拟除虫菊酯与有机磷农药的联合毒性与毒理学机制研究
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摘要
1、混配杀虫剂在提高药效、克服抗性、降低毒性及增加经济效益方面具有
明显作用，已成为农药的重要剂型进入市场，是我国今后农药发展的重要
趋势。混配杀虫剂主要有四种类型，其中拟除虫菊酯和有机磷类杀虫剂的
二元混配最为常见。随着混配杀虫剂的大量生产和使用，近年来急性中毒
的病例数也在不断增加，它已成为我国农民的主要职业危害和公共卫生问
题，是医学科学和环境科学面临的重大课题。针对目前国内外的研究现状，
本课题着重在拟除虫菊酯和有机磷杀虫剂的联合毒性、毒代动力学和毒作
用机制方面，进行了较为深入系统的研究，旨在为混配杀虫剂的优选开发
和中毒防治提供科学依据。
2、辛硫磷·氰戊菊酯、辛硫磷·三氟氯氰菊酯和丙溴磷·高效氯氰菊酯3组混
剂对棉蛉虫3龄幼虫的共毒系数分别为340、797和172，具有显著增效作
用。采用预期与实测LD_(50)对比法（E/O值）和Logistic回归分析法等判断
联合作用方式，E/O值为2.67、1.71和1.91，β值均＞0。对大鼠的共毒系
数分别为285、165和180，同样存在增毒效应或协同作用。
3、气相色谱法测定氰戊菊酯以及辛：氰混剂的毒代动力学结果表明：氰戊
菊酯以及辛：氰混剂的血药浓度-时间曲线均符合一级吸收一室开放模型，
主要毒代动力学参数分别为Ka=0.47h~(-1)，Ke=0.19h~(-1)，t_(1/2)(Ka)=1.6h，
t_(1/2)(Ke)=3.74h和Ke=0.04h~(-1)，t_(1/2)（Ke）=21.70h（无滞后时间）；辛硫磷可使氰
戊菊酯在生物体内的代谢消除速率减慢，辛：氰混配使用使氰戊菊酯对哺
乳动物的急性毒性有所增加。高效液相色谱法测定辛硫磷以及辛：氰混剂
的毒代动力学结果表明：辛硫磷以及辛：氰混剂的血药浓度-时间曲线也都
符合一级吸收一室开放模型，主要毒代动力学参数分别为Ka=1.87h~(-1)，
Ke=0.47h~(-1)，t_(1/2)（Ka）=0.37h，t_(1/2)（Ke）=1.47h和Ka=4.33h~(-1)，Ke=0.07h~(-1)，
t_(1/2)（Ka）=0.15h，t_(1/2)（Ke）=10.63h（有滞后时间）；与单剂辛硫磷染毒比较，氰
戊菊酯明显增加辛硫磷的吸收速率，延长消除半衰期，使机体对辛硫磷的
中 文摘要
代谢降解速率减慢。上述结果可部分解释辛：氰混剂增效、增毒的联合作
用机制。
4、通过兔疫组织化学和显微图像分析方法，研究了氰戊菊酯、辛硫磷及其
混剂对中枢谷氨酸（Gin）和Y．氨基丁酸（GABA）兔疫阳性细胞的影响。
结果表明，氰戊菊酯·辛硫磷组大鼠大脑皮层、海马、纹状体等部位GU的
免疫阳性细胞（hC）数目减少，阳性细胞面积比（Aa％）和积分光密度（IOD）
呈现不同程度的降低，而GABA的IRC各观察参数值均呈现不同程度的升“
高，但氰戊菊酯组与氰戊菊酯·辛硫磷组各观察值之间均未见显著性差异，
提示在对o 和GABA作用的影响上，氰戊菊酯与辛硫磷之间无协同作用，
但Q 和 GABA递质功能变化紊乱在拟除虫菊酯神经毒性中可能具有重要
意义。
5、应用膜片箱技术，研究了氰戊菊酯、辛硫磷及其混剂对大鼠背根神经节
（DRG）神经元钠通道的影响。结果表明，氰戊菊酯10、50、100pmol／L
组和对照组钠通道峰电流失活时间常数分别为 8．10rt．41、
11．78边76b＜001）、876土1．94O＜005）和641 士1．32ms，尾电流失活时间常
数分别 为 6．llto．52卜0．05）、7．82切、82卜0．05）、7、23ti．09卜0．05）和
4．gi土0．97ms，提示氰戊菊酯可影响ono钠电流和尾电流，对河豚毒素不敏
感型（TTXK）钠通道的作用大于敏感型门TX七〕 但未见辛：氰混剂对
钠通道的联合作用。
6、采用生化、电镜和计算机辅助精子分析系统，研究了氰戊菊酯、辛硫磷
及其混剂对雄性生殖功能的影响。设高剂量门／20LD。）染毒组辛硫磷
735mg／K＊、氰戊菊酉 30刀mg／Kg及其混齐、《剂量（l／180LDs。）染毒组辛
硫磷 8．Zing／Kg、氰戊菊酯 3．3Wb及其混剂和一个对照组。SD大鼠每日
灌胃一次，每周5天，连续60天。7个剂量组组成两个2X2析因设计实验，
通过观察睾丸组织病理学改变、精子数量和运动能力、睾丸标志酶活性、
微量元素和性激素变化等，发现氰戊菊酯和辛硫磷对雄性生殖毒性的联合
作用特征与所暴露的剂量水平有关，即低剂量水平无交互作用，联合作用
呈相加作用，高剂量水平表现为桔抗作用或相加作用；在高、低剂量水平
2
中 文摘耍
时，辛：氰混剂对哺乳动物雄性生殖毒性的联合作用与单剂相比未见明显
的增毒效应。以毛细管点滴法，分别研究了约LDs。剂量的氰戊菊酯、辛硫
磷及其混剂对棉蛀虫4龄初期幼虫的生长发育、精子发生与形成以及雄性
中胚层生殖腺的影响。结果表明，单剂与混剂均可使幼虫历期延长、羽化
率下降和蛹重降低，对真核精子发生亦有明显的抑制作用，混剂对棉岭虫
雄性生殖无增毒作用。
1. Mixed insecticides, with the significant effect on enhancing insecticidal effect,
postponing resistance development, decreasing mammalian toxicity and
increasing economy benefit, have been an important formulation and broken
into the pesticide market. It becomes a main stream in the pesticide industry in
this country. There are four kinds of the mixed insecticides, of which the most
common is the binary mixture derived from pyrethroid and organophosphorus
insecticides. As the mixed pesticides are widely produced and used, the cases
of acute poisoning have been increasing which has become an important
occupational hazard to peasants and a problem of public health in this country,
so scientists in the medical and environmental sciences are of great concern to
the grand project. According to the research progress at home and abroad, this
project was studied deeply and systematically in the joint action,
toxicokinetics and poisoning mechanism of the organophosphorus and
pyrethroid pesticides so as to provide scientific data for the control of the
mixed pesticide-poisoning.
2. The common toxicity coefficients(C.T.C) on the mixtures of phoxim and
fenvalerate,phoxim and cyhalothrin,cypermethrin and profenofos to the Larva
with instars of cotton bollworm were 340,797 and 172,respectively,which
exhibited significant insecticidal effects. The jointactions of the mixtures were
assessed using Comparative Method of Expected and Experimental LD50 (E/O
value) and Logistic Regression Method The increased insecticidal effects or
synergistic effects were testified according to the fact that the E/O values were
2.67,1.71 and 1.91, l3values>0, and CTC of the mixtures to SD rat were
285,165 and 180, respectively
3. The toxicokinetics of fenvalerate and the mixture derived from fenvalerate
and phoxim with gas chromatography showed that 1. concentration-time
profiles were fitted to one-compartment open model with first order
absorption, the main toxicokinetic parameters were respectively Ka=0.47h?
Ke=0.19 W1, t1,(Ka)1.60h, t112(Ke)3.74h and Ke=0.04 h? t1(Ke)=21.70h
(no lag time); 2. the elimination rate of fenvalerate was decreased, the
metabolizability and exclusion of fenvalerate in rat body was retarded. So the
acute toxicity of fenvalerate to mammal is increased after expoure to the
mixture. The toxicokinetics of phoxim and the mixture of phoxim and
fenvalerate with HIPLC showed that 1. concentration-time profiles were also
fitted to one-compartment open model with first order absorption, the main
toxicokinetic parameters were separately Ka1 .87h? Ke=0.47 h?
t1~(Ka)=0.37h, t1~(Ke)=l 47h and Ka=4.33 h? Ke=0.07 h? t112(Ka)=0.lSh,
t1,2(Ke)10.63h (with lag time); 2. as compared with expoure to single
phoxim, the toxicokinetic findings after exposure to the mixture exhibited that
absorption rate of phoxiin was significantly increased and half-life time of
elimination phase was delayed and metabolic degeneration of phoxim was
slowed because of fenvalerate involvement. These results could be used to
explain a part of the jointaction mechanism of the increased insecticidal
effects and toxicities resulted from the mixture.
4. By immunohistochemical method, the changes in glutamate(Glu) and gama-
aminobutyric acid(GABA) immunoreactive cells were observed in the central
nervous system of rats which were orally treated with fenvalerate(2omglkg),
phoxim( 1 60mg/kg), and fenvalerate(2Omg/kg) plu
明显作用，已成为农药的重要剂型进入市场，是我国今后农药发展的重要
趋势。混配杀虫剂主要有四种类型，其中拟除虫菊酯和有机磷类杀虫剂的
二元混配最为常见。随着混配杀虫剂的大量生产和使用，近年来急性中毒
的病例数也在不断增加，它已成为我国农民的主要职业危害和公共卫生问
题，是医学科学和环境科学面临的重大课题。针对目前国内外的研究现状，
本课题着重在拟除虫菊酯和有机磷杀虫剂的联合毒性、毒代动力学和毒作
用机制方面，进行了较为深入系统的研究，旨在为混配杀虫剂的优选开发
和中毒防治提供科学依据。
2、辛硫磷·氰戊菊酯、辛硫磷·三氟氯氰菊酯和丙溴磷·高效氯氰菊酯3组混
剂对棉蛉虫3龄幼虫的共毒系数分别为340、797和172，具有显著增效作
用。采用预期与实测LD_(50)对比法（E/O值）和Logistic回归分析法等判断
联合作用方式，E/O值为2.67、1.71和1.91，β值均＞0。对大鼠的共毒系
数分别为285、165和180，同样存在增毒效应或协同作用。
3、气相色谱法测定氰戊菊酯以及辛：氰混剂的毒代动力学结果表明：氰戊
菊酯以及辛：氰混剂的血药浓度-时间曲线均符合一级吸收一室开放模型，
主要毒代动力学参数分别为Ka=0.47h~(-1)，Ke=0.19h~(-1)，t_(1/2)(Ka)=1.6h，
t_(1/2)(Ke)=3.74h和Ke=0.04h~(-1)，t_(1/2)（Ke）=21.70h（无滞后时间）；辛硫磷可使氰
戊菊酯在生物体内的代谢消除速率减慢，辛：氰混配使用使氰戊菊酯对哺
乳动物的急性毒性有所增加。高效液相色谱法测定辛硫磷以及辛：氰混剂
的毒代动力学结果表明：辛硫磷以及辛：氰混剂的血药浓度-时间曲线也都
符合一级吸收一室开放模型，主要毒代动力学参数分别为Ka=1.87h~(-1)，
Ke=0.47h~(-1)，t_(1/2)（Ka）=0.37h，t_(1/2)（Ke）=1.47h和Ka=4.33h~(-1)，Ke=0.07h~(-1)，
t_(1/2)（Ka）=0.15h，t_(1/2)（Ke）=10.63h（有滞后时间）；与单剂辛硫磷染毒比较，氰
戊菊酯明显增加辛硫磷的吸收速率，延长消除半衰期，使机体对辛硫磷的
中 文摘要
代谢降解速率减慢。上述结果可部分解释辛：氰混剂增效、增毒的联合作
用机制。
4、通过兔疫组织化学和显微图像分析方法，研究了氰戊菊酯、辛硫磷及其
混剂对中枢谷氨酸（Gin）和Y．氨基丁酸（GABA）兔疫阳性细胞的影响。
结果表明，氰戊菊酯·辛硫磷组大鼠大脑皮层、海马、纹状体等部位GU的
免疫阳性细胞（hC）数目减少，阳性细胞面积比（Aa％）和积分光密度（IOD）
呈现不同程度的降低，而GABA的IRC各观察参数值均呈现不同程度的升“
高，但氰戊菊酯组与氰戊菊酯·辛硫磷组各观察值之间均未见显著性差异，
提示在对o 和GABA作用的影响上，氰戊菊酯与辛硫磷之间无协同作用，
但Q 和 GABA递质功能变化紊乱在拟除虫菊酯神经毒性中可能具有重要
意义。
5、应用膜片箱技术，研究了氰戊菊酯、辛硫磷及其混剂对大鼠背根神经节
（DRG）神经元钠通道的影响。结果表明，氰戊菊酯10、50、100pmol／L
组和对照组钠通道峰电流失活时间常数分别为 8．10rt．41、
11．78边76b＜001）、876土1．94O＜005）和641 士1．32ms，尾电流失活时间常
数分别 为 6．llto．52卜0．05）、7．82切、82卜0．05）、7、23ti．09卜0．05）和
4．gi土0．97ms，提示氰戊菊酯可影响ono钠电流和尾电流，对河豚毒素不敏
感型（TTXK）钠通道的作用大于敏感型门TX七〕 但未见辛：氰混剂对
钠通道的联合作用。
6、采用生化、电镜和计算机辅助精子分析系统，研究了氰戊菊酯、辛硫磷
及其混剂对雄性生殖功能的影响。设高剂量门／20LD。）染毒组辛硫磷
735mg／K＊、氰戊菊酉 30刀mg／Kg及其混齐、《剂量（l／180LDs。）染毒组辛
硫磷 8．Zing／Kg、氰戊菊酯 3．3Wb及其混剂和一个对照组。SD大鼠每日
灌胃一次，每周5天，连续60天。7个剂量组组成两个2X2析因设计实验，
通过观察睾丸组织病理学改变、精子数量和运动能力、睾丸标志酶活性、
微量元素和性激素变化等，发现氰戊菊酯和辛硫磷对雄性生殖毒性的联合
作用特征与所暴露的剂量水平有关，即低剂量水平无交互作用，联合作用
呈相加作用，高剂量水平表现为桔抗作用或相加作用；在高、低剂量水平
2
中 文摘耍
时，辛：氰混剂对哺乳动物雄性生殖毒性的联合作用与单剂相比未见明显
的增毒效应。以毛细管点滴法，分别研究了约LDs。剂量的氰戊菊酯、辛硫
磷及其混剂对棉蛀虫4龄初期幼虫的生长发育、精子发生与形成以及雄性
中胚层生殖腺的影响。结果表明，单剂与混剂均可使幼虫历期延长、羽化
率下降和蛹重降低，对真核精子发生亦有明显的抑制作用，混剂对棉岭虫
雄性生殖无增毒作用。
1. Mixed insecticides, with the significant effect on enhancing insecticidal effect,
postponing resistance development, decreasing mammalian toxicity and
increasing economy benefit, have been an important formulation and broken
into the pesticide market. It becomes a main stream in the pesticide industry in
this country. There are four kinds of the mixed insecticides, of which the most
common is the binary mixture derived from pyrethroid and organophosphorus
insecticides. As the mixed pesticides are widely produced and used, the cases
of acute poisoning have been increasing which has become an important
occupational hazard to peasants and a problem of public health in this country,
so scientists in the medical and environmental sciences are of great concern to
the grand project. According to the research progress at home and abroad, this
project was studied deeply and systematically in the joint action,
toxicokinetics and poisoning mechanism of the organophosphorus and
pyrethroid pesticides so as to provide scientific data for the control of the
mixed pesticide-poisoning.
2. The common toxicity coefficients(C.T.C) on the mixtures of phoxim and
fenvalerate,phoxim and cyhalothrin,cypermethrin and profenofos to the Larva
with instars of cotton bollworm were 340,797 and 172,respectively,which
exhibited significant insecticidal effects. The jointactions of the mixtures were
assessed using Comparative Method of Expected and Experimental LD50 (E/O
value) and Logistic Regression Method The increased insecticidal effects or
synergistic effects were testified according to the fact that the E/O values were
2.67,1.71 and 1.91, l3values>0, and CTC of the mixtures to SD rat were
285,165 and 180, respectively
3. The toxicokinetics of fenvalerate and the mixture derived from fenvalerate
and phoxim with gas chromatography showed that 1. concentration-time
profiles were fitted to one-compartment open model with first order
absorption, the main toxicokinetic parameters were respectively Ka=0.47h?
Ke=0.19 W1, t1,(Ka)1.60h, t112(Ke)3.74h and Ke=0.04 h? t1(Ke)=21.70h
(no lag time); 2. the elimination rate of fenvalerate was decreased, the
metabolizability and exclusion of fenvalerate in rat body was retarded. So the
acute toxicity of fenvalerate to mammal is increased after expoure to the
mixture. The toxicokinetics of phoxim and the mixture of phoxim and
fenvalerate with HIPLC showed that 1. concentration-time profiles were also
fitted to one-compartment open model with first order absorption, the main
toxicokinetic parameters were separately Ka1 .87h? Ke=0.47 h?
t1~(Ka)=0.37h, t1~(Ke)=l 47h and Ka=4.33 h? Ke=0.07 h? t112(Ka)=0.lSh,
t1,2(Ke)10.63h (with lag time); 2. as compared with expoure to single
phoxim, the toxicokinetic findings after exposure to the mixture exhibited that
absorption rate of phoxiin was significantly increased and half-life time of
elimination phase was delayed and metabolic degeneration of phoxim was
slowed because of fenvalerate involvement. These results could be used to
explain a part of the jointaction mechanism of the increased insecticidal
effects and toxicities resulted from the mixture.
4. By immunohistochemical method, the changes in glutamate(Glu) and gama-
aminobutyric acid(GABA) immunoreactive cells were observed in the central
nervous system of rats which were orally treated with fenvalerate(2omglkg),
phoxim( 1 60mg/kg), and fenvalerate(2Omg/kg) plu
引文
1．于鸣，杨铭鼎，陈秉衡．毒物联合作用分类评价方法的探讨．新疆医学院学报，1985；8(2)：169-173
2．王心如，翟为雷．气管灌注氰戊菊酯对大鼠肺泡巨噬细胞超微结构的影响．中国药理学报，1991；12：415-420
3．王心如，等．氰戊菊酯在大鼠体内的毒物动力学研究．中华预防医学杂志(待发表)
4．王心如，何冬宁，石云，吴建平，金念祖，肖杭，何凤生．有机磷与拟除菊酯农药的急性联合毒性及其评价中国公共卫生，2000a；16(3)：206-207
5．王心如，吴建平，肖杭，石云，戴晓青，何风生．氰戊菊酯和辛硫磷对大鼠中枢谷氨酸及γ-氨基丁酸免疫阳性细胞的影响，卫生研究；2000b；29(1)；1-3
6．王荫长．高温对小地老虎和粘虫精子发生和形成的影响．昆虫学报，1996；39(3)：253-259王焕民，张子明主编．新编农药手册．第一版．北京：农业出版社．1991
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