【作者】 张增利；

【导师】 童建；

【作者基本信息】 苏州大学 ， 劳动卫生与环境卫生， 2001， 硕士

【摘要】 农药混配在增强杀虫效果、减少抗性、降低毒性及增加经济效益方面具有突出的作用，已成为农药的主要剂型，是我国今后农药发展的趋势。拟除虫菊酯类和有机磷酸酯类杀虫剂混配是目前国内应用最多、也是最有效的一类。但随之而来的是混配农药中毒病例也在逐年增多。 本课题研究了混配农药的毒代动力学及毒效应，从中毒症状、代谢动力学、脑组织生化、基因表达几个方面，探讨混配农药对机体的损伤作用，为阐明混配农药的毒作用机理提供理论依据。 采用霍恩式法计算辛硫磷和氰戊菊酯各单剂的LD₅₀，分别是1470、215mg/kg。按等毒配比法制备混配农药，计算出混配农药的LD₅₀=464mg/kg。按照联合作用系数法计算其预测值=840.8mg/kg。其毒性比（toxicity rate，TR）=1.81。根据Keplinger建议的评价标准，此混配农药属协同联合作用。混配农药中毒症状以兴奋为主，与氰戊菊酯中毒症状相似，但症状重，死亡率高。死亡时间较单剂短，但死亡持续时间长（动物死亡持续至24小时）。 毒代动力学有助于定量了解农药被机体吸收的速度、在体内存留时间的长短、分布特征和从机体清除的速度，以便预测和判断农药对机体的生物效应。本课题采用同位素示踪技术，研究¹⁴C-氰戊菊酯单剂在小鼠体内的代谢和分布，以及与辛硫磷混配后的代谢和分布。结果发现，氰戊菊酯组和混配组的¹⁴C-氰戊菊酯代谢过程均 混配农药的甫代动力学及毒效应 中文摘要 呈二室开放模型。氰戊菊酯组血upm值－时间函数的解析表达式为 C－10 0 0 e’们‘’＋2 9 5 e”·0的’。理论值与实测值经拟合度检验， 才关指数R’二0．86。消除常数K；。为0＊36min＊，分布相半衰期T；。。 为2．12min，清除相半衰期T；；邓为77．gmin，’℃－氰戊菊酯dPm值－时 间曲线下面积为 36271 dpm·min·InL”’。混配组血dpm值－时间函数的 解析表达式为C；－870e”＊’‘’＋309e”＊“‘’。理论值与实测值经 拟合度检验，相关指数Rteo．sl。消除常数K；。为 0刀Zlmin－‘，分布 相半衰期T；仇为3·22min，清除相半衰期T；；邓为124min，‘℃－氰戊 菊酯 dpm值J间曲线下面积为 59207 dpm·min·mL”’。结果显示，辛 硫磷明显延缓了氰戊菊酯的代谢，单剂组与混配组动力学参数比较 有统计学意义。静脉注射后，‘℃－氰戊菊酯在肺脏中分布最高，是 肝脏的5．3倍。16小时后，才与肝脏浓度接近。而腹腔注射染毒的 结果，’℃－氰戊菊酯在小鼠体内的分布以肝脏、脾脏较高，肺脏次 之。这说明肝脏的首过效应在氰戊菊酯的代谢分布中起了重要作＼ 乒干习。i ＋三主三个叁辜个目巨工多二主g目低言一S己上妄二主菩丢有卫巨多自三f一卜一丁二，工)＼的辜辜享幂矗喜二左了三于〔主菱三口刁FOA土套氢 吸入，所以肺脏的慢性毒性应引起重视。 两个化学物质的联合作用是复杂的c混配农药除了在代谢动力 学方面以外，是否存在其它的联合作用机理值得进一步研究。己知 这两种农药都具有神经毒性，但目前国内外末见混配农药的神经系 统联合毒性研究。本课题通过氰戊菊酯与辛硫磷混配对小鼠脑组织 c－fos、cdun基因表达及一些生化指标的影响，来评价其神经毒性。 结果显示：小鼠腹腔注射氰戊菊酯后，5分钟即开始有c－fos、Cdun 基因表达，一直持续到4小时，其中以15分钟组表达最高。混配 组与氰戊菊酯单剂组比较，Cdun基因表达无明显不同，c－fos基因 表达幅度无明显变化，但表达时程延长。氰戊菊酯对乙酚胆碱酯酶 （AChE）无抑制作用，但抑制单胺氧化酶(MAO＼ 超氧化物歧化 酶（SOD）活性。辛硫磷明显抑制 AChE，以染毒后 1小时最明显， 4小时后即开始恢复。辛硫磷还抑制MAO、SOD活性，4小时后恢 n 3 馄配农药的丙代动力学及毒效应 中文柄要 复正常。未发现两个农药分别对丙二醛(MDA人一氧化氮（NO） 有影响。二者混配后，析因分析未发现有相互作用。研究结果提示： c－fos、Cdun基因与氰戊菊酯的神经毒性相关。氰戊菊酯与辛硫磷混 配后，C－fos基因的长时程表达与其毒性的增加有关。氰戊菊酯对 AChE无抑制作用，但可以加强辛硫磷抑制A讪E的作用。可能的 原因之一是氰戊菊酯减慢了辛硫磷的代谢分解。更多还原

【Abstract】 Combined pesticides are known to have increased insecticidal effect and decreased resistance, especially in combination of organophosphorus with pyrethroid insecticides. Subsequently, cases of poisoning were also increased gradually. The toxicities of phoxim and fenvalerate were determined individually and in mixture against mice. The LD50 of phoxim, fenvalerate and the mixture was 1470mg/kg, 21 5mg/kg and 464mg/kg respectively. The predictive LD50 of the mixture was 840.8mg/kg according to the joint action coefficient. The interaction between phoxim and fenvalerate was found synergistic. The symptoms of poisoning with the mixture in mice were hyperexcitability and tremors , but more severe and with a higher mortality than fenvalerate poisoning. Using ?C-Fenvalerate as tracing agent, a single dose of fenvalerate and mixture of fenvalerate and phoxim was given intravenously to mice. From 0.5 to 120 mm after the administration, nine blood samples were taken for measurements. Eight samples from brain, heart, liver and lung were also taken respectively from 8 to 960 mm. The samples were measured by 3-scintillation counter. The data of blood samples were analyzed by residual method for the estimation of toxicokinetic parameters. The toxicokinetics of fenvalerate was fitted to the two-compartment model with distribution phase Tta of 2.12 mm, elimination phase T1 of 77.9 mm and area under the blood dpm-time curve of 36271 dpm-in-V The toxicokinetics of fenvalerate in mixture was fitted to the two-compartment model with distribution phase T112,, of 3.22 mm, elimination phase T1 of 124 mm and area under the blood dpm-time curve of 59207 dpm-min-m1^-1 Toxicokinetic parameters of fenvalerate were significantly different from those of the mixture. The result indicated that the metabolism of fenvalerate was postponed by phoxim. The lung has the highest concentration of ?C-fenvalerate residues and was close to liver 16 hours after intravenous administration. After intraperitoneal administration, however the highest concentration of ?C-fenvalerate residues was found in the liver, followed by the spleen and lung. The results suggested that the first-pass effect in liver altered the distribution of fenvalerate. Since pesticide workers are repeatedly exposed to low-concentration fenvalerate by respiration, pulmonal toxicity induced by the insecticide should be stressed. Although both phoxim and fenvalerate vere neurotoxic, little was knovn about the brain responses to them in molecular level, especially when combined. In this study, expression of c-fos and c-jun immediate- early genes was studied in mice after intraperitoneal administration of the insecticides. The levels of c-fos and c-jun rnRNA were determined by RT-PCR. A time-course study indicated that the induction of c-fos and c-jun mRNA was shown as early as 5 minutes, reached a peak at 15 minutes, and returned to the basal level at 24hour after exposure to fenvalerate. After exposure to combined insecticides, the levels of c-fos and c-jun mRNA did not change significantly, but the time course of c- fos mRNA was prolonged compared to that of fenvalerate exposure alone. The effects of insecticides on the activities of AchE, SOD, MAO, NO and MDA in brain of mice were also studied. The activities of SOD and MAO significantly decreased in all the phoxim group, fenvalerate group and mixture group, compared with the control gr更多还原