Pharmacology and Toxicology of Some Important Economic Poisons C. H. HINE
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School of Medicine, University of California, San Francisco, Calif., and School of Public Health, University of California, Berkeley, Calif.
Some of the more important pharmacologic and toxicologic principles that have been highlighted by government, commercial, and university laboratories are outlined. Cooperative research by chemists and toxicologists is needed, directed toward the development of economic poisons possessing a greater margin of safety for man and animals.
T h e pharmacology and toxicology of certain economic poisons have been developed to a degree which surpasses investigations of any other class of nonmedicinal compounds. I n certain instances more is known concerning the site and mechanism of action, the absorption, distribution, and excretion of these substances than is known concerning some of the more commonly used pharmaceutical compounds. This has come about as a result of the conscientious recognition of the public health hazards which are inherent i n the economic poisons. This review outlines some of the more important pharmacologic and toxicologic principles which have been highlighted b y the work of the government, commercial, and university laboratories that have been concerned with this problem (8, 5,13,16).
Portals of Entry A s far as man and animals are concerned, the economic poisons exert their harmful and deleterious effect after absorption and distribution through the blood stream. Relatively few agents are irritating or corrosive i n their action, and their effect on the intact skin may be considered secondary (5, 8). Toxic action of economic poisons is exerted by alteration i n physiologic or biochemical activity of various systems, organs, and cells. The portals of entry through which the poisons gain access to the body are determined largely by the nature of the exposure. The use of sprays and aerosols in dispersing media has greatly increased the hazards of absorption through the respiratory tract. A b sorption is influenced markedly by the physical properties of the particular compound. When the portal of entry is v i a the gastroenteric route, the compounds with high water solubility such as soluble arsenates, strychnine, thallium, and 1080 are much more hazardous. Absorption through the skin depends on high lipide solubility, and the ratio of fatwater solubilities may also be important with respect to gut absorption and transfer by the blood stream. Accidental poisoning i n children not infrequently occurs. Economic poisons, not properly labeled, are of great concern both for children and adults. The more extensive problem of poisoning i n man and domestic animals, however, arises from the ingestion of residual poisons remaining on agricultural products, on weeds, and i n impregnated soil (1, 6). 39
AGRICULTURAL CONTROL CHEMICALS Advances in Chemistry; American Chemical Society: Washington, DC, 1950.
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Percutaneous absorption has been shown to be a definite hazard with the organic phosphates. I n animals, fantastically small quantities applied to the intact skin or the mucous membranes result i n absorption with fatal consequence. The work of Horton and others has indicated the inadvisability of incorporating benzene hexachloride (hexachlorocyclohexane) i n clothing for miticidal purposes. A s Woodard has pointed out, it is of paramount importance to determine the absorption, metabolism, excretion, and storage of a toxic compound i n mammals. Once having gained access into the body, the economic poison is carried by the blood stream and distributed throughout the tissues i n a manner regulated by the agent's physical and chemical activity. Eventually an equilibrium is established between absorption on the one hand and storage, detoxication, and excretion on the other. The relative rate of this reaction determines, i n part, the toxicity of the i n secticide or other poison. The majority of the fat-soluble compounds which are halogenated are absorbed through the skin or across mucous membranes, are distributed to the liver and other parenchymal organs, and may be stored i n the body fat i n a quantity which is determined by the characteristics of the lipoid matter of the animal and the dosage of the compound (6).
Toxicity It is a first principle of toxicology that no chemical substance is a poison at all concentrations; toxicity occurs only when a critical concentration is reached within vital cells. Whether or not an economic poison will exert a particular deleterious effect depends on the relative rates of absorption as compared with detoxication and elimination, its i n herent toxicity, and the physiologic status of the organism. Poisoning may be acute, delayed, subacute, or chronic, depending upon the intensity and duration of exposure and the susceptibility of the species. Quantities of D D T may be stored i n the body i n amounts which, if taken i n an acute dose, would be rapidly toxic. This is true of lead and other agents, as well. However, conversely, the organic phosphates and nicotine, which exert an extremely deleterious effect when absorbed i n large quantities over a short period of time may, when absorbed i n lesser quantities over a considerable time, exert no appreciable untoward effects. Furthermore, the summation of repeated minimal injuries may result i n eventual serious damage to an organ or cell. The more highly developed cells of the body, such as are found i n the central and peripheral nervous systems and the conducting mechanism of the heart, are more sensitive to the toxic effects of economic poisons than are the less specialized cells of muscles, fat, and bone. It has been demonstrated with several of these agents that gross effects, such as retardation of growth and normal activity, may not occur at absorption levels which produce significant tissue damage. This emphasizes the necessity for more complete toxicologic studies, with special reference to histologie-pathologie changes. Tolerance i n insects to increasing amounts of D D T , B H C , and several of the inorganic agents, such as arsenic, is known to occur. However, i n animals, this phenomenon has not been demonstrated to the same degree. A b i l i t y of the cells of insects to function i n the environment of a toxic agent, without alteration of cellular function, is one of the most striking of biologic phenomena. This review does not attempt a discussion of detailed pharmacologic knowledge which has arisen concerning many of the principal agents. However, a simple approach can be made to the toxicology of these agents by classifying them according to the vital systems, upon which they exert their primary effect. If a toxic agent exerts a significant effect upon a particular tissue, organ, or system, i t will cause one of the following changes. (1) stimulation, (2) depression, or (3) degeneration. A summary of the principal effects resulting from the more common economic poisons is given i n Table I . It is true that the degree of system damage may be determined i n part by the nature of the exposure; thus, i n mammals, high concentrations of D D T may produce central nervous system stimulation and cardiac irregularities, while low concentrations, absorbed over a period of time, may produce damage primarily to parenchymal tissues (3). Generally, similar chemical types exert approximately similar qualitative physiologic AGRICULTURAL CONTROL CHEMICALS Advances in Chemistry; American Chemical Society: Washington, DC, 1950.
HINE—PHARMACOLOGY AND TOXICOLOGY OF SOME IMPORTANT ECONOMIC POISONS
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effects and pathologic changes; however, pathologic changes i n tissues are i n addition occasionally specific for particular agents. A n example of this is seen when the deleterious effects of D D T on the liver and muscle are compared with the action of D D D on the adrenal glands and of chlordan on the optic nerve. Table I.
Chief Effects of Economic Poisons on Tissues, Organs, and Systems of Man
Organ or System
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Central nervous system
Stimulation Nicotine, strychnine, arsenic, halogenated hydrocarbons, organic phosphates, dinitrophenols, fluoroacetate (1080)
Effect Depression Nicotine
Peripheral nervous system
Nicotine, organic phosphates
....
Lung
Organic phosphates, ethylene dibromide, ethylene dichloride, ethylene chlorohydrin
....
Liver
....
Heart
D D T , fluoroacetate (1080)
Degeneration Arsenic, methyl bromide
Arsenic, phosphorus, D D T , benzene hexachloride, chlordan, toxaphene, carbon tetrachloride, D D , ethylene chlorohydrin Halogenated hydrocarbons
Kidneys
....
Arsenic, methoxychlor, benzene hexachloride, ethylene chlorohydrin, carbon tetrachloride, D D T phenols
Gastroenteric tract
....
Arsenic, phosphorus, fluorides, petroleum oils, calcium oxide and hydroxide, phenols
Muscles
Organic phosphates
....
Blood pigment
....
Chlorates
Bone
....
Fluorides, phosphorus
....
Arsenic
Hair Body as a whole
Dinitrophenols
....
Exposure to a toxic agent does not necessarily result in poisoning. A definite concentration must result i n vital tissues before irreversible toxic effects occur. The most effective method of treating poisoning is to prevent its occurrence. This having failed, the sine qua non is removal of the unabsorbed portion, or alteration chemically or physically so that the absorbed portion does not remain i n contact with cells i n toxic amounts. Unfortunately, most of the antidotal treatment of poisoning from agents of economic importance is symptomatic—that is, physiologic i n nature. F o r example, the acute, excitatory effects of the halogenated hydrocarbons on the central nervous and cardiovascular systems predominate i n acute poisoning. Phénobarbital has proved to be useful for control of experimentally induced poisoning i n animals and is apparently the drug of choice i n human therapy (10). Procaine may be of value i n the treatment of cardiac arrhythmias which may arise i n man following exposure to 1080. A t present, no effective agent has been devised to combat the hyperglycemia and depletion of liver glycogen which result from acute poisoning with A N T U (4). The intense pulmonary edema and pleural effusion seen with this compound may respond to oxygen under increased pressures. Fortunately, the minimum toxic dose is high i n man, i n contrast to other species. The organic phosphate esters are among the most potentially dangerous economic poisons with which we have to deal. Fortunately, specific antidotes against the phosphates are now available. The inhibition of choline esterase and resulting excessive parasympathetic nervous stimulation which are caused b y these agents may be successfully combated b y means of magnesium salts and atropine (9). Unfortunately, i t has not been possible to develop an ideal economic poison which has a low order of toxicity for man and is effective over a wide variety of field conditions. Cooperative research on the part of chemists and toxicologists should be directed toward the development of economic poisons possessing a greater margin of safety for man and animals. AGRICULTURAL CONTROL CHEMICALS Advances in Chemistry; American Chemical Society: Washington, DC, 1950.
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Bibliography (1) Carter, R. H . , Ind. Eng. Chem., 40, 716 (1948). (2) Chenoweth, M . B., and Gilman, Alfred, J. Pharmacol., 87, 90-103 (1946). (3) Draize, J . H . , Woodard, Geoffrey, Fitzhugh, O. G., Nelson, Α. Α., Smith, R. B . , Jr., and Cal very, H . O., Chem. Eng. News, 22, 1503 (1944). (4) Dubois, K . P., et al., Proc. Soc. Exptl. Biol. Med., 61, 102-4 (1946). (5) Dunn, J . E., Dunn, R. C., and Smith, B. S., Pub. Health Repts., 61, 1614-20 (Nov. 8, 1946); Reprint 2754. (6) Fitzhugh, O. G., Ind. Eng. Chem., 40, 704 (1948). (7) Hall, S. Α., and Jacobson, Martin, Ibid., 40, 694 (1948). (8) Horton, R. G., Karel, L . , and Chadwick, L . E., Science, 107 (No. 2775), 246-7 (1948). (9) Jones, H . W., et al., Federation Proc., 7 (No. I), 231 (1948). (10) McNamara, B. P., and Krop, Stephen, J. Pharmacol., 92, 147-52 (1948). (11) McNamara, B. P., et al., Ibid., 88, 27-33 (1946). (12) Neal, P. Α., Sweeney, T. R., Spicer, S. S., and von Oettingen, W. F., Pub. Health Repts., 61, (No. 12), 403-9 (March 22, 1946); Reprint 2698. (13) Neal, P. Α., von Oettingen, W. F., Smith, W. W., Malmo, R. B., Dunn, R. C., Moran, Η. E . , Sweeney, T . R., Armstrong, D . W., and White, W. C., Pub. Health Reports, Supplement 177 (1945). (14) Philips, F . S., and Gilman, Alfred, J. Pharmacol., 86, 213-21 (1946). (15) Philips, F. S., Gilman, Alfred, and Crescitelli, F . N . , Ibid., 86, 222-8 (1946). (16) Stammers, F . M . G., and Whitfield, F . G . S., Bull. Entomol. Research, 38, 1-73 (1947).
AGRICULTURAL CONTROL CHEMICALS Advances in Chemistry; American Chemical Society: Washington, DC, 1950.
