农药辛硫磷与氰戊菊酯混配后的毒代动力学及毒效应研究
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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LD_(50)，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
LD_(50)=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~(14)C-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~(14)C-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。
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
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LD_(50)，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
LD_(50)=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~(14)C-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~(14)C-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。
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
引文
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24Nigg-HN,Knaak-JB. Blood cholinesterases as human biomarkers of organophosphorus pesticide exposure. Rev-Environ-Contam-Toxicol. 2000;163:29-111
25Lassiter-TL,Barone-S Jr, Moser-VC, et al. Gestational exposure to chlorpyrifos: dose response profiles for cholinesterase and carboxylesterase activity. Toxicol-Sci. 1999 52(1):92-100
26 Quistad-GB, Casida-JE. Sensitivity of blood-clotting factors and digestive enzymes to inhibition by organophosphorus pesticides. J-Biochem-Mol-Toxicol. 2000;14(1):51-6
27 Gauhan, Engel JL, Casida JE. Pesticide interaction:Effects of organophosphorus pesticide of the metabolism, toxicity and persistence of selected pyrethroid insecticide. Pestic Biochem physiol, 1980,14:81-85
28 IPCS. Deltamethrin. In:WHO Environmental Health Criteria. 97: Geneva: WHO 1996.81-82
29 孙金秀，陈波，姚佩佩．有机磷与拟除虫菊酯农药联合作用的毒性评价．卫生毒理学杂志，2000，14(3)：141-144
30 Mileson-BE, Chambers-JE, Chen-WL, et al. Common mechanism of toxicity: a case study of organophosphorus pesticides. Toxico-Sci, 1998,41(1):8-20
31 方荣美．4种有机磷农药对小鼠血脑胆碱酯酶活力的抑制作用．北京医科大学学报，1995．27(2)：141-142
32 张伟华，贺锡雯．氰戊菊酯可诱导大鼠肝脏P450 2B1/2B2．中国药理学与毒理学杂志，1997，11(2)：124
33 Santoni-G, Cantalamessa-F, Spreghini-E, et al. Piccoli-M. Alterations of T cell distribution and functions in prenatally cypermethrinexposed rats: possible involvement of catecholamines: Toxicology. 1999,138(3):175-87
34 Maiti-PK, Kar-A. Dual role of testosterone in fenvalerate-treated mice with respect to thyroid function and lipid peroxidation. J-Appl-Toxicol. 1997,17(2):127-31
35 Kale-M, Rathore-N, John-S, et al. Lipid peroxidative damage on pyrethroid exposure and alterations in antioxidant status in rat erythrocytes: a possible involvement of reactive oxygen species. Toxicol-Lett. 1999,105(3): 197-205
36 Maiti-PK, Kar-A, Gupta-P, et al. Loss of membrane integrity and inhibition of type-Ⅰ iodothyronine 5'-monodeiodinase activity by fenvalerate in female mouse. Biochem-Biophys-Res-Commun. 1995, 214(3): 905-9
37 Poovala-VS, Kanji-VK, Tachikawa-H, et al. Role of oxidant stress and antioxidant protection in acephate-induced renal tubular cytotoxicity. Toxicol-Sci. 1998 Dec; 46(2): 403-9
38 Poovala-VS, Huang-H, Salahudeen-AK. Role of reactive oxygen metabolites in organophosphate-bidrin-induced renal tubular cytotoxicity. J-Am-Soc-Nephrol. 1999 Aug; 10(8): 1746-52
39 Banerjee-BD, Seth-V, Bhattacharya-A, et al. Biochemical effets of some pesticides on lipid peroxidation and free-radical scavengers. Toxicol-Lett. 1999 Jun 30; 107(1-3): 33-47
40 张铣，刘毓谷．毒理学．北京：北京医科大学中国协和医科大学联合出版社，1997：136-150．
41 施畅，廖明阳．环磷酰胺与异环磷酰胺致肝毒性机制的比较．卫生毒理学杂志，2000，14(2)：99-102
42 谢克勤，赵丽，张曼，等．氯丙烯对神经细胞NO、MDA、GSH含量和NOS、SOD活性的影响．卫生毒理学杂志，2000，14(4)：212-213
43 方福德．基因组研究与预防医学．中华预防医学杂志．2001，35(1)：6-7
44 Chomozgnski P, Sacchi N. Single step method of RNA isolation by acid Guanicyanate-phenol-chloroform extraction. Anal Biochem, 1987, 162: 156-159
45 叶鑫生．细胞调控的探索．北京：军事医学出版社，1999：163-169．
46 杨东仁，牛勇，何凤生．c-fos基因在乐果中毒后肌无力大鼠肌组织中的表达．卫生研究，1999，28(2)：72-73
47 刘亢丁，苏志强，饶明俐，等．用逆转录多聚酶链反应检测局灶脑缺血及再灌注后c-fos和c-jun基因表达．中风与神经疾病杂志，1997，14(3)：42-45
48 黄培堂，俞炜源，陈添弥，等译．PCR技术实验指南．北京：科学技术出版社．1999：34-35
49 Morgan JI, Cohen D, Hanpstead J, et al. Mapping patterns of c-fos antigen in the central nervous system after seizure. Science, 1987, 237: 192～197.
50 Gillardon-F, Skutella-T, Uhlmann-E, et al. Activation of c-fos contributes to amyloid beta-peptide-induced neurotoxicity. Brain-Res. 1996, 706(1): 169-72
51 Wollnik-F, Brysch-W, Uhlmann-E, et al. Block of c-Fos and JunB expression by antisense oligonucleotides inhibits light-induced phase shifts of the mammalian circadian clock. Eur-J-Neurosci. 1995, 7(3): 388-93
52 Imaki T, Shibasaki T, Wang XQ, et al. Intraxerebroventricular administraton of corticotropin-releasing factor antagonist attenuates c-los mRNA expression in the paraventricular nucleus after stress. Neuroendocrinology, 1995, 61: 445
53 Hassouna-I, Wickert-H, el-Elaimy-I, et al. Systemic application of pyrethroid insecticides evokes differential expression of c-Fos and c-Jun proteins in rat brain. Neurotoxicology. 1996, 17(2): 415-31
54 Morgan JI, Curran T. Immediate-early genes: ten years on. Trends Neurosci, 1995, 18: 66.
55 Dragunow M, Luke W, Steel L, et al. Induntion of c-fos mRNA and protein in neurons and glia traumatic brain injury: Pharmacolgical characterization. Exp Neurol, 1990, 107: 236.
56 贺锡雯，殷若元，陈寅红，等．拟除虫菊酯对神经细胞膜Na+、Ca2+离子通道的影响．中华劳动卫生职业病杂志1997，15(5)：261-264
57 殷若元，贺锡雯，张金松，等．拟除虫菊酯和马拉硫磷对鼠脑细胞肌醇磷酸酯代谢的影响．中华劳动卫生职业病杂志．1996，14(5)：259-263
58 王心如，吴建平，肖杭，等．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2000 29(1)：1～3．
59 王克万，杨志焕，王正国，等．培养大鼠脑皮层神经元损伤后c-fos蛋白表达．中华创伤杂志，1998，14(4)：219-222
2和有杰，刘瑞苍，和平编著．农药复配与新剂型．第一版，北京：北京科学技术文献出版社．1994：56-61
3何凤生．加强混配农药中毒的防治研究．中华预防医学杂志，1997，4：197-198
4甘文奇，陶炳根，文保元，等．混配农药中毒的流行病学研究．中华预防医学杂志，2001，35(1)：13-15
5谢卓丘，童英，冯致英，等．溴氢菊酯对大鼠脊髓中氨基酸递质含量的影响．卫生毒理学杂志，1987，1(1)：12-14
6任春兰，高坚瑞，殷若元，等．氯戊菊酯与甲苯对小鼠脑细胞氧化性损伤作用的研究．卫生研究 1995，24(1)：12-14
7刘毓谷．卫生毒理学基础．北京：人民卫生出版社，第二版．1997：48-49
8Berenbaum-MC. What is synergy? Pharmacol rev, 1989,41:93-141
9王心如，何冬宁，石云，等．有机磷与拟除虫菊酯农药的急性联合毒性及其评价．中国公共卫生．2000，16(3)：206-207
10顾兵，王心如，何凤生．氰戊菊酯对肟硫磷毒物代谢动力学的影响．中国工业医学杂志，2001，35(1)：6-7
11朱寿彭，张澜生．医用同位素示踪技术．北京：原子能出版社，1989：108-109
12刘毓谷．卫生毒理学基础．北京：人民卫生出版社，第二版．1996：34-37
13金丕焕．医用统计方法学．上海：上海医科大学出版社，1997：134-135
14王青定，陈惠琼，李凤珍，等．有机磷化合物解毒酶在人体组织中的分布．卫生毒理学杂志，1997，11(1)：40
15Leng-G, Lewalter-J, Rohrig-B, et al. The influence of individral susceptibility in pyrethroid exposure. Toxicol-Lett. 1999,107(1-3):123-30
16IPCS. fenvalerate. In:WHO Environmental Health Criteria. 95:Geneva: WHO 1990.49-50
17Sheets-LP, Doherty-JD, Law-MW, et al. Age-dependent differences in the susceptibility of rats to deltamethrin. Toxicol-Appl-Pharmacol. 1994,126(1):186-90
18胡云平，周志俊，薛寿征．Ⅱ型拟除虫菊酯类农药对豚鼠心血管系统的影响．职业卫生与应急救援 1999，17(1)：10-14
19胡云平，周志俊，薛寿征．氰戊菊酯对包装工人心血管功能的亚临床影响．劳动医学 1999，16(1)：13-15
20Gianessi, C. P, Anderson, J. E. Pesticide use in U. S. crop production: national summary report. National Center For Food and Agricultural Policy, Washington. DC.
21贺全仁，聂星湖．拟除虫菊酯类农药的临床毒理学研究现状．中国工业医学杂志，1997，10(1)：46-48
22Christophe-M, Maher-D, Terry-R, et al. Differential Induction of Hepatic Drug-Metabolizing Enzymes by Fenvaleric Acid in Male Rats. Toxicological Sciences. 1999,52,148-153.
23夏元洵．化学物质毒性全书．上海：上海科学技术文献出版社，1991：649-653
24Nigg-HN,Knaak-JB. Blood cholinesterases as human biomarkers of organophosphorus pesticide exposure. Rev-Environ-Contam-Toxicol. 2000;163:29-111
25Lassiter-TL,Barone-S Jr, Moser-VC, et al. Gestational exposure to chlorpyrifos: dose response profiles for cholinesterase and carboxylesterase activity. Toxicol-Sci. 1999 52(1):92-100
26 Quistad-GB, Casida-JE. Sensitivity of blood-clotting factors and digestive enzymes to inhibition by organophosphorus pesticides. J-Biochem-Mol-Toxicol. 2000;14(1):51-6
27 Gauhan, Engel JL, Casida JE. Pesticide interaction:Effects of organophosphorus pesticide of the metabolism, toxicity and persistence of selected pyrethroid insecticide. Pestic Biochem physiol, 1980,14:81-85
28 IPCS. Deltamethrin. In:WHO Environmental Health Criteria. 97: Geneva: WHO 1996.81-82
29 孙金秀，陈波，姚佩佩．有机磷与拟除虫菊酯农药联合作用的毒性评价．卫生毒理学杂志，2000，14(3)：141-144
30 Mileson-BE, Chambers-JE, Chen-WL, et al. Common mechanism of toxicity: a case study of organophosphorus pesticides. Toxico-Sci, 1998,41(1):8-20
31 方荣美．4种有机磷农药对小鼠血脑胆碱酯酶活力的抑制作用．北京医科大学学报，1995．27(2)：141-142
32 张伟华，贺锡雯．氰戊菊酯可诱导大鼠肝脏P450 2B1/2B2．中国药理学与毒理学杂志，1997，11(2)：124
33 Santoni-G, Cantalamessa-F, Spreghini-E, et al. Piccoli-M. Alterations of T cell distribution and functions in prenatally cypermethrinexposed rats: possible involvement of catecholamines: Toxicology. 1999,138(3):175-87
34 Maiti-PK, Kar-A. Dual role of testosterone in fenvalerate-treated mice with respect to thyroid function and lipid peroxidation. J-Appl-Toxicol. 1997,17(2):127-31
35 Kale-M, Rathore-N, John-S, et al. Lipid peroxidative damage on pyrethroid exposure and alterations in antioxidant status in rat erythrocytes: a possible involvement of reactive oxygen species. Toxicol-Lett. 1999,105(3): 197-205
36 Maiti-PK, Kar-A, Gupta-P, et al. Loss of membrane integrity and inhibition of type-Ⅰ iodothyronine 5'-monodeiodinase activity by fenvalerate in female mouse. Biochem-Biophys-Res-Commun. 1995, 214(3): 905-9
37 Poovala-VS, Kanji-VK, Tachikawa-H, et al. Role of oxidant stress and antioxidant protection in acephate-induced renal tubular cytotoxicity. Toxicol-Sci. 1998 Dec; 46(2): 403-9
38 Poovala-VS, Huang-H, Salahudeen-AK. Role of reactive oxygen metabolites in organophosphate-bidrin-induced renal tubular cytotoxicity. J-Am-Soc-Nephrol. 1999 Aug; 10(8): 1746-52
39 Banerjee-BD, Seth-V, Bhattacharya-A, et al. Biochemical effets of some pesticides on lipid peroxidation and free-radical scavengers. Toxicol-Lett. 1999 Jun 30; 107(1-3): 33-47
40 张铣，刘毓谷．毒理学．北京：北京医科大学中国协和医科大学联合出版社，1997：136-150．
41 施畅，廖明阳．环磷酰胺与异环磷酰胺致肝毒性机制的比较．卫生毒理学杂志，2000，14(2)：99-102
42 谢克勤，赵丽，张曼，等．氯丙烯对神经细胞NO、MDA、GSH含量和NOS、SOD活性的影响．卫生毒理学杂志，2000，14(4)：212-213
43 方福德．基因组研究与预防医学．中华预防医学杂志．2001，35(1)：6-7
44 Chomozgnski P, Sacchi N. Single step method of RNA isolation by acid Guanicyanate-phenol-chloroform extraction. Anal Biochem, 1987, 162: 156-159
45 叶鑫生．细胞调控的探索．北京：军事医学出版社，1999：163-169．
46 杨东仁，牛勇，何凤生．c-fos基因在乐果中毒后肌无力大鼠肌组织中的表达．卫生研究，1999，28(2)：72-73
47 刘亢丁，苏志强，饶明俐，等．用逆转录多聚酶链反应检测局灶脑缺血及再灌注后c-fos和c-jun基因表达．中风与神经疾病杂志，1997，14(3)：42-45
48 黄培堂，俞炜源，陈添弥，等译．PCR技术实验指南．北京：科学技术出版社．1999：34-35
49 Morgan JI, Cohen D, Hanpstead J, et al. Mapping patterns of c-fos antigen in the central nervous system after seizure. Science, 1987, 237: 192～197.
50 Gillardon-F, Skutella-T, Uhlmann-E, et al. Activation of c-fos contributes to amyloid beta-peptide-induced neurotoxicity. Brain-Res. 1996, 706(1): 169-72
51 Wollnik-F, Brysch-W, Uhlmann-E, et al. Block of c-Fos and JunB expression by antisense oligonucleotides inhibits light-induced phase shifts of the mammalian circadian clock. Eur-J-Neurosci. 1995, 7(3): 388-93
52 Imaki T, Shibasaki T, Wang XQ, et al. Intraxerebroventricular administraton of corticotropin-releasing factor antagonist attenuates c-los mRNA expression in the paraventricular nucleus after stress. Neuroendocrinology, 1995, 61: 445
53 Hassouna-I, Wickert-H, el-Elaimy-I, et al. Systemic application of pyrethroid insecticides evokes differential expression of c-Fos and c-Jun proteins in rat brain. Neurotoxicology. 1996, 17(2): 415-31
54 Morgan JI, Curran T. Immediate-early genes: ten years on. Trends Neurosci, 1995, 18: 66.
55 Dragunow M, Luke W, Steel L, et al. Induntion of c-fos mRNA and protein in neurons and glia traumatic brain injury: Pharmacolgical characterization. Exp Neurol, 1990, 107: 236.
56 贺锡雯，殷若元，陈寅红，等．拟除虫菊酯对神经细胞膜Na+、Ca2+离子通道的影响．中华劳动卫生职业病杂志1997，15(5)：261-264
57 殷若元，贺锡雯，张金松，等．拟除虫菊酯和马拉硫磷对鼠脑细胞肌醇磷酸酯代谢的影响．中华劳动卫生职业病杂志．1996，14(5)：259-263
58 王心如，吴建平，肖杭，等．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2000 29(1)：1～3．
59 王克万，杨志焕，王正国，等．培养大鼠脑皮层神经元损伤后c-fos蛋白表达．中华创伤杂志，1998，14(4)：219-222