In studying the mode of action of an insecticide, we often rely for clues on what we know of the action of the poi- Hoyv Insecticides son on man or other higher animals. Sometimes the mode of action may be Poison Insects similar in vertebrates and in insects, but without experimental evidence it is John J. Pratt, Jr,, Frank H. Bahers unwise to assume that such a similarity exists. The poisonous properties of the in- Somebody has said that because in- organic arsenic compounds (paris sects are small an insecticide kills them green, calcium and lead arsenate, all over. Our knowledge of the subject sodium arsenite ) are due to the forma- is incomplete, but it is enough to belie tion of the w^ater-soluble compounds, the statement. arsenious or arsenic acid, in the diges- Poisons affect the normal functions tive tract. of specific cells and tissues of insects Arsenic is considered a general pro- just as they are known to do in humans toplasmic poison ; that is, it poisons the and other higher animals. Basically contents of all types of cells. Most tis- some chemical process in the animal is sues and organs therefore are affected affected so as to bring about changes in arsenic poisoning. One well-known in its functions. Those changes are sec- effect of arsenic on vertebrate animals ondary to the original process that was is the abrasion and destruction of the affected and arc frequently mistaken lining of the intestine. A similar de- for the initial action of the poison. struction occurs in the mid-intestine of A complete knowledge of the way a insects. Often it is said that such de- chemical poisons an insect would have struction is the primary reason that great value in the formulation of in- arsenic insecticides kill insects. If that secticides. While preparing an insecti- were true, it still would not explain cidal mixture, for example, we could what biochemical process is disturbed add a substance that would help the in order to bring about destruction of poison reach the target—the organ or the intestinal cells. Investigations with tissue it acts upon. Chemicals could be vertebrate animals have shown that added to weaken or destroy the mecha- arsenic poisons unidentified enzymes, nisms that protect the insect against which function in the metabolism of the poison in question. If we know how carbohydrates by cells. Probably arse- one poison acts, we could select or nic acts on the insect system in the same synthesize other chemicals of similar manner. action. Research is giving us that Nicotine first stimulates and then de- knowledge so that before too long such presses the nervous system of animals. ideals should become realities. Paralysis follows rapidly and results in Insecticides have been classified ac- the failure of organs to function. In cording to the way they get into the insects, as in higher animals, the poi- insect's body cavity: Stomach poisons soning action of nicotine occurs in the are eaten, contact poisons enter nerve ganglia, which are clumps of through the skin, and fumigants enter nerve tissue at various places in the through the breathing tubes or the skin nervous system. Nicotine seems to have as gases. Some insecticides may enter practically no effect on nerve fibers or by all three routes. But often such a on the junctions of nerves v^^ith mus- classification is used wrongly to refer cles. The chemical process of nicotine to the mode of actioîi of an insecti- poisoning in insects is not known. cide—an entirely different term, which Pyrethrum powder, the ground flow- means the way in which a chemical ers of certain species of the chrysan- acts on an animal's system. themum, contains the chemicals, py- OTOiríé^-.^í— 15 205 206 Yearbook of Agriculture 1952 rethrin I and II and cinerin I and 11, Station indicates that a similar action which are the main toxic principles. occurs in insects. E. H. Smith and G. The rapid paralyzing action of pyre- W. Pearce of the New York State Agri- thrum is evident to anybody who has cultural Experiment Station demon- sprayed a room with a household fly strated that oil does not kill eggs of spray and watched the flies drop almost the oriental fruit moth by depriving immediately to the floor. The insects them of oxygen (suffocation). They ob- recover from the paralysis, however, tained some evidence that the oil pre- unless a lethal amount of the poison vented unknown poisonous substances gets on them. Pyrethrin acts directly on formed by the egg from passing out- the central nervous system of insects. ward through the eggshell. The paralysis is a result of the block- The dinitrophenols are used in sev- ing of transmission of nerve impulses. eral phases of insect control—most We know that destructive changes oc- commonly the sodium, calcium, and cur in the nervous tissue of insects poi- dicyclohexylamine salts of 2,4,dinitro- soned with pyrethrin, but the reason 6-cyclohexylphenol and the sodium and for the changes is obscure. calcium salts of 4,6,dinitro-o-crcsol. Rotenone causes paralysis of the Dinitrophenol increases the meta- breathing mechanism in mammals, bolic rate of warm-blooded animals. possibly by acting on bronchial tissues. Perhaps the poison acts directly on All we know now about the method by cells, causing them to increase the rate which rotenone kills insects is that it at which they use oxygen. Fat metab- slows the rate of heart action and olism is involved because the excess breathing. The symptoms may indicate oxygen is used only for burning this disturbances in the functions of prac- body food. Dinitrophenol and dinitro- tically any tissues so they really tell us cresol act in the same manner on in- little of the fundamental basis for sects and raise the oxygen require- rotenone poisoning. ments by as much as three times the Several theories have been advanced normal amount. The mechanism by to explain how oils kill insects: Oils which the dinitrophenols cause cells to penetrate the insect's breathing tubes, use abnormally high amounts of oxy- thus causing suffocation; or they pene- gen has not been determined. trate the tissues and poison them; or The characteristic tremors of DDT certain poisonous, volatile substances poisoning are symptoms of a disturb- in the oils kill by penetrating the tissues ance of the nervous system. as gases. None of the theories has been The sensory nerves—which carry proved. Maybe each may have some impulses to the central nervous sys- merit, depending on the oil in ques- tem—are the most sensitive to DDT tion. poisoning, the nerve ganglia the least Nonvolatile oils (such as mineral sensitive. When DDT gets on an in- oil) that contain no poisonous com- sect's body, it affects hundreds of sen- pounds might kill an insect through sory nerve endings. The nerves then suffocation. For oils (such as kerosene) produce impulses faster and stronger that contain volatile, poisonous con- than normal. These cause the nerves stituents, the second and third theories responsible for moving muscles to pro- might account for the killing action. duce the tremors typical of DDT poi- In vertebrates, such volatile petro- soning. The capacity of the central leums as gasoline act first as stimulants nervous system to coordinate sensory then as depressants of the central nerv- impulses is also disrupted—as seen in ous system. Death is due to respiratory the stumbling gait and general in- failure if the animal is exposed to the stability of the insect. oil for a long time. Work done by We do not know why DDT poisons George D. Shafer many years ago at nervous tissue. It has been suspected the Michigan Agricultural Experiment that DDT poisons the enzymes cholin- How Insecticides Poison Insects 207 esterase, which is important in the B vitamins—that is, it might compete proper functioning of nerves, but con- with and replace m^i"o-inositol in some siderable research has failed to show vital physiological process. Meso-moú- that DDT affects the enzyme. Perhaps tol will alleviate somewhat the poison- another enzyme system in nervous ing of certain yeasts by gamma benzene tissue is involved. One theory is that hexachloride, but several attempts to DDT causes a depletion of calcium in demonstrate a similar process in ins(xts nervous tissue, w'hich in turn causes have failed. Chemical investigations, spontaneous activity of the nerve. which now indicate that mi?5o-inositol Promising leads are emerging from and gamma benzene hexachloride do research on house flies that are resistant not have similar molecular shapes, may to DDT. Flies can change DDT in explain the failure- to prove the hy- their bodies to a nonpoisonous sub- pothesis. stance and DDT-resistant flies can do The organic phosphates—hexaethyl this faster than susceptible flies can. tetraphosphate (HETP), tetraethyl llie chemical processes involved in pyrophosphate (TEPP), and diethyl this breakdown of DDT are being elu- p-nitrophenyl thiophosphate (para- cidated and should tell us much about thion) —are highly toxic to animals. In the mode of action of DDT. insects and in warm-blooded animals, Other efl'ects of DDT on the physi- they poison the cholinesterase. ology of insects include an increase in A chemical called acetylcholine is the consumption of oxygen and a de- formed in certain nerves and aids in crease in the amount of stored food the transmission of nerve impulses. substances in the body. Those are If it is not destroyed immediately probably secondary efl'ects of DDT after it has served its purpose, it will poisoning. continue to cause impulses to move Benzene hexachloride occurs in sev- along the nerve. The enzyme cholin- eral forms, or isomers, each of which esterase is always at hand to destroy the has a slightly difl'erent molecular shape. acetylcholine. The organic phosphate Of the 16 possible isomers, 5 are insecticides poison the enzyme, thus known—the alpha, beta, gamma, delta, allowing the acetylcholine to accu- and epsilon. The gamma isomer, com- mulate, and cause uncoordinated nerv- monly called lindane, is several hun- ous activity through the whole animal. dred times more toxic to insects than The results are tremors, convulsions, the others are. muscle paralysis, and finally death. It In vertebrate animals, gamma ben- is possible that the organic phosphates zene hexachloride causes stimulation poison insects in other ways, but the of the central nervous system, but the action we described is the major one beta and delta isomers cause depres- now known. sion. The external symptoms of poison- Another organic phosphorus com- ing in insects resemble those of DDT, pound that shows much promise for except that they usually appear more control of some insects and mites is rapidly. As in DDT poisoning, the schradan (octamethyl pyrophosphora- tremors suggest an effect upon the mide). Many plants absorb it from nervous system, but whether the mech- the soil. Insects and mites that feed on anism of poisoning is the same as that the plant sap are poisoned. Schradan of DDT remains for future research seems to have little effect on the cho- to explain. linesterase system of insects; it is not Shortly after the insecticidal prop- particularly toxic when it is sprayed erties of benzene hexachloride were on them. But the fact that the sap of discovered, it was suggested that (be- plants that have taken it up is highly cause of possible similarity in molecular poisonous to cholinesterase indicates shape) the poison might act as an anti- that the mode of action is the same as mctabolitc to meso-moúiol, one of the that of the other phosphates—only. 208 Yearbook of Agriculture 1952 however, after it has been changed in be able to predict whether a chemical some manner by plant tissue. Animal will be poisonous and to what insects. liver cells also increase the anticholin- Then we can make insecticides to suit esterase activity of schradan. our needs, Of the cyanides used in controlling insects, hydrocyanic acid, or prussic JOHN J. PRATT, JR., is an entomol- acid, is a liquid that evaporates rap- ogist in the Bureau of Entomology and idly; calcium cyanide is a solid that Plant Quarantine. He has degrees gives off hydrogen cyanide gas more from the University of Massachusetts, slowly. Both are classed as fumigants North Carolina State College, and because the killing action is due to gas- Cornell University. During the war he eous hydrogen cyanide. served with the Army and the United Hydrogen cyanide is extremely toxic States Public Health Service, and and acts quickly on all animals. In joined the Bureau of Entomology and warm-blooded animals it poisons the Plant Quarantine in 1948. Dr. Pratt enzymes that enable cells to use the conducts research on the physiology oxygen supplied to them. As all living of insects. cells require a constant supply of FRANK H. BABERS, a biochemist in oxygen, the failure of the supply results the Bureau of Entomology and Plant in the rapid and widespread poisoning Quarantine, has charge of research on of tissues that is characteristic of insect physiology and the mode of cyanide. The poisoning action of cya- action of insecticides. nide on insects is probably the same, for the enzymes involved are common For further reading: to practically all living cells. Dietrich Bodenstein: Investigation on the Locus of Action of DDT in Flies (Droso- Methyl bromide, also used as a phila), Biological Bulletin, volume go, pages fumigant, is less toxic than hydrogen 148-157. 1946. cyanide, and its poisoning action is G. J. Coble and R. L. Patton: The Mode much slower. of Toxic Action of Dinitro Compounds on The mode of action of methyl bro- the Honeybee, Journal of Economic En- tomology, volume 39, pages iyy—i8o. 1946. mide on insects has not been studied. Louis Goodman and Alfred Gilman: Research with vertebrates has yielded The Pharmacological Basis of Therapeutics, two opposing theories. One states The Macmillan Co., New York. 1941. that methyl bromide is changed in the Harold T, Gordon and John H. Welsh: animal to methyl alcohol and a harm- The Role of Ions in Axon Surface Reac- tions to Toxic Organic Compounds, Journal less bromine salt. The methyl alcohol of Cellular and Comparative Physiology, then poisons the animal. Another the- volume 31, pages 395-420. 1948. ory proposes that the methyl bromide W. M. Hoskins: Recent Contributions of is not changed in the animal but poi- Insect Physiology to Insect Toxicology and sons as methyl bromide. Whatever the Control, Hilgardia, volume 13, pages 3oy— mode of action may be in vertebrates, 386. 1940. D. D. Irish, E. M. Adams, H. C. Spencer, it will probably be similar in insects, and V. K. Rowe: Chemical Changes of for the effects of methyl bromide seem Methyl Bromide in the Animal Body in Re- to be common to all animals. lation to Its Physiological Effects, Journal of Ten years ago we had a dozen or so Industrial Hygiene and Toxicology, volume insecticides and knew little about their 22, pages 408-411. 1941. S. Kirkwood and Paul H. Phillips: The modes of action. Today we have sev- Antiinositol Effect of y-Hcxachlorocyclo- eral dozen new ones and know nothing hexane. Journal of Biological Chemistry, of how they act. Entomologists are volume 163, pages 251-254. 1946. gradually turning from trial-and-error Bernard P. McNamara and Stephen Krop: Observations on the Pharmacology of ways of discovering new insecticides, the Isomers of Hcxachlorocyclohcxane, however. These are being replaced by Journal of Pharmacology and Experimental research on the fundamental aspects Therapeutics, volume 92, pages 140-146. of poisoning action. Eventually we will 1948. Robert L. Metcalf: The Mode oí Action of Organic Insecticides, National Research Council^ Washington, 1948; Studies of the Mode of Action of Parathion and Its Deriva- tives and Their Toxicity to Insects, with The Organic Ralph B. March, Journal of Economic En- tomology, volume 42, pages y21-^28, 1949. Insecticides W. E, Ripper, R. M. Greenslade, and L. A. Lickerish: Combined Chemical and Bio- logical Control of Insects by Means of a C,V,Bowen,S.A.Hall Systemic Insecticide, Nature {London), volume 16s, pages y8y-y89. 1949. Kenneth D. Roeder and Elizabeth A. The best known of the synthetic or- Weiant: The Site of Action of DDT in the ganic insecticides is DDT, but it was Cockroach, Science, volume 103, pages 304- 3oy, 1946; The Effect of DDT on Sensory not the first. Some of them have been and Motor Structures in the Cockroach Leg, in use for decades. Carbon disulfide, Journal of Cellular and Comparative Physi- /;-dichlorobcnzcnc5 and naphthalene ology, volume 32, pages iy5- 186, 1948. stand out as old-timers. Ethylene di- George D. Shafer: How Contact Insecti- chloridc, ethylene dibromidc, methyl cides Kill. I and II, Michigan Agricultural College Technical Bulletin 11, 1911 ; How bromide, and thiocyanates have been Contact Insecticides Kill. Ill, Technical used for the past quarter century. Bulletin 21, 1915. Thousands of similar compounds—r E. H. Smith and 0. W. Pearce: The Mode man-made materials whose basis is of Action of Petroleum Oils as Ovicides, carbon—have been investigated as to Journal of Economic Entomology, volume 41, pages jy3-i8o. 1948. insecticidal Value. The Department of J, M. Tobias and J. J. Kollros: Loci of Agriculture in 1922 or so began a study Action of DDT in the Cockroach (Peri- of their use as repellents and fumigants planeta americana), Biological Bulletin, and began later the synthesis of mate- volume 91, pages 24y-255. 1946. rials for testing as poisons for insects. 0. W. van Vloten, Ch. A. Kruissink, B. Strijk, and J. M. Bijvoet: Crystal Structure Phenothiazine, thiodiphenylamine, of "Gammexane," Nature (London), vol- introduced as an insecticide in 1935, urne 162, page yyi. 1948. may be considered one of the early J. Franklin Y eager and Sam C. Munson: members of the newer synthetic age. It Physiological Evidence of a Site of Action is used now to only a limited extent as of DDT in an Insect, Science, volume I02j pages 305-3oy. 1945. a codling moth insecticide, but it is used extensively for the internal medi- cation of livestock for the control and removal of injurious nematodes that infest cattle, horses, sheep, and goats. TÍ II C S C / \ / \^/ \ HC c C CH I! I c CH \ / \ / c N C H H H Phenothiazine Azobenzene, an orange crystalline material, was found in 1943 to be efiFec- tive as a fumigant for the control of mites in greenhouses. Because azoben- zene sublimes readily, a solution con- taining it may be. applied to steam Flea beetle. pipes and allowed to vaporize. The de- 209