The toxicity of poisons applied jointly
The toxicity of poisons applied jointly
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DOI：
10.1111/j.1744-7348.1939.tb06990.x
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发表时间：
1939-08-01
影响因子：
2.6
通讯作者：
Bliss, CI
中科院分区：
文献类型：
--
作者：
Bliss, CI
对联合使用的药物或毒物的毒性进行定量分析，要求以若干剂量以含有固定比例成分的混合物给药。根据对几种此类混合物的剂量-死亡率曲线的研究，最好与分离活性成分的等效曲线进行比较，大多数联合作用的情况可以分为三种类型之一：(1)第一类是成分独立而多样地起作用，因此可以根据分离成分的毒性和对两种成分的敏感性的关联来预测任何组合的毒性。关联系数可以通过实验测量，并且在所有成分的比例下都应该是恒定的。当浓度高时，混合物的毒性降低。对几种假设混合物的剂量-死亡率曲线的形式进行了检验。当假设两组分的曲线斜率不同时，混合物的曲线会出现一个相对突然的弯曲，断裂上方和下方的直线段的斜率接近原始组分的值。这一观察结果表明，在均匀种群中，剂量-死亡率曲线的斜率具有毒理学意义。由于如果一种毒药在动物体内有两种独立的致死效应，预计会有相同的数值关系，因此，在转化为概率和对数后发生中断时，可以分别拟合剂量-死亡率曲线的线性段，这是有理论基础的。这一论点已被扩展到时间-死亡率实验中，以解释自然死亡率的平滑凹曲线特征。(2)第二类联合作用是各成分独立但相似地起作用，因此一种成分可以在一秒钟内以恒定的比例被取代而不改变混合物的毒性。在均质人群中，单独成分和所有混合物的剂量-死亡率曲线应该是平行的。虽然根据假设，对一种成分的易感性与对另一种成分的易感性完全相关，但这一类混合物比前一类的毒性更大，后者的关联可能从0到1不等。用含有除虫菊酯和鱼藤酮的溶液对家蝇的毒性实验说明了数值关系。除虫菊酯和鱼藤酮的等量单位略少于4个的混合物与定义非常一致，但其中成分大致相等的混合物的毒性明显大于根据独立作用假设所预期的毒性，表明存在协同作用。(3)协同作用形成第三种联合作用，其特点是毒性大于对分离成分的研究预测。这是对抗的反面，它没有被直接考虑。提出了两种分析协同效应的方法。更直接的方法是将混合物的等量剂量与其活性成分的百分比组成联系起来。当两者都是对数时，关系在一个有用的组合范围内是线性的。这个程序保留了实验的原始结构，可以很容易地扩展到三种或更多的成分，并导致一个方便的实用结果。理论上，它不如第二种方法令人满意，在第二种方法中，对于每种混合物的等量剂量，一种成分(a)的含量与另一种成分(b)的含量相关。最完全满足这种关系的方程是（1 +k1A）Bi=k2，其中三个常数被计算…
SummaryA quantitative analysis of the toxicity of drugs or poisons applied jointly requires that they be administered at several dosages in mixtures containing fixed proportions of the ingredients. From a study of the dosage‐mortality curves for several such mixtures, preferably in comparison with equivalent curves for the isolated active ingredients, most cases of combined action can be classified into one of three types:(1) The first type is that in which the constituents act independently and diversely, so that the toxicity of any combination can be predicted from that of the isolated components and from the association of susceptibilities to the two components. The coefficient of association can be measured experimentally and should be constant at all proportions of the ingredients. When high, the toxicity of the mixture is reduced. The form of the dosage‐mortality curve has been examined for several hypothetical mixtures. Whenever the curves for the two constituents were assumed to differ in slope, there was a relatively abrupt bend in the curve for the mixture, the rectilinear segments above and below the break approaching in slope the values for the original constituents. This observation indicates that in homogeneous populations the slope of a dosage‐mortality curve is of toxicological significance. Since the same numerical relations would be expected if a single poison were to have two independent lethal effects within the animal, there is theoretical basis for fitting the linear segments of a dosage‐mortality curve separately when a break occurs after transformation to probits and logarithms. This argument has been extended to time‐mortality experiments to explain the smoothly concave curves characteristic of natural mortality.(2) The second type of joint action is that in which the constituents act independently but similarly, so that one ingredient can be substituted at a constant ratio for any proportion of a second without altering the toxicity of the mixture. With homogeneous populations, dosage‐mortality curves for the separate ingredients and for all mixtures should be parallel. Although by hypothesis the susceptibility to one ingredient is completely correlated with that to the other, mixtures in this category are more toxic than in the preceding class where association may vary from 0 to 1. The numerical relations have been illustrated by an experiment on the toxicity to the house‐fly of solutions containing pyrethrin and rotenone. A mixture with a little less than four equitoxic units of pyrethrin to one of rotenone agreed closely with the definition but one in which the ingredients were about equally balanced showed a significantly greater toxicity than expected on the hypothesis of independent action, indicating the presence of synergism.(3) Synergism forms the third type of joint action, characterized by a toxicity greater than that predicted from studies on the isolated constituents. It is the reverse of antagonism, which has not been considered directly. Two methods are proposed for the analysis of synergism. The more direct is to relate equitoxic dosages of mixture to its percentage composition in terms of the more active ingredient. When both are in logarithms the relation is linear over a useful range of compositions. This procedure preserves the original structure of the experiment, can be extended readily to three or more ingredients and leads to a convenient practical result. Theoretically it is less satisfactory than a second method in which for equitoxic dosages of each mixture the content of one ingredient (A) is related to the content of the other (B.) The equation which satisfies this relation most completely is (1 +k1A)Bi=k2, where the three constants are computed …