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

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enforces compliance with them. It also requires assurance that the material is effective for the use proposed. The manufacturer must assume, in addition to his responsibility with respect to public health, the usual responsibility for performance of the product as claimed. He should be granted reason- able freedom to incur well calculated risks pertaining to crop damage and performance of the material as a pesti- cide. The effectiveness and safety of a new pesticide, when it is used in the pro- posed manner for the specified purpose, must be clearly established before the pesticide is marketed. The chemical and physical properties and the function of the proposed pesticide, its toxicity, both acute and chronic, and time and method of application will determine the amount of information required to establish adequately its effectiveness and relative safety. Data on important points should be of such nature and magnitude as to be reasonably conclusive. The following proposals are presented as both practical and adequate require- ments for the pre-marketing evaluation of a new agricultural pesticide. Many chemicals may have very restricted uses or for other reasons may not require or warrant the thorough investigation in- dicated by all proposals listed. The re- quirements for evaluation can be re- stricted in accordance with proposed uses of the product. I. Chemical and Physical Data Information in conformance with the following should be as complete as pos- sible and should pertain to the commer- cial or chemically pure grade of the pes- ticidal chemical and not to formulations thereof. A. Chemical name and strucutural formula. Trade names, abbreviations, code numbers, and any other designa- tions used to identify the compound in the literature and elsewhere, should be cited. B. Degree of purity of the pesticidal chemical product, with statement of any materials other than the principal active ingredient known to be present in the commercial grade material. C. Physical and chemical properties which may affect use or acceptability, e.g., flash point, freezing point, inflam- mability, taste, odor, color, etc. D. Solubility in water and other sol- vents. Data on solubility in oils, fats, waxes, organic solvents, and body fluids are important. E. Melting and/or boiling point. F. Vapor pressure at 25° C. and over the temperature range of use. G. Other physical and chemical iden- tifying characteristics, including partic- ularly spectra and refractive index. These characteristics are especially necessary if the pesticide is not a pure chemical compound. H. Stability and reactivity. Informa- tion on rate of decomposition before and after application, compatibility with other pesticides, and other reactions of interest to the user, such as corrosion of equipment, reaction with •hard water, etc., is important. I. Suggested analytical methods for macro- and micro-quantities of the ac- tive ingredients, including methods of extraction from plant and animal tis- sues. J. Methods of removal and decontam- ination by physical or chemical proced- ures of residual quantities of the pesti- cide remaining on crops. II. Biological or Use Data Pesticidal effectiveness should be es- tablished in terms of percentage reduc- 8

tion or control of pests, increase in yield or quality of crop, or other economic gain or practical benefit following ap- plication of the specified pesticide under the conditions prescribed, compared with results from standard treatments and/or untreated controls. Examples of economic gains or practical benefits other than pest control are: economy or ease of production, harvest, or storage of the crop; flexibility in time of planting or harvest, even at the possible sacrifice of yield; and general benefit to livestock, plants, or human welfare not necessarily related to yield. A. Establishment of pesticidal effectiveness 1. Laboratory tests. The results of laboratory tests for the effective- ness of the product against the pest in question and related species should be made available. Consid- erable weight should be placed on such tests from the standpoint of the measurements of pest response. Characteristics of the product and its proposed use will largely deter- mine the suitability of such data as a principal basis for evaluations. 2. Small-plot tests. The amount of data obtained in small-plot tests should be adequate to demonstrate performance under natural condi- tions. The proposed use, the nature of the pesticide, the method of ap- plication, and the amount and con- sistency of the data will determine the weight to be given such evi- dence in the evaluation of a prod- uct. Data pertaining to specified uses should be based on tests con- ducted for at least one growing season under environmental condi- tions similar to those prevailing in the area where use of the material is proposed. 3. Large-scale field tests. These should be made on farms, using commer- cial-type equipment under farm conditions. The data obtained in such tests are considered the most reliable indications of how the ma- terial may be expected to perform in practice. Depending upon cir- cumstances and conditions, data from laboratory and small-scale field tests may replace or supple- ment field test data. 4. Supplemental information. Supple- mental information accompanying experimental data should provide a comprehensive description of the material and its use and should in- clude the following points where applicable: a. Names and percentages of ac- tive ingredients and such addi- tional information as is neces- sary for proper evaluation for ultimate commercial use. The public declaration of so-called "trade secrets" as to methods of formulation and minor adjuvant ingredients should not be con- sidered essential. b. Extent of dilution for use c. Rates of application (per acre, per animal, etc.) d. Methods of application e. Pests controlled, prevented, or repelled, or other benefits f. Dates of treatment and dates when results were taken g. Description and identity of plants or animals treated, to- gether with a statement of their approximate development, age, or size when tests were started and when completed h. Identity of application areas and description thereof if neith- 9

er food plants nor animals were treated (barns, ornamentals, etc.) i. Geographical site of the tests j. Identity of persons and organi- zations conducting the tests k. Results in detail, with informa- tion as to the immediate and delayed effects and pertinent data on environmental condi- tions prevailing during the test period B. Safety for plants and animals 1. Plants. Data on plant injury should be collected in connection with the performance tests. If injury oc- curs, careful notation should be made of the type of injury, e.g., stunting, reduced yield, leaf drop, tip burn, spotting of the leaves, etc. Where plant injury seems prob- able, appropriate warnings should be made available. 2. Animals. If the pesticide is pro- posed for use on animals, data should be obtained on its irritant or other injurious properties. C. Compatibility Data on compatibility with other ma- terials are desirable and should be pro- vided where such materials would ob- viously be used in the same spray sched- ule in accordance with recognized prac- tices. D. Reduction in quality of food In connection with the performance tests, observations should be made for any departure from the normal in flavor or appearance which may affect the ac- ceptability of food items. £. Accumulation in soils As a part of the performance tests, observations should be made to deter- mine whether the pesticide is stable and tending to accumulate or unstable and transitory in soils. Observations from laboratory, greenhouse, or small-plot tests will generally be adequate. F. Residues Data should be obtained on the amount of residue remaining on or in foods at harvest under the proposed method of treatment. The amount of such data required will depend upon (1) the recommended use, dosage, and time of application of the pesticide; (2) the acute and chronic toxicity of the chemi- cal; (3) its physical and chemical prop- erties ; and (4) its rate of disappearance. If pesticide residues may be antici- pated on or in the food product at the time of harvest or slaughter, residue data should be established indicating the residue likely to remain after effec- tive dosages of the pesticide have been made under optimum conditions for re- tention and over the maximum time period of application. These data, which may be obtained by analyzing represent- ative crop material harvested from the tests on pesticidal effectiveness, should show the total amount of chemical found on and/or in a stated weight of the food product. Fewer residue data will be required for pesticides that are not toxic to warm-blooded animals at recommended use levels, are highly volatile or other- wise non-residual, or are decomposed to nontoxic components before harvest. If a potential hazard is disclosed by the preliminary data on the amount of residue or the toxicity of the compound, more extensive data on the magnitude of residues remaining at harvest on repre- sentative food crops produced under representative environmental conditions should be obtained. 10

Either chemical or bioassay methods of demonstrated reliability may be used for residue determinations. Methods for removal of excessive resi- dues should be developed. G. Operational hazards Proper precautionary procedures rela- tive to handling and use should be de- veloped. III. Toxicologic Data Many of the pesticides are known to be toxic to warm-blooded animals. Data are needed to provide for: first, a clear understanding of the toxicity of the compound; second, an assessment of the hazard to consumers created by use of the compound to meet specific pesticidal needs; and third, an estimate of the hazard to those who must handle the material in manufacturing, formulation, crop testing, and application. In studies of toxicity, special attention should be given to: (1) uniformity of response within and among species; (2) rate, extent, and mode of detoxification and elimination; (3) tendency toward accumulation in the body; (4) occur- rence of unusual or alarming reactions such as carcinogenesis; (5) occurrence of sensitivity, tolerance, or idiosyncrasy in response to the compound; (6) the possibility of synergistic action; and (7) the possibility of degradation of the compound before ingestion to a sub- stance more toxic than the original. Toxicity must be established in terms of generally accepted indices of injury such as structural, biochemical, and physiologic changes in specific organs or body systems. Toxicity testing is often guided by a knowledge of the chemical or physical properties of the substance at hand and of the effect of substances of similar properties or structure. Tests should be so designed as to emphasize any suspected potential of the substance for injury in order to give as stringent a test as possible. Such considerations may influence the choice of a test animal in order to obtain information in the most sensitive species. The dosage levels investigated should range from an absence of the pesticide in controls through a series of inter- mediate levels and through at least one producing significant effects. The mate- rial should be fed at a sufficient number of levels to determine the maximum level of no response and to indicate the nature of the response at the higher levels. These observations will allow an estimate of safety in the species under study and will serve as a basis for ex- trapolation to the other species. In growth studies, differences may not be interpretable unless caloric intakes are equalized or otherwise taken into ac- count. It is not possible to design a single program that will apply to every pesti- cide in all its applications. As an inves- tigation progresses, data obtained may indicate the advisability of altering the program of study as originally designed. With the above considerations in mind, the following tests are suggested as a program which can be reasonably expected to yield the toxicologic data needed to assess hazard: A. Determination of toxicity 1. Acute toxicity. The approxi- mate lethal single oral dose should be determined in at least three species, at least one of which is a non-rodent such as the dog. This information is of value in planning studies of sub- acute or chronic toxicity and in the recognition of symptoms. Extension of these acute tests may occasionally be desirable. 11

As a basis for estimating op- erational hazards, information should be developed with respect to the irritating and sensitizing properties of the compound. Also, data concerning toxicity by percutaneous absorption and by inhalation should be obtained if there is presumptive evidence of hazard via these routes. The signs, clinical course, gross and microscopic tissue changes, and, if possible, the mode of death should be de- scribed. Surviving animals should be observed until com- pletely recovered. 2. Subacute toxicity a. Oral. Results from a 90-day feeding test with ten rats of each sex at each of several feeding levels may make pos- sible a decision as to whether the proposed use is too haz- ardous to warrant further toxicologic study. The infor- mation obtained may also serve as a guide in selecting feeding levels for the chronic toxicity study. The dose-re- sponse relationship should be examined. The data sought may in- clude, at each of the several feeding levels, the effects on food consumption, growth, mortality, blood and urine composition, and organs as measured by weight and his- topathologic findings. Any al- terations in functions and behavior should be noted. If a known physiologic or bio- chemical system is affected by the pesticide, periodic meas- urements of the cumulative effect on the system should be made. Effects on digestibility and utilization of the ration may be important. The subacute feeding tests with rats may be so designed that enough rats are used at each dietary level to provide animals to be continued in tests for chronic toxicity, in the event it becomes advisable to conduct such tests. b. Percutaneous. As a general rule three or more rabbits are treated at each of several dos- age levels for at least three weeks. The material under study is applied periodically to a clipped area of skin, care being exercised to prevent in- gestion by the animal. Obser- vations as indicated in the preceding section are made of the animals. 3. Chronic oral toxicity. Long-term tests are conducted on the pre- mise that the possible effects of the lifetime ingestion of a pesti- cide in food by man cannot be predicted from results of tests less stringent than lifetime feeding in a short-lived animal (approximately two years in the case of the rat) and one year or longer feeding in the dog or monkey. Obviously, these tests may be either inadequate to the purpose or more exacting than necessary, but past experience has not supplied a more rational alternative. In the tests with rats the ma- terial is fed at selected levels in the diet to groups of 25 or more weanling animals of each sex. The levels to be fed should be 12

chosen on the basis of the data obtained in the subacute feeding tests. The two-year tests may in- clude observations on: food con- sumption; growth; absorption, excretion, and tissue storage of the material; mortality; organ weights; histopathology and he- matology; blood and urine chem- istry; such changes in behavior and function as may be deter- mined by gross observation; and such other effects as may be in- dicated in special circumstances. Effects on ration digestibility and utilization and on reproduc- tion and lactation may be es- pecially significant. In the case of dogs or monkeys, the usual procedure is to feed the material under test to groups of three or more animals at three or more intake levels for one year or longer. Observations are similar to those made in the chronic feeding test with rats. The dog or monkey tests are generally started after the rat studies have been in progress long enough to provide data to aid in selecting the feeding levels likely to be most informative. Where human exposure to the pesticide has occurred, all ap- propriate tests should be em- ployed to determine whether there have been any adverse ef- fects. 4. Pharmacodynamic and biochem- ical investigations a. Pharmacodynamic. The aim of pharmacodynamic tests is to describe the mode of action by which the compound brings about changes in functional systems. There is no succinct way of describing the extent of investigation necessary, this being variable with the systems affected and the technics available for the study of such functional ef- fects. The program should at least provide a basis for the treatment of accidental pois- oning if technically possible. b. Biochemical. These investi- gations should be designed to study the absorption, excre- tion, storage, and metabolic fate of the pesticide. The scope of the investigation will vary from compound to com- pound and with the intricacy of the processes. The minimal program should seek to de- scribe the routes of absorption and excretion, the extent and sites of storage, the rate of release from depots, and the functional implications there- of. Since many pesticides ex- hibit their effects by inhibit- ing enzymatic activity and in other ways interfering with normal metabolic pathways, knowledge of the mode of ac- tion may be important. The influence of a pesticide upon the nutritional contribu- tion of the foods in which it may appear must be consid- ered. It is important to ascer- tain the effect of the pesticide on the stability of nutrients in the foods, as well as on the digestibility and utilization of the ration. B. Determination of hazard Once the toxicologic data have been assessed and the toxicity of the com- pound adequately described, there re- 13

mains the task of estimating hazard. Hazard is estimated from knowledge of toxicity and the anticipated levels and patterns of consumption. In order to estimate the probable in- take level of the additive, information on its proposed use is essential. This information includes (a) the amount of the pesticide remaining on foods, (b) the proportion of the usual diet com- posed of foods in which residues of the pesticide may appear, and (c) the ex- tremes of probable intakes of these foods. From this information the maxi- mum potential consumption by individu- als or special groups as well as the aver- age potential consumption for the gen- eral population can be estimated. The translation of toxicologic data into terms of human use levels and mar- gins of safety is one of the most diffi- cult problems in the interpretation of such "data. Each substance presents problems peculiar to itself and requires individual consideration by those compe- tent to exercise objective judgment of all the available evidence. Generally the assumption is made that man is more susceptible to poisons than are the lab- oratory animals. The decision as to a safe level for a pesticide residue in foods should be based upon such factors as the maximum dietary level that produced no unfavor- able response in test animals, the sever- ity of response in test animals at dietary levels above the no-response level, and the estimated potential for human con- sumption of the food or foods for which the additive is proposed. LEGAL PROCESSES FOR PROTECTING THE PUBLIC Legal restrictions on the use of pesti- cides in food production are provided for by the Federal Food, Drug, and Cos- metic Act of 1938 as amended in 1954 by Public Law 518 and in 1956 by Public Law 905, and the Federal Insecticide, Fungicide, and Rodenticide Act of 1947. These two acts recognize pesticides as essential to food production and provide the machinery for establishing non- hazardous tolerances and enforcing com- pliance with them. Before any new pesticide can be moved in interstate commerce it must be regis- tered with the Pesticide Regulation Sec- tion, Plant Pest Control Branch, Agri- cultural Research Service, USDA, under terms of the Insecticide, Fungicide, and Rodenticide Act. The registrant must present data such as those suggested in the preceding section to prove its usefulness, safety to the public when label precautions are followed, compati- bility on various crops as recommended, and safety of the treated crop product for use as a livestock feed or food for human consumption. Suitable analytical procedures for identifying the material and measuring its residue on crop prod- uce must be given the authorities. Any labeling appearing upon the pes- ticide package, accompanying the pesti- cide at any time, or referred to on the label or in literature accompanying the pesticide must be approved and must bear suitable warnings if any use hazard is involved. When any risk of harm to the public health is anticipated from the use of the product, the Administrator of the Act confers with officials of the Public Health Service as to the accuracy of the evidence submitted to show that the warning statements are adequate, when complied with, to protect the pub- lic. In addition, when food contamina- tion is involved, the Administrator of the Act confers with representatives of the Food and Drug Administration re- garding the completeness of the toxi- cologic data, the accuracy of the residue 14