毒物毒性作用的主要概念与基本

1、毒物（toxicant/poison)- 以较小剂量引起生物机体功能性或器质性损害的化学物质； 任何物质都是毒物l毒性-一种物质能引起机体损害的性质和能力；剂量l危险度- 引起机体某种不良效应发生的概率，可定量估计；vs. 危险性Dose 剂量剂量Amount of chemical injected into the tissue;Oral administrated;Target tissues after oral ingestion;Whole body burden in small organisms;Exposure concentration times time mg/bod

2、y kg or mg/m3, m/LDose IILD50-half lethal dose; LC50-concentration in mg/m3 or mg/L; EC50 medium effective concentration; NOEC: no observable effect concentrationDose-response curve may have different shapes and slopes. Typically short term (48 or 96 h).Dose-response curveMostly common used: Probit

3、(概率）概率） transformation Sigmoid against log concentration LC10 and LC90 may also be important for a complete pictureNOEC and LOEC效应 （effect）-毒物与集体接触后所引起的生物学变化； 量效应vs. 质效应；反应 （response)- 呈现某种效应并达到一定程度的比率； 联合毒性作用joint toxic effect两种或两种以上的化学物同时或短期内先后作用于机体所产生的综合毒性作用；类型相加作用 ； 相同结构， 靶，机制类似协同作用： 促进增强： 其中一种毒

4、物无毒性拮抗作用：干扰， 减弱， 独立作用： 互不影响Antagonism拮抗作用拮抗作用Antagonism characterized by its mechanism. Functional antagonism Two chemicals elicit opposite physiological effects and counter-balance each other. Chemical antagonism, Two toxicants react with one another to produce a less toxic product. Dispositional a

5、ntagonism Involves the uptake, movement within the organism, deposition at specific sites, and elimination of the toxicants. The presence of the two toxicants together shifts one or more of these processes to lower the impact of the toxicants on the site(s) of action or target organ(s). Receptor ant

6、agonismTwo or more toxicants bind to the same receptor and each toxicant blocks the other from fully expressing its toxicity.毒性作用的机制干扰正常受体-配体的相互作用；神经毒素有机磷等；细胞膜损伤；干扰细胞内钙稳态； 硝基酚、醌、过氧化物、醛类、二噁英、卤化链烃、镉等重金属离子，胞质中Ca升高，膜磷脂分解等等干扰细胞能量的产生； 氰化物、硫化氢等， 呼吸链断裂， ATP 缺乏自由基与氧化损伤具有奇数电子的分子， 脂质过氧化，膜流动性受损，影响膜镶嵌蛋白的活力， 线粒体和

7、溶酶体，核酸，其他毒性作用的机制与核酸的结合，引起DNA链的局部扭曲和二级结构异常，RNA与亲电子化合物结合，结构和功能发生改变；蛋白质和酶；脂质： 自由基的结合，细胞损伤和死亡；选择性细胞致死；非致死性遗传改变： 干扰DNA复制和修复，致畸。影响毒性作用的因素毒物的结构与性质同系物的C数；基团： 烃基，卤素，羟基（芳香族），酯基， 胺基，巯基，电负性基团；酸基分子饱和度： 不饱和键多，构型：酶对化学物质构型存在高度特异性；有机磷化合物结构R与毒性： PR(O)R(O)Y(O,S)X R 、R 为烷基，n ，毒性 Y OS X 酸根， 苯基, -NO2-CN-Cl-H-CH3比较O毒死蜱甲基对

8、硫磷物理性质与毒性脂/水分配系数KOW 甲基汞溶解度 在体液当中的溶解度大，毒性大 解离度 与排出难易有关挥发性和蒸气压 分散度纯度机体状况 种属和个体差异毒物代谢酶的有无， 活性高低性别与激素年龄 凡经代谢转化后毒性增加的化学物，对新生和幼年动物的毒性低； 凡在体内迅速代谢失活的化合物，毒性大。（图3-3）营养与健康 生物节律 生物钟或昼夜节律接触条件 接触途径 吸收、分布、首先到达的组织器官不同，对其代谢转化、毒性反应的性质和程度也有影响溶剂助溶剂： 水，生理盐水、植物油、二甲基亚砜等毒物浓度与容积浓溶液稀溶液交叉接触环境因素 气温 气湿毒性作用大气压 光照联合作用类型评定(一）急性毒性实

9、验； LD50联合作用系数法：假设： 相加作用联合作用系数（K）=混合物的预期LD50/混合物实测LD50K与联合作用类型拮抗作用拮抗作用相加作用相加作用协同作用协同作用Smyth法2.70Keplinger法1.75Models of joint toxic effectII- Toxic unit approach TOXIC UNITS毒性单位毒性单位Mixture effects are often illustrated using the simplified concept of toxic units (TU), amounts or concentrations of dif

10、ferent toxicants expressed in units of lethality such as units of LD50 or LC50. In the beginning, the toxic unit was most often expressed as a fraction of the incipient median lethal concentration起始半致死浓度. Models of joint toxic effectToxi c Uni t s of Toxi cant BToxi c Uni t s of Toxi cant BToxi c Un

11、i ts of Toxi cant AToxi c Uni ts of Toxi cant A1 10 00 01 1Synergi smSynergi smAntagoni smAntagoni smAddi ti vi t yAddi ti vi t y0.5TUB +0.5TUATakes less than this to cause one TU of mortality.Toxic unit approach based on Concentration Additivity浓度相浓度相加性加性 - after adjustment for relative potency, co

12、ncentrations of toxicants can be added together to predict effects under the assumption of additivity.However, toxicant concentration (or dose) is often related to lethal effect by a sigmoid, not a linear relationship. Some relationships are pseudolinear over a range of concentrations of interest an

13、d concentration additivity can be used to approximate effects. Models of joint toxic effectTo progress to a more involved treatment of mixtures, the distinction must be made between toxicants that act independently or similarly.Similar joint action they act by the same mechanism (i.e., have identica

14、l modes of action) and “one component can be substituted at a constant proportion for the other toxicity of a mixture is predictable directly from that of the constituents if their relative proportions are known” Independent joint actionExists if each toxicant produces an effect independent of the o

15、ther and by a different mode of action. Quantifying joint “mixtures whose constituents act independently, the mortalities, not the doses, are additive.” Models of Joint action IIIEffect AdditivitySum of the predicted effects could be compared to the observed effect of the actual combination of the t

16、wo concentrations of A and B in order to assess conformity to or deviations from effect additivity. For example, the separate effects of 2 toxicants on the proportion of exposed individuals dying (PA and PB) are estimated with the equations:)(log)(Pr)(log)(PrBBBBAAAAionConcentratSlopeInterceptPobiti

17、onConcentratSlopeInterceptPobitModels of Joint action IIITwo Independently Acting Toxicants)1 (PrABABAPPPPedictedBABABAPPPPPedictedPr)1)(1(1BABAPPPCan include several contaminants).1)(1)(1 (1.CBACBAPPPPModels of Joint action IIITwo Similarly Acting ToxicantsToxicants with similar action have paralle

18、l slopesin their probit models ).(log)(Pr),(log)(PrBBBAAAionConcentratSlopeInterceptPobitionConcentratSlopeInterceptPobitSlopeInterceptInterceptABB)(logThe log of the relative potencyCan predict joint actionProbit(PA + PB)=Intercept+Slope*log(ConcentrationA + B*ConcentrationB)Models of Joint action IIICombined effects are often illustrated using the simplified concept of toxic units (TU), amounts or concentrations of dif