Summary of Toxicological Studies of the Insecticide D D T 2,2-Bis (p-chlorophenyl) 1 /I ,1 -trichloroethane JOHN H. DRAIZE, GEOFFREY W O O D A R D , O . GARTH FITZHUGH, ARTHUR A . NELSON, U. BLACKWELL SMITH, JR., AND HERBERT O . CALVERY* Division of Pharmacology, Food and Drug Administration, Federal Security Agency, Washington, D. C. RESENTED here is a brief résumé of the toxicological studies in this laboratory of the synthetic insecticide DDT (/). Detailed reports of these investigations will appear elsewhere (#, S, 4)· Experiments to determine the toxicity and action of DDT have been carried out along the following lines:
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Acute and subacute application to the akin rf rabbits, rats, guinea pigs, and dogs. Acute and subacute feeding to rats, mice, guinea pips, and chicks. Chronic feeding to rats and dogs. Skin irritation and sensitization. Pharmacological investigations as to the site and mode of action. Gross and microscopic pathology and blood studies of poisoned animals.
Skin Application Solid. DDT in micronized powder form did not penetrate the intact rabbit skin sufficiently to produce signs of toxicity or irritation, perhaps because of the insoluble nature of this compound. Solution. When DDT in 30% solution in dimethyl phthalate was applied in single doses of 3.9, 6.0, and 9.4 ml. per kg. to intact and abraded rabbit skin, all animals showed signs of toxicity but none died. However, when this solution was applied daily for 13 weeks or until death in doses of 0.5, 1.0, 2.0, and 4.0 ml. per kg. to the intact skin of rabbits, rats, and guinea pigs, deaths occurred at all levels, preceded by characteristic toxic signs—anorexia, weight loss, nervousness, tremors, and, in final stages, clonic convulsions. The action of D D T is singular, in that some animals survive rather large doses whereas others are poisoned by very small doses. Thus, it is difficult to determine a dose below which no toxic signs would be produced. The rats, guinea pigs, and rabbits were about equally sensitive to DDT when applied to the skin. The guinea pigs did not always show the nervous symptoms as markedly as did the rats and rabbits. > Work done under a transfer of funds, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the Division of Pharmacology of the Food and Drug Administration. * With the assistance of Virginia D . Johnson, Diana S. Kramer, J. M. Glass man, Ruth B. Lang, C. C. Boone, P. M. Jenner, and C. M. Montgomery.
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As the toxicity produced by single oral doses of aqueous suspensions of DDT was irregular, the LD50 was not determined. When D D T was dissolved in corn oil and administered orally, however, the LD50 for rats was approximately 200 mg. per kg-, for guinea pigs 400 mg. per kg., and for mice 400 mg. per kg. Rabbits and chicks were more resistant to acute oral doses. As was observed with skin application, the toxicity is irregular so that it is difficult to establish a dose below which there would be no toxicity in a large group of animals. DDT was mixed with the diet and fed subacutely to rats, mice, guinea pigs, and chicks. Doses of 500 and 1,000 p.p.m. killed all chicks with characteristic toxic signs within 2 weeks. Diets containing 500 p.p.m. produced toxicity in rats and guinea pigs within a few weeks. This level corresponds to a daily intake of about 30 mg. per kg. for the rat and 40 mg. per kg. for the guinea pig. Mice are adversely affected at equally low levels.
Chronic Toxicity Rats have been fed diets containing 100, 200, 400, and 800 p.p.m. for 50 weeks. Within the first 2 weeks, approximately one half of the animals died on the 800 p.p.m. Nervous symptoms have been observed on 400 p.p.m., and a slight effect on growth has been observed on 200 p.p.m. Dogs have been given by mouth 10, 50, and 100 mg. per kg. per day, 6 days per week, in gelatin capsules. The animals on the high level died with characteristic toxic signs at varying times within the first 7 weeks. One dog on the 50 mg. level exhibited anorexia and consequent weight loss for a long period and died after 34 weeks on experiment. The other dogs appeared normal at the 50th week.
Skin irritation and Sensitization D D T as solid or in solution was not appreciably irritating to the skin of rabbits, guinea pigs, or rats. Sensitization has not been observed in rabbits, but using the Landsteiner technique, slight but definite sensitization has been obtained in guinea pigs.
Pharmacological Investigations Subcutaneous or intraperitoneal injections of solutions of DDT in corn oil
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1944
are slowly absorbed and therefore are not so toxic as equivalent doses administered by mouth. However, such injections produced prolonged nervous reactions and were useful for pharmacological experiments designed to indicate the site of action of DDT. Tremors produced by DDT poisoning are abolished when the animal is under a general anesthetic such as ether or sodium pentothal, but reappear as the animal recovers from the anesthesia. Section of the spinal cord at various levels abolished tremors below the section. The production of tremors in the rat by DDT was antagonized by sodium phénobarbital. The administration of thiamine to DDTpoisoned animals was without effect.
Pathology and Hematology The significant pathological changes that occur in animals receiving DDT vary with the dosage. In the rabbits they include focal necrosis of the liver, gall bladder, voluntary muscle and stomach mucosa, some focal nephritis, atrophy of testis, and, after repeated application to the skin, usually a slight dermatitis, occasional effects on the bone marrow and spleen, and often slight focal myocardial necrosis with effects observed in a few instances to other tissues and organs. The dogs showed moderate central necrosis and atrophy of the liver, and focal colloid depletion in the thyroid. The guinea pigs, rats, and mice rather uniformly showed slight to moderate liver damage which, however, varied, appearing as focal necrosis, atrophy, hydropic degeneration, or combinations of these. Occasionally there was testicular atrophy with some degeneration in the thyroid. The incidence of encephalitis in rabbits receiving D D T is higher than is usually encountered spontaneously. During the course of these investigations of DDT numerous examinations of blood have been made for morphological changes. In rats there was an occasional fall in the hemoglobin and a decrease in the absolute leukocyte count, the per cent of lymphocytes falling but the per cent of heterophiles rising. In rabbits, the leukocyte count often rose, with a sharp increase in the percentage of heterophiles. 1503
Conclusions Toxicoiogical investigations of D D T have shtown that it is a poisonous substance* which should be used only .«iftrr adequate investigations have shown it »«· be safe for the particular IISI·. Since D D T in solution i* ;ΙΙ»ΟΓΙΚ«Ι through t h e skin, it should be handled with care and its use on the skin should be carefully restricted. T h e wide range of dosage over which toxic signs can be produced in animal* show?» that it is either irregularly absorbed or irregularly metabolized, thus making it difficult to establish an absolutely *:iti level for ingestion. D D T i n solid form is not readily ab sorbed through the skin of animals. Subacute and chronic feeding Woodard, G.. Nelson. A. Α., and Calvery, H. 0 . £ J. Pharmacol, and Experimental Therapeutic* 'submitted for publica tion).
W a r Training Courses E S M W T lour courses in chemistry will he griven v\ St. John's University. Brooklyn, commencing Sept. 25. Registrations will lie accepted until Sept. 28. The course» are tuition-free and are given at night. Courses arc held on two evenings per week for α period of 12 weeks. The subjects are: the chemistry and technology of plastics and resins; topics in physical chemistry for industry (part 1): colloidal and surface chemistry; qualitative organic analysis. Information and applications should IK» obtained, in person, at St. John's University. 7ό Lewis Ave.. Brooklyn. X. Y .
Use of Color in Industry Postwar uses of color in industry and art will lx» the theme of a new course given at the School of Architecture of Columbia Uni versity during the 1944 winter term by Miss Lorain Fawcett, director of color of the Allcolor Co., Inc.. New York.
Envisioning the increased use of color with the return to normal production after the war, Miss Faweett will devote 15 evening sessions to the theory of color and its application to printing inks, fabrics, paints, floorings, packages, designs, and numerous industrial uses, and to practical experience in mixing, rolling, and matching colors.
Institute o n Postwar Reconstruction The Institute on Postwar Reconstruction at New York University will open a series of weekly conferences beginning Sept. 27 on "America's Place in the World Economy*'. Individual meetings will consider America's international economic policy, the future of the nation's foreign trade, the investment of American capital abroad, the gold standard, the possible use of stabilization funds and an international bank, immigration and world population movements, and international cartels and private trade agreements.
Trainins Engineers for Reconversion An opportunity for engineers now employed in war industries to fit themselves for new types of work under the reconversion program will be offered during the coming year by the Cooper Union School of Engineering, New York. The school will admit qualified workers to advanced evening courses opening October 2, without charge, except for small laboratory fees, and without the formality of entrance examinations.
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The third in a series of surveys made by the Twentieth Century Fund, New York, "Postwar Planning i n the United States. An Organization Directory**, shows a striking increase over the 105 organizations listed in 1942 and 137 in 1943. Nearly 200 public and private agencies of national scope are now actively doing research or public education on postwar problems.
Adjustment o f Production Cut-Backs A booklet, "Adjustment of Production Cut-backs," has been prepared by the Army Service Forces, Bureau of Public Relations, Washington, D . C. Its purpose is to outline the careful consideration and planning that the Army accords to reduction in production programs and resultant cancellation of contracts.
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Mitosis A scientific survey by Franz Schrader. published by the Columbia University Press, summarizes studies on the movement of chromosomes, made over a 25-year period, and indicates the meagernees of known facte concerning mitosis. The Standardization of Volumetric Solutions. R. B. Brodstreet. 2nd ed. Chemical Publishing Co., Inc., 26 Court St.. Brooklyn 2. Ν . Υ. Price. $3.75.
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