臺灣博碩士論文加值系統

前言：氫氧化四甲基銨 [tetramethylammonium hydroxide, TMAH; (CH3)4NOH, CAS no. 75-59-2] 在業界被廣泛運用，在台灣已引起三人死亡。溶液中TMAH解離產生四甲基銨離子[tetramethylammonium ion, TMA; (CH3)4N+]，可能是造成死亡的原因。TMA具有擬膽鹼作用，可結合菸鹼性及膽鹼性受器。然而，回顧文獻後我們並未發現探討TMA中毒後致命機轉或解毒劑的相關研究。為了瞭解皮膚暴露TMAH的急毒性反應，我們計畫以動物模式探討：(1)皮下注射TMA後的臨床表現、(2)TMA對於動脈血氧濃度及心跳血壓的影響、(3)皮下注射TMA是否因引起呼吸衰竭造成死亡？(4)菸鹼性與毒蕈鹼性阻斷劑對TMA呼吸毒性的影響、(5)菸鹼性或/與毒蕈鹼性阻斷劑前處理是否避免TMA造成死亡、(6) 菸鹼性或/與毒蕈鹼性阻斷劑的後處理是否可減少TMA造成死亡、(7)氫氧根離子引起的灼傷是否增加皮膚接觸TMA的毒性？
研究方法與材料：我們使用雄性Wistar大鼠建立皮下注射TMA的動物模式。 由工業使用的TMAH進行酸鹼中和，或購買取得TMA。在未麻醉的動物模式中我們觀查TMA的中毒表現並計算死亡劑量反應曲線。建立動物模式後，我們量測心跳、血壓及動脈氣體濃度，並比較使用人工呼吸或阿托品（atropine）前處理是否可避免老鼠死亡。我們進一步比較六甲溴銨（hexamethonium）或新斯狄明（neostigmine）前處理是否可預防TMA造成死亡；並在低濃度TMA中毒模式中比較上述藥物的治療結果。最後，我們利用氫氧化鈉及氯化四甲基銨（tetramethylammonium chloride, TMACl）的兩階段皮膚暴露模式，觀察氫氧化鈉是否造成毒性。
結果：皮下注射TMA後，實驗動物出現躁動不安、虛弱、垂涎、流淚、顫抖、呼吸困難、痙攣、休克及死亡。接受死亡劑量組別的動物出現呼吸性酸中毒，而預先開始人工換氣可以有效避免死亡。單獨使用atropine，或合併使用新斯狄明進行前處理，可顯著延長存活時間。但在治療模式中，只有TMA給藥後十五分鐘給于的新斯狄明治療可延長存活時間。皮膚接觸生理食鹽水後再接觸2.75 莫耳濃度的TMACl 造成輕微短暫的影響，而先給予2.75 莫耳濃度氫氧化鈉後再給予生理食鹽水則幾乎不造成任何毒性，當給予的氫氧化鈉或TMACl 濃度越高時，給予TMACl後的心跳、血壓及死亡反應也越明顯。
討論與結論：在大鼠TMA皮下注射的急毒性動物模式中，我們觀察到TMA引起呼吸衰竭進而造成死亡。在注射0.25莫耳濃度的TMA動物模式中，早期的呼吸衰竭與周邊膽鹼性受器有關，但在注射0.05莫耳濃度的TMA動物模式中則無此現象。
實驗也發現TMA造成的呼吸衰竭的機制中，可能還有atropine以外的作用，此作用與hexamethonium無關，但可能與神經肌肉阻斷有關。當造成肌肉阻斷的TMA暴露時間較長或劑量較高時，可能由第一型阻斷轉變為第二型阻斷，此時neostigmine可作為拮抗劑。
在皮膚暴露TMAH模式中，氫氧根離子造成的腐蝕傷口可能增加TMA的吸收，造成比過去誤食含有TMA食物更危險的毒性。

Introduction: Tetramethylammonium hydroxide [TMAH; (CH3)4NOH, CAS no. 75-59-2] is widely applied in the industries and has caused three mortalities in Taiwan. Tetramethylammonium ion [TMA; (CH3)4N+] dissociating from TMAH solution is considered to be responsible to the mortalities. TMA is a cholinergic agonist that combines with the muscarinic and nicotinic receptors. However, we could not find any previous reports addressing the lethal mechanism or efficacy of antidotes in TMA intoxication. In order to investigate the acute toxicity of dermal exposure to TMAH, the present study is purposed to answer: (1) the clinical presentation in male Wistar rats after subcutaneously injected TMA; (2) the effects of TMA on the arterial blood gas and cardiovascular parameters; (3) Dose subcutaneously injected TMA induce the respiratory failure related mortality? (4) The effect of muscarinic or nicotinic antagonists on the respiratory function. (5) Dose the pretreated muscarinic or/and nicotinic antagonists prevent from the mortality? (6) Dose the post-treated muscarinic or/and nicotinic antagonists prevent from the mortality? (7) Does the chemical burn caused by hydroxide ion facilitate the toxicity of dermal exposure to TMA?
Materials and methods: Adult Wistar rats were used for the animal model of acute intoxication of subcutaneously injected TMA. TMA solution was obtained from either neutralized industrial TMAH or Sigma-Aldrich Chemical Co. In the first experiment, we observed the presentation and calculated the lethal dose response curve of acute TMA intoxication in the animals without anesthesia. In the second and third experiments, we measured the parameters of cardiovascular and arterial blood gases in the animals under anesthesia and tried to compare the effects of mechanical ventilation and atropinization with the lethal dose group. In the fourth experiment, in order to identify the possible pathways in the mortality, we pretreated atropine, hexamethonium and/or neostigmine and compared the prophylactic effects with the lethal dose group. Further the effective prophylactic agents were treated after TMA administration to evaluate the efficacy for antidotes. In the final experiment, we conducted a two-step treatment with dermal exposure to NaOH and tetramethylammonium chloride (TMACl) to compare the effects of hydroxide.
Results: The animals showed irritation, weakness, salivation, lacrimation, tremor, dyspnea, convulsion, coma and death after TMA administration subcutaneously. The animals suffered from death showed acute respiratory acidosis and mechanical ventilation pretreatment prevented from death in the lethal dose group. In the later experiments, pretreatment with atropinization alone significantly prolonged survival time and the pretreatment combination with atropine and neostigmine improved further. However treatment with neostigmine at the 15th min improved survival time after pretreatment with TMA. Dermal exposure to saline and then 2.75 M TMACl introduced limited and temporary non-fatal effects. Exposure to 2.75 M NaOH and then saline had almost no effects and caused no deaths. After the dosing of TMACl, treatment with more concentrated NaOH or TMACl resulted in more suppression of MAP and HR, and deaths.
Discussion and conclusion: In the rat model of acute TMA intoxication with subcutaneously injection, we demonstrated respiratory failure contributed to the TMA related death. In the mortality after injection with TMA at the concentration of 0.25 M, the peripheral muscuranic effects contributed to the early respiratory failure. However, the mortality after treatment with TMA at the concentration of 0.05 M did not showed the muscarinic sensitive effects.
In the meanwhile the respiratory failure also resulted from the atropine insensitive depression, which was not related to ganglion blockade and probably consisted of neuromuscular block. With the enough exposed duration and concentration, phase I block of TMA on neuromuscular junction would covert to phase II block, which was antagonized by neostigmine.
In the scenario of dermal exposure to TMAH, the caustic wound induced by hydroxide ions might facilitate the toxicity of TMA and pose a fatal hazard comparing to the intoxication through eating TMA containing seafood in the past.

Chapter 1. INTRODUCTION - 1 -
1.1. The Cases Dermally Exposed to TMAH - 2 -
1.2. Clinical Pictures of TMA Intoxication through Oral Intake - 4 -
1.3. Toxicokinetics of TMA - 7 -
1.4. The Effects of TMA on Experiment Animals in Vivo and in Vitro - 9 -
1.5. Muscuranic and Nicotinic Acetylcholine Receptor - 13 -
1.6. The Deduction of TMAH Related Fatal Cause - 15 -
1.7. Significance - 16 -
Chapter 2. OBJECTIVES - 17 -
Chapter 3. MATERIALS AND METHODS - 18 -
3.1. Animals - 18 -
3.2. Drugs - 18 -
3.3. Catheterization and Cardiovascular Parameters Recording - 18 -
3.4. Blood Sampling and Analysis - 19 -
3.5. Protocols - 19 -
3.6. Statistics - 24 -
Chapter 4. RESULTS - 25 -
4.1. The Clinical Presentation and Dose-Mortality Curve - 25 -
4.2. The Effects on the ABG and Cardiovascular Parameters - 26 -
4.3. Dose Subcutaneously Injected TMA Induce the Respiratory Failure Related Mortality? - 27 -
4.4. The Effect of Muscarinic or Nicotinic Antagonists on the Cardiac and Respiratory Parameters - 28 -
4.5. Dose the Pretreated Muscarinic or/and Nicotinic Antagonists Prevent from the Mortality after Subcutaneously Injected TMA? - 31 -
4.6. Dose the Post-treated Muscarinic or/and Nicotinic Antagonists Prevent from the Mortality after Subcutaneously Injected TMA? - 32 -
4.7. Does the Chemical Burn Caused by Hydroxide Ion Facilitate the Toxicity of Dermal Exposure to Tetramethylammonium Ion? - 33 -
Chapter 5. DISCUSSION - 35 -
5.1. The Clinical Presentation after Subcutaneously Injected TMA and Dose-mortality Curve of the Rat Model - 35 -
5.2. The Effects on the Arterial Blood Gas and Cardiovascular Parameters - 36 -
5.3. Dose Subcutaneously Injected TMA Induce the Respiratory Failure Related Mortality? - 37 -
5.4. The Effect of Pretreated Muscarinic or/and Nicotinic Antagonists on the Cardiac and Respiratory Parameters - 39 -
5.5. Dose the Pretreated Muscarinic or/and Nicotinic Antagonists Prevent from the Mortality after Subcutaneously Injected TMA? - 40 -
5.6. Dose the Post-treated Muscarinic or Nicotinic Antagonists Prevent from the Mortality after Subcutaneously Injected TMA? - 43 -
5.7. Does the Chemical Burn Caused by Hydroxide Ion Facilitate the Toxicity of Dermal Exposure to Tetramethylammonium Ion? - 44 -
5.8. Limitations - 46 -
Chapter 6. CONCLUSION - 48 -
6.1. The Lethal Mechanisms in Acute TMA Intoxication - 48 -
6.2. Suggestion of the First Aid for Dermal Exposure to TMAH - 49 -
Chapter 7. REFERENCES - 50 -
Chapter 8. TABLES - 60 -
Chapter 9. FIGURES - 76 -
Chapter 10. APPENDIXES - 106 -
10.1. List of publications - 107 -

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