有机磷农药的联合毒性及其毒理学机理研究
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摘要
有机磷农药是我国目前使用范围最广、用量最大的农药。与其他种类农药相比,具有杀虫谱广、残效期短、价格低廉及抗药性不显著等特点,被广泛用于家庭和农业的防虫抗害中。正因为如此,使得有机磷农药残留成为我国食物中农药残留最突出的问题。长期以来,对农药残留的风险评估都是一个个的进行,而实际上在食品和环境中残留几乎都是多种农药的残留,人群普遍同时或连续暴露在有机磷农药混合物中,其对健康产生的联合风险有待评估。本文研究了有机磷二元混合物的联合急性和亚慢性毒性,从联合神经毒性、对代谢酶的联合作用、联合雄性生殖毒性、对表征雄性生殖正常功能的标志物基因表达影响等几个方面,探讨了有机磷农药二元混合物对机体的损伤作用,阐明有机磷农药混和物的危害效应和毒作用机理,为完善有机磷农药混合物的风险评估提供理论依据。
本研究选择食品中常见的有机磷农药残留品种,氧化乐果、毒死蜱、敌敌畏、辛硫磷、甲基对硫磷,采用霍恩氏法计算了各单剂的LD50,结果与文献记载的一致,分别为79.4、147、126、1260、14.7mg/kg.BW。按等毒比法制备混配农药,测定有机磷二元混合物的实际LD50。按照联合作用系数法计算其预测LD50,计算实际LD50与预测LD50的比值。根据Keplinger建议的评价标准:二元混合物能产生不同模式的联合急性毒性,氧化乐果和毒死蜱、氧化乐果和甲基对硫磷按等毒比混配后,实际LD50与预测LD50的比值均大于1.75,急性神经毒性联合作用表现为协同作用。敌敌畏和毒死蜱混合后,实际LD50与预测LD50的比值小于0.57,联合作用表现为拮抗;其余有机磷农药混和物实际LD50与预测LD50的比值在0.57～1.75表现为相加。在此基础上,选取氧化乐果和毒死蜱作为急性毒性机制和亚慢性毒性及机制的研究对象。
化学物产生联合毒性的机制与代谢酶密切相关。本研究通过氧化乐果和毒死蜱对关键代谢酶活力的联合作用的研究,以期阐明产生协同急性神经毒性的机理。氧化乐果和毒死蜱混合物以各自1/2LD50mg/kg剂量混和后,对SD大鼠一次染毒后,采用2×3析因设计,研究染毒后4、8、24h时混合物对肝脏、血清中的羧酸酯酶和胆碱酯酶的联合影响。结果表明:在8h时能显著降低混合组脑组织中AchE的活力,联合作用呈协同作用,其较正常对照组降低了60%,表明产生了协同神经毒性。混合物能显著抑制肝脏和血清中CE活力,协同作用分别出现在染毒4h和8h后。对血清和肝脏CE活力的协同抑制可能是引起协同神经毒性的机理之一。氧化乐果和毒死蜱在染毒8h后对血清中ChE活力产生协同抑制作用,延长了农药在体内持续时间,而增强了急性神经毒性。
本文研究了氧化乐果和毒死蜱单独染毒对SD大鼠的亚慢性生殖毒性,并得到亚慢性生殖毒性的未观察到有害作用剂量(NOAEL),为完善毒死蜱和氧化乐果的风险评估提供了数据支持,并为下一步联合毒性的研究提供了剂量依据。结果表明:氧化乐果和毒死蜱单剂均对大鼠产生雄性生殖毒性,能显著降低精子数、精子活动率和增加精子的畸形率;诱导雄性大鼠生精管损伤,各级生精细胞较少、变性、脱落、水肿,间质增宽。而产生生殖毒性的机制主要为:氧化乐果能使FSH上升和T含量下降,表明大鼠睾丸的支持细胞是氧化乐果作用的靶位点;毒死蜱能升高睾丸组织LH水平和减少T的含量,减少间质细胞的数量,表明大鼠睾丸间质细胞是毒死蜱作用的靶位点。氧化乐果和毒死蜱染毒的睾丸中标志酶LDH、ACP、AKP、γ-GT的活力都发生了变化,与对照组有显著差异,这与氧化乐果和毒死蜱诱导精子质量下降(精子数、精子活动率、精子畸形率)存在一定的关系。氧化乐果和毒死蜱染毒后,大鼠睾丸组织的抗氧化平衡受到破坏。打破了生精细胞凋亡维持精子发生过程的正常动态平衡,这可能是导致雄性大鼠生殖毒性的其中一个毒性机理。氧乐果对于SD雄性大鼠生殖毒性的最大无作用剂量NOAEL是0.44 mg/(kg.d),而毒死蜱的则是为0.82mg/(kg.d)。
氧化乐果和毒死蜱混合物染毒SD大鼠后能产生雄性生殖毒性,表现为协同作用。混和物能显著增加附睾系数、降低精子数和精子活力,联合作用均表现为协同作用;通过电镜和光镜观察结果表明:混合物能引起曲细精管的萎缩,精子数量下降,支持细胞减少,精子从支持细胞上脱落,基底膜脱落。畸形精子增多,生精细胞坏死,胞浆溶解,线粒体空泡化,支持细胞坏死。其联合作用机制主要有:第一,氧化乐果和毒死蜱混合物染毒的睾丸标志酶LDH、ACP、AKP、γ-GT的活力都发生了变化,表现为显著下降,联合作用为协同作用。这与混合物诱导精子质量下降(精子数、精子活动率)存在一定的关系。第二,混合物对大鼠的FSH和T水平存在交互作用,表明混合物对支持细胞的影响存在交互作用,染毒后混合物对LH水平的影响表现为相加作用,则协同作用主要体现了氧化乐果对支持细胞的损伤作用。
本研究还利用体外大鼠睾丸支持细胞培养模型,采用荧光半定量逆转录—聚合酶链式反应技术研究了氧乐果和毒死蜱混合物产生协同雄性生殖毒性的机理。混合物能显著减少支持细胞标志物雄激素结合蛋白(ABP)基因的表达量,联合作用表现为协同作用;混合物对ABP的协同作用表明了以下两点:一是氧化乐果和毒死蜱混合物能对睾丸内生精过程平衡产生强烈的破坏,其破坏程度强于氧化乐果和毒死蜱的两种单剂对生精过程的破坏作用的总和;二是氧化乐果和毒死蜱通过对ABP基因表达的协同降低,使支持细胞受损,而间接对生精过程产生协同损伤,从而产协同生雄性生殖毒性。
有机磷农药混配后,能对大鼠产生协同的神经毒性和亚慢型雄性生殖毒性,毒性效应增强。人体暴露在有机磷农药混合物后对健康的风险增大,因此在制定有机磷农药在环境、农产品中的最大残留限量标准时,不能仅从单剂的剂量—效应关系出发,还需要考虑到混合有机磷农药的增毒作用,从而制定出合理的环境和食品标准,保障人群的健康安全。
Organophosphorus pesticides (OP) are widely used in the control of insects around the home and in agriculture practice in China. It has broad-spectrum in controlling insecticide, short residual period and low price, which are easy to be accepted by farmer. OP residue is the most outstanding issue in pesticide residue in food. Risk assessment of single OP in food was fully evaluated, but human exposure to OP, whether occupationally or environmentally, is rarely limited to a single OP. People are always sequential or concurrent exposure in OP pesticides, which health hazard to people was be appraised. According to the research progress at home and abroad, this project was studied deeply and systematically in the interactive action, acute neurotoxicity, effects on metabolic enzyme, male rats reproductive toxicity and relative gene expression so as to reveal damage to organism and provide scientific data for the risk assessment of mixtures of OP pesticides.
The acute oral toxicity (LD50) of two OP pesticides was evaluated by Horns method on equal toxicity doses. The mixtures of two OP pesticides omethoate plus phoxim, omethoate plus dichlorovos, dichlorvos plus phoxim, and dichlorovos plus methyl parathion showed additive effects; dichlorovos plus chlorpyrifos and omethoate plus methyl patathion showed synergistic effects; dichlorovos plus chlorpyrifos showed antagonistic effects. On the basis of the results, the mixture of omethoate and chlorpyrifos were used to launch the following research.
The interactive toxicity of chemical mixture is closely related to metabolic enzyme. The interactive effect on critical metabolism enzyme was studied so as to elucidate the mechanism of synergistic acute neurotoxicity. Omehoate and chlorpyrifos were mixed with 1/2 LD50 dose, and lavage mixture to SD rats .The interactive effects on carboxylesterase (CE) and cholinesterase activity (ChE) in liver and blood serum was evaluated by the means of both concomitant treatments using 2×3 factorial design .Results indicated that the AchE activity of brain tissue was significantly decreased by 60% comparing with control group after exposure to the mixture. The neurotoxicity occurred. The mixture can be decrease significantly CE activity of liver and blood serum After exposure for 4 and 8 hours, the synergistic effect showed up. The decrease of CE activity was one of the possible mechanisms that resulted in synergistic neurotoxicity.
The effects of chlorpyrifs and omehoate on the reproductive function in male SD rats were studied and got the no obserber adverse effect level (NOAEL) of the two OP pesticides that providing scientific supports for those risk assessment. The Results showed: chlorpyrifs and omehoate can induce male reproductive toxicity, and had a significant fall in the total sperm count, the percentage of sperm mobility and increase 0f the sperm abnormality; and lead to injury of testicular follicle. The amount of spermatogenic cell decreased,and it was occure with degeneration, defluxion, dropsy. The mechanism of produceing male toxicity goes as follows. Firstly, Omethoate can significantly increase FSH and T in testicular tissue, decrease the amount of sertolic cells which revealed SC as the target site of omethoate; chlorpyrifs can increase LH, decrease T and amount of cell of leydig which signed the leydig’s cell as the target cell of chlorpyrifs. Secondly, the activites of lactate dehydrogenase (LDH), alkaline phosphatase (AKP), acid phosphatas (ACP) andγ-glutamyltransferase (γ-GT) were changed after exposure to omethoate or chlorpyrifs, which had correlations with the decrease of sperm quality. At last, the antioxygen balance was broken down, which destroyed the normal dynamic equilibrium of apoptosis of spermatogenic cell to sustain spermatogenesis process. There was another possible mechanism to cause male reproductive toxicity. The NOAEL of omehoate is 0.44mg/kg, and one of chlorpyrifs is 0.82mg/kg.
The mixture of omethoate and chlorpyrifs can produce male reproductive toxicity, which interactive toxicity showed synergistic effect. Mixture can significantly increase the epididymal viscera coefficients and decrease total sperm count, the percentage of sperm mobility, which has synergistic effect. By the electron microscope and light microscope, the following can be observed: atrophia of the contorted seminiferous tubules, decrease of sperm and SC amount, sperm shedding from SC, decrease of sperms’abnormity, necrosisi of sperm and SC. The mechanism of producing interactive male toxicity is following. Firstly, the activites of lactate dehydrogenase (LDH), alkaline phosphatase (AKP), acid phosphatas (ACP) andγ-glutamyltransferase (γ-GT) were changed after exposure to mixtures, which show synergistic effects. There was joint action in FSH and T after exposure to omthoate and chlorpyrifs, which the effect of sertolic cell has synergistic effect. As the effect on LH of mixture is additive, the synergistic effect mainly showed damage to SC.
In this project, the SC culture mold was used to study mechanism of male reproductive toxicity after exposure to omehoate and chlorpyrifs. The fluorescence semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) technique was utilized to explore effects of insecticide mixtures on the expression of androgen binding protein (ABP), inhibin B mRNA in testis SC of SD rats. The expression of ABP mRNA in SC dropped significantly, which showed synergistic effects. It is rectified that mixture can strongly destroy the balance of spermatogenesis process, and the extent are more extensive than the total toxicity of individual insecticide separately; One of the mechanisms resulting in synergistic male reproductive is that mixture synergistically decreased the expression of ABP mRNA .
OP pesticides can produce synergistic acute neurotoxicity and subchronic male reproductive, which has more powerful toxicity than the add one of single OP pesticides. The risk to people’s health increased after being exposed to phosphate mixtures, so it’s necessary to consider the increase of toxicity after mixing pesticides when formulate the maximum residue limit that is proper and reasonable to protect people’s health.
本研究选择食品中常见的有机磷农药残留品种,氧化乐果、毒死蜱、敌敌畏、辛硫磷、甲基对硫磷,采用霍恩氏法计算了各单剂的LD50,结果与文献记载的一致,分别为79.4、147、126、1260、14.7mg/kg.BW。按等毒比法制备混配农药,测定有机磷二元混合物的实际LD50。按照联合作用系数法计算其预测LD50,计算实际LD50与预测LD50的比值。根据Keplinger建议的评价标准:二元混合物能产生不同模式的联合急性毒性,氧化乐果和毒死蜱、氧化乐果和甲基对硫磷按等毒比混配后,实际LD50与预测LD50的比值均大于1.75,急性神经毒性联合作用表现为协同作用。敌敌畏和毒死蜱混合后,实际LD50与预测LD50的比值小于0.57,联合作用表现为拮抗;其余有机磷农药混和物实际LD50与预测LD50的比值在0.57～1.75表现为相加。在此基础上,选取氧化乐果和毒死蜱作为急性毒性机制和亚慢性毒性及机制的研究对象。
化学物产生联合毒性的机制与代谢酶密切相关。本研究通过氧化乐果和毒死蜱对关键代谢酶活力的联合作用的研究,以期阐明产生协同急性神经毒性的机理。氧化乐果和毒死蜱混合物以各自1/2LD50mg/kg剂量混和后,对SD大鼠一次染毒后,采用2×3析因设计,研究染毒后4、8、24h时混合物对肝脏、血清中的羧酸酯酶和胆碱酯酶的联合影响。结果表明:在8h时能显著降低混合组脑组织中AchE的活力,联合作用呈协同作用,其较正常对照组降低了60%,表明产生了协同神经毒性。混合物能显著抑制肝脏和血清中CE活力,协同作用分别出现在染毒4h和8h后。对血清和肝脏CE活力的协同抑制可能是引起协同神经毒性的机理之一。氧化乐果和毒死蜱在染毒8h后对血清中ChE活力产生协同抑制作用,延长了农药在体内持续时间,而增强了急性神经毒性。
本文研究了氧化乐果和毒死蜱单独染毒对SD大鼠的亚慢性生殖毒性,并得到亚慢性生殖毒性的未观察到有害作用剂量(NOAEL),为完善毒死蜱和氧化乐果的风险评估提供了数据支持,并为下一步联合毒性的研究提供了剂量依据。结果表明:氧化乐果和毒死蜱单剂均对大鼠产生雄性生殖毒性,能显著降低精子数、精子活动率和增加精子的畸形率;诱导雄性大鼠生精管损伤,各级生精细胞较少、变性、脱落、水肿,间质增宽。而产生生殖毒性的机制主要为:氧化乐果能使FSH上升和T含量下降,表明大鼠睾丸的支持细胞是氧化乐果作用的靶位点;毒死蜱能升高睾丸组织LH水平和减少T的含量,减少间质细胞的数量,表明大鼠睾丸间质细胞是毒死蜱作用的靶位点。氧化乐果和毒死蜱染毒的睾丸中标志酶LDH、ACP、AKP、γ-GT的活力都发生了变化,与对照组有显著差异,这与氧化乐果和毒死蜱诱导精子质量下降(精子数、精子活动率、精子畸形率)存在一定的关系。氧化乐果和毒死蜱染毒后,大鼠睾丸组织的抗氧化平衡受到破坏。打破了生精细胞凋亡维持精子发生过程的正常动态平衡,这可能是导致雄性大鼠生殖毒性的其中一个毒性机理。氧乐果对于SD雄性大鼠生殖毒性的最大无作用剂量NOAEL是0.44 mg/(kg.d),而毒死蜱的则是为0.82mg/(kg.d)。
氧化乐果和毒死蜱混合物染毒SD大鼠后能产生雄性生殖毒性,表现为协同作用。混和物能显著增加附睾系数、降低精子数和精子活力,联合作用均表现为协同作用;通过电镜和光镜观察结果表明:混合物能引起曲细精管的萎缩,精子数量下降,支持细胞减少,精子从支持细胞上脱落,基底膜脱落。畸形精子增多,生精细胞坏死,胞浆溶解,线粒体空泡化,支持细胞坏死。其联合作用机制主要有:第一,氧化乐果和毒死蜱混合物染毒的睾丸标志酶LDH、ACP、AKP、γ-GT的活力都发生了变化,表现为显著下降,联合作用为协同作用。这与混合物诱导精子质量下降(精子数、精子活动率)存在一定的关系。第二,混合物对大鼠的FSH和T水平存在交互作用,表明混合物对支持细胞的影响存在交互作用,染毒后混合物对LH水平的影响表现为相加作用,则协同作用主要体现了氧化乐果对支持细胞的损伤作用。
本研究还利用体外大鼠睾丸支持细胞培养模型,采用荧光半定量逆转录—聚合酶链式反应技术研究了氧乐果和毒死蜱混合物产生协同雄性生殖毒性的机理。混合物能显著减少支持细胞标志物雄激素结合蛋白(ABP)基因的表达量,联合作用表现为协同作用;混合物对ABP的协同作用表明了以下两点:一是氧化乐果和毒死蜱混合物能对睾丸内生精过程平衡产生强烈的破坏,其破坏程度强于氧化乐果和毒死蜱的两种单剂对生精过程的破坏作用的总和;二是氧化乐果和毒死蜱通过对ABP基因表达的协同降低,使支持细胞受损,而间接对生精过程产生协同损伤,从而产协同生雄性生殖毒性。
有机磷农药混配后,能对大鼠产生协同的神经毒性和亚慢型雄性生殖毒性,毒性效应增强。人体暴露在有机磷农药混合物后对健康的风险增大,因此在制定有机磷农药在环境、农产品中的最大残留限量标准时,不能仅从单剂的剂量—效应关系出发,还需要考虑到混合有机磷农药的增毒作用,从而制定出合理的环境和食品标准,保障人群的健康安全。
Organophosphorus pesticides (OP) are widely used in the control of insects around the home and in agriculture practice in China. It has broad-spectrum in controlling insecticide, short residual period and low price, which are easy to be accepted by farmer. OP residue is the most outstanding issue in pesticide residue in food. Risk assessment of single OP in food was fully evaluated, but human exposure to OP, whether occupationally or environmentally, is rarely limited to a single OP. People are always sequential or concurrent exposure in OP pesticides, which health hazard to people was be appraised. According to the research progress at home and abroad, this project was studied deeply and systematically in the interactive action, acute neurotoxicity, effects on metabolic enzyme, male rats reproductive toxicity and relative gene expression so as to reveal damage to organism and provide scientific data for the risk assessment of mixtures of OP pesticides.
The acute oral toxicity (LD50) of two OP pesticides was evaluated by Horns method on equal toxicity doses. The mixtures of two OP pesticides omethoate plus phoxim, omethoate plus dichlorovos, dichlorvos plus phoxim, and dichlorovos plus methyl parathion showed additive effects; dichlorovos plus chlorpyrifos and omethoate plus methyl patathion showed synergistic effects; dichlorovos plus chlorpyrifos showed antagonistic effects. On the basis of the results, the mixture of omethoate and chlorpyrifos were used to launch the following research.
The interactive toxicity of chemical mixture is closely related to metabolic enzyme. The interactive effect on critical metabolism enzyme was studied so as to elucidate the mechanism of synergistic acute neurotoxicity. Omehoate and chlorpyrifos were mixed with 1/2 LD50 dose, and lavage mixture to SD rats .The interactive effects on carboxylesterase (CE) and cholinesterase activity (ChE) in liver and blood serum was evaluated by the means of both concomitant treatments using 2×3 factorial design .Results indicated that the AchE activity of brain tissue was significantly decreased by 60% comparing with control group after exposure to the mixture. The neurotoxicity occurred. The mixture can be decrease significantly CE activity of liver and blood serum After exposure for 4 and 8 hours, the synergistic effect showed up. The decrease of CE activity was one of the possible mechanisms that resulted in synergistic neurotoxicity.
The effects of chlorpyrifs and omehoate on the reproductive function in male SD rats were studied and got the no obserber adverse effect level (NOAEL) of the two OP pesticides that providing scientific supports for those risk assessment. The Results showed: chlorpyrifs and omehoate can induce male reproductive toxicity, and had a significant fall in the total sperm count, the percentage of sperm mobility and increase 0f the sperm abnormality; and lead to injury of testicular follicle. The amount of spermatogenic cell decreased,and it was occure with degeneration, defluxion, dropsy. The mechanism of produceing male toxicity goes as follows. Firstly, Omethoate can significantly increase FSH and T in testicular tissue, decrease the amount of sertolic cells which revealed SC as the target site of omethoate; chlorpyrifs can increase LH, decrease T and amount of cell of leydig which signed the leydig’s cell as the target cell of chlorpyrifs. Secondly, the activites of lactate dehydrogenase (LDH), alkaline phosphatase (AKP), acid phosphatas (ACP) andγ-glutamyltransferase (γ-GT) were changed after exposure to omethoate or chlorpyrifs, which had correlations with the decrease of sperm quality. At last, the antioxygen balance was broken down, which destroyed the normal dynamic equilibrium of apoptosis of spermatogenic cell to sustain spermatogenesis process. There was another possible mechanism to cause male reproductive toxicity. The NOAEL of omehoate is 0.44mg/kg, and one of chlorpyrifs is 0.82mg/kg.
The mixture of omethoate and chlorpyrifs can produce male reproductive toxicity, which interactive toxicity showed synergistic effect. Mixture can significantly increase the epididymal viscera coefficients and decrease total sperm count, the percentage of sperm mobility, which has synergistic effect. By the electron microscope and light microscope, the following can be observed: atrophia of the contorted seminiferous tubules, decrease of sperm and SC amount, sperm shedding from SC, decrease of sperms’abnormity, necrosisi of sperm and SC. The mechanism of producing interactive male toxicity is following. Firstly, the activites of lactate dehydrogenase (LDH), alkaline phosphatase (AKP), acid phosphatas (ACP) andγ-glutamyltransferase (γ-GT) were changed after exposure to mixtures, which show synergistic effects. There was joint action in FSH and T after exposure to omthoate and chlorpyrifs, which the effect of sertolic cell has synergistic effect. As the effect on LH of mixture is additive, the synergistic effect mainly showed damage to SC.
In this project, the SC culture mold was used to study mechanism of male reproductive toxicity after exposure to omehoate and chlorpyrifs. The fluorescence semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) technique was utilized to explore effects of insecticide mixtures on the expression of androgen binding protein (ABP), inhibin B mRNA in testis SC of SD rats. The expression of ABP mRNA in SC dropped significantly, which showed synergistic effects. It is rectified that mixture can strongly destroy the balance of spermatogenesis process, and the extent are more extensive than the total toxicity of individual insecticide separately; One of the mechanisms resulting in synergistic male reproductive is that mixture synergistically decreased the expression of ABP mRNA .
OP pesticides can produce synergistic acute neurotoxicity and subchronic male reproductive, which has more powerful toxicity than the add one of single OP pesticides. The risk to people’s health increased after being exposed to phosphate mixtures, so it’s necessary to consider the increase of toxicity after mixing pesticides when formulate the maximum residue limit that is proper and reasonable to protect people’s health.
引文
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