FIELDS M and N 

 Columns 45 and 46; 

 47 and 48 



1 1 . Dosage (amount administered per unit time) to be coded when, during a test, the dose per 

 unit time is altered; discussion of coding production of "tolerance" and "sensitivity" 

 (induction of tolerance increase and sensitization ) 



If the dosage is deliberately varied so that two or more are used in sequence in a single test 

 run (i. e. , so that essentially two regimens are employed), frequently more significance can be attached 

 to one dose than to the other and that may be coded in preference to leaving Fields M and N uncoded. 

 Consider the following example: 1. ml given daily for two days followed by 0. 05 ml given daily until 

 evaluation was made two weeks after beginning of treatment. In this example, the dose given over the 

 longest period of time might be coded, though, if a large number of compounds were being tested and 

 the comparison was on the basis of the most efficacious initial dose or if the initial dose level of a 

 single compound were varied with consecutive test runs to find its most efficacious level, the initial 

 dose would be the most sensibly coded. In any case, under these circumstances of such a varied 

 dosage regimen, no evaluation of the line should be based on the entry of Field M or N. 



Because the phenomenon of an organism's developing an increased tolerance to a test compound 

 (Field T-2, Symbol 51) involves administration of two or more doses, frequently at two or more levels, 

 it will be discussed thoroughly here rather than in Field T-2. In this discussion, tolerated doses refer 

 to sub- threshold doses for any detrimental response and not just to sub-lethal doses. Unless the 

 reader is specifically interested in the coding of tolerance or sensitivity, it is suggested that the 

 remaining rather involved explanations of this division be disregarded. 



A. Tolerance increase: 



An increased tolerance may be evidenced by only the test observation that the same dose 

 level given repeatedly over a period of time elicits increasingly lower response. In this case, when 

 the test dose remains constant and the response diminishes , code Fields M and N with the single dose 

 level, Fields O and P with the administration schedule, and Fields T- 1 and T-2 with "causes increased 

 tolerance" (T- 1 1, T-2 51). The evaluation is ordinarily with Criterion 01 in Field X with Symbol in 

 Field Y, except that if the actual per cent decrease in response is reported or can be calculated, 

 Criterion 62 may be used. If the time to produce threshold decrease in response is the basis for 

 evaluation, one of the criteria basing evaluation on time values may be used. 



On the other hand, a test compound might be administered for the express purpose of deter- 

 mining the ability of the test organism to develop an increased tolerance of any degree or for determining 

 to what actual maximum level the tolerance may be increased. This is done by the technique of giving 

 a series of doses which may be uniform in size but are usually of increasing size and which may be 

 maximum tolerated doses or may be doses below the maximum tolerated level. Regardless of size of 

 the dosage series administered to bring about increased tolerance, the final determination of the in- 

 crease in tolerance is by administration of a dose larger than the original maximum tolerated dose to 

 determine if the latter has been significantly raised. When an increase in tolerance (increase in 

 resistance) is thereby in evidence, the CBCC codes, as a convention, the highest level shown to be 

 tolerated (either a new tolerated level or new maximum tolerated level), but when there is indicated 

 no increase in tolerance (no increase in resistance), Fields M and N are coded with the lowest dose 

 not tolerated. The lower dosages used to develop this tolerance increase are not coded in Fields M 

 and N, but are included in the written abstract. With this test method in which essentially the test 

 dose is increased in pursuance of a diminishing response (when the increase in tolerance is expressed 

 as the increase in dosage tolerated rather than the decrease in response to a given dosage), the criteria 

 of Field X that may be used to evaluate tolerance production to the level of tolerance indicated by the 

 dose in Fields M and N are limited and, in particular, Criteria 20 and 21 are not to be used. Criterion 

 20 (Minimum Effective Dose) is inappropriate, because the dose being coded is instead the tolerated 

 dose or the maximum tolerated dose after any tolerance increase. Criterion 21 (Maximum Tolerated 

 Dose) is inappropriate, because the CBCC prefers to define all maximum tolerated doses as applying 

 to normal test organisms (organisms with no acquired tolerance). Also, the evaluation of tolerance 

 increase should be based on the degree of elevation of tolerance to the test compound. Evaluation of 

 tolerance increase is by comparing the original maximum tolerated level (not coded) to the final toler- 

 ated level (coded), when these are known, using Criterion 18; if only one of these levels is given, 

 Criterion 01 is used, indicating either no tolerance increase by Symbol 1 of Field Y (in which case the 

 dose coded in Fields M and N is the lowest final dose to which the test organism was not tolerant) 

 or positive tolerance production by Symbol of Field Y (in which case the dose coded in Fields M 



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