53 E O 0) -Q E a'3 iii 51s5 D « QC United States Environmental Protec EPA-540/9-80-005 1982 Agencv vvEPA Recognition and Management of I < Pesticide Poisonings Third Edition ------- ------- RECOGNITION AND MANAGEMENT OF PESTICIDE POISONINGS Donald P. Morgan, M.D., Ph.D.* Support for this publication was provided by the National Pesticide Hazard Assessment Program, Health Effects Branch, Hazard Evaluation Division, Office of Pesticide Programs, U.S. Environmental Protection Agency, Wash- ington, D.C. 20460. *lowa Pesticide Hazard Assessment Project, located at University of Iowa Medical School, Iowa City, Iowa 52240. Third Edition US [iV.vi-onrf.pntcil Promotion Agency Re-p..on V, Lici'.'.y 2'0 ^'.•,:!-, 0 V'ibo.'r; ociCGt. -_ .,-• Chicago, iiiinois 60604. For sale by the Superintendent of Documents, U.S Government Printing Office, Washington, D.C. 20402 ------- U,S. Environmental Protection Agency ------- Contents Page INTRODUCTION v CHAPTER 1—ORGANOPHOSPHATE CHOLINESTERASE-INHIBITING PESTICIDES 1 CHAPTER 2—CARBAMATE CHOLINESTERASE- INHIBITING PESTICIDES 9 CHAPTER 3—SOLID ORGANOCHLORINE PESTICIDES 14 CHAPTER 4—PENTACHLOROPHENOL 19 CHAPTER 5—NITROPHENOLIC AND NITROCRESOLIC HERBICIDES .... 23 CHAPTER 6—CHLOROPHENOXYCOMPOUNDS.. 27 CHAPTER 7—PARAQUAT AND DIQUAT 31 CHAPTER 8—DITHIOCARBAMATES AND THIOCARBAMATES 36 CHAPTER 9—PYRETHRUM, PYRETHRINS, PYRETHROIDS AND PIPERONYL BUTOXIDE 42 CHAPTER 10—ARSENICAL PESTICIDES 46 CHAPTER 11—RODENTICIDES 54 CHAPTER 12—FUMIGANTS 68 CHAPTER 13—MISCELLANEOUS PESTICIDES OF HIGHTOXICITY 77 CHAPTER 14—MISCELLANEOUS PESTICIDES OF LOW OR MODERATE TOXICITY .... 82 INDEX TO PESTICIDE POISONINGS BY SYMPTOMS AND SIGNS 88 PESTICIDE INDEX 94 ------- ------- INTRODUCTION This manual is designed to help professionals responsible for the health of persons exposed to pesticides to recognize and treat properly poisonings by these substances. This third edition discusses many more compounds than were dealt with in previous editions, and it updates particular management methods according to recently published clinical literature. No text or manual on so complex a topic can presume to take the place of good clinical judgment. But it is unrealistic to expect health professionals con- fronted with a pesticide poisoning emergency to assemble quickly the many details of toxicology, diagnosis, and treatment that are essential to optimal management. This manual provides such information in a concise format. A deliberate effort has been made to suggest treatment that can be imple- mented (or at least initiated) in small hospitals and clinics where victims of pesticide poisonings are likely to be received. At the expense of some repeti- tion, details of treatment have been spelled out sequentially for the common classes of chemical poisonings. The author is deeply indebted to the following reviewers who have con- tributed generously to this edition: S. H. Sandifer, M.D., Professor J. R. Reigart, M.D., Assoc. Professor Director, Division of Preventive Medicine Department of Pediatrics Department of Family Practice College of Medicine College of Medicine Medical University of South Carolina Medical University of South Carolina Charleston, South Carolina 29403 Charleston, South Carolina 29403 Harold E. Trammel, Pharm.D., Assoc. Prof. John E. Davies, M.D., M.P.H. Director of Poison Information Center Professor and Chairman College of Pharmacy Department of Epidemiology Medical University of South Carolina and Public Health Charleston, South Carolina University of Miami School of Medicine Arthur D. Nelson, M.D. Jon E. Ford, Ph.D. Director Environmental Toxicologist Scottsdale Memorial Hospital Chevron Environmental Health Center Scottsdale, Arizona Standard Oil Company of California Victor B. Beat, D.V.M., of the Iowa Pesticide Hazard Assessment Project compiled the many proprietary names of the products listed in the manual. Mrs. Pamela Mason and Ms. Diane Cornwall of the Iowa Project have pa- tiently typed the manuscript drafts. Ms. Martha Finan of the Information Support Services Branch, Manage- ment Support Division, Office of Pesticides and Toxic Substances of the United States Environmental Protection Agency has skillfully edited the manuscript. Staff of the Health Effects Branch, Hazard Evaluation Division of the Office of Pesticides and Toxic Substances, United States Environmental Protection Agency, have prepared the index and attended to the details of publication. ------- ------- Chapter 1 ORGANOPHOSPHATE CHOLINESTERASE-INHIBITING PESTICIDES GENERAL CHEMICAL STRUCTURE C2H5O or CH3O \ ^ S (or O) . P C2H5OorCH3O COMMON COMMERCIAL PESTICIDE PRODUCTS* Highly toxic: tetraethyl pyrophosphate (TEPP), phorate (Thimet), disulfo- tonf (Di-Syston), fensulfothion (Dasanit), demetont (Systox), terbufos (Counter), mevinphos (Phosdrin), methidathion (Supracide), chlormephos (Dotan, MC2188), sulfotepp (Bladafum, Dithione), chlorthiophos (Celathion), monocrotophos (Azodrin), fonofos (Dyfonate), prothoate (Fac), fenamiphos (Nemacur), phosfolan (Cyolane), methyl parathion (Dalf, Penncap-M), schradan (OMPA), chlorfenvinphos (Birlane), ethyl parathion (Parathion, thiophos), azinphos-methyl (Guthion), phosphamidon (Dimecron), methamidophos (Monitor), dicrotophos (Bidrin), isofenphos (Amaze, Oftanol), bomyl (Swat), carbophenothion (Trithion), EPN, fam- phur, (Warbex, Bo-Ana, Famfos), fenophosphon (Agritox, trichloronate), dialifor (Torak), cyanofenphos (Surecide). Moderately toxic: bromophos-ethyl (Nexagan), leptophos (Phosvel), dichlorvos (DDVP, Vapona), coumaphos (Co-Ral), ethoprop (Mocap), quinalphos (Bayrusil), triazophos (Hostathion), demeton-methylt (Metasystox), propetamphos (Safrotin), chlorpyrifos (Lorsban, Dursban), sulprofos (Bolstar), dioxathion (Delnav), isoxathion (Karphos), phosalone (Zolone), thiometon (Ekatin), heptenophos (Hostaquick), crotoxyphos (Ciodrin), cythioate (Proban), phencapton (G28029), DBF (De-Green, E-Z- off D), ethion, dimethoate (Cygon, De-Fend), fenthion (Baytex, Entex, Tiguvon, Spotton, Lysoff), dichlofenthion (Mobilawn), EPBP (S-Seven), These are listed approximately in order of descending toxicity. "Highly toxic" organophosphates have listed oral LD50 values (rat) less than 50 mg/kg; "moderately toxic" agents have LD50 values in excess of 50 mg/kg. These organophosphates are systemic; i.e., they are taken up by the plant and translocated into foliage and sometimes into the fruit. 1 ------- diazinon (Spectracide), phosmet (Imidan, Prolate), formothion (Anthio), pro- fenofos (Curacron), naled (Dibrom), phenthoate, trichlorfon (Dylox, Dipterex, Neguvon), pyrazophos (Afugan, Curamil), fenitrothion (Agrothion, Sumithion), cyanophos (Cyanox), pyridaphenthion (Ofunack), propylthio- pyrophosphate (Aspon), acephate (Orthene), merphos (Folex), malathion (Cythion), etrimfos (Ekamet), phoxim (Baythion), pirimiphosmethyl (Actellic), iodofenphos (Nuvanol-N), bromophos (Nexion), tetrachlorvinphos (Gardona, Rabon), temephos (Abate, Abathion). TOXICOLOGY Organophosphates poison insects and mammals primarily by phosphoryla- tion of the acetylcholinesterase enzyme at nerve endings. The enzyme is critical to normal transmission of nerve impulses from nerve fibers to innervated tissues. Some critical proportion of the tissue enzyme mass must be inactivated by phosphorylation before symptoms and signs of poisoning are manifest. At sufficient dosage, loss of enzyme function allows accumulation of acetylcholine (the impulse-transmitter substance) at cholinergic neuroeffector junctions (muscarinic effects), and at skeletal myoneural junctions and in autonomic ganglia (nicotinic effects). Organophosphates also impair nerve im- pulse transmission in the brain, causing disturbances in sensorium, motor function, behavior, and respiratory drive. Depression of respiration is the usual cause of death in organophosphate poisoning. Recovery depends ulti- mately on generation of new enzyme. Organophosphates are efficiently absorbed by inhalation, ingestion, and skin penetration. To a degree, toxicity depends on the rate at which specific Organophosphates are metabolized in the body (principally by hydrolysis in the liver), thus limiting the amount of pesticide available to attack acetylcholinesterase enzyme in other tissues. Many Organophosphates readily undergo conversion from -thions to -oxons (replacement of sulfur by oxygen). In general, -oxons are much more toxic than -thions. This conversion occurs in the environment under the influence of sunlight and in the body, mainly by the action of liver microsomes. Ultimate- ly, both -oxons and -thions are inactivated by hydrolysis at the ester linkage, yielding alkyl phosphates and phenols which are readily excreted. The hydrolysis products present little toxic hazard. One to two days after organophosphate absorption, depending on the specific organophosphate, some phosphorylated acetylcholinesterase enzyme can be de-phosphorylated (reactivated) by certain oxime antidotes. After this interval, the nature of the enzyme-phosphoryl bond changes, rendering the enzyme inactivation irreversible. New enzyme must then be generated. Very rarely, organophosphate pesticides have produced a different type of neurotoxicity, consisting of damage to the myelin substance of peripheral nerves. This leads to a protracted peripheral neuropathy, characterized by numbness, pain, and weakness in the extremities, which persists for months or years. Organophosphates associated with these chronic illnesses have included ------- some whose acute toxic potential is low; i.e., there appears to be no relation- ship between acute toxicity and the likelihood of a chronic neuropathic effect. Particularly suspect as neurotoxic agents of this type are the phenylphospho- nothioate series, cyanofenphos, EPN, leptophos, and EPBP. Other unusual properties of specific organophosphates may render them more hazardous than basic toxicity data suggest. By-products can develop in long-stored malathion which strongly inhibit the hepatic enzymes operative in malathion catabolism, thus enhancing its toxicity. Certain organophosphates are exceptionally prone to storage in fat tissue, prolonging the need for an- tidote when stored pesticide is released back into the circulation. It is possible that other unrecognized factors modify the toxicity of organophosphates. FREQUENT SYMPTOMS AND SIGNS OF POISONING Symptoms of acute poisoning develop during exposure or within 12 hours (usually within four hours) of contact. HEADACHE, DIZZINESS, WEAK- NESS, INCOORDINATION, MUSCLE TWITCHING, TREMOR, NAUSEA, ABDOMINAL CRAMPS, DIARRHEA, and SWEATING are common early symptoms. Blurred or dark vision, confusion, tightness in the chest, wheezing, productive cough, and PULMONARY EDEMA may occur. Incontinence, un- consciousness and convulsions indicate very severe poisoning. SLOW HEARTBEAT, salivation, and tearing are common. TOXIC PSYCHOSIS, with manic or bizarre behavior, has led to misdiagnosis of acute alcoholism. Slowing of the heartbeat may rarely progress to complete sinus arrest. RESPI- RATORY DEPRESSION may be fatal. Continuing daily absorption of organophosphate at intermediate dosage may cause an INFLUENZA-LIKE ILLNESS characterized by weakness, anorexia, and malaise. The very few individuals who have suffered peripheral neuropathy follow- ing organophosphate exposure exhibited diverse clinical courses. Onset of symptoms was generally slow, sometimes after an asymptomatic interval of several days following exposure. Principal symptoms have been numbness, tingling, pain and weakness of the arms and legs. Some recovered fully in a few weeks; a few others experienced muscle atrophy, leaving a degree of paresis and sensory loss. CONFIRMATION OF DIAGNOSIS CAUTION: If there are strong clinical indications of organophosphate poisoning, treat patient immediately. DO NOT WAIT for laboratory confirmation. Depressions of plasma pseudocholinesterase and/or RBC acetylcholinester- ase enzyme activities are the most satisfactory and generally available bio- chemical indices of excessive organophosphate absorption. A minimum amount of organophosphate must be absorbed to depress blood cholinesterase activities, but activities are lowered by dosage considerably less than are re- quired to cause symptomatic poisoning. The enzyme depression is usually ap- parent immediately after, or within 12-24 hours of, significant absorption of ------- organophosphate. Depression of the plasma enzyme generally persists several days to a few weeks; the RBC enzyme activity usually remains depressed longer, sometimes 1-3 months. Table 1 lists APPROXIMATE LOWER LIMITS OF NORMAL FOR PLASMA and RBC CHOHNESTERASE AC- TIVITIES of human blood, measured by generally available methods. LOWER LEVELS usually indicate excessive absorption of a cholinesterase- inhibiting chemical. Whenever possible, comparison of the test sample with a pre-exposure value offers the best confirmation of organophosphate absorp- tion: a depression of 25% or more is strong evidence of excessive absorption. In certain conditions, the activities of plasma and RBC cholinesterase are depressed in the absence of chemical inhibition. About 3% of individuals have a genetically determined low level of plasma cholinesterase. These persons are particularly vulnerable to the action of cholinesterase-inhibiting pesticides and to the drug succinylcholine, often administered to surgical patients. Patients with advanced liver disease, malnutrition, chronic alcoholism and dermato- myositis exhibit low plasma cholinesterase activities. A number of toxicants, notably carbon disulfide, benzalkonium salts, organic mercury compounds, ciguatoxins, and solanines may reduce plasma pseudocholinesterase activity. The RBC acetylcholinesterase is less likely than the plasma enzyme to be af- fected by factors other than organophosphates. It is reduced, however, in cer- tain conditions that damage the red cell membrane, such as hemolytic anemias. The alkyl phosphates and phenols to which organophosphates are hydro- lyzed in the body can often be detected in the urine during pesticide absorption and up to 48 hours thereafter. These analyses are useful in identifying the ac- tual pesticide to which workers have been exposed. Alkyl phosphate and phenol analyses can demonstrate organophosphate absorption at lower dosages than those required to depress cholinesterase activities. Detection of intact organophosphates in the blood is usually not possible ex- cept after extreme exposures, such as ingestions of pesticide. Few organophos- phates remain unhydrolyzed in the blood more than a few minutes or hours, unless the quantity absorbed is extraordinary or the hydrolyzing liver enzymes are inhibited. TREATMENT CAUTION: Persons attending the victim should avoid direct contact with heavily contaminated clothing and vomitus. Wear rubber gloves while washing pesticide from skin and hair. 1. Establish CLEAR AIRWAY by aspiration of secretions. Administer OXYGEN by mechanically assisted pulmonary ventilation. Improve tissue oxygenation as much as possible before administering atropine to minimize the risk of ventricular fibrillation. 2. Administer ATROPINE SULFATE intravenously, or intramuscularly, if IV injection is not possible. Atropine protects the muscarinic end-organs from excessive concentrations of acetylcholine. It does not reactivate the ------- TABLE 1. Approximate Lower Limits of Normal Plasma and Red Cell Cholinesterase Activities in Humans* METHOD A pH (Michel) pH Stat (Nabb- Whitfield) ChE-tel (Pfizer) A ChE-tel (Pfizer) BMC Reagent Set (Ellman-Boehringer) 1-Test Cholinesterase (EM Diagnostics) Acholest Test Paper Dupont ACA Garry-Routh (Micro) Merckotest GLC Method (Cranmer) Technicon PLASMA RBC 0.45 0.55 2.3 40 1875 3.6 >20 < 8 2.1 2.0 WHOLE BLOOD 8.0 210 Male 7.8 Female 5.8 3.0 8.2 8.0 UNITS A pH per hr per ml per min per ml ChE-tel units A ChE-tel units 3000 mU per min per ml Units per ml Minutes Units per ml /xM-SH per 3 min per ml Units per ml per min per ml per min per ml * Because measurement technique varies among laboratories, more accurate estimates of minimum normal values are usually provided by individual laboratories. Cholinesterase enzyme. Recrudescence of poisoning may occur if tissue concentrations of organophosphate remain high when the effect of atropine wears off. Atropine is the ideal antidote for muscarinic manifes- tations; it is ineffective against nicotinic actions: muscle weakness and twitching, and respiratory depression. In MODERATELY SEVERE poisoning: Adult dosage, including children over 12 years: 0.4-2.0 mg repeated every 15 minutes until atropinization is achieved: tachycardia (pulse of 140 per minute), flushing, dry mouth, dilated pupils. Maintain atropinization by repeated doses for 2-12 hours or longer depending on severity of poison- ing. Rales in the lung bases indicate inadequate atropinization. Miosis, nausea, bradycardia, and other cholinergic manifestations are also in- dicative. Dosage for children under 12 years: 0.05 mg/kg body weight, repeated every 15 minutes until atropinization is achieved. Maintain atropinization with repeated dosage of 0.02-0.05 mg/kg. SEVERELY POISONED individuals may exhibit remarkable tolerance to atropine; two or more times the dosages suggested above may be ------- needed. Persons not poisoned or only slightly poisoned, however, may develop signs of atropine toxicity from such large dosages: FEVER, muscle fibrillations, and delirium are the main signs of atropine toxicity. If these signs appear while the patient is fully atropinized, atropine administration should be discontinued, at least temporarily. 3. Draw a BLOOD SAMPLE for PLASMA and RBC CHOLINESTERASE analysis. 4. Administer PRALIDOXIME (Protopam®-Ayerst, 2-PAM) in cases of severe poisoning by organophosphate pesticides in which respiratory depression, muscle weakness and twitchings are severe. When adminis- tered early (usually less than 36 hours after poisoning) pralidoxime relieves the nicotinic effects of poisoning. Note: Pralidoxime is of questionable value in poisonings by the cholin- esterase-inhibiting carbamate compounds. (See Chapter 2). Adult dosage (including children over 12 years): 1.0 gm intravenously at no more than 0.5 gm per minute. Child's dose (under 12 years): 20-50 mg/kg (depending on severity of poisoning) intravenously, injecting no more than half the total dose per minute. Dosage of pralidoxime may be repeated in 1-2 hours, then at 10-12 hour intervals if needed. In very severe poisonings, dosage rates may be doubled. Note: slow administration of pralidoxime is strongly recommended, and may be achieved by administering the total dose in 250 ml 5% glucose solution over 30-60 minutes. If intravenous injection is not possible, pralidoxime may be given by deep intramuscular injection. CAUTION: Be prepared to assist pulmonary ventilation mechanically if respiration is depressed during and after pralidoxime in- jection. 5. OBSERVE PATIENT CLOSELY for at least 24 hours to insure that symptoms (sweating, visual disturbances, vomiting, diarrhea, chest and abdominal distress and sometimes PULMONARY EDEMA) do not recur as atropinization wears off. In very severe poisonings by ingested organophosphates, particularly the more lipophilic and slowly hydro- lyzed compounds, metabolic disposition of toxicant may require as many as 5-10 days, during which atropinization must be maintained. Rising levels of blood cholinesterase activity are a useful signal that atropine dosage can be tapered off by lengthening the intervals between doses. As dosage is reduced, the lung bases should be checked frequently for rales. If rales are heard, or if there is a return of miosis, bradycardia, sweating or other cholinergic signs, atropinization must be re-established promptly. 6. BATHE and SHAMPOO victim with soap and water if there is any chance that SKIN and HAIR are contaminated. ------- 7. IF PESTICIDE HAS BEEN INGESTED in quantity sufficient to cause poisoning, empty the stomach and intestine. A. IF victim is ALERT and respiration is not depressed, give SYRUP OF IPECAC, followed by 1-2 glasses of water to induce vomiting. Adults (12 years and over): 30 ml; children under 12 years: 15 ml. CAUTION: OBSERVE victim closely AFTER administering IPECAC. If consciousness level declines, or if vomit- ing has not occurred in 15 minutes, proceed immedi- ately to INTUBATE the stomach. Following emesis, have victim drink a suspension of 30-50 gm ACTIVATED CHARCOAL in 3-4 ounces of water to limit absorp- tion of toxicant remaining in the gut. B. IF victim is OBTUNDED or respiration is depressed, empty stomach by INTUBATION, ASPIRATION, and LAV AGE, using isotonic saline or 5% sodium bicarbonate. Because many pesticides are dissolved in petroleum distillates, emesis and intubation of the stomach involve a serious risk that solvent will be aspirated, leading to chemical pneumonitis. For this reason: (a). If victim is unconscious or obtunded and facilities are at hand, insert ENDOTRACHEAL TUBE (cuffed, if available) prior to gastric intubation. (b). Keep victim's HEAD BELOW LEVEL OF STOMACH dur- ing intubation and lavage (Trendelenburg, or left lateral decubitus, with head of table tipped downward). Keep victim's head turned to left. (c). ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. After aspiration of gastric contents and washing of stomach, instill 30-50 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through stomach tube to limit absorption of remain- ing toxicant. C. SAVE A SAMPLE of emesis, or the initial gastric washings, for chemical analysis. D. If bowel movement has not occurred in 4 hours, and if patient is fully conscious, give SODIUM SULFATE, 0.25 gm/kg, in 1-6 ounces water, as a cathartic. Magnesium sulfate and citrate are equally suitable at similar dosage if renal function is adequate. Re- tained magnesium may depress CNS function. 8. DO NOT give morphine, aminophylline, phenothiazines, reserpine, furosemide, or ethacrynic acid in poisonings by organophosphates. 9. Give adrenergic amines ONLY if there is a specific indication, such as marked hypotension. ------- 10. Rarely, in severe organophosphate poisonings, CONVULSIONS occur which are unresponsive to atropine and pralidoxime. Insure that causes unrelated to pesticide toxicity are not responsible: head trauma, cerebral anoxia, or mixed poisoning. DIAZEPAM (Valium), 5-10 mg for adults, 0.1 mg/kg for children under 6 years or 23 kg is probably the safest and most reliable anticonvulsant to use under these circumstances. Give SLOWLY (no more than half the total dose per minute) intravenously. Se-vere protracted convulsions may require additional medication, as sug- gested in the chapter on Solid Organochlorine Pesticides. CAUTION: Be prepared to assist pulmonary ventilation mechanically if respiration is depressed; to intubate the trachea, if laryngospasm occurs; and to counteract hypotensive reac- tions. 11. Persons who have been clinically poisoned by organophosphate pesticides should not be re-exposed to cholinesterase-inhibiting chemicals until symptoms and signs have resolved completely and blood cholines- terase activities have returned to at least 80 percent of pre-poisoning levels. If blood cholinesterase was not measured prior to poisoning, blood enzyme activities should reach at least minimum normal levels (Table 1) before the patient is returned to a pesticide-contaminated envi- ronment. 12. DO NOT administer atropine or pralidoxime prophylactically to workers exposed to organophosphate pesticides. It is neither practical nor medically sound to do so. ------- Chapter 2 CARBAMATE CHOLINESTERASE-INHIBITING PESTICIDES GENERAL CHEMICAL STRUCTURE o H H3C -C—O— LEAVING GROUP COMMON COMMERCIAL PESTICIDE PRODUCTS* Highly toxic**: aldicarbf (Temik), oxamyl (Vydate), carbofuran (Furadan), methomyl (Lannate, Nudrin), formetanate HC1 (Carzol, Dicarzol), aminocarb (Matacil), dimetilan (Snip Fly Bands). Moderately toxic***: promecarb (Carbamult), methiocarb (Mesurol, Draza), propoxur (Baygon), pirimicarb (Pirimor, Aphox, Rapid), bufencarb (Bux), carbaryl (Sevin). TOXICOLOGY Insecticides of this class cause reversible carbamylation of acetylcholinester- ase enzyme, allowing accumulation of acetylcholine at cholinergic neuroeffec- tor junctions (muscarinic effects), and at skeletal muscle myoneural junctions and in autonomic ganglia (nicotinic effects). Poison also impairs CNS func- tion. The carbamyl-enzyme combination dissociates more readily than the phosphorylated enzyme produced by organophosphate insecticides. This lability tends to mitigate the toxicity of carbamates, but also limits the useful- ness of blood enzyme measurements in diagnosis of poisoning. Carbamates are absorbed by inhalation, ingestion, and dermal penetration. They are ac- tively metabolized by the liver, and the degradation products are excreted by the liver and kidneys. * Listed approximately in order of decreasing toxicity. ** Acute oral LD5o in the rat less than 50 mg/kg. *** Acute oral LD50 in the rat above 50 mg/kg. t This carbamate is a systemic, i.e., it is taken up by the plant and trans- located into foliage and sometimes into the fruit. 9 ------- A few carbamate insecticides are formulated in methyl (wood) alcohol. In cases of ingestion of these formulations, the toxicology of the methanol must be taken fully into consideration: severe gastroenteric irritation, acidosis, CNS injury, and neuropathy. FREQUENT SYMPTOMS AND SIGNS OF POISONING DIARRHEA, NAUSEA, VOMITING, ABDOMINAL PAIN, PROFUSE SWEATING, SALIVATION, and BLURRED VISION are frequently reported. Other common symptoms have been dyspnea, tremor, muscle twitching, ataxia, and headache. Temporary paralysis of the extremities has also occurred. Most reported illnesses have not exceeded a few hours, and the prognosis is generally better than in organophosphate intoxications. However, in severe poisonings, one should anticipate the possibility of RESPIRATORY DEPRESSION, pulmonary edema, and convulsions. Continuing absorption of intermediate quantities may cause protracted MALAISE, weakness, and anorexia, resembling influenza. CONFIRMATION OF DIAGNOSIS CAUTION: If there is strong clinical evidence of poisoning, treat pa- tient immediately. DO NOT WAIT for laboratory confir- mation. Depressions of plasma and/or RBC cholinesterase activities may be observed following absorption of extraordinary amounts of carbamate insecticide. However, enzyme activities commonly revert to normal within a few minutes or hours. They are not, therefore, reliable detectors of carbamate poisoning; i.e., intoxication may exist when blood cholinesterase activities are normal. The rapid methods for cholinesterase estimation (ACHOLTEST, ChE-tel, MERCKOTEST) are more likely to detect depressions than the longer test methods. Table 1 in the chapter on ORGANOPHOSPHATE PESTICIDES lists the approximate lower limits of normal plasma and red cell cholinesterase- inhibiting carbamates. A normal value does not preclude carbamate insecticide poisoning. Whenever possible, comparison of the test sample with pre- exposure values offers the best confirmation of excessive carbamate absorp- tion: a depression of 25% or more is strong evidence of excessive absorption. Consult the chapter on ORGANOPHOSPHATE PESTICIDES for detailed interpretation of the blood cholinesterase tests. Measurement of carbamate metabolites in urine within 48 hours of exposure represents a specific and sensitive method for confirming absorption of several pesticides of this class. A number of government and university laboratories in contact with poison control centers can perform these tests. Specimens for such analysis should be collected as promptly as possible after exposure. 10 ------- TREATMENT CAUTION: Persons attending the victim should avoid direct contact with heavily contaminated clothing and vomitus. Wear rubber gloves while decontaminating skin and hair. 1. Establish CLEAR AIRWAY and TISSUE OXYGENATION by aspira- tion of secretions, and if necessary, by assisted pulmonary ventilation with oxygen. Improve tissue oxygenation as much as possible before ad- ministering atropine to minimize the risk of ventricular fibrillation. 2. Administer ATROPINE SULFATE intravenously, or intramuscularly if IV injection is not possible. Atropine protects the end-organs from ex- cessive concentrations of acetylcholine. It does not reactivate the cholin- esterase enzyme. Recrudescence of poisoning may occur if tissue concen- trations of carbamate remain high when the effect of atropine wears off. Atropine is the ideal antidote for muscarinic symptoms; it is ineffective against nicotinic actions such as muscle weakness and twitching, and respiratory depression. In MODERATELY SEVERE poisoning: Adult dosage, including children over 12 years: 0.4-2.0 mg repeated every 15 minutes until atropinization is achieved (tachycardia, flushing, dry mouth, mydriasis). Maintain atropinization by repeated doses for 2-12 hours, or longer, depending on severity of poisoning. The appearance of rales in the lung bases, miosis, salivation, nausea, bradycardia, are all indications of in- adequate atropinization. Dosage for children under 12 years: 0.05 mg/kg body weight repeated every 15 minutes until atropinization is achieved. Maintain atropiniza- tion with repeated dosage of 0.02-0.05 mg/kg. SEVERELY POISONED individuals may exhibit remarkable tolerance to atropine; twice the doses suggested above may be needed. Persons not poisoned, or only slightly poisoned, may develop signs of atropine toxici- ty if large doses are given: FEVER, muscle fibrillations, and delirium. If these appear while the patient is fully atropinized, atropine should be dis- continued, at least temporarily. 3. Pralidoxime (Protopam®-Ayerst, 2-PAM) is of doubtful value in poisonings by carbamate inhibitors of cholinesterase. Atropine alone is almost always an adequate antidote. Pralidoxime is probably contrain- dicated in poisonings by carbaryl, specifically. If victim of carbamate poisoning exhibits severe muscle weakness and/or respiratory depres- sion, or if poisoning involves a combination of carbamate and organo- phosphate, a dilute solution of pralidoxime (total dose in 250 ml 5°/o glucose solution) may be given cautiously IV. The infusion should be ter- minated if patient's condition worsens. Pralidoxime dosage: adults, 1.0 gm; for children under 12 years, 20-50 mg/kg. 4. OBSERVE treated patients closely at least 24 HOURS to insure that symptoms (possibly pulmonary edema) do not recur as atropinization wears off. In very severe poisonings, metabolic disposition of toxicant 11 ------- may require several hours or days during which atropinization must be maintained. Markedly lower levels of urinary metabolites indicate that atropine dosage can be tapered off. As dosage is reduced, check the lung bases frequently for rales. If rales are heard, or if nausea, salivation, or bradycardia returns, RE-ESTABLISH ATROPINIZATION promptly. 5. BATHE and SHAMPOO victim with soap and water if there is any chance that SKIN and HAIR are contaminated. 6. If pesticide has been INGESTED in quantity sufficient to cause poison- ing, empty the stomach and intestine. A. If victim is alert and respiration is not depressed, give SYRUP OF IPECAC, followed by 1-2 glasses of water to induce vomiting; adults (including children over 12), 30 ml; children (under 12 years), 15ml. CAUTION: OBSERVE victim closely AFTER administering IPECAC. If consciousness level declines, or if vomit- ing has not occurred in 15 minutes, proceed immedi- ately to INTUBATE the stomach. Following emesis, have victim drink a suspension of 30-50 gm ACTIVATED CHARCOAL in 3-4 ounces of water to bind toxicant remaining in the gastrointestinal tract. B. If victim is OBTUNDED or respiration is depressed, empty stomach by INTUBATION, ASPIRATION, and LAV AGE, using isotonic saline or 5% sodium bicarbonate. Because many pesticides are dissolved in petroleum distillates, emesis and intubation of the stomach involve a serious risk that solvent will be aspirated, leading to chemical pneumonitis. For this reason: (a). If victim is unconscious or obtunded and facilities are at hand, insert ENDOTRACHEAL TUBE (cuffed, if available) prior to gastric intubation. (b). Keep victim's HEAD BELOW LEVEL OF STOMACH dur- ing intubation and lavage (Trendelenburg, or left lateral decubitus, with head of table tipped downward). Keep victim's head turned to left. (c). ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. After aspiration of gastric contents and washing of stomach, instill 30-50 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through the tube to limit absorption of remaining toxicant. C. SAVE A SAMPLE of emesis or initial gastric washings for chemical analysis. D. If bowel movement has not occurred in 4 hours and patient is fully conscious, give SODIUM SULFATE, 0.25 gm/kg in 1-6 ounces of water, as a cathartic. Magnesium sulfate or citrate is equally suitable if renal function is satisfactory. 12 ------- 7. DO NOT give morphine, aminophylline, phenothiazines, reserpine, furosemide, or ethacrynic acid. 8. Give adrenergic amines ONLY if there is a specific indication, such as severe hypotension. 9. CONVULSIONS are RARE manifestations of poisoning by carbamates. If they occur, causes other than direct carbamate action should be con- sidered: cerebral anoxia, head trauma, mixed poisoning. Although not tested in these circumstances, DIAZEPAM (Valium) is probably the an- ticonvulsant of choice. Dosage for adults and children over 6 years or 23 kg body weight is 5-10 mg given slowly intravenously (no more than half total dose per minute), or intramuscularly (deep). Dosage for children under 6 years or 23 kg body weight is 0.1 mg/kg. Repeat this dosage every 2-4 hours if needed to control convulsions. Be prepared to intubate and to assist pulmonary ventilaton mechanically if respiration is depressed. Hypotensive reactions may also occur. 10. Persons who have been clinically poisoned by carbamate pesticides should not be re-exposed to cholinesterase-inhibiting chemicals until symptoms and signs have resolved completely, and normal blood cholin- esterase activities have been demonstrated. 11. DO NOT administer atropine prophylactically to workers exposed to car- bamate insecticides. It is neither practical nor medically sound to do so. 13 ------- Chapters SOLID ORGANOCHLORINE PESTICIDES CHEMICAL STRUCTURES HEXACHLOROBENZENE ENDOSULFAN HEPTACHLOR METHOXYCHLOR * COMMON COMMERCIAL PESTICIDE PRODUCTS Highly toxic: endrin (Hexadrin), a stereoisomer of dieldrin. Moderately toxic: aldrin (Aldrite, Drinox), endosulfan (Thiodan), dieldrin (Dieldrite), toxaphene (Toxakil, Strobane-T), lindane (Gammexane), benzene hexachloride (BHC, HCH), DDT (chlorophenothane), heptachlor, kepone, terpene polychlorinates (Strobane), chlordane (Chlordan), dicofol (Kelthane), chlorobenzilate (Acaraben), mirex, methoxychlor (Marlate), dienochlor (Pen- tac), hexachlorobenzene (HCB), ethylan (Perthane). All except HCB are insec- ticides or acaricides; HCB is a fungicide. The U.S. Environmental Protection Agency has sharply curtailed the availability of many organochlorines, particularly DDT, dieldrin, and chlor- dane. Others, however, are still the active ingredients of various home and garden products and some agricultural and structural pest control agents. Hex- achlorobenzene is used as a seed protectant. Lindane may no longer be used in continuous vaporizers, but it is the active ingredient of many products for pest control in the home and on the farm. It is the active ingredient of the scabicide Kwell®. TOXICOLOGY Most organochlorines are efficiently absorbed from the gut and across the skin. In adequate dosage, they interfere with axonic transmission of nerve im- pulses and, therefore, disrupt the function of the nervous system, principally that of the brain. This results in behavioral changes, sensory and equilibrium disturbances, involuntary muscle activity, and depression of vital centers, par- ticularly those controlling respiration. Adequate doses of some organo- chlorines increase myocardial irritability, and stimulate synthesis of hepatic drug-metabolizing enzymes. Listed approximately in order of decreasing toxicity. 14 ------- Chlordane has apparently induced a few cases of self-limited megaloblastic anemia after protracted low-level exposures. The condition has resolved following termination of exposure. Kepone has caused nervousness, tremor, incoordination, weakness and in- fertility in excessively exposed workers. Clinical improvement has occurred as the pesticide was excreted. Endrin is more toxic to the liver and kidneys than the other organochlorines at comparable dosages. Prolonged ingestion of HCB-treated grain produced porphyria cutanea tar- da in several thousand Turkish citizens who mistakenly ate the seed grain. Disease was manifest as excretion of red urine, bullous dermatitis, hyper- pigmentation, generalized hair growth, muscle wasting and liver enlargement. Slow improvement occurred when HCB ingestion was stopped. A series of anecdotal reports of bone marrow injury has tended to indict lin- dane as a hematotoxic agent in certain predisposed individuals, but no rela- tionship has been proved. Lindane, methoxychlor, terpene poly chlorinates, chlorobenzilate, dicofol, and the constituents of chlordane, except heptachlor and oxychlordane, are excreted rapidly by humans, usually within 3-4 days of ingestion. Dieldrin, aldrin, endrin, hexachlorobenzene, heptachlor, and oxychlordane are excreted within weeks to several months of absorption by humans. DDT, kepone, mirex, and the beta isomer of benzene hexachloride are excreted very slowly, requiring months or years for elimination. The excretion kinetics of perthane, kelthane, and dienochlor are not known. Because of their lipophilicity, all organochlorines are likely to be excreted in the milk of lactating women. FREQUENT SYMPTOMS AND SIGNS OF POISONING APPREHENSION, EXCITABILITY, DIZZINESS, HEADACHE, DIS- ORIENTATION, WEAKNESS, PARESTHESIAE, muscle twitching, tremor, tonic and clonic CONVULSIONS (often epileptiform), and uncon- sciousness are the major manifestations. Soon after ingestion, nausea and vomiting commonly occur. When chemicals are absorbed dermally, apprehen- sion, twitching, tremors, confusion, and convulsions may be the first symp- toms. Respiratory depression is caused by the pesticide and by the petroleum solvents in which these pesticides are usually dissolved. Pallor occurs in moderate to severe poisoning. Cyanosis may result as convulsive activity in- terferes with respiration. Even though convulsive activity may be severe, the prognosis in poisonings by these agents is far from hopeless. Although fatalities have occurred follow- ing absorption of large amounts of some organochlorines, there is a substan- tial likelihood of complete recovery if convulsions can be controlled, and vital functions sustained. 15 ------- CONFIRMATION OF DIAGNOSIS Pesticide and/or metabolites can usually be identified in blood or urine by gas-liquid chromatographic examination of samples taken within 72 hours of poisoning. These tests can be performed by some private laboratories, and by state health department and university laboratories supported by the U.S. En- vironmental Protection Agency. Such laboratories can be reached through poison control centers. Some chlorinated hydrocarbon pesticides (notably DDT) persist in the serum for weeks or months after absorption, but most are excreted in a few days. DO NOT DELAY TREATMENT of acute poisoning pending confirmatory blood analysis. Detection of chlorinated hydrocarbon residues in blood or tissues does not, of itself, indicate poisoning; actual con- centrations are critical to a diagnosis of poisoning. TREATMENT 1. Establish CLEAR AIRWAY and TISSUE OXYGENATION by aspira- tion of secretions, and, if necessary, by assisted pulmonary ventilation with oxygen. 2. CONTROL CONVULSIONS. DIAZEPAM (VALIUM®) is a valuable anticonvulsant. Adult dosage, including children over 6 years of age or 23 kg in weight: 5-10 mg (1-2 ml) slowly, intravenously (no faster than one ml per minute), or give total dose intramuscularly (deep). Repeat in 2-4 hours if needed. Dosage for children under 6 years or 23 kg in weight: 0.1 mg/kg (0.02 ml/kg) intravenously, no faster than half the total dose per minute, or give total dose intramuscularly (deep). Repeat in 2-4 hours if needed. CAUTION: Administer intravenous diazepam slowly to avoid irrita- tion of the vein, hypotension, and respiratory depression. A. Persons suffering SEVERE PROTRACTED CONVULSIONS may require additional anticonvulsant medication. Agents that have been used successfully in the past are pentobarbital (Numbutal®), phenytoin (Dilantin®), thiopental (Pentothal®), and succinyl- choline (Anectine®). CAUTION: Be prepared to maintain pulmonary ventilation me- chanically if respiration is depressed during adminis- tration of anticonvulsants. Laryngospasm sometimes occurs during anticonvulsant therapy, and may neces- sitate tracheostomy. (a). PENTOBARBITAL: 5 mg/kg body weight, or 0.20 ml/kg body weight, using the usual 2.5% solution. If possible, inject solution intravenously, at a rate not exceeding 25 mg (one ml) 16 ------- per minute until convulsions are controlled. If intravenous ad- ministration is not possible, give total dose rectally, not ex- ceeding 5 mg/kg body weight (0.20 ml/kg of 2.5% solution). (b). PHENYTOIN: loading dose 15-18 mg/kg. Maintenance dose 4-8 mg/kg q 4-24 hours as needed. Intramuscular administra- tion is not recommended. Give IV slowly at no more than 20% total dose per minute. (c). THIOPENTAL (PENTOTHAL): a solution of one gm in 500 ml of 5% glucose in water is given by intravenous drip at a rate just sufficient to suppress convulsions. (d). SUCCINYLCHOLINE: occasionally, curarization may be re- quired to stop seizures. Prior to curarization, the trachea must be intubated, and pulmonary ventilation maintained mechani- cally. Blood gases and pH must be monitored. A person expe- rienced in general anesthesia should conduct these procedures. 3. BATHE and SHAMPOO the victim vigorously with soap and water if skin and hair have been contaminated. 4. IF PESTICIDE HAS BEEN INGESTED in quantity sufficient to cause poisoning, the stomach and intestine must be emptied. A. IF victim is ALERT and gag reflex is not depressed, give SYRUP OF IPECAC to induce vomiting (adults and children 12 years and older: 30 ml; children under 12: 15 ml), followed by 1-2 glasses of water. CAUTION: OBSERVE the VICTIM closely after administering IPECAC. If consciousness level declines, or if vomiting has not occurred in 15 minutes, proceed im- mediately to INTUBATE stomach. Following emesis, have victim drink a suspension of 30-50 gm AC- TIVATED CHARCOAL in 3-4 ounces of water to limit absorption of toxicant remaining in the gut. B. If the victim is NOT FULLY ALERT, empty the stomach immedi- ately by INTUBATION, ASPIRATION, and LAV AGE, using isotonic saline or 5% sodium bicarbonate. Because many pesticides are dissolved in petroleum distillates, emesis and intubation of the stomach involve a serious risk that solvent will be aspirated, leading to chemical pneumonitis. For this reason: (a). If victim is unconscious or obtunded and if facilities are at hand, insert an ENDOTRACHEAL TUBE (cuffed, if avail- able) prior to gastric intubation. (b). Keep victim's HEAD BELOW LEVEL OF STOMACH and turned to left during intubation and lavage. (Trendelenburg, or left lateral decubitus, with head of table tipped downward). (c). ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. 17 ------- C. After aspiration of gastric contents and washing of stomach, instill 30-50 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through stomach tube to limit absorption of remaining toxicant. DO NOT instill milk, cream, or other substances containing vegetable or animal fats, which enhance absorption of chlorinated hydrocarbons. D. -SAVE A SAMPLE of emesis or gastric washings for chemical analysis. E. If bowel movement has not occurred in 4 hours and if patient is fully conscious, give SODIUM SULFATE, 0.25 gm/kg in 1-6 ounces of water, as a cathartic. Magnesium sulfate and citrate are as suitable as sodium sulfate if renal function is adequate. Retained magnesium may depress CNS function. 5. DO NOT give epinephrine or other adrenergic amines, because of the enhanced myocardial irritability induced by chlorinated hydrocarbons. 6. CHOLESTYRAMINE resin may accelerate the biliary-gastrointestinal excretion of the more slowly eliminated organochlorine compounds. This is usually administered in 3-8 gm doses, 4 times a day, before meals and at bedtime. Dose should be mixed with a pulpy fruit or liquid. Prolonged treatment (several weeks or months) may be necessary. 7. During convalescence, enhance CARBOHYDRATE, PROTEIN, and VITAMIN intake by diet or parenteral therapy to minimize injury to the liver. 18 ------- Chapter 4 PENTACHLOROPHENOL CHEMICAL STRUCTURE Cl Cl Cl Cl COMMON COMMERCIAL PESTICIDE PRODUCTS Pentachlorophenol or Sodium Pentachlorophenate, PCP, Dow Pentachlo- rophenol, Dowicide EC-7, Penchlorol, Pentacon, Penwar, Veg-I-Kill, penta, Wood Preserver, Wood Tox 140, Purina Insect Oil Concentrate, Garden Ter- mi Tox, Usol Cabin Oil, Certified KiltroI-74 Weed Killer, Ciba-Geigy On- track OSS, 4 or 5, Ortho Triox Liquid Vegetation Killer, Black Leaf Grass Weed and Vegetation Killer Spray, DP-2 Antimicrobial, Priltox, Sinituho. Pentachlorophenol is used as an herbicide, defoliant, wood preservative, germicide, fungicide, and molluscicide. It is an ingredient of many formulated mixtures sold for one or more of these purposes. Pentachlorophenol volatilizes from treated wood and fabric. Excessively treated interior surfaces may represent a source of intensive PCP exposure. TOXICOLOGY Pentachlorophenol irritates the skin, eyes, and upper respiratory mucous membranes. It is efficiently absorbed across the skin, the lung, and the gastro- intestinal lining. Like the nitrophenolic compounds, it stimulates cellular ox- idative metabolism by uncoupling phosphorylation. In common with other phenols, it is toxic to the liver, kidney, and central nervous system. Impurities in the technical formulation may be responsible for chloracne in workers regularly exposed. Most severe poisonings have occurred in workers exposed to hot environ- ments. However, a major epidemic of poisoning occurred in an American hospital among newborn infants who absorbed PCP from treated diapers. Dehydration and metabolic acidosis are important features of poisoning in children. Albuminuria, glycosuria, and elevated BUN reflect renal injury. Liver enlargement has been observed in some cases. Anemia and leukopenia have occurred in some chronically exposed workers, but leukocytosis is more com- monly found in acute poisoning. 19 ------- FREQUENT SYMPTOMS AND SIGNS OF POISONING IRRITATION of nose, throat, eyes, and skin is the most common symptom of exposure to PCP. Severe or protracted exposure may result in CONTACT DERMATITIS. Intensive occupational exposure has resulted in chloracne. PROFUSE SWEATING, HEADACHE, WEAKNESS, and NAUSEA are the most consistent presenting symptoms of systemic poisoning by absorbed PCP. FEVER is usually present but may be minimal or absent. TACHYCAR- DIA, TACHYPNEA, and PAIN in the CHEST and ABDOMEN are often prominent. THIRST is usually intense, but may be masked by nausea and vomiting. DECLINING MENTAL ALERTNESS may progress to stupor and/or convulsions. Protracted exposure may result in WEIGHT LOSS from increased basal metabolic rate. CONFIRMATION OF DIAGNOSIS PCP can be measured in blood, urine, and adipose tissue by gas-liquid chromatography. Up to about 100 parts per billion may be found in the blood and urine of persons having no recognized exposure. Based on studies of per- sons occupationally exposed to PCP, manifestations of systemic toxicity prob- ably do not appear in adults until blood and urine concentrations reach at least one part per million (0.1 mg%, or 1,000 parts per billion). If poisoning is strongly suspected on grounds of exposure, symptoms, and signs, DO NOT POSTPONE TREATMENT until diagnosis is confirmed. TREATMENT 1. BATHE and SHAMPOO contaminated SKIN and HAIR promptly with soap and water, or water alone if soap is not available. 2. FLUSH chemical from EYES with copious amounts of clean water. 3. IN EVENT OF SYSTEMIC POISONING: A. REDUCE ELEVATED BODY TEMPERATURE BY PHYSICAL MEANS. Administer sponge baths and cover victim with low- temperature blankets. In fully conscious patients, administer cold, sugar-containing liquids by mouth as tolerated. B. Administer OXYGEN continuously by mask to minimize tissue anoxia. C. Unless there are manifestations of cerebral edema, administer IN- TRAVENOUS FLUIDS at maximum tolerated rates to enhance urinary excretion of toxicant and to support physiologic mechan- isms for heat loss. Monitor fluid balance, blood electrolytes and sugar, adjusting IV infusions to stabilize electrolyte concentra- tions, Follow urine contents of albumin and cells. In the presence of CEREBRAL EDEMA, intravenous FLUIDS must be administered very CAUTIOUSLY to avoid increasing the cerebral injury. 20 ------- D. Administer SEDATIVES, if necessary, to control apprehension and excitement. DIAZEPAM® (Valium) should be valuable, although its use has not been reported in this type of poisoning. Give slowly, intravenously, 5-10 mg in the adult, 0.1 mg/kg in children. Amobarbital or pentobarbital, 100-200 mg IM or slowly IV, every 4-6 hours may be needed. (Children's dose: up to 5 mg/kg.) CAUTION: Be prepared to assist pulmonary ventilation mechani- cally in event of respiratory depression, and to counteract hypotensive reactions. 4. If toxicant has been INGESTED, evacuate the stomach and intestine. A. If victim is alert and respiration is not depressed, give SYRUP OF IPECAC, followed by 1-2 glasses of water, to induce vomiting. (Adults, 12 years and older: 30 ml; children under 12: 15 ml). CAUTION: OBSERVE the victim closely AFTER administering IPECAC. If consciousness level declines, or if vomit- ing has not occurred in 15 minutes, proceed im- mediately to INTUBATE the stomach. Following emesis, have the victim drink a suspension of 30-50 gm ACTIVATED CHARCOAL in 3-4 ounces of water to bind toxicant remaining in the gastrointestinal tract. B. If victim is not fully alert, empty the stomach immediately by IN- TUBATION, ASPIRATION, and LAV AGE, using isotonic saline or 5% sodium bicarbonate. Because PCP is commonly dissolved in petroleum distillates, emesis and intubation of the stomach involve a serious risk that solvent will be aspirated, leading to chemical pneumonitis. For this reason: (a). If victim is unconscious or obtunded and facilities are at hand, insert an ENDOTRACHEAL TUBE (cuffed, if available) prior to gastric intubation. (b). Keep victim's HEAD BELOW LEVEL OF THE STOMACH, turned to left, during intubation and lavage. (Trendelenburg, or left lateral decubitus, with head of table tipped downward). (c). ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. (d). After aspiration of gastric contents and washing of stomach, instill 30 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through a stomach tube to limit absorption of remain- ing toxicant. Do NOT instill milk, cream, or other materials containing vegetable or animal fats, which are likely to enhance absorption. C. If bowel movement has not occurred in 4 hours and patient is fully conscious, give SODIUM SULFATE as a cathartic: 0.25 gm/kg body weight in 1-6 ounces of water. Magnesium sulfate and citrate 21 ------- are equally suitable unless renal function is impaired; retention of magnesium may depress CNS function and alter myocardial irrita- bility. 5. DO NOT administer atropine, aspirin, or other antipyretics to control fever. These are likely to enhance the toxicity of phenolic compounds. 6. During convalescence, administer high-calorie, high-vitamin diet to restore body fat and carbohydrate. 7. Discourage subsequent contact with the toxicant for at least 4 weeks to allow full restoration of normal metabolic processes. 8. HEMODIALYSIS and HEMOPERFUSION may be considered in PCP poisoning, although phenols are extensively bound to plasma protein. EXCHANGE TRANSFUSION was used to rescue the infants inadver- tently poisoned by PCP in a hospital. Unless renal and liver functions are impaired, PCP is rapidly eliminated from the blood and tissues. 22 ------- Chapter 5 NITROPHENOLIC AND NITROCRESOLIC HERBICIDES GENERAL CHEMICAL STRUCTURE NO2 O2N V ^O—H (or ESTER) (ALKYL) (ALKYL) COMMON COMMERCIAL PESTICIDE PRODUCTS Dinitrophenol (Chemox PE), dinitrocresol (DNOC, DNC, Sinox, Chemsect DNOC, Elgetol 30, Nitrador, Selinon, Trifocide), dinoseb (DNBP, Dinitro, Basanite, Caldon, Chemox General, Chemox PE, Chemsect DNBP, Dinitro-3, Dinitro General, Dow General Weed Killer, Dow Selective Weed Killer, Dynamyte, Elgetol 318, Gebutox, Kiloseb, Nitropone C, Premerge 3, Sinox General, Subitex, Unicrop DNBP, Vertac Dinitro Weed Killer), dinosam (DNAP), dinoprop, dinoterbon, dinoterb, dinosulfon, bmapacryl (Morocide, Endosan, Ambox, Dapacryl), dinobuton (Acrex, Dessin, Dinofen, Drawinol, Talan), dinopenton, dinocap (Crotothane, Karathane). Several combinations are widely used: Dyanap and Klean Krop = dinoseb + nap- talam; Ancrack = sodium salts of dinoseb + naptalam; Naptro = dinitrophenol + naptalam. TOXICOLOGY These materials should be regarded as highly toxic to humans and animals. Most nitrophenols and nitrocresols are well absorbed from the gastrointestinal tract, across the skin, and by the lung when fine droplets are inhaled. Except in a few sensitive individuals, aromatic nitro-compounds are only moderately irritating to the skin. Like other phenols, they are toxic to the liver, kidney, and nervous system. The basic mechanism of toxicity is a stimulation of oxida- tive metabolism in cell mitochondria, by interference with the normal coupling of carbohydrate oxidation to phosphorylation (ADP to ATP). Increased oxi- dative metabolism leads to pyrexia, tachycardia, and dehydration, and ulti- mately depletes carbohydrate and fat stores. Most severe poisonings from absorption of these compounds have occurred in workers who were concur- rently exposed to hot environments. Pyrexia and direct action on the brain cause cerebral edema, manifest clinically as a toxic psychosis and sometimes 23 ------- convulsions. Liver parenchyma and renal tubules show degenerative changes. Albuminuria, pyuria, hematuria, and increased BUN are often prominent signs of renal injury. Agranulocytosis has occurred in humans following large doses of dinitrophenol. Cataracts have occurred in some chronically poisoned laboratory species, but this effect has not been observed in humans. Nitrophenols and nitrocresols are efficiently excreted by the kidneys, and there is some hepatic excretion into the bile. Unless the absorbed dose was ex- tremely high, or kidney function is impaired, nearly complete elimination from the body can be expected within 3-4 days. Death in nitrophenol poisoning is followed promptly by intense rigor mortis. FREQUENT SYMPTOMS AND SIGNS OF POISONING YELLOW STAINING of skin and hair often signify contact with a nitro- phenolic chemical. Staining of the sclerae and urine indicate absorption of potentially toxic amounts. PROFUSE SWEATING, HEADACHE, THIRST, MALAISE, and LASSITUDE are the common early symptoms of poisoning. WARM, FLUSHED SKIN, TACHYCARDIA, and FEVER characterize a serious degree of poisoning. APPREHENSION, restlessness, anxiety, manic behavior, or unconsciousness reflect severe cerebral injury. CONVULSIONS occur in the most severe poisonings. Cyanosis, tachypnea and dyspnea result from stimulation of metabolism, pyrexia, and tissue anoxia. Weight loss oc- curs in persons chronically poisoned at low dosages. CONFIRMATION OF DIAGNOSIS Unmetabolized nitrophenols and nitrocresols can be identified spectro- photometrically, or by gas-liquid chromatography, in the serum and urine at concentrations well below those necessary to cause poisoning. If poisoning is probable, DO NOT AWAIT CONFIRMATION before commencing treat- ment. TREATMENT 1. WASH contaminated SKIN and HAIR promptly with soap and water, or with water alone if soap is not available. 2. FLUSH chemical from EYES with copious amounts of clean water. 3. IN EVENT OF SYSTEMIC POISONING: A. REDUCE ELEVATED BODY TEMPERATURE BY PHYSICAL MEANS. Administer sponge baths and cover victim with Idw- temperature blankets. In fully conscious patients, administer cold, sugar-containing liquids by mouth as tolerated. B. Administer OXYGEN continuously by mask to minimize tissue anoxia. 24 ------- C. Unless there are manifestations of cerebral edema, administer IN- TRAVENOUS FLUIDS at maximum tolerated rates to enhance uri- nary excretion of toxicant and to support physiologic mechanisms for heat loss. IN the presence of CEREBRAL EDEMA, intravenous FLUIDS must be administered very CAUTIOUSLY to avoid increas- ing the cerebral injury. Monitor fluid balance, blood electrolytes and sugar, adjusting IV infusions to stabilize electrolyte concentrations. Follow urine contents of albumin and cells. Follow serum alkaline phosphatase, GOT, and LDH to evaluate liver injury. D. Administer SEDATIVES, if necessary, to control apprehension, ex- citement, and/or convulsions. Although not previously used in this type of poisoning, DIAZEPAM (Valium® ) should help: adult dose, 5-10 mg slowly IV, or IM (deep); child's dose, 0.1 mg/kg. Repeat every 2-4 hours as needed. Amobarbital or pentobarbital may be needed. Dose in adults: 200 mg, IM or slowly IV, every 4-6 hours; child's dose: up to 5 mg/kg. CAUTION: Be prepared to counteract respiratory depression and hypotension which may follow administration of anticonvulsants and sedatives. 4. If toxicant has been INGESTED, evacuate the stomach and intestine. A. If victim is alert and respiration is not depressed, give SYRUP of IPECAC, followed by 1-2 glasses of water, to induce vomiting (adults 12 years and older: 30 ml; children under 12: 15 ml). CAUTION: OBSERVE victim closely AFTER administering IP- ECAC. If consciousness level declines, or if vomiting has not occurred in 15 minutes, immediately IN- TUBATE, ASPIRATE, and LAV AGE the stomach. Following emesis, have victim drink a suspension of 30-50 gm AC- TIVATED CHARCOAL in 3-4 ounces of water to bind toxicant remaining in the gastrointestinal tract. B. IF VICTIM IS NOT FULLY ALERT, empty the stomach immedi- ately by INTUBATION, ASPIRATION, and LAV AGE, using isotonic saline or 5% sodium bicarbonate. Because these pesticides are usually dissolved in petroleum distillates, emesis and intubation of the stomach involve serious risk that solvent will be aspirated, leading to chemical pneumonitis. For this reason: (a). If victim is unconscious or obtunded and facilities are at hand, insert an ENDOTRACHEAL TUBE (cuffed, if available) prior to gastric intubation. (b). Keep victim's HEAD BELOW LEVEL OF THE STOMACH and turned to the left, during intubation and lavage (Trendelenburg, or left lateral decubitus, with head of table tipped downward). 25 ------- (c). ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. (d). After aspiration of gastric contents and washing of stomach, instill 30-50 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through the stomach tube to limit absorption of re- maining toxicant. Do NOT instill cream, milk, or other materials containing vegetable or animal fats, as these are like- ly to enhance absorption. C. If bowel movement has not occurred in 4 hours, and if patient is fully conscious, give SODIUM SULFATE as a cathartic: 0.25 gm/kg body weight in 1-6 ounces of water. Magnesium sulfate and citrate are equally suitable unless renal function is impaired; retention of magnesium may depress CNS function and alter myocardial irrita- bility. 5. DO NOT administer atropine, aspirin, or other antipyretics to control fever. Animal tests indicate that aspirin enhances, rather than reduces, the toxicity of nitrophenolic and nitrocresolic compounds. 6. During convalescence, administer high-calorie, high-vitamin diet to facil- itate repletion of body fat and carbohydrate. 7. Discourage subsequent contact with the toxicant for at least 4 weeks, to allow full restoration of normal metabolic processes. 8. HEMODIALYSIS and HEMOPERFUSION may be considered in severe poisonings by aromatic nitro-compounds, although most phenols are extensively bound to plasma proteins. EXCHANGE TRANSFU- SION is another option in poisonings characterized by impaired renal function. So long as renal and liver functions are intact, these com- pounds are efficiently excreted. 26 ------- Chapter 6 CHLOROPHENOXY COMPOUNDS GENERAL CHEMICAL STRUCTURE (or CH3) Cl Cl — O — (Cl) O II _ C — O — H or n COMMON COMMERCIAL PESTICIDE PRODUCTS Several hundred commercial products contain chlorophenoxy herbicides in various concentrations and combinations. Following are names of widely advertised formulations. In some cases, the same name is used for products with different ingredients. Exact composition must therefore be determined from product label. 2,4-D, or 2,4-dichlorophenoxyacetic acid (Weedonef, Agrotec, Amoxone, Aqua-Kleen, BH 2,4-D, Chipco Turf Herbicide "D", Chloroxone, Crop Rider, D50, Dacamine 4D, Ded-Weed, Desormone, Dinoxol, DMA4, Dor- mone, Emulsamine BK, Emulsamine E-3, Envert DT or 171, Esteron 99 Con- centrate, Esteron Four, Esteron Brush Killer, Estone, Fernoxone, Fernimine, Ferxone, Fernesta, Formula 40, Hedonal, Herbidal, Lawn-Keep, Macondray, Miracle, Netagrone 600, Pennamine D, Planotox, Plantgard, Rhodia, Salvof, Spritz-Hormin/2,4-D, Spritz-Hormit/2,4-D, Superormone Concentre, Super D Weedone, Transamine, U46, Verton 2D, Visko-Rhap, Weed-B-Gon, Weedar, Weed-Rhap, Weed Tox, Weedtrol, De broussaillant 600, Lithate, Dicotox, Field Clean Weed Killer). 2,4-DB is the butyric acid homologue of 2,4-D. Dichlorprop is the propionic acid homologue. 2,4,5-T or 2,4,5-trichlorophenoxyacetic acid (Brush-Rhap, Dacamine 4T, Debroussaillant Concentre, Ded-Weed Brush Killer, Esteron 245, Fence Rider, Forron, Inverton 245, Line Rider, Spontox, Super D Weedone, Tormona, Transamine, Trinoxol, Trioxone, U46, Veon 245, Verton 2T, Weedar, Weedone Envert T). Common mixtures of 2,4-D and 2,4,5-T are: Dacamine 2D/2T, Esteron Brush Killer, Rhodia Low Volatile Brush Killer No. 2, U46 Special, Tributon, Visko-Rhap LV2D-2T, and Transamine. f A product of identical name containing pentachlorophenol (Chapter 4) as the active ingredient has been discontinued by Amchem Products Co. t A product of identical name marketed by the Crystal Chemical Company contains cacodylic acid as the active ingredient (Chapter 10). 27 ------- 2,4,5-TP (Silvex) is the propionic acid homologue of 2,4,5-T. Kuron is a low volatile ester of 2,4,5-TP. 2,4,5-TB is the butyric acid homologue of 2,4,5-T. Fenac or chlorfenac is 2,3,6-trichlorophenylacetic acid. Dicamba (Banvel) is dichloroanisic acid. MCPA, MCPB, MCPB-Ethyl, MCPCA and MCPP (Mecoprop) are 2-methyl, 4-chlorophenoxy aliphatic acids and esters. TOXICOLOGY Some of the chlorophenoxy acids, salts, and esters are moderately irritating to skin, eyes, and respiratory and gastrointestinal linings. In a few individuals, local depigmentation has apparently resulted from prolonged and repeated dermal contact with chlorophenoxy materials. The chlorophenoxy compounds are absorbed across the gut wall, lung, and skin. They are not significantly fat storable. Excretion occurs within hours, or at most, days, primarily in the urine. Given in large doses to experimental animals, 2,4-D causes vomiting, diar- rhea, anorexia, weight loss, ulcers of the mouth and pharynx, and toxic injury to the liver, kidneys, and central nervous system. Myotonia (stiffness and in- coordination of hind extremities) develops in some species and is apparently due to CNS damage: demyelination has been observed in the dorsal columns of the cord, and EEC changes have indicated functional disturbances in the brains of heavily dosed experimental animals. Ingestion of large amounts of chlorophenoxy acids has resulted in severe metabolic acidosis in humans. Such cases have been associated with electro- cardiographic changes, myotonia, muscle weakness, myoglobinuria, and ele- vated serum creatine phosphokinase, all reflecting injury to striated muscle. Because chlorophenoxy acids are weak uncouplers of oxidative phosphoryla- tion, extraordinary doses may produce hyperthermia from increased produc- tion of body heat. PolyChlorinated DibenzoDioxin (CDD) compounds are generated in the synthesis of 2,4,5-T. The 2,3,7,8-Tetra CDD form is extraordinarily toxic to multiple mammalian tissues. Hexa- hepta-, and octa-compounds exhibit less systemic toxicity, but are the likely cause of chloracne (a chronic, disfiguring skin condition) seen in workers engaged in the manufacture of 2,4,5-T, and certain other chlorinated organic compounds. Although toxic effects, notably chloracne, have been observed in manufacturing plant workers, they have not been observed in formulators or applicators regularly exposed to 2,4,5-T. The medical literature contains several reports of peripheral neuropathy following what seemed to be minor dermal exposures to 2,4-D. It is not cer- tain that exposures to other neurotoxicants were entirely excluded in these cases. Single doses of 5 mg/kg body weight of 2,4-D and 2,4,5-T have been ad- ministered to human subjects without any adverse effects. One subject con- sumed 500 mg of 2,4-D per day for 3 weeks without experiencing symptoms or signs of illness. 28 ------- FREQUENT SYMPTOMS AND SIGNS OF POISONING Chlorophenoxy compounds are moderately IRRITATING to skin and mucous membranes. Inhalation of sprays may cause burning sensations in the nasopharynx and chest, and coughing may result. Prolonged inhalation some- times causes dizziness. When INGESTED, high concentrations of chlorophenoxy compounds may irritate the mouth, throat, and gastrointestinal tract. Prompt EMESIS, CHEST PAIN (from esophagitis), ABDOMINAL PAIN, and DIARRHEA commonly ensue. Injury to the GI tract does not usually progress to ulceration or perforation. Absorbed chlorophenoxy compounds have caused FIBRILLARY MUSCLE TWITCHING, skeletal muscle tenderness, and MYOTONIA (stiffness of muscles of the extremities). Ingestion of very large amounts has produced METABOLIC ACIDOSIS, fever, tachycardia, hyper- ventilation, vasodilatation and sweating. Particular cases have been charac- terized by coma and convulsions. CONFIRMATION OF DIAGNOSIS Gas-liquid chromatographic methods are available for detecting and mea- suring the chlorophenoxy compounds in blood and urine. These analyses are useful in confirming and assessing the magnitude of chlorophenoxy absorp- tion. Urine samples should be collected as soon as possible after exposure because the herbicides may be almost completely excreted in 24-72 hours, depending on the extent of toxicant absorption. Analyses can be performed at special laboratories operated by state health departments, chemical com- panies, universities, and government facilities. If circumstances indicate strongly that excessive exposure to any of these compounds has occurred, ini- tiate appropriate treatment measures immediately, not waiting for chemical confirmation of toxicant absorption. TREATMENT 1. BATHE and SHAMPOO with soap and water to remove chemicals from skin and hair. Individuals with chronic skin disease or known sensitivity to chemicals should either avoid using these herbicides or take extraordi- nary measures to avoid contact. 2. FLUSH contaminating chemicals from eyes with copious amounts of clean water for 10-15 minutes. 3. If symptoms of illness occur during or following inhalation of spray, REMOVE victim FROM CONTACT with the material for at least two days. Allow subsequent contact with chlorophenoxy compounds only if effective respiratory protection is practiced. 4. IF substantial amounts of chlorophenoxy compounds have been IN- GESTED, spontaneous emesis usually occurs. Ordinarily, this empties the stomach as effectively as intubation and lavage. If vigorous emesis 29 ------- has not occurred and IF VICTIM IS FULLY ALERT, induce EMESIS with SYRUP OF IPECAC (adults 12 years and older, 30 ml; children under 12 years, 15 ml), followed by 1-2 glasses of water. Following emesis, administer 30-50 gm of ACTIVATED CHARCOAL in a slurry of 6-8 ounces tap water, to limit absorption of herbicide remaining in the gut. 5. IF CONSCIOUSNESS LEVEL IS DEPRESSED or other signs of NEUROTOXICITY appear, SUSPECT additional or alternative in- gested toxicants. Evacuate the stomach by INTUBATION, ASPIRA- TION, and LAV AGE. Because petroleum distillates are commonly in- cluded in chlorophenoxy formulations, gastric intubation incurs a risk of hydrocarbon pneumonitis from aspiration. For this reason: A. If victim is unconscious or obtunded and facilities are at hand, in- sert an ENDOTRACHEAL TUBE (cuffed, if available) prior to gastric intubation. B. Keep victim's HEAD BELOW LEVEL OF THE STOMACH dur- ing intubation and lavage (Trendelenburg, or left lateral decubitus, with head of table tipped downward). Keep victim's head turned to left. C. ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. After aspiration of gastric contents and washing of stomach, instill 30-50 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through the stomach tube to limit absorption of remaining toxicant. Do NOT instill milk, cream, or other materials containing vegetable or animal fats, as these are likely to enhance absorption. 6. If bowel movement has not occurred in 4 hours and patient is fully con- scious, give SODIUM SULFATE, 0.25 gm/kg, as a cathartic. Magne- sium sulfate and citrate, in comparable dosages, are equally suitable if renal function is adequate. Retained magnesium may depress CNS func- tion. 7. In SEVERE POISONINGS by very large amounts of ingested chloro- phenoxy acids, forced ALKALINE DIURESIS may save the victim's life. Assess serum electrolyte concentrations, and serum and urine pH. If a metabolic acidosis is present, infuse solutions of sodium bicarbonate at rates sufficient to keep the urine distinctly alkaline, continuing until plasma concentrations of chlorophenoxy compounds are less than about 10Mg/ml. [Prescott, L F. et al., Br. J. Clin. Pharmacol. 7:11 (1979)] 30 ------- ^\ II iki'\y\-^- f \ f \ \5 Chapter 7 PARAQUAT AND DIQUAT CHEMICAL STRUCTURES 'CHs v_rv 2Cr ™ ** CH2—CH2 2 Br~ PARAQUAT DIQUAT COMMON COMMERCIAL PESTICIDE PRODUCTS Paraquat products: paraquat dichloride (usually as a 21% concentrate). Other names: Ortho paraquat-CL, Crisquat, Dextrone X, Esgram. Mix- tures: Priglone, Preeglone, Weedol—with diquat; Simpar, Terraklene—with simazine; Gramonol, Mofisal—with monolinuron; Pathclear—with diquat and simazine; TotaCol, Dexuron—with diuron. Diquat products: diquat (Reglone, Reglox, Aquacide, Dextrone, Weed- trine-D). Mixtures: Priglone, Preeglone, Weedol—with paraquat; Pathclear— with paraquat and simazine. TOXICOLOGY These dipyridyls injure the epithelial tissues: skin, nails, cornea, liver, kid- ney, and the linings of the GI and respiratory tracts. In addition to direct irri- tant effects, injury may involve peroxidation of intracellular and extracellular phospholipids and inhibition of surfactant synthesis by lung tissue. These toxic properties may derive from the capacity of dipyridyls to generate free radicals in tissues. The injury is usually reversible; however, the pulmonary reaction which follows ingestion of paraquat is often fatal. Certain injuries have followed occupational contact with paraquat. Contact with the concentrate may cause irritation and fissuring of the skin of the hands, and cracking, discoloration, and sometimes loss of the fingernails. Splashed in the eye, paraquat concentrate causes conjunctivitis and, if not promptly removed, may result in protracted opacification of the cornea. Although nearly all systemic intoxications by paraquat have followed inges- tion of the chemical, occasional poisonings have resulted from excessive dermal contact. Absorption of toxic amounts is much more likely to occur if the skin is abraded. Persons who have experienced extraordinary dermal contact with paraquat (especially the concentrate) should be examined, and tested for hazardous concentrations of the agent in the blood and urine (see section on Confirmation of Diagnosis). 31 ------- Inhalation of dilute spray mist may irritate the upper respiratory passages, causing a scratchy throat and nosebleed. Effects induced by dilute paraquat sprays ordinarily resolve promptly following withdrawal from exposure. If ingested, paraquat produces inflammation of the mouth and GI tract, sometimes progressing to ulceration within 1-4 days. Once absorbed, it damages the parenchymal cells of the liver and tubule cells of the kidney. In most instances, the victim survives these injuries. Paraquat is actively concen- trated in the pneumocytes of lung tissue. Several days after ingestion these cells die, after which there is rapid proliferation of connective tissue cells which fill the alveolar spaces. Although some victims have survived, death from asphyxia usually occurs once this degree of lung damage has been sustained. In sur- vivors, recovery of normal lung function requires weeks or months. In a few instances, ingestion of large quantities of paraquat has induced protracted pulmonary edema. Myocardial injury has also been noted in some poisonings. Diquat appears less likely than paraquat to cause death. Information from suicidal ingestions and from orally dosed monkeys indicates that the principal target organs in diquat toxicity are the gastrointestinal tract, kidney, and liver. Diquat produces intense congestion and ulceration of the stomach and bowel. Fatty liver and acute renal tubular necrosis are produced by adequate doses. Smaller doses administered chronically have caused lens cataracts in animals. Diquat is not concentrated in lung tissue as paraquat is, and pulmonary lesions are limited to punctate hemorrhages. Hemorrhages in brain tissue have been reported after diquat ingestion. FREQUENT SYMPTOMS AND SIGNS OF POISONING The irritant effects of paraquat on skin, eye, and upper respiratory tract have been described under TOXICOLOGY. The earliest (1-4 days) symptoms of injury and signs following ingestion of a toxic dose of PARAQUAT are burning PAIN (oral, substernal, abdominal), NAUSEA, VOMITING, DIARRHEA, and sometimes melena. Early symp- toms are sometimes so mild that vigorous treatment is improperly delayed. From 24-72 hours, indications of renal and hepatic insult appear. Albumin- uria, hematuria, pyuria, and ELEVATED BUN and CREATININE may occur. OLIGURIA may develop, and this signals severe poisoning. JAUNDICE and elevations of serum GOT, GPT, LDH, and alkaline phosphatase reflect hepatocellular injury. These injuries are usually reversible, although severe renal tubular damage may require extracorporeal hemodialysis. A progressive decline in arterial oxygen tension and CO diffusion capacity commonly precedes the appearance of pulmonary symptomatology. COUGH, DYSPNEA, and TACHYPNEA usually appear 72-96 hours after paraquat in- gestion, but may be delayed as long as 14 days. Progressive CYANOSIS reflects deteriorating gas exchange caused by the fibrogenic reaction in the alveolar sacs. In a few cases, the production of COPIOUS WATERY SPUTUM (pulmonary edema) has followed ingestions of large amounts (200 ml) of para- quat or diquat concentrate. 32 ------- DIQUAT INGESTION results in intense NAUSEA, VOMITING, and DIARRHEA, with accompanying dehydration, and in melena and hematemesis from gastrointestinal ulceration. INCREASED serum BUN and CREATININE, and ANURIA result from acute tubular necrosis. Serum GOT, GPT, and LDH and alkaline phosphatase elevations reflect liver injury. Early COMA has sometimes occurred following suicidal ingestion of large amounts and has also been noted in experimentally poisoned monkeys. This could be a consequence of profound dehydration, with electrolyte distur- bances, or of diffuse hemorrhages in the central nervous system, as noted in one human poisoning. CONFIRMATION OF DIAGNOSIS Qualitative and quantitative methods for paraquat and diquat in blood and urine are available at some local, private, and government toxicology labora- tories, and at the Chevron Environmental Health Center, Box 1272, Rich- mond, California 94802. The Chevron Chemical Company maintains a 24-hour toxicology consultation service through an emergency telephone number: (415) 233-3737. Sales representatives are prepared to deliver bentonite to virtually any location in the United States, and to arrange for the prompt delivery of biologic specimens for dipyridyl analysis to the Environmental Health Center. Company toxicologists are available 24 hours a day for assis- tance in management of poisonings by Chevron products. TREATMENT 1. Contaminated SKIN must be FLUSHED with copious amounts of water. Material splashed in the EYES must be removed by PROLONGED IRRIGATION with clean water. Eye contamination should thereafter be treated by an ophthalmologist. Mild skin reactions usually respond to simple avoidance of further contact, but the irritation may take several weeks to resolve. Severe injuries, with cracking, secondary infection, or nail injury, should be treated by a dermatologist. 2. After a DIPYRIDYL compound has been INGESTED, EVACUATE the STOMACH, then LOAD the gastrointestinal tract with an effective ADSORBENT, to minimize toxicant absorption. These measures must be undertaken immediately, even though the patient is free of signs of systemic toxicity, and even when, by all accounts, the in- gested dose was probably small and was taken as long as several days prior to treatment. INTUBATE the STOMACH, ASPIRATE contents, then LAV AGE with at least two liters of a slurry of ADSORBENT in normal saline. Then, slowly instill several hundred additional ml of adsorbent slurry, allowing the stomach and intestine to accommodate this volume without overdistension and vomiting. 33 ------- A. The ideal adsorbent is BENTONITE, administered as a 7 gm per 100 ml suspension. If not immediately available, use ACTIVATED CHARCOAL, 30-50 gm in 300-400 ml of water, or any concentra- tion that will flow through the tube. As soon as bentonite has been obtained, administer it as rapidly as the patient will tolerate it. If pa- tient cannot swallow bentonite, administer it by stomach tube at the highest concentration that will flow through the tube. B. Initiate SALINE CATHARSIS. Give SODIUM SULFATE, 0.25 gm/kg, and repeat in two hours if no bowel movement has oc- curred. Magnesium salts are probably contraindicated, because of the risk of magnesium retention in the presence of impaired renal function. C. Continue administering bentonite suspension and sodium sulfate until the gut has been thoroughly flushed. This may require several days. 3. Secure samples of blood and urine for dipyridyl analysis. (See Confirma- tion of Diagnosis.) 4. Commence INTRAVENOUS INFUSIONS of glucose and electrolyte to minimize toxicant concentrations in the tissues, and expedite excretion of the dipyridyl. Attempt to establish a diuresis of 10-15 liters per day. CAUTION: Monitor fluid balance and electrolytes continuously to in- sure against fluid overload if acute tubular necrosis supervenes. 5. Although cases of paraquat poisoning have been successfully managed by forced diuresis regimens alone, it is more effective to use extracorporeal HEMODIALYSIS and/or HEMOPERFUSION over specially coated charcoal. This procedure for toxicant removal is best executed in tertiary care centers where blood levels of paraquat can be monitored regularly, and various complications of hemoperfusion can be detected and fore- stalled. The prognosis is generally good when blood levels do not exceed 0.05 to 0.10 ppm by 24-48 hours after paraquat ingestion. 6. DO NOT ADMINISTER SUPPLEMENTAL OXYGEN in paraquat poisoning. Increased levels of alveolar oxygen accelerate the pathologic process in the lung caused by paraquat. Some clinicians recommend maintaining the patient in an atmosphere of 15-16% oxygen as soon as possible, to retard the fibrogenic process. 7. The tubular necrosis produced by large doses of DIQUAT may require protracted EXTRACORPOREAL HEMODIALYSIS. 8. The topical injuries to mucous membranes produced by ingested dipyridyls are painful and may require topical local anesthetic. 9. The effectiveness of various medicines and procedures in paraquat poisoning remains uncertain. The free-radical scavenger super oxide dismutase is theoretically appropriate as an antidote, but is unproved. Corticosteroids are often given, and may be helpful. There is limited 34 ------- laboratory evidence supporting the use of propranolol and expectorants: glyceryl guaicolate, anise oil, terpin hydrate, ammonium chloride and potassium iodide. One victim is thought to have benefited from a com- bination of azathioprine and potassium aminobenzoate. Lung transplant in one case of paraquat poisoning was not successful. 35 ------- Chapters DITHIOCARBAMATES AND THIOCARBAMATES CHEMICAL STRUCTURES AND COMMON COMMERCIAL PRODUCTS These functional classes include many fungicides and herbicides. There are several subclasses: BIS DITHIOCARBAMATES s s CH3 || II CH3 ^ N-C-S-S-C-N THIRAM COMMERCIAL PRODUCTS thiram (Arasan, Thiramad, Thirasan, Thylate, Tirampa, Pomarsol forte, TMTDS, Thiotex, Fernasan, Nomersan, Tersan, Thiuramin, Tuads, AAtack, Aules, Chipco Thiram 75, Fermide 850, Trametan, Hexathir, Mer- curam, Polyram-Ultra, Spotrete, Tripomol, Tersan 75, Tetrapom, Thioknock). Thiram is a fungicide. METALLO BIS DITHIOCARBAMATES -CH3 \ / II N -C-S — Zn, Na, or Fe COMMERCIAL PRODUCTS ziram (Z-C Spray, Carbazinc, Corozate, Cuman, Drupina 90, Fuclasin Ultra, Fuklasin, Fungostop, Hexazir, Mezene, Pomarsol Z Forte, Prodaram, Tricarbamix Z, Triscabol, Zerlate, Vancide MZ-96, Zincmate, Ziram Technical, Ziramvis, Zirasan 90, Zirberk, Zirex 90, Ziride); nabam (Dithane D14, Chem Bam, DSE, Nabasan, Parzate, Spring-Bak); ferbam (Ferberk, Hexaferb, Knockmate, Trifungol, Vancide FE-95). These chemicals are fungicides. 36 ------- ETHYLENE BIS DITHIOCARBAMATES H H S I I II HC-N-C-S, I Mn or Zn H H S COMMERCIAL PRODUCTS maneb (Dithane M22, Griffin Manex, Kypman 80, Manebgan, Manesan, Manzate, Nespor, Manzeb, Polyram M, Manzin, Tersan LSR, Trimangol, Tubothane, Vancide Maneb 80); zineb (Aspor, Dipher, Dithane Z-78, Hexathane, Kypzin, Lonacol, Parzate, Polyram Z, Tiezene, Tritoftorol, Zeb- tox, Zinosan). These fungicides are often combined with thiram and with various inorganic salts of copper, manganese, and zinc in commercial preparations. Mancozeb (Dithane M45) is essentially a combination of maneb and zineb. (MONO) THIOCARBAMATES R o x II N - C - S - R" Aror R' COMMERCIAL PRODUCTS butylate (Sutan), cycloate (Ro-Neet), pebulate (Tillam), vernolate (Veraam, Surpass), EPTC (Eptam), diallate (Avadex), triallate (Far-Go, Avadex-BW). These chemicals are selective herbicides. TOXICOLOGY Although these agents have chemical similarities, the separate classes are metabolized differently by mammals, and effects on human health are also different. In general, mammalian toxicity, as measured by oral dosing studies in laboratory rodents, is low. Occupational exposures have, however, caused acute adverse effects, and laboratory investigations have suggested potential chronic effects from some agents. 37 ------- None of these agents is a cholinesterase inhibitor. Thiram is irritating to skin and mucous membranes. It has sensitized some individuals, generally after contact with rubber products containing residues of thiram used as a curing agent. The metallo dithiocarbamates and ethylene dithiocarbamates are moderately irritating to skin and the respiratory mucous membranes following contact with sprays or dusts. Thiram is the methyl analogue of disulfiram (Antabuse), an agent used to condition alcoholics against beverage alcohol. Much more is known of the tox- ic effects-of disulfiram than of thiram, although the acute toxicity of thiram in laboratory animals is substantially greater. Given to animals in extreme doses, disulfiram has caused gastrointestinal irritation, demyelinization of CNS tissues, and necrosis of liver, splenic, and kidney tissues. Peripheral neuropa- thy and psychotic reactions have occurred in humans taking large doses of disulfiram regularly. Functional and anatomic CNS damage has been demonstrated in rats on high chronic dosage regimens of iron and zinc dimethyldithiocarbamates. Because all of these agents are degraded partly to carbon disulfide in the body, a role of this metabolite in neurotoxic effects is suspected. Both thiram and disulfiram inhibit aldehyde dehydrogenase, and are there- fore capable of inducing "Antabuse" reactions in persons who consume beverage alcohol following substantial absorption of dithiocarbamates. Reac- tions may have occurred rarely in workers who imbibed after extraordinary oc- cupational exposure to thiram. Theoretically, the metallo dithiocarbamates may also predispose to an "Antabuse" reaction. Peripheral vasodilation is the main pathophysiologic feature of the disulfiram-alcohol reaction, probably due to high tissue levels of acetaldehyde. This may occasionally lead to shock, and even more rarely, to myocardial ischemia, cardiac arrhythmias, circula- tory failure, and death. Animal experimentation has suggested certain other biochemical mechanisms of toxicity involving reaction products of ethanol and disulfiram. The ethylene bis dithiocarbamates do not inhibit aldehyde dehydrogenase, and there is no evidence of neurotoxicity from them. They do, however, degrade in the environment, and in mammalian tissues, to ethylene thiourea, a compound known as a goitrogen and carcinogen in laboratory animals. This feature mandates extra care in the protection of harvesters, and in removal of residues from harvested crops. Except for some moderate irritant effects on skin, respiratory tract, and eyes, the (mono) thiocarbamate herbicides do not appear to be highly toxic. Extreme doses in laboratory animals do produce paralysis. There is a very remote possibility of "Antabuse" reactions from ethanol following extraor- dinary exposure to these (mono) thiocarbamates. They do not form ethylene thiourea on degradation. 38 ------- SYMPTOMS AND SIGNS OF POISONING Thiram and metallo bis dithiocarbamates Itching, redness, and eczematoid DERMATITIS have resulted when predis- posed individuals have come into contact with these agents. Inhaled sprays and dusts have caused NASAL STUFFINESS, hoarseness, cough, and, rarely, pneumonitis. Repeated contact may produce sensitization. Ingestion of large amounts may produce nausea, VOMITING, and DIARRHEA. HYPO- THERMIA and ataxia are characteristic of poisoning. Muscle WEAKNESS and/or ascending paralysis may progress to respiratory paralysis if absorbed dosages are equivalent to those tested in experimental animals. The reaction to beverage alcohol that may follow exceptional absorption of thiram and metallo bis dithiocarbamates is characterized by FLUSHING, HEADACHE, SWEATING, warm sensations, weakness, nasal congestion, labored breathing, tightness in the chest, tachycardia, palpitation, and hypo- tension. Extreme dosages may result in shock, convulsions, respiratory depres- sion, and/or unconsciousness. Reactions are not likely to occur unless the absorbed dose is extraordinary. Ethylene bis dithiocarbamates and (mono) thiocarbamates Some of these agents are irritating to skin and respiratory mucous mem- branes, causing ITCHING, SCRATCHY THROAT, SNEEZING, and COUGH, if excessive amounts of spray or dust are inhaled. Apart from this effect, toxic potential is low. Neurotoxic and post-ethanol "Antabuse" reac- tions are not known to occur as a result of contact with these particular com- pounds. CONFIRMATION OF DIAGNOSIS Skin testing may be useful in identifying sensitization to these agents. In general, these compounds are so rapidly metabolized in the body and ex- creted, that detection in blood is rarely possible. There are methods for detec- tion of ethylene thiourea (from the ethylene bis dithiocarbamates) in urine. TREATMENT 1. WASH contaminating chemical from SKIN and HAIR with soap and water. Persons sensitive to thiram (rubber-sensitive) should be per- manently REMOVED FROM CONTACT with compounds of this nature. 2. FLUSH contaminant from EYES with fresh water for 10-15 minutes. 3. If THIRAM or METALLO DITHIOCARBAMATE compounds have been INGESTED: 39 ------- A. If vigorous emesis has not already occurred and victim is fully alert, give SYRUP OF IPECAC, followed by 1-2 glasses of water to in- duce vomiting (adults, 12 years and older: 30 ml; children under 12: 15 ml). CAUTION: OBSERVE victim closely AFTER administering IPECAC. If CONSCIOUSNESS level declines or vomiting has not occurred in 15 minutes, empty the stomach by INTUBATION, ASPIRATION, and LAVAGE. B. IF consciousness level or respiration is DEPRESSED, empty the stomach by INTUBATION, ASPIRATION, and LAVAGE, using all available means to avoid aspiration of vomitus: left lateral Trendelenburg position, frequent aspiration of the pharynx and, in unconscious victims, tracheal intubation (using a cuffed tube) prior to gastric intubation. After aspiration of the stomach and washing with isotonic saline or sodium bicarbonate, instill 30-50 gm of ACTIVATED CHAR- COAL in 3-4 ounces of water through the stomach tube to limit absorption of remaining toxicant. C. If the irritant properties of the toxicant fail to produce a bowel movement in 4 hours, administer SODIUM or MAGNESIUM SULFATE as a cathartic: 0.25 gm/kg body weight in 1-6 ounces of water. D. Administer glucose-containing fluids intravenously to accelerate ex- cretion of toxicant. E. For adults and children over 12 years, inject 1.0 gm ASCORBIC ACID (Vitamin C) intravenously at a rate not exceeding 0.2 gm/minute. For children under 12, give 10-20 mg/kg body weight. As a hydrogen-donor, ascorbic acid may have significant antidotal action against absorbed, but unreacted, dithiocarbamate com- pounds. F. The victim must AVOID consumption of any ALCOHOLIC bever- age for 3 weeks. Gastrointestinal absorption of these substances is slow, and the enzyme inhibition which they cause is slowly reversed. 4. Management of a reaction to ETHANOL, following absorption of a DITHIOCARBAMATE: A. Administer 100% OXYGEN as long as the reaction continues. Ox- ygen usually gives substantial relief from the distressing symptoms of vasodilation and hypotension. CAUTION: If respiration is depressed, administer oxygen by an intermittent positive pressure breathing device and observe the victim closely to maintain pulmonary ventilation mechanically in case of apnea. 40 ------- B. Gastric evacuation, charcoal administration, catharsis, intravenous fluids, and ascorbic acid administration (3 A,B,C,D, and E) may be appropriate, depending on the amount of dithiocarbamate absorbed, the time interval between exposure and treatment, and the severity of symptoms. C. If the victim has suffered from arteriosclerosis, myocardial insuffi- ciency, diabetes, neuropathy, cirrhosis, or other severe chronic disease, OBSERVE him CAREFULLY for 48 hours to insure that complications (especially myocardial infarction, toxic psychosis, and neuropathy) are treated promptly. 5. If an ETHYLENE BIS DITHIOCARBAMATE, or (mono) THIOCAR- BAM ATE have been ingested: A. Give SYRUP OF IPECAC, followed by 1-2 glasses of water, to in- duce vomiting (adults: 30 ml; children under 12 years: 15 ml). Fol- lowing emesis, administer 30-50 gm ACTIVATED CHARCOAL to bind toxicant remaining in the gut. B. Follow charcoal with SODIUM or MAGNESIUM SULFATE, 0.25 gm/kg, to remove toxicant from the gut by catharsis. 41 ------- Chapters PYRETHRUM, PYRETHRINS, PYRETHROIDS, AND PIPERONYL BUTOXIDE Pyrethrum is the partly refined extract of the chrysanthemum flower which has been used as an insecticide for more than 60 years. Pyrethrins are the insec- ticidally active ingredients of pyrethrum, now known to consist of keto- alcohol esters of pyrethric and chrysanthemic acids. The alcohols are pyrethro- lone, cinerolone, and jasmololone, whose respective esters are known as pyrethrins, cinerins, and jasmolins. Pyrethroids are synthetic compounds based structurally on the pyrethrin molecule but modified to improve stability in the natural environment (light, heat, etc.) GENERAL CHEMICAL STRUCTURE R H H CH3 11 I H O H ' C = C - C I II \ /<% I |^C-C-0-C C-R' CH3 CHa-C^ | | I H C — C = O CH3 H COMMON COMMERCIAL PESTICIDE PRODUCTS Pyrethrins: There are several hundred commercial products containing pyrethrins and pyrethroids. Commonly, these products combine pyrethrins or pyrethroids with a synergist, such as piperonyl butoxide, and an additional pesticide, for increased killing power. Many of these combinations are pack- aged with a propellant in a spray can or bug-bomb. Pyrethroids: Allethrin (Pynamin), barthrin, bioresmethrin, cypermethrin (Ripcord), decamethrin, fenothrin, fenpropanate, fenvalerate (Belmark, Pydrin), permethrin (Ambush, Ectiban, Pounce), phthalthrin or tetramethrin (Neo-Pynamin), resmethrin (Synthrin, Chrysron). TOXICOLOGY These esters rapidly paralyze the insect nervous system, making them famous for their quick "knockdown" effect. Mammalian toxicity, however, is extraordinarily low for pyrethrins and pyrethroids. Oral LD5o values for these compounds in rats are several hundred or thousand mg/kg body weight. There is apparently less efficient absorption of pyrethrins across the GI lining and 42 ------- skin than across insect chitin, and much more rapid biodegradation (hydrolysis and oxidation) by the mammalian liver than by insect tissues. Some of the less purified pyrethrum extracts contain allergenic substances that induce attacks of allergic rhinitis and asthma in humans. Rarely, hyper- sensitivity pneumonitis has followed pyrethrum inhalation. Administered orally to rodents in extraordinary dosage, pyrethrins and pyrethroids cause nervous irritability, tremors, and motor ataxia. Bloody tears and urinary incontinence have also been observed. Manifestations of toxicity occur at much lower dosage following intravenous administration than after oral dosing. Chronic feeding of these chemicals induces an increase in liver size and bile duct hyperplasia. To date, neither pyrethrins nor pyrethroids have been identified as mutagenic, carcinogenic, or teratogenic. Piperonyl butoxide inhibits the mixed function oxidase enzymes of the liver which catabolize pyrethrins and pyrethroids. The amount absorbed by humans during ordinary exposure is not likely to affect liver function measurably. FREQUENT SYMPTOMS AND SIGNS OF UNDUE EXPOSURE A STUFFY, RUNNY NOSE and scratchy throat from inhalation of partly purified pyrethrum extract is the most common adverse effect of these agents. Asthmatic WHEEZING may be precipitated by exposure of predisposed indi- viduals. Sudden bronchospasm, swelling of oral and laryngeal mucous membranes, and shock (anaphylaxis) have been reported after pyrethrum inhalation. Delayed appearance of dyspnea, cough and fever, with patchy lung infiltrates on x-ray, suggest hypersensitivity pneumonitis. Nervous irritability, tremors, and ataxia have occurred rarely in persons who have had massive inhalation exposure to pyrethrins. Halocarbon propellents in bug-bomb products present a risk of CARDIAC ARRHYTHMIA and possibly fibrillation if inhaled to excess. Hydrocarbons used as solvents in spray products are likely to result in COUGH, FEVER, and CHEST PAIN (hydrocarbon pneumonitis) if these liquids are inadvertently aspirated. CONFIRMATION OF DIAGNOSIS Skin tests sometimes identify sensitivity to pyrethrum. Neither pyrethrins nor pyrethroids inhibit cholinesterase enzymes. There are gas-chromato- graphic methods for identifying some of these insecticides in environmental samples, but they are not likely to be useful in diagnosing poisoning because of the rapid metabolism of the esters following absorption. There are no methods for identifying urinary metabolites. 43 ------- TREATMENT 1. WASH contaminating pesticide from the EYE with copious amounts of water. Wash contaminated SKIN with soap and water. 2. For life-threatening allergic reaction to pyrethrum (severe ASTHMA or ANAPHYLAXIS), give 0.1 to 0.5 ml of 1:1000 ADRENALIN intramus- cularly, or slowly intravenously. Repeat if necessary to relieve respiratory distress and maintain blood pressure. Intravenous AMINOPHYLLINE (10 ml, slowly) may be indicated. Give HYDROCORTISONE (50-100 mg), or equivalent steroid, intravenously. Less severe allergic reactions (rhinitis) can be managed with ANTI- HISTAMINES and DECONGESTANTS, given orally. HYPERSENSITIVITY PNEUMONITIS may require oxygen, ste- roids, antibiotics and several days bedrest, depending on severity. 3. INGESTION of a SMALL AMOUNT of a pyrethrin or pyrethroid for- mulation is not likely to cause poisoning. EXAMINE THE LABEL to identify additional insecticides, which may be more toxic. BASE TREATMENT ON THE MOST TOXIC ingredients. A. If a formulation contains ONLY pyrethrins, or pyrethroids, and synergists, ingestion of a small amount (up to about 5 mg/kg) is probably best treated by large doses of ACTIVATED CHAR- COAL, 30-50 gm in 3-4 ounces of water, followed by cathartic doses of SODIUM or MAGNESIUM SULFATE, 0.25 gm/kg body weight in 1-6 ounces of water. 4. If LARGE AMOUNTS of pyrethrin or pyrethroid formulation have been INGESTED, the stomach and intestine must be evacuated: A. IF victim is ALERT and respiration is not depressed, give SYRUP OF IPECAC, followed by 1-2 glasses of water, to induce vomiting (adults and children 12 years and older: 30 ml; children under 12 years: 15 ml). CAUTION: OBSERVE VICTIM closely AFTER administering IPECAC. If consciousness level declines or vomiting has not occurred in 15 minutes, INTUBATE the stomach immediately. Following emesis, have victim drink a suspension of 30-50 gm AC- TIVATED CHARCOAL in 3-4 ounces of water to limit absorption of toxicant remaining in the gut. B. IF victim is NOT FULLY ALERT, empty stomach immediately by INTUBATION, ASPIRATION, and LAVAGE, using isotonic saline or 5% sodium bicarbonate. Because many pesticides are dis- solved in petroleum distillates, emesis and intubation of the stomach involve a risk that solvent will be aspirated, leading to chemical pneumonitis. For this reason: 44 ------- (a). If victim is unconscious or obtunded and facilities are at hand, insert an ENDOTRACHEAL TUBE (cuffed, if available) prior to gastric intubation. (b). Keep victim's HEAD BELOW LEVEL OF THE STOMACH during intubation and lavage (Trendelenburg, or left lateral decubitus, with head of table tipped downward). Keep victim's head turned to left. (c). ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. (d). After aspiration of gastric contents and washing of stomach, instill 30-50 gm of ACTIVATED CHARCOAL in 3-4 ounces of water through stomach tube to limit absorption of remain- ing toxicant. (e). If bowel movement has not occurred in 4 hours and patient is fully conscious, give SODIUM or MAGNESIUM SULFATE as a cathartic: 0.25 gm/kg body weight in 1-6 ounces of water. 5. Do NOT administer or instill milk, cream, or other substances containing vegetable or animal fats, which enhance absorption of lipophilic sub- stances, such as pyrethrins and pyrethroids. 6. DIAZEPAM (Valium®), 5-10 mg in adults, 0.1 mg/kg in children, given orally or slowly IV, should control nervousness and tremors in rare cases having these symptoms after extraordinary exposure to pyrethrins and pyrethroids. 45 ------- Chapter 10 ARSENICAL PESTICIDES CHEMICAL STRUCTURES INORGANIC ARSENICALS Extremely Toxic As - O - As Na - O - As = O K - O - As = O ARSENIC TRIOXIDE SODIUM ARSENITE POTASSIUM ARSENITE Cu - (O - C - CH3) 2 n • 0 3Cu - (As O2)2 COPPER ACETOARSENITE Highly Toxic Ca3(As 04) 2 CALCIUM ARSENATE Moderately Toxic Ca (As O2) 2 CALCIUM ARSENITE Cu - (AsO2) I O H COPPER ARSENITE (HO)3 AS = O ARSENIC ACID Pb As = O O H LEAD ARSENATE 46 ------- ORGANIC ARSENICALS Moderately Toxic CH3 ^ CH3 / AS\ O^ OH CACODYLIC ACID As METHANE ARSONIC ACID (MAA) . As <> \ O OH MONOSODIUM METHYL ARSONATE (MSMA) CH3x ^ONa s- As ° ONa DISODIUM METHYL ARSONATE (DSMA) ,\ /ONH4 As O^ OH MONOAMMONIUM METHANE ARSONATE 47 ------- COMMON COMMERCIAL ARSENIC PRODUCTS 1. Arsenic trioxide 2. Sodium arsenite: 3. Calcium arsenite: 4. Copper arsenite: 5. Copper acetoarsenite: 6. Arsenic acid: 7. Sodium arsenate: 8. Calcium arsenate: 9. Lead arsenate: 10. Methane arsonic acid: 11. Monosodium methyl arsonate: 12. Disodium methyl arsonate: 13. Monoammonium methyl arsonate: 14. Calcium acid methanearsonate: 15. Cacodylic acid: "White arsenic," arsenious oxide (registered only for ant pastes, veterinary medicinals, and marine antifouling preparations). Chem Pels C, Chem-Sen 56, Kill- All, Penite, Prodalumnol Double. Mono-calcium arsenite. Chemonite. Paris green, Schweinfurt green, emerald green, French green, mitis green. Desiccant L-10, Hi-Yield Desic- cant H-10. Jones Ant Killer, Terro Ant Killer. Pencal, Spra-cal, Security. Gypsine, Security, Soprabel, Talbot. MAA. MSMA, Ansar 17OHC, methane arsonate, Ansar 529HC, Arsonate liquid, Bueno 6, Daconate 6, Dal- E-Rad, Herb-All, Merge 823, Mesamate, Target MSMA, Trans- Vert, Weed-E-Rad, Weed-Hoe. DSMA, Ansar 8100, methane ar- sonate, Ansar DSMA liquid, Ar- rhenal, Arsinyl, Chipco Crab Kleen, Crab-E-Rad, Dal-E-Rad 100, Di-Tac, DMA, DMA 100, Methar, Namate, Sodar, Weed-E- Rad, Weed-E-Rad 360, Weed-E- Rad DMA Powder, Weed-Hoe. MAMA, monoammonium meth- anearsonate. CAMA, Super Crab-E-Rad-Calar, Super Dal-E-Rad "Calar". Dilic, Phytar 560, Rad-E-Cate 25, Salvo, f [Crystal Chemical Com- pany) A product of identical name marketed by Crystal Chemical Company contains 2,4-D as the active ingredient (Chapter 6). 48 ------- TOXICOLOGY Although there may be some degree of dermal and pulmonary absorption of arsenical liquids and sprays, ingestion is the route of intake involved in virtual- ly all acute poisonings by the solid arsenicals. Inhalation of arsine gas (sometimes generated inadvertently in pesticide manufacturing plants) has caused serious illness and death by hemolytic action. Generally, the organic (methylated) pentavalent arsenicals are considerably less toxic than the trivalent inorganic arsenicals. In fact, methylation is the principal mechanism of detoxification of inorganic arsenicals in mammals. The less soluble inorganic forms (notably lead arsenate, and even arsenic triox- ide) present less hazard than the highly soluble salts such as sodium arsenite and copper acetoarsenite. But because gastric pH, gastrointestinal motility, and gut bacterial action can enhance the absorption and toxicity of ingested compounds, it is safest to manage cases of arsenic ingestion as though all forms of arsenic are highly toxic. Trivalent arsenicals (or, more likely, an arsenious acid metabolite) bind effi- ciently to the functional thiol groups of many tissue components, including en- zymes. The affinity for thiol groups in keratin accounts for the accumulation of arsenic in skin, nails, and hair in cases of chronic poisoning. When absorbed across the gut wall, these arsenicals injure the splanchnic vasculature, causing abdominal pain, colic, and diarrhea. Once absorbed into the blood, they cause toxic damage to the liver, kidneys, brain, bone marrow, and peripheral nerves. Liver injury is manifest as hepatomegaly, jaundice, and increase in circulating hepatocellular enzymes LDH and GOT. Renal damage is reflected in albumin- uria, hematuria, pyuria, cylindruria, then azotemia. Acute tubular necrosis may occur in severe poisoning. Injury to blood-forming tissues can take the form of agranulocytosis, aplastic anemia, thrombocytopenia, or pancytopenia. Toxic encephalopathy may be manifest as speech and behavioral disturbances. Peripheral neuropathy occurs in both acute and chronic forms. Sequelae of arsenic poisoning include cirrhosis, hypoplastic bone marrow, renal insufficiency, and peripheral neuropathy. Excessive exposures to arseni- cals have caused hyperkeratosis and skin cancers. Excessive inhalation of dusts may cause bronchitis and pneumonia; protracted inhalation has been asso- ciated epidemiologically with increased occurrence of lung cancer. FREQUENT SYMPTOMS AND SIGNS OF POISONING ACUTE arsenic poisoning COLIC, BURNING ABDOMINAL PAIN, VOMITING, and WATERY or BLOODY DIARRHEA are the primary manifestations of ingestion of solid arsenical poisons. Symptoms following ingestion of inorganic arsenicals are much more severe than those resulting from ingestion of pentavalent organic arsenicals. Symptoms are sometimes delayed for minutes or even hours after ingestion. HEADACHE, DIZZINESS, MUSCLE SPASMS, DELIRIUM, 49 ------- and sometimes CONVULSIONS reflect direct injury to the central nervous system, as well as extracellular electrolyte disturbances and shock. A GARLIC ODOR to the breath and feces helps to identify the responsible toxicant. SHOCK, TOXIC NEPHROSIS, HEPATITIS (hepatomegaly and jaundice), and NEUROLOGIC INJURY (delirium, paralysis, respiratory depression) may progress to a fatal outcome. SUBACUTE arsenic poisoning Repeated intakes less than those necessary to produce severe acute symp- toms are known to cause CHRONIC HEADACHE, ABDOMINAL DIS- TRESS, SALIVATION, LOW-GRADE FEVER, and PERSISTENT symp- toms of UPPER RESPIRATORY IRRITATION. Stomatitis and garlicky breath are characteristic. CHRONIC arsenic poisoning Prolonged low intakes of arsenic cause peripheral neuropathy (PARES- THESIAE, PAIN, anesthesia, paresis, ataxia), encephalopathy (APATHY, disorientation), dermatologic disorders (KERATOSES, pigmentation, eczema, brittle nails, loss of hair), toxic hepatitis (HEPATOMEGALY, some- times progressing to cirrhosis with ascites), and bone marrow injury (ANEMIA, leukopenia, WEAKNESS). Local EDEMA, frequently of the eye- lids, characterizes some poisonings. ACUTE arsine gas poisoning The gas causes hemolysis of red blood cells, in addition to inhibition of cellular sulfhydryl respiratory enzymes. Hemolysis causes HEMOGLOBINE- MIA and HEMOGLOBINURIA. This in turn, causes acute tubular necrosis. Early symptoms of poisoning (CHILLS, weakness, burning sensations) are followed by abdominal CRAMPS, vomiting, and prostration. Failing renal function deteriorates to ANURIA. CONFIRMATION OF DIAGNOSIS Measurement of 24-hour urinary excretion of arsenic is probably the best way to confirm excessive arsenic absorption, although methods for blood arsenic concentration are available. Persons on ordinary diets usually excrete less than 20 Mg/day but diets rich in seafood may generate as much as 200 Mg/day. Excretions above 100 Mg/day should be viewed with suspicion and tests should be repeated. Excretions above 200 Mg/day reflect a toxic intake, unless seafood was ingested. (The arsenic in seafood is apparently bound firm- ly to an organic moiety that renders the arsenic essentially nontoxic and highly excretable.) The qualitative Gutzeit test for arsenic in the urine is available in most hospital laboratories, and is useful in identifying acute poisonings promptly. 50 ------- Chronic storage of arsenic can be detected by analysis of hair or fingernails. The hemoglobinuria caused by arsine is identified by finding free hemoglo- bin in fresh urine. TREATMENT OF POISONING BY SOLID ARSENICALS 1. Flush contaminated EYES, HAIR and SKIN with copious amounts of fresh water. WASH SKIN and HAIR with soap and water. 2. In poisonings by INGESTED ARSENICALS A. INTUBATE the stomach, ASPIRATE, and LAV AGE with 3 liters of isotonic saline or 5% sodium bicarbonate. Use all possible pre- cautions to avoid aspiration of vomitus: (1) If victim is unconscious or obtunded, insert an ENDO- TRACHEAL TUBE (cuffed, if available) prior to gastric intu- bation. (2) Keep victim's HEAD BELOW LEVEL OF THE STOMACH during intubation (Trendelenburg, or left lateral decubitus, with head of table tipped downward). Keep victim's head turned to the left. (3) ASPIRATE pharynx as regularly as possible to remove gagged or vomited stomach contents. B. After lavage, INSTILL 30-50 gm ACTIVATED CHARCOAL in the smallest amount of water necessary to deliver the charcoal through the tube. C. If diarrhea or colic has not ensued within an hour of gastric lavage and charcoal administration, give SODIUM SULFATE as a cathar- tic 0.25 gm/kg body weight in 1-6 ounces of water. 3. An ABDOMINAL X-RAY film is useful in detecting concretions of the less soluble arsenicals (As2O3 and lead arsenate) in the gut. If not re- moved these may become a repository of slowly absorbed toxicant. 4. Administer INTRAVENOUS ELECTROLYTE and GLUCOSE solu- tions to maintain hydration and to accelerate toxicant excretion. COM- BAT SHOCK with TRANSFUSIONS of WHOLE BLOOD, and by in- halation of 100% OXYGEN. CAUTION: Monitor urine flow via catheter. Monitor fluid balance, body weight, and/or central venous pressure to guard against fluid overload that may result if tubular necrosis (anuria) supervenes. 5. Administer DIMERCAPROL (BAL) and PENICILLAMINE to acceler- ate arsenic excretion. A. Give dimercaprol, 3-5 mg/kg q4h intramuscularly until abdominal pain and diarrhea subside and patient is regularly passing admin- istered charcoal in the feces. IF victim is ALLERGIC to 51 ------- PENICILLIN, continue dimercaprol therapy at 3-5 mg/kg q6h x 4 doses, then q!2h x 2 doses, then q24h x 10 doses, monitoring urine arsenic excretion periodically to judge effectiveness. CAUTION: DIMERCAPROL can cause troublesome side effects (hypertension, tachycardia, nausea, headache, pares- thesiae and pain, lacrimation, sweating, anxiety, and restlessness). Although usually not so severe as to preclude treatment, they may require antihistaminic therapy. B. IF victim is NOT ALLERGIC to PENICILLIN, oral d-PENICIL- LAMINE is the therapy of choice and should REPLACE dimer- caprol treatment as soon as the feces are laden with charcoal, limiting gut absorption of arsenic. Adult dosage is 0.5 gm four times daily (2 gm/day), given before meals, for 5 days. Dosage for children is 0.025 gm/kg four times daily, not to exceed 2 gm/day for 5 days. CAUTION: Although oral d-penicillamine therapy is usually better tolerated than intramuscular dimercaprol, serious reactions to it have occurred: the most common has been maculopapular rash, with fever, leukopenia, thrombocytopenia, eosinophilia, arthralgia and lym- phadenopathy. It has also induced the nephrotic syn- drome on occasion, and has caused thrombophlebitis, cheilosis, angioneurotic edema, and even fatal agran- ulocytosis in particular patients given the drug over long periods for conditions unrelated to arsenic poi- soning. Penicillin sensitive individuals are likely to be sensitive to d-penicillamine. (a). A single 5 day course of d-penicillamine therapy is usually suf- ficient. However, if symptoms recur after treatment, addi- tional d-penicillamine should be given at a dosage just suffi- cient to abolish symptoms. 6. Intense abdominal pain may require morphine (adults, 12 years and older: 4-15 mg; children under 12 years: 0.1-0.2 mg/kg). 7. Severe poisoning (especially when renal function is impaired) may re- quire HEMODIALYSIS to remove arsenic combined with dimercaprol from the blood, and to control extracellular fluid composition. HEMO- PERFUSION may be useful, but its effectiveness has not been reported. TREATMENT OF POISONING BY ARSINE GAS 1. REMOVE victim to FRESH AIR. 2. MAINTAIN RESPIRATION and CIRCULATION by resuscitation and cardiac massage, if necessary. 52 ------- 3. Administer INTRAVENOUS FLUIDS promptly to dilute free hemoglo- bin and minimize tubular injury. Include enough sodium bicarbonate to keep the urine alkaline. CAUTION: Monitor urine flow via catheter. Monitor fluid balance, body weight, and/or central venous pressure to guard against fluid overload resulting from acute tubular necrosis. 4. Administer DIMERCAPROL as recommended in 5A even though it has only limited effect in arsine poisoning. 5. EXCHANGE BLOOD TRANSFUSIONS and PERITONEAL DIALY- SIS have saved the lives of victims of arsine poisoning suffering acute tubular necrosis. 53 ------- Chapter 11 RODENTICIDES STRUCTURES OF PRINCIPAL COMPOUNDS ALKYL, PHENYL, i DIPHENYLACETYL or CHLORODIPHENYLACETYL WARFARIN 1,3 INDANDIONE C = S a-NAPHTHYL THIOUREA H O I H F - C - C-ONa I H SODIUM FLUOROACETATE Zn / \ P - Zn - P \ / Zn ZINC PHOSPHIDE \ / P YELLOW PHOSPHORUS 54 ------- SCILLIROSIDE (Active principle of Red Squill) = O STRYCHNINE ,— C-N-C-N—V \ -NO, H H II H O RH- 787 (Active ingredient of VACOR and DLP-787) CH3-C II H -C 'C-CI I N I N NORBORMIDE CRIMIDINE 55 ------- COMMON COMMERCIAL RODENTICIDE PRODUCTS Coumarins: warfarin, coumafene, zoocoumarin (Kypfarin, Ratox, RAX, Rodex, Tox-Hid, Warfarin Plus); coumafuryl (Tomarin, Fumarin); bromadiolone (Bromone, Super-Caid, Ratimus), coumachlor (Tomorin). Indandiones: diphacinone (Diphacin, Promar, Ramik); chlorophacinone (Caid, Drat, Liphadione, Microzul, Ramucide, Ratomet, Raviac, Rozol, Topitox); pindone or pivaldione (Pival, Pivacin, Pivalyn, Tri-ban). Other anticoagulant rodenticides of different structure: difenacoum (Ratak); brodifacoum (Talon). Sodium fluoroacetate: 1080, Fratol, Yasoknock. Zinc phosphide: Phosvin, Zinc-Tox. Yellow phosphorus and strychnine have limited use and are generally identi- fied by these long established common names. Crimidine: Castrix. RH-787: This product is no longer available for sale, but existing stocks present a continuing threat of poisoning. Commercial products are: Vacor Rat Killer (2% RH-787 in vehicle resembling corn meal); DLP-787 Bait (2% RH-787 in vehicle resembling corn meal); DLP-787 House Mouse Tracking Powder (10% RH-787 in a light green powder). Red squill: Dethdiet, Rodine. Antu: Krysid. Norbormide: Shoxin, Raticate. TOXICOLOGY Rodent poisons are generally added to baits, i.e., grain or paste designed to encourage consumption. Safety for pets, domestic animals, and humans depends on the toxicity of the agents, concentration of active ingredients in the baits, and the likelihood that a toxic dose will be consumed by nontarget species. The coumarins are reasonably effective against pest rodents and have a good safety record. This is due mainly to the low concentration of active in- gredient in the bait: about 100 gm of the commercial bait must be ingested to yield 25 mg of anticoagulant. This is important in evaluating suspected poison- ings by anticoagulants, which are the most widely available rodenticides for public use. Very small amounts of the extremely toxic rodenticides—sodium fluoro- acetate, zinc phosphide, crimidine, strychnine, and yellow phosphorus—can cause fatal poisoning. Vacor should be considered highly toxic. Ingestion of less than 1 gm by an adult has caused severe poisoning. Antu, red squill, and norbormide present considerably less toxic hazard to humans and to domestic animals. t A rodenticide of identical trade name is still available in some areas which contains thallium sulfate as the active ingredient. Use of thallium in the United States is now restricted. 56 ------- Coumarins, indandiones, and other anticoagulants: Gastrointestinal absorp- tion of these toxicants is efficient, beginning within minutes of ingestion and continuing for 2 to 3 days. Apparently warfarin can also be absorbed across the skin, although the circumstances under which this occurred were extraordi- nary. These agents depress the hepatic synthesis of substances essential to blood clotting: prothrombin (factor II) and factors VII, IX, and X. The antipro- thrombin effect is best known, and provides the basis for detection and assess- ment of clinical poisoning. Direct damage to capillary permeability occurs concurrently. The ultimate effect of these actions is to induce widespread in- ternal hemorrhage. This generally occurs in the rodent after several days of bait ingestion, although the modern products (diphacinone, chlorophacinone, pindone, difenacoum, and brodifacoum) may be lethal after fewer feedings. These modern agents should be considered more toxic than warfarin. In rare instances, coumarin-type anticoagulants have caused ecchymosis and extensive skin necrosis in humans for reasons not related to excessive dosage. Unlike the coumarin anticoagulants, the indandiones cause symptoms and signs of neurologic and cardiopulmonary injury in laboratory rats; these often lead to death before hemorrhage occurs. These actions may account for the somewhat greater toxicity of this class of anticoagulants. Neither cardiopul- monary nor neurologic symptoms or signs have been reported in human poisonings. Lengthened prothrombin time from a toxic dose is usually evident within 24 hours of ingestion and reaches a maximum in 36 to 72 hours. Without inter- vention, hypoprothrombinemia may persist 10 to 15 days, depending on the agent and dosage. Prothrombin depression occurs in response to doses much lower than those necessary to cause hemorrhage. Sodium fluoroacetate: the fluorocitrate metabolite of this poison blocks energy production in mammalian cells at the level of the tricarboxylic acid cy- cle. The critical sites of toxic effect in humans are the myocardium (where ven- tricular fibrillation is the usual cause of death) and the brain, where seizures are induced and respiration is depressed. Seizures, respiratory depression, and ventricular fibrillation are all causes of death. Zinc phosphide: this inorganic compound produces severe gastrointestinal irritation. It degrades in the gut to phosphine gas which, when absorbed, causes pulmonary edema and severe liver, kidney, CNS, and myocardial injury. Yellow phosphorus: this agent causes severe gastrointestinal irritation result- ing in vomiting, diarrhea, and melena. Circulatory collapse may occur and prove irreversible. Liver necrosis and acute renal tubular necrosis are equally ominous threats to life. Hemorrhage, from hypoprothrombinemia, and car- diac arrest or fibrillation, account for some deaths. Strychnine: this natural poison acts directly on the cells of the brain and spinal cord to cause convulsions. Death is caused by convulsive interference with pulmonary gas exchange, by depression of respiratory center activity, or both. 57 ------- Crimidine: this is a synthetic pesticide which, although unrelated chemically to strychnine, exerts toxic effects similar to those of strychnine, producing violent convulsions and secondary tissue anoxia by its action on the CNS. Vacor, DLP-787: the exact mechanism of RH-787 toxicity is not known although one established effect in rats is interference with nicotinamide metabolism. RH-787 has no anticoagulant action. Symptoms and signs in poisoned animals suggest toxic actions on the brain, peripheral nerves, myoneural junctions, pancreatic islet tissues, autonomic nervous system, and the conducting tissues of the heart. Abnormalities of renal and vascular func- tion may be direct effects of poisoning, or they may reflect metabolic and autonomic nervous system disturbances, impaired vascular reactivity in par- ticular. Red squill: this biological agent is unlikely to present a serious toxic hazard to humans or other vomiting species, because 1) it usually induces prompt emesis, 2) it is poorly absorbed from the gut, and 3) the active principles are in low concentration, and are rapidly excreted. Natural squill contains digitalis- like glycosides, which might, theoretically, produce manifestations of digitali- zation in humans. The glycoside known as scilliroside is the probable cause of convulsive death in the rat; convulsions have not been observed in human poisonings. Antu: this agent exhibits selective toxicity for the rat, causing pulmonary edema and pleural effusion. Only one human poisoning is recorded, and it was induced by a large suicidal dose. Vomiting was followed by dyspnea, cyanosis, and pulmonary rales, presumably reflecting pulmonary edema. The patient recovered. Norbormide: this is selectively toxic to Norway and roof rats, which it kills by inducing a generalized, sudden, and intense vasoconstriction. Other vari- eties of rats are resistant, and the chemical is only moderately toxic to other mammals, including humans. Oral doses of 300 mg cause transient lowering of blood pressure and body temperature in humans. FREQUENT SYMPTOMS AND SIGNS OF POISONING Coumarins, indandiones, and other anticoagulants: In most cases of inges- tion of anticoagulants, victims have remained asymptomatic, due to the small dosage taken. Even in cases involving ingestion of substantial amounts of anti- coagulant compound (more often medication than rodenticide), hypopro- thrombinemia has occurred without symptoms of poisoning. Hemorrhage ap- pears only when extraordinary amounts have been absorbed. In reported cases, the anticoagulants were either taken deliberately, were absorbed over long periods out of neglect of elementary hygienic standards, or were ingested by starving indigents who used quantities of rodent bait as food. Victims of large doses exhibit HEMATURIA, NOSEBLEED, HEMATO- MATA, BLEEDING GUMS, and MELENA. ABDOMINAL PAIN and BACK PAIN probably reflect hemorrhage in the abdominal and retroperito- neal tissues. WEAKNESS occurs as a result of ANEMIA. RENAL COLIC 58 ------- often complicates severe hematuria. Nasal and gastrointestinal hemorrhages have occasionally caused death from exsanguination. Sodium fluoroacetate: A delay of several minutes or even hours may be ex- pected before symptoms appear. Epigastric distress and vomiting often occur. Apprehension, PARESTHESIAE and hallucinations are the usual premonitory symptoms, leading to epileptiform CONVULSIONS. CARDIAC IRREGULARITIES (ectopic beats, pulsus alternans, ventricular tachycardia and fibrillation) appear after seizures commence. These are frequently fatal. Zinc phosphide: Intense NAUSEA, abdominal pain, excitement, and chills are early symptoms. Tightness in the chest, DYSPNEA and COUGH, produc- tive of FROTHY SPUTUM, reflect pulmonary edema. SHOCK from toxic myocarditis is common. If these conditions are survived, JAUNDICE from liver necrosis, and ANURIA from renal tubular injury are later complications. Hypocalcemic TETANY and PURPURA have occurred in some poisonings. Yellow phosphorus: BURNING PAIN in the throat, chest, and abdomen reflect severe mucosal irritation. Vomiting and diarrhea ensue. Breath has garlicky odor. Feces may luminesce and "smoke" from phosphorus fumes. SHOCK often progresses to death in 1 to 2 days. The patient who survives may then be relatively symptom-free for several hours or even days, after which the delayed manifestations appear due to liver, CNS, myocardial and renal injury. Nausea and VOMITING persist. HEMORRHAGE at various sites reflects mainly depression of clotting-factor synthesis in the liver. SHOCK may be due to hemorrhage and/or toxic myocarditis. CONVUL- SIONS, delirium, and coma are common. ANURIA usually ensues as a result of direct nephrotoxic effect of phosphorus, enhanced by biliary nephrosis (hepatorenal syndrome). Strychnine: Within 10 to 60 minutes of ingestion of an adequate dose (as lit- tle as 16 mg), the victim suffers VIOLENT CONVULSIONS caused by clonic, then tonic contraction of all the skeletal muscles of the body. Cyanosis develops promptly. Brief periods of relaxation may occur, followed by even more severe seizures. Opisthotonus is common, and the muscles of the face are drawn into a grimace. Death is usually due to ASPHYXIA, a consequence of convulsive spasm of the respiratory muscles. Crimidine: Ingestion is followed promptly by VIOLENT CONVULSIONS, essentially like those caused by strychnine (see preceding paragraph). Vacor, DLP-787: Minimum toxic and lethal doses in humans are not known. Ingested amounts less than one gram have proved severely toxic. Symptoms may not appear for 4 to 48 hours after ingestion. Earliest symp- toms are usually NAUSEA, vomiting, abdominal cramps, CHILLS, and CONFUSION. Later manifestations are aching and fine tremors of the ex- tremities, dilated pupils, plantar hyperesthesia, MUSCLE WEAKNESS, dysphagia, chest pain, postural hypotension, anorexia, diarrhea, urinary retention, and HYPOTHERMIA. Subsequently, DIABETES MELLITUS commonly develops, manifest as glycosuria, polyuria, ketoacidosis, and dehydration. Death may result from respiratory failure, cardiovascular col- lapse, or ketoacidosis. Survivors of the acute phase of the poisoning are often 59 ------- left with permanent sequelae: postural hypotension, diabetes mellitus, bladder dystonia (retention or frequency), bowel dystonia (constipation or diarrhea), and peripheral neuropathy. Abnormal laboratory findings include hyperglycemia, glycosuria, ketosis (acidosis and electrolyte disturbances), and elevation of serum amylase and lipase activities. Red squill: Nausea and VOMITING are the predominant effects. In the unlikely event that significant amounts of glycosides are absorbed, cardiac ar- rhythmias and slowing might be expected. Convulsions have not been observed in humans as they have in rats. Antu: Pulmonary rales, DYSPNEA and cyanosis may be expected follow- ing ingestion of large amounts. Norbormide: No human poisonings have been reported. Ingestion of 300 mg by an individual caused a slight fall in body temperature and blood pressure. CONFIRMATION OF DIAGNOSIS Coumarins, indandiones, and other anticoagulants: Increase of the pro- thrombin time (Quick) reflects a reduction in serum prothrombin concentra- tion, and occurs in response to physiologically significant absorption of these toxicants. This widely available clinical test offers a sensitive and reliable diagnostic method for detecting a toxic effect of these compounds. Readily detectable change in prothrombin time appears within 24 to 48 hours of inges- tion of anticoagulant. Zinc phosphide and phosphorus: Zinc phosphide smells like rotten fish and imparts a garlicky odor to the breath. Luminescence of vomitus or feces in- dicates yellow phosphorus ingestion. Other rodenticides: There are analytical methods available for identifying some remaining rodenticides in food or liquids suspected of contamination, in gastric contents, and sometimes in blood and urine. (See Sunshine, I., Hand- book of Analytical Toxicology (1969) published by the Chemical Rubber Company, 18901 Cranwood Parkway, Cleveland, Ohio 44128.) These methods are generally complex and must be performed by a toxicology labora- tory experienced in these tests. Analysis is often time-consuming, limiting the usefulness of the results in clinical management. Analyses may be important, however, for legal reasons. TREATMENT Coumarins, indandiones, and other anticoagulants 1. If only a few grains of anticoagulant bait have been ingested by an adult or child having no antecedent liver or blood clotting disease, treatment is probably unnecessary. 60 ------- A. If there is uncertainty about the amount of bait ingested or the general health of the patient, PHYTONADIONE (vitamin K,, Mephyton®) given orally protects against the anticoagulant effect of these rodenticides. For adults, give 15-25 mg; for children under 12, give 5-10 mg. Alternatively, a colloidal solution of phytona- dione, Aquamephyton®, may be given intramuscularly. For adults, give 5-10 mg; for children under 12, give 1-5 mg. CAUTION: PHYTONADIONE, specifically, is required. Neither vitamin K3 (menadione, Hykinone®) nor vitamin K4 (menadiol) is an antidote for these anticoagulants. B. Whatever the doage, insure that patients (especially children) will be CAREFULLY OBSERVED for 4-5 days after ingestion. The indan- diones and the more recently introduced anticoagulants have toxic effects apart from anticoagulation that are not yet well defined. 2. If LARGE AMOUNTS of anticoagulant were ingested in the preceding 2-3 hours, INDUCE VOMITING with SYRUP OF IPECAC, followed by 1-2 glasses of water. For adults, give 30 ml; for children under 12, 15 ml. Following emesis, give 30-50 gm ACTIVATED CHARCOAL in 4-6 ounces of water to limit absorption of anticoagulant remaining in the gut. 3. If anticoagulant has been ingested any time in the preceding 15 days, determination of PROTHROMBIN TIME provides a basis for judging the severity of poisoning. A. If the prothrombin time is lengthened, give Aquamephyton®, in- tramuscularly: adult dose, 5-10 mg; child's dose: 1-5 mg. Decide dose according to the degree of prothrombin time lengthening and, in children, the age and weight of the child. B. Repeat prothrombin time in 24 hours. If it has not decreased from the original value, repeat Aquamephyton® dosage. 4. If victim shows SYMPTOMS or SIGNS of ANTICOAGULANT POI- SONING (bleeding) in addition to hypoprothrombinemia, administer Aquamephyton® intramuscularly, up to 25 mg in the adult, and up to 0.6 mg/kg in children under 12 years. Phytonadione administration may be repeated in 24 hours if bleeding continues. A. In cases of SEVERE BLEEDING, it may be necessary to give Aquamephyton® intravenously. This is especially true if the bleeding tendency is so severe that intramuscular injection is likely to cause hematoma formation. Dosage is up to 25 mg in the adult, up to 0.6 mg/kg in children under 12 years. Repeat this dose in 24 hours if bleeding continues. Inject at rates not exceeding 5% of the total dose per minute. INTRAVENOUS INFUSION of the Aquamephyton® DILUTED IN SALINE OR GLUCOSE SOLU- TION is recommended. Bleeding is usually controlled in 3-6 hours. 61 ------- CAUTION: Adverse reactions, some fatal, have occurred from INTRAVENOUS phytonadione injections, even when recommended dosage limits and injection rates were observed. For this reason, the INTRAVENOUS route should be used ONLY IN cases of SEVERE POISONING. Flushing, dizziness, hypotension, dyspnea, and cyanosis have characterized adverse reactions. B. Antidotal therapy IN cases of SEVERE BLEEDING should be sup- plemented with TRANSFUSIONS of FRESH BLOOD or FRESH FROZEN PLASMA. Use of fresh blood or plasma represents the most rapidly effective method of stopping hemorrhage due to these anticoagulants. C. Determine PROTHROMBIN TIMES (and hemoglobin concentra- tions, if appropriate) every 6-12 hours to assess effectiveness of anti- hemorrhagic measures. D. When normal blood coagulation is restored, it may be advisable to drain large hematomata. E. Ferrous sulfate therapy may be appropriate in the recuperative period to rebuild lost erythrocyte mass. Sodium fluoroacetate 1. If this substance has been INGESTED, empty the stomach immediately by INTUBATION, ASPIRATION, and LAV AGE, using 5% sodium bicarbonate. Before withdrawing the lavage tube, instill a slurry of 30-50 gm ACTIVATED CHARCOAL. 2. MONITOR cardiac rhythm by continuous ELECTROCARDIOG- RAPHY. 3. MONOACETIN (glyceryl monoacetate) has antidotal properties in ex- perimental animals. The liberated acetate competes successfully with fluorocitrate in the tricarboxylic acid cycle. However, there is no sterile pharmaceutical preparation of this compound: high-quality, fresh laboratory grade material must be used. A. If victim is fully conscious and not convulsing, administer 100 ml of monoacetin in 500 ml of water, by mouth. Repeat in one hour. (Arena, J. M. Poisoning, 1970.) B. If victim is obtunded, unconscious, or convulsing, give 0.1-0.5 ml/kg of undiluted monoacetin by deep intramuscular injection every half hour for 4-6 hours, rotating the injection sites to minimize pain and swelling. Monoacetin can also be given intra- venously on the same schedule, using a 1:5 dilution in sterile isotonic saline. 62 ------- CAUTION: The use of parenteral monoacetin is hazardous. Tech- nical grade material contains glycerin which, in ade- quate dosage, may cause hemolysis, hypotension, convulsions, and paralysis. If a nonsterile solution is injected, the monoacetin should be cultured to guide the administration of antibiotics if sepsis develops. 4. CONTROL CONVULSIONS A. Administer 100% OXYGEN by positive pressure to provide as much pulmonary gas exchange as possible, despite seizures. B. ANTICONVULSANT DRUGS CAUTION: It may be difficult or impossible to stop the seizure activity without stopping respiration. Be prepared to maintain pulmonary ventilation mechanically. Tracheostomy may be necessary if seizures are pro- longed. (a). Diazepam (VALIUM®) usually controls mild convulsions. For adults, give 5-10 mg, slowly, intravenously; for children under 6 years or 23 kg body weight, give 0.1 mg/kg body weight, slowly, IV. Repeat in 4-6 hours if necessary. (b). Pentobarbital may be needed in addition to control severe convulsions. Dosage: 5 mg/kg body weight, or 0.20 ml/kg body weight, using the usual 2.5% solution. If possible, inject solution intravenously, at a rate not exceeding 25 mg (one ml) per minute until convulsions are controlled. If intravenous ad- ministration is not possible, give total dose by deep intramus- cular injection, not exceeding 5 mg/kg body weight (0.20 ml/kg of 2.5% solution). (c). Phenytoin (DILANTIN®) has prolonged anticonvulsant ac- tion. Dosage: loading dose 15-18 mg/kg. Maintenance dose 4-8 mg/kg q 4-24 hours as needed. Intramuscular adminis- tration is not recommended. Give IV slowly at no more than 20% total dose per minute. (d). Thiopental (PENTOTHAL®), by continuous intravenous in- fusion, may help to control severe seizures. Dissolve one gram in 500 ml of glucose solution, and infuse at a rate just suffi- cient to stop seizures. CAUTION: Laryngospasm is a complication of anticonvul- sant therapy and may require tracheostomy. (e). In some instances, curari/ation with succinylcholine or a similar agent is required to stop convulsions. This requires tracheal intubation or tracheostomy and mechanical pulmo- nary ventilation, with regular monitoring of blood gases and pH. 63 ------- 5. Many other agents tested in fluoroacetate poisoning are NOT EFFEC- TIVE: sodium acetate, calcium chloride, ethanol, propylene glycol, digitalis glycosides, di- and tri-acetates of glycerol. 6. Administer IV electrolyte solutions cautiously to avoid fluid overload in presence of a weak and irritable myocardium. Zinc phosphide and yellow phosphorus 1. WASH SKIN BURNS due to yellow phosphorus with water and a 1% copper sulfate solution. Make sure all particles of phosphorus have been removed. Cover burned area with ointment. 2. Poisonings by INGESTED yellow phosphorus or zinc phosphide are ex- tremely difficult to manage. The mortality rate of 50% is the result of either shock or pulmonary edema in the first few hours or days, or coma, seizures, and/or liver, kidney and myocardial damage in the ensuing days or weeks. CAUTION: Highly toxic phosphine gas may evolve from emesis, lavage fluid, and feces of victims of these poisons. The pa- tient's room should be well ventilated. A. INTUBATE and ASPIRATE the stomach. LAVAGE with several quarts of 1:5000 potassium permanganate solution. CAUTION: Persons attending victim must avoid contact with yellow phosphorus, which causes skin burns. B. Combat shock and acidosis with TRANSFUSIONS of whole blood and INFUSIONS of glucose and electrolyte solutions. Monitor fluid balance and central venous pressure to avoid fluid overload. Monitor blood electrolytes and pH to guide choice of intravenous solutions. C. Administer 100% OXYGEN by mask or nasal tube. D. Combat pulmonary edema with intermittent or continuous POSI- TIVE PRESSURE OXYGEN. E. MONITOR URINE albumin, glucose, and sediment to detect early renal injury. Monitor EKG to detect myocardial impairment. Moni- tor serum alkaline phosphatase, LDH, prothrombin time, and bilirubin to evaluate liver damage. F. Include Aquamephyton® (vitamin K]) in intravenous infusions if prothrombin level declines. Dosage of 10-50 mg per day may be re- quired. Administer Aquamephyton® slowly, intravenously; stop infusion if Mushing, cyanosis, paresthesiae, hypotension, or dyspnea occurs. G. MORPHINE SULFATE, 8-16 mg every few hours may be necessary to control pain. Child's dose: 0.1-0.2 mg/kg. H. CONTROL CONVULSIONS with diazepam, barbiturates, and/or phenytoin as suggested under treatment of sodium fluoroacetate poisoning. I. CORTICOSTEROIDS at high dosages may be beneficial. 64 ------- Strychnine and crimidine 1. Administer 100% OXYGEN by positive pressure. 2. CONTROL CONVULSIONS. This may be attempted with intravenous diazepam, barbiturates, and/or phenytoin, as described under manage- ment of sodium fluoroacetate poisoning. A. CURARIZATION is often required, using succinylcholine or similar agent. Tracheal intubation or tracheostomy and continuous mechanical pulmonary ventilation are necessary. Blood gases and pH must be monitored. 3. FORCED DIURESIS with mannitol accelerates the excretion of strychnine. Infusion of SODIUM BICARBONATE relieves metabolic acidosis. There may be some benefit from peritoneal dialysis, hemodialysis, and hemoperfusion. 4. Once seizures have been controlled, remove unabsorbed toxicant from the stomach by gastric INTUBATION, ASPIRATION, and LAV AGE. Leave a slurry of 30-50 gm ACTIVATED CHARCOAL in the stomach. Follow charcoal with SODIUM or MAGNESIUM SULFATE, 0.25 gm/kg, in 1-6 ounces of tap water, to induce catharsis. Repeat cathartic dosage as needed. Vacor, DLP-787 (Active ingredient RH-787) 1. If toxicant was ingested recently, EVACUATE the STOMACH by IN- TUBATION, ASPIRATION, and LAVAGE with 2-3 liters isotonic saline. A. Before withdrawing stomach tube, instill 30-50 gm of ACTIVATED CHARCOAL as a slurry in 3-4 ounces of water, to limit absorption of remaining toxicant. B. As soon as patient can tolerate oral fluids after withdrawal of stomach tube, give SODIUM or MAGNESIUM SULFATE, 0.25 gm/kg body weight in 1-6 ounces of water to induce catharsis. Repeat dose in 4 hours if patient has had no bowel movement. 2. Administer NICOTINAMIDE (niacinamide) intravenously, slowly, or intramuscularly. For adults and children over 12 years, give 500 mg im- mediately, then repeat injections of 200-400 mg every 4 hours for 10-12 doses. Within this range, select the dose on the basis of body weight and the estimated quantity of RH-787 ingested. If manifestations of RH-787 toxicity appear, give nicotinamide by continuous IV infusion at about 100 mg per hour. There is probably no advantage in giving more than 3000 mg per day of nicotinamide. A. Dosage of nicotinamide for children under 12 years, or 23 kg, is about half the dosage suggested for adults. B. After 2-3 days of parenteral therapy, give nicotinamide by mouth, 100 mg four times daily, for 2 weeks. 65 ------- 3. MONITOR blood and urine sugar concentrations, serum alkaline phosphatase, amylase, LDH, and GOT activities, urine ketone concentra- tions, blood electrolytes and BUN. Examine the electrocardiogram for arrhythmias. 4. Unless the patient is able to void easily, put in place a RETENTION CATHETER to monitor urine flow and urinary glucose excretion. 5. Infuse ELECTROLYTE SOLUTIONS intravenously to accelerate toxi- cant excretion and correct errors in specific ion concentrations. If ketoacidosis appears, use bicarbonate or Ringer's-lactate to control acidosis. 6. If DIABETIC KETOACIDOSIS appears (ketonuria, metabolic acidosis, hyperglycemia) administer enough regular insulin to control the acidosis and hyperglycemia, as in naturally occurring diabetic ketosis. The diabetes resulting from RH-787 tends to be brittle and correspondingly difficult to control. 7. In all cases of ingestion of Vacor or DLP-787 (whether or not acute poisoning occurs), follow the patient's clinical status carefully for at least 6 months. Look for indications of diabetes mellitus (glycosuria, hyper- glycemia), and for consequences of autonomic nervous system damage: orthostatic hypotension, urinary retention, constipation, diarrhea, ab- dominal cramping, pain and weakness in the limbs'. Red squill 1. Significant toxicity is not expected from this agent. If, for some reason, a significant amount is retained in the stomach, remove it by gastric IN- TUBATION, ASPIRATION, and LAV AGE, followed by 0.25 gm/kg SODIUM or MAGNESIUM SULFATE in 1-6 ounces water. 2. Monitor ELECTROCARDIOGRAM for arrhythmias and conduction disturbances characteristic of digitalis. Antu 1. Significant toxicity is not expected from this agent. If an extraordinary amount has been ingested, empty the gut. Administer SYRUP OF IPECAC, then 1-2 glasses of water, to induce vomiting. Adult dose: 30 ml; dose for children under 12 years: 15 ml. Follow with 30-50 gm ac- tivated charcoal in 3-4 ounces of water, then 0.25 gm/kg SODIUM or MAGNESIUM SULFATE in 1-6 ounces water. 2. If dyspnea appears, administer OXYGEN by continuous flow or by intermittent POSITIVE PRESSURE. Norbormide 1. Significant toxicity is not expected from this agent. If an extraordinary amount has been ingested, empty the gut. Administer SYRUP OF 66 ------- IPECAC, then 1-2 glasses of water, to induce vomiting. Adult dose: 30 ml; dose for children under 12 years: 15 ml. Follow with 30-50 gm AC- TIVATED CHARCOAL in 3-4 ounces of water, then 0.25 gm/kg SODIUM or MAGNESIUM SULFATE in 1-6 ounces water. 2. Monitor BLOOD PRESSURE and BODY TEMPERATURE for several hours, if a large amount has been absorbed. 67 ------- Chapter 12 FUMIGANTS CHEMICAL STRUCTURES HALOCARBONS Cl 1 CI-C-CI 1 Cl Carbon Tetrachloride Cl 1 CI-C-H 1 Cl Chloroform Cl 1 Cl - C - NO2 Cl Chloropicrm H I 1 H - C - Br 1 H Methyl Bromide Br Br 1 1 H -C— C-H 1 1 H H Ethylene Dibromide Cl H Cl 1 1 1 H -C - C = C 1 1 H H 1,3-Dichloro- propene Br Br Cl Ii i 1 1 H - C -C - C - H 1 1 1 H H H Dibromo- chloropropane Cl Cl i i 1 1 H - C -C - H | | H H Ethylene Dichloride OXIDES AND H ALDEHYDES O ' ^ CH2- CH2 Ethylene Oxide O / \ GH2 - CH • CHg Propylene Oxide H C= 0 H Formaldehyde O [•f] L. — 1 Paraformaldehyde H H H 1 1 1 C = C-C = O 1 H Acrolein SULFUR AND PHOSPHORUS COMPOUNDS O = S = O Sulfur Dioxide S = C = S Carbon Disulfide _ \ S = O F Sulfuryl Fluoride ii ii p I I H Phosphme (from MZP+ H20) CYANIDES H-C = N Hydrogen Cyanide H H 1 1 C = C-C = N 1 H Acrylonitrile 68 ------- COMMON COMMERCIAL FUMIGANT PRODUCTS Chloroform, carbon tetrachloride, methyl bromide (Brom-O-Gas, Fumi- gant-1, Kayafume, Me Br, Meth-O-Gas, Pestmaster, Profume); chloropicrin (Acquinite, Chlor-O-Pic, Pic-Clor, Picfume, Tri-Clor); ethylene dichloride (EDC), ethylene dibromide (EDB, Bromofume, Celmide, Dowfume W-85, Kop-Fume, Nephis, Pestmaster EDB-85, Soilbrom); dichloroprop-ene and -ane (Telone, D-D), sulfuryl fluoride (Vikane), dibromochloropropane (DBCP). The Dowfume fumigants manufactured by the Dow Chemical Company are mixtures of halocarbons, mainly EDC, EDB, carbon tetrachloride, Me Br, and chloropicrin, formulated to meet specific needs. Ethylene oxide (ETO, oxirane); propylene oxide (epoxypropane); formalde- hyde (Formalin is a 40% aqueous solution), propenal (Acrolein, Aqualin, Acrylaldehyde); carbon di- (or bi-) sulfide; hydrogen cyanide (prussic acid, Cyclon); acrylonitrile (ingredient of fumigant mixtures Acrylofume, Acritet, Carbacryl); aluminum phosphide (Phostoxin). TOXICOLOGY Fumigants have extraordinary power to penetrate the lining membranes of the respiratory and gastrointestinal tracts, and the skin. They also penetrate the rubber and plastics used in protective garb and they are not efficiently taken up by conventional adsorbents used in ordinary respirators. These prop- erties make the protection of applicator personnel very difficult, essentially mandating methods of use that do not require on-site operator handling. Because these chemicals are either gases or volatile liquids at room tempera- ture, inhalation is the most common route of absorption. Dermal injury does follow contact with some fumigants, ranging in severity from a mild chemical burn to vesiculation and ulceration. Fumigant gases irritate the eyes; liquid fumigant may cause blindness from corneal ulceration. Respiratory tract irritation is the most common and serious injury caused by fumigants. Some agents such as sulfur dioxide, chloropicrin, formaldehyde and acrolein cause so much irritation of the upper respiratory tract that the ex- posed individual is unlikely to inhale a quantity of fumigant capable of damag- ing the lung. Rarely, laryngeal edema or bronchospasm results from inhalation of high concentrations. Other gases, such as methyl bromide, phosphine, and ethylene oxide, are not so irritating to the nose, eyes, throat, and bronchi, but cause serious injury to the cells lining the fine air sacs of the lung. Thus, they are more likely than other fumigants to induce pulmonary edema, a major cause of death from fumigant exposure. In varying degrees, these fumigants depress the central nervous system. As in the case of the anesthetic chloroform, adequate dosage may lead to uncon- sciousness. Depression or cessation of respiration is a major hazard of acute inhalation exposure to fumigants. Acute exposures to methyl bromide have in- duced convulsions. Absorbed in lower concentrations over several consecutive 69 ------- days, methyl bromide has impaired basal ganglion function in humans, caus- ing ataxia for weeks or months after exposure. Protracted exposure to carbon disulfide has caused peripheral neuropathy and changes in CNS function (chronic encephalopathy) of chronically exposed workers. The halocarbon fumigants increase the irritability of the heart muscle. In- tensive exposures may lead to sudden death as a result of ventricular fibrilla- tion. Liver and kidney damage occurs commonly following excessive exposure to fumigants. Liver injury may take the form of fatty infiltration, diffuse necrosis or massive necrosis. Elevated serum levels of GOT, LDH, alkaline phosphatase, and bilirubin reflect hepatocellular injury. The fumigants may inflict direct injury on glomerular and tubular elements of the kidney, leading to functional proteinuria and glycosuria, or to acute renal failure, depending on severity of toxicant exposure. In addition, hyperbilirubinemia resulting from liver damage may compound the tubular injury (hepatorenal syndrome). Inhaled phosphine gas (PH3) and ingested metal phosphides cause pulmonary edema, CNS depression, toxic myocarditis, and circulatory col- lapse. Victims who survive these immediate actions suffer liver injury (fatty degeneration and necrosis) and acute renal tubular necrosis. Unlike its analogue arsine, phosphine is not hemolytic. Enzymatic mechanisms of toxici- ty are not known. Ingested metal phosphide (from which phosphine is gener- ated) causes intense gastrointestinal irritation, followed by degenerative and necrotizing lesions of the liver, kidney, and heart. Death is often due either to cardiogenic shock or pulmonary edema. Hydrogen cyanide (HCN) and its salts poison by inactivating the cytochrome oxidase of cells in critical tissues, primarily the heart and brain. Acrylonitrile degrades slowly to HCN in the body, and therefore acts primarily by the same mechanism, although the slow release of free cyanide renders it somewhat less toxic than HCN itself. Both HCN and acrylonitrile are suffi- ciently absorbable across the skin to cause poisoning in the absence of inhala- tion exposure. Manifestations of poisoning are due mainly to intracellular anoxia of brain tissue (leading to respiratory failure), and to the circulatory in- sufficiency that results from myocardial weakness. The liver has substantial capacity for converting cyanide to the less toxic thiocyanate, a metabolic con- version that is accelerated by therapeutically administered thiosulfate. Dibromochloropropane has reportedly caused sterility in manufacturing plant workers and reduced sperm counts in highly exposed applicators. FREQUENT SYMPTOMS AND SIGNS OF POISONING HEADACHE, DIZZINESS, NAUSEA, and vomiting are prominent early symptoms of excessive exposure to these gases. Sulfur dioxide, formaldehyde, chloropicrin, and acrolein are strong irritants, causing BURNING SENSA- TIONS in the nose and throat, TEARING, COUGH, and sometimes hoarse- ness and wheezing. Exposures to methyl bromide, phosphine and ethylene ox- ide are more likely to produce prompt pulmonary edema: COUGHING of 70 ------- copious amounts of FROTHY FLUID, associated with severe SHORTNESS OF BREATH and cyanosis. The remaining fumigants are less likely to cause respiratory tract injury. DROWSINESS, TREMORS, double vision, and weakness are the common early manifestations of central nervous system impairment. Tremors may progress to myoclonic movements, then to generalized SEIZURES, UNCON- SCIOUSNESS, and death. Protracted low level exposure to methyl bromide causes ATAXIA and impairment of manual coordination. Injuries to the skin by liquid fumigants may be manifest as areas of redness or as BLISTERS which rupture, leaving raw skin or deep ulcers. If ingested, the LIQUID forms of HALOCARBONS often cause pulmonary edema and SHOCK within a few moments. If victim survives, injuries to the brain, liver and kidney are life-threatening. Longer-term low level inhalation of CHLOROCARBONS may cause liver damage, first manifest as ANOREXIA, then as JAUNDICE. Biochemical studies confirm hepatocellular injury. Poisoning by excessive inhalation of CARBON DISULFIDE is character- ized by DIZZINESS, headache, nausea, and sometimes disorientation, pares- thesiae, hallucinations, and, rarely, convulsions. Protracted low level exposures produce PAIN, tingling, WEAKNESS of the extremities, and deterioration of mental functions. Poisoning by PHOSPHINE gas is usually heralded by weakness, TREMORS, vomiting, a sense of pressure in the chest, COUGH, and dyspnea, sometimes progressing to PULMONARY EDEMA. Intense thirst results from hypotension and diarrhea. Severe poisonings lead to CONVULSIONS, coma, and death. Those who survive the acute phase suffer LIVER INJURY (eleva- tion of serum GOT, LDH, and alkaline phosphatase, and sometimes, reduced prothrombin concentration, hemorrhage, and jaundice) and kidney damage (hematuria and sometimes anuria). Chronic exposures to lesser amounts have caused pain in the eyes and nose, nosebleeds, and abdominal pain. Ingestion of METAL PHOSPHIDES leads promptly to NAUSEA and VOMITING, followed by injury to the lung, liver, kidney, heart and central nervous system. Hypocalcemic tetany (from hyperphosphatemia) and metabolic acidosis develop several hours after ingestion of solid phosphides. Excessive inhalation of SULFURYL FLUORIDE may induce muscle twitch- ing and convulsions. Persons repeatedly exposed risk injury to the lung (im- paired pulmonary function) and kidney (proteinuria and azotemia). Poisoning by HYDROGEN CYANIDE or ACRYLONITRILE may pro- duce sudden UNCONSCIOUSNESS and respiratory arrest without warning symptoms. Lesser exposures cause HEADACHE, nausea, and a sense of con- striction in the throat, followed by hyperpnea, dizziness, and apprehension. Pulse and respiratory movements then become weak, slow, and irregular as consciousness is lost. CONVULSIONS, either tonic or epileptiform, may supervene. Opisthotonus and trismus commonly appear, and sphincter control is usually lost. The heart often continues to beat after respiration has stopped. The skin generally remains pink. 71 ------- CONFIRMATION OF DIAGNOSIS Large industrial concerns monitor human absorption of halocarbons by analysis of expired air. Similar technology is available in many departments of anesthesiology. Such analyses are not often needed to identify the offending toxicant, because this is known from the exposure history. In managing dif- ficult cases of poisoning, however, it may help to monitor breath concentra- tions of toxic gas. Blood bromide concentrations t have some value in identifying poisonings by methyl bromide, and possibly ethylene dibromide, provided it can be estab- lished that the person exposed to the fumigant has not recently taken inorganic bromide medication. A level of organic bromide higher than 5 mg/100 ml in- dicates excessive absorption of fumigant. A blood concentration of more than 10 mg/100 ml of organic bromide represents a serious threat to health. A blood level of more than 15 mg/100 ml indicates an immediate threat to life. Methods for detecting the organic oxides, aldehydes, sulfur dioxide, and phosphine are not generally available, but they are rarely needed. A simple method is available for detecting carbon disulfide in urine (Djuric et al. Brit. J. Indust. Med. 22:321-323. 1965). Cyanide can be detected and measured in blood and tissues, as can the thiocyanate metabolite in urine and saliva. Odors of gases on the victim's breath are sometimes helpful diagnostic clues: cyanide smells like bitter almonds, carbon disulfide like rotten cabbage, and phosphine somewhat like garlic or acetylene. TREATMENT 1. FLUSH contaminating fumigant from the SKIN and EYES with copious amounts of water for at least 15 minutes. Contact with LIQUID fumigant can cause BLINDNESS or DEATH. Treat injuries IM- MEDIATELY. 2. REMOVE victims of fumigant inhalation TO FRESH AIR. Even though initial symptoms and signs are mild, keep victim quiet, in a semireclining position. Reduction in physical activity reduces the likelihood of pulmo- nary edema. 3. If victim is not breathing, RESUSCITATE with positive pressure oxygen breathing apparatus, if available. If apparatus is not available, use mouth-to-mouth or mouth-to-nose methods. If victim is pulseless,use cardiac resuscitation. 4. If PULMONARY EDEMA is evident, there are several measures avail- able to sustain life. Medical judgment must be relied upon, however, in the management of each case. The following procedures are generally recommended: A. Put the victim in a SITTING position with a backrest. Conway, E. J. Microdiffusion Analysis and Volumetric Error, 3rd edition. Crosby Lockwood, London 1950. 72 ------- B. Use intermittent and/or continuous positive pressure OXYGEN to relieve hypoxemia. (Do not give oxygen at greater concentrations or longer periods than necessary, because it may exaggerate the fumi- gant injury to lung tissue. Monitor arterial p O2). C. Apply TOURNIQUETS in rotation to arms and legs to limit venous return. D. Administer AMINOPHYLLINE (0.25-0.50 gm) slowly, intraven- ously. E. Administer MORPHINE in small doses (5-10 mg), slowly, intra- venously, to allay anxiety and promote deeper respiratory excur- sions. Children's dose, 0.1-0.2 mg/kg. F. Digitalization may be considered, but be alert to the serious risk of arrhythmias in an anoxic mycardium. G. Slowly administer FUROSEMIDE, 40 mg, or SODIUM ETHACRYNATE, 50 mg, to reduce venous load by inducing diuresis. H. TRACHEOSTOMY may be necessary in some cases to facilitate aspiration of large amounts of edema fluid. I. Epinephrine, atropine, and expectorants are generally NOT HELPFUL and may complicate treatment. J. STEROIDS at high dosage are usually recommended, although their effectiveness is unproved. K. If secondary pneumonitis occurs, administer ANTIBIOTICS. L. Watch for RECURRENT PULMONARY EDEMA, even up to 2 weeks after the initial episode. Limit victim's physical activity for at least 4 weeks. Severe physical weakness usually indicates persistent pulmonary injury. Serial pulmonary function testing may be useful in assessing recovery. 5. Combat SHOCK by placing victim in the Trendelenburg position and ad- ministering blood plasma and/or electrolyte and glucose solutions intra- venously, with great care, to avoid pulmonary edema. Central venous pressure should be monitored continuously. Vasopressor amines must be given with great caution, because of the irritability of the myocardium. 6. Control CONVULSIONS. Seizures are most likely to occur in poisonings by methyl bromide, carbon disulfide, phosphine, metal phosphide, cyanide, and acrylonitrile. A. Establish pulmonary gas exchange at the best possible level by ad- ministering 100% OXYGEN by IPPB. B. In poisoning by CYANIDE and acrylonitrile, proceed directly with ANTIDOTAL therapy (see below, paragraph IOC). C. Control convulsions caused by other agents with careful IV injec- tion of DIAZEPAM, 5-10 mg in the adult, 0.1 mg/kg in children under 12 years. Repeat dosage in 4-6 hours if necessary. CAUTION: Be prepared to maintain pulmonary ventilation mechanically, and to manage hypotension and car- diac arrhythmias. 73 ------- D. In methyl bromide poisoning, it may be necessary to give diazepam or barbiturates orally for some time after the acute poisoning to control involuntary motor activity, 7. If FUMIGANT LIQUIDS have been INGESTED, quantities remaining in the gut must be removed as effectively as possible by gastric INTUBA- TION, ASPIRATION, and LAVAGE. A. IF victim is UNCONSCIOUS, put in place a cuffed endotracheal tube prior to gastric intubation. B. Place conscious victim in a left lateral Trendelenburg position for intubation, and aspirate the pharynx as effectively as possible to minimize likelihood of tracheal aspiration. C. After aspirating stomach contents, LAVAGE the stomach with 2-3 liters 0.9% saline or 5% sodium bicarbonate, containing 30-50 gm ACTIVATED CHARCOAL. After lavage, leave 30-50 gm activated charcoal in stomach before withdrawing tube. D. If diarrhea does not develop spontaneously, give SODIUM SULFATE orally, 0.25 mg/kg, to induce catharsis. 8. Intravenous INFUSIONS of GLUCOSE are valuable in limiting the hepatotoxicity of fumigants. Monitor central venous pressure to avoid precipitating, or aggravating, pulmonary edema by fluid overload. 9. MONITOR fumigant poisoning victims closely for recurrent pulmonary edema and bronchopneumonia. Chart fluid balance and check urine sediment regularly to detect incipient tubular necrosis. Measure serum alkaline phosphatase, LDH, and bilirubin to assess liver injury. 10. Certain SPECIFIC MEASURES are recommended in poisonings by par- ticular fumigants: A. If given very soon after exposure to METHYL BROMIDE, there may be some value in administering DIMERCAPROL (BAL) in vegetable oil intramuscularly. For adults, give 3-5 mg/kg q6h for 4 doses. CAUTION: DIMERCAPROL may cause troublesome side ef- fects (hypertension, tachycardia, nausea, headache, paresthesiae, pain, lacrimation, sweating, anxiety, and restlessness). Although usually not so severe as to preclude treatment, these manifestation may require antihistamine therapy for adequate control. B. Mild poisonings by CARBON DISULFIDE inhalation may be man- aged best by no more than careful observation, even though sensory hallucinations, delirium, and behavioral aberrations can be alarm- ing. Severe poisonings may require specific measures: 1. CAFFEINE and sodium benzoate (0.5 gm subcutaneously) may help to relieve CNS depression. 74 ------- 2. If manic behavior threatens the safety of the victim, DIAZEPAM, 5-10 mg, 0.1 mg/kg in children, adminis- tered cautiously, intravenously, may be helpful as a tran- quilizer. Do not give catecholamine-releasing agents such as reserpine and amphetamines. C. Poisonings by HYDROGEN CYANIDE and ACRYLONITRILE gases are treated in essentially the same way as poisoning by cyanide salts. In addition to the general treatment described earlier, specific ANTIDOTES are required. (See line 6 for pediatric regimen). 1. Administer AMYL NITRITE (perles) by inhalation for 15-30 seconds of every minute, while a fresh solution of 3 % sodium nitrite is being prepared. 2. As soon as solution is available, inject intravenously 10 ml of 3% SODIUM NITRITE solution over a 2-4 minute interval, keeping the NEEDLE IN PLACE. CAUTION: Monitor PULSE and BLOOD PRESSURE dur- ing administration of amyl nitrite and sodium nitrite. If systolic blood pressure falls below 80 mm Hg, slow or stop nitrite administration un- til blood pressure recovers. 3. Follow sodium nitrite injection with an infusion of 50 ml of 25% aqueous solution of SODIUM THIOSULFATE admin- istered over 10-minute period. Initial adult dose should not ex- ceed 12.5 gm. 4. If symptoms persist or recur, treatment by sodium nitrite and sodium thiosulfate should be REPEATED AT HALF THE DOSAGES listed in paragraphs 2 and 3. 5. Measure hemoglobin and methemoglobin in blood. If more than 50% of total hemoglobin has been converted to methe- moglobin, BLOOD TRANSFUSION or exchange transfusion should be considered, because conversion back to normal hemoglobin proceeds slowly. 6. Dosage of ANTIDOTES in CHILDREN: C. M. Berlin (Pediatrics 46:793-796, 1970) has recom- mended the following procedures in case of cyanide poi- soning in children: (a) Children over 25 kg body weight should receive adult dosages of sodium nitrite and sodium thiosulfate. (b) Children less than 25 kg body weight should first have two 3-4 ml samples of blood drawn and then, through the same needle, receive 10 mg/kg (0.33 ml/kg of 3% solu- tion) of SODIUM NITRITE injected over a 2-4 minute in- terval. Following sodium nitrite, administer an infusion of 75 ------- 1.65 ml/kg of 25% SODIUM THIOSULFATE at rate of 3-5 ml per minute. (c) At this point, determine the hemoglobin content of the original blood sample. If symptoms and signs of poison- ing persist or return, give supplemental infusions of sodium nitrite and sodium thiosulfate based on hemoglo- bin level, as presented in TABLE 2. (These recommended quantities are calculated to avoid life-threatening methe- moglobinemia in anemic children). TABLE 2. Initial Hemoglobin Concentration, gm/100 ml 14.0 13.0 12.0 11.0 10.0 9.0 8.0 7.0 Recommended dosages of supplemental sodium nitrite and sodium thiosulfate based on hemoglobin level. Supplemental Volume of 3% Sodium Nitrite, ml/kg 0.26 0.21 0.17 0.12 0.07 0.04 0 0 Supplemental Volume of 25% Sodium Thiosulfate, ml/kg 1.28 1.05 0.83 0.60 0.38 0.23 0 0 (d) When possible, monitor BLOOD LEVELS of METHE- MOGLOBIN to achieve approximately 40% conversion of hemoglobin to methemoglobin. 76 ------- Chapter 13 MISCELLANEOUS PESTICIDES OF HIGH TOXICITY Pesticides included in this chapter are not similar in chemical structure or toxicologic actions to the major classes of pesticidal toxicants (organophos- phates, arsenicals, etc.) In general, they are not widely used and opportunities for serious human exposure are rare. However, those included here are charac- terized by either high toxicity or an important unique mechanism of toxic ac- tion. Occasional poisonings by these chemicals have occurred in humans and domestic animals. 4-aminopyridine (Avitrol, 4-AP) This chemical, now used as a bird repellant, has caused severe poisoning in adult humans at dosages no greater than about 60 mg. This is only 2-3 times the dosage employed clinically in managing certain rare neuromuscular dis- orders. The principal pharmacologic action of 4-aminopyridine is to facilitate release of transmitter substances at neuroeffector junctions and at synapses throughout the nervous system. Human poisonings have been characterized by thirst, nausea, dizziness, weakness, and intense diaphoresis, followed by toxic psychosis, ataxia, tremors, dyspnea, and tonic-clonic convulsions. Metabolic acidosis, leukocy- tosis, and elevations of serum GOT, LDH, and alkaline phosphatase were notable laboratory findings. EKG may show nonspecific ST-T wave changes. Treatment Promptly evacuate gut by intubation, lavage, activated charcoal administra- tion, and saline catharsis. Control convulsions with diazepam. Initiate diuresis with intravenous infusions, including mannitol. To date, poisoning victims have recovered in 24-48 hours without severe sequelae. Pancuronium is an antagonist of 4-aminopyridine, and can control seizures. It must be administered under the supervision of an anesthesiologist because of the likelihood of generalized paralysis. Propranolol may help to limit car- diac toxicity. Atropine controls the gastrointestinal symptoms. Chlordimeform (Acaron, Fundal, Fundex, Galecron, Spanone) Although the acute toxicity of this ovicidal agent is low (oral LDJO in the rat about 200 mg/kg), it is now known from an incident of excessive respiratory and dermal exposure to chlordimeform powder that it can cause acute illness and urinary bladder irritation. In all likelihood, the offending metabolite is 2-methyl-4-chloroaniline. Principal symptoms are dysuria, gross hematuria, urethral discharge, abdominal and back pain, and a hot sensation all over. Sleepiness, skin rash, anorexia, and a sweet taste in the mouth have also been 77 ------- reported. Cystoscopic examination of victims of excessive exposure demonstrated acute hemorrhagic cystitis. Methods are available for detecting the 2-methyl-4-chloroaniline metabolite in the urine. Treatment Flush contaminant from eyes and wash from skin. Symptoms resulting from undue occupational exposure resolve in a few days if exposure is terminated. If chlordimeform has been recently ingested, it should be removed from the gut either by administering Syrup of Ipecac, or by gastric intubation, aspiration, and lavage with 0.9% sodium chloride, followed by activated charcoal and sodium sulfate catharsis. Serial urinanalyses should be performed to assess in- jury to the urinary tract. Copper salts and organic complexes (oxide, hydroxide, arsenite, carbonate, chloride, oxalate, phosphate, silicate, sulfate, zinc chromate, acetate, naphthenate, oleate, quinolinolate, and resinate). These are commonly used as fungicides, either alone or in combination with other agents. There are several dozen proprietary products. LDi0 values vary from 6 to 1000 mg/kg, depending mainly on the solubility and degree of ionization of the copper compound. Toxicity of copper-arsenite salts is due mainly to the arsenic content. All of these salts irritate the skin and eyes and damage mucous membranes. When ingested, they are powerfully emetic: the stomach usually empties promptly and automatically in fully conscious individuals. When retained and absorbed, toxic injury affects the gastrointestinal lining, capillaries, brain, liver, kidney, and formed elements of the blood. Copper salts are hemolytic. Manifestations of poisoning include burning pain in the chest and abdomen, intense nausea, vomiting, diarrhea, headache, sweating and shock. Later, the liver is enlarged. Jaundice may reflect hemolysis or liver damage or both. Anuria indicates kidney injury by copper and/or free hemoglobin. Death may occur from convulsions, coma, or hepatorenal failure. Elevated serum copper levels (maximum normal level is 125 jug per 100 ml) indicate severity of poison- ing. Treatment Wash contaminated skin and flush eyes with copious amounts of water. If copper salts have been ingested, lavage the stomach with 0.1% potassium ferrocyanide, then instill a suspension of egg white. Intravenous fluids ac- celerate excretion. If signs of systemic poisoning develop, give dimercaprol (see Arsenical Pesticides for dosage) or penicillamine, 0.5 gm orally four times daily, if patient can retain oral medication. Shock may require blood trans- fusions and pain may require morphine. Exchange transfusions may be consid- ered in severe poisonings. Renal failure may require protracted hemodialysis. Cycloheximide (naramycin, Acti-dione, Actispray, Hizarocin) This is an antibiotic fungicide of high toxicity: oral LD,0 in rats is 2 mg/kg. 78 ------- Dermal absorption is probably not efficient. When ingested, the agent causes excitement, tremors, salivation, diarrhea, and melena. Mechanisms of toxicity are not well defined, but probably include irritation of the gut, stimulation of sympathetic and parasympathetic nervous systems, renal in- jury, and damage to the adrenal cortex. There are no chemical tests to confirm cycloheximide poisoning. Treatment Remove toxicant from gut by lavage. Instill activated charcoal, then a cathartic dose of sodium sulfate. Intravenous fluids accelerate excretion. Hydrocortisone appears to be antidotal, particularly in combination with the adrenergic agent methoxyphenamine (Orthoxine®). Atropine relieves the cholinergic symptoms. Endothall (Accelerate, Aquathol, Des-i-cate, Hydout, Hydrothol) Acute oral LD50 of this herbicide is 51 mg/kg. Dermal absorption of the commonly used salts is probably slight. It is irritating to eyes, mucous mem- branes and skin, but it is not sensitizing. Mechanisms of systemic toxicity are not clear, but the central nervous system, heart, blood vessels, and gastrointes- tinal lining appear to be primary targets. Poisoned animals exhibit ataxia, con- vulsions, shock, and respiratory depression. Erosions and ulcers of the gastro- intestinal tract follow ingestion. There are no standard analytical methods for confirming poisoning. Treatment Wash contaminated skin and flush eyes with copious amounts of water. In- stead of gastric evacuation following ingestion, administer cold milk or aluminum hydroxide gel. This may be followed by saline catharsis. There is no specific antidote. Shock may require blood transfusions. Use of adrenergic amines is probably hazardous in view of myocardial irritability. Nicotine sulfate (Black Leaf 40) This time-honored natural insecticide is still used in horticulture. Lethal dose in humans is about 60 mg. Nicotine preparations, especially those using the free alkaloid, are well absorbed across the gut wall, lung, and skin. Poisoning symptoms from excessive doses appear promptly. They are due to transient stimulation, then prolonged depression, of the central nervous system, autonomic ganglia, and motor end-plates of skeletal muscle. Central nervous system injury is manifest as headache, dizziness, incoordination, tremors, then clonic convulsions leading to tonic-extensor convulsions which are often fatal. In some instances, convulsive activity is minimal and death by respiratory arrest occurs within a few minutes. Effects on autonomic ganglia give rise to sweating, salivation, nausea, abdominal pain, diarrhea, and hyper- tension. The heart is usually slow, and often arrhythmic. Block of skeletal muscle motor end-plates causes profound weakness, then paralysis. Death may occur from respiratory depression or from shock. Nicotine can be measured in blood and urine to confirm poisoning. 79 ------- Treatment Promptly wash contaminated skin and flush eyes with water. Ingestion of nicotine requires immediate gastric intubation, aspiration, and lavage, the lat- ter preferably with 1.5% tannic acid solution, or 1:5000 potassium perman- ganate solution. Before withdrawing the lavage tube, instill 3-4 ounces of ac- tivated charcoal in a slurry of water. Diazepam and/or barbiturates may be re- quired to control convulsions. Atropine and phenoxybenzamine (Diben- zaline®) may help to control the autonomic manifestations. Positive pressure ventilation of the lungs with oxygen may be necessary to sustain life when respiration is arrested. Phenylmercuric salts. Most commonly used is phenylmercuric acetate (PMA, Agrosan, Cekusil, Gallotox, Hong Nien, Luquiphene, Mersolite, Phenmad, Phix, PMAS, Shimmer-ex) Phenylmercuric acetate is a widely used fungicide. Acute oral LDSO in the rat is 22 mg/kg. Other salts are also highly toxic. They probably undergo some dermal absorption. Because of lower volatility and less penetration of the brain, they are somewhat less toxic than alkyl mercury compounds. Early manifestations reflect injury to the central nervous system: ataxia, muscle weakness, visual impairment, and delirium. After a single moderate ex- posure, these symptoms usually resolve promptly. Repeated intensive exposures cause symptoms and signs resembling amyotrophic lateral sclerosis: weakness and incoordination of the arms, difficulty in swallowing and talking, weakness and spasticity of the legs. Concurrent or later manifestations of excessive ab- sorption reflect renal injury: albuminuria, hematuria, azotemia, and some- times acute tubular necrosis. Induction of nephrotic syndrome has been reported. This is characterized by massive albuminuria, generalized edema, and hypercholesterolemia. Methods are available at specialized toxicology laboratories for measuring phenylmercuric compounds in urine. Treatment Wash contaminated skin and flush eyes with water. If ingested, remove the chemical from the gut by prompt gastric intubation, aspiration, and lavage with 5% sodium bicarbonate solution and instillation of activated charcoal, followed by catharsis with sodium or magnesium sulfate. Intravenous infu- sions of fluids accelerate excretion of mercurials and limit kidney damage. There is no specific antidote; dimercaprol is not very effective in limiting tox- icity. Sodium chlorate (De-Fol-Ate, Drexel Defol, Drop-Leaf, Fall, Grain Sorghum Harvest-Aid, Klorex, Kusatol, Tumbleaf) Although the oral LD30 in the rat is high (1200 mg/kg), there have been sev- eral deaths from this herbicide-defoliant in the past decade. The principal mechanisms of toxicity are irritation of the gastrointestinal lining, central ner- vous system depression, hemolysis, oxidation of free hemoglobin to methemo- globin, and renal tubular injury. Dermal absorption is minimal. If ingested, 80 ------- chlorate causes swelling of the oral and pharyngeal membranes and pain in the chest and abdomen. The victim is first restless, then apathetic. On the third or fourth day after ingestion, lumbar pain, albuminuria, hematuria, then anuria with azotemia, reflect renal injury. Death may be due to hyperkalemia (hemolysis), tissue anoxia (methemoglobinemia), or renal failure. Although chlorate itself is not readily measured in the blood, free hemoglobin and methemoglobin in the plasma point to poisoning by an oxidiz- ing agent. Treatment Remove from gut by prompt gastric intubation, aspiration, and lavage using 3 gm sodium thiosulfate in 300 ml 5% sodium bicarbonate. Instill 30-50 gm ac- tivated charcoal in a slurry. Pain may require narcotics. Both hemodialysis and exchange transfusions have been used successfully in treating poisonings. Methylene blue is of no value in reducing the extracellular methemoglobin. In- travenous infusions of 1% sodium thiosulfate (100-500 ml) limit the concen- tration of circulating chlorate. Monitor serum electrolytes. Hemodialysis may be needed to sustain life in the event of extensive renal tubular necrosis. Sodium cyanide (Cymag) Occasionally, this is used as a rodenticide. Toxicity is extreme, similar to that of hydrogen cyanide gas used as a fumigant. CONSULT Chapter 12 on FUMIGANTS (hydrogen cyanide) for toxicology, poisoning manifestations, diagnosis, and management. Cyanide salts are not adsorbed on activated char- coal. 81 ------- Chapter 14 MISCELLANEOUS PESTICIDES OF LOW OR MODERATE TOXICITY These compounds are included in the manual because their wide use generates inquiries as to their potential for causing adverse effects. Description of the toxic potential of these chemicals as low or moderate does not preclude the need for cautious handling. Many agents have irritant prop- erties, and individuals vary widely in their reactions to them. Certain predisposed persons may suffer dermal and respiratory illness from substances that have no effect on other persons or experimental animals. It is also true that the sum total of potential effects of a chemical, and by-products formed in synthesis and storage, plus the metabolites formed into vivo is never fully known. Reasonable precautions to avoid contact with pesticides are always recommended regardless of the reported toxicity of the principal active ingre- dient. Lowest reported acute oral LD50 in the rat is cited in this listing as an indica- tion of overall toxicity, manifest as killing power. The LD50 rating says nothing of dosages necessary to produce symptoms or signs, disease conditions characterized by long latency, subclinical biochemical effects, or other non- lethal effects on health. It is essential that high LD50 ratings not be interpreted as indications that the subject chemicals are innocuous. Knowledge of use is sometimes helpful in identifying chemicals. Agents on this list are used as herbicides (H), fungicides (F), or insecticides (I). There are many proprietary MIXTURES of these chemicals and it is common to tank mix many of them according to the grower's requirements. Intelligent management of exposures requires that the full list of active ingredients in mix- tures be ascertained from the producer or applicator. In general, management is aimed at the most toxic ingredient. Chemical Clan Acetamldes Acetanilides Generic Name allidochlor metolachlor alachlor propachlor Use H H H H "-DSO 750 2,780 1,800 710 Proprietary Known or Suspected Name Advert* EHeet* Randox, CDAA Dual, Bleep, Primagram, ~ Primextra Moderately Irritating to skin and eyes. Lasso, Lazo, Alanex Mild Irritant Ramrod, Bexton Dermal irritant and sensltlzer propanil 1,384 DPA, Propanex, Riselect, Ros- |~~ anil, Stam F34, Strel, Super- I M nox, Surcopur, Surpur, Vertac H Mild Irritant 82 ------- Chemical Cla»« Aliphatic Acids Alumlnofluorlde salt Benzenes Benzole and Benzlllc Acid Derivatives Benzonitrlles Carbamates Carbanllate Dicarboxlmides Dlnltrotoluldlne Compounds Generic Name dichloro- propionic acid trichloro- acetic acid sodium fluoro- alumlnate hexachloro- benzene (perchloroben- zene) paradichloro- benzene pentachloro- nitrobenzene benzyl benzoate chlorobenzllate trichloro- benzole acid chlorothalonll dlchlobenil asulam benomyl chlorpropham terbucarb barban captafol captan folpet (thlophal) benefin butralin dinitroamine fluchloralm isopropalin oryzalin pendimethalin profluralin Use H H 1 F 1 F 1 1 H F H H F H H H F F F H H H H H H H H LD50 970 5,000 >1 0,000 10,000 500 1,700 1,700 960 1,370 10,000 3,160 5,000 10,000 3,800 34,000 600 6,200 10,000 10,000 10,000 12,600 3,700 1,550 5,000 10,000 1,250 1,808 83 Proprietary Known or Suspected Name Adverse Effects Dalapon, Dowpon, Crisapon, |~~ Basfapon _] Skin and eye ~"| irritants TCA L- Cryolite, Kryocide Slight irritant HCB, No Bunt, Anticarie I Chronic ingestlon — causes porphyrla cutanea tarda PDB, Paracide [Mild respiratory — irritant and Ihepatotoxin PCNB, Terrachlor Skin irritant Benzyl benzoate Acaraben, Akar, Benzllan, Kop~ Mite, Benz-0-Chlor Benzac, TBA, TCBA, Tribac Bravo, Daconil 2787 Casoron, Du-Sprex Asulox 40, Asulox F Benlate, Tersan 1991 Furloe, Chloro IPC, CIPC, ~~ Sprout Nip, Taterpex, Unicrop CIPC Azak, Azac, Azar Irritating to skin and eyes. - Moderately Irritating to skin and respiratory tract Mild irritants. These carbamates do not Inhibit chollnesterase enzyme. - Carbyne, Neoban, Caryne Irritant and dermal sensltizer. Oifolatan Skin irritant Captan, Merpan, Orthocide Skin irritant Phaltan, Folpan Skin irritant Benfluralin, Bethrodine, Balfin, Benefex, Quilan Amex Dinitramme, Cobex Basalm Paarlan Surflan, Rycelan, Ryzelan Prowl, Herbadox, Stomp Tolban, Pregard Slightly to moderately irritating to skin, eyes, and mucous membranes. These agents do not uncouple oxidatlve phosphorylation. „_ ------- Chemical Class Oxadiazollnone Phthalate Picolinic acid Derivative Pyridazinone Phosphonomethyl glycine Thladiazin (ol) Triazines Generic Name trifluralin oxadlazon chlorthal- dimethyl picloram maleic hydrazide glyphosate bentazon terrazole ametryn anilazlne atraton atrazine cyanazine desmetryn isomethiozin metribuzin prometone prometryn propazine Simazine Use LD50 H >1 0,000 H 3,500 H 3,000 H 8,200 Growth 6,950 retardant H 4,300 H 2,063 F 1,077 H 1,750 H 5,000 H 1,465 H 3,080 H 334 H 1,390 H 10,000 H 1,100 H 2,980 H 5,235 H >5,000 H >1 0,000 Proprietary Known or Suspected Name Adverse Effects Tteflan, Crisalma, Digermin, Elancolan, Ipersan - Slightly to to moderately irritating to skin, eyes, and mucous membranes. These agents do not uncouple oxldatlve phosphorylation. Ronstar Irritating to skin and eyes Dacthal, DCPA Mild irritant Tordon, Amdon pTrrltating to skin, -I eyes, and Ljespiratory tract Burtolm, Chemform, De-Cut, De-Sprout, Regulox, KMH, Slightly Irritating Maintain, Stunt-Man Roundup Irritant to eyes and respiratory tract Basagran _ Terrazole _ Evik, Ametrex, Gesapax Dyrene, Direz, Kemate, Triasyn Atratone, Gesatamin AAtrex, Atranex, Gesaprim, Primatol A, Atred, Crisazine, Vectal SC Bladex, SO 15418 Semeron — Tantizon Sencor, Lexone, Sencorex, Sencoral Pramitol, Gesafram-50, Pro- meton, Primatol 25E Caparol, Gesagard, Primatol Q. Prometrex Milogard, Gesamil, Primatol P, Prozinex Prmcep, Gasatop, Simadex, Moderately irritating to skin, eyes, respiratory tract. On ingestion, has caused vomiting, diarrhea, dyspnea, tremors, weakness. "Moderately Irritating to skin, eyes, and respiratory tract. - Some triazines are mildly irritating to skin, eyes, and up- per respiratory tract. Systemic toxicity is unlikely unless very large amounts have been ingested. Simanex 84 ------- Chemical Class Triazmes Uracils Urea Derivatives ' Generic Name terbuthylazme terbutryn bromacil lenacil terbacil chloroxuron chlortoluron difenoxuron diflubenzuron diuron fluometuron isoproturon Imuron methabenz- thiazuron metobromuron metoxuron monolmuron monuron neburon siduron tebuthiuron tetrafluoron Use H H H H H H H H 1 H H H H H H H H H H H H H "-DSD 2,610 2,500 5,200 11,000 5,000 3,700 10,000 7,750 4,640 3,400 6,416 1,826 1,500 2,500 3,000 3,200 1,800 3,600 11,000 7,500 644 1,265 Proprietary Known or Suspected Name Adverse Effects Pnmatol-M, Gardoprim, GS 13529 Igran, Terbutrex Some triazmes are mildly irritating to skin, eyes, and up- per respiratory tract Systemic toxicity is unlikely unless very large amounts have been ingested Hyvar X, Uragan, Urox B, Urox Irritant to skin, eyes, HX and respiratory tract Venzar Sinbar Tenoran, Chloroxifemdim Dicuran, Tolurex, Clortokem Lironion Dimilm Cekiuron, Crisuron, Gallon, Dialer, Di-on, Diurex, Dirurol Dynex, Karmex, Unidron, Urox D, Vonduron Cotoran, Lanex, Cottonex Arelon, Belgran, Grammon, Tolkan Atalon, Hoe 2810, Lmurex, Lorox, Premalm, Sarclex Tribunil Patoran, Pattonex Deftor, Dosanex, Dosaflo, Punvel Aresm, Afesm, Arresm, Premalm Monurex Granurex, Kloben, Neburex Tupersan Spike Tomilon Moderately irritating Many substituted ureas are moderate- ly irritating to skin, eyes, and mucous membranes. 85 ------- TOXICOLOGY Many of these compounds are primary irritants to skin, eyes, and respira- tory tract. The ureas and uracils are perhaps the most common offenders, although captafol and chlorothalonil have apparently caused contact der- matitis in some agricultural workers. Propachlor is a dermal sensitizer in predisposed individuals. Although hexachlorobenzene has low acute toxicity, long-term ingestion of HCB-treated seed grain caused an epidemic of porphyria cutanea tarda among Turkish farm families in the 1950's. No such effect has been found in HCB handlers in the United States. Given to cattle in extreme dosage, some triazines have caused neuromuscu- lar abnormalities and damage to internal organs. It is unlikely that domestic animals would consume these amounts voluntarily, and still less likely that humans would be exposed to such extreme dosage. CONFIRMATION OF ABSORPTION The benzene derivatives and benzonitriles can be identified in plasma by gas- liquid chromatography. Methods for benzoic acid and triazine metabolites in urine have been developed. Analytical methods used for agricultural residues of the remaining compounds might be adapted to analysis of gastric contents or skin wipings. Samples must be collected within hours of exposure, because most of these chemicals are promptly excreted. It is unlikely that such analyses will be required in cases of human exposure to these agents. In the event that workers experiencing protracted heavy ex- posure develop suspicious manifestations of injury or toxicity, urine or blood analyses may help to confirm chemical absorption. Tests may be conducted in private or university laboratories, or laboratories supported by the state or federal government, i.e., the United States Environmental Protection Agency or Occupational Safety and Health Administration. TREATMENT 1. WASH contaminated SKIN with soap and water. 2. FLUSH contaminated EYES with copious amounts of fresh water for 15 minutes. 3. INGESTIONS of SMALL amounts (less than 10 mg/kg body weight) oc- curring less than an hour before treatment, are probably best treated by: A. SYRUP OF IPECAC, followed by 1-2 glasses of water. Dose for adults and children over 12 years: 30 ml. Dose for children under 12 years: 15 ml. B. ACTIVATED CHARCOAL Administer 30-50 gm as a slurry in tap water, after vomiting stops. C. SODIUM OR MAGNESIUM SULFATE, 0.25 gm/kg in tap water, as a cathartic. 86 ------- 4. INGESTIONS of LARGE amounts (more than 10 mg/kg) occurring less than an hour before treatment, should probably be treated by gastric lavage: A. INTUBATE stomach and ASPIRATE contents. B. LAVAGE stomach with slurry of ACTIVATED CHARCOAL in 0.9% saline. Leave 30-50 gm activated charcoal in the stomach be- fore withdrawing tube. C. SODIUM SULFATE, 0.25 gm/kg in tap water, as a cathartic. CAUTION: Hydrocarbons (kerosene, petroleum distillates) are included in some formulations of these chemicals. In- gestion of very LARGE AMOUNTS may cause CNS depression. In this case, IPECAC IS CONTRAIN- DICATED. Also, gastric intubation incurs a risk of HYDROCARBON PNEUMONITIS. For this reason observe the following precautions: (1) If the victim is unconscious or obtunded and facilities are at hand, insert an ENDOTRA- CHEAL TUBE (cuffed, if available) prior to gastric intubation. (2) Keep victim's HEAD BELOW LEVEL OF STOMACH during intubation and lavage (Trendelenburg, or left lateral decubitus, with head of table tipped downward). Keep victim's head turned to the left. (3) ASPIRATE PHARYNX as regularly as possible to remove gagged or vomited stomach contents. 5. INGESTIONS occurring MORE THAN an HOUR before treatment are probably best treated only by ACTIVATED CHARCOAL, 30-50 gm, and SODIUM or MAGNESIUM SULFATE, 0.25 gm/kg, as described above. 6. There are no specific antidotes for these chemicals. Because manifesta- tions of toxicity do occasionally occur in peculiarly predisposed individ- uals, MAINTAIN CONTACT with victim for at least 72 hours so that unexpected adverse effects can be treated promptly. 87 ------- INDEX TO PESTICIDE POISONINGS BY SYMPTOMS AND SIGNS A listing of pesticides capable of causing specific symptoms and signs may be of some help to professionals confronted with illnesses possibly caused by pesticides. However, the limitations of this kind of index should be clearly understood. Rarely are particular manifestations always present in poisonings by a given chemical, and many poisonings are characterized by unexpected symptoms. Furthermore, there are usually many causes of particular symp- toms and signs. The purpose of these lists is, therefore, only to direct the professional's at- tention to a series of chemicals possibly responsible for various symptoms and signs, based on past experience. Starting from the major presenting feature of the illness, the interviewer can inquire closely into possible exposures to the principal causative toxicants, and then, if appropriate, assemble more substan- tive evidence for or against a poisoning diagnosis, e.g., concurrence of multi- ple manifestations of specific poisonings, and laboratory test findings. Not all manifestations of illness are included. Some symptoms, such as dizziness and weakness, are caused by so many chemicals by either direct or in- direct mechanisms that they have little value diagnostically. This approach to clinical toxicology has been developed by Alan K. Done, M.D., of Wayne State School of Medicine. His general format of classifica- tion (Solving the Poison Puzzle, Emergency Medicine, February 1979) is used in the following tables. Chemicals appearing in the lists headed "Characteristic of These Poisonings" have been substantially consistent in producing the symptoms or signs identified in the left column. Agents listed in the column headed "Occurs in These Poisonings" are found with sufficient frequency to deserve mention, but the association is not highly consistent. CHARACTERISTIC OF OCCURS IN MANIFESTATIONS THESE POISONINGS THESE POISONINGS General Breath odor of. Garlic Arsenic Phosphorus Phosphides Phosphine Bitter almonds Cyanide Rotten cabbage Carbon disulfide Fever Nitro-, chloro- phenols Chlorophenoxy compounds Hypothermia Vacor Myalgia Chlorophenoxy compounds Chills Arsine Vacor 88 ------- MANIFESTATIONS CHARACTERISTIC OF THESE POISONINGS OCCURS IN THESE POISONINGS Thirst Anorexia Hot sensations Skin and Mucous Membranes Dry, cracked skin of hands Loss of nails Brittle nails Loss of hair Sweating Pallor Cyanosis Scratchy throat and Irritated eyes Blisters or burns Rash Yellow stain Eccrtymoses Keratoses Nitro-, chloro-, phenols Aminopyridine Phosphine Organophosphates Carbamate Insecticides Nicotine Chlordimeform Arslne Paraquat Petroleum distillates Weed oil Paraquat Inorganic arsenicals Thallium Inorganic arsenicals Organosphates Carbamate insecticides Nitro-, chloro- phenols Nicotine Aminopyridine Organchlorlnes Paraquat Strychnine Crimidine Nicotine Sodium fluoroacetate Sulfur dioxide Acrolein Chloropicrin Nitro-, chloro- phenols Formaldehyde Pyrethrins Copper compounds Endothall Sodium chlorate Methyl bromide Phosphorus Sulfur Thiram Propachlor Barban Nitrophenols Anticoagulant rodenticides Phosphorus Phosphides Inorganic arsenicals Fumlgants Nitro-, chloro-, phenols Arsenicals Anticoagulant rodenticides Organophosphates Carbamate insecticides Organochlorlnes Paraquat Blsdlthlocarbamates Ethylene bisdlthlocarbamates Chloroallphatlc acids Liquid methyl bromide or ethylene oxide Plcloram Dlfolatan Captan Chlorothalonll Nitro-, chloro- phenols Many other herbicides and fungicides 89 ------- MANIFESTATIONS CHARACTERISTIC OF THESE POISONINGS OCCURS IN THESE POISONINGS Jaundice Central Nervous System Headache Ataxia Convulsions Muscle twitching Tremors Mental confusion Sudden unconsciousness Central Nervous System Tingling and numbness in the extremities Tetany Myotonia Phosphorus Phosphides Phosphme Halocarbon fumigants Organophosphates Carbamate insecticides Organochlorines Fumigants Nicotine Inorganic arsenicals Organophosphates Carbamate insecticides Endothall Nicotine Phenyl mercuric acetate Organochlorines Strychnine Crimldine Phosphorus Cyanide Sodium fluoroacetate Nicotine Aminopyridine Endothall Organophosphates Carbamate insecticides Sulfuryl fluoride Organophosphates Carbamates insecticides Phosphine Aminopyridine Cycloheximide Nicotine Organophosphates Carbamate insecticides Nitrophenols Chlorophenols Cyanide Organochlorines Vacor Sodium fluoroacetate Carbon disulfide Aminopyridine Cycloheximide Cyanide Carbon disulfide Vacor Sodium fluoroacetate Phosphorus Phosphides Paraquat Inorganic arsenicals Nitrophenols Chlorophenols Fumigants Inorganic arsenicals Organochlorines Nitro-, chloro- phenols Organophosphates Carbamate insecticides Sulfuryl fluoride Chlorophenoxy compounds Pyrethrins Nitro-, chloro- phenols Bentazon Sulfuryl fluoride Strychnine Crimidine Nicotine Inorganic arsenicals Organophosphates Diquat Carbamate insecticides Halocarbon fumigants Inorganic arsenicals Chlorophenoxy compounds 90 ------- MANIFESTATIONS CHARACTERISTIC OF THESE POISONINGS OCCURS IN THESE POISONINGS Mlosls Organophosphates Carbamate insecticides Gastrointestinal Tract Nausea, vomiting, abdominal cramps, diarrhea Salivation Respiratory System Stuffy nose, wheezing Nosebleed Coughing frothy sputum (pulmonary edema) Rhinorrhea Tachypnea Respiratory depression Labored breathing Chest pain Organophosphates Carbamate insecticides Diquat Phosphorus Phosphides Phosphine Inorganic arsenlcals Arslne Fumlgants Red squill Cyclohexlmide Endothall Nicotine Chlorates Copper Compounds Organophosphates Carbamate Insecticides Cycloheximlde Nicotine Pyrethrum Bisdithiocarbamates plus alcohol Methyl bromide Phosphine Phosphorus Phosphides Ethylene oxide Organophosphates Carbamate insecticides Fumigants Nitro-, chloro- phenols Organophosphates Carbamate insecticides Fumlgants Cyanide Acrylomtrile Nicotine Endothall Sodium chlorate Methyl bromide Organophosphates Carbamate Insecticides Phosphine Phosphides Phosphorus Fumlgants Sodium chlorate Organochlorines Chloro-, nitro- phenols Bisdithiocarbamates Ethylene bisdithiocarbamates Chlorophenoxy compounds Organic arsenicals Paraquat Bentazon Chloroaliphatic acids Paraquat Organophosphates Carbamate insecticides ANTU Organochlorines Sulfuryl fluoride Organophosphates Carbamate Insecticides Chlorophenoxy herbicides Nitro-, chloro- phenols Chloroaliphatic acids 91 ------- MANIFESTATIONS CHARACTERISTIC OF THESE POISONINGS OCCURS IN THESE POISONINGS Cardiovascular System Bradycardia Hypertension Renal System Renal failure Urinary frequency, dysuria Renal colic Blood Anemia Leukopenia Hypoprothrombmernia Depressed cholmesterase enzyme activities Methemoglobinemia Free hemoglobin in plasma Elevated alkaline phosphatase, GOT, LDH Elevated blood bromide Hyperbilirubmemia Organophosphates Carbamate insecticides Cyanide Tachycardia Hypotension, shock Irregular heart beat Nitrophenols Chlorophenols Phosphorus Phosphides Phosphine Vacor Endothall Cyanide Sodium fluoroacetate Halocarbon fumigants Endothall Organochlorines Bisdithiocarbam; Inorganic arsenic Anticoagulant ro< Organochlorines Red squill Nicotine Arsine Fumigants Cycloheximide Chlorates Chlordimeform Vacor Anticoagulant rodenticides Chlorates Naphthalene Anticoagulant rodenticides Anticoagulant rodenticides Organophosphates Chlorates Naphthalene Arsine Copper compounds Sodium chlorate Halocarbon fumigants Inorganic arsenicals Diquat Paraquat Aminopyndine Methyl bromide Paraquat Diquat Phosphine Phosphorus Phosphides Copper compounds Inorganic arsenicals Paraquat Diquat Inorganic arsenicals Copper compounds Inorganic arsenicals Nitrophenols Inorganic arsenicals Carbamate insecticides (targe dosage) Endnn Halocarbon fumigants 92 ------- MANIFESTATIONS CHARACTERISTIC OF THESE POISONINGS OCCURS IN THESE POISONINGS Elevated BUN, creatinine Hyperkalemia Urine Proteinuria Hematuna Ketonuria Hemoglobinuria Myoglobinuria Porphyrinuria Bilirubinuria Glycosuna Feces Blood present (melena) Luminescence Semen Low sperm count Paraquat Diquat Fumigants Chlorates Inorganic arsenicals Naphthalene Chlorates Copper compounds Diquat Paraquat Nitro-, chloro-, phenols Fumigants Cycloheximide Copper compounds Phenyl mercuric acetate Sodium chlorate Anticoagulant rodentlcldes Sodium chlorate Cycloheximide Chlordlmeform Vacor Aminopyridine Naphthalene Arsine Sodium chlorate Hexachlorobenzene Halocarbon fumigants Phosphorus Phosphides Phosphine Vacor Diquat Sodium chlorate Anticoagulant rodentlcides Phosphorus Phosphides Endothall Cycloheximide Phosphorus Sulfuryl fluoride Nitro-, chloro-, phenols Endothall Sulfuryl fluoride Chlordimeform Fumigants Paraquat Diquat Phosphorus Phosphides Chlorophenoxy compounds Paraquat Dibromochloropropane Kepone 93 ------- PESTICIDES INDEX Pagef 1080 .................................... 54 AAtack ................................. 36 AAtrex .................................. 82 Abate ................................... 1 Abathion ................................ 1 Acaraben ................................ 14, 82 Acaron .................................. 77 Accelerate ............................... 77 acephate ................................. 1 Acquinite ................................ 68 Acrex ................................... 23 Acritet .................................. 68 Acrolein ................................. 68 Acrylaldehyde ............................ 68 Acrylofume .............................. 68 acrylonitrile .............................. 68 Actellic .................................. 1 Acti-dione ............................... 77 Actispray ................................ 77 Afalon .................................. 82 Afesin ................................... 82 African .................................. 1 Agritox .................................. 1 Agrosan ................................. 77 Agrotec ................................. 27 Agrothion ............................... 1 Akar .................................... 82 alachlor ................................. 82 Alanex .................................. 82 aldicarb ................................. 9 aldrin ................................... 14 Aldrite .................................. 14 allethrin ................................. 42 allidochlor ............................... 82 alumino fluoride salt ...................... 82 aluminum phosphide ...................... 68 Amaze .................................. 1 tPage number refers to the beginning page of the chapter in which the pesticide is covered. 94 ------- Ambox 23 Ambush 42 Amdon 82 Ametrex 82 ametryn 82 Amex 82 aminocarb 9 4-aminopyridine 77 Amoxone 27 Ancrack 23 anilazine 82 Ansar 170 HC 46 Ansar 529 HC 46 Ansar 8100 46 Ansar DSMA liquid 46 Anthio 1 Anticarie 82 Anticoagulent rodenticides 54 antu 54 4-AP 77 Aphox 9 Aquacide 31 Aqua-Kleen 27 Aqualin 68 Aquathol 77 Arasan 36 Arelon 82 Aresin 82 Arresin 82 Arrhenal 46 arsenic 46 arsenic acid 46 arsenic trioxide 46 arsenious oxide 46 arsine 46 Arsinyl 46 Arsonate liquid 46 Aspon 1 Aspor 36 asulam 82 Asulox 40 82 Asulox F 82 Atranex 82 atraton 82 95 ------- atrazine 82 Atred 82 Aules 36 Avadex 36 Avadex-BW 36 Avitrol 77 Azac 82 Azak 82 Azar 82 azinphos-methyl 1 Azodrin 1 —B— Balfin 82 Banvel 27 barban 82 barthrin 42 Basagran 82 Basalin 82 Basanite 23 Basfapon 82 Baygon 9 Bayrusil 1 Baytex 1 Baythion 1 Belgran 82 Belmark 42 Benefex 82 benefin 82 Benfluralin 82 Benlate 82 benomyl 82 bentazon 82 Benzac 82 benzene hexachloride 14 Benzilan 82 Benz-O-Chlor 82 Benzyl benzoate 82 bethrodine 82 Bexton 82 BH 2,4-D 27 BHC 14 Bicep 82 96 ------- Bidrin 1 binapacryl 23 bioresmethrin 42 Birlane 1 Black Leaf 40 77 Black Leaf Grass, Weed and Vegetation Killer Spray 19 Bladafum 1 Bladex 82 Bo-Ana 1 Bolstar 1 bomyl 1 Bravo 82 brodifacoum 54 bromacil 82 bromadiolone 54 Bromofume 68 Brom-O-Gas 68 Bromone 54 bromophos 1 bromophos-ethyl 1 Brush-Rhap 27 Bueno 6 46 bufencarb 9 Burtolin 82 butralin 82 butylate 36 Bux 9 r< cacodylic acid 46 Caid 54 calcium acid methanearsonate 46 calcium arsenate 46 calcium arsenite 46 Caldon 23 CAMA 46 Caparol 82 captafol 82 captan 82 Carbacryl 68 Carbamult 9 Carbamates-cholinesterase-inhibiting 9 97 ------- carbaryl 9 Carbazinc 36 carbofuran 9 carbon bisulfide 68 carbon disulfide 68 carbon tetrachloride 68 carbophenothion 1 Carbyne 82 Caryne 82 Carzol 9 Casoron 82 Castrix 54 CDAA 82 Cekiuron 82 Cekusil 77 Celathion 1 Celmide 68 Certified Kiltrol-74 Weed Killer 19 Chem Bam 36 Chemform 82 Chemonite 46 Chemox General 23 Chemox PE 23 Chem Pels C 46 Chemsect DNBP 23 Chemsect DNOC 23 Chem-Sen 56 46 Chipco Crab Kleen 46 Chipco Thiram 75 36 Chipco Turf Herbicide "D" 27 Chlordan 14 chlordane 14 chlordimeform 77 chlorfenac 27 chlorfenvinphos 1 chlormephos 1 chlorobenzilate 14 chloroform 68 chloro IPC 82 chlorophacinone 54 chlorophenothane 14 Chlorophenoxy compounds 27 Chlor-O-Pic 68 chloropicrin 68 98 ------- chlorothalonil 82 chloroxifenidim 82 Chloroxone 27 chloroxuron 82 chlorpropham 82 chlorpyrifos 1 chlorthaldimethyl 82 chlorthiophos 1 chlortoluron 82 Chrysron 42 Ciba-Geigy Ontrack (OS 3,4 or 5) 19 cinerins 42 Ciodrin 1 CIPC 82 Clortokem 82 Cobex 82 copper acetate 77 copper acetoarsenite 46 copper arsenite 46,77 copper carbonate 77 copper chloride 77 copper hydroxide 77 copper naphthenate 77 copper oleate 77 copper oxalate 77 copper oxide 77 copper phosphate 77 copper quinolinolate 77 copper resinate 77 copper salts 77 copper silicate 77 copper sulfate 77 copper zinc chromate 77 Co-Ral 1 Corozate 36 Cotoran 82 Cottonex 82 coumachlor 54 coumafene 54 coumafuryl 54 coumaphos 1 counter 1 Crab-E-Rad 46 crimidine 54 99 ------- Crisalina 82 Crisapon 82 crisazine 82 Crisquat 31 Crisuron 82 Crop Rider 27 Crotothane 23 crotoxyphos 1 cryolite 82 Cuman 36 Curacron 1 Curamil 1 cyanazine 82 cyanofenphos 1 cyanophos 1 Cyanox 1 cycloate 36 cycloheximide 77 Cyclon 68 Cygon 1 Cymag 77 Cyolane 1 cypermethrin 42 cythioate 1 Cythion 1 —D— 2,4-D 27 D 50 27 decamethrin 42 Dacamine 2D/2T 27 Dacamine 4D 27 Dacamine4T 27 Daconate 6 46 Daconil 2787 82 Dacthal 82 Dailon 82 dalapon 82 Dal-E-Rad 46 Dalf 1 Dapacryl 23 Dasanit 1 2,4-DB 27 100 ------- DBCP 68 DCPA 82 D-D 68 DDT 14 DDVP 1 De broussaillant 600 27 De broussaillant Concentre 27 De-Cut 82 Ded-Weed 27 Ded-Weed Brush Killer 27 DBF 1 De-Fend 1 De-Fol-Ate 77 Deftor 82 De-Green 1 Delnav 1 demeton 1 demeton-methyl 1 Des-I-Cate 77 Desiccant L-10 46 desmetryn 82 Desormone 27 De-Sprout 82 Dessin 23 Dethdiet 54 Dextrone 31 Dextrone X 31 Dexuron 31 dialifor 1 diallate 36 Dialer 82 diazinon 1 Dibrom 1 dibromochloropropane 68 dicamba 27 dicarzol 9 dichlobenil 82 dichloroanisic acid 27 2,4-dichlorophenoxyacetic acid 27 dichloropropene (ane) 68 dichlofenthion 1 dichloropropionic acid 82 dichlorprop 27 dichlorvos 1 101 ------- dicofol 14 Dicotox 27 dicrotophos 1 Dicuran 82 dieldrin 14 Dieldrite 14 dienochlor 14 difenacoum 54 difenoxuron 82 diflubenzuron 82 Difolatan 82 Digermin 82 Dilic 46 Dimecron 1 dimethoate 1 dimetilan 9 Dimilin 82 Dinitramine 82 dinitro 23 Dinitro-3 23 dinitroamine 82 dinitrocresol 23 Dinitro General 23 dinitrophenol 23 dinobuton 23 dinocap 23 Dinofen 23 dinopenton 23 dinoprop 23 dinosam 23 dinoseb 23 dinosulfon 23 dinoterb 23 dinoterbon 23 Dinoxol 27 Di-on 82 dioxathion 1 Diphacin 54 diphacinone 54 Dipher 36 Dipterex 1 diquat 31 Direz 82 disodium methyl arsonate 46 102 ------- disulfoton 1 Di-Syston 1 Di-Tac 46 Dithane (D14, M22, M45, or Z78) 36 Dithiocarbamates 36 Dithione 1 Diurex 82 Diurol 82 diuron 82 DLP-787 54 DMA 46 DMA 4 27 DMA 100 46 DNAP 23 DNBP 23 DNC 23 DNOC 23 Dormone 27 Dosaflo 82 Dosanex 82 Dotan 1 Dow General Weed Killer 23 Dow Pentachlorophenol 19 Dow Selective Weed Killer 23 Dowfume fumigants 68 Dowicide EC-7 19 Dowpon 82 DP-2 Antimicrobial 19 DPA 82 Drat 54 Drawinol 23 Draza 9 Drexel Defol 77 Drinox 14 Drop-Leaf 77 Drupina 90 36 DSE 36 DSMA 46 Dual 82 Dursban 1 Du-Sprex 82 Dyanap 23 Dyfonate 1 Dylox 1 103 ------- Dynamyte 23 Dynex 82 Dyrene 82 —E— Ectiban 42 EDB 68 EDC 68 Ekamet 1 Ekatin 1 Elancolan 82 Elgetol 30 23 Elgetol318 23 emerald green 46 Emulsamine BK 27 Emulsamine E-3 27 Endosan 23 endosulfan 14 Endothall 77 endrin 14 Entex 1 Envert DT, T or 171 27 EPBP 1 EPN 1 epoxypropane 68 Eptam 36 EPTC 36 Esgram 31 Esteron Brush Killer 27 Esteron Four 27 Esteron 99 Concentrate 27 Esteron 245 27 Estone 27 ethion 1 ethoprop 1 Ethylan 14 ethyl parathion 1 ethylene dibromide 68 ethylene dichloride 68 ethylene oxide 68 ETO 68 etrimfos 1 Evik 82 E-Z-OffD 1 104 ------- —F— Fac 1 Fall 77 Famfos 1 famphur 1 Far-Go 36 fenac 27 fenamiphos 1 Fence Rider 27 fenitrothion 1 fenophosphon 1 fenothrin 42 fenpropanate 42 fensulfothion 1 fenthion 1 f envalerate 42 ferbam 36 Ferberk 36 Fermide 850 36 Fernasan 36 Fernesta 27 Fernimine 27 Fernoxone 27 Ferxone 27 Field Clean Weed Killer 27 fluchloralin 82 fluometuron 82 Folex 1 Folpan 82 folpet 82 fonofos 1 formaldehyde 68 Formalin 68 formetanate HCI 9 formothion 1 Formula 40 27 Forron 27 Framed 82 Fratol 54 French green 46 Fuclasin Ultra 36 Fuklasin 36 Fumarin 54 Fumigant-1 68 Fumigants 68 105 ------- Fundal 77 Fundex 77 Fungostop 36 Furadan 9 Furloe 82 —G— G 28029 1 Galecron 77 Gallotox 77 Gammexane 14 Garden Termi Tox 19 Gardona 1 Gardoprim 82 Gebutox 23 Gesafram 50 82 Gesagard 82 Gesamil 82 Gesapax 82 Gesaprim 82 Gesatamin 82 Gesatop 82 glyphosate 82 Grain Sorghum Harvest-Aid 77 Graminon 82 Gramonol 31 Granurex 82 Griffin Manex 36 GS 13529 82 Guthion 1 Gypsine 46 —H— HCB 82 HCH 14 Hedonal 27 heptachlor 14 heptenophos 1 Herbadox 82 Herb-All 46 Herbidal 27 hexachlorobenzene 82 106 ------- Hexadrin 14 Hexaferb 36 Hexathane 36 Hexathir 36 Hexazir 36 Hi-Yield Desiccant H-10 46 Hizarocin 77 Hoe 2810 82 Hong Nien 77 Hostaquick 1 Hostathion 1 Hydout 77 hydrogen cyanide 68 Hydrothol 77 Hyvar X 82 I Igran 82 Imidan 1 Inorganic arsenicals 46 Inverton 245 27 iodofenphos 1 Ipersan 82 isofenphos 1 isomethiozin 82 isopropalin 82 isoproturon 82 isoxathion 1 —J_ jasmolins 42 Jones Ant Killer 46 —K— Karathane 23 Karmex 82 Karphos 1 Kayafume 68 Kelthane 14 Kemate 82 kepone 14 107 ------- Kill-All 46 Kiloseb 23 Klean Krop 23 Kloben 82 Klorex 77 KMH 82 Knockmate 36 Kop-Fume 68 Kop-Mite 82 Kryocide 82 Krysid 54 Kuron 27 Kusatol 77 Kwell 14 Kypfarin 54 Kypman 80 36 Kypzin 36 ' winjj^^— Lanex 82 Lannate 9 Lasso 82 Lawn-Keep 27 Lazo 82 lead arsenate 46 lenacil 82 leptophos 1 Lexone 82 lindane 14 Line Rider 27 Linurex 82 linuron 82 Liphadione 54 Liquiphene 77 Lironion 82 Lithate 27 Lonacol 36 Lorox 82 Lorsban 1 Lysoff 1 108 ------- —M— MAA 46 Macondray 27 Maintain 82 malathion 1 maleic hydrazide 82 MAMA 46 Mancozeb 36 maneb 36 Manebgan 36 Manesan 36 Manzate 36 Manzeb 36 Manzin 36 Marlate 14 Matacil 9 MC2188 1 MCPA 27 MCPB 27 MCPB-Ethyl 27 MCPCA 27 MCPP 27 MeBr 68 Mecoprop 27 Mercuram 36 Merge 823 46 Merpan 82 merphos 1 Mersolite 77 Mesamate 46 Mesurol 9 Metasystox 1 methabenzthiazuron 82 methamidophos 1 methane arsonate 46 methane arsonic acid 46 Methar 46 methidathion 1 methiocarb 9 Meth-O-Gas 68 methomyl 9 methoxychlor 14 methyl bromide 68 methyl parathion 1 metobromuron 82 109 ------- metolachlor 82 metoxuron 82 metribuzin 82 mevinphos 1 Mezene 36 Microzul 54 Milogard 82 Miracle 27 mirex 14 mitis green 46 Mobilawn 1 Mocap 1 Mofisal 31 Monitor 1 monoammonium methane arsonate 46 monoammonium methyl arsonate 46 mono-calcium arsenite 46 monocrotophos 1 monolinuron 82 monosodium methyl arsonate 46 Monurex 82 monuron 82 Morocide 23 MSMA 46 —N— nabam 36 Nabasan 36 naled 1 Namate 46 naptalam 23 Naptro 23 naramycin 77 Neburex 82 neburon 82 Neguvon 1 Nemacur 1 Neoban 82 Neo-Pynamin 42 Nephis 68 Nespor 36 Netagrone 600 27 Nexagan 1 110 ------- Nexion 1 nicotine sulf ate 77 Nitrador 23 Nitrophenolic and nitrocresolic herbicides 23 Nitropone C 23 No Bunt 82 Nomersan 36 norbormide 54 Nudrin 9 Nuvanol-N 1 —O— Oftanol 1 Ofunack 1 OMPA 1 Organochlorines-solid 14 Organophosphates-cholinesterase-inhibiting .. 1 Orthene 1 Orthocide 82 Ortho paraquat CL 31 Ortho Triox Liquid Vegetation Killer 19 oryzalin 82 oxadiazon 82 oxamyl 9 oxirane 68 —P— Paarlan 82 Paracide 82 paradichlorobenzene 82 paraquat 31 paraquat dichloride 31 parathion 1 paris green 46 Parzate 36 Pathclear 31 Patoran 82 Pattonex 82 PCNB 82 PCP 19 PDB 82 pebulate 36 111 ------- Pencal 46 Penchlorol 19 pendimethalin 82 Penite 46 Pennamine D 27 Penncap-M 1 penta 19 Pentac 14 pentachloronitrobenzene 82 pentachlorophenol 19 Pentacon 19 Penwar 19 perchlorobenzene 82 permethrin 42 Perthane 14 Pestmaster (EDB-85) 68 Phaltan 82 phencapton 1 Phenmad 77 phenthoate 1 phenylmercuric acetate 77 Phix 77 phorate 1 phosalone 1 Phosdrin 1 phosfolan 1 phosmet 1 phosphamidon 1 phosphine 68 phosphonomethyl glycine 82 phosphorus 54 Phostoxin 68 Phosvel 1 Phosvin 54 phoxim 1 phthalthrin 42 Phytar 560 46 Pic-Clor 68 Picfume 68 picloram 82 pindone 54 pirimicarb 9 Pirimor 9 piperonyl butoxide 42 112 ------- pirimiphos-methyl 1 Pivacin 54 Rival 54 pivaldione 54 Pivalyn 54 Planotox 27 Plantgard 27 PMA 77 PMAS 77 Polyram M 36 Polyram Ultra 36 Polyram Z 36 Pomarsol forte 36 Pomarsol Z Forte 36 Pounce 42 Pramitol 82 Preeglone 31 Pregard 82 Premalin 82 Premerge 3 23 Priglone 31 Priltox 19 Primagram 82 Primatol (A, 25E, M, P, Q, or S) 82 Primextra 82 Princep 82 Proban 1 Prodalumnol Double 46 Prodaram 36 profenofos 1 profluralin 82 Profume 68 Prolate 1 Promar 54 promecarb 9 Prometon 82 Prometone 82 Prometrex 82 prometryn 82 propachlor 82 Propanex 82 propanil 82 propazine 82 propenal 68 propetamphos 1 113 ------- prdpoxur 9 propylene oxide 68 propylthiopyrophosphate 1 prothoate 1 Prowl 82 Prozinex 82 prussic acid 68 Purina Insect Oil Concentrate 19 Purivel 82 Pydrin 42 Pynamin 42 pyrazophos 1 pyrethrins 42 pyrethroids 42 pyrethrum 42 pyridaphenthion 1 -Q- Quilan 82 quinalphos 1 —R— Rabon 1 Rad-E-Cate25 46 Ramik 54 Ramrod 82 Ramucide 54 Randox 82 Rapid 9 Ratak 54 Raticate 54 Ratimus 54 Ratomet 54 Ratox 54 Raviac 54 Rax 54 Red Squill 54 Reglone 31 Reglox 31 resmethrin 42 RH-787 54 Rhodia 27 Rhodia Low Volatile Brush Killer no. 2 27 114 ------- Ripcord 42 Riselect 82 Rodenticides 54 Rodex 54 Rodine 54 Ro-Neet 36 Ronstar 82 Rosanil 82 Roundup 82 Rozol 54 Rycelan 82 Ryzelan 82 —S— Safrotin 1 Salvo 27,46 Sarclex 82 schradan 1 Schweinfurt green 46 SD 15418 82 Security 46 Selinon 23 Semeron 82 Sencor 82 Sencoral 82 Sencorex 82 Sevin 9 Shimmer-ex 77 Shoxin 54 siduron 82 Silvex 27 Simadex 82 Simanex 82 simazine 82 Simpar 31 Sinbar 77 Sinituho 19 Sinox General 23 Snip Fly Bands 9 Sodar 46 sodium arsenate 46 sodium arsenite 46 sodium chlorate 77 sodium cyanide 77 115 ------- sodium fluoroacetate 54 sodium fluoroaluminate 82 sodium pentachlorophenate 19 Soilbrom 68 Soprabel 46 Spanone 77 Spectracide 1 Spike 82 Spontox 27 Spotrete 36 Spotton 1 Spra-cal 46 Spring-Bak 36 Spritz-Hormin/2,4-D 27 Spritz-Hormit/2,4-D 27 Sprout Nip 82 S-Seven 1 Stam F34 82 Stomp 82 Strel 82 Strobane 14 Strobane-T 14 strychnine 54 Stunt-Man 82 Subitex 23 sulfotepp 1 sulfuryl fluoride 68 sulprofos 1 Sumithion 1 Super-Caid 54 Super Crab-E-Rad-Calar 46 Super D Weedone 27 Super Dal-E-Rad-Calar 46 Supernox 82 Superormone Concentre 27 Supracide 1 Surcopur 82 Surecide 1 Surflan 82 Surpass 36 Surpur 82 Sutan 36 Swat 1 Synthrin 42 Systox 1 116 ------- —T— 2,4,5-T 27 Talan 23 Talbot 46 Talon 54 Tantizon 82 Target MSMA 46 Taterpex 82 2,4,5-TB 27 TEA 82 TCA 82 TCBA 82 tebuthiuron 82 Telone 68 tempephos 1 Temik 9 Tenoran 82 TEPP 1 terbacil 82 terbucarb 82 terbufos 1 terbuthylazine 82 Terbutrex 82 terbutryn 82 terpene polychlorinates 14 Terrachlor 82 Terraklene 31 Terrazole 82 Tersan 36 Tersan 75 36 Tersan 1991 82 Tersan LSR 36 tetrachlorvinphos 1 tetraethyl pyrophosphate 1 tetrafluoron 82 tetramethrin 42 Tetrapom 36 Thimet 1 Thiodan 14 Thioknock 36 thiometon 1 Thiophal 82 Thiophos 1 Thiotex 36 thiram 36 117 ------- Thiramad 36 Thirasan 36 Thiuramin 36 Thylate 36 Tiezene 36 Tiguvon 1 Tillam 36 Tirampa 36 TMTDS 36 Tolban 82 Tolkan 82 Tolurex 82 Tomilon 82 Tomorin 54 Topitox 54 Torak 1 Tordon 82 Tormona 27 TotaCol 31 Toxakil 14 toxaphene 14 Tox-Hid 54 2,4,5-TP 27 Trametan 36 Transamine 27 Trans-Vert 46 Treflan 82 triallate 36 Triasyn 82 triazophos 1 Tribac 82 Tri-ban 54 Tribunil 82 Tributon 27 Tricarbamix Z 36 trichlorfon 1 trichloroacetic acid 82 trichloronate 1 2,4,5-trichlorophenoxyacetic acid 27 2,3,6 trichlorophenylacetic acid 27 Tri-Clor 68 trifluralin 82 Trifocide 23 Trifungol 36 118 ------- Trimangol ............................... 36 Trinoxol ................................. 27 Trioxone ................................ 27 Tripomol ................................ 36 Triscabol ................................ 36 Trithion ................................. 1 Tritoftorol ............................... 36 Tuads ................................... 36 Tubothane ............................... 36 Tumbleaf ................................ 77 Tupersan ................................ 82 — U— U 46 .................................... 27 U 46 Special .............................. 27 Unicrop CIPC ............................ 82 Unicrop DNBP ........................... 23 Unidron ................................. 82 Uragan .................................. 82 Urox (B, D, or Hx) ........................ 82 Usol Cabin Oil ........................... 4 Vacor Rat Killer .......................... 54 Vancide FE-95 ............................ 36 Vancide Maneb 80 ........................ 36 Vancide MZ-96 ........................... 36 Vapona ................................. 1 Vectal SC ................................ 82 Veg-I-Kill ................................ 19 Venzar .................................. 82 Veon 245 ................................ 27 Vernam ................................. 36 vernolate ................................ 36 Vertac Dinitro Weed Killer ................. 23 Verton 2D ............................... 27 Verton2T ............................... 27 Vikane .................................. 68 Visko-Rhap .............................. 27 Visko-Rhap LV 2D-2T ..................... 27 Vonduron ............................... 82 Vydate .................................. 9 119 ------- — w— Warbex ................................. 1 warfarin ................................. 54 Warfarin Plus ............................ 54 Weed-B-Gon ............................. 27 Weed-E-Rad ............................. 46 Weed-E-Rad 360 .......................... 46 Weed-E-Rad DMA Powder ................. 46 Weed-Hoe ............................... 46 Weed-Rhap .............................. 27 Weed Tox ............................... 27 Weedar .................................. 27 Weedol .................................. 31 Weedone ................................ 27 Weedtrine-D ............................. 31 Weedtrol ................................ 27 white arsenic ............................. 46 Wood Preserver .......................... 19 Wood Tox 140 ............................ 19 Yasoknock ............................... 54 yellow phosphorus ........................ 54 — Z— Z-C Spray ............................... 36 Zebtox .................................. 36 Zerlate .................................. 36 Zincmate ................................ 36 zinc phosphide ........................... 54 Zinc-Tox ................................ 54 zineb .................................... 36 Zinosan ................................. 36 ziram ................................... 36 Ziramvis ................................. 36 Zirasan 90 ............................... 36 Zirberk .................................. 36 Zirex90 ................................. 36 Ziride ................................... 36 Zolone .................................. 1 zoocoumarin ............................. 54 JJ.U.S. GOVERNMENT PRINTING OFFICE. 1 98 2 -3 5 4 - 7 5 0 / 8 2 6 6 120 ------- ------- U.O. fj^'i'-op.n'?:-,:.:-,! ProlGction Agency R .-7:0,5 V, ! if-,-ary 230 S'y-th jea:born Street x Chicago, ijlir.ois .60604; ^^^ ------- |