Safe Use of Pesticides in Food Production; a Report [by] W.J. Darby, Chairman ... [Et Al.] (1956)

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the more toxic compounds are quickly destroyed through chemical change or lost through decomposition or evapora- tion. The magnitude of the residue on edi- ble portions of the crop must be deter- mined before hazard can be estimated. The factors influencing amount of resi- due may be summarized as follows: 1. Rate of application, i.e., magnitude of initial deposit 2. Time of application relative to: a. Development of edible plant parts b. Exposure of edible parts to treatment c. Time elapsed between last ap- plication and crop harvest 3. Rate of loss of a pesticide deposit from the plant a. Rate of decomposition or degra- dation of active ingredient as affected by: (1) Fluctuations in tempera- ture, moisture, sunlight (2) Plant secretions b. Rate of evaporation of volatile materials as affected by envi- ronmental conditions c. Rate of erosion of residual de- posits as affected by: (1) Rainfall (2) Wind 4. Dilution due to growth of plant 5. Adherence to "or absorption by plant parts 6. Efficiency of residue removal meth- ods and extent of their use 7. Miscellaneous practices in applica- tion a. Effect of changes in formulation on any of the listed factors b. Number of applications and, particularly, the date of last ap- plication THE PROCESS OF DISCOVERING AND DEVELOP- ING A SAFE PESTICIDE Chemicals for use in agricultural pest control are discovered by extensive test- ing of materials from four sources: 1. Inorganic compounds usually con- taining a metal or sulfur but no carbon or nitrogen 2. Synthetic organic compounds con- taining carbon, hydrogen, oxygen, nitrogen, sulfur, phosphorus, and the halogens in various combina- tions of two or more elements 3. Antibiotics produced by molds or bacteria. These are organic chem- icals, usually of complex composi- tion. 4. Products of higher plants Several years have elapsed since a major new pesticide from higher plants has been introduced into commercial usage. The antibiotics have just begun to be used, and few are on the market for use as pesticides. The inorganic pes- ticides dominated the field from 1880 to 1940, but practically no new ones are being proposed for use at this time. The use of synthetic organic pesticides has grown continuously since their use- fulness was established in the period 1934-1942. Almost limitless possibilities are available in developing new types of organic chemicals. Many classes of com- pounds are available to work upon, and the chemist can modify the chemicals so that they will have subtle differences in biological activity. Jt may be possible, therefore, to develop additional useful fungicides, insecticides, nematocides, and herbicides by accentuating their ability to kill plant pests and by sup- pressing the tendency to kill or injure the crop. It is likely that extensive ex-

ploration of the field of organic chem- istry for safer, more effective pesticides will go on for several decades. These are the chemicals that dominate our think- ing as we try to formulate policies for encouraging the orderly development and safe use of agricultural chemicals. Several companies ordinarily test 1000 to 3000 new organic compounds for pes- ticidal properties each year. By the best estimates available only about one of each 2000 candidates proves to be com- mercially acceptable. By the time one successful compound is conceived of by a chemist, evaluated by a biologist, synthesized commercially by chemical engineers, evaluated for field perform- ance by industry and public agencies, certified for activity by government, and shown to be safe for use, a bill of one to two million dollars may have been incurred. This includes not only the actual cost of the one successful com- pound but also the costs incurred by all the failures encountered. The items of cost vary widely for different compounds, but reasonable esti- mates for various items are about as follows. The cost of synthesizing each compound will be $350 to $500. A series of thorough laboratory and greenhouse tests made upon it will cost some $200 to $350. The more promising survivors will have to be subjected to small-scale, replicated field trials for the particular use under consideration. Each such test involving comparisons with standard commercial products will cost $500 to $2000. The test must be repeated at least once in the season and in two geographic areas before an adequate ap- praisal can be assured. Since local weath- er and other crop production conditions may frequently defeat the purpose of the test, many tests must be repeated. If the material survives the small-plot tests, its sponsor may then consult re- search specialists in the state experi- ment stations, the U. S. Department of Agriculture, and elsewhere on the po- tential usefulness of such a material. He may provide them with samples for study in relation to problems peculiar to their geographical regions. The produc- tion of these experimental quantities of the material and the collection and in- terpretation of data from perhaps scores of collaborators will cost $3000 to $40,000. If the collaborative testing ex- tends over several years, the cost will be much higher than indicated. This in- vestment provides the sponsor with data confirming or contradicting his own ob- servations, data on a wide variety of pests to determine the scope of useful- ness of the material, and observations on the effect of local climate and soil con- ditions on its performance and safety. Before the sponsor of a chemical en- ters into this collaborative period with state and federal agencies he must make certain policy decisions and commit- ments. First, he must decide whether the material has a chance of competing with other pesticides on the market. If it is likely to be too expensive at the dosage indicated in his preliminary trials as necessary for pest control, he must abandon it or delay field research until he has found a cheaper method of manufacturing it. Second, he must be- gin research on process development. This will cost $10,000 to $500,000, de- pending upon the complexity of the molecule and the physical conditions necessary to synthesize it and purify the final product. Third, he must develop analytical methods to check the purity of the pesticide in the factory and to de- termine residues in or on foods. Often the residue method will have to be sensi- tive to as little as 0.02 parts per million in or on a product. A cost of $1000 to $25,000 may be anticipated. Fourth, he

must initiate studies on toxicology. These will cost about $3000 in the pre- liminary stages and will extend to $30,000 to $50,000 if the entire battery of tests is completed. It is obvious that the policy decisions at this point are difficult because of the magnitude of the expenditures involved and the many intangible factors that lie ahead and cannot be appraised. Us- ually a stepwise program of research is started simultaneously on field perform- ance, process development, analytical methods, and toxicology in such a man- ner that the entire program can be abandoned or accelerated as indicated by available information. The initial toxicology tests should be made as early as possible and before a chemical is placed in pilot plant or fac- tory production or is given to outside collaborators. The initial program con- sists of dermatological tests, first on ani- mals then on human subjects, and acute toxicity tests on animals to determine the minimum lethal dosage by mouth. These two tests will indicate whether extreme hazards are likely to be involved in routine field trials on small plots. Fur- ther knowledge of toxicity is not neces- sary at this time, since all produce from the plots will be discarded or used for laboratory testing for residues and none will be used for human food or livestock feed. After extensive small-plot field trials have indicated that a material is an effective pesticide and may be com- mercially developed, it should be sub- jected to feeding tests on animals to de- termine subacute and chronic toxicity. While the chronic toxicity tests are in progress, analytical procedures must be perfected and data obtained on residues remaining in or on the edible portions of various crops at harvest time. It is expected that residue data will be ob- tained for plants treated so as to control the pest under representative conditions. At the end of this period of evaluation, sufficient data may be available to war- rant initiating large-scale field trials on representative farms and to place the new product in the hands of a few farm- ers in each of several localities for their appraisal. In this intermediate stage of product development, testing under farm conditions is absolutely essential for de- tecting any flaws that would prohibit the practical use of the product. Since in these tests the product will be used on marketable crops, it must first be ap- proved for this use by the regulatory agencies. A limited license for experi- mental use may be granted at this time if adequate data are available to assure the responsible officials that the mate- rial is safe and sufficiently promising to warrant extensive trials. However, more residue data from the proposed field trials may be required before release of the material for unrestricted com- mercial use is approved. This explora- tory period provides an opportunity under closely supervised conditions to perfect the use of the product and assure its safety. The series of steps described above may be summarized graphically as oc- curring in six stages according to the scheme shown on the following page. DATA REQUIRED BEFORE MARKETING A NEW PESTICIDE The manufacturer of a new pesticide and the appropriate regulatory agencies must assume certain responsibilities to the public when the pesticide is placed in commercial use. Government has the responsibility of safeguarding public health and of protecting the public from fraud. It establishes maximum residue tolerances for materials that may pre- sent a hazard to the public if excessive amounts occur on food commodities and 6