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Clinical Toxicolou CLINTON H. T\t HIENES, M.D., Ph.D. Emeritus fi&, HUM'- InaW of Applied Medical Research, Huntington Metnurid Hospital, Pasadena; Emeritus Adjunct Professor of Phanocology and Tozicology, School of Medicine, Unioctsity of Southern California, Los Angeles; Emeritwr Attending Pathologist ( T o z i c O ~ )L, or Angeks County Hospital; Consulting Member of Stuffs of Hunfingh Memorial Hospital, Glendcrle Adventist Hospital, Memofioz Hospihl of Glendale, Missiol,Hospital, Huntinqton Park, and Temple Hospitrrl, Los Angeles. THOMAS J. HALEY, PhD. Adjunct Professor of Pha7macoh, Schools of Medicine? and Phurmaqi, University of North Carolina;Cmuultant, Deparhncnt of Heaw1, Education and Welfare;Food and Drzlg Adminislrdwn, Wodrinpton, D.C.; Research Triangle Insti&&, Research Triangle Park, N d Carolina. FIFTH EDITION ILLUSTRATED 1i L E A & F E B I G E R Philadelphia 1972 Copyright 0 1972 by Lea & Febiger. Copyright under the International Copyright Union. All rights reserved. This book is protected by copyright. No part of it m y be reprodud in any munw or by any means, without written pmissim from the publisher. First Edition, 1940 Second Edition, 1948 Third Edition, 1955 Fourth Edition, 1964 Fifth Edition, 1972 ISBN 0-81214237-1 Library of Congress Catalog Card Number: 73-152032 Published in Great Britain by Henry Kimpton Publishers, London PRINTED IN THE UNITED STATES OF AMERICA iylene-02 .e are excyclopro;en,2.5 to .nd cycloto carbon . The re- the lungs. treatment ory failure a1 respiralioxide are Lrbon dioxbe must be bject's face 1 high con-essant and. k may be tered intra0.5 to 2 mg : (Neo-Syniethoxamine tine sulfate. Id not be used causing vm- ' .Veuropathology. ases. Chicago, Guedel, A. E.: lopropane anes941. .: Heart under n Med., 57, 3, ZENE AND 4NE oro-2-brom-2)id and smooth d recovery and of experienced no indication ises a reduction ;bane increases rases blood presproduce sympam sensitize the Toxicology of General Anesthesia 55 myocardium to catecholamines. It also of ethyl alcohol. For this reason, chloroform produces some degree of myocardial depres- for anesthesia contains 1%ethanol. sion but as great as the other anesthetics. Divinyl Ether. On exposure to light and Myocardial arrhythmias have also been re- air, divinyl oxide polymerizes, and also de- ported. Halothane has been shown to composes to aldehydes. Such altered samples inhibit uterine contractility and depress of the drug are quite irritating to the nose gastrointestinal motility. Transient fatty and throat and have a "stinging odor," ac- changes in the liver but not the kidney have cording to Chen and Leake. been reported but this subject is highly Ether. Aldehydes, acetic acid and perox- controversial. ides are found in ether which has been Methoxyflurane, l,l,-difluoro-2,2-dichloro- exposed to air and sunlight. It is doubtful ethylmethyl ether (Penthrane), is similar in whether these substances are of sufficient its effects to halothane and in addition it toxicity to warrant the waste of ether now causes profound muscle relaxation. There is obtaining in hospitals where small cam in- a high degree of accumulation of the drug in stead of drums of ether are purchased and body fat which causes a slow recovery. where ether that has stood in an opened Blood sugar is also increased. This agent can more than 24 hours is considered unfit has a profound depressant effect on pul- for anesthetic purposes. (See papers by monary ventilation. Gold and Dooley and their collaborators.) Fluoroxene, 2,2,2-trifluorethylvinyl ether, However, Mendenhall and C O M O ~ ~reY- has the drawback of being flammable. It is ported ether containing aldehydes and perox- similar in most respects to the other two ides to be more toxic to cilia than pure agents. ether, and Knoefel found such impure ether Fate and Excretion. Halothane is con- to produce anesthesia in mice more slowly verted into bromide, chloride, trifluoro- than high purity ether. acetic acid and trifluoroethanol glucuronide The fact that the U.S.P. recognizes by the liver and excreted in the urine. Ether, intended for anesthesia, and the Fluoroxene is metabolized similarly to National Formulary recognizes Ethyl Oxide halothane; methoxyfhrane is metabolized to or solvent ether, may lead to a mistake. fluoride, chloride, Cor, formaldehyde, 1,l- Ethylene. Carbon monoxide was an diflu0ro-2,2-dichloroethanol1 2,2-dichloro- occasional contaminant of ethylene in the ethanol, 2-hydroxy-lll-difluoroethylmethyI early years of its use, but more refined ether, and perhaps methoxydifluoroacetic methods of manufacture have eliminated acid, hydroxyfluoroacetic acid and oxalic this hazard. acid, and excreted into the urine, partly as Nitrous Oxide. Rarely are there irritat- glucuronides. I n two patients recently re- ing oxides present in nitrous oxide now ported by Taves et al.,the fluoride in blood marketed for anesthesia. However, at- and tissues reached toxic concentrations, mospheric nitrogen is present in excessive with degeneration of liver and kidneys, and amounts more frequently than is generally eventual death. appreciated (Chaney and Lombard). Be- cause of the greater volatility of nitlogen, it IMPURITIES IN ANESTHETIC DRUGS escapes from the liquefied gases in the cylindersmore rapidly than nitrous oxide. There- Chloroform. Oxidation of chloroform fore the first patients anesthetized from yields phosgene, a gas highly irritating to such cylinders require a dangerous degree of pulmonary structures. For this reason only asphyxia to produce anesthesia. It is quite freshly opened bottles should be employed probable that the delayed toxic effect of for anesthesia. Chloroform oxidizes less nitrous oxide anesthesia occasionally seen in rapidly when protected by a small amount large hospitals can be attributed to the pro- 3 Chapter 15 Cardiac Poisons The cardiac actions of chloroform (Chap- ter s), of cocaine and other local anesthetics (Chapter l), of aconite and veratrum (Chapter 2), nicotine (Chapters 1, 2, 3) and of epinephrine, ephedrine, amphetamine and similar compounds (Chapter 13) have been discussed. Benzene is included in this chapter because of its ability to produce fatal cardiac arrhythmia, Toluene and xylene are included because of the chemical but not toxicologica1 similarity. BENZENE Toxic Dose. TNOml by mouth may produce symptoms, and 10 ml may be fatal. The TLV in air is 25 ppm (80 mg per cu M). Inhalation of 100 ppm for several hours causes headache and a sense of fatigue; 1500 ppm for an hour causes marked depression, 3000 ppm is irritating to the eyes and nose on but a few minutes' exposure and 7,500 ppm for half an hour or 20,000 ppm for a few minutes may cause death. Daily inhalation of 100 ppm may cause bone marrow injury with pancytopenia of the blood. The odor is detectable a t 1.5 to 5 ppm. Absorption. Benzene is absorbed from the alimentary tract, through the skin and, as the vapor, from the lungs. Etiology of Poisoning. Benzene is widely used as a commercial solvent. Some motor fuels contain 20 to 50% or more of benzene. Benzene may be a contaminant (0.5-7%) of commercial xylene, toluene, cyclohexane and light and heavy naphthas which are largely xylene, toluene and cumene. Many cases of poisoning are due to inhalation of the vapor in improperly ventilated rooms, or from contact with the skin. Several deaths have occurred among workmen cleaning out tank cars. Symptoms and Actions. The symptoms are due to gastric irritation and to depression of the central nervous system, myocardium and bone marrow. There is vomiting if the drug is taken orally; giddiness, vertigo, muscular incoordination and unconsciousness may follow one another quickly, following either ingestion or inhalation of toxic amounts. Fever often develops in acute and subacute poisoning. Muscle twitchings and convulsions may precede acute death. The heart beat becomes weak and irregular. Injection of epinephrine into bemene poisoned animals readily produces v e n t r i c k fibrillation. Many acute deaths are due to ventricular fibrillation due to effort and release of epinephrine. This was probabIy the mechanism involved in the death of workem in tank cars which had contained benzene. Frequently, the man who went into the tank car to carry out an unconscious worker died during the effort of lifting the unconscio@ man up the ladder. There is prolonged 124 306 Chemical Diagnosis of Poisoning i! FIG.10. Blood Cst Apparatus. ( A )Sulfide trap containing lead acetate cotton. ( B )Blood sample tube. (C)Reaction mixture tubes. Table 33. calibration Data for Determination of -4ropnatics in Blood COmpt.7lLd Benzene n-Butyl Benzene Sec. Butyl Benzene Ethyl Benzene Kerosene n-Propyl Benzene Toluene m-Xylene pXylene * Absorption Band nm 255 268 267 268 272 268 269 273 274 Base Line nm 240-275 230-275 235-275 230-276 245-310 230-275 240-275 235-280 235-285 Cone. Range 0.023-0.210 0.034-0.269 0.039-0.308 0.039-0.310 0.025-0.388 0.016-0.340 0.046-0.184 0.036-0.284 0.016-0.124 Abe. Range 0.060-0.550 0.038-0.348 0.045-0.363 0.062-0.541 0.017-0.431 0.015-0.490 0.107-0.442 0.083-0.712 0.090-0.752 3 drops of octyl alcohol. Place 1.25 ml of reaction mixture in tubes C and connect the apparatus to a vacuum pump. Pass air through the apparatus for 30 minutes. After 15 more minutes mix together the contents of the tubes C and determinethe absorbence in a photoelectric colorimeter using a green filter. Compare with a similarly derived standard curve. BENZENE .. If benzene is suspected place the tissue into a flask, add 400 ml of distilled water and a few ml of concentrated sulfuric acid. Steam distill using a long condenser fitted with an adapter projecting below a layer of carbon tetrachloride in a small receiving flask. Allow the distillate to separate and draw o f f the tetrachloride layer, which will contain the benzene. To the benzene-carbon tetrachloride mixture add 10ml of 2:l nitric- sulfuric acid mixture and shake. Evaporate off the carbon tetrachloride on a water bath and allow to cool. Add 50 ml of water, and shake out with three portions of ether in a separatory funnel. Collect the three ether fractions and evaporate over a water bathNitrobenzene remains as a yellow residue. This may be identified by tests already described (p. 300). Quantitative Estimation of Benzene, AI- kylbenzenesand Kerosene in Blood (Gue* and Gerarde, Arch. Ind. Health, 20, 26% 1959). REAGENTS. Cyclohexane spectrophob metric grade. Hydrochloric acid 0.1 N- DETERMINATIONMS BLOOD. Deliver 5 nd 1 Chapter 24 Bone Marrow Poisoning There is a list of drugs and chemicals of anemia and 13 of miscellaneous effects. reputed to cause anenlia and leukopenia Table 23 lists the 11 drugs or drug groups through bone marrow suppression or in- with the highest number of cases. The jury. Those drugs known to or strongly sus- frequency of dosage is not linown. In many pected of having occasionally affected the instances, other drugs were being used at the blood-forming cells are included in Table 22. same time, hence, cause and effect are not Evidence for involvement of most of these certain. chemicals is imndicient for proof. Chronic administration or exposure is ANTINEOPLASTIC DRUGS necessary for bone marrow injury by most Antineoplastic drugs which injure the of the effective substances, although amino- blood-forming organs and produce anemia, pyrine is reported20 have caused granu- leukopenia or both, are the alkylating agents lopenia in sensitive patients after a single and the antimetabolites. These drugs in dose, and a single dose of benzene may therapeutically effective doses usually pro- cause anemia. duce unpleasant side reactions. Larger Various drugs, vitamins and tissue extracts doses can be fatal. have been reputed of value in treating pa- Alkylating Agents. These drugs belong tients with bone marrow damage. Most of to the group of compounds known as nitro- these are probably ineffective; transfusions gen mustards and sulfur mustards, so named of whole blood or of red or white blood cells because in World War I the sulfur mus- where specifically indicated are often life- tards, particulary, had somewhat the odor saving. of mustard oil and were used militarily as Most of the bone marrow poisons are dis- cutaneous vesicants. They are employed (*usedin detail under other headings. For therapeutically against a wide variety of example, benzene is described among the malignant tumors. Since they are highly Wdiac poisons, because of its acute effects reactive substances, they must be adminis- 011 the heart. A few, however, need addi- tered intravenously or intra-arterially. The tional discussion here. principal side reactions are nausea, vomiting, Of 1676 cases of drug-associated blood diarrhea, erosions of lips and oral mucosa, dYscrasiasreported in1959 to 1961,inclusive, glossitis, amenorrhea, anhidrosis, skin pig- there were 438 cases of pancytopenia, 183 of mentation, alopecia, pulmonary fibrosis and thrombocytopenia, 449 of leukopenia, 112 interference with blood cell maturation. 227 I 1' 1't i :, ; j I' :I I ,I I ;* 1:' 1 ;; .I iji1\itrl8' ,I +' 1 240 Poisons of the Blood and Hematopoietic Organs cases have lived for as long as 4 days before succumbing to acute poisoning. Chronic poisoning persists for an indefinite period before death or recovery. Pathology. Hematoporphyrinuria and hepatic and renal degeneration and often degenerative lesions of the central and peripheral nervous system are found a t death. Diagplosis. Hematoporphyrinuria may be due to a constitutional or idiopathic disorder. In such cases, close relatives often exhibit the same dysfunction. Identification of the drug in urine or tissues and a history of taking the drug will establish the toxic etiology of the condition. Causeof Death. Respiratory failureresults from acute poisoning; in chronic poisoning, death may be due to anemia, renal or hepatic degeneration or depression of the central nervous system. Treatment. I n acute poisoning, empty the stomach; for respiratory depression give caffeine and sodium benzoate (1 Gm) or pentylenetetrazol (0.1 Gm) intravenously, or if necessary, artificial respiration, with oxygen. The liver and kidneys should be protected by carbohydrates and alkalies. For excessive hematoporphyrin formation, bleeding, with subsequent blood transfusion may be indicated. 264 An Outline of Differential Diagnosis loids, snake bite, stingray, tribromoethanol, veratrum. 7. Vasoconstriction, Gangrene. h p h e t a - mine, chloroquine (retina), ephedrine, epi- nephrine, ergot, lead, nicotine, posterior pituitary extract, tobacco. 8. Hemorrhage, Petechiae, Purpura. Ar- senic, benzene, chlorthiazides, corrosives, dicumarol, digitalis,ethacrynic acid, heparin, parathyroid, quinidine, Sedorniid, sulfonamides, thiouracil. 9. Changes in Blood Cells. ( a ) Anemia: alcohol (chronic),arsenic, barbital (chronic), benzene (chronic), favism, lead, morphine addiction, nitrofurantoin, nitrogen mus- tards, perchlorate, phenylhydrazine, radium, sulfonamides, trinitrotoluene. (b) Brown Blood: acetanilid, aniline derivatives, nitrites, sulfanilamide, sulfites. (c)Hemolysis: Arsine, castor bean, chlorates, copper sulfate, dimethyl sulfate, dinitrophenol, favism, mephenesin, naphthalene, nitrofurantoin, phenylhydrazine, quinine substitutes, snake venom, sulfonamides. ( d ) Leukocytosis: pilocarpine, titanium tetrachloride. (e) Leukopenia: Aminopyrine, aniline derivatives, antimonials, arsenicals, benzene, chloram- phenizol, lead, perchlorate, radium, sulfonamides, thiouracil. ( j ) Polycythemia: acetanilid (chronic), aniline derivatives (chronic), arsenical dysentery, carbon monoxide (chronic), cathartics, cobalt. (9) Stippling: antimony, bismuth, lead, phenobarbital (chronic). mide, sulfides, tetrahydrozoline, tricyclic antidepressants, vitamin D. CONSTIPATION Adrenergic blocking agents, calcium salts, cathartics (chronic use), dihydromorphinone (Dilaudid),ergot, ganglionic blocking agents, lead, morphine, opium. CONVULSIONS 1. Tonic OT Tetanic Convulsions. Antibiotics, asphyxia, camphor, carbon monoxide, cocaine, cyanide, fluoride, fluoroacetate, insulin, metaldehyde, illetrazol, naphthalene, nicotine, nitrogen mustard (children), prochlorperazine, rotenone, strychnine, tetanus, tricyclic antidepressants, uremia, zinc phosphide. 2. Clonic Convulsions. Absinthe, antihistamines, asphyxia, atropine, caffeine, camphor, carbon disulfide (chronic), chlori- nated hydrocarbon insecticides (DDT, lindane, etc.), chromium, cocaine, codeine, coriamyrtin, ergot, insulin, mushrooms (chil- dren), phenol, picrotoxin, rotenone, strych- nine (early), theophylline. 3. Tremor. Alcohol, amphetanline, ar- senic, barbiturates, barium, chlorinated hy- drocarbon insecticides (DDT, lindane, etc.), chloroquine, ergot, ephedrine, epinephrine, insulin, lathyrism, lead, manganese (chronic), mercury (chronic, by inhalation or as methyl- mercury orally),methylphenidate, milk-sick, neostigmine, nicotine, physostigmine, reserpine, thyroid, tranquilizers, uremia. COMA OR DROWSINESS COUGH Alcohol, amphetamine withdrawal, anesthetics, anticonvulsants, antihistamines, aromatic hydroearbons, arsenic, barbiturates, bromides, cannabis, carbon disulfide, carbon monoxide, carbon tetrachloride, chloral hydrate, chloroquine, cyanide, diabetic coma, diazepam, herbicides, hydrocarbons, glutethimide, insulin, iodine, lithium, mercurial nephritis, metaldehyde, methyl bromide, methyl chloride, naphazoline, naphthalene, opium derivatives, pentachlorophenol, phenol, salicylates, somnifacients, sulfada- Acid fumes, beryllium, cadmium, castor bean meal, chlorine, chromium, dimethyl sulfate, formaldehyde, hydrazine, metal fumes, nickel carbonyl, nitrogen oxides, organic phosphate insecticides, silica, sulfur dioxide, tellurium, titanium tetrachloride, toluene diisocyanate, vanadium oxide. EXCITEMENT, DELIRIUM AND INSANITY Alcohol, amphetamine, anti-adrenergicsi arsenic, atropine, barbiturates, bromide, I . "