A role for solvents in the toxicity of agricultural organophosphorus pesticides
A role for solvents in the toxicity of agricultural organophosphorus pesticides
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DOI：
10.1016/j.tox.2012.02.005
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发表时间：
2012-04-11
期刊：
影响因子：
4.5
通讯作者：
Clutton, R. Eddie
中科院分区：
文献类型：
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作者：
Eddleston, Michael;Street, Jonathan M.;Clutton, R. Eddie
有机磷（OP）杀虫剂自我中毒是全球约四分之一的自杀事件的原因。治疗重点是OP化合物抑制乙酰胆碱酯酶（AChE）这一事实：然而，AChE重新激活药物对中毒的人没有好处。因此，我们研究了在农业OP中毒的新型小型猪模型中溶剂助剂在OP毒性中的作用。哥廷根小型猪口服中毒与临床相关剂量的农业可降解浓缩物（EC）的乐果，乐果活性成分（AI）单独，或溶剂。监测呼吸生理和神经肌肉（NMJ）功能，血AChE活性，和动脉乳酸浓度为12小时，以评估中毒的严重程度。农用乐果EC 40中毒30 min内引起呼吸骤停，严重的分布性休克和NMJ功能障碍，与人体中毒相似。中毒猪的平均动脉乳酸盐升高至15.6 [SD 2.8] mm，而对照组为1.4 [0.4] mm。单独使用乐果AI或主要溶剂环己酮会导致中度毒性。乐果与环己酮混用再现了农用乐果乳油中毒的重度中毒特征。不含环己酮的制剂显示出较低的哺乳动物毒性。这些结果表明，溶剂在乐果毒性中起着至关重要的作用。农药毒性的监管评估应包括溶剂以及目前主导评估的人工智能。改变有机磷杀虫剂的配方，以确保农产品对哺乳动物的毒性较低，这可能会减少自杀性摄入后的死亡人数，并迅速降低全球自杀率。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
Organophosphorus (OP) insecticide self-poisoning is responsible for about one-quarter of global suicides. Treatment focuses on the fact that OP compounds inhibit acetylcholinesterase (AChE): however, AChE-reactivating drugs do not benefit poisoned humans. We therefore studied the role of solvent coformulants in OP toxicity in a novel minipig model of agricultural OP poisoning. Gottingen minipigs were orally poisoned with clinically relevant doses of agricultural emulsifiable concentrate (EC) dimethoate, dimethoate active ingredient (AI) alone, or solvents. Cardiorespiratory physiology and neuromuscular (NMJ) function, blood AChE activity, and arterial lactate concentration were monitored for 12 h to assess poisoning severity. Poisoning with agricultural dimethoate EC40, but not saline, caused respiratory arrest within 30 min, severe distributive shock and NMJ dysfunction, that was similar to human poisoning. Mean arterial lactate rose to 15.6 [SD 2.8] mm in poisoned pigs compared to 1,4[0.4] in controls. Moderate toxicity resulted from poisoning with dimethoate AI alone, or the major solvent cyclohexanone. Combining dimethoate with cyclohexanone reproduced severe poisoning characteristic of agricultural dimethoate EC poisoning. A formulation without cyclohexanone showed less mammalian toxicity. These results indicate that solvents play a crucial role in dimethoate toxicity. Regulatory assessment of pesticide toxicity should include solvents as well as the AIs which currently dominate the assessment. Reformulation of OP insecticides to ensure that the agricultural product has lower mammalian toxicity could result in fewer deaths after suicidal ingestion and rapidly reduce global suicide rates. (C) 2012 Elsevier Ireland Ltd. All rights reserved.