FIELD T-l 

 Column 57 



Of these five, definitions are discussed first. In this general discussion of definitions and in 

 the specific definitions, the second of the aspects listed above is essentially ignored so that, in the 

 paragraphs immediately following, any reference to the test compound and the secondary compound 

 should be accepted as implying that the choice of compounds as the test compound and secondary 

 compound has been made appropriately. The final part of this division discusses the second, third, 

 and fourth of the aspects listed above. The criteria for evaluation (the fifth aspect) are indicated 

 immediately following the discussion of each of the definitions. 



Concepts of meaning of any of the terms, "antagonism", "synergism", and "additive effect" 

 are not always constant; for example, a given measure of depressant effect of a test compound on the 

 action of a secondary compound may represent antagonism according to one author's concept, but not 

 to another's concept. To establish consistency in coding, these terms have each been given a precise 

 definition for CBCC use to which definitions the coder must match the data presented by the author to 

 determine if those data demonstrate synergism (Symbol 8), antagonism (Symbol 9), or additive effect 

 (Symbol C), according to those CBCC definitions. These three test compound effects or influences on 

 the actions of secondary compounds are distinguished on the basis of measurement of intensity of re- 

 sponse of the test organism to the secondary compound administered alone and the measurement of 

 intensity of response of the test organism to the test compound administered alone and the comparison 

 of the calculated sum of these two intensity measurements to the measurement of actual intensity of 

 response when the two compounds are administered together (i. e. , administered so that they are exert- 

 ing their effects [on the test organism and each other] simultaneously). Use of the expression 

 "administered together" in this division does not imply that the physical act of administration of the 

 two compounds need be simultaneous, such as simultaneous injection or administration as a mixture. 



In organizing these definitions of effects or influences of the test compound, they have been 

 grouped under two headings, (A) enhancement of that intensity of the organism's response to the 

 secondary compound (i. e. , enhancement of the intensity of response to the secondary compound 

 administered alone) and (B) depression of that intensity of the organism's response to the secondary 

 compound administered alone. Four graphic representations are included, as Figures 1 through 4, 

 to assist in understanding these definitions. 



A. The test compound enhances the intensity of the organism's response to the secondar, 

 compound, as determined by comparison to the intensity of response when the secondary 

 compound is administered alone: (1) synergism or (2) additive effect. These are distin- 

 guished below specifically by statements (1) and (2), qualified by conditions expressed as 

 I and II. 



I. Action of the test compound and of the secondary compound, when administered alone, 

 are KNOWN to be the same (i. e. , their actions are known not to be opposing) and 

 intensity of action of the test compound when administered alone is KNOWN. (See 

 Figure 1. ) 



(1) Synergism (See Figure 1. ): The intensity of action, when the compounds are 



administered together, is greater than the sum of the intensities of action of the 

 two compounds when each was administered separately and in the same dose 

 quantity as when administered with the other. For this, use Symbol 8. Example: 

 Compound B, when administered alone at 100 mg/kg, caused 40% increase in a 

 normal physiological process (e. g. , blood pressure); Compound C, when adminis- 

 tered alone at 50 mg/kg, caused 10% increase in the same physiological process; 

 when administered together (100 mg/kg of Compound B and 50 mg/kg of Compound 

 C), the response intensity was 80% increase in that physiological process. This 

 being 30% greater than the sum of the intensities of the action of the two compounds 

 when administered alone, the test compound's influence is interpreted as synergism. 

 (To be a synergist, a test compound need not cause the response to any degree 

 when administered alone, though it may as suggested by the definition above and 

 the figure. ) 



Evaluation of Synergism: For this effect or influence of the test compound on the 

 action of the secondary compound, no special criterion is included in Field X. It 

 is coded only by Criterion 61 or 62 by which is expressed the per cent increase 

 of intensity of action, over the sum of the intensities of action of the two 

 compounds when administered alone. (Earlier efforts to establish a criterion for 

 synergism [correlating with the synergistic increase in intensity of response the 



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