mg/Kg BW) and then decontamination with water or NAC solution could increase the survival ratio and survival time. The concentrations of TMA+ group were analyzed by LC MS/MS. TMAH could absorbed by skin and distributed to different organ very quickly, and excreted by the kidney after few hours. In addition, preliminary data show that the highest value of blood pressure and heart rate are presented about 2-5 minute after exposure to lethal doses of TMAH of the animal, and then gradually decreased until death. In addition, ST wave suppression of ECG were shown in some animals, it mean that toxic effects were associated with the neural inhibition and myocardial hypoxia. Therefore, the death of animals was more likely to be related to the development of respiratory failure and toxicity effects on the cardiovascular system after acute dermal exposure.