II 111!! I \WOODS HOLT OCEANOGRAPHIC /WSTITUTION /\T /LABORATORY OK COLLECTION Marine Biological Laboraiory LIBRARY JUL 5 1977 Woods Hole, Mass. BiBcnAcA omm TO., / Sz11 KEY to the Biology Code of the CHEMICAL-BIOLOGICAL COORDINATION CENTER KEY to the Biology Code of the CHEMICAL-BIOLOGICAL COORDINATION CENTER A manual for the use of the symbols of the Code, for coding results, pro- cedures, and conditions of tests for biological responses to chemicals Edited by Philip G. Seitner in cooperation with George A. Livingston and Ann S. Williams // 'J* Ate* a// Publication 790K NATIONAL ACADEMY OF SCIENCES-NATIONAL RESEARCH COUNCIL Washington 25, D. C. 1960 Library of Congress Catalog Number 60-60056 CONTENTS Page FOREWORD 1 FIELDS OF THE CODE; DESCRIPTIONS AND DIRECTIONS FOR THE USE OF SYMBOLS OF EACH FIELD IN CODING CHEMICAL- BIOLOGICAL INFORMATION. Field A: Physical State of the Test Compound; Dispersion or Non- dispersion of the Test Compound; Indication that In- formation on Correlation of Chemical Structure and Biological Response Occurs in the Information Source 3 Field B: Conditioning Agent; Miscellaneous Information about the Test Compound Administration; Indication that in the Data Source there is Information on the Effect of pH on the Chemical Action 7 Field C: Solvent or Vehicle for the Test Compound 10 Field D: Secondary Compound 12 Field E: Organism or Pathological Condition Treated General Discussion 18 Taxonomy Code; Coding of Taxonomic Categories to Derive Field E Code Symbols for Organisms 25 Tumor Code; Classification of Tumors and Derivation of Field E Code Symbols for Distinguishing /Identifying Tumors 31 Pathology Code Introduction 38 Derivation of Code Symbols for Pathologies, Information Coded in Field E about Specific Non-infectious Pathology 40 Field F: Sex and Stage of Development of the Test Organism; Miscellaneous Information Concerning Tumors 45 Fields G-l and G-2: Pretreatment or Experimental State of the Test Organism or of the Organ, Tissue, or Cell of the Test Organism 48 Fields H-l and H-2: Gross Anatomy; Primary Anatomical Structures and Secondary Anatomical Structures 58 Field I: Tissues, Cells, and Fluids 66 Field J: Host Organism; Test Environment 68 Field K: Sex and Stage of Development of the Host Organism 7 5 Field L: Pretreatment or Experimental State of the Host Organism or of the Organ, Tissue, or Cell (of the Host Organism) which is the Site of the Parasite, Non-infectious Pathology, or Tumor 76 Fields M and N: Dosage; Concentration of the Test Compound and Quantity of the Test Compound 82 Field O: Dosage Frequency; Sequence of Administration of the Secondary Compound and the Test Compound 95 Page Field P: Duration of Treatment; Time between Administration of the Test Compound and a Secondary Compound 99 Field Q: Size of Inoculum or Implant 103 Field R: Time of Treatment Relative to Inoculation, Tumor Implantation, Sensitization, or Incitation of Non-infectious Pathology 105 Field S: Route and Manner of Administration of the Inoculum or Implant (Field S-l), of the Secondary Compound (Field S-2), and of the Test Compound (Field S-3) 108 Field T: Effect of the Test Compound; General Introduction and Discussion 113 Field T-l: Action of the Test Compound on the Biological State, Quality, or Process Coded in Field T-2 114 Field T-2: Biological State, Quality, or Process Acted on or Produced by the Test Compound or Secondary Compound 133 Field T-3: Category of the Test Compound's Effect, Representing Practical Use 155 Field U: Miscellaneous Time Values: Duration of Response to the Test Compound; Alteration of the Survival Time by the Test Com- pound; Time to Any Response to the Test Compound other than Death; Killing Time of the Test Compound; and Persistence of Activity of a Residue of the Test Compound 1 58 Field V: Time to Evaluation of the Response to the Test Compound 168 Fields W, X, and Y: Criterion for Evaluation (Field X); Evaluation: Negative Response or Degree of Positive Response at the Coded Dosage (Field Y), and Qualification of the Negative and Positive Character of Test Results (Field W) 17 1 - tv - FOREWORD This manual has been prepared as a guide to the use of symbols of the CBCC Biology Code for coding information about tests for biological responses to chemicals. It is also a description and ex- planation for each of the Code's parts. The Key and Code must be regarded as a single unit. Their composition reflects the assumption that one volume will always be accompanied by the other. The development and use of the Biology Code is discussed, against the background of the history, objectives, and procedures of the Chemical-Biological Coordination Center, in the Introduction and Appendix included with the Code. In that Introduction, the Key is described and the need for it is ex- plained. In the Foreword to the Code, the definition of a field and the divisions of the Code into fields are explained; the major divisions of the Key follow those of the Code. The frequency of cross references in the Key has demanded a standard nomenclature for its parts. In each field, the three major parts are referred to as sections ; the sections, particularly the Specific Directions and Explanations Section of each field's description, are organized into numbered divisions , under some of which it has been convenient to make lettered sub-divisions . The first section of each field describes such things as (1) the extent of the area of the field, in terms of the number of IBM punched card columns used, (2) the classification scheme of the items of the field, (3) the way symbols have been assigned or constructed according to the classification of the items, and (4) the number of items, of the particular category represented by the field, needed by the CBCC. The second section of each field's discussion, General Use, describes briefly the nature of the items classified and coded in the field and the relationship of the field to all other fields relative to coding, as a whole, information from chemical-biological tests. The final section is devoted to more specific details of directions and cautions for use of the code symbols and to explanations for coding patterns. In each field, the final divisions of this section indicate briefly what symbols are available for expansion of the field, whether the CBCC has established a special file of IBM punched cards arranged according to entries in the field, and whether more than a single code entry can be made in any of the code boxes of the Code Sheet (and consequently, whether only one or two or more separate symbols having distinct meanings can be punched in the same column of a single IBM punched card). With regard to the structure of symbols, it will be discovered that within any given field, the code symbols are constructed according to a special pattern appropriate to the classification of the items of the field. Making the code symbols for the field actually represents a coding process for the items of that particular field, preliminary to and separate from the ultimate process of coding chemical- biological data using those previously prepared symbols. This process can be visualized as restricted to coding information about each item within a given field according to appropriate identifying criteria or indexes. In certain fields, the complexity and number of the items are such that this preliminary coding process, resulting in symbols for the field, demands special attention and considerable expla- nation. For example, in Field E, symbols for test organisms are constructed to carry specification of the phylum, class, order, family, and genus to which each species belongs. Likewise, in Field H, the symbols reflect the major system to which each specific organ of this list belongs. Any and all explanations for this process are part of that first Key section for each field. Attention is called to Field E of the Code ; it is seen to be composed of three separate parts for the three separate categories which can be coded in the Field. The three categories are (1) test organisms, (2) tumors, and (3) pathologies, one or the other of which represents the biological system treated (for the coding of which Field E is intended) in every chemical-biological test. Thus, Field E is made up of the Taxonomy (Test Organism) Code, Tumor Code, and Pathology Code. In the Key , separate sections have been appended for each of the Taxonomy Code, Tumor Code, and Pathology Code, explaining the information coded into the symbol for each organism, the symbol for each tumor, and the symbol for each pathology. These three sections are actually comparable to the initial (Organization) section of other fields; at the beginning of the General Discussion of Field E, the brief Organization section functions primarily to refer to the three later sections that substitute for it. In the General Discussion of Field E, prior to the three special sections just described, the section on Specific Directions and Explanations is also divided exceptionally into five "Parts" for considering separately five subcategories of the major category of information represented in Field E. Fields G-l and G-2 have been discussed in the Key as a unit, since the same general type of information is coded in both fields and symbols used for coding in both fields are from the identical list in the Code. Distinguishing the uses of the two fields is also facilitated by discussing the two together. For the same reason, Fields H-l and H-2 are described as a unit, as well as Fields S-l, S-2, and S-3. Discussing Fields M and N as a unit is not due to their having an identical list of code symbols, but due to both fields being concerned with a similar type of information. The uses of the two fields can be distinguished more easily by considering them together. For the same reason, the descriptions of Fields W, X, and Y are presented essentially as a unit, though, like Fields M and N, each of Fields W, X, and Y has a different set of items and symbols in the Code. Each of Fields T-l, T-2, and T-3 is discussed individually, even though all three deal generally with only a single category of information. Nevertheless, it has been convenient to introduce these three fields by a separate discussion of Field T, embodying explanation of the general objective shared by the three fields and general distinction in their use. In all symbols of the Code to which reference is made in the Key, the capital letter O is indi- cated by the special symbol "0" to give it obvious distinction from the numerical zero. For convenience, the term "double coding" has been used in the Key and Code with a limited definition; therefore, two symbols being entered in one column in one code line does not necessarily represent "double coding". The definition assigned to the term hinges on the evaluation of test results, ordinarily of two or more tests; in these tests, some condition of the test method differs (ordinarily, only one condition is involved), yet the test results are so nearly the same that the code evaluation of the biological response in both or all tests is by the identical symbol in Field Y. Both or all of such tests might be coded by a single code line in which the field coding the variable test condition (e. g. , dose size, inoculum size, or route of administration) would have "double coded" the symbols for both or all of the variations of that condition (e. g. , the range of doses or the various inoculum sizes or the various administration routes [Field M, Q, or S], giving test result evaluations indistinguishable by code in Field Y). Thus, "double coding" refers to the use of two symbols in one column representing variation in a single category of information. In certain fields, symbols are provided for two different categories of information (e.g. , Fields A, B, F, G, O, W) and, in these fields, the symbols of one information catetory (Symbol of Field A, e. g. ) can be entered in the same column of the same code line as symbols of the other category (symbols other than Symbol of Field A, e.g. ), whenever information of both categories is available for the test. These two entries in a single column, however, do not represent "double coding", as defined above. In either case ("double coding" of the same category of information from two or more tests or the use of two or more symbols for two different categories of information in one test), the multiple coding of the column is punched on the same IBM card in that column. However, fields for which the CBCC has established separate IBM punched card files ("filing fields", Fields D, E. H, I, J, T-2, and T-3) are never "double coded". Even if this were permitted, instructions would be given to punch two IBM cards, identical except in the field double coded on the Code Sheet. The reason for this is simply that a card is needed for each entry in one of these fields, in order to have the entry filed in the proper category. The free use of underscoring in the Key perhaps needs some clarification. For some readers the underscoring may be distracting, but in general, the emphasis placed on a given word or phrase by an underscore has seemed to assist far more than to deter in extracting the intended meaning from explanations which have been sometimes difficult and necessarily complex. - 2 - FIELD A Column 9 (1) PHYSICAL STATE OF THE TEST COMPOUND (2) INDICATION OF DIRECT, MASS APPLICATION VS. REMOTE, PARTICULATE APPLICATION (I. E , DISPERSION VS. APPLICATION OF THE UNDISPERSED COMPOUND) 1 (3) INDICATION THAT INFORMATION ON CORRELATION OF ACTIVITY AND CHEMICAL STRUCTURES OCCURS IN THE DATA SOURCE Organization Organization of Field A is based on seven major items, represented by Symbols 1, 2, 3, 4, 5, 6, and 7. (Consult the Code for definitions of these symbols. ) Each of these seven symbols is modi- fied by IBM zone punches to form related symbols for indicating dispersion . (See the explanation of the IBM card in the Appendix for the definition of zone punches. ) For example, Symbol 2 (one punch only, in the 2 position on the IBM card) codes a liquid, pure compound, applied undispersed ; Symbol B (two punches on the IBM card in Column 9: one in the 2 position and one in the 12 zone punch) codes a liquid, pure compound, applied as a spray ; Symbol K (two punches in Column 9: one in the 2 position and one in the 11 zone punch) codes a liquid, pure compound, applied as a mist or aerosol. Thus, one punch is provided (in the 2 position) common to all three of these code units so that if in a file it were important to be able to sort out all liquid, pure compounds, it might be done with a single sort on that common punch. General Use In Field A is coded the state of the test compound at the time of its introduction to the biological component or components; this is consistent with the coding of all other fields dealing with the appli- cation of the chemical (Fields B, C, M, N, O, P, and S-3) in which application is also described in terms of the conditions existing at the time of application to the organism to which direct application is made, whether it is the host organism or the test organism. Ordinarily, the presence of a host coded in Field J implies application being made directly to that host; therefore, all coding of conditions of application refers to that direct application to that host and no coding implication is made as to the condition of the test compound when it reaches the test organism. (Only two exceptions are made. When, for clarity of a coded statement, there is coded in Field J an inanimate, liquid [or semi- liquid] environment as a host [in essence, a solvent or vehicle] in which the test compound is dispersed, coding of application, in Fields A, B, C, M, N, O, P, and S-3, describes application to the test organism . The second exception is described in Division 3 of the Specific Directions and Explanations below. ) The dispersing of a compound in applying it may appear to be a manner of application, the coding of which has been assigned to Field S-3. However, distinction between the second use of Field A (indicating whether the compound is applied dispersed or undispersed) and the use of Field S-3 can be understood by examination of the two fields. Field A is concerned with describing the compound that is being administered and is particularly concerned with the condition of that compound when introduced to the animal or plant. Coding the compound's being mechanically dispersed as a spray or aerosol is as much a description of its condition as is the coding of its being a liquid or a solid or dissolved, etc. "Dispersion" is used here to mean scattering the test material by use of a sprayer, atomizer, duster, aerosol; "dispersion" is NOT used in Field A definitions of the Code to describe mechanical spreading or smearing of the test material over the surface of--or diffusing through the substance of- -a test organism or host. An examination of the Code terms will clarify this. 3 - FIELD A Column 9 Field S-3, on the other hand, has as its objective the description of the route of the test compound to or into the animal or plant, regardless of the condition of the compound. It is true that certain routes would not be practical for all states in which the compound might be; nevertheless, the use of Field S excludes any actual description of the condition of the compound- -except by implication in specifying the route (e. g. , specifying in Field S "fumigation" or "inhalation" which implies appli- cation of a compound as a mist or aerosol, but which makes no pretense at actually expressing by code that condition of the compound). This is discussed also in Division 4 of the Specific Ejections and Explanations for Field S-3. The third distinct use of Field A is discussed in Division 8 below. It is a means of retrieving from the file of coded data those Biology Code Sheets containing literature (or other) references in which the author has made observations on correlation of chemical structures and biological response to those chemicals. The observations themselves are not coded nor are the details included in the Code Sheet's written abstract of Field A; there is merely the coded indication in Field A that the infor- mation can be found in the reference. In the written abstract portion of Field A, only a brief synopsis is made of the specific correlations the author discusses in the article. Specific Directions and Explanations 1. Coding in Field A when the test compound is applied to the test organism When the test compound is applied directly to the test organism in Field E (and when there is no host coded in Field J), use the code symbol best describing the state of the test compound at the time of application to the test organism. 2. Coding in Field A when the test compound is applied to the host organism When the test compound is applied directly to the host ORGANISM (Field J) in or on which is located the test organism (Field E), use the code symbol best describing the state of the test compound at the time of application to the host. (See Division 5 for an exception, related to NON- LIVING hosts. ) 3. Coding in Field A when the test compound is applied DIRECTLY to the test organism , even when it is on or in a host When the test compound is applied directly to the test organism (Field E) on or in a host (Field J) (e. g. , applied by dropping it on a tick attached to a dog or injecting it into a tapeworm cyst in a rabbit), use the code symbol best describing the state of the test compound at the time of appli- cation to the test organism. 4. Coding in Field A when the test compound is applied to a host prior to inoculation with the test organism When the test compound is applied to a host (or environment), coded in Field J, prior to the introduction of the test organism , use the term which describes the state at the time of application to the host, regardless of the state at the time the test organism is introduced. (See the following division for an exception. ) 5. Coding in Field A when the test compound is applied to a non-living host The provisions for application to hosts (Divisions 2 and 4 above) have as an exception the situation in which the test organism is added to water , saline , or nutrient media , for example (i. e. , inanimate, liquid or semi-liquid hosts or host environments coded in Field J), in which the pure test compound (liquid, gas, or solid) has been dispersed in amounts to bring it to the test concentration as coded in Fields M and N (by dissolution, emulsification, suspension, or mechanical mixing). In this case, the host coded in Field J is the solvent or vehicle which is under other circumstances always coded in Field C; the CBCC has not coded Field C in such instances--not necessarily because it would represent coding duplication with Field J, but because many of the specific materials such as culture media have not been included as items of Field C. Field C could be coded, if this host in Field J happens to be also one of the specific items of Field C. Since coding Field A with liquid, gas, or 4 - FIELD A Column 9 solid (the state prior to introduction into the water, saline, etc. ) would not serve any useful purpose in this situation, this field should be coded with the state of the compound in the host water or nutrient (i. e. , the state as applied to the test organism) rather than with the state when added to those hosts. 6. Coding in Field A when the test compound has been applied to a surface as a residue Occasionally, a test compound is introduced onto a surface (or in a cloth, filter paper, etc. ) in an organic solvent, for example, which is subsequently allowed to evaporate, leaving the test compound as a residue. (I) If the technique dictates that the test organism is then exposed to the residue, Field A is correctly coded with the state when applied to the surface, according to Division 4 above. (II) However, if this treated surface (e. g. , an aquarium inner surface, microscope depression slide, Petri dish, a filter paper disc, etc. ) is then immersed in water, for a test with aquatic organisms, "water" is to be coded in Field J, nothing need be coded in Field C, and Field A is to be coded only if it is known or stated that the compound is completely soluble in water; otherwise, Field A will be left uncoded. 7. Coding in Field A when the test compound is a gas If the test compound is administered as a gas and its concentration is expressed by the author only in terms of this gas (e. g. , per cent test gas in N, O z , or air) which is subsequently streamed through (1) a bath or perfusate of an organ, tissue, or immersed organism, or (2) a suspending medium of a tissue macerate or an enzyme-containing secretion (e. g. , milk), the concentration of the test compound in the gas will be coded in Field M. Therefore, in this case, Field A must be coded with "gas", Symbol 1, and Field C need not be coded, since the suspending solvent is implied in coding the preparation as a homogenate (Field G) or secretion (Field I) or in coding the diluent of the homog- enate (Field J). Note, however, that if the author should actually have determined the dissolved con- centration of the test compound, coding in Fields M and C should be based on that concentration and solvent and Field A should be coded with "solution", Symbol 4. 8. Indication of information on correlation between chemical structure and biological activity The Symbol is used (either alone or with one of the symbols for physical state) to indicate that the article contains information on correlation of chemical structure and biological response. The information may deal only with the compound under test or with a series of which the test compound is a part. When an article contains information about the relationship of chemical structure to a certain biological effect, Symbol should be coded in Field A in each code line which describes that effect (Field T) for all the compounds whose chemical structure is discussed. Symbol should not be coded in lines for other actions which happen to be in the article but for which the relationship to chemical structure is not discussed. When using Symbol 0, it is necessary to give some idea, in the language portion of the code line, of the information contained in the article. Do not write merely, "structure-activity"; write (e. g. ), "activity of q, (3, y isomers studied" or "effect of methyl, propyl groups studied". 9. The nature of items 2, B, K, 3, and C Note that Symbols 2, B, K, 3, and C refer to undiluted compounds. 10. Symbols available for additional items of Field A The following symbols have not been used and are available for items of Field A: 8, 9, H, I, J, L, P, 0, and R. Symbols S through Z are not available, because the IBM zone punch has been used as a special symbol. If the available symbols are used to conform to the established organization of the field, Symbol J should be used for a gaseous state as are Symbols 1 and A; Symbol L should be used for a state of an undiluted solid compound as are Symbols 3 and C; and Symbol P should be used for a suspension-in-a-solid state as are Symbols 7 and G. The six remaining symbols can form two new groups: (1) 8, H, and Q and (2) 9, I, and R. 5 - FIELD A Column 9 1 1. File of coded biology data on IBM punched cards arranged according to symbols for states of chemical compounds The CBCC has established no separate file of coded biology data on IBM punched cards arranged by Field A entries. 12. Double coding in Field A If several tests are run, with the only difference in the tests being the state of the test compound, and the results are so similar that all the tests would be coded identically in every coding field except Field A, the tests are NOT to be all combined into a single code line with all the states used coded (i. e. , double coded) in Field A. The CBCC has refrained from this partly because the double punching of letter symbols and numerical symbols (both of which are in Field A) is not possible (though actually any of Symbols 1-9 could be double coded) and partly because the state is so intimately associated with solvents, carriers, and conditioning agents (i. e. , Fields B and C) that it is improbable that the difference in such tests would involve only Field A, but would also involve Fields B and C. The mechan- ics of double coding all of Fields A, B, and C, therefore, represents more confusion and difficulty than would be justified for those particular coding fields. For these reasons, the CBCC prefers to simplify coding procedure by the policy of never double coding in Field A, even if it makes necessary coding two or more lines for tests identical in results and procedure except for the state of the compound. (Field A can have two entries in the special case of using Symbol with a symbol for the state of the compound, but this does not represent double coding as it is described above. If Symbol is used with another symbol in Column 9, both symbols are punched in that column on a single IBM card). 6 - FIELD B Column 10 (1) CONDITIONING AGENT (2) MISCELLANEOUS INFORMATION ABOUT THE TEST COMPOUND ADMINISTRATION (3) INDICATION THAT IN THE DATA SOURCE THERE IS INFORMATION ON THE EFFECT OF pH ON THE CHEMICAL ACTION General Use This field is principally for recording the presence of inert materials which are administered, with the test compound and its solvent or vehicle , for providing increased viscosity, facilitating emulsification or spreading, etc. In general, when a material regarded as an inert conditioning agent is administered with the test compound, it is adequate merely to code the fact of its presence, rather than attempt to assign code symbols to each agent or to each type of agent. Symbol 1 is used for this purpose. However, symbols have been given to a number of specific materials used very frequently for changing viscosity or imparting physical stability of a preparation. Note that in this field, coding of agar or gelatin, for example, is not a record of any use of the materials as biological culture media ingredients, but describes exclusively their use in conditioning test compound preparations . Field B h3S afforded space for making a coded record of certain information relevant to the conditions of administration, which may affect the interpretation of the coded line (e. g. , administration of mixtures or precursors). Finally, a symbol has been provided to permit recovery of all references with information on specific effects of pH on biological responses. Specific Directions and Explanations 1. Information about influence of pH on the test compound's action on the test organism Symbol 9 in Field B is used to indicate that the article from which the data were taken contains information on the effect of pH on the effect of the test compound coded in Fields T- 1 and T-2. 2. Use of Symbol 7; administration of the test compound as its precursor Symbol 7 should be used only when it has been demonstrated that the predecessor of the test compound j_s converted to the test compound and does not itself affect the action coded in Fields T- 1 and T-2. Under the conditions when Symbol 7 can be used, a separate Code Sheet is always made for the administered compound, on which Field B is not coded with Symbol 7, recording the administered compound's conversion (Symbol Series FE--, Field T-2). Unless definite evidence is given by the author that the administered compound is inactive (relative to the action coded in Fields T- 1 and T-2) and that its conversion product is active, that conversion product can not be coded as a test compound with Symbol 7 in Field B. When such evidence is lacking or even if it is well known by the coder but not so described by the author, the action must be coded only as being that of the compound adminis- tered (i. e. , as being the result of administering that compound). The symbol is useful mostly in coding distribution studies (Symbol Series F9-- and FA--, e. g. , of Field T-2) when the compound deposited and measured is shown to be a derivative of the compound administered and concentration is expressed in terms of the derivative. Example: Penicillin is more highly concentrated in lung tissue when introduced as Leocillin (from which penicillin is biologically derived by degradation) than when penicillin is itself administered. To record that penicillin is deposited in greatest - 7 - HELD B Column 10 amounts when administered as a given dose of Leocillin, penicillin is treated by the coder as the test compound and Field B is coded with Symbol 7 to record that the compound was administered as a dose of a precursor (Leocillin), coded in Fields M or N. On a separate code sheet for Leocillin, the conversion of this compound to penicillin is coded. 3. Formulations Symbol 6 is a provision for coding the fact that the test compound is administered as an ingre- dient of a formulation. A formulation is defined as a product containing a given proportion of the test compound, the remaining ingredients being disregarded and presumably inert. Symbol 6 accommodates only cases in which the action is attributed to a single ingredient. The coded dose of such a formu- lation should be the calculated amount of the test compound. When the author specifically states that he is administering mixtures of two or more compounds, any of which is being tested as an antagonist, synergist, or simulant for any one of the others, none of the compounds is to be coded except by the procedure described in Division 5 below. The percentage of the test compound in the formulation administered or the percentage purity (which percentage values have been used in calculating the dose coded in Fields M and N) should be given in the written abstract portion of Field B with the name of the formulation, if given by the author. Do not place the formulation name or the per cent purity on the chemistry side of the Code Sheet; place there only the test compound name. The CBCC policy has been to admit few data from tests using formulations. 4. Mixtures Symbol is provided to allow, when it is so desired, the coding of data from tests in which a mixture of compounds is administered, the results of the test not being attributable to any one compound of the mixture. In such a case, the mixture is not assigned a unique Chemical Serial Number; instead, the data are recorded first on a Code Sheet for one of the compounds, with Symbol coded in Field B. Unless there is reason to do otherwise, the line must be duplicated on separate Sheets for each compound of the mixture. In coding test compound mixtures, the dose coded is expressed in terms of the total mixture. In selecting chemical-biological test data, the CBCC has seldom elected to include data from tests of chemical mixtures. Mixtures, as discussed here, exclude cases in which there are given data for each of the mixture's compounds tested separately so that the results can be interpreted in terms of synergism, antagonism, or additive effects. 5. Symbols available for additional items of Field B Symbol 8 and all letter symbols, with the exception of letters F, G, I, 0, P, R, and S through Z may be used for additional items of Field B. (Letters S-Z are unavailable by having used the IBM zone punch as a symbol and the other six letters are unavailable because Symbols 6, 7, and 9 can be double punched with any one of Symbols 1, 2, 3, 4, 5, and 9). 6. File of coded biology data arranged according to symbols for conditioning agents No separate file of coded biology data on IBM punched cards, arranged by Field B entries, is maintained by the CBCC. 7. Double coding in Field B, as distinguished from coding of two types of information in Field B in the same line The CBCC has not double-coded two or more conditioning agents used in separate test runs, for the same general reasons as given for not double-coding two or more states of the test compound in Field A. (See the last division of the Specific Directions and Explanations section for Field A. ) Note that the definitions of "formulation" and "mixture of compounds" do not include the mixture of isomeric forms of a compound; the latter would be regarded chemically as a single compound for coding purposes. - 8 FIELD B Column 10 Any of Symbols 9, 6, 7, or 0, each of which codes unique information o ther than conditioning agents, can be coded in the same code line (and punched on the same IBM card) with any of the code symbols for conditioning agents (Symbols 1, 2, 3, 4, and 5). FIELD C Column 1 1 SOLVENT OR VEHICLE Organization The items of Field C are solvents and vehicles which have been encountered during the period of CBCC coding. The list has been found generally adequate, but there remain 11 symbols (exclusive of zone punches which may be used alone) available for additions. For this edition, the solvents have been arranged by alphabetical sequence. Only liquids (or solids such as fats, with melting points fairly close to room temperature) have been included in Field C. Solids (charcoal, Bentonite, talcum, solid foods, etc. ) are considered merely "fillers", are assumed to be inert, and are not materials that can "carry" the test compound to or into the test organism in the same sense that liquid materials are "carriers". The fact that the test compound may be diluted by a solid "filler" is indicated by appropriate coding in Field A rather than Field C and in the written abstract of the Code Sheet. General Use Solvents or vehicles are expressed in Field C. The purpose of the field is not primarily to record the solubility property of the test compound (which information is more appropriate on the chemistry records), but to record the material in which the compound is distributed. By virtue of being the material "carrying" the test compound to or into the test organism, the solvent or vehicle used and its relative efficiency may be most significant in the outcome of a test. Specific Directions and Explanations 1. The test compound in a non-living host or host environment coded in Field J When the test compound is dissolved or suspended in a culture medium or solution coded in Field J as the test environment, it is not necessary to code anything in Field C. As a result of such applications to the habitat or culture medium coded in Field J, the test compound diffuses through the host and reaches the test organism in a lower concentration than that applied to the host. If the concentration after such dilution is known , that is preferably the dosage coded in Fields M and N. For coding of this dosage and Field C, consult Fields M and N, Specific Directions and Explanations section, Division 7. 2. Solvent MIXTURES; solvents and VEHICLES; STOCK SOLUTION solvents; solvents EVAPORATED to leave residues of the test compound If more than one solvent is present (e. g. , 95% alcohol and 5% water or 75% acetone and 25% alcohol), one of the following procedures is used: (a) When solvent mixtures are present, do not attempt to code any specific solvent. Code "mixture", Symbol A (b) When both a solvent and a vehicle occur (as in emulsions, in which a compound is dis- solved in a solvent which is emulsified in the vehicle), code the continuous phase, i. e. , the vehicle (the substance that "carries" the compound and its solvent to or into the test organism), in Field C. The actual solvent of the test compound is to be recorded in the written abstract portion of Field C. (c) Compounds are frequently dissolved in alcohol, acetone, or other solvent to provide a stock solution from which a given dilution is made with water, particularly in tests with aquatic organisms (fish, snails, etc. ). In such cases, the aqueous diluent is coded in Field C, with Symbol R. - 10 - FIELD C Column 1 1 (d) When a test compound, dissolved or suspended in water or any other solvent, is applied to a surface which is subsequently dried to give a test compound residue, followed by submergence of the surface in water for exposure of aquatic organisms (in which case "water" would be the host coded in Field J), Field C is not coded. See Division 5 of Specific Directions and Explanations for Field A for this coding procedure. 3. Symbol 1 may be used to indicate NON- NEUTRALITY (pH acidic or basic) of an AQUEOUS solvent The acidic and basic solutions included in the definition for Symbol 1 refer ONLY to aqueous solutions. The symbol is not intended for unadulterated acids or bases as solvents (e. g. , lactic acid). 4. Symbols available for additional items of Field C Symbols 8, C, D, E, F, J, L, V, X, Y, and Z are available for additional items for Field C. 5. File of coded biology data on IBM punched cards arranged according to symbols for solvents The CBCC has established no separate file of biology data arranged by Field C entries. 6. Double coding in Field C When experiments, performed with a given test compound, are repeated using different solvents and the results differ in a degree that can be distinguished by code in the evaluation fields or in the action fields, separate lines should be coded to record the influence of the solvent. If the results are so nearly alike that they can not be distinguished by code in Field Y, only a single line, with a single solvent coded in Field C, should be constructed, with the remaining data of the other tests entered in the written abstract (i. e. , Field C should not be double coded). 11 FIELD D Columns 12, 13, 14, 15, 16, and 17 SECONDARY COMPOUND Organization In this field, six IBM punched card columns are provided for entering the Serial Number of a chemical compound. The basic CBCC Chemical Serial Number consists of six units (six letters or numbers); however, there is in addition a 2- unit system for designation of salts and radioactivity. Since there is not sufficient space in this 6-column secondary compound field for entering the two final units indicating a salt or specific radioactivity, the latter information, when known, must be included in the written abstract portion of the field. In the following descriptions, "coding" a secondary compound in Field D refers to the use of the compound's Serial Number as a code symbol, not to the structural coding which is found only in the Chemistry Files. General Use Field D is used for coding a compound other than the test compound (i. e. , it is for coding a "secondary" compound). Coding a compound in Field D is restricted to instances when any of certain specific relation- ships exist between the action of a test compound and another (a "secondary") compound. These circumstances under which Field D is coded are indicated in the definitions of the code symbols of other fields; therefore, Field D is never coded unless there are specific directions, with the code symbol of some other field , to code a compound in Field D. The four general uses of Field D are listed at the end of this section. In a case when it is appropriate to use Field D, the name of the compound and the structural formula are written on the Code Sheet, in the written abstract portion of the field. It is essential to indicate all double bonds, group positions, etc. , in full. Do not use abbreviations, such as PABA for para-aminobenzoic acid, if the full name is given in the paper. The coding of the compound requires that the coder have access to the CBCC Chemistry Index Card File arranged alphabetically by name; on each card of this file is the basic six-unit CBCC Serial Number assigned to the compound represented on the card. If this file is not available to the coder, Field D must be left uncoded and the code boxes left open for filling in by someone who does have access to the Chemistry Index Card File. In this case, however, the coder must always have completed the written abstract for the field as well as any of the three special code designations in Column 16 or 17, when the latter are appropriate. (See Divisions 3, 4, 5, 10A, and 10B, in the following section, Specific Directions and Explanations, relative to these special symbols. ) Field D is used to express: 1. A compound whose action is synergized or potentiated (Field T-l, 8); antagonized, neutralized, or antidoted (Field T- 1, 9); simulated or replaced (Field T-l, A) by the test compound; or additive with the test compound (Field T- 1, C). 2. A compound, naturally occurring or administered, whose uptake (Field T-2, F6--), synthesis (Field T-2, F8--), distribution (Field T-2, F9--), storage or concentration (Field T-2, FA--), absorption (Field T-2, FB--), excretion (Field T-2, FC--), ability to permeate (Field T-2, FG--), incorporation (Field T-2, FH--), withdrawal (Field T-2, FI--), alteration (Field T-2, FE--), or elimination (Field T-2, FF--) is affected by the test compound. 3. A compound which serves as a standard for comparison with the test compound (Field X, Criterion 03 or 04). (This use of the field is distinguished by coding an asterisk in Column 17. ) 12 - FIELD D Columns 12, 13, 14, 15, 16, and 17 A compound to which cross tolerance or cross tachyphylaxis, is produced by administration of the test compound. (See Symbols 514 and 5131 in Field T-2. ) Specific Directions and Explanations 1. Use of Field D is determined and directed by other fields of the Code As explained above, under "General Use", Field D is coded only when the definition of a symbol in another field of the Code specifically directs the coder to do so; these specific uses of Field D are described in subsequent divisions. 2. Field D can never have more than one compound coded in any one line Double coding (i. e. , coding two compounds) in Field D is never permitted, because it is impossible to designate, in any way that will distinguish them, more than a single compound in a given field on an IBM punched card. Therefore, in a situation where two (or more) secondary compounds, each administered with the test compound in independent tests, are found to have their actions affected by the test compound to so nearly the same degree that the coding of the data would be identical for both of the compounds (except for coding in Field D), Field D can not be double coded with all of the secondary compounds to condense the data into a single line. A separate line must be coded for each secondary compound, even though the code lines are identical except for Field D. 3. Two or more secondary compounds, all essential and all administered together; Symbol ff in Column 16 Occasionally, data are encountered in which the test compound is tested for an effect on the action of two or more essential secondary compounds administered together , (i. e. , the action of the secondary compounds would not occur if one of them were absent) rather than on the action of a single secondary compound. (Note that this does not refer to mere mixtures of secondary compounds, any one compound of which may produce the action; mixtures are seldom, if ever, coded in Field D by the CBCC. ) In this situation, the two or more secondary compounds are all essential components of a single test (in contrast to the situation described in Division 2 above, where the two or more secondary compounds bear relationship to the action of the test compound through independent tests). Since Field D can be coded with but a single chemical and since it is important that there be coded all of those secondary compounds that produce together the action affected by the test compound, A CODE LINE IS PREPARED FOR EACH MEMBER OF THE SECONDARY COMPOUND COMBINATION, all the lines being identical except for Field D. As a means of relating these lines and indicating by code the situation just described, SYMBOL # IS PLACED IN COLUMN 16 of each of these related lines; Symbol # is used in Column 16 ONLY in coding this situation. Place this symbol at the top of the code box so that room is left in the box for the entry of the fifth unit of the compound's symbol. 4. Standard of comparison coded as a secondary compound; Symbol * in Column 17 To designate that a compound is used as a standard for comparison in evaluating the test compound action, place Symbol * in Column 17. Place this asterisk at the top of the code box so that room is left for the entry of the sixth unit of the compound's symbol in the box. The presence of an asterisk in this column indicates that the secondary compound is known to produce the action coded in Field T-2 when tested alone and the degree of action of the test compound is evaluated by compar- ison to the known degree of action of the secondary compound; it distinguishes this use of Field D from the other uses of the field. 5. Radioactivity of the secondary compound; Symbol * in Column 16 To designate that the secondary compound is radioactive , enter Symbol * in Column 16. Place this symbol at the top of the code box so that room is left for the entry of the fifth unit of the compound's symbol in the box. Note that the asterisk in Column 16 merely gives added information about a special property of the secondary compound. It does not affect the interpretation that the test compound alters - 13 - FIELD D Columns 12, 13, 14, 15, 16, and 17 the action, coded in Field T-2, produced by the secondary compound; i. e. , it does not signify a special use for Field D as does an asterisk in Column 17 (see Division 4). 6. Data from tests using secondary compounds of uncertain identity are coded only exceptionally Test data involving secondary compounds that are ill- defined have not ordinarily been selected for inclusion in the CBCC files, just as data involving test compounds of uncertain identity have seldom been selected. For example, data involving materials such as natural or synthetic mixtures, extracts, vaccines, etc. have seldom been coded. Occasionally, exceptions have been made and such data are coded, necessitating classifying and assigning a CBCC designation to the material coded as a secondary compound. Materials known to be discrete chemicals have more frequently been given CBCC Serial Numbers than have extracts, vaccines, natural product mixtures, etc. , even though the lack of knowledge of their structures makes their processing irregular. In Field D, coding of materials of uncertain identity must be, for each case, the result of special deliberation and a decision, in order to bestow on that material recognition as a distinct chemistry file entry with a unique reference number. 7. Enzymes are NOT CODED IN FIELD D as secondary compounds when their BIOLOGICAL ACTIONS are affected by test compounds; however, if their metabolic fate is affected by the test compound, as indicated in Field T-2, they can be coded as secondary compounds in Field D The coding of a test compound's effect on the activity of an enzyme deviates slightly from the usual procedure of coding in Field D the compound whose activity is affected by the test compound. It will be noted that the Code provides for enzymes being coded in Field T-2, symbol series 7 — ; therefore, the purpose that would be served by placing this "secondary" compound, the enzyme, in Field D is satisfied by the entry in Field T-2 and placing it in Field D as well as in Field T-2 would be not only unnecessary but confusing to the interpretation of the code line. Therefore, when a test compound (1) has an effect on the action of an enzyme (e. g. , inhibits or enhances an enzyme's action ) or (2) has an effect on the action of a secondary compound which in turn affects an enzyme action (e. g. , antagonizes, synergizes, or simulates the secondary compound's action on an enzyme action ) or (3) is a coenzyme for an enzyme action , the enzyme is always coded in Field T-2 and never in Field D, even though it is in a sense a secondary compound. In contrast to this, when there is not being coded the test compound's effect on an enzyme action , but the test compound's effect on an enzyme's synthesis, destruction, excretion, etc. (Field T-2, Symbols F8--, FE--, FF--, etc. ), the enzyme is written and its CBCC serial number (not its Field T-2 symbol) is coded in Field D. The SUBSTRATE of an enzyme affected by a test compound is never to be considered as a secondary compound and is never coded in Field D. 8. A carcinogen that produced a tumor being treated is not a secondary compound In the case of coding the action of a test compound (which is not being tested as a carcinogen) on a tumor which was induced by a carcinogen, the carcinogen is not to be considered as a secondary compound and is therefore not to be coded in Field D. The description, origin, or source of the tumor is coded by Symbols S through Z in Field F. 9. The action of the secondary compound can not be coded When Field D is used to code a compound whose action is synergized, antagonized, or simulated by the test compound or is additive with the action of the test compound (see the first of the four uses itemized under the section on General Use), this is indicated by the Symbols 8, 9, A, or C of Field T-l. Note that it is the secondary compound's action that is affected by the test compound and it is the biological state, quality, or process on which the secondary compound acts that is coded in Field T-2. It is impossible to code the action of the secondary compound (Symbols I, 2, 3, e. g. ), because Field T- 1 must be used for the test compound's effect on the action (Symbols 8, 9, A, or C). Ideally, there should be a second Field T- 1 for coding the action of a secondary 14 FIELD D Columns 12, 13, 14, 15, 16, and 17 compound, but the CBCC has not made this provision. Therefore, this action of the secondary compound must always be included in the written abstract portion for Field T-2 and whenever a secondary compound's action is synergized, antagonized, or simulated by or is additive with the test compound, the written abstract on the code sheet must be consulted to understand the action of the secondary compound which has been affected, as indicated in Field T-l, by the test compound. 10. Procedures when conflicts occur in the use of Field D Ideally, a special coding field would be established for each of the four uses for a secondary compound listed in the General Use section. Then, if a test technique involved two of those aspects (e. g. , antagonism evaluated by comparison to a standard), each could be indicated in its respective position on the Code Sheet and IBM punched card. The great infrequency of tests in which this occurs, however, makes impractical reserving so many IBM columns (12 columns for two of the uses or 24 columns for all four uses of secondary compounds). For this reason, only the single field of 6 columns has been reserved for any one of four possible uses. As a result, when occasionally test data involve two secondary compounds used in two of the four possible ways, having only one field, Field D, for all the uses of secondary compound poses a problem of competition for the field. The competition occurs with at least four general situations. These are described below as Conflicts A, B, C, and D, with an explanation of CBCC procedure for each case. A. When there is an antagonized, synergized, or simulated compound or a compound whose action is additive with the test compound (i. e. , a Field D entry called for by Field T-l, Symbols 8, 9, A, or C) and the metabolism section of Field T-2 (Symbols F6--, F8--, F9--, etc. ) calls for the entry of a compound in Field D. In this case, the compound antagonized, synergized, or simulated or the compound whose action is additive with that of the test compound ( Field T- 1 ) is coded in Field D . The compound called for by Field T-2 is merely written on the Code Sheet, in the written abstract portion of Field T-2 ; the general class to which the compound belongs (i.e., --1 to --G under Symbols F6- -, F8--, etc., and 1 to L under Symbols FF1- to FFD-) is coded in Field T-2 in the usual way. That compound written in Field T-2 is not coded in Field D nor anywhere else. The code line will then state that the test compound antagonizes (or synergizes or simulates) the secondary compound's effect on the metabolism as coded in Field T-2. Note that the written description in Field T-2 must include the secondary compound's action, since there is no way to code this (inasmuch as Field T-l is occupied with the action of the test compound, as explained above in Division 9). B. When there is an antagonized or synergized compound or a compound whose action is additive with the test compound or which the test compound simulates (i. e. , a compound in Field D called for by-Field T- 1 Symbols 8, 9, A, or C) and the evaluation of the action is made by comparison with a standard (Field X, Symbols 03 or 04) which must also be in Field D. Two lines must be coded, if the action is positive. The first line is coded with the symbol for "antagonizes" (or "synergizes") in Field T- 1 and with the antagonized (or synergized) compound in Field D ; the criterion of evaluation for this line must be "Author's Evaluation", Field X, Symbol 01. The second line is also coded with the symbol for "antagonizes" (or "synergizes") in Field T-l and the standard compound , to which the test compound is compared for evaluation, is coded in Field D (including an asterisk in Column 17); the criterion for evaluation is either 03 or 04 of Field X. If the action is negative, this second line is not required. - 15 FIELD D Columns 12, 13, 14, 15, 16, and 17 C. Symbol FF-G of Field T-2: When there is a test compound which has an effect on the elimination of a metabolite of a compound and the metabolite is named . For example: The test compound causes an increase in urinary excretion of the metabolic product (Compound Y ) of Compound X , (In this example, Compounds X and Y vie for a place in Field D, since Symbol FF1G [metabolite of the chemical specified in Field D ] requires Compound X being in Field D and general directions require that the identity of the metabolic product [Compound Y] be coded in Field D when known. ) The parent compound is coded in Field D. In Field T-2, G is coded with whichever of Symbols FF1- to FFD- is appropriate (in the example above, FF1G); in the written abstract portion of Field T-2, the name of the metabolite is only written and is coded nowhere. A second line is not coded to indicate the action of the test compound on the elimination of the metabolite (which would provide a line with the metabolite coded in Field D), since the specification for coding the metabolite in Field D is merely a matter of adding supplementary information when it is known; the code name of the metabolite is not actually essential to the interpretation of the coded action of the test compound. D. When the test compound has an effect on the nutrient uptake, chemosynthesis, distribution, etc. (i.e., Field T-2, Symbols F6--, F8--, etc.), of a secondary compound whose name is specified and the action is evaluated by comparison with a standard. E. g. : The test compound causes an increase in absorption of Vitamin C, the degree of increase being evaluated by comparison to the increase caused by a standard, Compound X. (Since the vitamin is specified as Vitamin C, Vitamin C should be coded in Field D; however, the standard compound should also be in Field D. ) Two lines are to be coded, if the action is positive. In the first line, place in Field D the compound whose nutrient uptake, chemosynthesis, distribution, etc. , is affected. Evaluate the effectiveness by the Grid (percentage increase or decrease) or, if the actual control value and value following treatment are not reported, evaluate by Criterion 01 of Field X with an evaluation or 1 in Field Y. In any case, do not use Criterion 03 or 04. Code the second line to be like the first line in all fields except Field D and the evaluation fields; use Criterion 03 or 04 and code the standard compound in Field D, adding Symbol * (representing the IBM 12 zone punch) in Column 17 . In summary, it will be noted that the resolution of the conflicts reflects a precedence given to coding in Field D compounds whose actions have been affected by the test compound, as indicated by Symbols 8, 9, A, and C in Field T-l; such secondary compounds are always coded. (See Conflicts A and B. ) Second in the scale of precedence is the coding of compounds used as standards of comparison to the test compound; the CBCC also always codes the standard of comparison, even when a second code line is necessary to code a standard used to evaluate the effect of the test compound on the action of a secondary compound, using Symbol * in Column 17 of the line coding the standard compound in Field D. (See Conflicts B and D. ) Last in the list is the coding of compounds whose metabolic fate is affected- -or compounds to which tolerance/sensitization is produced- -by the test compound, indicated by certain symbols of Field T-2; if this last use conflicts with either of the first two major uses above, the CBCC prefers omitting coding the compound called for by Field T-2 on the grounds that it is of least importance. (See Conflict A. ) In view of this, retrieval of all compounds whose metabolic fate is affected (as indicated by coding in Field T-2) can not be accomplished by sorting in Field D for coded biology data. (The only practical way of finding these would be by selecting IBM cards with the particular symbol or symbols in Field T-2 and sorting for Symbols 8, 9, A, or C in Field T- 1 and for a 12 zone punch in Column 17 of Field D; if none of these symbols of Fields T- 1 and D are on the cards, coding in Field D on all the IBM cards at hand is of compounds - 16 FIELD D Columns 12, 13, 14, 15, 16 and 17 related to the particular Field T-2 symbols, but if any of these symbols of Fields T- 1 and D are on any of the cards, reference must be made to the code sheets corresponding to these cards to learn the identity of the compound related to the Field T-2 symbol. ) The only alternatives to the procedure which involves the conflicts in Field D as described would be to omit coding of all but one of the major units of information (i. e. , all but one of the four uses of Field D as described in the section General Use) or to provide as many fields for secondary compounds as there are uses now for Field D. Neither of these has been practical for the CBCC and the present multiple use of a single field has been largely satisfactory, in spite of occasional conflicts and slightly greater complexity of use. 1 1. File of coded biology data on IBM punched cards arranged according to symbols for secondary compounds The CBCC maintains a separate file of all coded biology data (i. e. , all IBM biology punched cards) in which Field D has been coded, arranged by Field D entries. Thus, there are quickly retrievable biology data for any compound, or for all compounds, which have in some way been affected by test compounds or which have served as standards of comparison to the test compound. The latter are easily distinguished by the IBM 12 zone punch in Column 17. Further, after removing all cards with secondary compounds that are standards of comparison, the remaining cards can be sorted by Symbols 8, 9, A, and C in Field T-l, distinguishing the secondary compounds whose action has been affected by the test compound from those whose metabolic fate has been affected. These are simple and rapid card sorts, insignificant in terms of time and effort compared to the very large sort necessary to retrieve secondary compounds if a special file of biology data with Field D coding were not available. 12. Double Coding in Field D Double coding is not permitted in Field D. However, Symbol # or * in Column 16 or Symbol * in Column 17 may be coded, in addition to the symbol for the single secondary compound, and both are punched on the same IBM card. 17 FIELD E Columns 18, 19, 20, 21, 22, 23, 24, and 25 ORGANISM, TUMOR OR PATHOLOGICAL CONDITION ACTED ON BY THE TEST COMPOUND GENERAL DISCUSSION This field is for the entry of one of the following: I (1) TEST ORGANISM ACTED ON BY THE TEST COMPOUND (2) TUMOR ACTED ON BY THE TEST COMPOUND (3) PATHOLOGICAL CONDITION OTHER THAN TUMOR ACTED ON BY THE TEST COMPOUND II (4) TUMOR PRODUCED BY THE TEST COMPOUND Organization The Biology Code has been provided, as far as possible and to the extent of its anticipated needs , with unique symbols for the species of organism used or for the precise pathology treated. These symbols bear relationships to each other, based on relations between organisms or between diseases so that, first, retrieval of coded data is possible at any taxonomic level or at any level of pathology description and, secondly, appendage to the Code of new symbols for additional organisms or pathologies is possible in a logical relation to the pre-existing code items. The symbols for organisms, pathologies, and tumors are assigned according to definite schemes. Since each scheme is specially designed to provide symbols which reveal relationships between organisms, or pathologies, or tumors, by any of their several characteristics, each can be considered essentially as a separate Code. The Taxonomy Code requires, for example, that a new organism be assigned a symbol whose first unit represents the phylum to which it belongs. As another example, the Tumor Code rules specify that, when a symbol is assigned to a new tumor, the second and third units of that symbol must represent the organ in which the tumor originated. Every organism, every tumor, and every pathology is coded according to the rules of that particular Code. However, once it is coded, it is added to the list of organisms, pathologies, or tumors so that it need never be coded again. These Field E lists, then, are actually groups of pre-coded items, any one of which will never vary in the coding of its identity. The lists of organisms, pathologies, and tumors are included in the CBCC Biology Code as the Taxonomy, Pathology, and Tumor Codes of Field E. Following this general discussion of Field E is a separate discussion for each of the Taxonomy, Tumor, and Pathology Codes, explaining how the symbols are formed for organisms, tumors, and pathologies and what coded information about an organism, tumor, or pathology is incorporated into its symbols. General Use In Field E is coded the major biological component of the test data, the organism, the pathological condition, or tumor which is experimentally treated with the test compound. A pathological condition produced by the test compound (excepting tumors) is always identified specifically in Field T-2. When a compound is tested for its ability to induce tumors , the effect tested for is coded in Field T (Field T-l, Symbol 7; Field T-2, Symbol 43: "induces neoplasm"). However, to provide for coded identification of any tumor actually induced, the tumor identity is coded in Field E and the organism in which it is induced is placed in Field J. Only in the case of tumor induction (Symbol 43 of Field T-2) is Field E used to code the identity of the result of the test compound's action. In all other cases, as explained above, an entry in Field E represents the organism, pathology, or tumor treated by the test compound. It is important also that distinction between the uses and structures of symbols of Fields E and J be understood. Experience has proved that frequently the points of difference are not always - 18 - FIELD E Columns 18, 19, 20, 21, 22, 23, 24, and 25 immediately appreciated and errors in coding result. All data for which the CBCC Biology Code is in- tended have at least two major components, (1) a biological organism or condition treated with- -or a tumor produced by--(2) a test compound; a biological organism or condition treated (or a tumor induced) must be entered in Field E for every line of coded data. Field J, however, is coded only in the case of a pathological condition (coded in Field E) or when the test organism (coded in Field E) is growing in or maintained on a host. Field J, then, is for coding (1) the organism in which a pathological condition occurs or (2) the host organism or host substance in or on which a test organism is living. The symbols of one field are not in any way interchangeable with symbols of the other. Coding an organism in Field E, for example, must be by use of the Field E Taxonomy Code symbols and under no circumstances is by use of Field J symbols; Field J must never be coded with symbols from the Taxonomy Code of Field E. Specific Directions and Explanations Related to Field E in General 1. Symbols which do not fill all eight columns of Field E; unused final columns of Field E are cross-hatched In any of the Taxonomy, Tumor, or Pathology Codes, there are items represented by symbols of less than eight units. For example, if a test organism is only identified as to the family to which it belongs or if it were demonstrated that all members of the family respond to the test compound as the code line indicates, Field E would be coded with the symbol for the family. This would be a five-unit symbol, leaving Columns 23, 24, and 25 uncoded. As a second example, any non-specific, unnamed tumor would have a maximum of seven units, leaving Column 25 uncoded. The CBCC practice has been to cross-hatch any such final unused code boxes of Field E, since it thereby is assurance, when transferring the coding to IBM punched cards, that the final units are omitted intentionally and not because of an oversight or because a new symbol for a species or a named tumor is needed in the Code. 2. Symbols available for additional items of Field E Since the IBM zone punches have not been given special meanings in Field E, any number or letter not already used in any of the IBM columns may be used to construct symbols for organisms, tumors, or pathologies. 3. File of coded biology data on IBM punched cards arranged according to symbols for organisms, tumors, and pathologies in Field E The CBCC has maintained a complete file of IBM biology punched cards arranged by the Field E entries, referred to ordinarily as the "Taxonomy File". (Because the part of the Biology Code which has been entitled the "Taxonomy Code" is exclusively concerned with test organisms , this use of the "Taxonomy File" tends to be misleading. Possibly the file would better be referred to as the Test Organism-Tumor-Pathology file, since all of these are included in it. ) Thus, to retrieve all information about any organism or group of organisms, or on any tumor or tumor type, or on any pathology, this file permits direct manual retrieval of the appropriate cards. The cards thereby obtained can then be sorted for any other specifically requested information coded in another field. 4. Double coding in Field E IBM punching prohibits more than a single Field E entry on a single IBM punched card. There- fore, if two or more tests demonstrate that two or more organisms (or two or more tumors or pathologies) respond so nearly identically to a test compound that the only variation in the code line would be the entry in Field E, coding can not be abbreviated by constructing only one line with all the organisms (or tumors or pathologies) so responding coded in Field E. A line must be constructed for each organism, for each tumor, or for each pathology of such a situation. - 19 FIELD E Columns 18, 19, 20, 21, 22, 23, 24, and 25 Specific Directions and Explanations Separately Outlined for the Use of Symbols for Test Organisms, Tumors, and Pathologies in Field E I. TEST ORGANISMS ( Taxonomy Code ) 1. Definition By the term "test organism", reference is made to the organism against which the action of the test compound is directed, when this organism is not affected with a pathology or tumor which is itself being specifically treated. This term does not refer to any organism which is used in a test as the experimental host . (See Parts II and IV of this section for a discussion of tumor and pathology coding. ) 2. Taxonomic categories below species are not distinguished by code in Field E The code symbols for test organisms are exclusively in the Taxonomy Code of Field E. These symbols permit taxonomic distinction of phyla (or plant divisions), classes, orders, families, genera, and species, but not strains or varieties. Therefore, when all conditions are the same except that two or more varieties are used, lines can not be constructed for results on each variety, since the coding in Field E would only be identical for each variety in each line and the lines would appear to be mere repetitions or contradictions of each other. (An exception to this is permitted by use of Symbol F in Field G, only under conditions as described in Division 4 below. A second rare exception is made by the eighth unit of the symbol as explained in Division 5 below. ) 3. Physiological strains may be indicated by code, but not in Field E The preceding paragraph points out that the Code does not distinguish taxonomic categories below species. However, physiologically distinct strains of a species frequently occur and a general provision has been made for distinguishing certain of these by code. This provision consists of items in Field G (Symbols F; G, H, and I; 6 and J). Examination of these items of Field G will explain the extent of strain distinction possible. Field E by itself does not provide for strain distinctions any more than for taxonomic varieties. 4. Several taxonomic varieties or physiological strains tested by the identical test methods ; coding procedure In the case of data from tests on a number of taxonomic varieties or physiological strains, only a single code line should be constructed for all the organism forms showing a positive response, regardless of the degree, using the indiscriminate evaluation criterion, "Author's Evaluation", Symbol 01 in Field X, and the general evaluation, "Active", Symbol in Field Y. If none of the varieties or strains of the series tested responded to the test compound (i. e. , if the responses of all organisms were negative), the evaluation in Field Y would be "Inactive", Symbol 1. If only a few of the series of organism varieties or strains showed a negative response, code one line combining those showing a positive response; code a single line, combining those showing a negative response; test-organism- distinction between these two lines is made by coding, in the line for the negative responses , Symbol F in Field G. (See Field G, Specific Directions and Explanations, Division 9. ) 5. Exceptional use, by the CBCC, of the eighth unit of the Taxonomy Code for indicating a variety or strain Although the CBCC has largely adhered to the provisions explained in Divisions 2, 3, and 4 above, restricting the use of the eighth place of the Taxonomy Code symbols to designating species, an occasional exception has been allowed. When a particular taxonomic strain (e.g. , cabbage: Brasslca oleracea capitata ) or a physiological strain (e. g. , the DDT-resistant housefly) is so exten- sively used experimentally that (1) many lines of data will be coded for it and (2) there would be con- siderable advantage in being able to retrieve information on that strain by a single file sort, the strain is given a unique code symbol just as if it were a distinct species. If all information on the housefly, for example, is subsequently to be retrieved from a file of coded data, not only must the search be for - 20 - FIELD E Columns 18, 19, 20, 21, 22, 23, 24, and 25 IBM punched cards with the symbol for the housefly otherwise undistinguished , but there must be included a search for cards with symbols of any and all housefly strains . Only by weighing the disad- vantage of this additional complication in retrieval against the advantage of having the particular strain distinguished in Field E, has the CBCC made the decisions, which were special in each case, to permit certain strain distinctions by unique Field E taxonomy symbols. 6. Test organism versus host; distinctions It is important that the coder understand the definition of a host organism, for which Field J is provided. In any experimental situation in which one organism is living as a parasite on another organism, there are three considerations to make, which will determine what will be coded in Field E: (A) Was the compound being tested for, or did it produce, an action on the parasite and thereby affect the host? If so, the parasite should be coded in Field E and the host in Field J. (E. g. , to code that the test compound causes some relief from malaria in chicks, the malarial organism is coded in Field E, the chick in Field J. ) (B) Was the compound being tested for, or did it produce, an action directly on the host , irrelevant to the parasite? If so, and that action is being coded, the host of this situation is actually the test organism to be coded in Field E and the infestation is merely an incidental condition which is indicated by coding Field G with Symbol 5. (E. g. , to code that the test compound causes increased heart rate and 50% mortality in chicks with intestinal roundworms [or body lice or coccidia, e. g. ] when the parasites in controls cause neither an altered heart rate nor death, the chicken is coded in Field E and Symbol 5 in Field G-l. ) (C) Was the test compound being tested for, or did it produce, an effect on some single symptom of the pathological condition of the host caused by the test organism, when the condition as a whole was not significantly affected? (This is a difficult coding problem; it is discussed later in this Section, in Part IV, Division 5. ) The host of this particular situation is coded in Field J and the test organism (whose symbol in the Taxonomy Code is given synonomy, in the CBCC Pathology Code, with the pathology syndrome it causes) is coded in Field E; the action on the symptom is coded by the appropriate code symbols in Field T. 7. General directions When coding of Field E is completed and this coding is not of a species but only of a genus or family so that one or more of the final code boxes in the field are left uncoded, those uncoded boxes are to be cross-hatched. In the language portion, the complete scientific name of the organism is written and under- lined. If the common name is given, it is also included, being written after the scientific name and not underlined. II. TUMORS AGAINST WHICH COMPOUNDS ARE TESTED; TUMORS PRODUCED BY COMPOUNDS (Tumor Code) 1. Tumor against which a compound is tested Any tumor, whether induced, transplanted, or spontaneous, that is treated with a test compound is coded in Field E by a symbol found in the Tumor Code of Field E. The animal, plant, or medium which harbors the tumor at the time of the test is coded in Field J as the host, whether or not that host is the parent source of the tumor. The parent source of the tumor, if different from the host in Field J and if not clearly implied by the tumor identity in Field E, can not be recorded by code, because providing a special coding field for this occurrence is impractical for the CBCC Code; however, this different parent source, under these conditions, must be recorded in the written abstract of Field E. For example, in coding data from a test with a mouse tumor transplanted to a culture medium, the medium would be coded in Field J, but the mouse origin can only be recorded in the written abstract. - 21 - F IELD E Columns 18, 19, 20, 21, 22, 23, 24, and 25 If the location of the tumor is described as one specific organ of the host coded in Field J (i. e. , any one specific item of Field H-l), that organ should be coded in Field H-l. This procedure satisfies the purpose of Field H-l which is to record the responding organ. If the tumor is a transplanted tumor, the one specific organ to which it is transplanted is coded in Field H-l, whether the organ of origin was of the host coded in Field J or of another organism. The CBCC Code considers the organ that is host to the transplanted tumor as being the diseased organ rather than the organ whose cells have altered to the tumorous state. Thus, if the organ of origin is different from the organ to which it is transplanted, the organ of origin is only recorded as part of the code symbol for the tumor. Whether the organ of origin is or is not indicated specifically by the tumor symbol in Field E, it should be included in the written abstract of Field E. Notice that there are being discussed here only transplanted tumors. For action on metastasizing of tumors, see Division 5 of the Specific Directions and Explanations of Field H-l and the Code definition for Symbol 46 of Field T-2. If the same tumor is described as being in more than a single organ (more than one specific item of Field H-l), it is ordinarily adequate to code only a single line with one of the organs coded in Field H-l. However, if the tumor response differs according to its anatomical location, as many code lines should be constructed as there are tumor locations that respond differently to a degree that can be distinguished by code in Field Y. In the case of tumors being treated which are known to have been chemically induced, the fact that they were so induced is indicated by Symbol T ("chemically induced") in Field F; if the identity of that carcinogen is known, it may be included in the written abstract, but it is not considered a significant component of the data being coded and is not coded in Field D. 2. Tumors produced by compounds Any tumor produced by a test compound is coded in Field E by symbols found in the Tumor Code of Field E. The organism in which the tumor is produced is coded in Field J, since it is the host of the tumor at the same time that it is the origin of the tumor. If the location of the produced tumor is described as being in one specific organ , that organ should be coded in Field H-l; if the same tumor is produced in more than one organ, ordinarily only a single line is necessary, with one of the organs coded in Field H-l. If a compound is tested as a carcinogen, yet no tumor is produced, Field E is coded merely with the Symbol S ("tumor, unspecified") in Column 18 and the organism treated with the candidate carcinogen is coded in Field J. This permits retrieving from the file all data on tumors, including negative carcinogenic data, by reference to a single field, Field E. 3. Coding distinction between tumors treated and tumors produced by the test compound Although there is not a coded distinction, in Field E, between tumors which test compounds affect and tumors which test compounds produce, the coder will recognize that the two are distinguished by the coding in Fields T-2 and T-3. 4. Pretreatment of the host of a tumor Any pretreatment given to the host or part of the host (including the anatomical site of a spontaneous or transplanted tumor), which results in a special experimental state of that host or structure, is coded only in Field L. III. SOURCES OF ENZYMES ACTED UPON BY TEST COMPOUNDS Enzymes are never coded in Field E; they are always coded in Field T-2. (See the Enzyme Code of Field T-2 and Division 22 of the Specific Directions and Explanations for Field T-2. ) The animal or plant source of the enzyme is coded in Field E (Taxonomy Code) and, if the organ from which the enzyme is derived is known, that organ is coded in Field H-l. Frequently, in enzyme studies, Field G is coded with one of the Symbols U through X, to indicate the test preparation. (See the Code for definitions of Symbols U through X which will explain their use in this situation. ) 22 - FIELD E Columns 18, 19, 20, 21, 22, 23, 24, and 25 In the case of enzymes described as purified, crystalline, recrystallized, etc. , especially commercially available enzymes so designated, and undesignated as to biological source, code the source in Field E with Symbol Z, Zl, or Z2 and record all information given (commercial source, number of crystallizations, assay, chemical properties of the lot, etc. ). IV. PATHOLOGY TREATED BY THE TEST COMPOUND ( Pathology Code ) 1. Pathology treated vs. pathology produced; distinction in coding procedure Only a pathological state that is treated by the test compound is coded in Field E, using symbols found in the Pathology Code of Field E. (The discussion of the Pathology Code will explain that a specific pathology is actually frequently represented by a basic pathology symbol in Field E combined with a specific code entry in Field H. ) The production of a pathological state by a test compound is coded in Fields T-l, T-2, and T-3. (Consult Part V below for this latter situation. ) 2. Host of the treated pathology The organism that is in the treated pathological state is coded in Field J as the host of the pathology. (The pathological state is essentially coded in Fields E and H. ) 3. Coexisting pathological conditions; only one is treated If a complex of apparently unrelated pathological conditions exists in an organism and the test compound is administered to treat only one, the treated condition is coded in Field E and Field L is coded with Symbol 7 (or other appropriate symbol) to indicate that there are coexisting pathological conditions. (E. g. , the test compound is administered to treat experimental hypertension in dogs which are incidentally anaemic and infected with mange. ) 4. Coexisting pathological conditions; any or all treated If a complex of apparently unrelated pathological conditions exists in an organism and the test compound is administered, with no clue as to which condition it was particularly intended to treat or with no intention of treating one more than the other, the policy is to code a line for each pathological state, recording either the negative or positive responses of each and indicating in each line (Field L) that coexisting pathological conditions exist. (E. g. , the test compound is administered to a dog with pulmonary edema, conjunctivitis, and tapeworms; no improvement in any of the three conditions is observed. ) 5. One pathological condition, several related conditions as symptoms (See also Part I, Division 6, Subdivision [C]. ) When the situation involves a complex of related conditions (i. e. , symptoms of a major pathology), the coding procedure must be based on the premise that it is desirable always to have coded in Fields E and H the major pathology , any or all of whose symptoms may be affected by the test compound. Therefore: (A) When a test compound is administered to an organism with a specified pathological condition and only one of the symptoms of that condition responds but there is no evidence that any of the remaining symptoms respond, the specified major pathological condition is coded in Field E and the symptom that responded and its response are coded by appropriate symbols in Fields T-l and T-2. If more than one, but not all such symptoms should respond, each symptom's response must be on a separate line in Field T-2. The symptoms which did not respond to the treatment should not be coded on separate lines. In this particular situation, the CBCC policy has been to use discretion so that usually only one or two of a group of affected symptoms are actually selected for coding. - 23 - FIELD E Columns 18, 19, 20, 21, 22, 23, 24, and 25 (B) When the specified major pathology is understood to be generally affected, either by all the symptoms being affected in the same way or by the author's specifically stating that one or more symptoms' responses are used merely as the author's basis for determining that the major pathology is generally affected, the major pathology is coded in Fields E and H, but the symptoms are not coded in Field T-2; instead, the general response of the major pathology is coded by one of the symbols of the 17-- or 16-- series in Field T-2 and there is recorded, in the written abstract portion of Field T-2, the evidence for that general effect on the major pathology. (C) When two or more coexisting pathological conditions are treated by a test compound and they seem possibly related but there is no specific indication by the author that these are all symptoms of a single major pathology nor is the coder absolutely confident that these all represent a single major pathology, each condition must be coded in a separate line in Field E; i. e. , each must be treated as a major pathology rather than the coder's attributing one to being a symptom of the other or, by conjecture, attributing both to a more general major pathology. 6. Pathological conditions caused by test organisms (infectious diseases ) The Pathology Code of Field E considers that each parasitic organism, by its own specificity, bears a unique relationship to its host and therefore causes a unique symptomatology, however small might be the distinctions in certain instances. On this assumption, any pathological condition caused by a specific organism can be defined most accurately by reference to that specific organism. There- fore, in the Pathology Code, there are a number of items referring to the pathological conditions caused by specific parasitic organisms and the symbol for each of these is merely the symbol for that parasitic organism in the Taxonomy Code of Field E. In other words, the symbol for each such infectious disease is exclusively etiological in nature, merely expressing the causative agent. The disease is made specific, when necessary, only by indicating in Field H in what organ or part the infectious disease is located. V. TEST ORGANISM IN WHICH PATHOLOGY IS PRODUCED BY THE TEST COMPOUND ( Field T; NOT the Pathology Code ) As pointed out in Division 1 of Part IV, above, when a pathological condition is produced by the test compound, the pathology is not coded in Field E, but it is coded by appropriate symbols in Fields T-l and T-2, as the response to the test compound. The test organism in which this effect occurs is coded in Field E. 24 FIELD E ; Taxomony Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 CODING OF TEST ORGANISMS GENERAL DISCUSSION OF THE CBCC TAXONOMY CODE 1. S ymbols for organisms; the taxonomic significance of parts of the symbols for organisms Deriving the symbol for any specific test organism is itself a coding process. Once the taxonomic information about a given organism has been coded, the assembled coding represents, as a unit, the code symbol for the organism. The symbol remains constant for any given organism in the same way that symbols remain constant for organs in Field H or physical states of chemicals in Field A, etc. This coding of the taxonomic categories to which a specific organism belongs is dealt with here. Field E provides eight IBM punched card columns for identifying the test organism. The total area of eight columns is divided into six sub- areas, each conveying unique taxonomic information. The eight units of the Taxonomy Code symbols (i. e. , the eight IBM punched card columns of Field E) are apportioned as follows: 1, the animal phylum or plant division; 2, the class; 3, the order; 4 and 5, the family; 6 and 7, the genus; and 8, the species. This permits distinguishing 35 phyla; of each phylum, 35 classes can be distinguished; and, of each class, 35 orders can be distinguished. The two units for each of the family and genus designations permit distinguishing in each order hundreds of families and, in each family, hundreds of genera. The CBCC has elected to use as far as possible only numerical units for the familial and generic designations, (i. e. , 01 through 99, rather than 01 through 0Z followed by 11 through 1Z and 21 through 2Z, etc. ). This simplifies IBM punched card sorting, since letter designations, incorporated into the code symbols, can be indicated only by a combination of a zone punch and numerical punch and this double punch would require sorting the cards twice to retrieve any given letter designation. Thus, when a coder uses a symbol for a specific organism, he is actually coding six pieces of pre-coded information, the identity of the phylum, class, order, family, and genus to which the organism species used in the test belongs. 2. Limitation of the number of species for which biological responses to chemicals are experimentally determined In devising the Taxonomy Code, the primary objective was to satisfy the needs of the CBCC in the process of coding only the results of tests for biological responses. In other words, the ultimate objective of the CBCC Taxonomy Code was not the coding of all organisms; information about responses to chemicals may be expected for only a fraction of the total number of known species of organisms. While the CBCC has no reason to provide code symbols for all organisms nor necessarily for all organisms of any given group, its pattern for coding organisms has to permit coding taxonomic infor- mation about any given organism. 3. Essential taxonomic information about a test organism In a coding project in which the information being coded involves only a few organisms, the identities of the organisms could conceivably be indicated very simply merely by assigning symbols in sequence. For example, a species of Aspergillus might be assigned symbol 1; a species of Clostridium, symbol 2; a species of Bacillus , symbol 3; a species of Amoeba , symbol 4; etc. The needs of the CBCC for coded taxonomic information exceed any such simple scheme. It is necessary that the Center be able to associate all chemical-biological information related to all organisms of a given family, or of a given phylum, or of any other taxonomic category. Also, an organism is occasionally identified by the author only as a member of a broad taxonomic category, such as a member of a specific order or of a specific family, and the CBCC must be able to code in such a way that the code entry is clearly identified as a family or order and identified as to which family or order. Therefore, the scheme as described above in Division 1 was established, by which each organism species is coded to indicate the phylum, class, order, family, and genus to which it belongs. - 25 - FIELD E ; Taxonomy Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 This particular scheme also provides unique symbols for all the organisms for which symbols are apt to be needed in coding results of chemical-biological tests. (See Division 2, above. ) While the CBCC Taxonomy Code does not pretend to be able to accommodate all known organisms (all species and all taxonomic categories) with the limited space of eight IBM punched card columns, the symbols available for each taxonomic category are actually in most cases more than sufficient to include all known members of the category. For example, 3 5 symbols of one IBM punched card column are ordinarily adequate to encompass all recognized phyla, or all classes of any one phylum, or all orders of any one class. If a phylum is organized into more than 35 classes or a class into more than 35 orders, the CBCC Code could not conveniently provide symbols for all of them, but since it is not probable that chemical- biological data will be encountered for species from all of such a large number of classes of a single phylum (or of orders of a single class), or even from any but a part of 3 5 classes (or orders), a provision for more than 35 symbols has seemed, and has so far proved, unnecessary. It will be noted that the coding scheme of the CBCC does not provide for distinguishing, by code, taxonomic intergroups (subgroups and supergroups), such as subclasses and superclasses. Any intergroup has the same symbol as the major group of which the intergroup is a member. For example, all of the suborders, Trichostomata, Gymnostomata, Astomata, etc. , have the same code symbol (Symbol 121) as the order to which they belong (Holotricha). Therefore, it is not possible to use the symbol for an intergroup to sort out all information on only that single specific intergroup, since the symbol represents all intergroups of the major group (e. g. , all suborders of a given order). The retrieval of information on all members of a suborder, for example, could be made by selecting coded information for all families known to be included in the suborder or by retrieving all information coded by the single symbol for the order and all its suborders, followed by inspection and manual selection for information on the suborder. While this complication appears to be a disadvantage, the actual improbability or infrequency of need for retrieval of information on an intergroup justifies omitting distinguishing code designations of sub- and supergroups. 4. The sequence of symbols in any one taxonomic category is only the sequence by which the names of taxonomic groups are added to the Code list Generally, the taxonomic groups or species are added to the Code only when the need arises. Thus, to date, not only are a very limited number of species to be found included in the list, but, in most phyla, only a limited number of genera, families, orders, and classes. (Initially, an attempt was made to provide a basically complete list of phyla, classes, and in some phyla, orders. ) When data are encounteied involving an organism not yet in the CBCC list, the new symbol assigned to that organism consists of the seven-unit symbol indicating the phylum, class, order, family, and genus to which it belongs and a unique final unit which is simply the next sequential number or letter following that given to the last-added species of that genus. In the same way, if a genus is new to the list, the symbol given it consists of the five-unit symbol indicating the phylum, class, order, and family to which it belongs plus a new generic symbol (the sixth and seventh units of the total symbol) which is merely the next two-unit number or letter combination sequentially following that given to the last- added genus of that family. In a similar way, new families, orders, classes, and phyla are added to the list. Thus, within any single taxonomic category (e. g. , an order), the symbols of its member groups (e. g. , the families of an order) do not occur in a sequence that attempts to represent a natural phylogenetic relationship (i. e. , more primitive families succeeded in the list by increasingly advanced families) nor is there any other organization such as an alphabetization of families within an order. Instead, the sequence of symbols for families within a single order represents merely the sequence in which they were added to the Taxonomy Code; the same is true for the sequence of symbols for the orders of a given class or genera of a given family, etc. The feature that permits any new member to be appended to the end of a list (rather than having to insert a new member into an organized list which would require altering the list to make it conform to the organization scheme) is sometimes referred to by the term "open-end". It will be noted that, in compiling the original lists, the phyla and, in many cases, the classes and orders, were placed in the list and given symbols in an order reflecting a natural taxonomic sequence, though no special significance is attached to it. Inasmuch as natural relationships are as yet so little understood in many groups of organisms, natural classifications are in many cases still impossible; in some cases, much disagreement exists among students concerning taxonomy within a given group, for any of several reasons. Thus, no - 26 - FIELD E ; Taxonomy Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 contemporary attempt to establish a taxonomy code on a single existing taxonomic scheme can be expected to satisfy all persons nor posterity. Prior to publication, an effort has been made to review the organization of this Taxonomy Code, consulting what are believed to be authoritative sources of contemporary opinion. A number of revisions have been made which have resulted, in a few instances, in changed symbols for organisms already recorded at the CBCC. (When such a change in a code symbol is made, all IBM punched cards and code sheets on which the old symbol is punched or written must be recalled from the files and altered to conform with the new symbol. ) 5. Indication of common names, synonyms, and intergroup names in the Taxonomy Code Sources of chemical-biological data, whether published or unpublished, vary widely, not only in terms of investigators and geographic locations, but in temporal terms. Taxonomic identities, therefore, may vary accordingly, so that a name accepted at one time or by one person may be unac- ceptable at a later time or by another person, because of new information or because of differences in interpretation and opinion. Further, there are frequently encountered data in which identity of the organism is with only a common name. Names of intergroups (sub- and supergroups) are sometimes of importance, because a test organism may be identified only as to the intergroup of which it is a taxonomic member. Variations in classification permit one scheme to bestow full rank (e.g. , order or class) on a group which another scheme considers as an intergroup (e. g. , superorder or subclass, etc. ). For the above reasons, there have been included certain of these names in this Code, for convenience in identification, as described in the following paragraphs. When an intergroup is listed, the taxonomic groups included in that intergroup are defined to indicate their relationship, because the code symbols can not do this. For example, in the Pelecypoda (Mollusca), there are listed several suborders, for some of which several families are listed; the code symbols for the families can only indicate the order to which they belong, but, in each of these families' definitions , the suborder to which it belongs is indicated. The question as to whether the groups considered here as suborders, for example, should instead be given the rank of orders and the orders given the rank of subclasses may often be academic or arbitrary, but proves vexing in composing code symbols because of sharp divergences of opinion among taxonomists. In making code symbols, however, some decision has had to be made in such cases, since the code symbols could not be constructed, according to the present method, to satisfy both or all of varying taxonomic opinions and organizations. This would suggest the difficulty attending any effort to invent a coding scheme for this category of information whose classification must shift with changing concepts of phylogenic relationships. When it has been an advantage to do so, names are entered in the taxonomy lists to record slightly different taxonomic schemes. This has been attempted in some detail in the case of the phylum Chordata and the fishes and occasionally in other groups. For example, in the list of Protozoa, the name Rhizopoda is listed twice, once as a synonym of Sarcodina, being considered as a class; however, Rhizopoda appears in other schemes as a subclass of Sarcodina and is listed a second time to indicate this. Subsequently, the family Vampyrellidae is listed as belonging to either of two orders, according to the taxonomic scheme preferred, Amoebozoa (order of class Sarcodina) or Proteomyxa (order of subclass Rhizopoda). Certain synonymous names are included in the list. These synonyms for a given group or a given species are assigned the identical code symbol. The synonymous names might all have been listed together (in series) as a single entry; they are listed separately because, when scanning the list, a name is not easily found if it is not aligned with all other names in the list. In some instances, a name has been included which is for a group (e. g. , an order) that the CBCC Code has considered as two or more separate groups (e.g. , two or more orders). In this case, the name is included in the list essentially for reference purposes only; the symbols listed with the name are not to be used as such for coding, except that, if an author should express the chemical action as being generally on all organisms of this composite group, it must be assumed that organisms of each group recognized by the CBCC code as separate groups are affected as described and, to code this completely, a code line for each group would be necessary. For example, the Coelenterate order Hydrocorallina is listed, but only with both Symbols 313 and 314, indicating that this term is not - 27 - FIELD E ; Taxonomy Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 recognized except historically by the CBCC code as having once been described to encompass organisms of the recognized order Milleporina (Symbol 3 13) as well as organisms of the order Stylasterina (Symbol 314). If an organism is identified only as to such a composite taxonomic group of which it is a member, it is usually advisable to code a single line, with the organism coded only to the category above the composite category (e. g. , to the family of a composite genus with which the test organism has been identified). Where there are included in the list names for groups which the CBCC Code recognizes as being incorporated into a single group (e. g. , two or more orders being recognized by this list as a single order), the symbol for each of the smaller groups is identical to that for the single CBCC-recognized group. Accompanying each such name in the list is the explanation that it is considered as being included in another, specified, single group. For example, classes Chondrichthyes and Osteichthyes are both considered as being incorporated into the single class Gnathostomata, Symbol A, and therefore are both assigned Symbol A, with an explanation with each that they are represented by the composite class Gnathostomata. If a chemical response is described as generally typical of all organisms of a group which the CBCC Code recognizes as being incorporated into a group of another name, the coding is unable to distinguish the restriction of the response to the group described by the author and it is important that, besides writing the name of the group which the author describes, there be included in the written abstract the notation that the group is incorporated into the composite group which is represented by the CBCC symbol used. Names for sub- and supergroups are incorporated into the list as part of the taxonomic schemes, although they cannot be distinigushed by code. Refer to Division 3. Common names are given a symbol identical to that for the scientific name of the species or group. In no case is there pretended a completeness in the listing of common names, intergroups, or synonyms. 6. Adaptation of the CBCC Taxonomy Code The foregoing discussion has emphasized that the CBCC Taxonomy Code has been designed with the specific needs of the CBCC in mind. This approach in explanation has been made at the risk of creating an impression that the Taxonomy Code is in some way highly specialized and of little use other than for coding of chemical-biological information. That this is not true will be understood by even casual reflection. The Center has assumed that its Taxonomy Code represents a pattern of organization that could be used for virtually any project coding biological information when it is desirable to identify organisms by code. Since it has proved satisfactory for the CBCC, it is believed to be adequate for most purposes precisely in the form presented here. On the other hand, the pattern might be used, but simplified or expanded, according to special needs. 7. Other systems for coding organism identities Time has not permitted compiling a bibliography of taxonomic codification systems. When the CBCC organized its Taxonomy Code, there was nothing on which the CBCC might have patterned its code to suit its needs and there was therefore no recourse but to develop its own system. A system used by the Entomology Department of the State Plant Board of Florida and the Statistical Laboratory of the University of Florida, Gainesville, Florida, has been described in an article published in 1958 1 . This system is very similar to that used in making the CBCC Taxonomy Symbols; the essential difference is that of restricting symbols entirely to numerical units rather than using IBM zone punches to provide letter units. Thus, having available only nine numerical punching positions in each IBM punched card column, two columns have been used to provide 99 available symbols or three columns for 999 avail- able symbols. The two systems are compared by the following opposing lists. Taxonomic Codification of Biological Entitles by H. A. Denmark, H. V. Weems, Jr. , and Carlis Taylor; Science , Vol. 128, No. 3330, Oct. 24, 1958, pages 990-992. - 28 - FIELD E ; Taxonomy Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 Number of IBM punched card columns used and (parenthetically) the number of symbols made available thereby Taxonomic Category CBCC ED, SPBF, and SL, UF, Gainesville Kingdom Phylum Class Order Family Genus Species (Not Coded) 1 (35) 1 (35) 1 (35) 2 (1225), potential 1 2 (1225), potential 1 1 (35) 1 (9) 2 (99) 2 (99) 2 (99) 3 (999) 3 (999) 3 (999) The CBCC prefers to use only numerical symbols for families and genera (though for phyla, classes, orders, and species, both numerical and letter symbols are used). Thus, in practice, the CBCC Taxonomy Code accommodates only 99 families of each order and 99 genera of each family; however, if it proved necessary, letter symbols could be used for families and genera after numerical combinations were exhausted, to provide symbols for up to 1225 families and 122 5 genera. 8. References and acknowledgments. (Reference numbers in this division refer to a bibliographic listing at the end of the division. ) In reviewing the CBCC Taxonomy Code and making revisions when they seemed appropriate, various sources were consulted for the preferred taxonomic schemes on which to base the code symbols. In certain groups, it has seemed advisable, for this publication, to alter the scheme of code symbols from that set up earlier and used for CBCC coding. The Protozoa, Porifera, Cnidaria, Platyhelminthes, Acanthocephala, and Echinodermata have been somewhat revised, largely in accordance with opinion expressed in the volumes issued to date of The Invertebrates by Dr. Libbie H. Hyman . The classification of the Digenea (Platyhelminthes, Trematoda)--that on which is based the scheme of code symbols --now follows closely that of Dr. George LaRue , who was most kind in checking the Trematode list. For purposes of the present Code, this scheme was projected by the CBCC to cover all Trematoda. The Cestoda and Turbellaria arrangements are based largely on the schemes described in The Invertebrata, Volume III . In revising the list and code symbols of Nematoda, Mrs. May Belle Chitwood of the Parasite Station at the USDA Experiment Station, Beltsville, Maryland, has given valuable advice. For the Annelida, a number of references conveniently at hand were consulted, including organizations indicated in Fresh-Water Invertebrates of the United States by T. W. Pennak 3 and The Oligochaeta by J. Stephenson 4 , although older ("obsolete") names appearing in the list, included for reference purposes, are derived from certain older texts. However, the scheme on which are based the code symbols is the result of advice from Dr. Libbie Hyman (American Museum of Natural History, New York, N. Y. ) and Dr. Marion Pettibone (University of New Hampshire). Other taxonomic groups, after being checked as far as possible at the CBCC, were submitted during 1957 to authorities of the U. S. National Museum for review and criticism and for assistance in filling in certain omissions. For the generosity of advice and time given by these persons, the CBCC is most grateful. Mollusca Crustacea Insecta Fishes Amphibia and Reptilia Birds Mammalia Dr. Harold A. Rehder Dr. Fenner A. Chase, Jr. Dr. J. F. Gates Clarke Dr. Ernest A. Lachner Dr. Doris M. Cochran Dr. Herbert G. Deignan Dr. David H. Johnson 29 FIELD E ; Taxonomy Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 The publication prepared for the AAAS, Zoological Names, A List of Phyla, Classes, and Orders, edited by A. S. Pearse, Fourth Edition (1949) has been invaluable as a guide against which to check the taxonomic organization set up earlier by the CBCC and for preparation of revised lists prior to requesting final checks by the authorities listed above. The bacteria and virus sections of the Taxonomy Code have caused particular concern due to extensive revision of the sixth edition (1948) of Bergey's Manual of Determinative Bacteriology , upon which the CBCC bacteria and virus code lists were patterned. The present list represents a compilation in accordance with the new (1957) Manual , made during the time the Manual was being prepared for publication. This would not have been possible without the help of Dr. R. E. Buchanan of Iowa State College through whose kindness the CBCC was given the use of a secretarial galley proof of the seventh edition and who also checked the final list composed for the CBCC Taxonomy Code for accuracy in accordance with later editorial changes. Lieutenant Erwin F. Lessel, Jr. , of Walter Reed Army Medical Center, contributed considerable assistance in checking the validity of many genera and species of bacteria and viruses. The virus nomenclature retains the pattern of the sixth edition (1948) of the Manual of Determin - ative Bacteriology upon the advice of Dr. F. O. Holmes of the Rockefeller Institute for Medical Research. The American Type Culture Collection's list of bacteriophage strains was followed in listing the phages. In checking the list of plants in the Taxonomy Code, the following botanical reference books were used: A Dictionary of the Fungi by G. C. Ainsworth and G. R. Bisby (Second Edition, 1945); Genera Siphonogamarum by C. G. DeDalla Torre and H. Harms; Cryptogamic Botany, Vol. I, Algae and Fungi by G. M. Smith (1938); The Algae and Their Life Relations by J. E. Tilden (1935); and Cryptogamic Botany, Vol. II, Bryophytes aricTpteridophytes by G. M. Smith (1938). The list of Fungi were checked by John E. Stevenson, U. S. Department of Agriculture, Plant Research Station, Beltsville, Maryland. The Invertebrates by Libbie Henrietta Hyman, four volumes; McGraw-Hill Book Co. , Inc. : Protozoa through Ctenophora , Vol. 1, 1940; Platyhelminthes and Rhynchocoela , Vol. II, 1951; Acanthocephala , Aschelminthes, and Entoprocta , Vol. Ill, 1951; and Echinodermata , Vol. IV, 1955. The Classification of Digenetic Trematodes: A Review and a New System ; by George R. LaRue; Experimental Parasitology M3), May 1957, 306-349. Fresh-Water Invertebrates of the United States by R. W. Pennak; The Ronald Press Co. , N. Y. , 1953. 4 The Oligochaeta by John Stephenson; Oxford University Press, N. Y. , 193 0. Bergey's Manual of Determinative Bacteriology, Seventh Edition by R. S. Breed, E. G. D. Murray, N. R. Smith, et al; The Williams and Wilkins Company, 1957. 30 - FIELD E ; Columns 1! 22, 23, Tumor Code , 19, 20, 21, 24, and 25 CODING OF TUMORS GENERAL DISCUSSION OF THE CBCC TUMOR CODE 1. Information about a specific tumor Tumor symbols are derived by a coding pattern different from that for other pathologies. The list of tumors, with the symbols which represent coded information identifying the tumors, is therefore a separate and distinct list and is designated as the CBCC Tumor Code. This description of the Tumor Code is essentially concerned with the pattern for coding, within Field E, information about the tumors themselves. The coding of information about a given tumor results in a combination of symbols in IBM Columns 18-25, which collectively represent the total, fixed symbol for the tumor. The section of the Key giving specific directions for using in Field E that prepared symbol for a tumor, when coding information about chemical tests , is included in the preceding General Discussion of Field E. In coding identifying information about tumors, Field E is divided into five sub-areas for five specific categories of information about each tumor, just as, in the case of the Taxonomy Code, Field E is divided into six sub-areas for description of phylum, class, order, family, genus, and species. The diagram below illustrates, for tumor coding, the distribution of the eight IBM punched card columns (1-8, in the diagram) among the five sub-areas of Field E (I-V) and indicates the category of tumor information coded in each sub-area. The paragraphs that follow explain in turn each of the five parts. For consistency, the five sub-areas are referred to hereafter as "parts" of the total 8-"unit" tumor symbol. 7 Tumor. I Organ origin . II Tissue origin. Ill Description (Parts II-V) of the tumor (Part I). Combination of Parts II and III: Organ-tissue origin of the tumor. Modifier of the organ- tissue o rigin . IV Specific tumor de signat ion. V Tumor type, when not adequately distinguished by Part III (or by Part II, or by III and II combined.) I Symbol for a specific tumor made by attaching Part V to the organ-tissue site (Parts II, III, and IV, combined.) 31 FIELD E; Tumor Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 Each Field E symbol for a specific tumor is the result of a tumor coding procedure described by the diagram of the previous page and the following paragraphs, just as a total code line of chemical- biological data is the result of a coding procedure using all coding fields. (See also the second para- graph of the section on Organization, in the General Discussion of Field E. ) Any tumor not previously coded by the CBCC is coded by the procedure described below and is added to the tumor list in the Code. Therefore, when coding chemical-biological data involving that tumor, its symbol is quickly available, not only sparing coders from repeatedly having to code the tumor (i. e. , prepare the code symbol), but assuring uniformity when coding chemical-biological information on that specific tumor. 2. Part I of the tumor symbol (first unit, Column 18): identification of the symbol as a tumor symbol Of the eight places in the tumor symbol (for the eight columns of Field E), the first is used merely to distinguish all tumor symbols from any other entry in Field E (i. e. , from symbols for test organisms and for non-infective diseases). Thus, by retrieving from a file of coded data all Field E entries with this first unit (Symbol S) which is common to all tumor symbols, all information on tumors, but only on tumors, can be obtained. Since tumors are coded in the same field in which organisms as well as pathologies are coded when appropriate, this first identifying part is essential. However, it might be pointed out that, were tumors to be given a separate coding field (impractical as far as CBCC coding facilities are concerned) or if only tumor data were coded, Part I would be unnecessary. As the diagram indicates, the remaining four parts of the Tumor symbol describe and identify the tumor. 3. Part II of the tumor symbol (2nd and 3rd units, Columns 19 and 20): gross anatomical tumor origin (organ or system ) This independent, two-unit part of the symbol signifies the organ or organ system from which the tumor originated and it is referable to a separate code scheme for these organs or organ systems. Unlike the anatomy part of symbols of the CBCC Pathology Code, these anatomical symbols included in the Tumor Code symbol are not to be found in the code list of anatomical items for Fields H- 1 and H-2, but only in the special list included in the Code accompanying the list of tumors. This special anatomy code consists of a first unit, indicating the system of which the organ is a part, and a second unit, which is merely a sequential number assigned to each organ of that system. For the most part, organs (and tissues) of one chordate animal group are homologous to the organs (and tissues) of any other chordate group so that the same symbols are applicable to all Chordata. Organs and tissues of invertebrates (insects, e. g. ) are scarcely homologous to chordate organs and tissues, but these may be inserted in the list as specific invertebrate organ or invertebrate tissue items under the appropriate organ or tissue system of the list. Since so few invertebrate tumors may be expected to be chemically treated, experimentally, it is consequently expected that all such symbols needed (for invertebrate organ and tissue tumor origins) can be adequately accommodated by available symbol combinations. Thus, complete tumor symbols do not have any specific unit which indicates from which animal or animal taxonomic group the tumor originated. However, since tumors are seldom if ever transplanted to an animal of a phylum or class different from that of the tumor's origin, the phylum or class of the animal from which the tumor arose will be indicated in Field J (the tumor host). Rare exceptions to this occur in tissue culture studies (e. g. , a mouse tumor explanted to a chick embryo), in which case the animal in which the tumor originated is merely recorded in the written portion of Field E. See also the General Discussion of Field E, Division 1 of the special section on Specific Directions and Explanations for Tumors. If the CBCC Code were adopted for recording data from tumor tests especially or exclusively, a new field might be established for recording the specific organism in which the tumor originated, if different from the host coded in Field J. For example, such a field would be desirable if data were being recorded from tests dealing solely with attempts to establish tumors of one species or genus in another species or genus. Since the CBCC Code is designed exclusively for testing chemicals (as carcinogens or carcinostats, e. g. ), there is little anticipated need for identifying the organism in 32 FIELD E ; Tamor Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 which a tumor originated to provide for the relatively few occasions when it is different from the organism coded in Field J. The CBCC assumes that the organism in which the tumor is grown at the time of the chemical test has been demonstrated to be a satisfactory one, else it should not have been used for the test; assuming this, the information about the species origin of the tumor, when different from the organism in Field J, occurs too infrequently to justify reserving coding space on the IBM punched card for it. Plant structures are so different from animal structures that a separate group of organ symbols is provided for them in constructing tumor symbols, since data on chemical treatment of plant galls (tumors) do occur. These symbols for plant structures are all assigned Symbol S as a first unit, with the second and third units (Part II of the symbol) representing the specific structure. For example, S S6 is a tumor (gall) of a plant leaf . The coding of the anatomical origin of specific tumors, indicated by units two and three of the tumor symbol, does not duplicate entries in Field H-l. In the case of tumor test data, coding the site of the tumor in Field H-l is restricted to recording the site at the time of treatment . If the tumor is a spontaneous tumor and is treated by a test compound in the identical organ from which it arose, the anatomical coding in Field E (units two and three of the tumor symbol) and the anatomical coding in Field H-l are duplications in essence if not by definition; this would also be true if the tumor were transplanted, but to the same organ of another individual (e. g. , a mouse mammary carcinoma trans- planted to the mammary gland of another mouse of the same species or strain). However, many chemical-biological test data concern experimental techniques using a standard tumor transplanted to sites other than the organ or body part from which the tumor was derived. The organ of origin is indi- cated by the tumor symbol in Field E; the transplantation site is coded in Field H-l. Retrieval of information (from a file of coded data) on tumors with given specific organ origins will be by sorting in Field E, while retrieval of information on tumors in given specific organ locations (whether originating in those organs or not) will be by sorting in Field H- 1. Since the next part of the tumor symbol (units four through six, described in the next paragraph) occasionally implies the tumor's anatomical classification, the use of the second and third units (for anatomical association) may sometimes appear redundant. Indeed, in the case of occasional tumor symbols, considered individually, this redundancy is a fact. (For example, S3412301 is a symbol for a urinary bladder tumor of transitional epithelium. Since transitional epithelium is almost restricted to the urinary bladder and associated structures, Part II [-34 ] is near redundancy to Part III [ 123--]. ) However, it will be noted that essentially standard tumor classification is based on general tissue types rather than on specific organs in which they have originated and it is on this organization by tissue types that units 4, 5, and 6 are correspondingly organized. Since, in a general way, organs and organ systems are constructed of more than a single tissue, an organ or organ system may given rise to tumors of not only one, but frequently more than one tissue type. Connective tissue tumors, in particular, serve to illustrate this, since such a tumor would be classified with all other connective tissue tumors, regardless of the organ in which it specifically arose. Therefore, a code symbol, which indicated only that it was a connective tissue tumor and did NOT indicate that it was of a specific organ, would not permit that tumor's organ-relation (i. e. , association with any and all other tumors of that specific organ) being indicated by code. However, by providing the units for specifying the organ or organ system, when a tumor i_s specifically associated with (i. e. , has arisen from) an organ or organ system, it is possible to retrieve, from a file of coded data, information on all tumors of any given organ or system by a single mechanical sort (e. g. , information on all tumors of the mammary gland, regardless of their being adenocarcinomas [epithelial], fibrosarcomas [connective tissue], melanomas, or otherwise). 4. Part HI of the tumor symbol (4th, 5th, and 6th units, Columns 21, 22, and 23): tissue origin The fourth, fifth, and sixth units of the tumor symbol are organized to parallel standard tumor classification and nomenclature, which is essentially based on tissue types. The fourth unit of the tumor symbol (i. e. , the first unit of Part III) indicates to which large general histological group the tumor belongs. Thus, symbols for this fourth unit have the following definitions. 33 FIELD E; Tumor Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 Symbol for the fourth unit (Column 21) Animal tumors 1 Epithelial tumors (including all tumors derived from glandular tissue, regardless of its being endocrine or exocrine gland tissue) 2 Hemopoietic tumors: tumors of blood and lymph and blood- and lymph-forming tissues 3 Connective tissue tumors 4 Miscellaneous tumor tissue types difficult to identify with normal tissues: "round cell tumors", "spindle cell tumors", etc. 5 Muscle tissue tumors 6 Vascular tissue tumors; endothelial tumors 7 Nerve tissue tumors and tumors of tissues of the nerve sheath, meninges, etc. 8 Pigment tissue: melanin-forming-tissue tumors (often related to, or are of, nerve tissue origins) 9 Tumors of mixed tissues including teratomas A Embryonic tissue tumors Plant tumors J Epidermal tissue tumors (plant) K Vascular tissue tumors (plant) L Parenchymal tissue tumors (plant) M Pigment tissue tumors (plant) N Embryonic tissue and mixed tissue tumors (plant) The tumors included in this published edition of the CBCC Biology Code are listed according to their tissue origins. Therefore, that list itself includes, in consecutive sequence, the definitions of the above symbols for major tissue types. In addition, by virtue of this arrangement of the tumors, the definitions for symbols of units five and six (see the following paragraphs) are likewise evident in the Tumor Code list. This makes unnecessary a special listing of the tissues and their symbols, either here or in the Code, beyond the introductory outline above. The fifth unit represents a subdivision of the major tissue type of tumor. For example, when Symbol 1 (tumors of epithelial tissue) is the fourth unit, Symbol 1 as the fifth unit signifies a tumor of glandular epithelium, while Symbol 2 in the fifth place indicates a tumor of non-glandular epithelium. In the same way, the sixth unit represents a subdivision of the tissue type indicated by the fifth. For example, Symbol S — 111 represents tumors of endocrine glandular epithelium, whereas S--112 represents tumors of exocrine glandular epithelium. Although the organ-designating part of the tumor symbol (the second and third units) and the tissue-designating part (the fourth, fifth, and sixth units) have independent meanings, it is the combination of the two parts in any given tumor symbol that serves to identify exactly the place of origin of the tumor. Therefore, these five units (2-6), considered in combination , make up a single location-identifying unit, designating the origin of the tumor represented by the symbol. (See the diagram included in Division 1 of this description of the Tumor Code. ) 5. Part IV of the tumor symbol (seventh unit, Column 24): modifier for distinguishing tumors of identical organ-tissue origins (Parts II and III); causative agents of plant galls Since, in general, tumors have been regarded as being characterized by the tissues from which they arose and have been named to reflect this, the tissue designation of Part III (units 4, 5, and 6 of the tumor symbol) is frequently adequate for distinguishing a tumor type , or Part III and Part II (the organ origin), as a combination, is adequate. This is not always the case, however, and it is frequently important to be able to distinguish two or more types of tumor which are not distinguished merely by coding the organ and tissue origin. - 34 FIELD E ; Tumor Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 Part IV (unit seven of the tumor symbol) is used for the final distinction of any tumor type, whenever preceding units of the symbol have been inadequate. It is used very loosely and without a strict definition , since it is thereby more useful from the standpoint of providing unique symbols - Examples will explain best the use of the seventh unit: A. Tumors of glandular epithelium, unspecified (i. e. , when the type of gland is not specified, nor is the glandular organ specified, Symbol S0011 ) have been distinguished as unspecified adenocarcinoma, unspecified adenoma, and unspecified papilloma by using the seventh unit: S001101-, S001102-, andS001103-, respectively. This does not mean that it is intended that all adenocarcinomas are designated by Symbol 1 as the seventh unit, nor all papillomas by Symbol 3 as the seventh unit. (Pulmonary adenocarcinoma C4461, e.g. , is S21 112^1, Pulmonary Carcinoma MT8 is S21112_31. ) Instead, it serves in this particular case to modify the specific symbol, S0011 (i. e. , distinguishing three types of tumors described by the specific symbol, S00 11). B. Consider the epithelial tissue tumors of the lung. Here the seventh unit has been used to distinguish pulmonary adenomatosis (S2 1 1 12_1_-), pulmonary adenocarcinoma (S211122^), pulmonary carcinoma (S211122-). and pulmonary adenoma (S211124-). It does not mean that all adenocarcinomas are designated by Symbol 2 as the seventh unit (though all pulmonary adenocarcinomas are distinguished by it) nor all carcinomas by Symbol 3 as the seventh unit, etc. C. Note the two symbols, S5A1 1 1 1 and S5A1 1 12, both of which represent endocrine gland tumors ( 111--) of the ovary (-5A ). It happens that the ovary contains more than one tissue that is described as endocrine and tumors may arise from each. Thus, the seventh unit is used to distinguish ovarian endocrine granulosa cell tumors (S5A11H-) and ovarian endocrine luteomas (S5A1112-). D. The seventh unit has been used to distinguish any aleukemic form of leukemia (S--21-2-) from the more common type in which there is a great increase in blood leukocyte numbers (S--21-J_-). The seventh unit has an additional use, peculiar to plant tumor symbols, in distinguishing galls relative to their causative agents, such as microorganisms, insects, or chemicals. This factor of the causative agent has perhaps more significance relative to classification of galls than it has relative to classification of animal tumors and therefore one unit, the seventh, has been allotted this coding function in making symbols for galls. For example, Symbol SS6N001- is interpreted as: a chemically- induced ( _1~) tumor (S ) of mixed tissues ( NOP --) of a plant leaf (-S6 ). In coding such a plant tumor, the specific causative agent (in the example above, a specific gall- producing compound) must be included in the written abstract portion of Field E. In the case of animal tumors, the seventh unit has no special meaning or significance other than as a modifier. In other words, it is not reserved for especially indicating, for example, malignancy, tumor form, special tissue, nor special organ, though it may modify and provide specificity of the organ- tissue origin on the basis of any of these. For this reason, an arrangement of the Tumor Code items in a sequence according to Part IV (the seventh unit) would be meaningless (except that for plant galls the arrangement would be by causative agents). 6. Part V of the tumor symbol (eighth unit, Column 25): designation for specific, named, and transmissible tumors The eighth unit provides a final, distinguishing part for specific , named tumors. For example, there are included several specific ovarian granulosa cell tumors, all with units 1-7 being S5A1111-; the symbol for each of these specific tumors is completed by assigning a final, eighth, sequential unit determined merely by the arbitrary way of its being listed or added to the list. Thus, ovarian granulosa cell tumors 18C57, 0L, and E4478 are given the following unique CBCC code symbols: S5A111U, S5A11112, and SSAllll^. A non- specific ovarian granulosa cell tumor would be coded by Symbol S5A1111 (no eighth unit). In the case of plant galls , there are anticipated but few symbols with an eighth unit indicating a specific gall, since individual galls are seldom named and maintained as specific tumors, in the way certain experimental animal tumors are. In plant tumor symbols, nevertheless, the eighth unit is left open for any that might be so individually named and maintained. 35 FIELD_E; Tumor Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 For any given tumor type (indicated by units 1 through 7 of the tumor symbol), there may be several or many specific tumors which must be distinguished by unique symbols in the eighth place. Symbols 1 through 9 and A through Z in the eighth place permit unique code symbols for 35 specific tumors. In most cases, this is more than adequate provision. If more than 35 occur, however, and must be assigned symbols, they can be accommodated only by the procedure as described in the division immediately following. 7. Construction of symbols for specific tumors of identical organ- tissue origins, when more than 3 5 such tumors must be included in the Tumor Code When there are more than 3 5 specific tumors with identical organ and tissue-type origins, the SEVENTH unit, coding that tissue type, may be combined (on the IBM punched card) with a zone punch (which will make it a corresponding letter designation) and the sequential numbering of the EIGHTH place repeated for the next thirty-five tumors of that tissue-type. In the present tumor list, this occurs only once, in the case of mammary gland adenocarcinomas. After the 35th adenocarcinoma was listed (Symbol S911121Z), the 12 zone punch was added to the seventh unit (Symbol 1), which converted it to the corresponding letter (Symbol A) and sequential numbering and lettering was begun again in the eighth place; thus, the symbol for the 36th adenocarcinoma is S91112A1. In this example, by using both the 11 and 12 zone punches for combinations, it is possible to accommodate 105 mammary adeno- carcinomas in the list. (It happens that Symbol 1 can not be meaningfully combined with the IBM zone punch, though other numerical symbols, 2-9, can; see the following paragraphs. ) By this means, information on a_ll mammary adenocarcinomas can be retrieved from a file of coded data by sorting solely on the Symbol S911121, ignoring the zone punches, while information on any given mammary adeno- carcinoma can be found by sorting on its specific symbol, including any zone punch designation. (In this example, it should be noted that the letter designations formed by using the zone punches [letters A and J, formed by combining Symbol 1 with the two zone punches in turn] can not subsequently be used again as distinguishing seventh units for symbols for tumors of the type coded by the six- unit symbol, S91112--. For this reason, only numerical symbols 1 through 9 are used as a seventh unit [except as a continuation, as just described] in listing specific tumors of a given organ-tissue type. ) In the case of the seventh unit being any numerical symbol other than 1 ( and , discussed in the next paragraph), that symbol can be combined with the zone punch as well as with the 11 or 12 zone punches so that 140 specific tumors of a given organ-tissue source are possible in the list. (E. g. , combining Symbol 2 with all zone punches in turn makes possible a set of 35 tumors for each of the four symbols, 2, B, K, and S, as the seventh unit. ) When a symbol for any particular organ-tissue type of tumor (units one through seven) has less than seven units (e.g. , glandular tumors of the fundic stomach, S1A112--) and is incorporated into a specific tumor symbol, Symbol is used as a unit or units between the final unit of the tumor- type code designation and the eighth unit; for example, Carcinoma 303, S1A11201. (This is explained again, in a slightly different way, in Division 8, below. ) Thus, in the case of any specific named tumor, of a tumor type whose symbol is less than seven units, the seventh unit of the eight-unit total symbol is always 0; this seventh unit symbol, 0, can be combined with eighth units in only 35 ways for 35 specific tumors. This is due to the fact that numerical Symbol (= zone punch 0) can not be combined on the IBM punched card with the other numerical symbols (2-9) to make corresponding letter symbols, because this combination is reserved for those other numerical symbols when they occur as seventh units. (Refer to the first paragraph of this division. ) However, it is suggested that, in enlarging the Tumor Code, if there actually occurs a series of more than 35 specific tumors with identical organ-tissue origins and with their seventh units being Symbol 0, it will be possible to combine the with one of the other zone punches (written on the code sheet as * or *h to make 70 combinations for 70 more specific tumors. Even though specific tumor symbols may have Symbol as their seventh unit (or as any or all of their second to seventh units), or though specific tumor symbols may have letter symbols as their seventh units, neither Symbol nor any letter symbol in the seventh place can be interpreted as representing that tumor type . When searching information files for all data on tumors of a given type, therefore, the tumor list should be consulted for the symbol for that particular tumor type; that symbol will not end in nor, if it has seven units, will its seventh unit be any symbol other than numerical, 1 through 9. 36 FIELD E ; Tumor Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 8. Use of Symbol as a unit or units in constructing tumor symbols When any specific, named tumor on this list (i. e. , a tumor demanding an eighth unit in its symbol) is of such a general nature that there is no relation to a specific organ or organ system origin (i. e. , the second and third units of the tumor symbol), the third- -or the second and third- - units are assigned Symbols or 00, respectively. In the same way, if any specific tumor of the list is classified histologically (i. e. , the fourth to the sixth units) so that less than three units are needed, the sixth, or both the fifth and sixth, or all three places are assigned Symbol (i. e. , 0, 00, or 000, respectively). A specific and named tumor for which no histological or organic information exists may be added to the Tumor Code and assigned a symbol with any or all of the second through the seventh units being Symbol and with a distinguishing symbol as the eighth unit, so that this specific tumor will have a symbol with the full complement of eight units, indicating a distinct and specific tumor. Example: Sarcoma M4 (S0040001). (Notice that in coding tumor data in which the tumor is not named as a specific, unique, transmissible tumor, that tumor is not added to the Tumor Code and no specific symbol is assigned to it. It is coded merely as being a tumor, Symbol S, in the first column of Field E, with the other seven places blank, or as a tumor of a specific organ [the first three places only, of Field E], or as a tumor of a specific tissue type [the first and the fourth places only], etc. ) 9. CBCC Tumor Code: an initial and representative list; responsibility in making permanent additions Although this is a more extensive listing of tumors than would be represented by those for which the CBCC has actually found test data, it does not, on the other hand, pretend to be an exhaus- tive list of known, named tumors nor of tumor types. New tumors, however, can be added to the list and symbols can be constructed for them in the same way as tumors have been added in the past. It should be understood that construction of new symbols for the Tumor Code (or, for that matter, for the Pathology Code or the Taxonomy Code of Field E), is itself a coding procedure. The symbol that is assigned to any given specific tumor must have correctly incorporated into it, at the time of its construction , all the information about the tumor that it is possible to obtain. This may occasionally involve an elementary literature search or correspondence with the author of the data mentioning the new tumor, or with an authoritative source of tumor information in general. (E. g. , if a tumor is added to the code at a time when information about its tissue origin is not at hand and the tissue origin code unit of the tumor symbol is assigned merely a series of Symbols 0, and then, if one year later information about the tumor's tissue origin ^s learned, the tumor symbol cannot be changed without recalling all coded chemical- biological data with which that tumor symbol had been used and altering each tumor code entry. ) The list of tumor symbols included in the Code were for the most part constructed by using information assembled by Dr. Lucia J. Dunham and Dr. Harold L. Stewart and published in 1953. (A Survey of Transplantable and Transmissible Tumors; Journal of the National Cancer Institute, Vol. 13, No. 5, April 1953, pp 1299-1377. ) The authors pointed out in their introduction that it represented a first attempt and that subsequent information might be expected to reveal omissions. The CBCC code symbols for tumors of this list should always be reassessed in the light of any new information and appropriate changes should be made for any discrepancies with that new information. It should be specifically understood that the pattern for constructing tumor code symbols is not intended merely for these transplantable and transmissible animal tumors. The objective has been to provide a scheme for coding any tumor. It is assumed that any tumor (including spontaneous tumors of clinical data) can be designated in Field E by constructing a symbol of seven or less digits (if it is not a specific, named, transplantable form) or of eight digits (if it is a specific, named, trans- plantable form), which will designate organ and tissue origin, when known. Many general types have already been included in the list (i. e. , any of the items which are not actually named trans- plantable tumors), in the process of its organization. 37 FIELD E ; Pathology Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 CODING OF PATHOLOGIES GENERAL DISCUSSION OF THE CBCC PATHOLOGY CODE SECTION I: INTRODUCTION 1. General definition of patholog y; restriction of pathologies in the CBCC Pathology Code Disease or pathology is understood to define a condition deviating detrimentally from an anatomically or physiologically "normal" state. In general, disease originates (1) from an invasion of parasitic organisms (infectious diseases), (2) from damage by external physical forces (traumatic or radiation diseases, e. g. ), (3) from insufficiency of any essential material such as a specific food, oxygen, vitamins, etc. , (4) from chemical poisons, (5) from congenital defects, or (6) spontaneously from no known external cause (idiopathic diseases, such as those associated with aging, spontaneous atrophies and hypertrophies, certain inflammations, etc. ). Distinction is made hereafter between infectious diseases and diseases of other etiological types (i. e. , types by origin) by referring to the latter collectively as non-infectious diseases. This is by no means an absolute categorization; certain forms of disease, notably tumors, might have any of several possible origins. In the Pathology Code of Field E, diseases of all etiological types are incorporated. The follow- ing observations should be made, however. A. All tumors are organized into a special code for Field E, the Tumor Code, and therefore are not included with the items of the Pathology Code. In the Tumor Code, no provision is made for coding a tumor etiology specifically, even if known, although certain very general etiological information about a tumor can be coded by symbols provided in another field, Field F. B. In the Pathology Code, the non-infectious diseases (defined above) are organized and assigned symbols as described in Section II. C. Names of infectious diseases (defined above) are included in the Pathology Code list for convenience, but their symbols do not conform to the pattern for symbols of non-infectious diseases. Infectious diseases and their symbols, taken from the Taxonomy Code of Field E, are discussed later, in Division 2 of Section II. 2. Coding of non-infectious pathologies; factors determining the CBCC coding pattern The most extensive and generally used classifications of diseases are to be found in the two publications, Standard Nomenclature of Diseases and Operations (American Medical Association) and Manual of the Internatio nal Statistical Classification of Diseases, Injuries, and Causes of Death (World Health Organization)^ Both of these are the results of painstaking labor by highly qualified medical specialists. Because they claim different objectives, the two classifications are organized differently and their code symbols, though they are analogous, differ in structure and definition. 1. Standard Nomenclature of Diseases and Operations, 4th Edition; R. J. Plunkett, M. D. , Editor, and A. C. Hayden, R. R. L. , Associate Editor; published for The American Medical Association; McGraw-Hill Book Co. , Inc., 1952. 2. Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death, Sixth Revision of the International Lists of Diseases and Causes of Death, Adopted 1948; Bulletin of the World Health Organization Supplement I, 1948. 38 FIELD E ; Pathology Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 While the excellence of these standard lists favored the CBCC's acceptance of symbols of one or the other for coding non-infectious pathologies, certain features did not recommend the adoption. The following four points are discussed here, since they describe factors that made adopting symbols of the classification schemes mentioned above inadvisable; at the same time, they are factors that in- fluenced the development of the CBCC pattern of coding non-infectious pathologies. A. The CBCC made the initial decision to use Field E to identify the specific causative organism (i. e. , etiology) in coding information about chemical treatment of infectious diseases. Excluding infectious diseases reduced markedly the number of specific diseases for which a special Field E coding scheme would be needed to provide identifying code symbols. B. It will be noted that the CBCC collects only information on experimental testing of chemicals on biological systems; furthermore, because some lines had to be drawn to make practical limitations to the coverage of which the CBCC was capable in the beginning, general clinical results have not as a rule been selected for coding. Even were clinical data to be compre- hensively coded, the fact remains that, of the literally hundreds of specific conditions for which non-infectious pathology symbols may be constructed, only a limited number will be treated with chemicals experimentally, in spite of currently increasing chemotherapy practices. C. Certain of the other fields of the Biology Code bear relationships to Field E so that information about a pathology is coded in them which otherwise would need be incorporated into the pathology symbol. Field T-2 exemplifies this, since a code entry in that field frequently supplements a pathology symbol coded in Field E. Thus, by virtue of having Field T-2, the CBCC Pathology Code has been relieved of the bulk of unique symbols which would be necessary for specific symptoms of diseases (e. g., hemorrhage of ovary due to scurvy; inflammation accompanying infection by a specific parasite; fever due to a specific poisoning; etc. ). Likewise, use of Field H supplements pathology symbols so that frequently special symbols need not be constructed for the condition of each specific organ in a specific disease (e. g. , eczema of the arm; effects of frostbite on blood vessels ; effects on blood by hookworm infection; etc. ). D. A fourth factor that should be pointed out is that of limitation of space on a single IBM punched card. To leave coding space for all other factors of biological testing and confine biology coding to a single card, only eight places (i. e. , only eight IBM punched card columns) were reserved for a symbol for a pathology (or test organism or tumor). The CBCC's purpose is primarily to record the results of experimental chemical treatment, using available space of a single punched card for that experimental data; it is not to record full descriptions of pathologies which might demand a coding scheme using an entire punched card. (See the second paragraph of Division 3 below.) The factor of limited coding space on the IBM punched card, combined with the facts that the CBCC Biology Code would need only a limited number of non-infectious pathology terms and that these pathology terms would be supplemented by coding other than that in Field E, led to the formation of the special CBCC Pathology Code. 3. The CBCC pattern for coding identity of treated pathology is essentially a proposal, not actually tested by use It must be emphasized that the CBCC has attempted coding very little information about exper- imental chemotherapy of non-infectious pathology. A list of pathologies was compiled in the initial stages of the development of the Biology Code to which symbols were assigned by a pattern that was subsequently lost or forgotten. When the few occasions arose to do so, identification of non-infectious pathologies was made according to this list. For practical reasons, that list has been abandoned. The present scheme for coding non-infectious diseases, prepared for this published edition, must be regarded only as a proposal which seems reasonable under the conditions impressed by the total CBCC coding pattern and which would seem to satisfy the needs of the CBCC for its stated objectives and scope of pathology coverage. - 39 FIELD E ; Pathology Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 It is possible that, for effective coding treatment of non-infectious pathology, in a program dealing intensively or exhaustively with data from laboratory and clinical drug trials, a more elaborate pattern would be necessary. This might conceivably become comparable to the present CBCC handling of chemical structures, whereby a separate and special Code Sheet would be used for a given named pathology, an entire IBM punched card devoted to the pathology's complete description, and the identity of the pathology made on the general Biology Code Sheet only by a reference number comparable to the CBCC Chemical Serial Number. In any case, it would seem unlikely that the retrieval and correlation of information about responses of diseases to chemicals could be accomplished satisfactorily except by persons with some specific experience with the field of pathology and its nomenclature. SECTION II: CODE SYMBOLS FOR PATHOLOGY; INFORMATION CODED IN FIELD E ABOUT A SPECIFIC NON-INFECTIOUS PATHOLOGY 1. Symbols for NON-INFECTIOUS diseases; Part I of the pathology symbol (1st unit, Column 18) Inasmuch as non-infectious pathologies are coded in the same field as any test organism or tumor may be coded, it is necessary that the Pathology Code symbol for non-infectious diseases be distinguished from symbols of the Taxonomy Code and the Tumor Code. For this purpose, the first of the eight units of the total non-infectious pathology symbol is always Symbol T. As a result, only seven units (i. e. , seven IBM punched card columns) are actually available for symbols distinguishing pathologies of a non-infectious nature. 2. Symbols for INFECTIOUS diseases included in the Pathology Code list When a pathology is caused by an organism (e.g. , an invading bacterium, fungus, protozoan, or other parasite), that pathology is coded by using the symbol for the test organism taken from the Taxonomy Code list. Therefore, Symbol T, as the first unit of a symbol in Field E, signifies only disease of a non-infectious nature, as opposed to infectious diseases and tumors. In the case of infectious diseases, there is no question about designating in Field E a coded anatomical association, since the entire coding area is occupied with the etiological identification. The disadvantage afforded by this is minimal, since, in the case of most infectious diseases, the anatomical designation would be the non-specific "body as a whole". However, in the case of certain infectious diseases or a given instance of any infectious disease, it is important to be able to provide critical identification by naming the site of infection. By the CBCC coding pattern, this can only be done by utilizing Field H as well as Field E. Thus, any infectious disease whose identity demands not only identification of the etiology as the organism in Field E, but identification of the anatomical site, is listed in the Pathology Code with the taxonomic symbol for the organism and the anatomical symbol for the site which must be coded in Field H (in Field H-l, if the site is identical to the specific organ responding, or in Field H-2, if it is not identical to the specific organ responding). 3. Part II of the non-infectious pathology symbol (2nd, 3rd, and 4th units, Columns 19, 20, and 21); the anatomical structures affected by the disease Conventional pathology nomenclature, especially that for non-infectious pathologies, is based primarily on affected anatomy (i. e. , site of the pathology). Therefore, pathologies are assigned code symbols according to an anatomical classification. As pointed out previously, the anatomical site of an infectious pathology can never be indicated in Field E, because all eight IBM columns are occupied with the Taxonomy Code symbol of the infectious organism. The site of the infection can only be coded in Field H. For CBCC purposes, this coding is considered to be essentially adequate for distinguishing from each other all infectious diseases. For non- infectious diseases, Field H is available for indicating the site of the pathology, just as for infectious diseases. However, a greater facility is offered by embodying the anatomical 40 FIELD E ; Pathology Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 classification in the Field E symbols for non-infectious pathologies. Therefore, the coding of the primary anatomical classification of non-infectious diseases has been shifted to Field E, using, how- ever, the classification and symbols established in Field H. This primary anatomical designation is the second part of the total Field E non-infectious pathology symbol, represented by the 2nd, 3rd, and 4th units (Columns 19, 20, and 21). Coding of pathology in Field E has as its primary objective the identification of the specific condition treated, basing identity on anatomical and etiological relationships. Field H is used as a supplement to Field E in the case of pathology Identification, in addition to being used to code the anatomical part specifically responding to the test compound. 4. Relation between the anatomical part of the non-infectious pathology symbol and Field H In coding the identity of a pathology, coding in Field H indicates the location of the pathology, whether infectious or a tumor or even in the case of non-infectious pathologies whose primary or typical anatomical association is indicated in Field E. Field H-l is coded with the organ responding to, or candidate for responding to, the chemical treatment and this is assumed to be the organ site of the pathology; however, if an organ responds which happens to be an organ other than the site of the treated pathology, the organ coded in Field H-l will not represent the site of the pathology, the coding of which must be shifted to Field H-2. Thus, two areas are available for coding non-infectious pathology sites, (1) Columns 19, 20, and 21 of Field E and (2) Field H, a feature lending versatility to code identification of infectious pathologies, as the following explains. Many general non-infectious pathological conditions affect either the entire body or are non- specific and can affect any of a large number of sites; these particular conditions are assigned symbols with no specific site other than "body as a whole" (Symbol BOO), indicated in Columns 19, 20, and 21 of Field E. When such a general pathology is restricted, in the case treated, to only a given anatomical part, the specific location can be coded in Field H. Certain pathologies may be primarily disorders of specific anatomical parts, coded in Columns 19, 20, and 21 of Field E, rather than of the entire body generally, yet, in the case treated, an organ which is secondarily affected by the disease (and which responds to chemical treatment) may be an organ of another type; the second organ can only be coded in Field H (see the third, fifth, and sixth of the following examples). The outline on the following page demonstrates these relations of Fields E and H in coding the anatomical aspects of pathologies, using liver disorders as an example. In these examples of identifying pathologies by code, attention is called to the anatomy entry in Field E (the part of the pathology symbol underlined) and the anatomy entry in Field H-l and to the way these various combinations represent different statements of test conditions or results. 5. Part HI of the Pathology Code symbol (5th and 6th units, Columns 22 and 23); etiology Providing code symbols for specific pathological conditions is beset with problems arising from the nature of pathology and its resistance to classification. The organism is a physiological unit whose normal well being is dependent on the balanced and coordinated functioning of all its parts. When an initial disorder occurs, or when the organism is attacked by infection, the coordinate physiology is disrupted and a chain of subsidiary disorders may occur, contemporary with or subsequent to the initial disorder. The secondary disorders, while definable as entities, all too frequently bear characteristics peculiar to their origins in the primary disorder and, as a consequence, pathology nomenclature has evolved to embrace these origins in definitions. In the case of both infectious and non-infectious diseases, each definition of a pathology in the Code list is made in terms of the origin of the disease, in addition to the anatomical site. For infectious diseases, the origin is defined by the symbol identifying the infecting organism, taken from Taxonomy Code. When an item, included in the list of non- infectious pathologies, defines a pathological state that may have any of two or more known origins, it is assigned a symbol which Identifies the disease - 41 - FIELD E ; Pathology Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 CODING OF PATHOLOGY IDENTITY IN FIELDS E AND H (See Division 4. ) Field E Field H-l Organ responding to chemical treatment. (If the pathological organ is not identical to the organ responding, code the organ pathological in Field H-2 and an asterisk in Col. 30. ) Field H-2 Organ pathological, if different from the organ responding (always accompanied with an asterisk in Col. 30 of Field H-l). (1) Chloroform poisoning: TB002600 (Pathology of the organ- E (Liver) This outline of pro- cedure illustrates coding for: Any path- ology, regardless of primary location, which has affected the liver and which is being treated by the test compound- - or- -situations in which the liver re- sponds to the test compound, regardless of the location of the pathology treated. ism as a whole) (2) Yellow atrophy of the liver: TE10620G (Pathology of the liver) El_ (Liver parenchyma) (3) Periarteritis nodosa: T325X200 (Any organ other than the liver; in this case, it is an artery) E (Liver) (4) Syphilitic cirrhosis: JS902021 (No anatomical part; this is the symbol for the syphilis organism) E (Liver) (5) Cirrhosis TE100002 (Pathology of the liver) 323 (Any organ other than the liver; in this particular example, it is the portal vein. ) This outline of pro- cedure illustrates coding for: Any path- ology specifically hepatic (regardless of primary location) which has affected other anatomical structures which are in turn affected by chemical treatment --or --situ- ations in which organs other than the liver respond specifically to the test compound, although the condition treated is specifically hepatic. (6) B, y deficiency (the liver specifically patholog- ical and the portal vein affected by the test compound): TBOOF900 (Pathology capable of affecting any of several organs) ill (Any organ other than the liver; in this particular example, it is the portal vein. ) The organ affected specifically by the test compound. E (Liver) (When accompanied with an asterisk in Col. 30 of Field H-l, this coding in Field H-2 represents the specific organ which is the site of the path- ology coded in Field E.) (7) Clonorchiasis: 42103011 (No anatomical part; this is the symbol for the infecting trematode) ii (Any organ other than the liver; in this particular example, it is blood. ) The organ affected specifically by the test compound. E (Liver) (When accompanied with an asterisk in Col. 30 of Field H-l, this coding in Field H-2 represents the specific organ which is the site of the path- ology coded in Field E. ) 42 - FIELD E ; Pathology Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 anatomically only and which omits any etiological association; this is usually accompanied in the list by one or more items, each defining that state in which one of the possible known etiologies is specified and that specification is made in the symbol . Cirrhosis, for example, may have any of several recognized causes and cirrhosis is given a coding identity (by Parts II and IV of the symbol, Columns 19, 20, and 21 and 24 and 25) independent of the etiology (Part III, Columns 22 and 23). Cirrhosis is recognizable, therefore, even when no etiology is expressed (TE1 00002), as well as when it is due to a known cause (TE1 04202). On the other hand, when an item is included in the list defining a non-infectious state of whose origins medical science has no certain knowledge, it is assigned a definite etiological symbol specifying that (Symbol 7, G, P, or X, or 8, H, Q, or Y, in Column 22). All such diseases are given secondary classifications based on the anatomical effect of the disease or on the physiological action disrupted by the disease, whichever is the more characteristic manifestation of the pathology. Osteo- arthritis and rheumatic fever are examples of specific recognized diseases whose etiologies are still conjectural; the etiological symbols for those diseases specify this (T9307J0A and TB00G102, respectively). Coding etiological factors has necessitated constructing a special list of etiologies to which diseases can be referred and from which symbols can be taken to construct unique Field E symbols for the Pathology Code. For this, the etiology organization of the American Medical Association "Standard Nomenclature of Diseases and Operations" has been used as a guide. Columns 22 and 23 of Field E are designated for coding the etiology of a non-infectious pathology and these 4th and 5th units of the total Field E pathology symbol represent the third part of the symbol (i. e. , the third category of information identifying and indexing diseases). The special list of etiologies and their symbols is included in the Code following the list of pathologies for which symbols have been constructed. While the classification itself can scarcely be described as provisional or unproved, since it is basically that of the AMA scheme, the proposed rather rudimentary adaptation should be regarded as candidate for further study and development. By reference to the etiological classification in the Code, it will be seen that, in each of the eight major etiological categories, 140 symbols are available for specific etiologies. The basic symbol for each of the eight major categories is a numerical symbol in Column 22, Symbol 2, 3, 4, 5, 6, 7, 8, or 9. Each of the eight symbols can be combined with each of the three IBM zone punches to represent letter symbols. Thus, the first etiological category is represented in Column 22 by Symbol 2, Symbol B (the IBM punch in the "2" position plus the 12 zone punch), Symbol K (the 2 punch plus the 11 zone punch), and Symbol S (the 2 punch plus the zone punch). The second category is represented by by Symbols 3, C, L, and T; the third category by Symbols 4, D, M, and U; and so on. Symbol 1 has not been used in Column 22 for an etiological designation, because it can not be combined with the IBM zone punch and given meaningful interpretation on the IBM equipment used by the CBCC and because the remaining symbols (2 through 9) have seemed adequate for all the etiological categories needed. The two etiological categories, infectious organisms and tumors, are omitted, because they are given special coding treatment, although the eighth category (Symbol 9 in Column 22) refers to an infectious agent in the history of a disease as being the typical initial pre- disposing factor to the disease by definition. In the latter case, since the organism is no longer present, the chemical treatment of such a disease is incapable of affecting the infectious organism as a living system, and the basic reason for identifying the disease by a Taxonomy Code symbol there- fore does not exist. Within a major category, the available symbols have in most cases been distributed to provide a reasonable secondary classification of etiologies. For example, within the fifth category, the symbols are divided among specific subcategories so that Symbol 6 in Column 22 is designated to specify metabolic disorders and toxins of metabolic origin as causes of pathology, Symbols F and in Column 22 are assigned to specific deficiencies as causes of pathology, Symbols Wl through WR indicate endocrine functional abnormalities as causes of pathology, and Symbols WS through WZ indicate specific disorders in growth and development as causes of pathology. 43 FIELD E ; Pathology Code Columns 18, 19, 20, 21, 22, 23, 24, and 25 It seems improbable that coded etiologies will be found a highly useful index for chemical- biological information, except in the case of infective organisms which represent specific "biological systems" against which chemicals may be administered experimentally. CBCC interests are cen- tered on biological conditions specifically treated by and/ or responding to (or caused by) chemicals. In the case of treated non- infectious pathological conditions, the origin of that pathology is of little significance, because it may be assumed that that initiating factor is not specifically treated or responding. Etiologies of non- infectious diseases are incorporated in the coding scheme pre- sented here essentially because it has seemed the only reasonable solution to the problem of clas- sifying and identifying by code specific named pathology states treated. 6. Part IV of the Pathology Code symbol (units 7 and 8, Columns 24 and 25 ) Certain specific causes of disease produce such unvarying pathology pictures that identification of the causative factor is tantamount to identifying the disease; identifying infectious pathologies essen- tially by coding in Field E only the etiological agent (the infecting organism) is based on this concept. However, in the reverse, there are a number of pathological states of given anatomical parts, distinguished as pathology entities by standard nomenclature, which may have any of several causes. To provide a fixed symbol for such a named pathology, regardless of the causative agent, Columns 24 and 25 are used for a coding distinction of diseases of the anatomical part coded in Columns 19, 20, and 21 . Likewise, there are certain very general, yet uniquely named, pathological conditions that can be associated with almost any anatomical part and caused by many etiological factors. Two types of entries are made in these final IBM columns of Field E, one being distinguished by use of only numerical entries in Column 25, the other by only letter symbols in Column 25. Those entries of Columns 24 and 25 with only numerical symbols in Column 25 have no special meaning except to distinguish named diseases of a given anatomical structure which might not be distinguished by an etiology coded in Columns 22 and 23. For example, both "cough" and "dyspnea" are pathologies of the respiratory system and each may result from any of several causes. A symbol is constructed for each, with a nonspecific etiological part (Symbol 00 in Columns 22 and 23); the symbols for the two conditions are distinguished by assigning Symbol 01, in Columns 24 and 25, to "cough" and Symbol 02 for "dyspnea" (T500000J and T5000002, respectively). This type of entry which is distinguished by a numerical symbol in Column 25 has no " fixed " meaning. Thus, Symbol 01 in Columns 24 and 25 designates "cough", or "glaucoma", or "diarrhea", depending on the entry in Columns 1 9. 20, and 21. (Compare this with the second type of entry of Columns 24 and 25, which has a fixed meaning, described below. ) Subsequently, when a symbol is constructed for a cough due to any one specific cause, Symbol 01 in Columns 24 and 25 is used with Symbol 500 in Columns 19, 20, and 21 (invariably indicating "cough" when used together) and the nonspecific Symbol 00 in Columns 22 and 23 is substituted with the symbol for the cause. This will constitute a new entry in the Pathology Code. By using two columns (24 and 25) and only numerical symbols in each, 99 named pathologies can be distinguished for each anatomical structure coded in Columns 19, 20, and 21, in addition to pathologies of that same anatomical structure which are adequately distinguished by coding only the etiological factor in Columns 22 and 23. The second type of entry in Columns 24 and 25 (with letter symbols in Column 25) differs from the first in that each symbol is given a fixed meaning, regardless of either the anatomy entry in Columns 19, 20, and 21 or an etiological entry in Columns 22 and 23. These are ordinarily for certain general pathological states which can occur in many anatomical parts (or in any part) and which may have any one of many causes. A good example is the common "inflammation", which is always coded with Symbol 0A in Columns 24 and 25 when it is the chief manifestation of a disease, regardless of the site and etiology coded in Columns 19 through 23. A second such general condition, "shock", has been assigned Symbol 0B, "congestion" has been assigned Symbol 0C, etc. It is suggested that enough symbols for all such conditions needed by the CBCC (90 symbols) will be provided by using a single IBM zone punch, the \Z_ zone punch, so that only letters A through I should be used in Column 25, combined with any numerical symbol in Column 24. - 44 - FIELD F Column 26 SEX AND STAGE OF DEVELOPMENT OF THE TEST ORGANISM; MISCELLANEOUS INFORMATION CONCERNING TUMORS Organization In this field, the IBM zone punches 12 and 11 (coded as Symbols * and #, respectively) have been assigned special meanings, for which reason Symbols A through R (formed by the 12 or the 11 zone punch variously combined with the numerical punches 1 through 9) are unavailable for assignment. Symbols S through Z (formed by using the final [0] IBM zone punch with the numerical punches) have been used for coding certain tumor features. Thus, these symbols can not be used for stages of development of a test organism. As for the several lists of developmental stages, the definitions are arranged and assigned to Symbols 1 through 9 so that the youngest stage of development is represented by Symbol 1, followed by a step-wise progression to the oldest stage, assigned to Symbol 9. In the case of certain taxonomic groups, especially the lower plant forms, analogy with stages of other groups is not possible, since not only stages of one generation but of two or more generations needs distinction; however, an effort has been made to be consistent in retaining the gamete as a beginning point in life cycles. (The alternative would have been preparation of a list of stages for each generation of such an organism which is not practical for the CBCC purposes. ) General Use The sex and stage of development of the test organism , at the time of treatment with the test compound, is coded in this field by use of Symbols 1 through 9 and * and #. The sex and stage of development of host organisms is coded in Field K, rather than Field F. The stage of the test organism when observed , if older than the stage treated with the test compound, is not coded (either in Field F or elsewhere). If Field E is not coded with an organism but with a non-infectious pathology or tumor, Field F is not used except to code tumor information by use of Symbols S through Z, when appropriate. Specific Directions and Explanations 1. Relationship between Fields F and E Field F is used only to describe entries in Field E, either sex and stage of development of a test organism (Symbols * and # and 1 through 9) or information about a tumor coded in Field E (Symbols S through Z). Sex and stage of development of a host is never coded in Field F, but only in Field K. 2. Distinction between author's expressions of sex of organism used; coding of sex If the author designates that only one sex is used, it is important that that sex be coded in Field F. If the author indicates that "either sex" is used, code neither * nor # in Field F. I. e. , do not arbitrarily code * or #, because that procedure is reserved for indicating that a sex distinction was made and has significance, and do not code both sexes in Field F, since if either sex satisfies the requirements of the test, the distinction is unnecessary and it furthermore permits reserving coding of both sexes for the following situation. 45 FIELD F Column 26 If the author specifies that, in a group of test organisms used in a single test, both sexes are used, there is an implication that the choice of both sexes has some significance. Therefore, this fact is coded by entering both of Symbols * and # in Column 26. (See also Division 4 below, describing double coding, which differs from the use of both Symbols * and § as just described. ) 3. Stage of development to be coded in Field F When the lapse of time between application of the test compound and the observation of response is of such duration that the test organism progresses from one developmental stage to another, the question arises as to whether there should be coded the stage given the test compound or the stage in which the response is manifest, since there is only one field (Field F) provided for this category of information. The CBCC has defined its single Field F to limit it to coding the stage at which the test compound was administered, which makes for consistency in the code statement describing the adminis- tration of the test compound- -the dose recorded in Fields M and N, in the conditions recorded in Fields A, B, and C, by the route indicated by Field S-3, to the stage of the organism coded in Field F. Unfortunately, the stage on which the observation is made (if later than the stage to which the compound is administered) can not be coded, because the CBCC has not felt that the few occasions when a second Field F would be needed for this justified reserving IBM space for it. The stage responding must be described in the written abstract portion of the field. The action coded in Field T and the evaluation time coded in Field V may sometimes suggest that the responding stage is a later stage than the one treated (Field F). When Symbol is coded in Field S-3, indicating that the test compound was applied to the parent, with the response (coded in Field T) observed on the offspring, the stage of development of the offspring at the time of application of the test compound, if known, is coded in Field F. (This is par- ticularly in reference to viviparous organisms in which the developing young organism is exposed, just as an organ would be, to the test compound. ) If the stage of development at the time of administration of the compound is not specified by the author, nothing will be coded in Field F, because Symbol of Field S-3 describes the situation adequately. 4. Double coding of results from two or more tests with the only variable being sex or stage of development If separate sexes are used in separate test runs and the only difference in the procedure is the sex of the organism and if the results of the tests are so similar that they can not be distinguished by the Code, a single code line is adequate for both tests, with Field F coded with Symbols * and #. (This combination of two or more tests in a single line, accomplished by a double entry in one field, is re- ferred to as double coding. ) The written abstract of Field F should record clearly the fact that the code line represents separate tests using different sexes rather than a single test using both sexes . The latter is described in Division 2. If tests are made at each of several stages of development (the stages of development being the only variable in the tests) and the response and evaluation for all these tests are so nearly the same that they can not be distinguished by the Code, double coding with any of Symbols 1 through 9 is permitted. This double coding of stages does not interfere with double entry for both sexes in the same line. (See the last paragraph of Division 2. ) 5. Use of Field F to record tumor information When Field E has no test organism or infectious pathology coded in it (but is coded with a non- infectious pathology or tumor being treated ), there is no need for a field to code sex or stage of development of the entry in Field E. Therefore, under those circumstances, Field F is free for describing another Field E entry, a treated tumor, and Symbols S through Z have been assigned for coding this information. (Since, under the circumstances when Symbols S through Z can be used, Field F would not be used for coding sex and stage of development of an organism, Symbols 1 through 8 might have been given second meanings- -these tumor descriptions- -so that when an organism was coded in Field E, Symbol 1, for example, would represent a stage of development, but when a tumor was coded in Field E, Symbol 1 would represent a characteristic of that tumor. To make interpretation of one field [in this case, Field F] dependent on the entry of another field [Field E] when it can be avoided, is impractical and it was for this reason that Symbols S through Z were chosen rather than 46 - FIELD F Column 26 Symbols 1 through 8 [or A through H or J through Q, which represent IBM punches 1 through 8 plus one of the two zone punches, 11 and 12, used for another special purpose]. ) 6. Translation of size or age into stages of development When the stage of development is not specified, but information is given concerning the size or age of the test organism, the following table may prove helpful in selecting the correct code symbol to be employed. Code symbols for stages of development of test organisms. Code Symbol Organism Rat Mouse Guinea Pig Rabbit Angiosperms 5 weanling <50 g < 3 weeks weanling < 10 g < 1-1/2 wks weanling < 100 g weanling <300 g Having no fully expanded leaves beyond the primaries (usually up to about two weeks after planting) 6 immature 50-150 g 3-9 wks immature 10- 15 g 1-1/2 wks immature 100-250 g < 1 wk s immature 300 g - 2 kg <7 mos Vegetative; pre-flowering; young 7 ("Adolescent", in stages of development of animals; applies literally only to man. ) Bearing flower primordia or macroscopic flowers 8 150 g and up (plateaued) >9 wks 15 g and up > 5 wks 250 g and up > 10 wks 2 kg and up >7 mos Post-flowering; bearing fruit which may range from rudimentary to ripe and mature 9 (senile; having lost the power of reproduction) 7. Spermatophytes: further explanation of stages as defined in the Code Symbol l--indicating spore stage--is to be used to specify any stage of the haploid (gametophyte) generation of any of the spermatophytes (i. e. , microspores, megaspores, pollen grains and the nuclei of the embryo sac in the angiosperms or the megagametophyte, microspores, megaspore or pollen grains in the gymnosperms). Symbol 3--indicating embryo stage--is to be used to specify mature or immature embryos. Symbol 4 is to be used to indicate the mature embryo plus the seed coat (i. e. , the complete seed). Symbol 3 indicates complete embryos (cotyledon[s], radicle, hypocotyl and epicotyl) and may also be used to indicate embryos from which some part has been excised. The excision of a portion of the embryo for discard is indicated in Field G- 1 (or G-2) by Symbol P and the organ excised is specified in Field H-2 or the excision of a portion of the embryo to serve as the test organ is indicated in Field G- 1 (or G-2) by Symbol R and the excised organ is specified in Field H- 1. 8. Symbols available for additional items of Field F In the present organization of Field F, all symbols have been assigned. 9. File of coded biology data on IBM punched cards arranged according to symbols for stage of development of the test organism or sex of the test organism or tumor character The CBCC has not established a file of coded data (IBM punched cards) according to coding of Field F. 10. D ouble coding is permitted in Field F , as explained in Division 4. The two or more entries for sex and stage are punched on the same IBM card, as are the two or more symbols used in double coding either or both sex or /and stage. - 47 - FIELD G ( Field G-l) (Field G-Z) Column 27 Column 28 PRETREATMENT OR EXPERIMENTAL STATE OF THE TEST ORGANISM OR OF THE ORGAN, TISSUE, OR CELL OF THE TEST ORGANISM Symbol Z only: EXPERIMENTAL TREATMENT OF THE TEST ORGANISM OTHER THAN TREATMENT WITH THE TEST COMPOUND AND COMPOUND CODED IN FIELD D General Use 1. Field G (Fields G-l and G-2, considered collectively) Field G is used to code any state or condition of the test organism, preparatory for or coincidental with the experiment with the test compound. Such a state may be the result of appropriate chemical or surgical pretreatment , it may be a naturally occurring special state selected for the experi- ment, or it may be a condition which the test organism has by coincidence . The field is never used to code a condition which is specifically treated by the test compound; such a condition is always coded in Field E, not in Field G. In the following paragraphs discussing Field G, the expression "experimental state" is used in reference to those states or conditions (of the test organism or of the organ or tissue of the test organism) which are not being tested for a specific response to the test compound. Neither do these experimental states bring - about a state or condition (i. e. , a pathology) which is tested for response to the test compound. The experimental states coded in Field G include results of operative procedures that are merely to facilitate the test or the observations of the responses. For example, an organ of the test organism may be denervated to isolate the organ functionally from nervous control. This denervation, as an operative procedure, is not a condition being specifically treated, for it is scarcely conceivable that the test compound could alter that specific fact of the nerve's being severed. The purpose of such an operation is to provide an organ whose response to the test compound will be exclusively chemical response and not complicated by nervous responses. In this case, denervation is coded in Field G (Symbol Q), the test organism to which the test organ belonged is coded in Field E, and the organ isolated is coded in Field H-l. Included also among these experimental states are those indicating (1) that the test organism is of a selected type (e. g. , a resistant strain or a sensitive strain), though the peculiarity of that type is not a condition being specifically treated, or (2) that the individual organism used deviates in some degree from normality (e. g. , it has a nutrient or hormone deficiency, or it happens incidentally to have an infection, or it has been exposed to radiation, etc. ), though this deviation is not a condition being specifically treated. It is urged that the definitions of the field be studied, keeping in mind their use, since frequent coding errors occur due to misuse of the field, particularly in the case of beginning coders. A typical error occurs in coding a test compound's effect on a given hormone deficiency; an inexperienced coder 48 FIELDS G-l and G-2 Columns 27 and 28 might code this specifically affected condition in Field G and the organism in Field E, whereas the condition should be coded in Field E (since it was specifically affected) and the organism should be coded in Field J as the host of the condition. On the other hand, if the test compound caused an effect (e. g. , death or paralysis) on an organism which was reported to have a hormone deficiency, the coder might erroneously code the deficiency in Field E, whereas the effect was actually not on the hormone deficiency but on the test organism which should be coded in Field E, with the hormone deficiency coded in Field G. Field G is restricted to expressing an experimental state or condition of the test organism in Field E (or of the test organism's organ or tissue in Field H-l or I). It is not used to describe the host organism coded in Field J, since a separate field (Field L) is used for this purpose, nor does it apply to pathologies coded in Field E , except that Symbols F, G, H, I, and J (and possibly 6 and 8) may be used to distinguish infective diseases (i. e. , to distinguish physiological strains of pathogenic test organ- isms). In the case of tumors coded in Field E, certain items of Field G might conceivably be applicable, if the tumor itself exhibited the experimental condition; if the experimental state is of the host of the tumor (coded in Field J), that condition must never be coded in Field G, but only in Field L. In addition to the major purpose of Field G which the preceding paragraphs discuss, one symbol of the field, Symbol Z, has been provided for and restricted to another purpose. If the experimental factors (states) of Field G have been successfully defined, it will be understood that none of them is considered as part of the treatment of the test organism (in the way the test compound is the treatment), even though they may influence the outcome of the test. Symbol Z, however, is used to indicate a treatment of the test organism other than treatment with the test compound and secondary compounds and accompanying the treatment with the test compound. This single Field G symbol does not permit speci- fying the treatment (i. e. , whether it was radiation, thermal, shock, etc. ) so that if Symbol Z is used, the treatment must be specified in the written abstract of Field G-2. (Symbol Z is coded only in Field G-2 for sake of consistency. ) 2. Fields G-l and G-2, considered as separate fields In order to record the presence of more than a single experimental state (a situation that frequently occurs), there are provided two places, both having the general Field G coding use, as described above. These are referred to as Field G-l and Field G-2. If only one experimental state exists, it is coded in Field G-l. If a second state exists, it is coded in Field G-2. Field G-2, therefore, has no special use other than serving as a place to code a second condition when necessary. Since no space is available for coding more than two experimental states, a third can only be entered in the written abstract portion of the fields. If a non-chemical treatment is given with the chemical treatment, Symbol Z is used in Field G-2, leaving only Field G-l for coding states of the test organism. 3. Relationship of Field G to Fields E, H-l, H-2 and I While it would be more simple, in terms of interrelations, to have separate fields for describing states of the test organism, states of the responding organ, states of organs other than the responding organ, and states of the responding tissues, several reasons make impractical having more than a single area (Fields G-l and G-2) for coding these states. Therefore, coding in Field G can not specify whether it was the organism as a whole, or the organ in Field H-l, or the tissue in Field I (if all three fields have entries) that was given the pretreatment or that was in the state indicated by the Field G symbol, unless the symbol specifies by its definition that it was the organism, organ, or tissue. This is dis- cussed again in Division 4 of the section on Specific Directions and Explanations below. Field H-2 is used to supplement the coding of Field G in describing certain pretreatments or states (Symbols 0, P, B, S, and T) of entries in Fields E, H-l and I. 4. Significance of information about experimental states coded in Field G In most cases, responses to the test compound depend upon, or are modified by, the experi- mental state so that if that state were not present, the response would be to some degree different or might even not occur. Therefore, it is frequently of importance and is sometimes of such importance - 49 FIELDS G-l and G-Z Columns 27 and 28 that, if omitted, the total code line would be misleading. It is for this reason that Field G is provided for recording any experimental state of the test organism . Specific Directions and Explanations 1. Field G is related exclusively to Field E, NOT to Field J As explained more fully in the previous section, General Use of Field G, this field is used exclusively for: A. Describing entries in Field E (or the organ or tissue [Fields H or I] of that entry in Field E), usually test organisms, -- B. Describing conditions that, in a sense, are incidental in that they are not themselves being specifically treated, and-- C. Indicating experimental treatment of the test organism (Field E) other than treatment with the test compound and compound coded in Field D (Symbol Z only). 2. Coding when presence of a tumor is incidental When a test organism, coded in Field E, has a spontaneous tumor and the information being coded is unrelated to any response of the tumor to the test compound, the tumor's presence is merely incidental and should be coded in Field G with Symbol 7, N, or p, but not with Symbol 5. (If the incidental tumor is not spontaneous, but implanted, use Symbol S. ) 3. Use of Field G-l or both Fields G-l and G-2 When there is present only one experimental state, code this in Field G-l; when there are two such conditions, code either of them in Field G-l and the remaining condition in Field G-2, except that Symbol Z should always be coded in Field G-2. (See Division 17. ) 4. Use of Field G (both Fields G-l and G-2) relative to Fields E, H-l, H-2, and I A. Field H-2 In the description of Field H, it is explained that Field H-2 is used only to code an organ that is not an organ specifically responding to the test compound. (An organ specifically responding to the test compound is invariably coded in Field H- 1. ) This organ in Field H-2 may be an organ to which the test compound was applied when application was not to an organ specifically responding to the test compound (i. e. , when application was not to an organ coded in Field H-l). However, Field H-2 is also used with Symbols and P (and infrequently with Symbols B, S, and T) of Field G in describing those states of the test organism, organ, or tissue specifically responding to the test compound. B. Fields E, H-l, and I Division 3 of the section on General Use has described basically the relationship between Field G and Fields E, H-l, and I. Field G is used to describe (a) a state of the test organism or (b) a state of an organ which responds specifically to the test compound (and is therefore coded in Field H-l), or (c) a state of a tissue which responds specifically to the test compound (and is there- fore coded in Field I)- Certain of the items of Field G are defined so that any one of them may represent a pretreat- ment (and the experimental state) of the test organism OR a pretreatment specifically to the organ coded in Field H-l OR to the tissue in Field I. This is particularly true of those pretreatments (experimental states) coded by Symbols 1, 2, 3, 4, and M. For example, by coding Field G with Symbol 4 when Fields H- 1 and I are coded, there is no indication thereby as to whether the organism as a whole was - 50 F IELDS G-l and G-2 Columns 27 and 28 exposed to radiation (Field E), or whether radiation was given directly and specifically to the organ in Field H-l or to the tissue in Field I. Symbols N, Q, R, T, U, V, W, and X do not distinguish as to whether the pretreatments (states) coded by these symbols apply to the organ in Field H-l or to the tissue in Field I (if both Fields H-l and I are coded) except that it is probable in most instances that when a tissue is given pretreatment or is in a special state, the organ of which it is a part received the pretreatment or is in the same state. The same is true for Symbols 6, 8, B, C, D, E, J, and S, except that the pretreatments (states) coded by these symbols are by their nature apt to be restricted to refer to the organism as a whole. (The remaining symbols, 5, 7, 9, A, F, G, H, I, K, L, and P, present no problem in reference to Fields E, H-l, and I, since the relationship is implicit in their definitions. ) The ambiguity of reference of the symbols named could be avoided either by multiplying the number of symbols of the field (e. g. , three symbols for radiation instead of only Symbol 4, one for use when the organism as a whole is radiated, one for the radiation of the organ in Field H-l, and a third for radiation of the tissue in Field I) or by having a Field G equivalent for each of Fields E, H-l, and I. Since neither of these has seemed practical for the CBCC, the coding of Field G can be no more specific than the definitions imply. Therefore, when Field H-l has an entry (with no entry in Field I) and Field G is coded with any of Symbols 1, 2, 3, 4, 6, 8, B, C, D, E, J, M, or S, or when Fields H-l and I are both coded and Field G is coded with any of Symbols 1, 2, 3, 4, 6, 8, B, C, D, E, J, M, N, 0, R, S, T, U, V, W, or X, reference must be made to the written abstract on the code sheet to ascertain whether it was the organism as a whole, the organ in Field H-l, or the tissue in Field I to which the pretreatment was given or which is in the state indicated by the symbol. 5. Conflicts in Field H-2 Field H-2 has been endowed with two major uses and a third infrequent use. (See Divisions 2, 3, and 4 of the section, General Use, of Fields H-l and H-2 and Divisions 1 and 2 of the section, Specific Directions and Explanations, of Fields H-l and H-2. ) For this reason, if Field H-2 should be needed for more than one of these uses in a single code line, it is necessary to follow an established pattern of preference to permit correct interpretation of the coding. These conflicts of Field H-2 are discussed in Division 3 of Specific Directions and Explanations of Fields H-l and H-2. In short, any organ specifically responding to the test compound which is not coded in Field H-l, but is coded in Field H-2, with an asterisk (the 12 zone punch) in Column 30, is given preference over any other use of Field H-2. An organ in a special experimental state (indicated by Field G-l or G-2) is given pref- erence over an organ to which the test compound is administered (coded in Field S-3). Any organ that can not be coded in Field H-2, because of such a conflict, must be carefully recorded in the written abstract of Field G or Field S-3. In interpreting coding of Field H-2, note first if Column 30 has a 12 zone punch; if there is none, note whether any of Symbols 0, P, B, S, or T are coded in Field G- 1 or G-2. If so, the Field H-2 entry is an organ in the state described by that Field G symbol; if not, it is an organ to which the test compound was administered as described by the symbol in Field S-3. 6. An incidental pathological condition vs. a TREATED pathology The Symbols 5, 7, B, C, D, N, 0, and S are not used when the pathological conditions that these items can suggest are coded in Field E. These code symbols are used only when the pathological condition is incidental (i. e. , is not being treated) and, therefore, is not coded in Field E. 7. Adaptations (Symbol 1 ) Especially in the case of tests in the laboratory, animals must often become familiar with their surroundings and handling before they are tractable or can respond suitably to treatment. Such conditioning of plants to laboratory conditions for certain tests is not unusual. If this, or any adaptation, is described by the author as an important factor, it should be indicated by Symbol 1. 8. Nutrient and hormone deficiencies and excesses, as incidental conditions vs. treated conditions The code symbols, B (hormone deficient), C (hormone excess), D (nutrient deficient), and E (state of inanition), are used when the deficiencies or excesses are NOT the specific diseases treated. - 51 FIELDS G-l and G-2 Columns 27 and 28 In such cases, these conditions are subsidiary factors of the test preparation being treated and are properly coded in Field G. If. however, these deficiencies or excesses represent the pathology which is affected by the test compound, the condition is to be coded in Field E. Field G is not used to record an experimental procedure used to bring about a pathological condition coded in Field E. For example, if an endocrine gland is removed to bring about an endocrine deficiency which is to be experimentally treated, the endocrine deficiency is coded in Field E, but the gland's extirpation is not coded in Field G (with Symbol B), because this operation is not incidental but is (or brings about) the condition treated. 9. Symbol F of Field G is used to distinguish two code lines representing collective data from more than two tests using several test organism strains (Refer to Part I, Division 4, under the special section on Specific Directions and Explanations for the Taxonomy Code of Field E. ) The CBCC has used Symbol F in a special way somewhat contra- dictory to the definition which states that its use is restricted to indicating that a special taxonomic strain has been used in the test: it is used in the situation when a number of strains (either taxo- nomically or physiologically distinct) have been tested by the identical test method with a given test compound for a given response and some strains have responded while some have not, or some strains have given a positive response while others have given a negative response, or some strains have given a positive response of another level, etc. A single code line is customarily constructed for all those strains showing the response and a single, second line is constructed for all those strains show- ing no response or the opposing response. In the second of these lines, Field G is coded with Sym- bol F as a standard means of distinguishing the two lines and explaining the difference between the two in their evaluation fields. If responses of all of the responding varieties (coded by the first line) fall within the same range of effectiveness (i. e. , all their evaluations are coded by the same symbol in Field Y), Field Y will be coded with that symbol, but if they do not all fall in the same range of effectiveness, code only the response of the strain that seems most significant (if that can be deter- mined) or code Field Y only with Symbol 0. A single symbol can distinguish no more than two lines: Symbol F can be used only to distinguish (1) two lines, the first coding responding strains vs. a second coding non- responding strains, or (2) two lines, the first coding strains responding positively (i. e. , an increase over normal) vs. a second coding strains responding negatively (i. e. , a decrease over normal). It is for these two purposes that the CBCC uses Symbol F as a distinguishing symbol. Symbol F might also be used in a third or fourth way: to distinguish (3) two lines coding strains responding at two distinct positive levels (i. e. , increase over normal of 8 1 - 90% , coded by Symbol 8 in Field Y vs. increase over normal of 41-50%, coded by Symbol 4 in Field Y) or (4) two lines coding strains responding at two distinct negative levels; however, relative to the last two possible uses of Symbol F, the CBCC has always coded data of strains responding positively at two levels (or negatively at two levels) by combining them in a single line with Symbol or 1 in Field Y, merely as a means of saving coding time and space. In any case, those third and fourth uses of Symbol F could be made principally when only two strains are involved, simply because when several strains are tested, their responses seldom are so obliging as to fall in only two distinct scales of evaluation (although it is possible that they may and in that case Symbol F might be used to distinguish them); there is no way of distinguishing results which are at three or more distinct levels--i. e. , falling in three or more evaluation scales (e.g., 81-90%, 41-50%, and 1-10% re- sponses): to combine two of these in a second line with Field Y coded with Symbol would be meaning- less as a coding distinction from the first line and to code three lines with Symbol F in Field G of two of the lines would be equally meaningless. The two facts, (1) that the first line, of such pairs of lines, does not have coded in Field G that the test organism is a special strain and (2) the lack of any means of indicating in either line (nor on either IBM punched card) that it has a companion code line (or a companion IBM punched card) is no problem largely because any search in the files will retrieve both IBM cards which will lead to both code lines with the information about the strains responding. An alternative to this use of Field G for distinguishing strains in a non-specific way would be the addition to Field E of specific strain designations, thus permitting a code line and an IBM punched card for each test using a special strain. The infrequency of the CBCC's need for distinguishing special strains justifies not distinguishing strains in Field E and contending with occasional coding of non-specific strain designations as described above. - 52 - FIELDS G-I and G-2 Columns 27 and 28 10. Pretreatments represented by Symbols 2, P, Q, and R; distinctions of definitions and use of the four symbols Symbols 2, P, Q, and R represent experimental states that are often particularly significant and their use deserves some explanatory discussion. These conditions are the result of deliberate chemical or surgical pretreatments which are preparatory for the experiment with the test compound. Such pre- treatments might all have been assigned a single code symbol with the general definition "chemical or surgical pretreatment of the organism or organ". However, since there is advantage in being more specific, the pretreatments have been further classified into four types. For clarity in distinction, Symbols P, Q, and R are described prior to Symbol 2. NOTE THAT SYMBOLS 2, P, Q, and R, as well as all other symbols of Field G (with the exception of Symbol Z), DESCRIBE ONLY PRE TREATMENTS, according to the symbols' definitions, AND NEVER DESCRIBE A TREATMENT COMPARABLE TO THE TREATMENT WITH THE TEST COMPOUND. If, for example, the removal of an organ or a tissue is in part responsible for the action coded in Field T-2 (i. e. , if the response coded in Field T-2 is due to surgical treatment as well as treatment with the test compound), the surgical treatment can not be indicated by Symbols 2, P, Q, or R, nor can it be coded specifically by any symbol. Only by Symbol Z can the fact be coded that the test compound is not entirely respon- sible for the action and that another, non- chemical treatment was in part responsible. A. Symbols P, Q, and R The objective of the pretreatments included here is the isolation of the organism or organ from one or more physiological factors that normally influence it. Examples of such pre- treatments illustrate the distinction in uses of the three symbols, as follows: Symbol P (test compound action on the organism or organism part OTHER THAN the organ isolated ): (1) Isolation of the organism from the influence of one or more of its specific parts by extirpation of that part, such as removal of the spleen. The excised organ is not coded in Field H-l, because it is not an organ responding to treatment with the test compound, but is a discarded organ; what remains of the organism is treated with the test compound. (The excised organ is coded, however, in Field H-2. ) (2) Isolation of the organism from the activity of a specific organ left in situ . This is possible by selectively cutting or drugging the nerve supply of that organ, e. g. The organ rendered functionless is coded in Field H-2 (never in Field H-l). If the in situ preparation is accomplished by blocking or destroying nerves or blood vessels of the organ, the nerves or blood vessels can not be coded, but the procedure should be in the written abstract of Field G. On the other hand, if the organ rendered func- tionless is a specific nerve or group of nerves or a blood vessel, instead of an organ served by the nerve or vessel, it is coded in Field H-2 and it is understood that all effects of that nerve or blood vessel on all organs supplied by it are thereby abolished. The removal of a gland to produce a specific incidental hormonal deficiency (i. e. , a hormone deficiency not specifically treated by the test compound) would be coded by Symbol P except that a special symbol for this particular condition is provided (Symbol B) and should always be used rather than Symbol P. Symbol Q (test compound action on the in situ organ isolated): In situ isolation of the organ coded in Field H- 1. This includes the isolation of an organ from material it ordinarily processes, such as the short-circuiting of food around an isolated experimental part of the alimentary tract (Pavlov pouch, intestinal loop, etc. ). It also in- cludes isolation of an organ from the body as a whole, such as severing or freezinq the nerve supplying the organ or blood circulating to the organ (the nerve or blood vessel of which preparation would not be coded in Field H-2). - 53 FIELDS G-l and G-2 Columns 27 and 28 Symbol R (test compound action on the excised organ isolated ): Isolation of the organ coded in Field H-l, by EXCISION . For example, the removal of a turtle heart on which the action of the test compound is to be investigated, by perfusing it with test compound solutions; the fact that this heart is isolated and excised is coded with Symbol R in Field G. The preparations described by Symbols P, Q, and R are made because the isolation removes physiological factors from the organism or from the organ, as the case may be, which if present would mask wholly the effect of the test compound or would make extremely difficult the evaluation of the test compound's effect. The general definitions of the three symbols, P, 0, and R, are summarized by the following scheme. The symbols represent pretreatment which has as its objective: (1) The isolation of the organism (Symbol P) from the influence of one or more of its specific parts (the part being left in situ or excised ), or-- (2) The isolation of the organ (Symbols Q and R) from one or more of its specific parts, from material it normally processes, or from the organism of which it is a part. (Symbol Q is used to code the isolation of an organ in situ ; Symbol R is used to code the isolation of an organ by excision . ) When coding excised muscle- nerve preparations (see Division 8 of the Specific Directions and Explanations for Field H for a discussion of provisions for this), Symbol R is used in Field G. If the muscle-nerve or gland-nerve preparation is not excised or if the organ-nerve pair is isolated only by the nerve being sectioned, Symbol Q should be used in Field G. The standard heart- lung preparation requires the use of Symbol Q, since the organs are essentially not excised. B. Symbol 2 Any chemical, surgical, or electric shock pret reatment which does NOT have the objective of isolating the organism or the organ is coded by Symbol 2 (in contrast to the pretreatment indicated by Symbols P, Q, and R, as described above). This excludes, however, pretreat- ments by exposures to abnormal chemical or physical environments , Symbols I, 3, 4, etc. Included would be applications of dyes for visual distinctions, surgical exposure merely for observation, and any other special surgical or chemical preparations not adequately des- cribed by one of Symbols P, Q, or R. General anesthesia would also be coded by this symbol, but the CBCC has refrained from designating it, even when it is specifically mentioned by the author, because it is considered a common technical procedure which is assumed to have no significance relative to the outcome of the specific response to the test compound. If, however, the presence of the anesthesia were on some occasion demonstrated to have such significance, it should be indicated without fail by Symbol 2 in Field G. C. Chemical pretreatment is not equivalent to treatment with a secondary compound Any chemical pretreatment indicated by Symbol 2, P, or Q, is not in any way an interaction with the test compound (as pretreatment with a secondary compound or a test compound would be); it is merely an experimental technique permitting the response to the test compound to be revealed by removing factors that would obscure that response, or a technique for staining or observing an organ or tissue, or for quieting the animal or desensitizing it to pain, etc. D. The experimental state of physiological stress excluded from definitions of Symbols 2, P, Q, and R; stress coded by specific symbols Any pretreatment, whether chemical or surgical, which has as its objective the production - 54 FIELDS G-l and G-2 Columns 27 and 28 of experimental physiological stress should be coded by Symbol N, 0, or 7, not by Symbol 2, P, Q, or R. (E. g. , application of a hormone excess to cause a stress which is itself not the condition being treated would be coded by Symbol N, 0, or 7 and not by Symbol 2 or C; a surgical excision of an organ or one of a pair of organs to produce a stress which is not the condition being treated would be coded by Symbol N, 0, or 7, not by Symbol P. ) For example, if one kidney is removed to produce experimental stress on the remaining kidney, "kidney" is coded in Field H- 1 (with Symbol N in Field G) as the organ under stress (if the kidney is also the organ responding to the test compound) or in Field H-2 (with Symbol in Field G) as the organ under stress (if the kidney is not the organ specifically responding to the test compound or if the general organism response rather than a specific organ's response is being coded). 1 1. Use of Symbols 6 and J; STATES OF resistance to, or sensitivity to, the test compound vs . PRODUCTION OF THOSE STATES A. STATES of the test organism (1) Sensitivity (Symbol 6 ) (Biological "sensitivity" to a chemical is the responsiveness of an organism to a chemical; i. e. , any "action" of a test compound can be also described as due to a responsiveness or sensitivity of the test organism. A " produced sensitivity" or "increased sensitivity" [including "sensitization"] is a phenomenon which is not evinced on an initial exposure but is brought about by some biochemical adjustment during the first exposure. ) When a test organism develops a sensitivity to a test compound on exposure to that compound, the sensitivity is not revealed except by an application subsequent to that initial application. (This is self-evident, by definition, since if the sensitivity had been present at the initial exposure, it would not have been a "developed sensitivity", but merely a test organism "response". ) The CBCC codes the production of sensitivity in Field T as an action of that first exposure (Field T-2 symbols of the 51-- series and Symbol 58), even though evidence is from subsequent administrations. The actual sensitive response can not be coded in the code line which codes the first exposure to the test compound, since the response did not appear except on subsequent exposures. This is discussed also in Division 11 of the Specific Directions and Explanations for Fields M and N, and in Division 20 of the Specific Directions and Explanations for Field T-2. However, if a code line is constructed in which are actually coded in Field T the responses caused by or affected by the induced hypersensitivity, it is essential that Field G be coded with Symbol 6 to indicate that the response or degree of response was due to a previous exposure to the test compound (or to a secondary compound which caused a cross- sensitivity to the test compound). (2) Resistance (Symbol J ) When a test organism has been made refractory to the action of a test compound, prior to treatment with that compound in the test being coded, that response to the test compound will consequently be less than in an organism not having been so pretreated. Therefore, it is important that Field G be coded with Symbol J to indicate that the response and degree of response should be interpreted in the light of the results of that previous exposure to the test compound which has stimulated a resistance in the test organism (or a previous exposure to a secondary compound, or to an infectious organism that elaborated that secondary compound, which has caused a cross-resistance to the the test compound). B. PRODUCTION OF the states of resistance and sensitivity The production of resistance or sensitivity to a test compound is only revealed by exposures 55 - FIELDS G-l and G-2 Columns 27 and 28 subsequent to an initial exposure. The CBCC, however, codes the description of the initial exposure that produced the resistance or sensitivity. Therefore, when coding these actions (Field T-2, symbol series 51-- and Symbol 58), Field G is never coded with Symbols 6 or J, since at the time of that initial exposure (when the resistance or sensitivity was produced), the state of resistance or sensitivity did not exist. 12. Symbols F, G, H, and I represent characteristics intrinsic to the test organism and do not represent responses to the test compound Symbol G is not used when coding the production of cross tolerance by a test compound. Symbols F, G, H, and I are used only for strains that have naturally the attributes indicated or that have ac- quired the attributes prior to the experiment with the test compound, not for individuals made resistant, sensitive, dependent, etc. , during the course of the treatment being coded. As indicated in the definition for Symbol G, the four symbols, F, G, H, and I, are for distin- guishing physiological strains only (such as "resistant strain", "sensitive strain", etc. ). They are never used to distinguish a taxonomic strain (a breed of dogs or cows, a strain of bacteria, etc. ). The CBCC Code does not distinguish taxonomic strains of test organisms and when a strain _is given a special symbol in the Taxonomy Code, it represents an exception for which there has seemed adequate justification. The special use of Symbol F, described in Division 9, is not an exception to never indi- cating taxonomic strains by Field G, since it permits distinguishing a group of responding taxonomic strains from a group of unresponding taxonomic strains and therefore is really distinguishing organisms by a physiological characteristic. Occasionally, even a physiological strain can be given a special symbol in the Taxonomy Code (e. g. , the DDT-resistant housefly). Symbols F, G, H, and I need not be used if the test organism is of a physiological strain (resistant, sensitive, etc. ) which _i_s already adequately indicated by a special distinguishing symbol in Field E. 13. Test organisms, organs, or tissues WITH INCIDENTAL IMPLANTS Symbol S is used to indicate that the organism, organ, or tissue responding to the test compound has incidentally a structure implanted in it, regardless of whether the implanted structure is normal, a tumor, or a pathological structure, or causes a pathology, as long as the response of that implant to the test compound is not being coded. For example: There are reported observations on a compound's toxicity to mice with tumor implants (the tumors having been treated with the compound as a candidate carcinostat). In coding the toxicity, the mouse is coded in Field E, the toxicity response in Fields T, X, and Y, and Field G is coded with Symbol S. 14. Test organs or tissues Incidentally IMPLANTED into organisms, organs, or tissues Symbol T is used to code the implantation of a normal organ, tissue, or cell into another organism, organ, or tissue, when the response of the implanted organ, tissue, or cell to the test compound is being coded and when Field J is not coded because the implant and the organism receiving it may be considered as a normal biological unit rather than as a host-parasite or host-pathology relationship. Since these implanted structures are the responding structures (and their implantation is their experimental state), they will be coded in Fields H-l or I. This situation is given definition here and assigned Symbol T for sake of completeness, though it is improbable that frequent occasions will arise to use it. Symbol T might be used if chemicals are tested as means of making an implant successful; tissue grafts or organ implants, either embryonic or adult, might be given local chemical applications which would be candidate to assist the implant in establishing. (In this example, Field T would be coded to indicate prevention, by the test compound, of the atrophy or other fate the untreated implant would meet; Field G would be coded with Symbol T to indicate that the organ or tissue in Field H-l or I was an implant. ) (When the implanted structure is [1] not normal, i. e. , is [a] a tumor or [b] otherwise pathological or [2] if the implant brings about a pathological condition and there is being coded the response [to the test compound] of that tumor or of the pathology of the implant or of the pathology caused by the implant, the tumor or pathology will be coded in Field E and Field G will not be coded with Symbol T. ) 56 - FIELDS G-l and G-2 Columns 27 and 28 1 5. Indications that an extirpated test organ or tissue is whole (Symbol R) vs. the indication that the test organ or tissue has been macerated, sliced, etc. (Symbols U, V, W, and X) Symbol R is used to code the isolation of a whole organ (e. g. , the heart), a representative section of tissue (e. g. , liver tissue), a cell (e. g. , a neuron), or a representative sample of fluid (e. g. , whole blood), which is subsequently treated. Symbols U, V, W, and X, on the other hand, are used to describe specific experimental preparations following any isolation. For example, an isolated tissue might be macerated to a suspension (Symbol U), filtered for the extract (Symbol V), or subsequently grown on culture media (Symbol W), or micro- sliced (Symbol X). The manipulation of the tissues, implied by Symbols U, V, W, and X, represents the beginning of a preparation which may be preceded or followed, after some time interval, by introduction of the test compound. Time intervals such as this are ordinarily coded in Field R. For example, the time interval between (a) preparation of a TISSUE (Symbol U, V, W, or X in Field G) for an enzyme study and (b) the introduction of the test compound may be significant and, if given, warrants recording in Field R. 16. Symbols U, V, W, and X describe states of the test organism, organ, or tissue at the time of the chemical treatment When a compound is applied to an organism or organ which is later homogenized or made into slices or extracts, etc. , for purpose of reading the test results, Code Symbols U, V, W, and X can not be coded in Field G. This field is used only to describe the state or condition of the test organism at the time of the treatment. 17. Symbol Z (Field G-2 only) This symbol is used in a unique way and does not correspond to the other symbols of Field G in that it does not represent just a state of the organism during the test, but it represents, like the test compound, an active factor of the treatment. When this symbol is used, it indicates a treatment used on the test organism (which may be in any experimental state indicated by any of Symbols 1 through X), in conjunction with the test compound treatment (or test compound and secondary compound treatment). (See the first division [last paragraph] of the section on General Use of Field G. ) Symbol Z is coded only in Field G-2, for sake of consistency, and must be coded in any such test which in- cludes non-chemical treatment as defined in the Code. Symbol Z takes priority over Symbols 1 through X in Field G-2. 18. Symbols available for additional items of Field G All numerical and letter symbols available for Field G have been used, with the exception of Symbol Y. 19. File of coded biology data on IBM punched cards arranged according to symbols for experimental states The CBCC has established no special file of coded data in which Field G has been used (and arranged by Field G symbol sequence), because of the remote probabilities of a frequent need to search for all information on tests in which was a specific incidental condition of the test organism. 20. Double coding is not possible in Fields G-l and G-2 Having made use of all of numbers 1 through 9 and all 26 letters for code symbols in Field G, the IBM machine punching and retrieval procedures do not permit more than a single symbol in Field G in any one line. Therefore, when coding two or more tests whose details and outcomes are so nearly alike that the code lines for all tests would be identical except for differences in pretreatment or state of the test organism (Field G), the tests can not all be recorded by one code line with several entries (representing the several pretreatments or states) in a single column (either Field G-l or Field G-2). (A special circumstance allows condensing two or more tests in a single line by use of Symbol F of Field G [explained in Division 9], but this is not strictly comparable to double coding as it is described in the preceding sentence and even in this special case, Field G is occupied with but a single symbol. ) - 57 - FIELD H-I Columns 29, 30, and 31 FIELD H-2 Columns 32, 33, and 34 GROSS ANATOMICAL STRUCTURE: ORGAN, SYSTEM, BODY AREA Organization In this area of the CBCC Biology Code, six columns of the IBM punched card (and the Biology Code Sheet) are divided into two fields of three columns each, designated as Field H-l and Field H-2. In the Code, there is a single list of anatomical structures, the symbols of which may be used for coding either field. Due in part to the limitations of space on a single punched card and in part to the complexity of anatomical classification, a single symbol has in some cases been given a definition to include homologies as well as analogies. For example, Symbol B61 can apply to any of the following: arm, wing, pectoral Tin; paw, hand; or any other vertebrate anterior appendage or part thereof; Symbol 512 can be used for: spiracle, respiratory pore, or nostril. This presents no difficulty in interpretation, since the organism to which the structure belongs is identified in Field E or Field J. The first unit of the three- unit anatomy symbol represents the general system of which the structure is a part. When used alone, this unit represents the complete symbol for the system (e. g. , Symbol 1 in Column 29 or Column 32 represents the nervous system). The second unit represents a subdivision of a system (e. g. , central nervous system, Symbol 15) or it may represent a discrete organ of a system (e. g. , stomach , Symbol 66). The third unit distinguishes the least anatomical structural division of this field, whether it is an organ (e. g. , the spleen , Symbol 342) or whether it is an organ part (e. g. , the stomach cardia , Symbol 662^). Subsequent to preparing the initial list for the field, items have been added as they were needed. This is done by simply giving the new item a symbol whose first unit represents the system to which it belongs and whose second and third units are the next available sequential numbers or letters. For example, the symbols for right and left auricles might be expected to be 312 and 313, since the symbol for auricle is 311; however, since these structures were given distinguishing symbols after Symbols 312 through 31C had been used, they were assigned Symbols 3 ID and 3 IE. The procedure for adding new items to the list may result in the structure being listed distant from structures to which it is most nearly related. (In the example cited above, the right auricle is listed as a distinct item, Symbol 3 ID, 11 items away from auricle, Symbol 311. ) These items are listed again, merely for convenience, with the related structures. (Therefore, Symbols 3 ID and 3 IE will be found between the Symbols 311 and 312, as well as after Symbol 31C. Because certain organs, especially specific nerves and blood vessels, form an integral part of organs or systems, other than the system to which they actually belong, they are frequently listed twice, with the organ or system they supply ae well as with the system to which they belong. For example, the optic nerve is listed both with the cranial nerves (symbol series 13) and with the eye structures (symbol series 21), although its symbol is always 133 regardless of where it is listed. Similarly, certain gross organs are constituted of glandular components as well as non-glandular parts. The glandular structure or part of such an organ is assigned a symbol of the C or D series (according to whether it is endocrine or exocrine) and this symbol and structure is listed both with other glandular structures and with the gross organ of which it is a part. (Examples will be found in the reproductive organ list, symbol series 8. ) This double listing is merely for convenience. The list is haidly an exhaustive compilation. It might be expanded for special purposes and for data from new areas of investigation. For example, additional items might be needed under the autonomic nervous system and central nervous system for data from investigations on the tranquilizing drugs. The 12 zone punch (coded by Symbol *) has been given a special meaning when used in IBM Column 30. (See the following section, General Use. ) For this reason, none of letters A through I can be used for the second unit of symbols in Field H. 58 - FIELDS H-l and H-2 Columns 29, 30, 31, 32, 33, and 34 General Use In the case of many tests for biological responses to chemicals, specific anatomical parts of the organisms involved represent significant aspects of the test method or response. The area of the Code that is devoted to expressing these specific structures comprises Field H-l and Field H-2, for gross anatomical parts, and Field I, for tissue and cellular parts. Although this section, as well as the following section on Specific Directions and Explanations, concerns principally Fields H-l and H-2 (gross anatomy). Field I (microanatomy) will frequently be mentioned with them; the three fields together make a unit for coding of structural parts, since the relationships of each of the three fields to other fields of the Code are essentially identical. There are two fields in which an organism may be coded: Field E, for the test organism, and Field J for the host organism. Since the CBCC Code has only one area for coding anatomical structures, as indicated in the preceding paragraph, the anatomy fields (H-l, H-2, and I) must serve both Fields E and J. The relationships, however, are not difficult to understand: Whenever an organism is coded in Field J (indicated by any Field J symbol other than those beginning with letters S through Z), the entry in Field H must be a structure of the host coded in Field J. When Field J is not coded, or is coded with only a culture medium or environment (indicated by any Field J symbol beginning with letters S through Z), the entry in Field H must be a structure of the test organism coded in Field E. Frequently, a test involves two types of information (and occasionally more than two) which concern anatomical structures, both of which are significant. It is for this reason that two fields have been provided instead of a single one. The types of information coded in Fields H-l and H-2, the distinction between the use of Fields H-l and H-2, and the relationship between these two fields (H-l and H-2) and other fields (E, G, J, L, S, and T) are indicated briefly in the following paragraphs. There are four general uses for Fields H-l and H-2: 1 . To record the gross anatomical structure or system responding to the compound or the structure or system in which the response is measured, this structure or system being of the test organism or of the host, as explained above in the second paragraph of this section . This first use represents the primary purpose for a coding provision for anatomy. FOR THIS PURPOSE, ONLY FIELD H-l IS USED. The remaining three uses of Fields H-l and H-2 are for aspects other than specific responses of organs or systems to the test compound. 2. To record a gross anatomical structure or system which has been experimentally modified (chemically, surgically, etc. ) prior to treatment with the test compound . Such modification may be made on either the test organism (coded in Field E) or on the host organism (coded in Field J) and the specific modification is indicated in Field G (for a test organism) or L (for a host organism). When the experimental state coded in Field G or L refers to an anatomical structure that has been modified, the definition of the Field G symbol or Field L symbol in the Code includes the reference to Field H-l, H-2, or I. Therefore, if the experimental modification was to the organ specifically responding to the test compound or the organ in which the test response is measured (see Use Number 1 above), only a Field G or Field L entry can be used which refers to Field H-l. This is always indicated in the Field G or Field L definition (e. g. , Symbol N of Field G: organ studied [specified in Field H- 1] in a pathological state. . . ). Similarly, if the modification is made to an organ other than the organ specifically responding, the Field G or Field L entry refers to Field H-2 and the Field G or Field L definition always directs the coder to make the entry in Field H-2 (e. g. , Symbol of Field G: organ [specified in Field H-2] in a pathological state). 3. To record the gross anatomical structure or system to which the test compound was applied . Field H-2 is used to supplement the description of the route of administration (coded in Field S-3), when the route of administration is not to the organ specifically responding (in Field H-l) and when the symbol used in Field S-3 can not adequately specify the organ or body area to which application was made. See Division 2 of Specific Directions and Explanations. 4. To record the gross anatomical structure or system which is the site of the tumor or patholog- ical condition coded in Field E (Field H-l, rarely Field H-2). When Field J is coded with an organism 59 - FIELDS H-l and H-2 Columns 29, 30, 31, 32, 33, and 34 that is host to a tumor, noninfectious pathological condition, or parasitic organism, the anatomical entries of Fields H-l, H-2, and I always are structures of that host. (This was explained above in the second paragraph of this Section on General Use. ) THIS SITE OF A TUMOR OR PATHOLOGY IS ALWAYS CODED IN FIELD H-l, with certain exceptions for special infrequently occurring situations explained in Division 6 of the section on Specific Directions and Explanations below. (Even for such an exception, however, when the site of a pathology is by necessity entered in Field H-2 instead of Field H-l, the fact of the transfer of the entry to Field H-2 is always clearly indicated in Field H-l by the Symbol * [the IBM 12 zone punch] being used in Column 30. ) Specific Directions and Explanations 1. Distinction between uses of Fields H-l and H-2 This is discussed in the previous section on General Use. In summary, Field H- 1 is used for recording the primary organ, i. e. , (1) the organ actually treated and acted upon by the test compound or the organ in which the test observation for response was made, or (2) the organ in which a tumor, non-infectious pathology, or parasitic organism was experimentally treated. Field H-2 is used to record organs other than the primary organ: (1) an organ other than the primary organ, specially modified; (2) an organ, other than the primary organ, to which the test compound was applied (when application was not directly to the primary organ), or (3) (rarely, and with an asterisk coded in Column 30 of Field H-l) an organ in which a pathology was treated (coded in Field E), when the response and observation was actually on an organ other than the organ most specifically affected by the pathology (see the example given in the last paragraph of Division 6 below). 2. Use of Field H-2 to supplement coding in Field S-3; a specific organ or body area at which application is made when it is not the responding organ or body area in Field H-l In Field S-3 is coded the route of administration of a test compound. The descriptions of these routes often include designations of a specific anatomical structure to which or through which appli- cation is made. However, certain routes, as defined in Field S-3, are somewhat general, without specifying a structure (e. g. , intravascular, or in an exposed organ, or topical, etc. --without specifying which blood vessel, organ, body area, etc. , is actually treated). Since the specific organ or body area to which application is made is sometimes significant and indicated by the author, Field H is used with Field S-3 for coding it. If the administration (described in Field S-3) is directly to the organ which is the responding organ (in Field H-l), the responding organ and the organ to which application is made are identical and are both indicated by the identical entry in Field H-l. However, if administration is applied at a site other than the responding organ in Field H-l, this difference between the application site and the site of response must be recorded in Field S-3, both by code and by a written abstract. In coding this difference, it is necessary to supplement Field S-3 by designating a site of application (other than the responding organ in Field H-l) more specifically than the Field S-3 symbol is capable of doing, and for this Field H-2 is used. Field H-2 is used to supplement the following symbols of Field S-3: 3, 4, 5, 7, 8, B, C, D, E, F, G, I, 0, P, S, and Z. None of the other symbols (0, 1, 2, 6, 9, A, H, J, K, L, M, N, Q, R, T, U, V, W, X, and Y) need to be supplemented by coding in Field H-2. The following division explains how an entry in Field H-2 must be coded and subsequently interpreted relative to Field S-3 and Fields G-l and G-2 and L. It also explains that there would be some advantage to having a special field for supplementing coding of Field S-3, since Field H-2 can only be used for this purpose when it is not occupied with organs related to coding in Field G or L or Column 30 of Field H-l. The latter coding areas must be examined before it can be certain that coding in Field H-2 relates to Field S-3. 3. Conflicts in Field H-2 due to its multiple uses; order of preference in use The fields most especially related to Field H-2 may be regarded as two groups, (1) Fields G-l, G-2, and L, and (2) Field S-3, whose relationships to Field H-2 represent two distinct uses for Field H-2. There would be advantages in having three fields, each comparable to Field H-2--one for organs specially modified (Fields G-l, G-2, and L) and one for organs to which the test compound was - 60 FIELDS H-l and H-2 Columns 29, 30, 31. 32, 33, and 34 administered (Field S-3)--and a third for a site of a pathology coded in Field E when an organ other than that specific pathology site (yet affected by the pathology) is the organ responding to the test compound. However, the advantages of this were far outbalanced by advantages of restricting coding to a single IBM punched card, which did not permit more than the single Field H-2- -used for all purposes. Unfortunately, as a result, any entry in Field H-2, considered as an isolated entry, is subject to any of three interpretations and therefore the meaning of any entry in Field H-2 can only be learned by consulting Column 30, Field G and Field L, and Field S-3 (in that sequence), explained as follows. If an organ in Field H-2 is the site of a pathology coded in Field E, an asterisk will be in Column 30. (An explanation of the use of the asterisk and its importance is in Division 6. ) If the organ in Field H-2 is in a special experimental state. Field G (or Field L) will be coded with one of the following symbols: or P (or, less frequently, with S or T). If it is a specific organ to which the test compound was directly administered, Field S-3 will be coded with one of the following symbols: 3, 4, 5, 7, 8, B, C, D, E, F, G, 1,0, P, S, or Z. As might be expected, an occasional experimental design will present a conflict in Field H-2 which the CBCC resolves by observing the following coding procedure: A. If a pathology coded in Field E is specifically of an organ other than the organ in Field H-l, an asterisk is coded in Column 30 and Field H-2 must be used only for coding the site of the pathology. B. If Field H-2 is not used for the special (and infrequent) purpose of A, above, and any of Symbols 0, P, S, or T are coded in Field G- 1 or G-2, Field H-2 is used only for coding organs in the experimental states designated by these Field G symbols. C. If Field H-2 is not used for purposes A or B, above, it can be used with Field S-3 to code organs (other than the organ in Field H-l) to which the test compound is administered. This means that, in interpreting an entry in Field H-2, if an asterisk is coded in Column 30 (i. e. , a 12 zone punch in Column 30), any entry in Field H-2 represents the site of the pathology, regardless of what is coded in Field G-l, G-2, L, or S-3. If Field G or Field L is coded with any of Symbols 0, P, S, or T (and there is no 12 zone punch in Column 30), an entry in Field H-2 is always an organ related to that special state coded in Field G or Field L. If Field G or Field L is not coded with any of Symbols 0, P, S, or T (and no 12 zone punch in Column 30), an entry in Field H-2 is always an organ to which the test compound was administered. 4. Relationship between the anatomy coding (Fields H-l, H-2, and I) and Fields E (test organism, pathology, or tumor) and J (host organism) In the previous section, General Use, the four general uses of Fields H-l and H-2 are explained. Regardless of which of these four types of information is coded, there is the further matter of under- standing the correct coding correlation to one or the other of the test organism and the host, since there is only one area for coding anatomical structures and there are two places where organisms are coded. If Field J is not coded (i. e. , if there is no host ), any coding of anatomy (Fields H-l, H-2, and I) necessarily concerns only structures of the test organism. If there ij> a host organism , the anatomy fields always are used only to name structures of that host coded in Field J. However, Field J may be coded with non-living "hosts" (culture media, environments, etc.); since the anatomy fields have no use relative to Field J in such cases, they may be used to code structures of the test organism coded in Field E. (In Field J, non-living hosts have code symbols whose beginning units are restricted to letters S through Z--i. e. , symbols distinguished by beginning units which are indicated on the IBM punched card by combining numerical punches with the zone punch. ) In summary: When Field J is not coded , all coding in Fields H-l, H-2, and I designates structures of the test organism in Field E. When Field J is coded with a host organism (symbols beginning with any letter other than S through Z--i. e. , without the zone punch in Column 37), all coding in Fields H-l, H-2, and I designates structures of the host organism. When Field J is coded 61 FIELDS H-l and H-2 Columns 29, 30, 31, 32, 33, and 34 with a non-living host (symbols beginning with any of letters S through Z--i. e. , with the zone punch in Column 37), all coding in Fields H-l, H-2, and I designates structures of the test organism in Field E. 5. Relationship between the coding of anatomy (Fields H-l, H-2, and I) and the anatomical designations of TUMOR symbols (Field E) Since the anatomy fields (H-l, H-2, and I) are used basically to record the anatomical site of action of the test compound, they are used for coding the anatomical site of any tumor that is treated in testing for carcinostatic or carcinogenic action. Although the tumor symbol bears a code designation of the anatomical site of origin (when the organ origin is known), this site of origin is not always the site of the tumor's location when chemically treated. Most frequently, the common experimental animal tumors used for testing candidate carcinostatic drugs are transplantable and, for technical convenience, such a tumor is ordinarily implanted in an organ and tissue other than the organ or tissue in which it originated. Thus, organs and tissues of tumor origin (Field E) and organs and tissues of locations of tumors when treated (Fields H and I) can both be indicated by code. In order to permit efficient sorting in Field H, the anatomical site of a tumor is always coded in Field H-l when known, even when it duplicates the anatomical coding in Field E, as in the case of treatment of spontaneous tumors or tumors transplanted to other animals but at the same site as the tumor's origin. In retrieving information on all tumors having a specific anatomical origin , regardless of their location when treated, Field E must be searched. In retrieving information on all tumors in any given location, regardless of their origins, Field H-l must be searched. As can be seen by reference to the description of the Tumor Code, the symbols for organs and tissues incorporated into tumor symbols for Field E are not symbols of Fields H and I, but are derived from a special list of structures for the Tumor Code. The site of an induced tumor is always coded in Fields H-l and I when this information is known. When a compound is tested specifically for its effect on metastasis of a tumor (Symbol 46 of Field T-2), the data frequently indicate all the organs to which metastasis has extended. When Symbol 46 is coded in Field T-2, only one code line is prepared with the organ of origin coded in Field H-l. However, if the effect of a test compound is on a tumor which has metastasized from another site and the effect is not specifically on the process of metastasis (i. e. , when Field T-2 is not coded with Symbol 46), Field H- 1 is coded with the site of the affected tumor (not the organ of origin) and Field F is coded with Symbol Y. 6. Relationship between the coding of anatomy (Fields H-l, H-2, and I) and the anatomical designation of PATHOLOGY symbols (Field E) Fields H and I are always used to indicate the site of action of the test compound. Therefore, when a pathological condition is coded in Field E, Fields H and I are used to code the structures specifically affected by the experimental chemical treatment, regardless of whether the pathology (l) may be located exclusively in that structure, (2) is located (in addition to being a pathology of the responding structure) in several organs, a whole system, or the entire organism, or (3) is located in another part and affects only secondarily the structure responding to the chemical treatment. In the case of an infectious disease, the infecting organism is always coded in Field E, the host is coded in Field J, and the system, organ, or tissue, in which is located the infecting organism , is coded in Fields H and I. Similarly, a non- infectious disease is indicated by a special symbol coded in Field E and the system, organ, or tissue in which is located the condition responding to the chemical treatment is coded in Fields H and I. Non-infectious pathological conditions (e. g. , coronary sclerosis), recognized and named as specific diseases, are frequently restricted by their definitions to particular anatomical systems, organs, or tissues. When this is the case, the Field E symbol for the pathology includes a designation of that anatomical structure involved (e.g., T32DP200 indicates, by -32D that the disease is specifically of the coronary artery). This permits Field H to be used for "modifying" the coding of the system or organ indicated in the pathology symbol- -i. e. , to specify a structure of that part indi- cated in the pathology symbol, or the more gross system or organ of which the structure indicated in - 62 - FIELD S H-l and H-Z Columns 29, 30, 3 1, 32, 33, and 34 the pathology symbol is a part. (If the myocardium, or some other part of the heart, is affected by the test compound when treatment is given for arteriosclerosis or if some particular part of the vascular wall is affected, those responding parts may be indicated in Field H. ) Description of a given pathology condition is often very complex and the coding is necessarily difficult. As a result, the retrieval of information is not as simple as in the case of information on tumors or test organisms. To retrieve information on all diseases of a given anatomical structure, for example, not only must the anatomy Field H-l be searched, but Field E should be searched for pathology symbols with anatomical components designating the particular structure. Occasionally, the situation arises in which a test compound may have an effect on a disturbed organ which is itself not in the precise pathological state coded in Field E, although the organ exhibits pathology symptoms invariably associated with the condition coded in Field E. (An actual example encountered and coded was the experimental production of frostbite in a hamster leg which, when untreated, invariably caused a retarding of blood flow, as observed in peripheral vessels of the lining of the cheek pouch. Application of test compounds was specifically for treatment of the retarded blood flow [due to frostbite] observed in the cheek pouch. ) In coding such data, that organ in which the test compound has its effect and on which test observations are made is coded in Field H-l and the organ which is in the pathological state indicated in Field E is coded in Field H-2. To indicate that the organ in the pathological state coded in Field E is coded in Field H-2 rather than Field H-l, an asterisk (representing the IBM 12 zone punch) is coded in Column 30 of Field H-l. (Thus, for the example given above, "frostbite", Symbol TB003100, would be coded in Field E, "leg" [which would ordinarily be coded in Field H-l as the location of the frostbite] would be coded in Field H-2, with an asterisk in Column 30, and "parietal blood vessel" would be in Field H-l as the structure responding to the test compound. ) In coding the situation just described, if the specific site of administration of the test compound is at neither the organ with the specific pathology of Field E (in Field H-2) nor the organ responding to chemical treatment (in Field H-l), and it is not adequately indicated by the entry in Field S-3, code the two organs as directed; the site of administration will not be coded except in Field S-3 where the site of administration should be written in if it is not explicit by the coding of that field. A diagram illustrating the relationships between Field H and the pathology symbols and a further discussion of these is to be found in the Field E section describing the Pathology Code. 7. Relationship between the anatomy coding (Fields H-l, H-2, and I) and the dosage fields (Fields M and N ) The relationships between the dosage fields and the anatomical structures coded in Fields H-l, H-2, and I are thoroughly discussed in Division 5 of the Specific Directions and Explanations section of Fields M and N and reference should be made to that section and division. 8. Procedure for coding data from tests using special anatomical preparations consisting of an end organ and attached nerve (e. g. , muscle- nerve preparations) A common experimental procedure involves the use of an effector end organ and the nerve supplying the organ, the two organs being intact relative to each other, though they may be isolated from the animal or in situ . Under normal conditions, a stimulus applied to the nerve leads to a measurable response of the effector organ. Of these, the more common examples are nerve-muscle preparations, though data from nerve-gland preparations may occur. Use of such an experimental preparation may vary in its objective: (1) By appropriate technique, there may be demonstrated the transmission of impulse to the effector organ (muscle or gland) and subsequently the effect of test compounds on this neuro- effector organ impulse transmission; (2) on the other hand, the action of a test compound applied to the nerve-organ preparation may be expressed only as affecting in one direction or the other the normal response of the effector organ to stimulation by the nerve with no exact determination as to whether the chemical effect is on the nerve, on the effector organ, or on the neuro- effector transmission. If the test results are demonstrated by the author actually to be in terms of effects on trans- mission of the impulse (see Number 1 of the previous paragraph), the coding should record this by using the appropriate impulse transmission term in Field T-2 (e. g. , neuro-muscular transmission, Symbol 98). Field H-l should be coded with Symbol 17 or, if the specific nerve-organ pair are - 63 - FIELDS H-I and H-2 Columns 29, 30, 31, 32, 33, and 34 identified, with one of the 17- symbol series. In addition, if it is an isolated preparation, Field G should be coded with Symbol R. When results of a test using a specific nerve-effector organ preparation are expressed only as altering from normal the response of the organ to stimulation of the nerve (see Number 2 of the second paragraph above), the coder can not arbitrarily assume that the effect is on any specific one of the following: transmission of the impulse from nerve to effector, or on the effector organ, or on the nerve. The coding pattern instead should state only what was demonstrated by the test- -the alteration, by the test compound, of the normal action of the nerve on the organ. The correct entries in Fields T-2, H-l, and T-l, are as follows: (I) Field T-2 : The organ's activity or state normally regulated or caused by the nerve is indi- cated in Field T-2. For example, if the vagus-heart preparation is involved, Field T-2 is used to indicate the cardiac process normally affected by the vagus nerve, heart rate. The CBCC Code lacks a field for expressing the normal action of the nerve on the process or state coded in Field T-2, just as the action of a secondary compound can not be expressed. (Field T-l is used only to express the action of a test compound . ) In the present example, Field T-2 can be coded to indicate only the action of the heart (cardiac rate, Symbol CI); the action of the nerve on the heart action can only be, and must be, included in the written abstract portion of Field T-2. (An alternative to this procedure would be the pro- vision of many more special Field T-2 symbols such as "decreased cardiac rate due to vagal inhibition", but it was believed this would represent an unnecessary complication to Field T-2. The other alternative would have been the provision of another coding field for indicating action of nerves and secondary compound, but lack of space on the IBM card decided against it. ) (II) Field H- 1 : The organ pair (nerve and effector) is coded in Field H-l. A special group of such pairs are in Field H-l of the Code; when any experiment concerns a nerve and its effector organ not in the Code, such a combination must be added to the Code and assigned a symbol. (Note that if the test method provides for administration of the test compound so that only one member of the pair is exposed to the chemical, that nerve or effector organ is coded in Field H-2, with the symbol for the pair coded in Field H-l. ) This entry in Field H-l (any Field H symbol of the 17- series) lends a special interpretive significance to the entry in Field T-2, in the same way that any entry in Field D lends a particular mean- ing to Field T-2: any action (of the nerve or of the secondary compound) on the biological state or process coded in Field T-2 is not indicated by coding but is only in the written abstract of Field T-2. (See also the preceding paragraph on coding in Field T-2. ) (III) Field T- 1 : In Field T-l will be coded the action of the test compound on the action of the negve , as the latter is recorded in Field T-2. This is accomplished by Symbol D, E, F, or G of Field T-l. Example: The test compound reduces vagal slowing of the heart when the nerve is stimulated (using an isolated vagus-heart preparation). Field G Field H-l Field H-2 Field I Field T-l Field T-2 R 171 - - E CI (Isolated (Vagus - (Decreases (Cardiac prepara- heart) inhibition, by rate) tion) the nerve [H-l], of the process [T-2]) Written in Field T-2: cardiac rate (retarded by normal vagal stimulation). 9. Blood and its components (symbol series 33-), lymph (symbol series 35-), and reproductive cells (Symbols 81C and 82B), included with gross structures of Field H Although most properly these structures are considered as tissue and cellular units of the organism, they are included in Field H for reasons explained in Division 2 of the section on Specific Directions and Explanations of Field I. - 64 - FIELDS H-l and H-2 Columns 29, 30, 31, 32, 33, and 34 10. Symbols available for additional items of Field H In Column 30 (Field H-l), the IBM 12 zone punch (Symbol *) has been given a special meaning (see Division 6 above). Therefore, none of letters A through I may be used for the second unit (Column 30) of anatomy structures. If a special list were made for Field H-2, letters A through I might be used in Column 33, but the CBCC has found the nine numbers and 17 letters (J through Z) adequate for the second unit of the symbols and a special list for Field H-2 unnecessary. For additional systems of animals, Symbol 4 (Column 29) is available; for additional plant organ systems, Symbol R (Column 29) is available. Symbols T through Z are also available, if needed for animal or plant organ systems. 1 1. File of coded biology data on IBM punched cards arranged according to symbols for gross anatomical structures The CBCC maintains a special IBM punched card file of all coded information in which a primary organ has been involved and for which Field H-l has subsequently been coded. The file is arranged by Field H symbols so that all coded information on any given structure can be retrieved by simple manual removal from this file (e. g. , all coded information on the nervous system, in toto, or on the cerebellum, the heart, or the carotid sinus, etc. ). No such file has been established for secondary organs (Field H-2). 12. Double coding in Field H Double coding is not permitted in Field H-l or H-2. When Column 30 of Field H-l is coded with Symbol * plus any one of Symbols 1 through 9 and J through Z (representing essentially the coding of two information categories), two IBM cards are punched. On the first, both symbols of Column 30 are punched; the second card is punched to be identical to the first except that the punch in the 12 position is omitted from Column 3 0. In the IBM Punched Card File arranged according to entries in Field H-l, the second card is filed according to the symbol for the organ, but the first card is filed separately at the end of the file; in all the other IBM Punched Card Files, the two cards are filed together. So few instances of the use of Symbol * occur in Column 3 0, the number of duplicate cards for such code lines is negligible. - 65 FIELD I Columns 35 and 36 TISSUES, CELLS, AND FLUIDS Organization The list of histological and cytological anatomical structures is organized by natural groups and assigned two-unit symbols (two IBM columns). The first unit indicates the general type of tissue and the second indicates the specific tissue. For example, all symbols beginning with the digit 2 (Column 35) are connective tissues, while adipose connective tissue is specifically designated by the second unit, digit 6 (Column 36). General Use The terms listed in this field are to be used in conjunction with Field H- 1 (primary organs), to permit specific description of finer anatomical structures responding to test compounds. Occasionally, a tissue from Field I may be used in absence of an entry in Field H- 1, when the organ is not specified in the article or when the tissue is not restricted to a single organ system. Field I is coded only to relate to Field H- 1 and never to an organ in Field H-2. When Field E is used to code a pathology or a tumor, Field I, as well as Field H-l, is used only to describe the anatomical location of the tumor or pathology. Specific Directions and Explanations 1. Use of terms of Field I which are identical to terms of Field H Several terms occur in both Field H and Field I, due to anatomical complexity. For example, most organs are supplied with blood vessels and nerves, each of which can be considered themselves as organs. These structures which can be anatomical parts of more gross organs are included in Field I as well as Field H. Thus, when blood vessels of a specific organ are affected, it is possible to code the particular vessels by combined use of Fields H- 1 and I. On the other hand, if blood vessels are generally affected, regardless of their relationship to specific organs, they can be coded in Field H- 1 as the organ affected. The following examples demonstrate the foregoing. Example 1. The test compound caused inflammation of arterial walls as evidenced by observations on the femoral artery. Field T-l Field T-Z Field H-l 7 1132 325 (produces) (inflammation) (of the arteries) Example 2. In studying factors which affect the kidney blood flow, the test compound was found to produce inflammation of the nephric (kidney) blood vessels. Field T-l Field T-2 Field H-I Field I 7 1132 71 CI (produces) (inflammation) (of the kidney) (blood vessels) 2. Certain tissues included in Field H as organs: blood, lymph, and reproductive cells While blood is commonly considered as a specific tissue, the collective blood mass can at the same time be justifiably regarded as an organ constructed of but a single tissue. Lymph might similarly be regarded as an organ. If either were coded in Field I, as a tissue responding to the test compound, there would seldom be anything of significance (i. e. , only "blood vessel" or "body as a whole") needed 66 F IELD I Columns 35 and 36 in Field H, although to imply by such coding that a blood vessel or the body as a whole is affected because the fluid it contains is affected would be inaccurate. Therefore, blood and lymph are coded in Field H and are not included among the Field I items as tissues. There has been no occasion when "blood" has been needed in Field I to specify a tissue of a particular organ coded in Field H-l. I. e. , "arterial blood", "venous blood", "renal blood", "cerebra 1 blood", etc. , have not been distinctions the CBCC has found a necessity to make. However, if this is necessary, these particular designations can be added to Field H with new symbols of the 33 -series. Sexual reproductive cells are confined to the two structures, ovary and testis, although, in the normal course of events, they are discharged from the ovary or are propelled from the testis to traverse paths through other structures. Therefore, though they are by nature cells (or germinal tissues) rather than organs, their being coded in Field I, with ovary or testis coded in Field H-l, most often would represent a redundancy (i. e. , when sperm or ovum is coded, it may be assumed that they are in the testis or ovary or parts thereof). For this reason, the CBCC codes sperm and ovum in Field H, for the sake of expedience. If for some reason it becomes important to distinguish sperm of the seminiferous tubules from sperm of the epididymis, for example, the Code may be modified by adding new specific items to Field H (seminiferous tubule sperm, vasa efferential sperm, epididymal sperm, etc. ) or by adding sperm (and ovum) to Field I. 3. Symbol 64; the test compound's effect on a product of a gland When a normal component of a glandular product is increased or decreased in quantity by the test compound, the effect is coded with one of the FC-- symbol series in Field T-Z, with Field T- 1 Symbols 1, 2, 3, 4, or 5. However, there is no way of indicating by this coding in Field T-2 whether the component of the gland's secretion is produced in abnormal amounts due to merely altering the total volume of the gland's secretion or due to altering the relative composition of the secretion. Symbol 64 has been provided in Field I to distinguish these two effects of the test compound (though doubtless secretions are not ordinarily considered to be body fluids). The symbol indicates that the test compound affects that total secretory product (of the gland coded in Field H-l) in the manner indicated in Field T, by altering its basic c haracter (i. e. , by altering its composition relative to the component specifically coded by the Field T-2 symbol) rather than altering merely its volume. Therefore, when only volume of the total secretion has been altered, though the components of the secretion remain proportionately normal per unit volume, Symbol 64 must NOT be used in Field I. 4. Symbols available for additional items of Field I None of the IBM zone punches have been assigned a special meaning in Field I. Therefore, there are no restrictions in use of any letters in either column for constructing symbols. 5. File of coded biology data on IBM punched cards arranged according to symbols for tissues and cells The CBCC maintains a special IBM punched card file for all cards on which Field I has been coded, arranged according to Field I code symbols. Thus, all coded data in which a given tissue is affected by test compounds, or in which was located a pathology that is affected by test compounds, can be taken quickly and by manual selection from this file. 6. Double coding is not permitted in Field I. 67 - FIELD J Columns 37, 38, 39, 40, 41, and 42 HOST ORGANISM OR TEST ENVIRONMENT Organization The symbols of Field J have a maximum of six units corresponding to the six IBM columns used. As in the case of the code symbols for test organisms of Field E, symbols of Field J are constructed to indicate the taxonomic affinities of the host organism. Thus, Column 37 is used only for indicating phyla and the symbol for any given phylum or plant division is a single unit symbol of Column 37 (Protozoa , Symbol 1; Thallophyta , Symbol J, e. g. ). Column 38 is used only for coding classes of each phylum (the symbol for any one class is a two unit symbol of Columns 37 and 38 [ Sarcodina , Symbol 1 1; Ciliata , Symbol 12, e. g. ]). Similarly, Column 39 is used for distinguishing orders of each class ( Amoebozoa , Symbol 111; Foraminifera , Symbol 112, e. g. ) and Column 40 distinguishes families (Meleagrididae , Symbol A611; Phasianidae , Symbol A6 12). The phylum, class, and order designations of Field J (Columns 37, 38, and 39) are the same as those designations for test organisms in Field E (Columns 18, 19, and 20). This similarity has no coding significance; it was merely an expedience in constructing the Field J list subsequent to the construction of the taxonomy list for Field E. However, the similarity with Field E symbols ends with the designations of order; familial, generic, and specific units of Field J symbols are unique to Field J. The family to which the host belongs is indicated by a single unit (the fourth unit, Column 40), in contrast to the familial designation of Field E which uses two units (two IBM columns). The families of Field J are merely assigned sequential fourth-unit symbols as they are added to the list under each order. Thus, of the order Carnivora , Canidae was the first family listed in Field J and was subsequently assigned Symbol A721, while the second family listed of this order, Felidae , was assigned Symbol A722, etc. The final two units (Columns 41 and 42) are reserved for designation of specific members of the family, as well as for indicating particular varieties and strains. In other words, of the two final columns in the field, one has not been dedicated to coding the genus of a host and the other dedicated to coding the species of the genus. Instead, they are used together as a unit in which the host's genus and species names are coded as a single unit (e. g. , Cricetus cricetus, Symbol 01, Mesocricetus auratus. Symbol 02, etc., of family Geomyidae, Symbol A733- -). This is accomplished by the simple expedient of assigning sequential symbols to species or strains as they are added to the list, reserving blocks of symbols for further strains and varieties of a species when it is recognized that several strains exist and might be purposefully used in chemical tests. For example, of the family Canidae (Symbol A721), the first member listed was the dog, Canis domesticus , and this is assigned Symbol A72101 (defined as being an unspecified breed). Since there are many breeds of dogs and since it is probable that it will some time be of some importance to be able to code the breed distinction, a number of symbols are reserved for this purpose, A72102 through A7211Z, representing 69 symbols for 69 breeds. (Although no breeds have yet actually been entered in the list, the following possibilities are suggested as illustrations: Collie, A72102; German Shepherd, A72103; Doberman, A72104, etc.) The next species added was the wolf, Canis nubilis , to which is assigned the symbol A72121. Although it is improbable that Canis nubilis used as a host would be of a particular breed or variety, four symbols are nevertheless reserved for that possibility (A72122 through A72125). Thus, the next member of the list, the coyote, Canis latrans , is assigned symbol A72126 and four symbols reserved for coyote varieties (A72127 through A7212A). Inasmuch as the two columns, as they are used, permit 1260 symbols for as many different species and strains of each family , it is probable that the scheme is adequate for all hosts used in chemical-biological tests. Considering data from all chemical-biological testing, the organism species or forms used as hosts are many fewer than the number used as test organisms, largely because in many chemical- biological tests, a host plays no role (i. e. , Field J is not used); further, most therapeutic testing involves infection of vertebrates and higher plants and little data may be expected from chemical tests in which an invertebrate or lower plant is the host (one exception being bacterial hosts of viruses). - 68 - FIELD J Columns 37, 38, 39, 40, 41, and 42 For this reason, it has been unnecessary to use as much IBM space for as large a number of families, genera, and species in Field J as is necessary in Field E. When an organism is used as a host in a chemical test, there is introduced an experimental factor that is frequently of critical importance, the relationship between the parasite and its host. For scientific control in a test, it is important that a living host be as carefully selected and stand- ardized as a non-living host, whenever possible. To achieve maximum control, it is frequently not only a particular species that is selected as the parasite's host during the test, but a carefully selected, distinct strain of that species. Within a single species may be several strains which per- form with great dissimilarity as hosts to a given parasite species. Not only may the interrelationships between parasite and the host vary according to the strain of the host into which the parasite is inoc- ulated, but the response of the parasite to chemical treatment may vary with the host strain and the responses of different host strains to the test compound may vary. For this reason, Field J symbols have been endowed with strain (variety or breed) designations, as described above. General Use Field J is the area for coding the host of a test organism, when the test organism is in or on such a host. This host may be a livin g organism or it may be a non-living environment such as a specific culture medium, soil, stored food (flour and cereal, e. g. ), water, etc. , in or on which the test organism is resident when the test compound is applied. A pathology coded in Field E, whether it is infectious (caused by a pathogenic test organism) or non-infectious, is accompanied by an entry in Field J describing the host of the pathogen or pathol- ogy. Likewise, a tumor coded in Field E is accompanied by an entry in Field J describing the living (or, occasionally, non-living) host of the tumor. The host represents an important factor of chemical-biological tests, interposed as it most frequently is between the test compound and the object of the treatment in Field E (i. e. , the test organism, pathology, or tumor). A test compound, administered as an experimental therapeutic is applied at a selected (and presumably optimal) site of the host which means that it is often applied only indirectly to the infecting organism, site of pathology, or tumor. Frequently, little is known about the details of the host's metabolic handling and rate or path of disposition of the chemical (i. e. , the host's response to the treatment). Although this observation is made with living hosts particularly in mind, certain non-living host materials may represent unknown factors relative to the dilution/ concentration/alteration of the test compound. Therefore, when a host is involved, the outcome of a test--i. e. , the therapeutic evaluation of the test compound- -must always be interpreted by regarding the host as an agent which possibly acts to dilute, concentrate, or chemically alter the test compound. Division 8, of the following section, explains how this is related to coding procedure. Specific Directions and Explanations 1. An animal or plant PART, excised and maintained in a LIVING CONDITION, as a host; the bath or nutrient solution needed to maintain the excised part Occasionally, for convenience in testing, a test organism is in or on an excised part of a host organism rather than in or on the intact host, the excised part being maintained in a living condition or so little altered by excision that its performance as a host is thereby representative of the condition in the intact, living host, in contrast to organs or tissues in which the protoplasmic contents are altered by actual death. (Examples of these "excised living" hosts are organ slices, tissue slices, tissue breis, or excised organs such as the liver, leaves, or fruits. ) Since the results of such tests can reasonably be projected to the intact living organism as a host, Field J is coded with the symbol for the organism and Field L is coded with Symbol R (or Symbol T, as described below) to indicate that it was only a representative part of the host that was actually used in the test. The excised organ or tissue is coded in Field H-l or I. (See also Division 4, below. ) 69 FIELD J Columns 37, 38, 39, 40, 41, and 42 If it is desirable to maintain this excised part of the host for any period of time, a nutrient solution or saline bath, etc. (i. e. , a "secondary host") is frequently necessary. For this reason, a second coding area for this "secondary host" would appear useful. Because occasions have been so few when the CBCC needed a second coding field for such a secondary host, it has not been considered practical to reserve IBM punched card space for it. Therefore, having only one field for hosts, Field J is coded with the host organism donor of the excised part (as described in the previous paragraph), while the bath or nutrient solution (the "secondary host") can not be coded (except that sometimes coding in Field S-3 [Symbol C] implies the presence of a bath- -when the test compound is applied in the bath). However, when an excised part used as a host (ordinarily indicated by Symbol R of Field L) is placed in a "secondary host", always code Field L with Symbol T. It is necessary to include in the written abstract for Field L the specific solution, bath, etc. , which plays the role of secondary host. 2. Tumor hosts The discussion and description of the Tumor Code of Field E includes an explanation of tumor hosts and the use of Field J. Regardless of the organism in which the tumor originated, the organism in which the tumor is located at the time of the chemical test is coded in Field J. Thus, for chemical tests using transplanted tumors, the species and strain of the organism into which the tumor was trans- planted for the test is coded in Field J. In accordance with this procedure, any non-living host (nutrient medium, saline bath, etc. ) in which a tumor (or tumor slice, brei, etc. ) is maintained during a chemical test is coded in Field J, regardless of the organism in which the tumor arose. When a compound is tested to produce a tumor (i. e. , tested for carcinogenicity), the coding of this action is accompanied with an entry in Field J which is always the organism in which the compound was tested. 3. Non-living materials: discrimination between their uses as HOSTS and as mere CONVEYERS OF THE TEST COMPOUND Most often it is not difficult to distinguish between a non-living material which serves as a host to the test organism being treated and the other non-living materials or instruments used in the experiment. A non-living host is ordinarily a material on or in which the test organism normally is found, either permanently or occasionally, or it is a material which serves directly to nourish and sustain the test organism ; in either case, the material is representative of the organism's normal environment, however artificial may be the nutrient or sustaining medium. For example, in an experiment in which the test compound is a gas bubbled into an aquarium where algae are the test organisms, the host is the material constituting the normal intimate envi- ronment of the test organism--i. e. , water; it is not the tube leading the gas to the water, nor the glass aquarium housing the algae and water. Again, in experiments in which the test compound is deposited on or in a material (glass, wood, cloth, etc.) which flies (as test organisms) are induced to contact or on which are placed lice (as test organisms), the glass, wood, cloth, etc. , are properly regarded as hosts, since they were selected as representative of environmental surfaces which the test organism might normally contact. In an experiment in which a test compound mixed with an attractant is placed in a glass dish in a cage of flies, the glass can not be regarded as the host material but merely as the container of the test compound and attractant (in the same way as the tube of the aquatic experiment was only the conveyer of the test compound); in this situation there would be no entry in Field J. In any experiment in which a volatile test compound is deposited on a material (or placed in an open container) and in which the chemical acts as a gas diffused through the air, the material or container on or in which the chemical is deposited is not a host, but merely a conveyer; the host is the treated air. Similarly, if a water-soluble compound is deposited on a material (glass or cloth, e. g. ) which is subsequently immersed in water to treat aquatic organisms, the water is the host to be coded in Field J and the material on which the test compound was deposited is merely the conveyer. A written record of the conveying materials and instruments should be included in Field J as well as the actual host materials. - 70 FIELD J Columns 37, 38, 39, 40, 41, and 42 4. Excised parts of plants and animals used as hosts; coding of these in Field J, as "LIVING" or "NON-LIVING", is dependent on their representation of the normal, intact condition When an excised part of a plant or animal is used as a host, the code entry in Field J is some- times the symbol for the organism from which the organ or tissue was taken. Sometimes, however, the organ or tissue is coded in Field J merely as a general plant or animal product such as "meat", "grain", "eggs", "wood", etc. , unspecified as to the particular organism from which it came. Which of these two possible Field J entries should be used in a given situation is determined by the condition of the excised structure used as the host organ or tissue. If it is maintained in a relatively normal "living" state, even though excised, it and its function as a host are considered to be reasonably representative of that organ or tissue in the living, intact organism. Under such conditions, the organism is identified by code in Field J and Field L is coded with Symbol R or T to indicate that the organ or tissue coded in Field H-l or I is excised. This point was discussed also in Division 1, in explaining the coding of a bath or nutrient solution for such an excised host. (For the special problem of coding seeds and fruits as hosts, consult Division 5 below. ) In contrast to excised organs and tissues maintained in a state resembling that in the living, intact organism, there are those plant and animal organs and tissues, used as hosts, which have undergone death and the alterations characteristic thereto. (Although certain structures of the living, intact organism are dead, such as heartwood, hair, nails, etc. , the coding problem under discussion concerns only excised structures which are of living tissues in the intact state. ) When an excised plant or animal part is dead, it no longer is strictly comparable to the same organ or tissue when it is a living part of the intact organism, neither in response to the organism that would use it as a host nor in response to the chemical administered. Because it is not representative of the organ or tissue of a living, intact organism, it is coded for what it is, an animal or plant product , such as meat, fur, leather, eggs (dead), wood, straw, fiber, etc. (symbol series V- and W- of Field J). In this case, Fields K and L are not coded. Neither are Fields H-l and I coded when Field J is coded with any of the symbol series V- or W-, unless a particular organ or tissue of the test organism responds specif- ically to the test compound, in which case Fields H-l and I are considered available for coding that organ or tissue. When a host organism, coded in Field J, is used in one of the special experimental states, homogenate, extract, culture, or slice , Field L is coded to indicate this state. This preparation is not considered to be non-living and coding the organism in Field J, in one of these four states indi- cated in Field L, implies its living state (otherwise, Field J would be coded with one of the non-living hosts, symbol series S- through Z-). In this situation, the coder must never use the Field T-2 symbol serief 18- to code the test compound's action because those symbols are used only to describe the effect of the test compound on the test organism's development on non-living hosts. 5. Excised and stored FRUITS and SEEDS as hosts are identified as such by being described in Field K as the STAGE of the plant coded in Field J--OR--are coded in Field J as a general plant product, according to their STATE. (See also Division 6. ) Fruits and seeds, in particular, cause confusion in interpreting them as hosts, making necessary this explanation of the CBCC procedure relative to coding them. The confusion is due partly to their unique nature; they are living organs of the plant, predestined to be discarded by the plant, yet some part of the organ remains alive long after the organism has discarded it, the most persistent being the new, embryonic individual in the seed. When these discarded living organs are used as hosts, it is a question of knowing at what point to cease regarding them as living organs of a specific organism and when to consider them as merely a non-living plant product. Although the CBCC decision has been somewhat arbitrary, the following procedure should always be observed for sake of consistency. In the case of undehydrated fruits having fleshy parts (apples, tomatoes, bananas, oranges, etc. ) and in the case of seeds in the undehydrated condition (green beans, peas, sweet- corn, etc. ), in other words, in the case of fruit and seeds in the same general condition they were in as living organs on the intact plant , they are considered as living organs of the plant, since chemical treatment of excised fruit in the condition described is conceivably comparable to such treatment before excision when there is no question about their being considered as organs of the plant. Thus, the plant is identified by code in Field J, Field L is coded with Symbol R and the fruit or seed is coded in Field H-l. Field K is coded with "fruiting plant", Symbol 8. - 71 - FIELD J Columns 37, 38, 39, 40, 41, and 42 When the seed or fleshy part of the fruit has dehydrated (prunes, dried apricots, dried peanuts, dried corn and beans, etc. , including seeds and fruits which dry before removal from the plant) even though they may contain still living embryos, the CBCC has regarded them, for coding purposes, as being sufficiently altered from the living organ of the plant to be coded as a non-living host , i. e. , a plant "material". Thus, wheat, oats, corn, beans, peanuts, etc. , which have been dried sufficiently for successful storage are coded as non-living hosts (symbol series V- of Field J) when a test compound is applied to them to protect them from test organisms. In this case, Fields K, L, H-l, and I are not coded, except that Fields H-l and I are available for coding structures of the test organism . 6. Living seeds (or fruits containing living seeds), treated to affect a test organism on the EMBRYOS In general, coding of stored seeds and fruits as hosts is according to the procedure described in Division 5 above. However, if the treatment is made to the seed or fruit when the host structure is precisely the living, dormant or germinating embryo or young seedling in or on which is (or will be) the test organism, the treatment is considered as being to the young, living plant and the symbol for the plant should be coded in Field J (rather than the symbol for the plant seed or fruit), regardless of whether the seed or fruit is dehydrated; Field K should be coded with the stage treated (embryo), Field L should not be coded, Field H-l will be coded with "embryo unspecified" (or with the embryonic part on which is the test organism), and Field H-2 will be coded with the external coat of the seed or fruit on which the chemical application was made. 7. The material in which a plant, as a TEST ORGANISM, is rooted is not necessarily coded as the plant's host When a plant is the test organism and it is growing in ordinary, suitable soil, and when appli- cation of the test compound is directly to the aerial part of the plant, the soil is not a significantly variable factor of the test any more than is the air surrounding the plant. Therefore, neither soil nor air need be coded in Field J in this situation; i. e. , Field J will not be used. However, if the test compound is applied to the soil, rather than directly to the plant, the soil assumes an important role in the test and must be coded in Field J as the environmental "host" material through which the test organism receives the test compound. If a series of chemical tests are performed on plants which differ only in being potted in soil variants (sand, clay, loam, e. g. ) and the chemical is applied only to the aerial portion in each test, the soil assumes an importance that it does not have when only one soil type is used (which may be assumed to be the preferred soil for the plant). In the code line for each test of such a series, the soil type should be coded in Field J, even though the chemical application is not made to it. (For this situation in which Field J is coded, yet application of the test compound is directly to the test organism, note carefully the coding of Fields M and N, as explained in Division 8 below. ) When plants are grown in a medium in which they are not naturally found growing (i. e. , an artificial medium such as a nutrient solution, perlite, vermiculite, etc. , or a soil or water to which they are essentially alien), that medium is coded in Field J as the host, even when the test compound is not applied to it but directly to the test organism. (Note carefully the coding of Fields M and N in these situations, as described in Division 8, below. ) 8. Relationship between Field J and the dosage fields, M and N When Field J is coded, it is assumed that the dosage recorded in Fields M and N is the dosage administered to that host, by the route indicated in Field S-3. Any exception to this must be indicated by code in Fields M and/or N, according to whether one or both are coded. Thus, when the dose in Fields M and N is the dose to which the test organism (or tumor) is directly exposed, any entry in Field J must be accompanied by a symbol designating that the entry in Fields M and N is not the dose the host receives but is the dose to which the test organism or tumor is exposed; this distinguishing symbol is the IBM 11 zone punch in Columns 45 and/or 47 of Fields M and N (coded as Symbol #). If there should be determined the concentration to which was exposed a responding organ or tissue of a test organism in a host, this would be indicated by using the zone punch in Columns 45 and/or 47 (coded as Symbol 0). - 72 FIELD J Columns 37, 38, 39, 40, 41, and 42 The 1 1 or zone punch in Fields M and N, then, is interpreted as indicating that, in spite of an entry in Field J, the dose coded is the dose administered directly to the test organism or an organ of the test organism of Field E or that it is the concentration of the test compound in the host to which the test organism is exposed, as determined by analysis of the host some time after administration to the host. In other words, the 1 1 or zone punch indicates that the coded dose is not the dose (concentration or quantity) administered to the host coded in Field J. (This is explained also in Fields M and N, Specific Directions and Explanations section, Divisions 5, 6, and 8. ) 9. Relationship between Field J and the anatomy fields, H-l, H-2, and I When Field J is coded with a host organism , Fields H-l, H-2, and I are used only to code organs and tissues of that host organism . However, when Field J is coded with a non-living host (a nutrient medium, bath, etc. ), the anatomy fields are used only for coding parts of organs and tissues of the test organism . Symbols for non-living hosts all begin with letters recorded on the IBM punched card by using the zone punch (letters S through Z). Therefore, when Field J is coded with a symbol beginning with any of letters S through Z (i. e. , if it is punched with the zone punch in Column 37), any entry in Field H-l, H-2, or I represents anatomical parts of the test organism in Field E. When Field J is coded with a symbol beginning with any number or any letter A through R (i. e. , if it is not punched with the zone punch in Column 37), any entry in Field H-l, H-2, or I represents anatomical parts of the host organism in Field J. 10. Relationship between Field J and Fields K and L Rather than use a single coding area for coding special experimental conditions and sex and stage of the test organism (when no host organism is involved in the test) or of the host organism (when a host_is involved), the CBCC has found it necessary to have two such areas. Thus, Fields F and G represent the coding area used only for sex and stage and special experimental conditions of the test organism , whether or not the test organism is in a host. The two fields, K and L, describe the sex and stage and special experimental condition of any host and if no host is coded, Fields K and L are unused. 1 1. Variations of standard nutrient media and solutions Among the non-living hosts are listed a number of standard nutrient media or saline solutions (e. g. , Ringer's solution and Tyrode's solution). Occasionally, one of these will be altered slightly for some experimental reason and will be reported thus (e. g. , "potassium-free Tyrode's solution"). Instead of assigning a unique symbol to each of these many variants of a standard medium or solution, the CBCC uses the symbol for the standard solution and explains the deviation from the standard on the Code Sheet in the written abstract portion for Field J. 12. Definition of "culture medium"; use and significance of symbols of the X series Symbols of the X series (of the group of non-living hosts, S through Z ) are defined as "media" and, as such, refer to laboratory- prepared mixtures of known composition which have been determined to be adequate for satisfying the test organism's requirements for life, growth, and repro- duction. It is possible that a completely adequate culture medium may consist merely of one of the specific natural materials coded by Symbols S through W and Y and Z . For example, a sugar solution (Symbol T6) or cheese (Symbol W51) may be entirely adequate as a culture medium for growth of an organism (e. g. , a given mold) to be tested for response to a test compound; the natural materials (e. g. , yeast concentrates, eggs, flour, cheese, etc. ), however, lack the degree of standardization that is possible with artificially prepared mixtures. The symbols of series X in Field J are not necessarily conceived as making distinction between inadequacy and adequacy of a non-living host (i. e. , while items coded with symbols of series X are assumed to be adequate for the test organism, items coded with other symbols are not assumed to be inadequate for the organism being grown in or on it), nor to make an absolute dis- tinction between the artificiality or naturalness of the non-living host, nor between the standardization or non- standardization of the non-living host. Symbols of the X series pretend a function no broader - 73 - FIELD J Columns 37, 38, 39, 40, 41, and 42 than to code literally those specific artificial media when used in a test or when the substrate of the microorganism is described merely as "culture medium". 13. Code symbols of Field J having less than six units An author may occasionally identify a host only as to family, for example, for which reason only the symbol for the family would be used. Since this symbol has only four units, Columns 41 and 42 would be left uncoded. The CBCC has established the practice of cross-hatching any final unused "code boxes" of Field J on the Code Sheet when the entry is identified only as to family, order, class, or phylum; this is merely to assure the operator punching the IBM card that the short symbol of Field J is deliberate and that the unfilled code boxes do not represent unfinished coding. 14. Symbols available for additional items of Field J Zone punches have not been assigned special meanings in any of the Field J columns. Thus, there are no restrictions on use of any symbol in any column for constructing host symbols. The last animal symbol of the present list begins with the letter G and the first plant symbol begins with the letter J. Similarly, the last plant symbol begins with the letter M and the first non- living host symbol begins with the letter S. The letters H and I and N through R in Column 37 are available for expansion of animal hosts (H and I) and plant hosts (N through R). By restricting animal hosts to symbols beginning with 1 through 9 and A through I, plant hosts to symbols beginning with J through R, and non-living hosts to symbols beginning with S through Z, it permits all plant hosts to be recognized (and retrieved) by the IBM 11 zone punch and all non-living hosts to be recognized (and retrieved) by the IBM zone punch. 15. File of coded biology data on IBM punched cards arranged according to symbols for hosts The CBCC maintains a separate IBM punched card file of all the coded chemical- biological data in which a host plays a role, i. e. , all cards on which Field J is punched. This file is arranged according to the sequence of Field J symbols. Therefore, in searching for all information concerning a specific organism (or non-living host, for that matter) that has been used as a host (e.g. , all infor- mation concerning a specific organism that has been experimentally treated for diseases), the CBCC can quickly retrieve it from this field by a single manual action. 16. Double coding of hosts in Field J prohibited Since CBCC coding procedure is dependent on IBM punching methods, two hosts are never coded in a single code line. If all aspects of two tests are so similar that the coding of the two would be the same for all coding fields except that different hosts were used, the two tests could not be recorded in a single line by coding both test organisms in Field J; a separate line is necessary for each host. 74 FIELD K Column 43 SEX AND STAGE OF DEVELOPMENT OF THE HOST ORGANISM The organization, general use, and, for the most part, the specific directions and explanations for Field K are so nearly like those for Field F that repetition is unnecessary. Keeping in mind that coding in Field K describes the host in Field J, the discussions of Field F (describing the test organism in Field E) can be interpreted to apply to Field K. It will be noted that any reference to Symbols S through Z does not apply to Field K, for which reason none of Division 5 of the Specific Directions and Explanations for Field F is applicable to Field K. As in the case of Field F, the CBCC maintains no file of coded data (IBM punched cards) arranged by code entries in Field K. Double coding is permitted in Field K, just as double coding is permitted in Field F as described in Division 4 of Field F. 75 FIELD L Column 44 PRETREATMENT OR EXPERIMENTAL STATE OF THE HOST ORGANISM OR OF THE ORGAN, TISSUE, OR CELL (OF THE HOST ORGANISM) WHICH IS THE SITE OF THE PARASITE, NON- INFECTIOUS PATHOLOGY, OR TUMOR CODED IN FIELD E Symbol Z only: EXPERIMENTAL TREATMENT OF THE HOST OTHER THAN TREATMENT WITH THE TEST COMPOUND AND COMPOUND CODED IN FIELD D Note: The organization, general use, and specific directions and explanations for Field L are so similar to those for Field G that a complete account would be largely a copy of that for Field G. To avoid total repetition, the coder is requested to refer to the explanation of Field G, applying that explanation to Field L. The following description of Field L, therefore, is principally to distinguish its use and its relationships to Fields J, H-l, H-2, and I from the use of Field G and its relationships to Fields E, H-l, H-2, and I. Organization Most of the items of Field L are almost identical in definition and organization to those of Field G. The coder is referred to the explanation of the organization of Field G. However, in coding Field L, reference should be made only to the definitions of symbols in the Code section for Field L. General Use Field L is used only to code experimental states of a HOST organism coded in Field J. Since the relationships of Field L to Field J are so nearly identical to the relationships of Field G to Field E, the coder is referred to the explanation of the general use of Field G. In that discussion, references to "Field G", "Field E", "test organism", "test organism's organ or tissue", and "organ or tissue re- sponding to the test compound" can in general be translated to "Field L", "Field J", "host organism", "host's organ or tissue", and "organ or tissue site of the pathology in Field E", respectively, in order to apply the explanation to Field L. The following corresponds to the four divisions of the explanation of the general use of Field G. 1. Field L . (Read Division 1 of the General Use of Field G, applying that discussion to Field L. ) 2. Field L is a single column coding area, in contrast to Field G which is divided into two coding areas, G- 1 and G-2 For practical reasons, less coding space has been awarded to coding pretreatments and experi- mental states of host organisms than for coding pretreatments and states of test organisms. While it is true that occasionally a single coding area (Field L) is inadequate for coding all experimental states of a host, just as two areas (Fields G-l and G-2) are sometimes inadequate for coding all states of a test organism, the infrequency of need for more than one Field L justifies the CBCC's reserving only one IBM column for it. 3. Relationship of Field L to Fields J, H-l, H-2, and I . (Read the first two sentences of Division 3 of the section describing General Use of Field G, applying that discussion to Field L and Field J. ) The latter part of Division 3 of the General Use section of Field G can not be interpreted strictly to relate to Field L for the following reason. Although the relationships between Field L and Fields H-l, 76 FIELD L Column 44 H-2, and I are essentially the same as between Field G and Fields H-l, H-2, and I, the definition of anatomical entries in Fields H-l, H-2, and I varies, depending on the coding in Field J: when a living host is coded in Field J, Fields H-l, H-2, and I are used to code anatomical sites of the pathology in Field E (i. e. , anatomical parts of the host ), rather than anatomical parts which respond specifically to the test compound (i. e. , rather than anatomical parts of the entry in Field E). 4. Significance of information about experimental states coded in Field L . (Read Division 4 of the General Use of Field G, applying that discussion to Field L. ) Specific Directions and Explanations Note: In the following, reference need be made to the corresponding division of specific directions and explanations for Field G ONLY when it is suggested to do so. 1. Field L is related exclusively to Field J and to Fields H-l, H-2, and I THROUGH Field J 2. Coding when presence of a tumor in the host is incidental When a host has a spontaneous tumor and the information being coded is unrelated to any response of that tumor to the test compound, the tumor's presence is incidental and should be coded in Field L with Symbol 7, N, or 0, not with Symbol 5. (If the incidental tumor is not spontaneous , but implanted, use Symbol S. ) 3. More than one experimental state of the host If more than one experimental state characterizes the host, only one can be coded (whichever is the more significant, if a choice is possible). The other states must be described in the written abstract portion of the field. 4. Relationship of Field L to Fields J, H-l, H-2, and I Field H-2 : When Field J is coded with a host organism (any Field J symbols beginning with any of numbers 1 through 9 or letters A through R), Fields H-l and I are used only for coding the anatomical site of the pathogen, non-infectious pathology, or tumor coded in Field E. Field H-2 is used to code any organ other than the specific anatomical site of the pathology: an organ to which the test compound is admin- istered (when it is not administered to the organ in Field H-l), for example, or an organ (other than the organ in Field H-l) which is given special pretreatment or is in a special state as indicated by any of certain entries in Field L. (See Division 5 below for a more complete explanation of the uses for Field H-2. ) The point to be made here is that Field H-2 can be used with Symbol B, 0, P, or S of Field L to describe those experimental states of the host organism in Field J. Fields J, H-l, and I : When Field J is coded with a host ORGANISM (which is the only occasion when Fields H-l, H-2, or I relate directly to Field J rather than Field E), rather than a non-living host, Field L is used to describe a state of the host organism as a whole (Field J), or of the anatomical site of the pathology in Field E (Field H-l or I). Certain of the items of Field L have an ambiguity of reference to Fields J, H-l, and I. (This is true also of items of Field G in their relationships to Fields E, H-l, and I and it is discussed under Specific Directions and Explanations for Field G, Division 4. The coder should review that explanation. ) Except for items coded by Symbols 5, 7, 9, A, F, G, H, I, K, L, 0, and P which include in their definitions specific reference to Field J or H, reference must be made to the written abstract of the Code Sheet to ascertain that the pretreatment (or experimental state) coded in Field L was of the host organism as a whole in Field J, or particularly of the organ in Field H-l, or of the tissue or cell in Field I. Actually, items 1, 2, 3, 4, and M of Field L are the ones for which it might be most particularly useful to have a means of making distinctions of reference to Field J, H-l, or I. 77 - FIELD L Column 44 5. Conflicts in Field H-2 (See Division 5 of Specific Directions and Explanations for Field G. ) For reasons explained in Field G, precedence is established for the three possible uses of Field H-2: (1) the site of a pathology in Field E, when the organ in Field H-l is not the site of the pathology (accompanied by an asterisk coded in Column 30); (2) an organ, other than the site of the pathology, in a special state described by Symbols B, 0, P, or S of Field L; (3) an organ other than the organ of Field H-l to which the test compound is administered as indicated by coding in Field S-3. 6. An incidental pathological condition vs. a TREATED pathology Symbols 5, 7, B, C, D, N, 0, and S are used to code only pathological conditions which are not being treated with the test compound and which exist contemporarily with the pathology in Field E which is being treated with the test compound. 7. Adaptations (Symbol 1). (Refer to Division 7 of Specific Directions and Explanations of Field G, applying that explanation to Symbol 1 of Field L. ) 8. Nutrient and hormone deficiencies and excesses, as incidental conditions vs. treated conditions Field L is not used to code any pretreatment which brought about a pathological condition which was subsequently treated with the test compound for the test data being coded. In particular, any pretreatments producing deficiencies (extirpation of a gland, e. g. ) which are to be treated experimentally with test compounds are not indicated in Field L; the deficiency pathology will be coded in Field E and if it were artificially induced for experimental purposes, the induction must be explained only in Field E-- while Field L is left free for coding any experimental state incidental to this deficiency disease. 9. Coding of data from more than two tests using several host organism strains Field J symbols (in contrast to Field E symbols) designate specific taxonomic strains. Therefore, there is no need for a symbol of Field L to indicate that a special taxonomic strain of host organism has been used in any one test. (See Division 12 below. ) However, just as Symbol F in Field G is used to condense into two code lines data from several tests using several distinct strains of test organisms (ref. : Division 9 of Specific Directions and Explanations of Field G), Symbol F in Field L may be used to condense into two code lines data from several tests using several distinct strains of host organisms. The coder should refer to the part of Field G explaining this procedure, applying it to Fields J and L. To this extent (i. e. , to the extent that these several host strains may be taxonomic strains or varieties), Symbol F is used to distinguish in a non-specific way taxonomic strains, which represents an exception to the definition of the symbol implying that it is never used to indicate a taxonomic variety. 10. Pretreatments represented by Symbols 2, P, Q, and R; distinctions of definitions and use of the four symbols. (The explanation of these symbols is essentially the same as for Symbols 2, P, Q, and R of Field G. The coder is referred to Division 10 of Specific Directions and Explanations for Field G, applying that discussion to Symbols 2, P, Q, and R of Field L. ) 1 1. Use of Symbols 6 and J; STATES OF resistance or sensitization to the test compound vs . PRODUCTION OF THOSE STATES A. States of the host (1) Sensitivity (Symbol 6) Symbol 6 is used in Field L to indicate a sensitivity to the test compound having been produced in the host in Field J, in the same way as Symbol 6 of Field G is used when a similar sensitivity has been produced in the test organism. (Refer to Subdivision A of Division 1 1 of the Specific Directions and Explanations of Field G. ) (2) Resistance (Symbol J) Symbol J is used in Field L to indicate that the host has been made resistant to whatever effects the test compound normally has on that host- -EXCEPT the effect of relieving or curing the host of the pathology in Field E. In other words, if a test compound 78 - FIELD L Column 44 demonstrates a given therapeutic action which diminishes after the initial therapy, this should not be described as a refractoriness of the host, but a refractoriness of the pathogen, non- infectious pathology, or tumor in Field E. The state of the pathology's having been made refractory to the test compound, when recording the test compound's action subsequent to the production of refractoriness, should be coded in Field G with Symbol J rather than in Field L. Any production of such refractoriness to the test compound should be recorded by a code line in which refractoriness production is coded in Field T-2, as described in the next paragraph. B. Production of states of resistance and sensitivity of the host Any actual production of resistant or sensitive states of a host organism would never be coded in a line in which that organism was coded as a host, but only by a code line in which the organism is coded in Field E as a test organism in which there was induced an increase in resistance or sensitivity to the test compound or a secondary compound (Field T-2 symbol, symbol series 51 or 58). The coding of increase of resistance and increase of sensitivity is described in Fields M and N, Division 11, in Fields W, X, and Y, Division 13, and in Field T-2, Division 20. 12. Symbols F, G, H, and I represent characteristics intrinsic to the host organism and do not represent responses to the test compound . (The coder is referred to Division 12 of Specific Directions and Explanations for Field G, which discussion can be applied to Symbols F, G, H, and I of Field L. These symbols are never used in Field L to distinguish taxonomic strains, although, in the case of Field J, there is no actual need, since Field J itself distinguishes taxonomic strains. See Division 9 above, however, for the special use of Symbol F in condensing data into two code lines. ) 13. Host organisms, organs, or tissues with incidental IMPLANTS . (See Division 13 of the Specific Directions and Explanations for Field G. Example: Observations are reported on a compound's action on intestinal helminths in mice in which had been implanted tumors, the tumor implantation having been for the purpose of separate carcinostatic tests. In coding the anthelmintic action, the helminth would be coded in Field E, the mouse in Field J, the anthelmintic response and its evaluation in Fields T, X, and Y, and the fact that the host has an incidental implant [the tumor] is coded by Symbol S in Field L. ) 14. Host IMPLANTED in a secondary host Occasionally a test method involves maintaining the host (of the test organism) in a secondary host. While this is very unusual, though not impossible, in the case of whole organisms as hosts in chemical therapeutic tests, it is practically invariably the case that, when the "host" of the parasite, non-infectious pathology, or tumor is an excised organ or tissue of the host in Field J (indicated by Symbol R in Field L), that organ or tissue is maintained by a secondary, non-living "host" (i. e. , a saline bath, nutrient medium, etc. ). Unfortunately, a second Field J is not provided for coding such a second host of the primary host organism . The few occasions when it would be needed do not justify it for the CBCC's coding. At most, a provision is made to express the fact that a secondary host is involved, without identifying it: Symbol T of Field L. Since a non-living, secondary host is assumed for excised organ or tissue hosts, coding Field L with Symbol R carries that implication (expressed in the definition of Symbol R). The identity of the non-living secondary host (bath, nutrient medium, perfusate, etc. ) should always be included in the written abstract of Field L. Thus, Symbol T is available for use, however infrequent it may be, when the total host organism is maintained in a special secondary host organism or non-living secondary host. It is also used when this total host organism is a plant maintained fn a special and basically unnatural medium for the ex- perimental period (i. e. , other than the soils in which it would be given optimum support, such as plant nutrient solutions, water, agar, perlite, sand, etc. ) 79 FIELD L Column 44 15. Indications that an EXTIRPATED organ or tissue (site of pathology) is WHOLE (Symbol R) vs. the indication that the organ or tissue has been macerated, sliced, etc. (Symbols U, V, W, and X ). (Refer to Division 15 of Specific Directions and Explanations for Field G, applying that discus- sion to Symbols R, U, V, W, and X of Field L. ) 16. Symbols U, V, W, and X describe states of the host (or organ or tissue of the host) AT THE TIME OF CHEMICAL TREATMENT When a compound is applied to a host organism (or organ or tissue site of pathology) which is later homogenized or made into slices or extracts, etc. , for the purpose of reading the test results, Code Symbols U, V, W, and X can not be coded in Field L. This field is used only to describe the state or condition of the host or site of pathology at the time of treatment . 17. Symbol Y: resistance acquired to the test organism This symbol represents a factor unique to Fields L and J in that the host can develop an immunity to the biological factor coded in Field E against which the test compound is being administered. This is a factor that frequently deserves or demands recognition in recording and evaluation of a therapeutic action of a test compound. 18. Symbol Z This symbol is used in a unique way and does not correspond to the other symbols of Field L in that it does not represent just a pretreatment or state of the host during the test, but it represents, like the test compound, an active factor of therapy for the parasite, non-infectious pathology, or tumor. When this symbol is used, it indicates a therapeutic treatment given to the host (which may be in any experimental state indicated by any of Symbols 1 through Y), in conjunction with the test compound treatment (or test compound and secondary compound treatment). When any such test compounded of chemical and non-chemical treatment is coded, Symbol Z has precedence over any symbol for pretreat- ments and experimental states in Field L and the latter can only be recorded in the written abstract. The CBCC Code makes no provision for identification of such non-chemical therapeutic treatment so that there is no way of distinguishing two or more tests (i. e. , two or more code lines) according to variation in non-chemical therapy. A coding project concerned particularly with clinical data would doubtless find advantageous devising specific symbols, rather than a single non-specific symbol (Symbol Z), for various non- chemical therapeutic treatments. 19. Symbols available for additional items of Field L All numerical and letter symbols available for Field L have been used. However, since the IBM zone punches have not been given special meanings in Field L, each of them can be used alone as a symbol. 20. File of coded biology data on IBM punched cards arranged according to symbols for experimental states of host The CBCC has not established a s'pecial file of coded data in which Field L has been used (and arranged by Field L symbol sequence), because of the remote probabilities of a frequent need to search for all information on tests in which was a specific incidental condition of the host. The coding of Field L is more frequently used in "secondary" sorting of coded information and should be regarded as a means of recording biological aspects of chemical therapeutic tests that are frequently of prime sig- nificance in explaining the outcome, coded in Fields T, W, X, and Y. 21 . Double coding is not possible in Field L Having made use of all of numbers 1 through 9 and all 26 letters for code symbols in Field L, the IBM machine punching and retrieval procedures do not permit more than a single symbol in Field L in any one line. Therefore, when coding two or more tests whose details and outcomes are so nearly alike that the code lines for all tests would be identical except for differences in pretreatment or state of the host (Field L), the tests can not all be recorded by one code line with several entries (repre- senting the several pretreatments or states) in Field L. (A special circumstance allows condensing 80 FIELD L Column 44 two or more tests in a single line by use of Symbol F of Field L [explained in Division 9], but this is not strictly comparable to double coding as it is described in the preceding sentence and even in this special case, Field L is occupied with but a single symbol. ) - 81 - FIELD M Columns 45 and 46 FIELD N Columns 47 and 48 DOSAGE FIELD M- -PROPORTIONS OF TEST COMPOUND AND DILUENT : I. E. , CONCENTRATION OF TEST COMPOUND ADMINISTERED TO THE TEST ORGANISM OR HOST FIELD N--(l) QUANTITY OF PURE TEST COMPOUND ADMINISTERED; (2) PROPORTIONS OF PURE TEST COMPOUND PER UNIT OF TEST ORGANISM OR OF HOST Organization Fields M and N each have code symbols which consist of two units. These symbols are recorded by the CBCC in IBM punched card Columns 45 and 46 (Field M) and 47 and 48 (Field N). The first code unit in each field (Columns 45 and 47) designates the unit of measure in which the quantity is expressed (e. g. , in Field M, parts per million, molar concentration, etc. , and, in Field N, micro- grams, milligrams, etc. ). The second code unit of each field (Columns 46 and 48) indicates the actual quantitative value (e. g. , in Field M, the number of parts per million, the number of millimoles per cubic centimeter, etc. , and, in Field N, the number of micrograms or milligrams, etc. ). Thus, in both Fields M and N, a dosage is expressed by indicating (1) the unit of measure and (2) the measure or quantity itself. Providing code symbols for the first is merely a matter of assigning sequential numbers or letters to each unit of measure, such as Symbol 1 for parts per million, Symbol 2 for molar concentration, etc. The second, however, is not so simple as it may superficially appear. It is not practical to code specifically the numerical quantitative values themselves; therefore, code symbols must be assigned to represent ranges of quantitative values, such as a symbol which represents a range of 1 ppm to 5 ppm and another symbol for 5 ppm to 25 ppm, etc. Having made a definition for a symbol, such as > 1-5 ppm (i. e. , any number of ppm more than 1 up to and including 5 ppm), it is thereby impossible to distinguish by code 2 ppm from 4 ppm; it is only possible, by code, to distinguish between ranges , so that a dosage can be indicated only as being in the range of > 1-5 ppm or > 5-25 ppm, etc. Defining these ranges resolves itself into a problem of determining reasonable limits of each range. This is intimately linked with the coding field used for recording evaluations of test results (Field Y). Since the difference between evaluations is sometimes solely a reflection of the amount of test compound administered, it is important that the ranges not be so broad that this difference in responses can not be explained in code by appropriate dosage symbols in Field M and/or N. Consider, as an illustration, a given test compound which caused a given response, but at a very low or insignif- icant degree at a dosage of 0. 1 units; not until 50 units was administered was the response optimal. Since the dosage value for this data will be coded as a range in which lies the smallest dose causing the highest response (50 units), it is important that the range in which 50 units lies is narrow enough so that doses causing less response or no response are not in the same range. If the range covered by a single code symbol were 1-100 units, for example, the fact that the most effective dose was 50 units, whereas 20 units, 5 units, 1 unit, etc. , were less effective or totally ineffective, could not be dis- tinguished by code. All such a code symbol would indicate would be that somewhere between 1 and 100 units, the test compound produced the response to the degree indicated in Field Y. However, if the definition of a code symbol were a range of only 30-60, the use of that symbol would indicate at least that somewhere between 30 and 60 was the dose producing the response of the degree indicated in Field Y and that below 30 the response occurred at a lower degree or not at all. Thus, the more narrow the range represented by each code symbol, the more precise can be the coding of dosage administered producing the response to the degree coded in Field Y. Because of the relationship between the dosage fields (Fields M and N) and the evaluation field (Field Y) and because in Field Y the symbols available for evaluation coding are only digits and 1-9, the only symbols correspondingly permitted in Columns 46 and 48 of Field M and N are and 1-9. The value scales are divided, therefore, into 9 (or rarely 10) consecutive ranges. (Reference should be - 82 - FIELDS M and N Columns 45 and 46; 47 and 48 made to the discussion of Fields X and Y for a more complete account of coding evaluations and their interpretations. ) If a compound causes a given biological response (coded in Fields T and Y) when administered in very small quantities, it is indicative of a more highly sensitive biological system or a more highly active or efficient test compound than if that same response were achieved only by administering more massive doses. Further, when concerned with such sensitive responses, it is usually the case that the dose producing a given response is a more critical factor demanding a nicer distinction than when the biological response is only with large doses. For these reasons, the division of the total range of quantitative values has been basically by logarithmic progressions which provides wide ranges at the upper end of the scale and narrow ranges at the lower end (e. g. , >625 through 2, 525 ppm [Symbol 8] and 0. 04 through 0. 2 ppm [Symbol 2]). The total range for any given unit of measure (i. e. , for any given scale of quantities) is not necessarily consistent with total ranges for other units of measure. For example, in Field M, the scale for parts per million (Scale 1) ranges from <. 04 to >2, 525 ppm (= . 000004% to >. 2525%), whereas the scale for per cent weight or volume (Scale 4) ranges from >. 000001% to 100% (= . 01 ppm to 1, 000, 000 ppm) so that the percentage range (Scale 4) is broader than the parts per million range (Scale 1) and the individual symbols for the quantitative values, therefore, describe broader ranges of percentage values (Scale 4) than they do ranges of ppm (Scale 1). The reason for the difference in the case of these two total ranges is simply that an author's use of the unit, ppm, is ordinarily confined to expressing measurements of administered doses when they are of a fine and critical nature. When greater concentrations are used (e. g. , 10, 000, 100, 000, or 1, 000, 000 ppm), an author seldom ex- presses it in ppm, but in percentage concentration. Therefore, it was reasonable to set the limits of the total range for ppm closer than the limits of the total range for percentage and the advantage there- by gained for the ppm scale was a finer division into ranges for the quantitative symbols of the scale. The significant point to be observed is that in two or more scales which are comparable in that the quantitative values of one can be converted to quantitative values of the other (e. g. , 100 ppm can be converted to 0. 01%), the quantitative code symbols do not represent the identical quantitative ranges and are not therefore interchangeable so that whereas 100 ppm is coded with Symbol 6 by the ppm scale (Scale 1), it would be coded with Symbol 5 by the percentage scale (Scale 4). In Field N, Scales 1 and 2 do not have identical or even similar range limits. In this case, the two scales represent a continuum and do not overlap at all, essentially for the same reasons as for the difference in ranges of Scales 1 and 4 of Field M. In the case of Scales 1, 2, and 4 of Field N, by spreading the total range across the three, each scale benefits by having a more narrow range for each quantitative symbol than if each scale attempted covering the total range. It should be recorded that the scales for those units of measure expressing quantity of pure test compound per unit of test organism or per unit of host organism or host environment (e. g. , mg/kg, mg/sq. ft. , lbs/acre) might have been placed in Field M, since the pure test compound in such cases is understood to be distributed over or through the organism or environment on or into which it is placed and therefore the expressions are indicative of a final concentration of the test compound of which the organism or host environment serves as the diluent. If this were done, the definitions of and distinctions between the uses of the two Fields, M and N, would be altered. The fields would permit distinguishing between (I) any expression of "concentration" (either "initial" or "final") (in Field M) and (II) any expression of "quantity of pure compound disregarding organism or host environ- ment size" (in Field N). This distinction seems of less advantage or significance than the distinction according to whether there can be indicated (1) the administration of the compound at a given concen- tration, although the final total amount is not implied , as opposed to (2) the specific final total amount of compound applied (whether expressed as a total quantity per test organism, host, or host environ- ment or as a total quantity per unit of test organism, host, or host environment). Therefore, this latter distinction has been the basis for definitions of Fields M and N, respectively, and accordingly the scales for quantity per unit of test organism, host, or host environment are in Field N. Thus, with these definitions, when only Field M is coded, it may be assumed that nothing is known except the concentration of the test compound in the preparation administered ; the total amount administered is not known. However, when Field N is coded, either alone or with Field M, there is indicated that actual quantity of test compound administered to the test organism, host, or host environment, accord- ing to which of these three the administration was directly made. - 83 - FIELDS M and N Columns 45 and 46; 47 and 48 General Use Field M is used in cases when the test compound is applied in a diluent or carrier so that the quantity must be expressed in terms of a concentration of the test compound in the preparation admin- istered. In case a compound is administered at 100% concentration (i. e. , lacking any diluent) and the quantity is unknown so that it can not be expressed in Field N, Field M may be coded with Scale 4, Symbol 9. Field N expresses the amount of pure compound administered to the biological component of the test within a given unit of time expressed in Fields O and P. This field is used, therefore, when the test compound is applied in a pure and undiluted form - -so that the concentration is always 100% -- and when the quantity of this is known. However, Field N is also used to express the amount of pure compound represented by the total dose when administered at a given concentration less than 100% (the concentration being always expressed in Field M). The quantity in any case is always expressed in Field N in terms of amounts of the pure compound, such as pounds, grams, milligrams, etc. Specific Directions and Explanations 1. Both concentration and quantity coded when possible An author will seldom record both the concentration of the test compound preparation employed and the quantity of the test compound applied per organism, but he will often give information on the concentration in such a way that the quantity applied per organism can be calculated or will give quantity- dosage information from which concentration- dosage information can be calculated. When both concentration-dosage and quantity-dosage information are available or can be calculated, both should be recorded and coded. 2. S election of the scale (i. e. , the unit of measure) when the author's unit of measure can be converted; Field M Scales 1, 4, B, and 5 In Field M, some concentrations can be expressed, though not equally well in all cases, with any one of several scales by mathematically converting the dosage values. These are Scales 1, 4, and B. (Scale 5 represents a unit of measure, pounds/100 gallons, which can be converted to the units of measure of Scales 1, 4, and B, but the probabilities of frequency of such conversion is very remote. ) In Field N, none of the scales represent units of measure that can be converted to the unit of measure of another scale, except that when a dose of more than 81 micrograms (= 0. 081 milligrams) is admin- istered, for example, Scale 2 (the milligram scale) or Scale 4 (the gram scale) is used, since the microgram scale range is limited to a maximum of 81 micrograms and the milligram scale begins with 0. 081 milligrams (= 81 micrograms). Therefore, a dose of 200 micrograms, for example, would be "converted" to 0. 2 milligrams and coded by Scale 2. In the case of Field M, when an author expresses dosage in units other than those represented by Scales 1, 4, 5, and B, there is no choice but to use the scale for the unit of measure used by the author. In regard to making a choice of one of the Scales, 1, 4, B, and 5, of Field M, there should be considered whether greater accuracy of expression can be made with one of the scales. As an illus- tration, 4000 ppm (Scale 1 of Field M) would seldom be coded by use of Scale 1, since it could only be interpreted as > 2525 and it might therefore represent any concentration from 2526 to 1, 000, 000 ppm. By converting it to 0. 4%, it can be coded so that its interpretation is at least limited to between 0. 1% and 1. 0% (Scale 4). Within the overlapping parts of the total ranges of Scales 1, 4, and B, it is probably not too important as to which scale is used. For example, 100 ppm might be converted to 0. 01% or to 0. 1 mg/ml and, in code, this would be Symbols 16, 4_5, or B5, respectively. Thus, the code symbol for the quantity unit (underlined in the symbols) varies only by one digit (or at most two, with other dosage values) and this difference is not actually significant to evaluation when it is based on dosage (Field Y), since such evaluation accuracy is not pretended by this Code. 84 FIELDS M and N Columns 45 and 46; 47 and 48 Occasionally, when data are being coded from a research program in which many compounds were tested by a single method, it is desirable to code them so that the coding is comparable for all tests of that particular testing program. A single scale most suitable to the data has been selected by the CBCC in such cases and used consistently (e.g. , Scale 1, ppm) even if some of the tests used dosages which are beyond the maximum limit of the scale's range (e. g. , beyond 252 5 ppm). When two or more of the four scales of Field M (Scales 1, 4, 5, and B) seem equally adequate for expressing the dosage quantitatively, the field of biology which the data concern should be con- sidered. Thus, if one of the units of measure seems a more reasonable expression of the dosage, because that measure is more commonly used in that biological field, the choice should be made on that basis. For example, pounds per 100 gallons (Scale 5) is the unit of measure most conspicuously inappropriate for pharmacological data. In Field N, it is always best to express the dosage given per unit area or per unit mass of the test organism (or host, if administration is to a host) when this is possible. A practical example is the intravascular injection of 2 mg per 20-mg mouse (when each test mouse has been selected for approximately 20 grams weight). In this case, it is possible to code merely that the dose was 2 mg, with Scale 2 of Field N; however, in this expression, there is no correlation of the mass of the organism with the given dose. The difference between distribution of 2 mg through 20 grams of mouse and 40 grams of mouse (or through the 20-pound mass of a larger animal) is considerable and thus a scale which represents a correlation between the dose and the organism size permits a more accurate statement of the dosage to which each unit of the organism was exposed. Therefore, the CBCC coder would calculate the per-kilogram dosage and use Scale 6. 3. Dosage size as a basis for evaluation of a specific action or use Evaluation (Field Y) of a given chemical activity (Field T) based solely on dosage (Fields M and N) is actually not possible unless test data on only one type of biological activity were being collected and the experimental method remained comparatively standard. This is because compounds tested for certain practical uses (agricultural chemicals, e. g. ) may deserve a high activity evaluation when applied in comparatively large doses (because under the conditions of practical application only such large applications of known chemicals produce the response). If the test evaluation of compounds for such a practical use were made by reference to a standard dosage scale which was designed to permit expression of test doses for all possible test data, the evaluation would be misleading, for it would indicate only that since the dose was high, the relative chemical activity was poor and although this may be chemically- biologically true, it is not an adequate expression of the evaluation of the compound for the use for which it was tested. Although the preceding will be discussed again in Field Y, it is pointed out here to permit explaining more clearly that the use of symbols assigned to the nine ranges of each scale is primarily for expressing the most effective (or highest ineffective) dose administered . The symbols can not be used as a sole means of arriving at the evaluation of the compound for the specific action (i. e. , the specific use) for which it was tested . It might only be used this way if data on a single specific action were being collected, coded, and filed and if the dosage scale had been adjusted to evaluate chemicals for this one activity on a comparative basis. (See also the discussion of the organization of Field P. ) Relative to the above statements, however, the final observation should be made that use of such a scale as a basis in evaluating responses from test data on any and all chemical actions, would not be entirely without significance, since there would be expressed thereby the comparative basic sensitivities of the biological systems involved to each compound tested, varying only by the application method. 4. Dosage to be coded when application is to the (1) test organism, (2) host, or (3) parent When application of the test compound is made directly to the test organism, even if it is in or on a host, the dosage to be coded in Fields M and N is that dosage applied to the test organism. If the test organism is in or on a host or host environment coded in Field I and the application of the test compound is directly to the host or host environment (and therefore only indirectly to the test organism), the dosage coded in Fields M and N is the dosage applied to the host. Provision is made Through Field S for application to an egg or developing embryo when the application is only indirectly to the egg or embryonic stage but directly to the parent while the young stage is still intimately 85 - FIELDS M and N Columns 45 and 46; 47 and 48 connected to the parent: The dosage applied to the parent is recorded in Fields M and N and the fact that the response is read on the embryo or offspring (coded in Fields E and F) is indicated by Symbol in Field S-3. 5. Relationship between the dosage fields (Fields M and N) and Fields H and I; use of Symbol # when Field J is NOT coded. (See Divisions 6, 8, and 9 for the use of zone punches when Field J IS coded. ) Occasionally, data are encountered in which the test compound was applied to a test organism to determine the effect on some component organ or cell of the test organism and the author has deter- mined the actual concentration of the test compound, at the site of action within the organism, to which that organ or cell is exposed. For example, a 1% solution is administered to a test organism in a volume calculated to give a final dose of 10 mg/kg. An analysis revealed a blood level of 0. 1 mg/cc. The action was on leucocytes. In this case, since the action is stipulated as being local and at the organ where the 0. 1 mg/cc concentration existed, the dosage to be coded is the 0. 1 mg/cc. The dosage administered to the gross organism (1% solution to give 10 mg/kg) is not coded, though it should be included in the written abstract as a record of the technique that gave the 0. 1 mg/cc blood level. In such cases, the administration must no longer be regarded as being to the test organism (Field E) whose component was affected. Instead, it is the concentration to which the test organism component, the organ (Field H) or tissue (Field I), is exposed. For this reason, the IBM 11 zone punch (Code Symbol #) is used in the dosage fields, Columns 46 and/or 48, to give this special meaning to the dosage entry. Thus, when Field J is not coded and the Fields M and/or N are coded with Symbol #, the dosage coded is interpreted as the dose applied to the organ or tissue in Fields H or I and is not the dose applied to the gross test organism in Field E. (See the diagram of Division 9. ) 6. Significance of the relationship between the coding in the dosage fields (Fields M and N) and Field J; use of Symbol # (IBM 11 zone punch) when Field J is coded In nearly all cases when Field J is coded, administration of the test compound to that host or host environment is implied and it is assumed that the organism, pathology, or tumor in Field E received the test compound only to the same degree as any neighboring part of its host or host envi- ronment. In those more rare instances, when Field J is coded with a host or host environment, yet (1) application is actually directly to a test organism or tumor or pathological organ so that influence of the dosage expressed is fully upon the test organism, tumor, or diseased organ or (2) the author has determined the final concentration of the test compound in the host or host environment (although application is directly to the host or host environment ) so that the dosage expressed is the actual concentration to which the organism, pathology, or tumor in Field E is exposed, a coding expedient has been resorted to for indicating it. The IBM 11 zone punch, coded by the symbol #, is used in Fields M and N, Columns 46 and 48, to indicate that the coded dose was not the dose administered to the host coded in Field J but was the dose to which the organism, tumor, or disease coded in Field E was directly exposed, regardless of the actual route of administration indicated in Field S-3. Symbol # is used in Fields M and N when a host is coded in Field J and-- (1) the application is to the test organism and the dosage is expressed as a concentration or quantity to which the test organism is exposed, although the test organism is attached to a host coded in Field J, or-- (2) the application is to the host but the dosage expressed is the concentration to which the test organism (Field E) is exposed. Symbol # is no_t_used in Fields M and N when a host is coded in Field J and the application is to the host in terms of quantity per unit of the host (e. g. , mgAg- gal/acre, etc. ). Although this is admittedly an expression of the concentration to which the test organism is exposed (as in situation 2 above), the terms of the quantity-per-unit-of-organism-or-environment scales are applicable to the host . (I. e. , when administration is to the host or host environment, the terms of the scales represent quantity per unit of host or host environment , not quantity per unit of test organism. ) Symbol # would only be used with these scales (under circumstances of Field J being coded) if the application were to the test organism and the dosage was therefore in terms of quantity per unit of the test organism (as in situation 1 above). See Division 5 above and Division 9 for the use of Symbol # when Field J is not coded. - 86 - FIELDS M and N Columns 45 and 46; 47 and 48 7. Dosag e to be coded when the test compound is added to and distributed through a host MEDIUM and the final concentration is determined When a test compound is added to a host environment (i. e. , the environment of a test organism) coded in Field J (e. g. , a nutrient medium, a natural environment such as water or air, the fluid of a tissue or cell suspension, etc. ), the dosage to be coded in Fields M and N is preferably the concen- tration after complete dispersion in this host, whenever this is known or can be calculated. (This is also discussed in Division 6 above as Situation [2], ) When this final concentration is coded in Fields M and N as the dosage, the administration of that recorded concentration can no longer be regarded as being to the host environment coded in Field J but must be regarded as being to the test organism in Field E. Therefore, it is appropriate that all coding in Fields A, B, and C must describe the state after distribution through the test organism's environmental medium; the state and any solvents of the test compound prior to introduction to the host environment will not be coded. By coding the Symbol § in Fields M and/or N (whichever is used), the fact is indicated that the host coded in Field J is actually the diluent and that the coded dose is the dose applied to the test organism or tumor coded in Field E. If a test compound is applied to such a host environment or culture medium and only the quantity or concentration initially given to the medium is known (i. e. , the final concentration in the medium is unknown), the dose coded in Fields M and N will be that given to the medium, Fields M and N will not be coded with Symbol # and coding in Fields A, B, and C will describe the state when added to the medium. For example, if the concentration is given in terms of a gas which is subsequently streamed through, or otherwise exposed to, (1) a bath or perfusate of a tissue macerate or (2) an enzyme-containing secretion (e. g. , milk), the concentration of the applied gas may be coded in Field M, regardless of the unknown factor of its solubility. In this case, Field A must be coded with "gas", Symbol 1, and Fields B and C would not be coded, since the test compound was not in a solvent or conditioning agent when it was added to the host liquid. If, however, the author should actually have determined the dissolved concentration of the test compound, coding in Fields M and N should be based on that concentration with the Symbol # in Columns 46 and/or 48, Field A coded with "solution", and Field C is coded with the bath (water, saline, etc. ). 8. Relationship between the dosage fields (Fields M and N) and Fields E, H, and I when Field J is coded; use of Symbol (IBM zone punch) when Field J is coded A further provision is stipulated for a testing situation that is doubtless infrequent. It is described with the belief that by presenting and discussing all possible situations and all relations with other fields, the pattern of coding Fields M and N will be better comprehended. If an author has determined by some analytical procedure the actual amount of test compound at the site of action when the action is on an organ, tissue or cell structure of the test organism in Field E and this test organism is maintained in a host coded in Field J (living or non-living), that dosage should be the one coded in Fields M and N, rather than the amount given to the gross host or the gross test organism. In this case, the IBM zone punch is coded in Fields M and/or N, Columns 46 and/or 48, to designate that it is not the dose applied to the host in Field J nor the dose applied to the gross test organism in Field E, but it is the dose present at the organ or tissue site of action in the test organism . This organ or tissue may or may not be the organ or tissue coded in Fields H and I, as explained in the following two paragraphs. It will be recalled that if a culture medium or environment (i. e. , a non-living host) is coded in Field J, it is so indicated by the IBM zone punch in Column 37 of Field J (i. e. , by the use of code symbols beginning with any of letters S through Z in Field J) and this is in turn an indication that any accompanying coding in Fields H and I represents organs or tissues or cell parts of the test organism in Field E rather than of the entry in Field J. Therefore, when Fields M and N are coded with the zone punch in Columns 46 or 48, and Field J is coded with symbols beginning with any of letters S-Z in Column 37 (i. e. , is also coded with zone punch 0), the organ, tissue, or cell part to which the coded dose is applied will be the structure coded in Fields H and I. However, when Fields M and N are coded with the zone punch in Columns 46 and 48, and Field J is coded with symbols beginning with anything other than S-Z, the organ, tissue, or cell part - 87 FIELDS M and N Columns 45 and 46; 47 and 48 to which the coded dose is applied is only suggested by the coding in Field T-2, since in this case the coding in Fields H and I indicate only the location of the test organism, tumor, or pathology in the host. 9. Summary of Relations between Fields M and N and Fields J, E, M. and I and the use of Symbols # and in Columns 46 and 48 as described in Divisions 6, 7, 8, and 9 The following is a diagrammatic explanation of the coding procedure (or interpretation of coding) indicating the organism or structure to which the dose, as coded in Fields M and N, applies. The vertical arrow indicates in each case the field to which the dose coded in Field M or N applies. (Only Field N is used in these diagrams. ) The curved, broken- line arrows indicate the shift in meaning which is given by the zone punches in Fields M and N. With no zone punch in Field N (or M), the site of the dosage is directly to or in the test organism in Field E. With the 1 1 zone punch in Field N (or M), the site of the dosage is directly to or at the anatomical part coded in Field H (or I) instead of the organism in to to in Field E. (See Division 5. ) E X H 3 I N 16 Field J ,- -A not coded E X H 3 I N # 16 Field J coded E H X 3 J N A 16 E H X 3 I N A # _. 16 C-Ji ' E H X 3 J N 2 (_S) 16 -or- 0/ n,\ (=T) E X H 3 j(=A) N 16 -or- # 1 (=1) T-2 C With no zone punch in Field N (or M), the site of the dosage is directly to or in the host (living or non-living), in Field J. With the 11 zone punch in Field N (or M), the site of the dosage is directly to or in the test organism in Field E instead of the host In Field J. (See Divisions 6 and 7. ) With the zone punch in Field N (or M) and Field J coded with a symbol beginning with any of letters S-Z (Symbol S, e. g. , is formed by IBM 2 punch plus the zone punch in Field J; Symbol T by the 3 punch plus the zone punch, etc. ), the site of the dosage is directly to or at the test organism's anatomical part coded in Field H (or I) instead of either the host in Field J or the test organism in Field E. JSee Division 8, first two paragraphs. ) With the zone punch in Field N (or M) and Field J coded with a symbol beginning with any of letters 1-9 or A-R, the site of the dosage is directly to or in none of the host in Field J, the test organism in Field E, or the anatomy coded in Field H (or I), but the coding in Field T-2 may suggest the site. (See Division 8, last paragraph. ) 10. Dosage given in terms of the biologically active portion of the test compound molecule; use of Symbol * (the IBM 12 zone punch) in Column 46 or 48 Occasionally, an author expresses a dosage in terms of the part of the molecule that is known to be the biologically active portion. For example, in calculating the dosage of a test compound which is administered as any one of several salts, the dosage is calculated on the molecular weight of the base of the compound regardless of the total weight of the entire salt molecule. Since the total compound used must be regarded as the test compound, such as a salt, the fact that the dosage is not expressed as a weight-or volume of that total test compound, but only as the biologically active portion, is distinctively indicated by using the 12-zone punch, coded by Symbol *, in Columns 46 or 48 or both. - 88 - 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 - 89 FIELDS M and N Columns 45 and 46; 47 and 48 and N is the highest final dose to which the test organism was shown to be tolerant). In addition, tolerance increase might conceivably be evaluated by Criteria 10, 11, 12, 13, etc. , when appropriate time values are determined and are the author's basis for the test evaluation: duration of administration needed to bring the organism's tolerance to the level indicated in Fields M and N or duration of the increased tolerance level. If, however, the author were to have demonstrated a minimal dose which would initiate or induce tolerance of the organism to the test compound, Field X is always coded with Criterion 20 (Threshold Dose), and Fields M and N are coded with that minimal dose. B. Sensitivity increase: The development of sensitivity of an organism to a test compound is understood to be essen- tially the reverse of development of tolerance in that the organism becomes less tolerant to (i. e. , becomes more sensitive to) the test compound by an initial exposure or exposures to the test compound. This increased sensitivity is induced by an initial administration of the test compound. It is revealed by a second or more doses in which a biological response appears which either did not occur with the initial dose or which appeared to a greater degree than with the initial dose. As in the case of coding increase-of-tolerance data, coding increase-of-sensitivity data depends on the test technique and the way the evidence for a sensitivity increase or for production of a sensitive reaction is expressed. If the author merely states that the organism has developed an increased sensitivity or a specific sensitive response to the test compound during a program of administration, code in Fields M and N the lowest dose demonstrated to cause the sensitive reaction, code "causes increased sensi- tivity" in the action fields ( T- I 2, T-2 51), and Criterion 01 in Field X. If there is determined a measure of sensitivity production or sensitivity increase (i. e. , a new, lower maximum tolerated dose after sensitization), it may be expressed as (l) an increase in response with each successive admin- istration of the same dose (assuming that doses are spaced so that the response is evidence of increased sensitivity) or (2) the appearance of a response after a second or more administrations of the same dose . In this instance, Fields M and N are coded with the dose demonstrated to elicit the sensitivity; Field X is coded with Criterion 01, if the exposure results in the initial appearance of a sensitivity response or if the per cent increase in sensitivity response is unknown, or with Criterion 61 or 62, if the per cent increase in sensitivity response is known. The sensitivity production or increase might also conceivably be expressed as a decrease in dosage necessary to maintain a response of a given degree or decrease in dosage necessary to prevent a given response (i. e. , a decrease in the threshold and maximum tolerated doses). In this case, Fields M and N are coded with the lowest level to which this threshold dose or maximum tolerated dose has declined and Field X is coded with Criterion 01, or, if the original and final dose levels are known, Criterion 19 may be used. If the author should have demonstrated a minimum dose which will induce an increase of sensitivity, that dose may be coded in Fields M and N with Criterion 20 in Field Y. Only in this case should Criterion 20 be used with sensitivity data. Sensitization : The term "sensitization" is most often used in reference to a specific immunological phenomenon as defined in the Code by Symbol 58. When the test organism is sensitized to the test compound and Symbol 58 is used in Field T-2, Fields M and N are coded with the sensitizing dose. The typical responses (allergy, anaphylactic shock, etc. ) to the test compound on subsequent exposure are coded as such in Field T-2 and the dose coded in Fields M and N is the dose needed to elicit these responses after sensitization. 12. Dosage to be coded when the test compound is part of a formulation or when a mixture of test compounds is administered The CBCC has avoided treating formulations as specific test compounds, for a number of reasons. Therefore, when biology data are coded from tests using formulations, the single active component of the formulation must be known. That single component is coded as the test compound, Field B is coded with Symbol 6 (signifying that the compound is administered as part of a formulation, but that the dose coded in Fields M and N and the evaluation are based on the test compound itself), and Fields M and N are coded with the calculated amount of the test compound, not the amount of the - 90 - FIELDS M and N Columns 45 and 46; 47 and 48 total formulation. If the amount of the test compound (the active ingredient of the formulation) can not be determined, Fields M and N should not be coded. If it should be desirable to code data from tests using formulations in which the active ingre- dients are not specified, so that the "test compound" is only a proprietary formulation name, the procedure would have to be different: The formulation name would be coded as the "test compound", Field B would not be coded with Symbol 6 (since, in this case, the test compound is the formulation and is not a part of a formulation), and Fields M and N would be coded with the dosage based on the total formulation. The CBCC has coded data from tests using mixtures (i. e. , two or more test compounds known to be active and administered together or two or more test compounds, all candidate for the activity and administered together), but with considerable reserve. When it has seemed appropriate to include such test data, Field B is coded with Symbol (to indicate that the compound coded as being the test compound is actually only one of two or more compounds of a mixture and that the dosage in Fields M and N and the evaluation are based on the total mixture) and Fields M and N are coded with the amount of the total mixture administered. Subsequently, additional code sheets (and IBM cards) are made for each of the other compounds, recording the same biology test data. 13. Relation between Field N and Fields O and P Frequent coding errors justify talcing the precaution of examining carefully the coding in Fields N, O, and P. The quantity coded in Field N should never be more than the quantity administered within the time interval coded in Field O. The total dose given over the period of the test is the product of the dose in Field N multiplied by the frequency in Field O multiplied by the duration in Field P. 14. Coding of ad libitum feeding in Fields M, N, O, P, and S In coding information on ad libitum feeding, record and code in Field M the concentration of the test compound in the food. The fact that the test compound is consumed ad libitum is indicated in Field O by Symbol 2 and in Field S-3 by Symbol 4; the duration of the consumption of the test compound (i. e. , the time from presentation of the food- test compound mixture and its withdrawal from the animal) is coded in Field P. However, if after a period of ad libitum administration, the daily or weekly intake of the test compound is determined or can be calculated, that daily or weekly intake is coded in Fields M and N, the appropriate time interval (one day or one week, etc. ) is coded in Field O, the total duration is coded in Field P, and Field S-3 is coded with Symbol 2. 15. Relations between Fields M and N and Field Y; double coding in Fields M and N The ultimate concern of the discussion of this Division is with the collective data from two or more consecutive tests in each of which a different dosage level of the test compound has been admin- istered in an effort to discover an active level (or a tolerated level) or the most effective level (or the highest tolerated level). (Division 11 discusses coding of data from tests in which more than one level of the test compound were administered as a series in the same test. ) Before describing the procedure for coding the collective data from such a series of tests, the characteristics of the two fields, the dosage field (i. e. , Fields M and N) and the evaluation field (Field Y), and the relationships between them will be briefly reviewed. As mentioned in the section discussing organization of Fields M and N, quantitative values are reduced to code by dividing them into ranges, each range being assigned a code symbol. This is not exclusively true for Fields M and N. Other fields dealing with quantitative values must be simi- larly organized into code symbols, notably Fields P, Q, U, V, and Y. Any single code symbol repre- senting a quantitative value is therefore only as precise as the narrowness of the range it represents allows. I. e. , a symbol in Field N representing 50 to 60 mgs would code 55 mgs more precisely than would a symbol representing 1-100 mgs. In Field Y, a symbol representing evaluation of a 2-3 hours killing time would code more precisely the evaluation of a 2- hour killing time than a symbol represent- ing evaluation of a 1-5 hours killing time. It will be helpful if in the following discussion this fact is kept in mind- -that each symbol in Fields M, N, and Y represents not a single value, but a range of quantitative values. - 91 - FIELDS M and N Columns 45 and 46; 47 and 48 The relation between Fields M and N and Field Y will be understood by considering a single symbol in Field Y, e. g. , Symbol 3, which represents a specified range of effectiveness, e. g. , 31-40% mortality. It frequently happens that two or more dosage levels (Fields M and N) may cause responses lying within this one evaluation range (Field Y); for example, one dose may cause 32% mortality while a higher dose may cause 3 9% mortality. Since either of these response evaluations would be coded in Field Y with Symbol 3, they can not be distinguished by code. I. e. , the distinction between 32% and 39% is beyond the discrimination given significance by the CBCC Code, by virtue of the Code's having established the particular limits of this coding range as 31% and 40%. In this example, all test doses producing 31-40% kill are to be coded. To state this more broadly, all doses should be coded which have been shown to produce any response that falls within the definition of the symbol coded in Field Y as the evaluation. It must be remembered that dosages in Fields M and N are also expressed by symbols repre- senting ranges and reference should be made to the discussion of this under the section describing the organization of these dosage fields. If all doses which produce various responses lying within a single evaluation range in Field Y lie within a single dosage range in Field M or N, all of the data are represented by a single code line and distinctions between the dosage levels and the corresponding response evaluation are indicated only in the written abstract. If, however, the two or more doses producing the responses which are coded by the same symbol in Field Y do not lie within a single dosage range in Field M or N, each of the dosage ranges must be coded. This might be accomplished by either of two procedures (although of the two, the CBCC has always used the more practical, abbreviated procedure). To construct a separate code line for each of the dose ranges in which are dose levels giving results coded by a single Field Y symbol, each line differing only by the entry in Fields M and N, would be extravagant of time. As an alternative to this, the CBCC procedure is to code in Fields M and N, in a single code line, all the information that would otherwise be given by coding two or more separate lines. This is done by determining which doses, of all those tested, produced the single optimum response evaluation coded in Field Y. If there are two such dose ranges involved (e. g. , 24 and 2 5 in Field N, representing 5 mg and 10 mg), both are coded in Fields M and N, by coding one above the other in the same coding box in the same line. The CBCC refers to this as double coding and both entries are punched on the same IBM card. If doses which produced the response coded by a single symbol in Field Y are in more than two dosage ranges (e. g. , 24, 25, 26, in Field N, representing 5, 10, 25, and 50 mg doses in 4 tests), the highest and lowest ranges (e. g. , 24 and 26) should be coded in Fields M and/or N. 16. Special considerations for the procedure of double coding in Fields M and N; relation of Field X to Fields M, N, and Y Relative to the situation requiring double coding in Fields M and N, described in Division 15 above, is the special situation when the criterion for evaluation is based on a percentage response (Criteria 51 through 59 and Criterion 62, coded in Field X) and 100% response results from administered doses. When several doses have been demonstrated to produce high responses, all of which are coded by a single symbol in Field Y, and one or more of these doses produce 100% response and the doses producing the several responses coded by a single symbol in Field Y fall within two or more ranges in Fields M and N, the CBCC considers, for coding, only those doses which produce less than 100% response. For example, 5, 10, 25, 50, 100, 150, and 250 mg doses produced respectively 55%, 85%, 95%, 95%, 100%, 100%, and 100% responses. Since it is reasonable that optimum doses be described as the lowest producing the highest response, the doses to be considered here seem to be 25, 50, and 100 mgs, since 100 mgs is the lowest dose producing 100% response and responses of 95% and 100% (produced by 25, 50, and 100 mg) are all coded by the same symbol in Field Y. However, for specific reasons, the CBCC considers only doses giving less than 100%, as stated above; there- fore, in this case, only 25 and 50 mg producing 95% response would be considered. Field N would be double coded with Symbols 25 and 26 (the two dose ranges in which are included the two doses) and Field Y would be coded with a single symbol, either Symbol 9 (when using Criterion 62 in Field X) or a symbol derived by use of a special grid for correlating doses and responses of less than 100% (when using any of Criteria 51 through 59). (See the special discussion, in Fields X and Y, of the CBCC Log-probit Grid. ) It should be noted that the two criteria, 20 (Threshold Dose) and 21 (Maximum Tolerated Dose) each describe a dose level which is related to a single, standard level of response. Ordinarily, this is expressed as a single dose level for which reason Fields M and N would correspondingly be coded - 92 - FIELDS M and N Columns 45 and 46; 47 and 48 only with a single dose level. However, it is possible that as a result of several determinations using a number of organisms, a threshold dose or a maximum tolerated dose may be expressed as a range of doses, a given percentage of the organisms having the threshold or tolerance at one level, another percentage having the threshold or tolerance at a slightly different level, etc. In the latter case, Fields M or N should be coded to include both extremities of this range of threshold doses or maximum tolerated doses (double coding if necessary) and the Grid should be used to derive a Field Y rating as described in the specific directions and explanations for Fields W, X, and Y, Division 14 (paragraph 8) and Division 15 (paragraph 8). 17. Further consideration of double coding in Fields M and N; relations to double coding in other fields The construction of a single line for several tests (when there is variation in the test dosage, yet the test results are so similar that they can all be coded by a single symbol in Field Y) is described in the preceding divisions. This coding procedure, which calls for double coding in Fields M and N with that single code symbol in Field Y, is in general the same procedure as used when duration of administration (Field P) or duration of action (Field U) is the test variation rather than the dosage level. In such a case, Field P or U is double coded with a single evaluation symbol in Field Y and all entries are punched on the same IBM card. Occasionally, test data are encountered in which, in a series of tests, the variation in the tests is not just dosage size or just duration of administration, but variation in dosage size as well as duration of administration or duration of action, and the evaluation for two or more of these tests is expressed by a single symbol in Field Y. Since coders frequently attempt to double code the dosage fields and another field in the same line (Field P, U, or V, e. g. ) and err in doing so, it will be dis- cussed here briefly. Observe first that when only one field is double coded, the subsequent interpretation of the line is uncomplicated, as follows: The test evaluation given in Field Y was the test result regardless of whether the larger or smaller of the two values coded in the double- coded field was used in the test method. (E. g. , if Field N is double coded and Field Y is coded to indicate moderate activity [Symbol 5], that degree of activity resulted from any dose between the highest and lowest indicated by the coding in Field N. ) However, when two variables occur in a test method and when several of the tests give results that can be indicated by a single symbol in Field Y, if two fields are double coded to record the two variables, coding must permit the subsequent interpretation as direct and uncomplicated as in the example of the above paragraph. It is with this situation that the coder must exercise caution. The regulation which must be followed when two or more fields are double coded is explained diagram- matically below. In considering the double coding of more than one field in a single line, the coder must deliberate upon the inter-relations of the entries for those fields to be double coded, as indicated by the statements of the diagram. (It is possible to write in code that 10-mg doses given hourly for 4 days will give the same test results [or at least test results coded by the same symbol in Field Y] as 100-mg doses hourly for 12 hours; it is not possible to punch this and retrieve it by the IBM machines used by CBCC and retain the strict association between each dose and its own period of administration. The reasons for this procedure will be appreciated only through understanding that the IBM machine methods used by the CBCC will not allow any other procedure. 93 FIELDS M and N Columns 45 and 46; 47 and 48 Field M Column 46 Field P Column 51 Field Y Column 71 4 4 5 5 6 4 -^_^^ ^____j ^ 4 5 " "~"^^~""~~~~"~— ~ 6 4 6 5 5 4 5 If double coding occurs in the two Fields, M and P, it must mean that each duration in Field P is applicable to each dose in Field M-- otherwise, two lines are necessary (or only one of these is selected for coding, according to the coder's judgment, with the other information in the language portion). 18. Symbols available for additional items of Fields M and N Columns 46 and 48: Only Symbols and 1 through 9 are permitted in these columns by the CBCC. This restriction is made to permit direct correlation between the dosage fields (Fields M and N) and the evaluation field (Field Y). By virtue of this limitation, the IBM zone punches were made available for specific purposes. (See Divisions 5, 6, 7, 8, 9, and 10). Having assigned special meanings to the zone punches, letter symbols can not now be used in this column in any case. Columns 45 and 47: In Field M there are eleven scales, indicated by Symbols 1 through 9, A, and B. In Field N there are nineteen scales, indicated by Symbols 1 through 9 and A through J. There- fore, Symbols C through Z are available in Column 45 of Field M and Symbols K through Z are available in Column 47 of Field N for new scales. 19. File of coded biology data on IBM punched cards arranged according to symbols for dosage concentration and quantity The CBCC has not established files of IBM punched cards arranged according to entries in Field M and by entries in Field N. Although searches for information from the files often involve sorting according to designated dosage limitations, this particular sort is almost never a primary sort, but secondary to having first selected specific actions or specified test organisms, etc. , for which there are special IBM punched card files. 20. Double coding in Fields M and N Fields M and N can be double coded according to the explanations of Divisions 15, 16, and 17. Any two symbols coded in Column 46 or 48 are both punched in that column on the same IBM card. 94 FIELD O Column 49 (1) DOSAGE FREQUENCY (2) SEQUENCE OF ADMINISTRATION OF THE SECONDARY COMPOUND AND THE TEST COMPOUND Organization The frequency-of-dosage items of Field O have been limited to nine to which have been assigned only numerical symbols. This has permitted the remaining IBM punches (the three zone punches, 0, 11, and 12) to be used for a coding purpose distinct from frequency of dosage, namely, indicating the sequence of test compound and secondary compound administration. General Use Fields M, N, O, and P can be considered as a unit in that, together, they express the total amount of test compound administered during the test. (In Fields M and N are coded the size of the individual doses, in Field O is expressed the frequency at which the doses are given, and in Field P is indicated the period over which the doses are given at the frequency expressed in Field O. ) The three fields are provided for dosage, rather than a single field, because any of the experimental factors, individual dose size, frequency of administration, and duration of administration, even though their significance may be minor in certain tests, are critical factors in many tests. Besides its use for indicating the test compound dosage frequency, Field O is used for indicating the sequence of administration of test compound and secondary compound, when a secondary compound is involved. (See Divisions 7 and 8, below, and Division 3 of Specific Directions and Explanations for Field P, relative to this use of Field O. ) Thus, two types of information are coded in the same field (in a single column) and they may be both coded in the same line and both punched on the same IBM card. This double use of a single field, by which either or both of two entries may appear in the same IBM column, is distinct from "double coding". The latter expression, double coding, refers to the entry of two values of the same type of information- -for example, two dosage frequencies, two test compound- secondary compound frequencies, or (in Field N) two dose ranges. Specific Directions and Explanations 1. Suggested time ranges to be used in coding dosage frequencies Some explanation is appropriate for the frequency-of-dosage definitions for Symbols 1 through 9. As with other quantitative values (in Fields M, N, P, U, and V), the definitions must be interpreted as encompassing ranges of time intervals, even though each is expressed in rather precise terms. For example, although "three times daily", if accomplished by exact timing of intervals, would imply an administration every eight hours, other routines aru possible for a three-times-daily administration (e.g., daily at 7:00 a. m. , 2:00 p.m., and 9:00 p.m., which would be a 7-7- 10-hour series, or daily at 9:00 a.m., 1:00 p.m., and 5:00 p.m., a 4-4- 16-hour series). Thus, within a 24-hour period, intervals may vary, rather than be precisely equal, for a "three- times-daily" administration schedule or for a "twice daily" schedule. In addition, the intervals may be such that the schedule doesn't fit precisely the definition for the terms "hourly" or "daily". For example, administration every 9 hours would mean administration of only two doses within a 24-hour period, yet the intervals are actually more nearly three times daily than twice daily. Similarly, administration every 3 hours is more nearly hourly than three times daily. The following scale is provided as an aid in determining which symbol to use when an administration schedule does not fit precisely the definitions of the code. 95 FIELD O Column 49 Symbol Assigned time interval Time interval range scale 3 More frequent than hourly <45 minutes, but not continuous 4 1 hour 45 minutes through 4 hours 5 3 times daily > 4 hours through 10 hours 6 2 times daily > 10 hours through 18 hours 7 One day > 18 hours through 3 6 hours 8 Every other day > 36 hours through 60 hours 9 Every 3 days or less frequently ... >60 hours 2. Double coding of two frequency schedules or of two secondary compound- test compound sequences in two or more tests Double coding is described and defined in Division 15 of the Specific Directions and Explanations Section of Fields M and N (as it applies to those fields). If the evaluations from two or more tests are so alike that they are coded by the identical symbol in Field Y and if the only variations in the two or more tests are the schedules of administration ( Field O ), all the schedules used for those tests may be coded in Field O in a single line and all punched on the same IBM card. Similarly, if the only variation between two or more such tests is the sequence of administration of test compound and secondary compound, the sequences of administration may be coded in a single line and all punched on the same IBM card. (See Division 5 of this section concerning the situation of variation of frequency during a single test. ) Double coding in Field O and another field, in the same line, is seldom possible. Thus, if Field O is double coded with two frequencies of administration (e. g. , hourly and 3 times daily, Symbols 4 and 5), the dosage size (Fields M and N) and the duration of administration (Field P) must be the same for both frequencies of administration. For example, if the dosage size varies as well as the frequency of administration, it is impossible to indicate which of the doses double coded in Field M or N is related to either of the frequencies double coded in Field O. It is not possible, in other words, to indicate in one line that a large dose given at short intervals and a smaller dose given at longer intervals accomplish the same result; this can only be done by coding two lines. (See also Division 17 of the Specific Directions and Explanations for Fields M and N. ) 3. Coding of ad libitum feeding When the test compound is administered ad libitum , the CBCC codes Field O with the same symbol as for "continuous supply insured", Symbol 2. If, however, in ad libitum feeding, the total quantity of test compound consumed is determined and expressed as quantity per unit time , the quantity is recorded in Field N, the unit time is coded in Field O, and the total duration of treatment is expressed in Field P. 4. Distinction between use of Symbols 1 and 2 Symbols 1 and 2 are used to specify a single application of the test compound. This application technique may be designed to provide a continuous exposure of the organism to the test compound (Symbol 2) or the organism may be exposed to the test compound for only a very short period of time (Symbol 1). Symbol 1 is used for those application methods exemplified best by oral administrations and by single simple injections (intravascular, intraperitoneal, etc. ) which occupy only the time needed for swallowing or for puncture, injection of the test compound, and withdrawal of a syringe. Even in the case of special and tedious injections (certain intra-organal injections, e. g. ), the time is considered negligible. The fate of the ingested or injected material thereafter is essentially dependent on the biological-chemical interaction; the compound may be quickly dispersed and eliminated, or it may be only very slowly eliminated, or it may selectively accumulate in one tissue. In any case, if the pro- cedure of single administration did not provide for prolonged exposure of the treated test organism (or the treated anatomical part of the test organism) at the dosage level coded in Fields M and N, Field O should be coded with Symbol 1 and Field P will not be coded, since there is no significant duration of exposure guaranteed at the level indicated in Fields M and N . When the test procedure involves a single application which provides for a prolonged exposure to the test compound at the dose level indicated in Fields M and N, the duration of exposure is con- sidered significant and, if known, is coded in Field P. This application is indicated in Field O as - 96 - FIELD O Column 49 being continuous and is coded by Symbol 2. A continuous administration is exemplified by the method in which a regulated volume and concentration of test compound flows over a period of time into the venous circulation through a syringe fixed (i. e. , by single application) in a vein. An administration is also continuous when bacteria, fungi, animal larvae, etc. , are grown in or on a habitat or medium which has been impregnated with, dipped in, or painted with the test compound. An application of the test compound in a paste or ointment to plant or animal parts, when the concentration remains relatively constant over a considerable period of time, may also be properly considered as continuous and coded with Symbol 2 in Field O. 5. Two or more frequencies of administration during a single test If the frequency of administration is varied during the period of a single test , there is posed the problem of deciding which of these frequencies to code, since only one can be coded. It would be conven- ient in such a case to have a series of columns for coding each frequency in sequence or at least a symbol for Column 49 which would represent frequency variance. Lacking these, the coder must be responsible for making the most intelligent choice relative to the specific situation, as in the similar situation in Fields M and N when the dosage size varies in a single test (see the first paragraph, Division 11, Specific Directions and Explanations, for Fields M and N). The legend of the series of frequencies should be included in the written abstract portion of Field O. 6. Persistence of residue data: definition; coding in Field U; coding in Field O The expression, "persistence of residue", is used to refer to the length of the period over which a test compound, applied once to an environment or host, retains potency to produce a given specific action on a test organism. To determine persistence of residue, a series of exposures of the test organ- ism (i. e. , a series of tests) are made, separated by appropriate intervals, each being merely to determine whether the test compound residue is still capable of producing the action on the newly- exposed test organism after the period since the previous test. This persistence of potency of a residue is not itself a biological action of a test compound, but is instead a specific characteristic of the chemical, related directly to, or representing, its physical properties. (The CBCC has not devised a code for physical properties. Such a code would include this duration of potency, a characteristic that would fall in the same category as "stability" of compounds, "stability in the presence of light", "resistance to oxidation", "boiling point", etc. Such properties are not recorded in Field T-2 as if they were specific actions nor is there any other special coding area provided for them. ) The CBCC has nevertheless made exception for indicating this one property, persistence of potency, inasmuch as its importance seems to justify it. From the data of tests demonstrating persist- ence, the CBCC extracts the information about the biological action demonstrated by the first exposure of the test organism to the test compound residue. (Data from only that first test are coded; information on the effectiveness of the test compound upon any subsequent exposures of the test organism to the same residue are not coded. ) However, the entire period of time over which the residue was shown to be effective (i. e. , persistence of the residue) is recorded in Field U (Column 66) of the same code line that records the data from the first exposure. When this information is recorded in Field U, Symbol * is always coded in Column 66 to indicate that the coding of that field is not duration of action in a single test, but is the period of persistence of a residue. In a test demonstrating the action of a residue of the test compound ( whether or not the test is one of a series demonstrating persistence of the residue), the test organism is ordinarily exposed to the concentration in the residue for a measurable period of time. Therefore, the administration is coded in Field O as being continuous (Symbol 2) and the duration of this exposure is coded in Field P. The time between the introduction of the test organism to the residue and the reading of the initial result is coded in Field V. (See also Field U, Specific Directions and Explanations Division 4. ) 7. Sequence of administration of test compound and secondary compound This second use of Field O is with Symbols 0, #, and * (IBM zone punches 0, 11, and 12). (Since these symbols can be used independently of the symbols for frequency of administration of the test compound [Symbols 1 through 9], the single column of Field O can contain both types of information. In other words, any of Symbols 0, #, or * can be coded in Field O along with any of Symbols 1 through 9. ) 97 FIELD O Column 49 Either type of information may be double coded, if necessary (see Division 2), so that two or more of Symbols 0, #, or * can be double coded, two or more of Symbols 1 through 9 can be double coded, or both can be double coded, though the situation for which this would be necessary is improbable or infrequent. 8. Relationship between Fields O and P; the complication arising from Fields O and P having two uses Field P is used primarily to express the duration of administration of the test compound at the frequency indicated in Field O. However, when coding data from tests involving a secondary compound, Field P is always used to indicate the time between administration of the secondary compound and administration of the test compound. If the two compounds are administered simultaneously, however, there is no intervening time and Field P is therefore freed for indicating any period of administration of the test compound. The following coding pattern will be observed accordingly. When a secondary compound is administered prior to or after administration of the test compound and when, therefore, Field O is coded with either of Symbols (test compound administered prior to secondary compound) or # (test compound administered after secondary compound), the time between administration of the two compounds is coded in Field P. If doses of the test compound are subsequently administered so that a frequency of administration of the test compound is also coded in Field O, the duration of administration can not be coded in Field P or elsewhere, but it must be recorded in the written abstract portion of Field P. If Field O is double coded with both Symbols and # (see Division 2), the coder must use his best judgment as to which of the periods to code in Field P and which to include only in the written abstract portion of Field P. (In such a case, the two periods, corresponding to the two situations indicated by Symbols and # in Field O, are apt to be nearly the same. ) When a secondary compound is administered simultaneously with the test compound and when, therefore, Field O is coded with Symbol * (test compound and secondary compound administered together), Field P is not coded, although if doses of the test compound are subsequently administered so that a frequency of administration of the test compound is also coded in Field O, the duration of administration is coded in Field P. If Field O is double coded with Symbols and * or with Symbols # and *, Field P is coded with the time between administrations indicated by Symbol or by Symbol #, as described in the preceding paragraph. In summary: When Field O is coded with either or both of Symbols or #, Field P expresses the time between administrations of test compound and secondary compound. When Field O is coded with only Symbol *, or only with any of Symbols 1 through 9, or with Symbol * plus any of Symbols 1 through 9, an entry in Field P expresses the duration of administration of the test compound. 9. Symbols available for additional items of Field O Inasmuch as each of the three IBM zone punches have been given special meanings and can be used with any of the numerical punches (representing thereby two units of information), they can not be used in punching combination with numerical punches to form letters for symbols. Therefore, none of Symbols A through Z can be used in Field O as it is now designed, and all other available symbols have been used. 10. File of coded biology data on IBM punched cards arranged according to symbols for dosage frequency No file of coded biology data in which Field O has been used has been established and arranged by Field O entries. The information coded in Field O is of such a nature that sorting for it is almost invariably subsequent to retrieval of information by specific actions, test organisms, test compounds, etc. (for which there are special IBM files); after the initial sorts by other code fields, the number of IBM cards is sufficiently limited to make efficient a simple mechanical sort or visual interpretation of dosage frequency. 1 1. Double coding in Field O Double coding (with the restrictions noted in Division 8) is permitted in Field O. When Field O is coded with Symbol *, #, or and also with one of Symbols 1-9, both symbols are punched on the same IBM card in Column 49. If more than one of Symbols *, #, and are coded (double coding) or/and more than one of Symbols 1-9 are coded (double coding), all the symbols are punched on the same IBM card in Column 49. - 98 - FIELD P Columns 50 and 51 DURATION OF TREATMENT -or- TIME BETWEEN ADMINISTRATION OF THE TEST COMPOUND AND A SECONDARY COMPOUND Organization As in the case of other quantitative values (e.g. , values of Fields M, N, O, and Q), time values of Field P are not recorded literally (requiring three or more punched card columns), but are converted to one -unit code symbols by organizing the total range of time into limited ranges, each of which is repre- sented by a code symbol. In the case of Field P, the most simple organization would have been by divid- ing time into 35 ranges for 35 symbols (26 letter and 9 numerical symbols) for a single IBM column or, if two IBM columns were used, by dividing time into many more than 35 smaller ranges. In either case, such a simple arrangement would have been a continuum of time values. The actual pattern of organization, however, was determined by the fact that a test compound's activity may be evaluated on the basis of the duration of treatment. (Ordinarily, the less time the compound must be administered, the more efficacious can be considered the treatment. ) Thus, a relationship exists between Field Y of the Biology Code (the field expressing evaluation of the compound's action) and Field P. Since Field Y expresses evaluations only in broad terms, using only Symbols 1 through 9, the Field P symbols used for correlation with Field Y have likewise been restricted, in the second column, to Symbols 1 through 9. It was decided to incorporate into the pattern of organization of Field P some correlation to the type of biological action being tested. (The recording of a test compound's relative worth with respect to the action it has been demonstrated to produce is a persistent and difficult coding problem. ) For this reason, the total range of time of Field P has been broken into several overlapping ranges, each succeeding one expressing time values in broader terms than the one preceding it. For example, the seventh total range (referred to in the Code as Scale 7) expresses time values as < 6 hours to >32 days, whereas the sixth total range expresses time values at <45 minutes to >4 days. The purpose in this, as suggested above, is to provide a means of fitting the coding to the field of chemical- biological research in which the test was conducted and to the evaluation as it was derived and expressed by the author. The reader is referred to the discussion of Fields M and N, particularly to Division 3 of the Specific Directions and Explanations section, where it is explained that in those coding fields no such breakdown of total ranges is made for the purpose of correlation with differences between chemical- biological research fields. If it were, each scale of Fields M and N (e. g. , Scale 1 of Field M, ppm) would necessarily be broken into a number of overlapping ranges just as is total time in Field P. It may be questioned, then, whether the organization of Field P for the purpose of correlation to evaluation is justified when certain other coding fields of quantitative values, Fields M and N, have not been similarly organized. This can only be answered on the basis of the CBCC Code being an experimental one and subject to change. The pattern of Field P, as well as that of Field U, represents an effort to establish a coding relationship between any given field of chemical-biological research (insecticidal vs. plant growth regulation vs. enzymology, etc. ) and the basis of evaluation (duration of administration, duration of action, etc. ) of results from tests in that research field. Although the same has not been done in the case of Fields M and N, it must be recognized that in those dosage fields, the total range represented by any one scale and the division of the total range was not established in a purely arbitrary manner, but the scale was arranged to correspond to the field of chemical-biological research in which the unit of measure represented by the scale would be most appropriate and most apt to be used by an author. (See paragraph 5 of the Organization section of Fields M and N. ) Field P and Field U could each be reduced to a single continuous scale, while, in the reverse, Fields M and N could each be expanded so that each existing scale of those fields could be converted to a series of overlapping scales to be used selectively as the present scales of Fields P and U are now used. In adapting the CBCC Code, the patterns adopted in Field P (as well as Fields M, N, and U) will depend upon whether or not further emphasis is to be placed on attempts to express accurately test evaluations based on dosage size or time values, correlated with the chemical-biological research fields concerned. - 99 FIELD P Columns 50 and 51 General Use Coding in Field P may be considered as one component of a group of three which, together, express the amount of test compound administered: The dosage size (Fields M and N), the frequency of administration of that dose (Field O), and the length of time the test compound is administered (Field P), at that dosage size and frequency. Superimposed on this use of Field P is a second use, for the situation in which a secondary compound is administered in a test. In such a test, the test compound is usually administered only once and therefore a field is not frequently needed for expressing duration of treatment. Thus, under these circumstances, Field P is ordinarily free for this second use, the coding of the time between administration of the test compound and the secondary compound. Specific Directions and Explanations 1. Selection of the scale to be used for coding duration of administration The purpose in dividing total time into the several scales is explained in the section discussing organization of Field P. The coder will understand that the selection of a scale is left to his judgment. The scale should be used which seems the most reasonable choice relative to the field of chemical- biological research to which the test data belong, i. e. , the scale that will allow the most exact coding of all data from that testing field. This is not always easy. Whether there is always only one scale most appropriate for any one situation might be questioned. It is probably more accurate to consider that for each testing situation certain scales of Field P are more appropriate than others, rather than to suggest that for every situation there is one most appropriate scale. Testing of compounds for molluscacidal activity or for antimalarial activity represents fields of chemical-biological testing for which Scales 1, 2, 3, and 4 might be easily seen to be inappropriate, since such treatment is ordinarily much longer than any of the periods in those scales, so a higher scale would be considered, probably Scale 7, though under some conditions Scale 6 or Scale 8 might be used for molluscacidal or antimalarial data. In summary, an appropriate scale in Field P is: (1) the scale that allows the most accurate statement of the duration of treatment and-- (2) the scale whose time values might reasonably be expected to encompass all durations of treatment typically used in testing in the field of chemical- biological research involved. To illustrate the first of the above points, consider that to code a 6-minute duration of treatment, Scale 2 would not be the appropriate scale, because it could only be coded as being more than five minutes, which could be 6 minutes or 6 years. Scales 3 or 4 would be more appropriate scales for coding most accurately 6 minutes. To illustrate the second of the points, consider the observations made relative to antimalarial and molluscacidal tests in the paragraph above. If the coder has little basis for judging appropriateness of a scale relative to the type of activity for which the test was run, the scale should be chosen on which the observed time falls on (or as near as possible to) the mid-point (Symbol 5 in Column 51). For example, if the duration of administration is 14 days and there is no other basis for selecting another scale, Scale 8 would be selected only because 14 days falls at the mid- point of the scale. In making a selection on this basis, another prob- lem is sometimes encountered as illustrated by a time value of 7 days. In this case, the value is not at the mid-point of any scale and the question arises as to which scale to choose, Scale 7 or Scale 8, since 7 days is as near the mid-point of one as it is the other. In this case, when the scale is being selected only on the basis of proximity to the mid-point of a scale, the CBCC always uses the lower scale (in this case, Scale 7). When data are reported in terms such as "several hours" (or as other comparably indefinite expressions of time periods), Scale A should be used. 100 FIELD P Columns 50 and 51 If data from a single test are indefinitely reported as a range of time (e. g. , four days to two weeks), an average value (in this case, 9 days) will be coded. This occurs occasionally when the author describes a technique used in testing a series of compounds, and when he doesn't report the exact duration of administration for each test run. However, do not code an average for such a range unless the effectiveness, as coded in Field Y, is uniform over the total range. 2. Coding of the actual exposure time in Field P, regardless of the maximum exposure time characteristic of a special technique Care must be taken in coding Field P when an action is observed before the end of a standard exposure period. For example, consider the technique for a standard screening test for toxicity. In this test, each test compound is administered daily for a maximum of seven days. If the test compound did not cause death at the dosage given, Field P should be coded with "seven days", but if death resulted on the fourth day, Field P should be coded with "four days". Consider, as a second example, a technique in which compounds dissolved in water are tested for their herbicidal effect on water plants by growing the plants for three days in the test solution and then transferring them to tap water for an additional four days of observation before an evaluation of their herbicidal effect is made. In coding the herbicidal effect, "three days" (exposure time) would be coded in Field P and "seven days" in Field V (time of evaluation). If, in addition, it is desirable to code production of chlorosis two days after removal to tap water, the coding in Fields P and V would be 3 and 5 days, respectively. However, if the chlorosis were produced two days after initiation of the test (i. e. , prior to the appointed time for transfer to tap water), "two days" would be coded in both Fields P and V. 3. Relationship between Fields O and P; the complication arising from Fields O and P having two uses The two uses of Field P occasionally conflict. A thorough discussion of this will be found in the Specific Directions and Explanations section for Field O (Division 8) to which reference should be made. In brief, the information on time between administration of secondary and test compounds, when they are not administered simultaneously, is always given preference. In a test in which the test compound and secondary compound are not given simultaneously, and the test compound is subsequently administered over a measurable period of time (indicated by any of Symbols 1 through 9 in Field O), that duration of administration of the test compound can only be included in the written portion of Field P. 4. Symbols available for additional items of Field P Inasmuch as the IBM zone punches have not been given special meanings in either column of Field P, letter symbols are available for use, except that in Column 51 the CBCC restricts time range coding to numerical symbols (i. e. , Symbols 1 through 9), to correspond to evaluation ranges in Field Y. The ten scales now in the Code are fairly exhaustive of time ranges expected in most chemical- biological tests. (Letters B through Z are available for any new scales needed. ) 5. File of coded biology data on IBM punched cards arranged according to symbols for duration of treatment No file of coded biology data in which Field P has been used has been established and arranged by Field P entries. Information coded in Fields M, N, O, and P is of such a nature that sorting for it is almost invariably subsequent to retrieval of information by specific actions, test organisms, test compounds, etc. (for which there are special IBM files). 6. Double coding in Field P If the evaluations of two or more tests are so similar that they are coded by the identical symbol in Field Y and if the only variation in the two or more tests is the duration of administration (Field P), all the durations of administration may be coded in Field P in a single line (always by the same Field P scale, however, indicated in Column 50) and all punched in the same IBM card. (See the last paragraph of Division 1 for coding a variation or range during a single test. ) If the only variation in two or more such tests is the length of time between administration of the test compound and the secondary compound (indicated by Symbol or # in Field O), all these periods of time may be coded in Field P and all punched in the same line. - 101 FIELD P Columns 50 and 51 As in the case of certain other fields (Fields M, N, O, and V), it is seldom possible to double code in Field P and another field in the same line. For example, if Field M is double coded (to indicate that the test evaluation would be nearly the same whether the test compound was administered at either of the higher or lower doses indicated), Field P can not be double coded (to indicate, e. g. , that the test evaluation would be nearly the same whether the time between administration of the test compound and secondary compound was longer or shorter) unless each coded dose, administered after each of the coded periods, produced the same result . (This is also discussed, for combined double coding of Fields M or N and other fields, in Division 17 of the Specific Directions and Explanations for Fields M and N. ) If Field P is double coded, therefore, it is improbable that Fields M, N, O, and V can be also double coded in the same line. 102 FIELD Q Column 52 SEE OF INOCULUM OR IMPLANT Organization In Field Q, symbols are assigned to nine ranges of numbers, the range increment (xlO) being considered representative of typical inoculations and adequate for ordinary distinctions between tests differing in respect to inoculum size. The repetition of the list of symbols, expressing the definitions in a different way, is merely for convenience, since authors may express inoculum size in either terminology. General Use Field Q is used to record the number of individuals of the unicellular organism coded in Field E (e. g. , Protozoa or Bacteria) or the number of cells of the cancer coded in Field E, contained in the inoc- ulum or implant made to the host coded in Field J. The field is used also to record the number of indi- viduals of any infective stage of a parasitic test organism coded in Field E, introduced into the host coded in Field J. Specific Directions and Explanations 1. Coding in Field Q when the inoculum size is expressed as being within a range Occasionally an inoculation is made in which the size is expressed only as being somewhere between an upper and lower limit; for example, an inoculum of "from 10 3 to 10 5 cells". Field Q must never be coded with two symbols representing the possible minimum and maximum size of such an inoculum, because such coding would imply that two separate tests had been run, one with a small inoculum, the other with a large inoculum (as explained in Division 6). Instead, Field Q would be coded with an average. (In the example given, 50,500 cells would be coded, using Symbol 5. ) 2. Definition of the entry in Field Q The definitions for symbols of Field Q are exclusively in terms of the total number of cells or individuals of each inoculum or implant; therefore, a Field Q entry is never in terms of the number of cells or individuals per unit of volume or weight of the suspending medium. If data are given in terms of numbers per unit volume or weight of implant or inoculum and the total number of cells or individuals inoculated or implanted can not be calculated, no entry is to be made in this field. Development of a population of implanted organisms, subsequent to the implantation depends on the test organism species involved. Certain organisms, notably many helminths, can not complete their life cycles within the host into which they are inoculated and consequently the population resulting from the inoculation and the degree of severity of the associated pathology is limited to the number of individuals introduced. Other organisms (Bacteria and Protozoa) can reproduce indefinitely within the host and the final population and severity of an associated pathology is limited only by natural tissue barriers or immune factors in the host or by death of the host. The size of the population of test organ- isms, such as most Bacteria or Protozoa, at the time of treatment, or the size that would be expected at the time of evaluation , if there had been no treatment, is dependent on the two factors, size of the inoculum and length of time from inoculation. The CBCC has not required the coder to be able to distin- guish the two situations, thus no code symbol is provided for indicating that the inoculum size is the same as the final population size, as opposed to its being less than the final size. Thus, there is no indication in Field Q as to whether the inoculum size is finite (just as when six test organism individuals, not in a host, are used in a single test) or whether it represents only a beginning population which can reproduce to an indefinite size. The interpreter of the code line, however, must be able to interpret the coding of Field Q with respect to a knowledge of the test organism's capacity for reproduction in the host (i. e. , its life cycle) and with respect to the number of organisms normally expected after a given period of time. - 103 - FIELD Q Column 52 3. In vitro experiments Field Q may be used to record the inoculum size for in vitro experiments as well as in vivo experiments. 4. Symbols available for additional items of Field Q Since none of the IBM zone punches have been used for special purposes, any of Symbols A through Z are available for additional use in Field Q. However, as the size ranges are now, no further symbols are needed for that purpose. 5. File of coded biology data on IBM punched cards, arranged according to symbols for inoculum size The CBCC has no file of coded biology data arranged by Field Q symbols, because of the improbability of beginning an information search by looking for inoculum size. 6. Double coding in Field Q If the evaluations of two or more tests are so similar that they can be coded by the identical symbol in Field Y and the only difference between the two or more tests is the size of the inoculum, all the inoculum sizes may be coded in Field Q and all punched on the same IBM card. This is re- ferred to as double coding. For example, if the evaluation coding is the same regardless of whether the inoculum is 10, 50, or 100 cells, Field Q is coded with Symbol 2; whether the inoculum is 10, 100, or 500 cells, Field Q is coded with Symbols 2 and 3; whether with 100, 1000, or 10, 000 cells, Field Q is coded with Symbols 2 and 4. (See Division 1. ) 104 - FIELD R Column 53 TIME OF TREATMENT RELATIVE TO: (1) INOCULATION (2) TUMOR IMPLANTATION (3) SENSITIZATION (4) INCITATION OF NON- INFECTIOUS PATHOLOGY Organization As with all fields of the CBCC Biology Code concerned with quantitative data, each symbol of Field R designates a time range . As the symbols are listed in the Code, four groups can be recognized, according to the sequence of the administration of the test compound and the infection, implantation, etc. : 1. Test compound and infection, etc., administered at the same time - -or essentially at the same time (within an hour of each other). (Symbol 1) 2. Test compound administered after the infection, etc. (Symbols 2 through B) 3. Test compound administered before the infection, etc. (Symbols C through L) 4. Test compound administered before and after the infection, etc. (Symbol M) General Use The time between implantation, inoculation, sensitization to the test compound, infection, etc. , and the administration of the test compound is indicated in this field, when the time is relevant and important to the test. Time values coded in Field R are those between administration of the test compound and: 1. Implantation of a tumor (coded in Field E). 2. Inoculation of a host with the cells or individuals of an infective stage of a pathogenic test organism coded in Field E. 3. A subsequent dose of the same compound administered to determine sensitization by the primary dose. Thus, Field R may be used to code time between the administration of an initial dose given experimentally as a sensitizing dose (or as a dose which reduces tolerance) and the subsequent dose, when coding the sensitive response to the second dose (i. e. , when not coding sensitization or tolerance reduction [Symbol 58 or a symbol of the 51-- series], but indicating with Symbol 6 in Field G that the organism has been pretreated to account for the sensitivity resulting in the response coded in Field T at the dose administered). See the section on Specific Directions and Explanations for Field G, Division 11, Subdivision A, Part (1). 4. The inciting of a specific non- infectious pathological state (coded in Field E) to be treated with the test compound. (This inciting of a non- infectious pathology is never coded in Field G in which could be coded, in this situation, only pretreatments or conditions other than the pathology to be experimentally treated. ) Field R is not used to indicate the time interval between administration of the test compound and the secondary compound; that information is coded in Field P. - 105 FIELD R Column 53 Specific Directions and Explanations 1. Time to be coded when the test compound is administered PRIOR to a SINGLE implant If the administration of the test compound is by multiple application and the total treatment with the test compound is prior to implantation, inoculation, etc. , the time interval coded in Field R is the period between the last administration of the test compound and the implantation. If the administration of the test compound is by single application and the treatment with the test compound is prior to implantation, inoculation, etc. , the time interval coded in Field R is the period between the application of the test compound and the implantation. If the test compound is administered continuously for a period prior to implantation, the interval coded in Field R is the period between the end of the administration of the test compound and the implantation. (If the test compound is administered continuously up to the time of implantation, Field R must be coded with Symbol 1. ) 2. Time to be coded when the test compound is administered AFTER a SINGLE implant If the administration of the test compound is by multiple application and the treatment with the test compound occurs after implantation, inoculation, etc. , the time interval coded in Field R is the period between the implantation and the first application of the test compound. If the administration of the test compound is by single application and the treatment with the test compound occurs after implantation, inoculation, etc. , the time interval coded in Field R is the period between the implantation and the application of the test compound. If the test compound is administered continuously for a period after the implantation, the interval coded in Field R is the period between the implantation and the beginning of the administration of the compound. (If the test compound is administered continuously beginning at the time of implantation, Field R must be coded with Symbol 1. ) 3. Time to be coded when the test compound is administered PRIOR to MULTIPLE implants If the implantation, inoculation, etc. , is multiple and the administration of the test compound is prior to the implantation, the time interval coded in Field R is the period between (1) the last dose (when multiple doses of the test compound are given) and the initial implantation, or (2) the single dose and the initial implantation, or (3) the end of a continuous administration and the initial implantation. 4. Time to be coded when the test compound is administered AFTER MULTIPLE implants If the implantation, inoculation, etc. , is multiple and the administration of the test compound is after the implantation, the time interval coded in Field R is the period (1) between the last implantation and the initial dose (when multiple doses of the test compound are given), or (2) between the last implantation and the single dose, or (3) between the last implantation and the beginning of continuous administration. 5. Symbol 1 Symbol 1 is used to specify the administration of the test compound at the same time that implantation, inoculation, etc. , occurs. This symbol is also used when the administration of the test compound occurs within an hour before or after implantation, inoculation, etc. Although time periods less than one hour might have been given symbols, they are seldom of sufficient significance to justify it. When the time period is one hour or more, the other code symbols are used. 6. Instructions for miscellaneous irregular situations If data are indefinitely reported (e. g. , ". . . . treated 4 days to 2 weeks after implantation. . . "), code the symbol that represents the average value of the reported range. Record the entire range in the written abstract of the field. - 106 FIELD R Column 53 When an author indicates only that implantation, inoculation, etc. , was on the "day of the last dose" (in cases of multiple doses of the test compound), without specifying whether the time between the last dose and implantation was less than or more than an hour after the last dose, use Symbol C. In the same way, when it is known only that implantation, inoculation, etc. , was on the "day of the first dose of the test compound" or was "immediately after", use Symbol 2. In the case of a single or continuous administration of the test compound, if the author only states that the test compound administration was "on the same day" as the implantation, inoculation, etc. , without specifying which operation was performed first, use Symbol 1. When the author states that treatment is administered "on the day following" (or "prior to") implantation, etc. , there is posed the question as to whether the time interval was greater than, equal to, or less than 24 hours. Symbol 3 (or Symbol D in the case of "prior to") is to be used in these cases merely for consistency, since Symbols 2 and C are used for coding the expression "on the same day". 7. In vitro experiments Field R may be used for indicating time between time of treatment and time of inoculation of in vitro tests as well as in vivo tests. 8. Symbols available for additional items of Field R Inasmuch as the IBM zone punches have not been assigned for special purposes in Field R, any of the presently unused letters can be used as symbols (i. e. , N through Z), although it seems probable that the time periods already designated in the field are adequate. 9. File of coded biology data on IBM punched cards arranged according to symbols for time periods of Field R The CBCC has not established a file of coded biology data arranged by Field R symbols because of the improbability of beginning an information search by looking for inoculation- treatment relation- ships of tests. 10. Double coding in Field R When the evaluations of two or more tests are so similar that they can be coded by the identical symbol in Field Y and the only difference between the two or more tests is the period between implanta- tion, inoculation, etc. , and administration of the test compound, all the time periods may be coded in Field R in one line and all punched on the same IBM card. This is double coding. Double coding in Field R has restrictions, however; IT IS POSSIBLE ONLY IF THE SYMBOLS DOUBLE CODED ARE NUMERICAL, SYMBOLS 1 THROUGH 9. The IBM procedure will not permit double coding of two letter symbols or a letter and numerical combination. 107 FIELD S-l FIELD S-2 FIELD S-3 Columns 54, 55, and 56 ROUTE AND MANNER OF ADMINISTRATION OF: (1) INOCULUM OR IMPLANT (FIELD S-l) (2) SECONDARY COMPOUND (FIELD S-2) (3) TEST COMPOUND (FIELD S-3) Organization Although each of these three coding fields is used for recording a unique aspect of chemical- biological tests, basically a single list of items serves to provide symbols for all three. Since only a single IBM column has been provided for each of the fields, only 35 symbols are available. (38 sym- bols might be regarded as being available, if the 0, 11, and 12 zone punches, used alone, were assigned unique Field S meanings. ) The arrangement of the items is arbitrary except that, when the list was compiled, those bearing similarities to each other were generally listed together. Because certain items are not equally appropriate for all three fields, those symbols are given two or more definitions and where these multiple definitions occur, there is designated by each to which of the three fields, S-l, S-2, or S-3, its use is restricted. General Use FIELD S-l This Field (Column 54) is used for coding the route and manner of administration of the test organism or tumor (specified in Field E), as an inoculum or implant , to the host, living or non-living, specified in Field J. The size of this inoculum or implant (i. e. , the number of individuals of the test organism or the number of tumor cells, when this is estimated) is coded in Field Q. FIELD S-2 In this field (Column 55) is coded the route and manner of administration of a secondary compound (specified in Field D) to the test organism or to the host (either a living or non-living host)-- when this secondary compound is administered in the identical experiment in which the test compound Is administered so that the interaction of the two compounds on the organism is evaluated (antagonism, synergism, or additive effect, Symbols 8, 9, and C of Field T-l). (Field S-2 could be used when Symbol A [simulation] is coded in Field T-l, if the route of administration of the secondary compound simulated were stated by the author, even though the administration of the secondary compound is not in the same test as that of which the results are being coded. ) In other words, Field S-2 is not invariably used when there is an entry in Field D, but only under the circumstances just described; to be specific, it is not used when the entry in Field D is merely a standard of comparison or when it is a compound whose metabolic fate is affected by the test compound. When a compound is coded in Field D as a standard whose action is compared to the test compound's action, it would be assumed that that standard, if it were truly eligible for comparison, had been administered (in those tests demonstrating its action) by the same route and manner as the test compound (in the test being coded) or that any difference in the routes of administration of the two compounds had no significant effect on the outcome of the tests of the two compounds. Therefore, since there is no need for such distinction, no provision has been made in the CBCC Biology Code, in Field S-2 or elsewhere, to indicate the route and manner of administration of a standard compound. 108 FIELDS S-l, S-2, and S-3 Columns 54, 55, and 56 FIELD S-3 Field S-3 (Column 56) is used for coding the route and manner of administration of the test compound to the test organism or, if Field J is coded, to the host. In chemotherapy studies, when the test organism, tumor, or pathology (in Field E) is always in a host (Field J), it follows that, under those conditions, the coding in Field S-3 ordinarily describes administration of the test compound to that host. In such tests, if the administration is actually directly to the test organism or tumor rather than directly to the host coded in Field J, the coding of Field S-3 will apply to the test organism. Unfortunately, the CBCC coding of Field S-3 can not distinguish this fact and only by the general sense of the Field S-3 entry and by reference to the written abstract for Field S-3 can it be distinguished that the route coded refers to direct administration to the test organism or tumor. This is discussed also In Division 2 of the Specific Directions and Explanations for Field S-3 . (Three of the items of Field S-3, Symbols J, M, N, and R, invariably imply the test organism's being in or on a non-living host to which the test compound is administered and which is always recorded in Field J; i. e. , Symbols J, M, N, and R are restricted to reference to Field J by their definitions, so with these symbols there is no question as to whether the Field S-3 coding refers to the test organism or tumor in Field E or to the host in Field J. ) Specific Directions and Explanations FIELD S-l 1. Tumor transplants In cancer studies, a tumor transplanted into another animal is commonly introduced subcu- taneously. If the author has not specified its transplant location as being elsewhere, the CBCC assumes it is subcutaneous and codes it with Symbol 8. 2. Relationship of Field S-l with Fields H-l, H-2, and I Field S- I is not conceived as having a direct relationship to Fields H-l, H-2, and I. Although most frequently the site of administration of an inoculum (Field S-l) is also the site at which the inoculum (the test organism or tumor) establishes (Fields H and I), it is not invariably the case. Fields H-l and I are always used for coding the location of the test organism or tumor at the time of the test, when a host organism is coded in Field J, and never for coding the site of administration of the test organism or tumor; if the site of administration of the inoculum or implant (the test organism or tumor) is identical to the location of the test organism at the time of the test, it is only coincidental. Neither is Field H-2 used for coding sites of administration of inocula and tumors, but only for coding structures as described in the section discussing Field H-2. FIELD S-2 1. Use of Field S-2 is restricted to secondary compounds with which the test compound interacts, as signaled by certain symbols of Field T- 1 This has been explained in the section on General Use of Field S-2, above. When Symbol 8, 9, or C is used in Field T-l, Field S-2 can be used; otherwise, Field S-2 is always to be left uncoded. 2. Secondary compounds can be administered to hosts as well as to test organisms; use of Field S-2 when Field J is coded with a host Inasmuch as the test compound may antagonize, synergize, or have an additive effect on the therapeutic activity of a secondary compound. Field S-2 may be used when Field J is coded with a host organism- -or even with a non-living host (e. g. , Symbols J, M, and N of Field S-2). Thus, whenever Field J has an entry, any coding in Field S-2 is to be interpreted as being the route or manner of admin- istration of the secondary compound to the host coded in Field J. Just as the test compound may in an occasional test be applied directly to the test organism even when it is on a host (coded in Field J), so Is it possible that the secondary compound might be administered directly to the test organism when the test organism is on a host coded in Field J. Coding of Field S-2 can not distinguish, any more than 109 FIELDS S-l, S-2, and S-3 Columns 54, 55, and 56 can coding of Field S-3, whether the test organism or the host organism is referred to by the route indicated. (See the section on General Use of Field S-3. ) 3. Relationship of Field S-2 with Fields H-l, H-Z, and I Since Fields H-l and I always are used to code the specifically responding structure of the test organism (when Field J is not coded with a host organism) or are used to code the site of the pathogen or pathology as coded in Field E (when Field J _is coded with a host organism), those anatomy fields can not be used specifically to indicate the structure serving as the route of administration of the secondary compound. Neither can Field H-2 be used for this purpose, because it is reserved for describing the site of administration of the test compound, if this site is not the same as the site of response and if Field H-2 is not otherwise used. (See the description of Field H-2. ) FIELD S-3 1. Relationship of Field S-3 and Fields E and J The use of Field S-3 is described above in the section on General Use. When Field J is not coded, a code entry in Field S-3 represents the route and manner of administration of the test compound to the test organism in Field E. When Field J is coded, a code entry in Field S-3 always represents the route and manner of administration of the test compound to the host organism or inanimate host in Field J, unless the written abstract of Field S-3 indicates that administration was essentially directly to the test organism even though a host is coded in Field J, as described in the last paragraphs of the next Division. 2. Relationship of Field S-3 and Fields M and N and the relation of each of Fields S-3 and Fields M and N to Fields E and J The use of IBM 11 and zone punches in Fields M and N (Code Symbols # and 0) is described in Divisions 5, 6, 7, 8, and 9 of the Specific Directions and Explanations of Fields M and N. The IBM zone punches in Columns 46 and 48 do not alter the meaning of the coding in Field S-3. In Field S-3 is coded the technique of administration (i. e. , route and manner). The zone punches of Fields M and N designate to which of two or three biological units (the host, or the test organism, or the responding organ or tissue) the test compound was exposed at the dose level coded in Fields M and N, regardless of the technique (route and manner) of administration. For example, with the 12 zone punch (Symbol #) in Column 46 or 48, and with Field J coded, the dosage is the amount or concentration to which the test organism was exposed rather than the dosage administered to the host organism. This, however, is not synonymous with saying that the technique of administration (route of administration) has been likewise altered; in the example above, the actual route of administration (Field S-3) might have been directly to the host (Field J), in spite of the fact that the final concentration, as coded in Field M or N was determined as being the one to which the test organism was exposed, after distribution through the host. The zone punches in Columns 46 and 48 should not be considered to infer the actual route of administration which is coded only by Field S-3. In view of the foregoing, the coding in Field S-3 should follow the explanation as given above in Division 1, so that it describes only the technique of administration of the test compound. For example, aphids (Field E) on the leaves of rooted willow branches (Field J) were exposed to the test compound at Z ppm in the leaves (Field M, coded with Symbol #) when application was to the branches at 1 10 x Z ppm as a water solution in which the branches were placed (Field S-3, Symbol D). In this example, the route of administration (as coded in Field S-3) was to the host , in spite of Fields M and N indicating (by Symbol #) that the coded dosage was that to which the test organism was exposed. If there is an entry in Field J and the test procedure describes the administration as being actually directly to the test organism, the CBCC Code has no way of coding this distinction specifically in Field S-3; it must, however, be adequately explained in the written abstract of Field S-3. Consider the following three situations for illustration: (1) the application of a fumigant or a spray of the test compound (Field S-3, Symbol J or K) at X ppm to aphids (Field E) on leaves of willow branches (Field J); (2) the application of the test compound at X ppm directly onto the abdomen (Symbol G of Field S-3) of a tick (Field E) whose forebody is buried in the skin of a dog (Field J), or (3) the direct exposure of ectoparasites (Field E) on a fish (Field J) to the test compound at X ppm in the water (Symbol N of 110 FIELDS S-l, S-2, and S-3 Columns 54, 55, and 56 Field S-3). In all of these procedures, Field M would be coded with Symbol #, indicating that although a host was involved, the test organism was exposed to the dosage as coded in Field M; however, none of Symbols K, G, or N of Field S-3 explains (1) that the test compound was applied to the external surface of the aphids (and only coincidentally to the external surface of the willow leaves), or (2) that it was not applied to the abdomen of the dog, or (3) that it was applied to the habitat of the ectoparasites (and only coincidentally to the habitat of the fish). In such cases, the coder must always explain in the written abstract of Field S-3 this route of administration as being directly to the test organism rather than to the host of Field J. 3. Relationship between Fields S-3 and Field H-2 Of the uses for Field H-2, one relates particularly to Field S-3 (listed as Use #3 in the section on General Use of Field H): the gross anatomical site of administration of the test compound, when the site is other than an organ specifically responding in Field H-l, can be coded in Field H-2, pro- vided Field H-2 is not otherwise used and if the coding in Field S-3 does not adequately designate the specific route. This use of Field H-2 is discussed in detail in the section on Specific Directions and Explanations (Divisions 2 and 3) for Field H. Briefly, certain symbols of Field S-3 adequately indicate the site of application and, when they are used, Field H-2 need not be coded with the site of application under any circumstances: Symbols 0, 1, 2, 6, 9, A, H, J, K, L, M, N, Q, R, T, U, V, W, X, and Y. The other symbols of Field S-3 represent routes which do not include in their definitions specification of an anatomical site and it is to supplement the definitions of these that Field H-2 can be used: Symbols 3, 4, 5, 7, 8, B, C, D, E, F, G, I, 0, P, S, and Z. Ideally, a separate coding field (i. e. , other than the field used to supplement coding in Fields G and L) would be provided for this supple- mentary coding to Field S-3, but the CBCC decision to use a single field (Field H-2) for both uses was based on the belief that both of those uses for Field H-2 occurred with sufficient infrequency that con- flicts between the two uses would be correspondingly rare and that the significance of this small number of conflicts did not justify reserving another three IBM punched card columns for a special anatomy field to supplement Field S-3, when it was so important for efficiency to restrain the entire coding area to a single IBM punched card. Unfortunately, as is often the case when two uses are assigned to a single coding field, code entries in Field H-2 can be interpreted only by consulting the coding in Fields G, L, S-3, and H-l, as explained in Division 3 of the Specific Directions and Explanations section for Field H. In the process of retrieving from the coded files data on tests in which a specific organ is treated with the test compound, the file search must include sorting in Field S-3, as well as in Fields H-l and H-2. 4. Manners of application; Field S-3 and Field A distinctions Field S-3 distinguishes in its descriptions manners of application to the several routes. The route and manner of application are often intimately linked in a given technique, so that actually Field S does not code two items of information (a code symbol for a route, as distinguished from a code symbol for a manner), but only a single item (the route which by its nature frequently restricts the manner, both being described by a single symbol). The manners of application described in Field S are limited: injection and implantation, insertion in the alimentary tract, perfusing through an organism or organ, and placing on the organism surface (by any of several mechanical means: rubbing, painting, brushing, dripping, spraying, washing, immersing, dipping, fumigating, etc. ). These several manners of appli- cation, combined with selected specific anatomical parts (routes), make up the items of Field S, de- scribing the more common techniques of application. Observe that the manners of application just mentioned are not synonymous with nor do they include the description of the state of the compound (e. g. , liquid , solid , gas , as a continuous [ undispersed ] mass, or separated into particles to be discontinuous [i. e. , dispersed as a suspension or emulsion, dust, spray, mist, etc. ]). These states are coded only in Field A for the test compound, never in Field S-3, even though they may seem in some cases to be coded in Field S-3: certain manners and routes (e. g. , Symbol J) are restricted to a single state of the test compound and the implication of that state is so strong, therefore, that Field S-3 appears to be coding the state. This distinction between Field A and Field S-3 is discussed also in the section on the General Use of Field A. 5. Symbols available for expansion of Fields S-l, S-2, and S-3 FIELDS S-2 AND S-3 All of the items of the Code are applicable to Fields S-2 and S-3 and there are no further symbols available for new routes except that the IBM 1 1 and 12 zone punches might be used alone for two new items. - Ill - FIELDS S-l, S-Z, and S-3 Columns 54, 55, and 56 FIELD S-l Several of the items of the common Code list for Fields S-l, S-2, and S-3 are not ordinarily applicable for describing the administration of inocula. In particular, Symbols C and M have been designated in the Code as not being used in Field S-l. Thus, Symbols C, M, and the IBM 11 and 12 zone punches are available for additions to Field S-l. 6. File of coded biology data on IBM punched cards arranged according to symbols for routes of administration The CBCC has established no separate files of biology data arranged by entries in Field S-l, S-2, or S-3. 7. Double coding in Fields S-l, S-2, and S-3 If more than one route of administration of inoculum or implant, secondary compound, or test compound (Fields S-l, S-2, and S-3, respectively) have been employed and the results of the tests using the different routes are so similar that the coding for the tests would be identical except for the entry in Field S-l, S-2, or S-3, both routes can be coded in that field to accommodate both tests in a single code line. This coding of two or more tests in a single line is referred to as double coding. HOWEVER, double coding in these three fields is possible only if the code symbols for both of the two routes are numerical, i. e. , any of Symbols and 1 through 9; if one or both of the routes is coded by a letter symbol (Symbols A through Z), a separate code line must be constructed for each test using a different route of administration. If Field S-l, S-2, or S-3 is double coded with more than one of Symbols and 1-9, both or all of the coded symbols are punched on the same IBM card in the column for the field. 112 Introduction to Field T: Fields T-l, T-Z. T-3 Columns 57, 58, 59, 60, 61, 62, 63, and 64 ACTION OF THE TEST COMPOUND Organization of Field T This field is divided into three areas or sub- fields (Fields T-l, T-2, and T-3) in the same way that the general area for coding the administered dosage is divided into four areas (Fields M, N, O, and P). Fields T-l, T-2, and T-3 are assigned one, four, and three coding columns (i. e. , IBM punched card columns), respectively. The three areas are designated as: Specific Action (Field T-l) Specific Biological State, Quality, or Process Acted on or Caused (Field T-2) General Category of Effect; Practical Application (Field T-3) General Use of Field T; Distinctions between General Uses of Fields T-l, T-2, and T-3 In this area is coded the biological response--in other words, a description of the chemical action on the organism. The first of the three subsidiary coding areas of Field T, Field T-l, is used to describe the exact action and is therefore referred to as the field for coding specific action . The second, Field T-2, is used for coding the specific biological state, quality, or process acted on or caused. Finally, Field T-3 is used to re- state the information coded in Fields T-l and T-2 in terms of a general category of action . In describing responses of biological organisms to chemicals- -in other words, actions of test compounds on biological organisms- -it will be noted that the expression of biological response (chemical action) always consists of two components, essentially a verb and an object (considering the test compound as being the subject of the statement of the test result). For each of these two components of the statement of biological response, a separate code area has been established, Field T-2 for the object (i. e. , the state, quality, or process) and Field T-l for the verb (i. e. , the action of causing or affecting the state, quality, or process). Field T-3 supplements Fields T-l and T-2 in that it defines the chemical action in terms of a general category of effect and practical biological application. Examination of items of Fields T-3 and T-2 will help clarify the distinctions. Fields T-l and T-2 should be regarded as a coding unit, the entry in each of the two fields being essential to a complete statement of action of the test compound (i. e. , a complete statement of the response of the organism). Field T-3 is then a second coding unit, in which the chemical action (biological response) is re- stated in another, more general way. In programs of coding chemical- biological information which are of a considerably more restricted nature than that of the CBCC, it is conceivable that one of the units, (1) T-l and T-2 or (2) T-3, could be eliminated. - 113 FIELD T- 1 Column 57 SPECIFIC ACTION OF THE TEST COMPOUND ON THE BIOLOGICAL STATE, QUALITY, OR PROCESS CODED IN FIELD T-2 Organization Twenty-five items have been listed and assigned code symbols in Field T-l. In constructing this list, the arrangement of the test compound actions has followed no special pattern. General Use Field T-l is used to describe the test compound's action on the biological state, quality, or process coded in Field T-2 (or the action for which the compound is tested , even though the compound proved inactive). This general use of Field T-l is further distinguished in the previous section discussing Field T as a whole. Specific Directions and Explanations 1. Relations of Field T-l to Field T-2 None of the items of Field T- 1 represents an independently complete code statement. Exam- ination of the terms defining symbols of Field T-l will make clear that the Field T-l entry must be accompanied by an entry in Field T-2 to form a complete code statement of the test compound's effect on the biological system or of the test organism's effect on the test compound. EVERY LINE OF CODED BIOLOGY DATA DEMANDS AN ENTRY IN BOTH FIELD T-l AND FIELD T-2. 2. Action of the test compound on the biological system vs. action of the biological system on the test compound Most of the terms of Field T-l describe actions of the test compound on the biological system to which it has been administered. Certain tests, however, reveal the fate of the chemical itself instead of. or in addition to, the organism's specific response to it. For example, the biological system may store the compound, absorb it, alter it, etc. The terms of Field T-2 which describe these actions on the test compound are indicated by Symbols F9B, FAB, FBB, FGB, FIB, and any of the Symbol series FE-- and FF-B. With any of the Field T-2 terms above (coding the action of the biological system on the test compound), Field T-l is coded with Symbol 7. When used with these Field T-2 terms, Symbol 7 represents the term "undergoes" or "is", indicating the test compound's being acted on. With all other Field T-2 terms, Symbol 7 represents "causes", "produces", "induces", etc. 3. Field T-l coding is NOT influenced by the test result being NEGATIVE In collecting and recording chemical- biological data for future retrieval and study, it is as important to code specifically those actions which test compounds have been demonstrated unable to perform as it is to code those which test compounds have been demonstrated capable of performing. Therefore, when a test is run specifically to determine whether a chemical will perform a given action (or whether the chemical will be altered or otherwise affected in a given way by the test organism) and the chemical proves to be inactive (or to be unaffected by the test organism), Field T-l can not express the fact that the specific action was not produced (or that the test compound had not been affected by the test organism). The code statement of Field T (including Field T-l) is always positive; if the data are negative, the negation of the Field T statement is accomplished by code only in Fields X and Y. 114 FIELD T-l Column 57 In Division 5 below, a slight variance in coding of Field T-l for special negative data is discussed. 4. Field T- 1 coding IS influenced by the test result being the REVERSE of an action for which the compound was tested When a test compound has been administered in an effort to induce or affect in a given way a specific biological condition or process of Field T-2, the compound may prove to do the reverse (e. g. , it prevents instead of induces or it decreases instead of increases the state or process in Field T-2). In this case, Field T-l must be coded to record the action actually demonstrated; subsequently, it would be meaningless to construct a second line in which Field T-l would be coded with the action for which the test was made and negate it by coding in Fields X and Y. 5. Coding of Field T-l when a compound is tested for action on a specific biological state or process (coded in Field T-2), and the following factors all apply: (1) the state or process in Field T-2 is one that might be affected in either of two opposing ways, (2) the compound proved inactive, and (3) the author does not state for which of the two opposing actions the compound had been tested Under these conditions, the CBCC avoids coding arbitrarily the compound's failure to accomplish one or the other of the two possible effects on the condition or process coded in Field T-2. Instead, both are coded. In essence, this would involve two biology code lines, one with Field T-l coded with one action (e. g. , increase), the other with Field T-l coded with the opposing action (e. g. , decrease); in actual practice, however, the CBCC conserves space and coding time by combining the two lines, accomplished by coding both actions in Field T-l in the same line . An exception to combining these two lines into one must be made in the case of the specific states indicated by Symbols of the two series, 171- and 161-, of Field T-2 (the number of pathogenic organisms having been diminished or increased). The association of alteration of the number of organisms with improving or exacerbating an infectious pathology necessitates defining those Field T-2 symbols as either being a state of diminished numbers of organisms or of increased numbers of organisms and Field T-l is consequently coded with Symbol 7 to indicate that the state of diminished or increased numbers has been "caused". Since Field T-2 can never have more than one entry, two separate lines are necessary for this. It might be pointed out here that when the author reports the test compound as having no effect and in addition does not indicate any specific biological state or process that was being treated or initiated (so that there is no specific entry for Field T-2), Field T-l can be coded only with Symbol 0. (See Division 18 below. ) 6. Symbols 1 and 2; quantitative change or change of rate (exclusive of total abolishment or prevention) of the biological state or physiological process coded in Field T-2 These symbols are each given two meanings, though the sense of increase is implicit in both of the definitions for Symbol 1 and the sense of decrease is implicit in both of those for Symbol 2. Symbol 1; (a) increases (b) accelerates Symbol 2: (a) decreases (b) slows Thus, these two symbols can be used for coding the action of the test compound in increasing or decreasing size , number , or degree (e. g. , increasing or decreasing the number of fruits [Field T-2, Symbol 191], nuclear size [Symbol 225], number of blood cells [Symbol 851], organism weight [Symbol 2A1], prothrombin time [Symbol 8731], or circulatory rate [Symbol C6]), which represents a quantitative effect only. However, the symbols are used also for coding the action of the test compound in increas- ing or decreasing the rate of any physiological process which is not defined in Field T-2 as a rate (e. g. , accelerating or slowing the alteration of the test compound [Field T-2 Symbol series FE--], spiracular movement [Symbol B2], sol-gel transformation [Symbol 833], regional growth [Symbol 2A4]). 115 - FIELD T- 1 Column 57 There might be some advantage to having symbols unique from Symbols 1 and 2 for distinguishing in Field T- 1 that the action is one of altering a rate of a process rather than being one of alteration of number, size, or degree; this would permit clarifying the situation when certain biological conditions or processes are defined by Field T-2 terms which are somewhat ambiguous in this respect. For example, Symbol 1 of Field T-l, when coded with Symbol 261 of Field T-2 (seed germination), may indicate that the number of seeds germinated was increased or that the time (speed) of germination was shortened; a unique Field T-l symbol for "increase of rate" would permit distinguishing the latter effect on germination from the former effect. The CBCC has maintained the single symbol meaning both "increase" and "accelerate", as well as the single symbol meaning both "decrease" and "slow", because the symbols were so defined in the early editions of the Code and, after a given date, the extensiveness of past use of each symbol with both meanings made impractical changing their defini- tions. For a new coding program, separate code symbols could be provided in Field T- 1 for increase and accelerate, as well as for decrease and slow; the alternative to this would be to distinguish by separate definitions in Field T-2 quantitative change and change in rate when a single process may be affected by the test compound in either way. In the example given, this might be done by assigning Symbols 2611 and 2612 to those distinguishing terms, germination time and percentage germination. 7. Use of Symbols 1 and 2 when Field E is coded with a pathology and Field T-2 is coded with a symptom of that pathology and when the Field T-2 code symbol IDENTIFIES the state or process as being a pathological state or process Many of the items of Field T-2 represent pathological states or pathological processes which test compounds may " produce " (Symbol 7 of Field T-l). Pathological situations are often complex, however, and frequently it is only a symptom (of a total disease coded in Field E) which is specifically treated or specifically responds to the test compound. In this case, the CBCC codes in Field T-2 a pathological state which represents the treated or responding symptom of the infectious or non- infectious disease coded in Field E. Examination of the items of Field T-2 will reveal that many are defined so that the pathological aspect is clear. Examples of these are toxic symptoms (Symbol series 1 13-), abnormal morphologic changes (Symbol series 411-), histolysis (273), circulatory disturbances (Symbol series 87--), anemia (853), ventricular tachycardia (C122), etc. Other items of Field T-2 are defined as normal biological qualities, states, or processes that can be affected (i. e. , their definitions indicate no abnormality of these states or processes): e.g., number of fruits (191), nuclear shape (226), regeneration (272), aging (2C), venous pressure (8213), blood cell number (851), cardiac rate (CI), etc. Although none of these latter Field T-2 definitions include the word "normal", it is nevertheless implied. If the pathological symptom treated with the test compound is one of those of the first type described above (Symbols 113-, 41 1-, etc. ), the effect of the test compound is properly coded with Symbols 1 or 2 (or Symbol 3, if the condition is abolished or prevented). However, if the symptom is a pathological variation of one of those normal states or processes described above as the second type of Field T-2 items (Symbols 191, 226, etc. ), Symbols 1 and 2 must not be used, because they provide no indication that the test compound action coded in Field T-l is not an increase or decrease from the normal level rather than from an abnormal level. Special Field T-l items have been introduced which designate that the normal state or process in Field T-2 had been altered by pathology and that the test compound was administered to treat that altered Field T-2 state or process. These Field T- 1 symbols are J, K, L, M, N, 0, P, Q, and R. Symbol J, for example, is used for indicating that the normal state or process coded in Field T-2 had been diminished by the pathology coded in Field E and that the test compound had been administered to increase or speed the diminished state or process to bring it back to a normal level (i. e. , cure the diseased organism). Sym- bol K is used for the situation reversed from that for which Symbol J is used and Symbol L is used when the normal state or process has been affected by the pathology and the test compound has been adminis- tered to restore the normal level by some action other than increase or decrease. Symbols J, K, and L, which code a cure of the diseased organism, are used instead of Symbol 3. Symbols M, N, and are used to indicate improvement, but not a cure, of the organism and are analogous to Symbol 2. Symbols P, Q, and R code exacerbation of the disease and are used instead of Symbol 1. 116 FIELD T-l Column 57 In sorting the coded files for data on specific action of compounds, it is possible that one might want to retrieve data on all compounds that (e. g. ) increased a state or physiological process, regardless of whether it was or was not increased from the normal level . If such were the case, it would be somewhat advantageous if, for all instances of increase of the state or process, Field T-l were coded with Symbol 1, rather than having to sort out all that data for which Field T-l was coded with Symbols J, M, and Q, as well as that data for which Field T- 1 was coded with Symbols 1 and 2. However, in most cases, retrieval of data on all compounds that increase or speed a state or physio- logical process is preferably limited to those data in which the effect was an increase or acceleration from a normal level; i. e. , it is preferred not to have included, with that retrieved data, information on compounds which merely corrected a state or process pathologically diminished or which exacerbated a state or process pathologically increased or accelerated . For this reason, it is useful to have the two types of data distinguished; thus, when retrieving information on increase or acceleration of a state, quality, or process from a normal level, omission of any data on increase or acceleration from a pathological level can be accomplished by eliminating any Field T-2 items identified as pathologies associated with the state, quality, or process concerned in the search and by elimination of any infor- mation coded with Symbol J, M, or Q in Field T-l. In summary, when Field E is coded with a pathology and a symptom of the pathology is coded in Field T-2, Field T-l is coded with Symbol 1 or P, Q, or R; 2 or M, N, or 0; or 3 or J, K, or L, according to the character of the Field T-2 term. If the Field T-2 term is identifiable by its definition as a pathological state or process, Field T-l is coded with Symbol 1 or 2 (or Symbol 3, if the patho- logical state or process is abolished- -i. e. , if a cure is effected). If the Field T-2 term representing a pathological symptom is identifiable only as a normal state or process, Field T-l must be coded with Symbol J, K, L, M, N, 0, P, Q, or R. This is discussed more thoroughly in Divisions 16 and 17 which explain in more detail the specific use of Symbols J through R. 8. Symbol 3; complete abolishment or prevention of a normal or pathological biological state or physiological process coded in Field T-2 When a test compound stops or prevents or is tested to stop or prevent a specific normal biological state or physiological process, Symbol 3 Is used in Field T-l and evaluation (Field Y) is based on the ability of the test compound to stop or prevent the normal state or process, rather than on the ability to cause some degree of decrease or slowing of the normal state or process. However, when a test compound stops or prevents a specific pathological biological state or physiological process, the action is coded in Field T-l with Symbol 3 only with certain Field T-2 entries; with other Field T-2 entries, Field T-l must be coded with Symbol J, K, or L, as explained in the following paragraphs. In Division 7, Field T-2 terms were described as being of two major types, one being of normal states or processes (e. g. , number of flowers, Symbol 191; nuclear shape, Symbol 226; regeneration, Symbol 272), referred to in the first paragraph of the present discussion. The other type was described as consisting of pathological states or processes coded in Field T-2 (e. g. , local toxicity, Symbol 113; atrophy, Symbol 411). When a compound is administered to affect (rather than "cause", Symbol 7 of Field T-l) one of those pathological states or processes coded in Field T-2 as a term of the second type, that effect can be coded with Symbol 1 or 2, or if the pathological state or process is wholly abolished ( cured ) or prevented, the action can be coded with Symbol 3 . However, if a symptom (coded in Field T-2) of a pathology (coded in Field E) can be identified in Field T-2 only as a normal biological state or physiological process (i. e. , if there is no indication in Field T-2 that the normal state or process has been rendered abnormal by the pathology in Field E) and the test compound is administered to affect that pathologically altered state or process, Symbol 3 can not be used if the compound returns the state or process to complete normalcy, because it would only be interpreted as having abolished or prevented the normal state or process. As was pointed out in Division 7, when a pathology symptom is coded in Field T-2 only as the normal state or process which has been altered by the pathology, the special symbols J, K, and L must be used in Field T-l instead of Symbol 3. 117 FIELD T- 1 Column 57 It will be noted that Symbol 3 is defined as the ultimate degree of the action coded by Symbol 2. Thus, in this case, two symbols are provided for the action of diminishing the state or process in Field T-2, one for any degree short of complete abolition or prevention (Symbol 2) and one for complete abolition or prevention (Symbol 3). This is basically the reason for having the two sets of symbols, (1), J, K, and L and (2) M, N, and 0. If Symbols 3, J, K, and L were not included in Field T-l, all diminishing effects on states or processes in Field T-2 would necessarily have to be evaluated on the basis of the degree of diminution (Symbols 2, M, N, and 0) and total abolishment could only be evaluated as a high degree of diminution . 9. Symbols 4 and 5; increase (or decrease), followed by the reverse action, decrease (or increase), on the biological state or process coded in Field T-2 The occurrence of this phenomenon as an action of test compounds and the use of Symbols 4 and 5 is relatively infrequent. When such a two-phased response is demonstrated, the CBCC coder aiways constructs a code line with Field T-l coded with Symbol 4 or 5; if some circumstance makes apparently important the coding of an evaluation of only one phase of such a response (the increase or decrease phase), this must be done by a second code line with Field T- 1 coded appropriately with Symbol 1 or 2 and a full explanation in the written abstract that this was only one phase of the response. There is an evaluation problem (Fields X and Y) when the biological response to the test compound is characterized by reversing and when this reversal is indicated in Field T-l by Symbol 4 or 5. When Symbol 4 or 5 is used in Field T-l , evaluation (Field Y) must never be made only on one phase of the response (i. e. , on only the increase or only the decrease), but it must be made on the total response. This is possible with Criterion 62, if the percentage of individuals showing this characteristic reversal of response is determined (but not if the percentage measure is one of percentage of degree of increase and percentage of decrease); evaluation is possible also with the dosage criteria, 51, 52, and 53 (dose size vs. percentage of individuals showing the response with its characteristic reversal), or with Criterion 01. Evaluation might conceivably be possible with Criterion 13 or 54, if a time measure is the criterion and if evaluation is based on the total duration of response, both Increase and decrease, but the CBCC has established a practice of never using Criterion 13 or 54 when Field T-l is coded with Symbol 4 or 5; see Division 1 of the Specific Directions and Explanations for Field U. In other words, evaluation can not be made on the basis of any quantitative measure of only one of the phases of the response which involves two phases, if Field T-l is coded with Symbol 4 or 5 to indicate the two-phased nature of the action. 10. Symbol 6; alteration of a biological state or activity (coded in Field T-2) whose alterations by a test compound are not appropriately expressed as an increase or decrease (Symbols 1, 2, 3, 4, or 5). Effects on physiological processes which disrupt the continuity or the periodicity of the process in a more complex way than simple increase, decrease, abolishment, or increase/decrease followed by reversal A confusion in concept of the definition of Symbol 6 leads to occasional coding errors. This difficulty lies in misinterpreting the definition ("irregular", "fluctuating") to be a way of coding test results which indicate only that a physiological process was altered, but which do not indicate how it was altered (e. g. , increased, decreased, stopped, made irregular). The CBCC has OMITTED coding data in which the action is not described except to say that some action (undefined) occurred altering the biological state or process coded in Field T-2. When it is clear, however, that the action of the test compound has been to cause a physio- logical process to proceed irregularly (i. e. , when it is clear that the altered physiological process does not follow its normal "regular" pattern, and the alteration is not a simple acceleration, simple slowing, abolishment, or a simple reversal), Symbol 6 should be used in Field T-l. A number of Field T-2 items define normal biological balances . The disruption of a balance or of a normal proportion can not be expressed by the terms "increase" or "decrease". I. e. , a balance or proportion can not be increased or decreased; only one of the balanced components can be increased or decreased to disrupt the balance. Therefore, when the entry in Field T-2 refers to a balance (nitrogen balance, Symbol F171; blood cell proportion, Symbol 852; and acid-base balance, Symbol 884), it is necessary to use Symbol 6 in Field T-l to express the test compound's effect on it. 118 FIELD T-l Column 57 Similarly, the two Field T-2 items, general behavior of the individual or group (Symbols 55 and 56), can not be affected by test compounds in a way that can be described adequately as simply as "increased" or "decreased" or "stopped". Effects on behavior are complex and could only be coded by devising items for Field T-2 for those specific behaviors altered. Symbol 6 of Field T-l is used with Field T-2 Symbols 55 and 56 merely to record that behavior has been made "irregular". 1 1. Symbol 7; induction or initiation of a biological state or physiological process coded in Field T-2; Symbol 7 is used when coding alteration, synthesis, or metabolic fate of the test compound or induction or initiation of alteration, synthesis, or metabolic fate of a secondary compound Division 7 has pointed out that Field T-2 includes biological states, factors, or physiological processes of two general categories, the first being those that are normal (though they may be made abnormal), of which the following are examples: size of fruit, Symbol 191; hatching, Symbol 2E; appetite, Symbol F32; blood pressure, Symbol 821; fragility of blood cells, Symbol 874; clotting time, Symbol 87 32; and breathing rate, Symbol B13. The second category includes those that specifically represent pathological states or processes, of which the following are examples: death, Symbol 11, 112, or 113; toxicity symptoms other than death, Symbol series 113- through 116-; morphological changes, Symbol series 41--; anemia, Symbol 853; edema, Symbol 872; hyperpnea, Symbol B17; and A-V block, Symbol C136. With the former terms, which indicate normal states and processes, it is inappropriate to use Symbol 7, even if the process is discontinuous and the test compound influences it to occur at a time other than when it would normally occur (such as inducing "hatching" or "appetite" before they would normally occur). In other words, a test compound can be considered as increasing or decreasing appetite or speeding or retarding hatching, for example, but not as causing these normally occurring processes. (An exception might be the induction of a process which is normal in some organisms but happens to be unusual or does not occur in the particular test organism. For example, flowering might be induced in a plant species or variety which ordinarily seldom or never produces flowers but repro- duces only vegetatively; the induction of flowering on such a plant by a test compound might reasonably be coded by Symbol 7 of Field T- 1 . ) It is possibly more easy to discern the inappropriateness of using Symbol 7 with terms such as size of fruit, blood pressure, clotting time; these are not "caused" but are only "affected" (increased, decreased, or stopped) by test compounds. Even if these normal conditions and processes have been made abnormal by a pathology (i. e. , if that normal condition or process coded in Field T-2 is understood to have been rendered abnormal and is a symptom of a more general disease, because Field E is coded with a pathology symbol), Symbol 7 would never be appro- priate; in other words, if a normal process has been stopped as a result of the pathology coded in Field E, Symbol 7 should never be used to indicate that the test compound initiated the process again; this is done only by Symbol L or of Field T-l. It is with the second category of Field T-2 items (those whose definitions identify them as definite pathological states or processes) that Symbol 7 is properly used, but only when Field E is not coded with a pathology. Even under the condition of the test organism being in another, pre-existing pathological state, and even if the test compound had been administered with the intent to treat the pre-existing pathology, the pre-existing state would not be coded in Field E in the code line recording the test compound's action in producing (Symbol 7) a second pathology. Instead, the test organism would be coded in Field E and Field G would record the organism's being in an unspec- ified pathological state. Thus, if Field E is coded with a pathology of a host in Field J, any patho- logical aspect coded in Field T-2 must have been caused by that pathology in Field E; it can only be corrected or exacerbated by the test compound, the correction or exacerbation being indicated by Symbol 1, 2, or 3 in Field T-l, never by Symbol 7. Therefore, in general (see exceptions described below), Symbol 7 is used only to code the test compound's causing a pathological state which can be coded in Field T-2 with a symbol whose definition is explicitly of a pathological nature (i. e. , a Field T-2 item of the second category described above); the pathological state will be coded as having been caused in a test organism coded in Field E. Exceptions to the restrictions in use of Symbol 7 as just described (for causing a pathological state or process defined precisely as pathology by the symbol in Field T-2 and with Field E coded with the test organism) are described below, involving Field T-2 symbols of the following series: 16--, 17--, FE--, FF--, F6--, F8--, F9--, FA--, FB--, FC--, FG--, FH--, and FI--. 119 FIELD T-l Column 57 Symbols of the 16-- and 17-- series of Field T-2 are used when a pathology is coded in Field E, but they are somewhat unique in that they do not represent a pathological state (i. e. , they do not represent a symptom of the pathology coded in Field E). Instead, they represent a state (e. g. , "cure", "restraint", or "intensification") or symptom (e. g. , "reduction [or increase] of the number of pathogen individuals") of recovery from or of exacerbation of the general pathology coded in Field E. With any of these symbols in Field T-2, Symbol 7 is used in Field T-l, even though Field E is coded with a pathology, to code the test compound's "bringing about" that state of recovery or exacerbation. Symbol 7 is used to describe what is essentially an action of the biological system on the test compound (rather than an action of the test compound on the biological system), a use which is described in Division 2. This represents an exception to the general rule that Symbol 7 is never used when Field T-2 is coded with a symbol defined as a normal physiological process. These Field T-2 items deal with the alteration of the test compound or a secondary compound by the biological system (Symbol series FE--) or with the synthesis or metabolic fate of the test compound or secondary compound (Symbol series F6--, F8--, F9--, FA--, FB--, FC--, FF--, FG--, FH--, andFI--). When the test compound has been altered, synthesized, or metabolized, Field T-2 is coded with the appropriate term (FE--, FAB, FBB, FGB, FIB, or FF-B) and Symbol 7 is used in Field T-l to mean that the test compound "is oxidized", or '4s excreted" or "ij> stored", etc. (i. e. , "undergoes oxidation" or " undergoes excretion" or " undergoes storage", etc. ) by the normal organism coded in Field E. When the test compound affects the alteration, synthesis, or metabolism of a secondary compound, Field T-2 is coded with the appropriate term (FE-- with an asterisk in Column 61, F6-, F9-, FA-, FB-, FG-, FH-, FI-, or FF--) and Field T- 1 is ordinarily coded with Symbol 1, 2, or 3, since the affect is generally one of increase, decrease, or arrest. However, it is possible that the test compound may initiate or permit the alteration, synthesis, or metabolism of the secondary compound and for this Symbol 7 would be used. 12. Symbols 8, 9, and C; coding of the test compound's influence (Field T-l) on the action (not coded) of another compound (Field D) on a biological state or physiological process (Field T-2); depression ("antagonism") or enhancement (either "synergism" or simple "additive effect"); Symbols 9, 8, and C, respectively Five general aspects of experimental data demonstrating synergism, antagonism, or additive effect (Symbols 9, 8, and C) are dealt with in this division. (A related aspect, which might be con- sidered a sixth, is that concerned with coding of a test compound's being essential for or permitting the action of a secondary compound, coded by Symbol 8; to avoid making further complex the distinc- tions made here in Division 12, this matter is discussed separately as Division 13. ) These five are: (1) Definitions, according to which the test compound's effect can be distinguished as one or the other of antagonism, synergism, or additive effect. (2) Determination of which compound, of the two compounds involved in such investigations, should be coded as the test compound and which should be coded as the secondary compound. (3) The use of Field T-l to code these effects on the action of a second compound, a use which prevents coding that action affected. This problem includes the aspects of preparing code lines for recording the action antagonized , synergized , or supplemented , as well as the action of the antagonist , synergist , or additive agent when administered alone. (4) Coding when a compound is tested to affect (synergize, antagonize, or be additive in affecting) the synergistic or antagonistic effect of a secondary compound on a third compound's action on the biological state or physiological process coded in Field T-2. This coding procedure is dependent on factors and procedures related to the third aspect above. (5) The criteria (Field X) by which each of these three influences of test compounds (on actions of secondary compounds) can be evaluated (Field Y). - 120 - 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 - 121 - FIELD T-l Column 57 relative quantities of the test compound and secondary compound involved] have been felt insufficiently developed and too complex to include in the present edition of the Code. ) (2) Additive effect (See Figure 1. ): The intensity of action, when the compounds are administered together, is equal to or not significantly different from 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 C. Example: Consider the example used above to illustrate synergism: If the intensity of response when the two compounds were administered together were 50%, or not significantly greater than or less than 50%, the test compound's influence is interpreted as an additive effect. Note the following special situation and the provision for it: If the intensity of response when the two compounds are administered together is not as great as the sum of the re- sponse intensities when each is administered alone, yet is more than the intensity of response of the compound coded as the secondary compound when administered alone, the CBCC uses Symbol C. In the example used above to illustrate synergism: If the intensity of response when the two compounds administered together were of any degree more than 40% and less than 50%, the CBCC would code in Field T-l the effect or influence of the test compound on the action of the secondary compound as being "additive with the secondary compound", using Symbol C. However, if the intensity of response when the two compounds are administered together is not only less than the sum of the response intensities of each when each is administered alone, but is less than the intensity of response of the compound coded as the secondary compound when administered alone, the CBCC interprets the test compound effect as antagonism (Symbol 9), described below (B, I, [2]). II. Actions of the test compound and secondary compound when administered alone are NOT KNOWN to be the same (are not known to be the same or opposing) and/or intensity of action of the test compound when administered alone is NOT KNOWN. (See Figures 2 and 4. ) If the intensity of action of the secondary compound when administered alone is known, and the action of the test compound is known to be the same as the action of the secondary compound (Figure 2) or to be the opposing action (Figure 4), but the intensity of action of the test compound is unknown (both Figures 2 and 4), it can not be determined, when the intensity of response to the secondary compound is enhanced, if the influence of the test compound is synergistic or merely additive. In such cases (when the intensity of response to the secondary compound is enhanced), the CBCC has established the convention of coding Field T-l with Symbol C; i. e. , treating the data as additive. Under these circumstances, the written abstract should make clear in Field T- 1 that the test compound's being additive or synergistic has not been determined: If only one word is written in Field T-l, it should be "increase", rather than "additive", even though Symbol C is entered in the code box. Evaluation of additive effect: When a code line is constructed for recording specifically the fact that the two compounds administered together produce a response that is additive (i. e. , one compound does not synergize or antagonize the action of the other), there is a peculiar problem of evaluation in Field Y, since the quality of "additiveness" can scarcely be described in degree. Only Criterion 01 can be used in Field X when Field T- 1 is coded with Symbol C. However, because of the special provision, described in I (2) above, for using Symbol C under circumstances when the intensity of response to both compounds administered together is to a limited degree less than precisely additive, Field Y is coded in the following various ways: When the results are exactly additive (i. e. , an actual additive effect; for example, 50% in the illustration of A, I, [2]), it is indicated in Field Y by using Symbol 9 (Symbol C in Field T-l). On the other hand, if the response when the two compounds are administered together is only slightly more than the response of the most active of the compounds when - 122 FIELD T-l Column 57 administered alone (only slightly more than 40%, in the foregoing illustration), Field Y is coded with Symbol 3. Otherwise (42% through 49%, in the foregoing example), Field Y is coded with Symbol 0. Finally, in the event that response intensity should be only exactly equal to that of the most active of the compounds when administered alone (exactly 40%, in the foregoing illustration), Field T-l should be coded with either Symbol C or Symbol 9 and Field Y should be coded with Symbol 1 (with Criterion 01 coded in Field X) to indicate that the additive or antagonistic effect did not occur. Field T-l need not be double coded nor two lines prepared in this case, because by coding the fact that one (C or 9) occurred, it is implicit that the other (9 or C) did not occur. B. The test compound depresses the intensity of the organism's response to the secondary compound, as compared to the intensity of response when the secondary compound is administered alone. I. Specific action and intensity of action of each compound (of the two compounds involved), when it is administered alone, is KNOWN. (See Figures 1 and 3. ) If the intensity of action of the secondary compound when administered alone is known and the intensity of action of the test compound when administered alone is also known, it can be determined (when the two are administered together, each in the same quantity as when it was administered alone) whether the test compound's influence is one of antagonism to the secondary compound's action (Symbol 9). Antagonism of a secondary compound's action may be by a test compound which, when administered alone, performs the same action (though not to the same degree) as the secondary compound (e. g. , both increase or both decrease the biological state or physiological process coded in Field T-2) or the antagonism may be by a test compound which, when administered alone, performs the opposing action (one compound increases and the other decreases the biological state or physiological process coded in Field T-2, when administered alone). Antagonism is described below (1 and 2) for each of these situations. (1) Antagonism, when the test compound and secondary compound produce opposing responses when administered alone. (See Figure 3. ) If, when administered together, the response is the same as when the secondary compound was admin- istered alone, but at a lower intensity , the effect of the test compound is coded as antagonism; also, if no response occurs when the two are administered to- gether or even if a response occurs opposite to that made to the secondary compound when administered alone, the effect of the test compound is coded as antagonism. Note: In reference to the last- mentioned circumstance (when the response to the two compounds administered together opposes the response to the secondary compound when administered alone), the results should be coded as antagonism of the secondary compound as long as the intensity of that opposing response is equal to or less than the intensity of response to the test compound when administered alone. However, when the intensity of that response opposing the secondary compound's is greater than the intensity of response to the test compound when the test compound is administered alone, a second code sheet should always be prepared on which a code line is constructed whereby the secondary compound of the first line is coded as the test compound synergizing the action of the compound coded in the first line as the test compound. This is indicated by Figure 3. (2) Antagonism, when the test compound and secondary compound cause the same response but in different intensities when administered alone or when the test compound did not affect the biological state or physiological process of Field T-2 when administered alone . (See Figure 1. ) If the intensity of response, when the compounds are administered together, is less than the intensity of response to the secondary compound when administered alone, the effect of the test compound is coded as antagonism. 123 - FIELD T- I Column 57 Evaluation of antagonism : For this, Criteria 22 and 55 may be used, if the intensity of response has been reduced to zero (in case the test compound did not produce the response when administered alone) or if the intensity of response when the compounds are administered together is not greater than the intensity of response when the test compound was administered alone (if the test compound did produce the response when administered alone). Either of these intensities of antagonism represents 100% antagonism of the secondary compound's action for which Criteria 22 and 55 are defined. If the intensity of response to the two compounds administered together is more than the intensities just described (0 or more, but no greater than the intensity of response to the test compound when administered alone), Criterion 62 must be used. II. Intensity of action of the test compound, when administered alone, is NOT KNOWN and the action of the test compound is NOT KNOWN to be the same as or to be opposite to the action of the secondary compound. (See Figure 4. ) This situation is discussed above under heading A (A, II). If the intensity of response, when the two compounds are administered together, is greater than the intensity when the test compound is administered alone, the CBCC codes the compound's effect as being additive, Symbol C. If the intensity of response is less than the intensity when the secondary compound is administered alone, the CBCC codes the test compound's effect as being antagonism of the secondary compound, even if the action is opposite to that of the secondary compound when administered alone. Evaluation of the additive effect or of the antagonism is according to the explanation made above, following A, II and following B, I, (2). The four figures on the following page are included to assist the coder in understanding the foregoing explanations of antagonism, synergism and additive effect. The second aspect of coding synergism, antagonism, and additive effect, listed at the beginning of this division, is that of determining which, of two compounds administered together, shall be coded as the acting agent (test compound, synergist, antagonist, or additive agent) and which shall be coded as the affected compound (secondary compound, synergized or antagonized compound, or compound whose effectiveness is merely supplemented, any of which would be coded in Field D) or, particularly in the case of synergism and additive effects, whether each of the two compounds should be considered in turn as the synergist or additive agent. In most cases of antagonism (Symbol 9), the choice is not the coder's responsibility and has been stipulated by the author. Ordinarily, a compound candidate for antagonism of another compound is one that, when administered alone, causes no response or causes the response at a considerably lower intensity than do the compounds it is expected to antagonize. In any case, only one of the two compounds is to be regarded as the antagonist and only one line is to be coded. When synergism (Symbol 8) has been demonstrated, it is frequently impossible to ascribe the increased intensity of action of the two compounds administered together to one or the other of the two, even if one of the compounds were inactive when administered alone; i. e. , it is frequently impossible to discern which compound was synergized and which acted as a synergist. In the case of an additive effect (Symbol C), there is no real discrimination between the two compounds as being either the compound whose action was added or the compound whose action was added to . Nevertheless, the CBCC does not prepare a code line (on a second Code Sheet) for the second- ary compound in which that compound would be coded as the test compound synergizing or adding to the action of the compound coded on the first Sheet as the test compound. The CBCC restricts this coding to a single line by selecting only one of the compounds to be coded as synergist (or as a compound showing additive effect). With respect to this selection, if a whole series of chemicals are tested for their synergistic or additive effect with one chemical, the chemicals in the series should be regarded and coded as the test compounds and the single chemical against which they are tested should be regarded and coded as the secondary compound. Therefore, if the CBCC files are searched for (1) all activities of given compounds or for (2) all compounds showing synergism or 124 FIELD T-l Column 57 A+ Increase or B Increase or A+B decrease of Syner- decrease of the biological gism the biological Addi- tive state or pro- cess coded in Field T-2: 3__ Addi- tive state or pro- cess coded in Field T-2: B ' \ Antago- nism (A is unknown) Antago- nism response response 1 Figure 1 Figure 2 A+B A+B Increase (or Increase (or ' decrease) of Syner- decrease) of the biological state or pro- gism of B by A the biological state or pro- Addi- tive cess coded in Field T-2: B cess coded B > in Field T-2: N (A is response Antago- V nism response unknown) ; of B Decrease (or Antago- nism Decrease (or i increase) of Syner- increase) of the biological gism the biological state or pro- of A state or pro- cess coded by B cess coded in Field T-2: ' * in Field T-2: J Figure 3 Figure 4 Key to the figures: A — Intensity of response induced by the test compound when administered alone. B Intensity of response induced by the secondary compound when administered alone. A + B Intensity of response induced by the test compound and secondary compound when administered together. Figures 1 and 2: Figures 3 and 4: Figures 1 and 3: Figures 2 and 4: The test compound and secondary compound cause the same response when administered alone (though at different intensities). The test compound causes a response opposite to that caused by the secondary compound (Fig. 3) or the test compound's causing the same or the opposing response to the secondary compound is not known (Fig. 4). The intensity of response to the test compound when administered alone is known. The intensity of response to the test compound when administered alone is unknown. 125 - FIELD T- 1 Column 57 additive effects on a given test compound , it is necessary (and adequate ) to sort for IBM punched cards (and Code Sheets) with those compounds coded in Field D and with Symbols 8 or C in Field T-l; these will represent synergists or additive agents as well as the compounds coded as test compounds on those code sheets and IBM punched cards. For example, if there were wanted all compounds which have been tested as synergists or additive agents for Compound "X", all cards would be pulled for the Compound "X" from the serial file and a sort made for Symbol 8 or C in Field T-l; however, the compound may have been coded as the secondary compound in synergist or additive action tests and therefore the secondary compound file should also be checked for Compound "X" and a sort made in Field T-l for cards coded with Symbols 8 or C. Similarly, if there were wanted all compounds tested as antagonists of Compound "X", it is probable that, to be thorough in the search, the secondary compound file should be sorted for Compound "X" as well as the serial file, followed by a sort in Field T-l for Symbol 9. The third aspect listed at the beginning of the division is that of the inability to code the action of the secondary compound (i. e. , the action on the biological state or process coded in Field T-2) which has been antagonized, synergized, or supplemented; this is because Field T-l is used to code the antagonism, synergism, or additive effect. In support of the omission, it is pointed out that, in many instances, the secondary compound antagonized, synergized, or supplemented and its action on the biological state or physiological process coded in Field T-2 are so widely known (by persons coding data and subsequently correlating the coded data) that the code entries in Field D (the com- pound's identity) and Field T-2 (the biological state or physiological process affected by the secondary compound) are fully adequate to indicate the uncoded action of the secondary compound affected by the test compound. While this is a justifiable concept, and would be especially so in coding projects of limited scope, the wide and varied area which the CBCC attempts to cover does not permit ignoring coding the specific action of the secondary compound in all cases. Therefore, for CBCC coding, some attention must be paid to coding the action of the secondary compound affected by the test compound. Neither does the line in which is coded a test compound's antagonistic, synergistic, or additive effect permit a code indication of the test compound's action when administered alone . This also must be given some consideration. When coding antagonism, synergism, or additive effect, a second Code Sheet is never prepared by the coder to code the action (Field T-l) of the secondary compound, unless instructed to do so. However, the coder should always ascertain that a line is constructed for the test compound (antagonist, synergist, or additive agent) to accompany the line coded with Symbol 8, 9, or C (on the same code sheet), to code the test compound's action, when the data are given from a test demonstrating that action , on the biological state or process coded in Field T-2. This is because the compound tested as an antagonist, synergist, or additive agent is less apt to be a compound whose action is already recorded in the CBCC files and without such a code line, it would not be possible to retrieve data from the file basing a sort on that test compound's action on the biological state or process. The following example illustrates coding as just described. The example concerns an additive effect but it also illustrates the basic pattern for synergism and antagonism: Compound A and Compound B have an additive effect in reducing heart rate. Compound A reduced heart rate 5% when administered alone at 200 mg/kg and Compound B reduced it 10% when administered alone at 50 mg/kg. When Compounds A and B are administered together, each at the same dose level as when administered alone, the heart rate is reduced 15%. Selecting Compound A as the test compound: D N T- C 1 T-2 CI X Y Line 01: Cpd. B 67 01 9 Line 02: 67 ?, CI 62 (A line for these data might be constructed at the Center [not by the coder] for Compound B, on a second Code Sheet, identical to line 02 above [except for the Field N entry, which would be 66]; however, for the latter compound on the second Sheet, no "additive" code line would be prepared. ) Although the situation outlined as the fourth aspect at the beginning of this division occurs infrequently, it is not unknown; the CBCC has had to establish a coding precedent for it at least to indicate that two compounds were demonstrated to be additive in antagonizing the action of a third compound. - 126 - FIELD T- 1 Column 57 The following example illustrates the coding for the data of the type just described. Indole and skatole have an additive effect in inhibiting contraction caused by acetylcholine. (No other information is given. ) Selecting one ( indole ) of the two compounds (indole and skatole) as the test compound, the coding is as follows: __D T-l T-2 X Y Skatole C 813 01 In the language portion of Fields T-l and T-2 of the line above, write, "Additive with skatole in antagonizing muscle contraction caused by acetylcholine; see the line below. " A second line for that compound selected as the test compound (indole) would be constructed on the same Code Sheet, in the following pattern: D T-l T-2 X Y Acetylcholine 9 813 01 In the language portion of Field T-2 of the second line above, the following should be written: "Muscle contraction caused by acetylcholine; when administered with skatole, this activity for the two compounds is additive; see the line above. " (In addition to the two lines coded above for these data, a second Code Sheet is prepared especially for skatole to code a line identical to line 02 above. A second line on this second Sheet for the "additive effect" with indole will not be coded. The CBCC probably would find unnecessary preparing a third Code Sheet to code acetylcholine's action, "causes" [Symbol 7], on muscle contraction. ) Occasionally, evaluation of a synergistic or antagonistic action is made on the basis of comparison with a standard compound (Criterion 03 or 04 of Field X), resulting in competition for the use of Field D to code the antagonized or synergized compound as well as the standard compound to which comparison is made. This is resolved by coding two lines, both with Symbol 8 or 9 coded in Field T-l but with Field D coded differently; in one line, Field D is coded with the compound synergized or antagonized and evaluation is based on Criterion 01 only; in the second line, Field D is coded with the standard compound, Symbol * (the IBM 12 zone punch) is coded in Column 17 of Field D, and Field X is coded with Criterion 03 or 04. (See the specific directions and explanations for Field D, Division 11, Conflict B. ) 13. Coding of the test compound's being essential for (permitting or initiating) the action of the secondary compound The situation in which a compound shows no biological activity until it is administered with another compound is closely related to the situation in which the first compound does show biological activity when administered alone but is synergized by the compound administered with it to produce a much greater intensity of biological response. The CBCC uses Symbol 8 to code both situations. When a test compound has been demonstrated to be essential for (permit or initate) the alteration, synthesis, or metabolism of a secondary compound, Symbol 7 is used as explained in Division 1 1. 14. Symbol A; coding of the test compound's simulation of, or substitution for (replacement of) , a second compound coded in Field D Two compounds may affect a biological state or physiological process in a nearly identical fashion, even though their potencies for producing this effect may differ; in this respect, each can be considered as simulating the other. Ultimately, using this basic concept, all compounds shown to affect a given biological state or physiological process (e. g. , heart rate or smooth muscle con- traction) in the same way (e. g. , all compounds that increase h eart rate or all compounds that cause smooth muscle contraction) might be said to simulate each other with respect to this biological re- sponse. Most frequently, however, it is a relatively unknown or untried chemical that is described - 127 - FIELD T- 1 Column 57 as simulating, by its action, a chemical whose action is already familiar to the author or is widely known. Many compounds will come to mind whose actions have been so long observed and so thoroughly measured that their actions are virtually classic standards. Examples of these are the best known effects of digitalis, adrenaline, acetylcholine, curare, etc. However, compounds that are less familiar than the examples named may be demonstrated by test data as being simulated by the test compound. Besides considering "simulation" as restricted to comparison to chemicals whose simulated action has previously been investigated and understood, it should be noted that generally an author implies by the term "simulation" that the two compounds act through the same mechanism (i. e. , act through the same anatomical, physiological, or biochemical paths) to bring about the specific response such as reduction of heart rate, lowering of perspiration rate, increase of blood pressure, etc. Neither of these restrictions to the use of the term "simulation" for description of chemicals' actions is absolute, but they are mentioned here to help explain that merely because two compounds cause the same response, they are not always (or even frequently) specially described by an author as simulating each other except when, by doing so, it assists significantly in describing a test compound's action. Symbol A has been provided to code the fact that the test compound's action on the biological state or physiological process coded in Field T-2 is essentially similar to the action of another compound, to be coded in Field D. Simulation, as well as replacement, is ordinarily (although not necessarily always) expressed by an author only under the restrictive conditions mentioned in the first paragraphs of this division. Therefore, Symbol A is used only when an author states that the test compound has been demonstrated to simulate or substitute for a specific secondary compound. Simu- lation is sometimes expressed by the author with one of certain terms referring to a specific chemical and implying all aspects characteristic of its action, such as "nicotinic", "muscarinic", or "atropinic", For such data, nicotine, muscarine, or atropine would be coded in Field D and Symbol A would be coded in Field T-l, assuming that the nicotinic, muscarinic, or atropinic effect was on a specific biological state or physiological process coded in Field T-2. In case the author uses such terms to describe a test compound's general effects on an organism without specifying a biological state or process affected, this general simulation is not coded with Symbol A, but the general effect is coded in Field T-3, if the appropriate term is available in Field T-3 (nicotinic effect, atropinic, etc. ), Field T-2 is coded with Symbol 14 which refers to Field T-3, Field T-l is coded with Symbol 7 instead of Symbol A, and it is unnecessary to code in Field D the compound simulated. When the compound simulated is a normal constituent of the organism or an essential dietary component and the simulation is the test compound's ability to substitute adequately for that normally occurring compound, the test compound is more frequently described as functionally "replacing" that secondary compound than as simulating it. Each time the evaluation of a test compound's action is expressed in terms of comparison to a standard (Criteria 03 or 04 of Field X), the situation involves two compounds that simulate each other, even if their potencies for the action they both perform are not the same. Although Criteria 03 and 04 (Field X) necessarily involve two compounds simulating each other, they can not be used for evaluating that simulation or replacement (i. e. , when Field T-l is coded with Symbol A); in the reverse, when evaluation of a test compound's action is made on the basis of Criterion 03 or 04, Symbol A should not be substituted in Field T- 1 for the action being so evaluated. Note that by using Field T-l to denote that a test compound's action simulates or replaces, there is omitted any specification of the actual action performed and simulated. Therefore, a problem exists similar to the problem of not being able to code the action when Field T-l is coded with Symbol 8, 9, or C, discussed in Division 12. When Symbol A is used to indicate that the test compound replaces a normal constituent or dietary component, the role that constituent or dietary component normally plays in the organism need not be recorded and therefore a second line especially to code this is not constructed. However, when Symbol A is used to indicate that the test compound action simulates the action of a secondary compound which is not a normal constituent or dietary component, the action simulated is not to be construed by the CBCC coder as always obvious to every potential user of the coded information. When 128 FIELD T- 1 Column 57 the data include description of the action as well as the stipulation that the action simulates that of a second compound (instead of indicating only the fact that the test compound simulated the second), a line should be constructed to code this action of the test compound on the same Code Sheet. 15. Symbols D, E, F, and G; coding of the test compound's influence (Field T-l) on the action (not coded) of a nerve (Field H) on a physiological process (Field T-2) In the same way that a test compound may alter the action of a secondary compound (see Division 12, Symbols 8 and 9), a test compound can influence the action that a specific nerve has on a given biological part or process. Examples of such processes controlled or affected by nerves are heart rate (Field T-2, Symbol CI), vascular dilation (Symbol 8215), gland secretion (Symbol FC), skeletal muscle contraction (Symbol 813), etc. When a test compound intercedes in this nervous control or nerve effect, it should be coded specifically as such. The situation exists particularly in the case of those tests using anatomical preparations (frequently in vitro ) which consist of an effector end organ (heart, skeletal muscle, gland, etc. ) and its controlling anatomical nerve. The normal nervous effect on the end organ is demonstrated and measured by artificial stimulation of the nerve; subsequently, the test compound is administered, its effect being interpreted as the alteration of the degree of the end organ's response to the nerve, when the nerve is given a stimulus equal to that stimulus administered prior to administration of the chemical. For such special data, four symbols are provided, D, E, F, and G. Symbols D and E are used to indicate that the test compound acts to inhibit the nerve's normal action; Symbols F and G are used to indicate that the test compound acts to intensify the nerve's normal action. It will be recalled that, in the case of coding a test compound's effects on a secondary compound's action (e. g. , Symbols 8 and 9 of Field T-l), the secondary compound's action can not be coded; similarly, when coding a test compound's effect on the action of a nerve, there is no special coding field in which to code the nerve's normal action. This disadvantage, however, is largely compensated for by having two symbols for each of inhibitory and intensifying chemical action, one symbol (D or F) indicating that the nerve normally increased or caused the biological process coded in Field T-2, the other symbol (E or G) indicating that the nerve normally inhibited or prevented the biological process. Use of these symbols and coding of chemical effects on nerve actions on end organs is dis- cussed in Division 8 of Specific Directions and Explanations for Fields H-l and H-2. 16. Symbols J, K, L, M, N, and 0; coding of the test compound's ameliorative or curative action on a pathological state or process, coded in Field T-2 as a symptom of a disea se coded in Field E; return of the test organism to a normal state The coding of pathology is dealt with extensively in the Key section on the Pathology Code of Field E, as well as in certain previous divisions of these specific directions and explanations for Field T-l (Divisions 7, 8, and 11). In the section of the Pathology Code, it is explained that the CBCC takes advantage of Field T-2 to code specific symptoms of general pathological states coded in Field E, when the response of those specific symptoms represents the test compound's effect rather than the response of the entire symptomatology of the disease. As has been pointed out in previous divisions (especially Divisions 7, 8, and 11), the items of Field T-2 are of three categories. Of these, the two major types (distinguished in Divisions 7 and 8) are: (1) Those representing normal states or processes that can be affected by test compounds or by pathologies coded in Field E. (2) Those that represent pathological states or processes that can be caused by the test compound or treated by the test compound. The third category (described in Division 11) consists of Field T-2 terms representing stages of cure or partial recovery from a disease coded in Field E (Field T-2 items of the 17-- series) or stages of exacerbation of a disease coded in Field E (Field T-2 items of the 16-- series), all of which are coded only with Symbol 7 of Field T-l. 129 F IELD T-l Column 57 The coding of the test compound's producing a pathological state is discussed in Divisions 7 and 11: In coding the test compound's production of a pathological state or process (Symbol 7 of Field T-l), only those items of Field T-2 may be used which are of the second category described above. When a pre-existing pathological state (coded in Fields E and T-2) is treated with the test compound, Field T- 1 must be coded distinctively to indicate that the compound did not cause the pathology. The following paragraphs describe this specific coding. If the entire disease, as is coded in Field E, responds to the treatment, Field T-2 is coded with the appropriate symbol of the 17-- and 16-- series (the third of the categories of Field T-2 items) and Field T-l is coded with Symbol 7. However, if only the pathological symptom of the general disease coded in Field E responds to the treatment (this symptom being coded in Field T-2 as one of either the first or second categories of Field T-2 items), Field T-l must be coded to indicate the effect on that particular pathological state in returning it to normal ( curing it or stopping totally progress of a morphological change, even though morphologic normality is not restored), returning it toward normal (improving the organism's condition or restraining the progress of the pathology, but not curing it or not stopping totally progress of a morphological change), or worsening the condition ( exacerbating the pathological state). The coding of Field T-l to indicate a test compound's effect on a pathological symptom coded in Field T-2 depends on the category of the Field T-2 terms to which the symptom belongs, as follows. If the pathology symptom is one of the second category of Field T-2 items (i. e. , an item specifying pathology, such as apnea, anemia, etc. ) and if only the symptom coded in Field T-2 re- sponded to the test compound, the test compound's effect is coded by Symbols 1, 2, or 3. Partial reduction or arrest of progress but not a cure of the pathology symptom is coded by Symbol 2 of Field T-l (reduction of dyspnea, pain, anemia, or atrophy, e.g.); cure, total reduction, or prevention of the pathology symptom coded in Field T-2 or restoration of a pathologically totally suspended physi- ological process, is coded by Symbol 3 of Field T-l ( cure of or prevention of abscess, inflammation, or ventricular fibrillation, e. g. ; complete stoppage of necrosis; restoration of normal function from states of sinus arrest or respiratory arrest, e. g. ); and exacerbation of the symptom is coded by Symbol 1 ( increase of irritation, degeneration, edema, e. g. ). Note that if a test compound causes (Symbol 7 of Field T-l) a pathological state indicated by one of these Field T-2 items of this second category when it is administered to treat another pre-existing pathology, the pathology produced by the compound is not to be coded as a symptom of a disease coded in Field E; instead, the host of the general pathology is coded in Field E as the test organism and Field G is coded to indicate the fact that the organism is in an unspecified pathological state in which the test compound causes the pathological condition to be coded in Field T-2. If the pathology symptom is one of the first category of Field T-2 items (i. e. , an item describ- ing a normal biological condition or process) and if only the symptom coded in Field T-2 responds to the test compound, the test compound's effect must be coded by one of a group of symbols provided in Field T-l especially for this purpose. These are the nine symbols indicated on the IBM punched card by the 1 1 zone punch (Symbols J through R), J, K, and L being for curative effects, M, N, and for effects in improv