Document km42rVJn8EojQDmmyL77v393V

T a < L 3.1 o S O THE MACftfrLLAN COMPANY HZW YCMUd aOSTOK CHICAGO DALLAS atlamta sam rsumeo MACMILLAN * CO- Liwtrm LOMDOM - SOMSAV CALCUTTA MELOO<JRX THE MACMILLAN CO. OP CANADA. Lm TORONTO 'j INDUSTRIAL POISONS IN THE UNITED STATES BY ALICE HAMILTON, A.M, >1.0. Assistant Professor of Industrial Medicine, Harvard Medics! School, Boston, Hass.} Formerly Special Investigator of Poisonous Industries far the U. S. Bureau of Labor Statistics t, i&eto gor* THE MACMULAN COMPANY 1929 f8Ta 1916, ILLUf COKTiNT. nd printed. u*r< ** . , April. 1W t l*er l*I*ptyP>plBOlma rtM * M I-- t lid t4rj of A merits l-m 72fe3 H3 PREFACE t .1 Tile sources of our knowledge of industrial poisoning in tie United States are neither foil nor, for tie moat part, accurate. We lack tie sickness insurance system which obtains in all industrial countries in Europe and which brings to Kght the inmdftmy of illness of all kinds in all groups of workers. Nothing takes its place in this county Our private insurance companies sometimes gather important and trustworthy data, but these are never all- inclusive and never can be, they axe always restricted to the group of individuals insured in that company. The Oensua reports axe of deaths only, not illness, and die death records lose much of their value ^because of a'poor classification of workers, which puts into the same category men doing work of very different degrees of danger, as for instance paper-hanger* and painters. Trades union records are ael- S dom of value, with the exception of those gathered by the typography ~t ical unions which were reviewed carefully by Terrill* and found to - contain much that was interesting to the statistician. " It has been my task for many years to ^examine records of hos pitals and dispensaries and to interview physicians in many parts of the country in my search for information about a given poisonous trade Not one hospital in twenty has records which yield the sort of information which the student of industrial toxicology craves J and yet this is not elaborate. If the recording interne would only * treat the poison from which the man is suffering with as mucn < interest aa he gives to the coffee the patient has drunk and the tobacco he has smoked, if he would ask as carefully about the length of time he was exposed to the poison aa about the age at which . be had measles, the task of the searcher for the truth about indus trial poisons would be made so very much easier. I have often had to reject fully one-third of the cases of plumbism which have been treated in a hospital because the interne had no curiosity about the source.of the lead, contented himself with the notation, `Head worker," and so made it impossible for me to know from which of the many lead trades the man* came. Physicians in private practice have given me the greatest assist ance, jet tltere are. limitations to the value of the information - obtained in this way. The diagnosis must be accepted, of course^ as the Bureau of the accepts Che death certificates of all FACE ,s may have to be made. One must is kind the existence o a prejudice f some fira<rclasa men. Apparently ms to treat industrial diseases with f with which they approach those a the working classes. For.a strikis referred to a bulletin issued by >a a trade disease--not an intoxicaidence is given from a doctor who on and from two who were brought f is there the widest divergence of dan who was retained by the men r them as to quite dull his critical io companies accept evidence which d then indulge in moral observations n and the evils of trades-unionism, ining of information from physicians ge of workmen's compensation laws, oisons are handled now has its own uig to give out facts which may seem the other hand X have often had all me and been permitted to make what uld bo despised. Apothecaries, risit- ity workers, priests, often lot drop ts of tko men themselves should be cd up, and often they will prove to be For instance, down in the copper >f cases of profound anemia and loss jod in the electrolytic production of ion of the premises showed no ground set the tales, but closer study showed ncthod there is always the possibility nsoning, if the copper carries some slow poisoning from this gas would .ion as that described. The statement plant, that there was a good deal of ho made the blue , bed, seemed to me n handle, only clean lead buckles, but that, remnants of old corrosions were j covered with dusty white lead, and Dr tho cases. * enormous value for the physiological the mode cdirauce, bv,` it can tell us -- ........... tt q TtnrMii rtf nothing about the probable incidence of poisoning in American industry because our methods differ decidedly from the European. Some trades which are dangerous there are quite harmless here. For instance, the making of cheap kitchen ware is one of the bad lead trades of England,"here it is not a lead trade. Dyeing, cotton and. wool and handling them after dyeing, making files, polishing diamonds, these are occupations notoriously fraught with danger of lead poisoning in Europe, but not in the United States. On the other hand we have industries which are much more dangerous than theira, such as the making of white lead by a dry process instead of a wet one, the use of large quantities of nou-fritted white lead in. pottery glaring, and the use of lead-laden enamel powder for sanitary iron ware* It is not possible to draw conclusions as to the danger of any occupation in the United States by simply con sulting the foreign literature about it. - There has been an enormous increase in the interest of the medical world in industrial toxicology of late years, especially since our entrance into the war in 1917. There are already some studies of poisonous trades in the United States which for thoroughness leave nothing to be desired. Perhaps the study made by EdsaH, Wilbur and Drinker * on manganese poisoning stands at Che bead of these, for they were able to study the incidence in a large group of work men, the conditions under which poisoning occurred, the mode of entrance, and the clinical manifestations^ of early stages of poison ing, as well as of the later stages. At the foot would stand the single observation made by a physician in private practice on a case occurring in a plant to which he has no access and the descrip tion of which he must take from his patient. He cannot check up his findings, he cannot be certain, that this, to him new and unfamiliar poison, is really responsible for the lesions he has observed; all he can do is to present his findings, suggest their possible significance and let it go at that. But he it'rally per forming a valuable service when he does this, for such reports, incomplete as they must be, have often led to the exploration of a sew and important field of industrial toxicology. - I have called this a study of industrial poisoning in the United States aud have tried so far as possible to present American material, but obviously that is not always practicable and xnnch that we owe to foreign observers has had to he included. It has been my pur pose to avoid when I could the earlier writings which have been reviewed in the existing textbooks and to give as much new mate rial as possible. The literature up to January 1, 1934, has been included. * _ IHuffl, 1). I*., Wlltrpr, !F. P., *ad PrinVr, G, K. The Occurrence* Ceute iff of Cftrauo Fcuofiin?.. /2y?*i910-t0| l^VTV { *t } <e.-. h CONTENTS PaEJA.CS ................................................................................. bna ' _ X. Intbodcotion to Industrial Toxioologt ...... rxtx T 1 2.. Ltut>: Pathology................................................................ 19 3. Lead: Absobftion and Excretion. Quantity ... 40 4. Lead: Colic. Arthritis...........................................................58 5. Lead: Palsy ............................................. 2 6. Lead: Encephalopathy......................................... ..... . 74 7. Lead: Diagnosis ...................................................................... 94 8. Lead as a Bags Poison............................................... . . 110 9. Toxicity of Lead Compounds. Compounds Used in In- DUKCBT.................................. 116 10. Lead Hiking. Lead Shelting and Refining. Metallic T/p-td....................... 1............................ 124 11. The Pjuhtebs* Tjllde.................................................... ' . 140 12. White and Bed Lead. Storage Battbbizs........................... 163 13. Glazes and Enamels. The Pottery Trades .... 173 14. The Paxntsbs* TraDk ............................ 185 16. MISCELLANEOUS T.vin TRADES ...................................................201 16. Arsenic ..................................................................................... 206 17. Mxeouby . . . `........................................ 234 18. The puttees' Traps ........... 254 19. Copper, Zinc, Brass............................. -............................... 276 20. Manganese. Antimony. Cadmium. Kiozsl Carsontl . 291 21. Selenium. Tellurium. Vanadium. Phosphorus . . 303 22. Caustics. Ammonia. Chromates........................................317 23. Sulphurio Aam. Htdeoohlobio Acid. Phosgene . . 323 24. Kitkio Acid. Hyd&opluorio Acid . . . . . . 336 25. Hydrocyanic Aom and Ctanhs. Cyanogen Chlorid. , Oaloidk Ctanimid ...... - . . * 344 26. HYDROGEN Srir.-pwm P**W/W Tre-rrT.^~ nrt CONTENTS t MU Carboh Mokoxid. Mine Gases...................................................... 371 PETROLEUM X)l3TILLi-tE8 . . ` . ........................................ . 400 Oil FuBiwcoLoaiB and Tab Cahoer ........ 410 Methyl Aloohol ..................................................................................418 EtBZO. AlDEHYW. HEXAMETKYIEHKTETRAMiH. MeTOL. Amylaoetate. Dimethyl Sulphate . . . ... 429 METHYL CHLORIC. TeTBAOHLORMETHANE, TeTKACHLOEetoame^ Otheb Chlob Compounds, Methyl Bbomid, Ncteooltceein 441 Benzene................................................................................................. 453 . Benzene Debiyativzs ........... 483 The Coal Tab* Dye Industry.......................................... ...... The Bobber Trade . . . . . . V . ' . . . 512 . 523 Turpentine. Toraooo . . . . . 533 The Prevention op Industrial Poisoning V. .. . ;-. . 538 v- INDUSTRIAL POISONS IN THE UNITED STATES / / M % / Vi- 452 INDUSTRIAL POISONS IN THE UNITED STATES tremors of hands and outstretched tongue and a neurasthenic condition. This long continued neurotic condition ia noted by J&qnet (8) in his first case, and by Bing (4) in his first case. Floret (5) de scribes three cases in one of which there was nausea, double vision staggering gait, and after five days an attack of frenzy followed by coma and then by delirium with hallucinations, epileptiform attacks and prostration, followed by a prolonged period of mental apathy and languor and apparent muscular weakness. L:ffler and Riitimeyer (6), failing to find any bromin or bromin compounds at autopsy on a case of typical poisoning from methyl bromid, exposed guinea-pigs to the fumes, and found that, if the animal were killed immediately after exposure, the substance could be demonstrated in fluids and organs, but that if it lived for SO to 70 minutes after removal from the fumes it was if not quite, impossible to detect methyl bromid in the body. The last cases of industrial poisoning from methyl bromid re ported in the literature are Cade and Hazel's (7), from a French chemical factory. In the first case, as in that of Loffler and Riiti- meyer, the man was exposed several times to the fumes of methyl bromid and at last succumbed to an exposure rather greater than usual. A leak occurred which be tried to stop with cotton an hour before he left the works. Sixteen hours after the inhalation of fumes he bad diplopia with indistinct vision, his fingers and legs txscame useless, and he was unable to tell his name or to write it He had violent pains in the legs and marked motor incoordination. In a second case the man, aged 59, had been engaged at times for 32 years in the manufacture of antipyrin and had had four attacks of mild methyl bromid poisoning with complete recovery in the intervals. ' BtBUoaaxPEY j (1) Robre&, F. Fril/sehr. f. gerichil. }td., 1920, Series 8, 60, 51. (2) Goldschmid, and Kuhn, E. Zntrlbl. f.Oewtrbckyg., 1220, 8, 28. (3) Jaqcet. Quoted by R3hter (1). (4) Brno. Quoted by Robrer (2). (5) Floret. Quoted by Goldachmid sad Kuhn. (Q) Loftler, W., and ROtimeter, W. Vrlljschr. f. gerxehll. .1920, Series 3, 6, No. 1, 60. (7) Cade, A., and Hazel, P. BidZ. 8oc. mid. d. hop., 1223, 47, 722. ;.eo :td *>'' CHAPTER 33 ` BENZENE Bknxene, or benzol, as it is usually called, is one of the most important of the industrial poisons, but its use in industry is com paratively recent, and therefore tho literature concerning industrial poisoning by coal-tar benzene and its homologues, toluene and xylene, is not very full; indeed most of it has appeared too recently to be incorporated in the text-books. It seems wise, therefore, to handle this subject as completely as possible; for there is every prospect that the use of coal-tar distillates will continue to `increase in the near future, and it is of the greatest importance that the dangers attending them should be dearly understood. Cod-tar benzol ia properly called benzene and ia represented by the formula CH. Unfortunately this term ia likely to be confused with petroleum benzin, but it is the one insisted upon by the chem ists. Toluene (toluol) is methyl-benzene with the formula CHSCH, and xylene (xylol) is dimethylbenzene, C*H.*(CU3),. These bodies are obtained as by-products in coking coal, and in the produc tion of illuminating gas. They are collected in heavy oils, and dis tilled off. ( Pure benzene distills at 80* to 81* C. It is a very volatile color- lesa-fluid with a pleasant odor which is not locally irritating and ^which arouses no suspicion of danger. The vapors are three times as heavy as air. Toluene distills at 110* 0. and xylene at 187 to I'M*.* ,, Besides pure benzene and toluene and xylene, there are several kinds of commercial benzenes, which contain toluene, xylene, thiophene, and raTely traces of carbon disulphid. The usual commercial products are: Pure Benzene--A clear colorless liquid of a characteristic odor. BP. 79.7* O. , , .............. Ntmcty-peb cent Benzene--So called because in the distillation 90 per cent distills over at a temperature of less than 100 C. It is com posed of 80 to 85 per cent benzene, 18 to 15 per cent toluene, 2 to 8 per cent xylene, and sometimes contains as impurities traces of olefins, paraffins, sulphuretted -hydrogen and other bodies. Firry-pea CENT Benzene--This substance contains 50 per cent of constitu ents which dietOl below 100* C., and 60 per cent below 120* C.; it Sa a very m:?. 2 .redact, with only 40 to 50 per cent, benzene. di.______ /i fl r.nnwM. ttmA Phil*.. IMS n RS7. 454 INDUSTRIAL POISONS IN THE UNITED STATES Solvent NArimjc--Tliia material is called solvent naphtha because it la used extensively. (especially,^a^Englaud>*IaT dissolving Tubber. It is relatively free from benzene, and consists largely of xylene. In Germany commercial benzene, as used in the rubber trade especially, may contain a large proportion (from 16 to 00 per cent) ol carbon disulpbid. Thiophene is of no importance lexicologically. Uses.--Benzene is used on a large scale in solvent extraction work, extracting oil and greases, but this is done in hermetically scaled apparatus, the benzene being removed from the products before they are taken out so that the danger, as in benzene production, is only the risk of some accident to th6 machinery. In French dry cleaning, benzene was used for a while juat after the war, but the increased fire risk has led to its abandonment except in a few cases. AOpresant, benzene.is used,in every branch of rubber manufacture, not of course in all departments of every rubber works, but in some department in practically every individual plant. It is a much better solvent for gums, resins, and fats than is any petroleum deriva tive and it dries faster than high-test gasoline. It is used for cement-in shoe ..factwie^jin^^n^millinety^ manufacture^* in the making >o-fabrfk6i,' aftifici^ `^ea'thr,v; find - linoleum, in coating leather ior.upboLsteiy andfor^automobile tops,v<and as a constituent of shellacs, varnishes, gilding and bronzing fluids, varnish and paint removers, and quick-drying paints for interior work.f Enormous quantities of benzene rubber mixture are used in the making of so-called sanitary food cans. In the manufacture of pharmaceuti cal supplies, benzene is used to crystallize out coal-tar drugs. It is the starting point of many important intermediates in dye manu facture, such as anilin, and is also the starting point of synthetic carbolic acid and of the important explosive, picric acid. Copper and *xinc-are -cleaned witb.benzene in preparation for g8lvanoplatingj-^^d photoeogTavers \iaeit "to-dissolve rubber Aims. It is also, used in.the`manufactiirtfSsfkodaV'ffitfd''moving picture films. The largest commercial users of benzene at present, aside from the purveyors of motor car gasoline, are manufacturers of the following; rubber cement, rubber tires and shoes; brake linings, particularly for automobile brakes; artificial leather and fabrikoid; lacquers; cement for sanitary food cans; paint and varnish removers. All of these require the use of benzene in more or less open vessels or vessels which have to be opened from time to time. The National Safety Council undertook to study benzene poison ing in industry during tho year 1923 by sending out questionnaires The Ohio Stale Department of Health found Id one millinery cement 49.S per ceit h; volume, and in mother no ku than 92 per cent. I Some of the newer quick-drying 'flel cunt" pain la eenUtn benzene inappre ciable quantities. For instance, :#U'c- the liquiw^nedium is 10 per cent ben* tern* end the directions call for the addition of benzene if the paiot la lou.Uuck. t - ' INDUSTRIAL POISONS IN THE UNITED STATES 455 to tho producers and users of this compound, obtaining information from 67 firms. Thirty of these firms employed less than five in processes exposing them to benzene; four employed a hundred or over, the largest being a rublxir factory where 1080 were so employed. Of the firms employing ten or more people in benzene work, eight were rubber factories, five were chemical works, four were paint and varnish makers, three were gas plants recovering benzene as a by product, one was making celluloid and artificial leather, one japanned goods, and one was a can factory. The substitution of benzene for petroleum distillate iu motor ear fuel leads to a change in the composition of the exhaust gases and undoubtedly adds to the danger from these gases in garage work. Yandell Henderson (1) and bis colleagues have compared the amounts of CO found in the blood of dogs dying from exposure to various CO-containing gases and found that death occurred at a lower CO saturation when coal-tar distillate was burned than when gasoline was, and to a slighter degree this is true where il luminating gas is used. When pure CO was used, the blood at death contained 84 per cent CO; after illuminating gas poisoning, only 70 per cent CO was found in the blood; after death from gas from a motor car using gasoline, 83 per cent CO was found in the blood; but after death from gas from a car using coal distillate, only 62 per cent was found. The composition of this distillate was as follows; benzene, CO per cent; toluene, 15.5 per cent; solvent naphtha, 13.5 per cent; heavy naphtha, 2 per cent. The symptoms of illuminating gas poisoning differ from those of pure CO poisoning; for there is more respiratory excitement and quicker collapse, and there is nausea and vomiting. Apparently the action of gasoline exhaust gas depends entirely upon the CO that is present, hut the exhaust gas from coal distillate causes symp toms resembling illuminating gas poisoning and the difference is attributed to the presence in both of these gases of benzene vapor. Robert (2) also says that the greater toxicity of illuminating gas as compared with pure CO is to be explained by the presence of benzeno in the former, and SUehelin'e experiments prove the same. He was using CO on frogs; hut, running short of the pure gas, he undertook to substitute illuminating gaB, whereupon the frogs devel oped convulsions, as they had under CO. Stachelin (3) found that benzene vapor in the gas accounted for this difference. (See Hag gard's experiments with neuroblasts, p. 396.) There has been much controversy as to which is most toxic, pure benzene or crude benzene, or the mixtures of benzene and its homologucs commonly used in industry. Lcwin (4), testing vapor on animals, found impure benzene more toxic than the pure, o " Ghassevont and Garnier (5) say * - same. Lehmann (6) tested tin tnn fin wnmAr.i'al onA tkn I'M I r1< and -fmind fllAiri ni\t tArO {.00 INDUSTRIAL POISONS IN THE UNITED STATES ihe <*rvu\c being slightly the* most toxic, but the individual vunaiiciis in the susceptibility of animals rendered the conclusions dubious. Lehmann ears that the early symptoms comp on most quickly with benzene; but narcosis, tpdst quickly with toluene. On lie other hand, Robert (2) says toluene is much less toxic than Ikmizciic, but more irritating to the mucous membrane, though with less convulsive effect, for it is changed to hippuric acid in warm* Hooded animals. Rambousek (7) found pure benzene the most loxic. Toluene, xylene, and solvent naphtha (which, he says, is a mixture of tho higher benzenes, cumene, pseudocumene, and mesityl' one cumene) all cause less convulsive effect and slower narcosis. Xylcno is less poisonous than toluene. The recovery from toluene poisoning, however, is less rapid than from benzene poisoning. Agasse-L&font and Heim (8) also insist that pure benzene is more toxic than crude. Hcktoen and Brown (0) found far less striking and characteristic changes in chronic toluene poisoning than in chronic benzene poisoning. (Sec later.) Just recently FugUcae (10), investigating the cause of several deaths from benzene poisoning in a raincoat factory in Milan, tested the comparative toxicity of sev eral varieties of this solvent which were used in the factory, and found that pure C*H acted most rapidly and intensely on animals, while the irnpurest and most ill-smelling sample was the least toxic. Ho found toluene less poisonous than benzene, but the vapors more irritating to ttuicoup membranes, causing watering of the eyes, sneezing, and coughing.* Effect on Animals.--Benzene has a pronounced action on the central nervous system, narcotizing, anil lowering the body tempera ture- Animal experiments reveal a groat difference in suscepti bility, not only between different species but between different indi viduals in the same species. The vapors of benzene are toxic for animals when present in the proportion of .015 g. to 0.016 g. per liter of air (Rambousek). At this dilution the animal begins to show jerking of the leg muscles after 50 Minutes. This symptom cornea on immediately at a concentration of 0.056 g. per liter of air, convulsions develop in eight minutes, unconsciousness in ten. Dogs arc more susceptible than rabbits and die after 20 minutes1 exposure to 0.042 g. per liter of air. No after-effects are noted in animals surviving the experiment, and in those that die, nothing is found but moderate hyperemia of the brain, lungs, and mesenteric vessels. Lehmann, experimenting with cats, found & decided variation of susceptibility in .individuals, but all of them showed signs of irritation of tho mucous membrane, muscular twitchinga, and a fall of body temperature. In large doses there were convulsions; Casw of industrial poisoning from toluene are rare. British factory inaorc* lor* report a death from toluene fumes in a mao who entered^ without rpae msek . - Which ht l held toluene and some entmoaiacal . INDUSTRIAL POISONS IN THE UNITED STATES 457 narcosis; very deep respiration^ first quick then slow; quickened pulse, and death from respiratory paralysis. A narcotic effect begins iu cats after two hours' exjwsure to 0.02 g. per liter of air, and narcosis is complete in six Lours. With 0.00 g. the periods arc ffftcen minutes and one hour, respectively. In man 0.015 g. per liter of air produces listlessnosa and coufusiou after half an hour, and exposure to 0.02 to 0.U3 giu. (or from 2 to 3 parts per 100,000 parts of air), for a few hours may cause loss of consciousness. Lelimaun found the symptoms iu animals very uniform in char acter, although varying in degree. First .comea^restlcsaness aud excitement, partly from-irritation, of-the nose and throat, especially with crude benzene, toluene, or xylene. Next, and fairly quickly, coma symptoms of central irritation, dizziness, staggering, unco ordinated movements, and twitebings of the lasting from half an hour to many hoars and affecting single muscles or groups of muscles or whole limbs. The movements are clonic, sometimes tonic, but there is no tetanus. This condition makes observations on respiration and heart difficult; but apparently the former U first quickened then slowed, and the heart is rapid. At the end of the experiment a decided fall in temperature is always found, aud this may be the cause of tbe twitching. The animals recover completely with no after effects, or else they die suddenly from primary respira tory or heart paralysis. Nothing typical is found at autopsy except that the blood remains fluid for a loug time. Acute Industrial Poisoning.--The earliest cases of acute poison ing were reported from Gcrmauy. At the Brussels International Congress of Industrial Hygiene in 1910, Rambousek summarized the histories of 22 cases* which be bad gathered from the litera ture of that time. All these were acute cases and occurred in the following ways. Case 1 was distilling benzene, and forgot to turn on tlje cool water to condense the vapor. Case 2 was found dead before the building tho next morning after he had let 900 liters of bcDzenc overflow from a vat Cases 3, 4, and 5 were poisoned in a benzene vat in a rubber factory; the two latter entered it to rescue the first Cases 6 and 7 were exposod to benzene gas in a coke by-products plant Cases 8, 9, and 10 were exposed to a mixture of benzene, hydrogen suiphid, and cyanogen compounds. Cose 11 was cleaning apparatus in a benzene plant. Cases 12, 13, and 14 were reported by Lewin in 1907. They occurred in connection with work in a benzene extraction kettle. The next five were clean ing vats for the transport of benzene. Case 20 occurred in a rubber factory. Of the last two, one was making antipyrin, the other was painting an iron tank with asphalt dissolved in benzene. Eighteen of these cases were fatal. I have S&nic*on'i rice cases, which were chronic. 1, I 453 INDUSTRIAL POISONS IN THE UNITED STATES The literature of other European countries and of the United States have added many cases to this list during the thirteen years tl).it have elapsed since then. These-are typical histories selected from the mass of available material. Lewin, iu 1007, reported a case of fatal poisoning in a work man who had tried to rescue a man overcome with benzene fumes. A benzene kettle had stood ompty for 22 Lours, when it was washed out three times with cold water and twice with steam, and was allowed to stand all night filled with cold water. The man who was sent in to make repairs took with him & pipe through which was blowing a strong current of compressed air. Nevertheless, he fainted and fell to the bottom of the kettle. Several men tried to get him out, but all grew dizzy and confused and had to give up, until an engineer, with a diver's helmet succeeded in dragging him out. He was revived, but one of the men who tried to rescue him died ten minutes after climbing out of the kettle. The German factory inspection report for 1913 contains an ac count of a similar case. Here, also, the tank was supposedly thor oughly cleaned; for it was boiled out three times, but the workman who went in lost consciousness; and although the two men who had been Bet to watch him dragged him out promptly he never revived. Bciscle'a (11) esse was that of a man who died after only four minutes* exposure from dipping benzene out of a bowl. The earliest instances of acute benzene poisoning in.American industry were reported from establishments producing, and. using benzene for the manufacture of anilin and of explosives. By 1916, fourteen acute cases had been reported, seven of them fataL The first two were in ateamfitters employed in repairing pipes inside a. benzene still where the manhole through which they entered was just large enough to allow them to crawl through. As usual, the still had been not only emptied but washed out, and it was sup posed to be free from dangerous quantities) of benzene; but soon after the men went in one of them became excited and irrational, singing and shouting. It was realized that he must he got out as quickly as possible; but this was a difficult thing to do through a narrow manhole, especially since be was irrational enough to resist. It took about ten minutes to get him out, and during much of that time the manhole was completely closed by his body. The second workman, who had been helping to lift him out, was then found to bo lying unconscious on the floor of the stilL Even more difficulty was encountered in removing him, for he was quite helpless, and when ho was at last brought into the open air, which was after about twenty minutes, ho was found to be dead. . Tlio third and fourth cases had almost the same history. Tby, were-in men who were working insid'--^aiill which was sup ' nosed lo lv> frftft from benzene Tbev Iwron r enffor* -fr*\*n INDUSTRIAL POISONS IN THE UNITED STATES 4f>9 were dragged out in a state of coma, given vigorous treatment by the administration of oxygen and stimulants, but one died, and curiously enough he was the one who had had the shorter exposure. Two other fatal cases were caused by repair work in a benzene still. The fifth death was cause hy a leak from a still, and the sixth and seventh were in men working in the sulphonating department of a phenol plant where benzene was sulphonatcd and where fumes es caped from the supply pump, the sulphonating kettle, and the liming vat In many oases it has trccu imjiossiblc to say whether or not death was instantaneous because the victim was not found till some time after. Smy-Bicnz's (12) patient died in a very few minutes, as did Bcinhauer's (13); but Hcifter's (14) lived several hours. He was an assistant manager, and, accompanied by two helpers, he went into a cellar to open a benzene pipe which was stopped up. He started the flow, but could not stop it, and benzene 6pi ashed over his clothes. The helpers complained of feeling sick and he went upstairs with them, got two other men and went hack to the cellar for half an hour. 'When be came up he fell in a faint at the top of the stairs, and although oxygen was administered for three hours he never revived. I have the history of a case of acute benzene poisoning from a Pennsylvania plienol plant in which oxygen was given for more than two hours without saving the man. It. is noteworthy that exertion increases the severity of the poisoning,'or at least that seems, the pjjlj^^y4o^c:xp]ainthe^nsid*rable'numbcr`of accidents in which it is the rescuer who dies while the original victim, though sometimes exposed longer, survives. Of course individual suscepti bility plays a great part. Lehmann (6) believes that this is the underlying cause of sudden death from benzene poisoning in indus try. One of the many illustrative instances in the literature is a case described by Lewin. A workman had gone into a benzene extraction kettle and had fainted. His helper climbed part way in to rescue him, felt himself growing dizzy and confused, and backed out at once, but died in ton minutes, while the first man, who lay unconscious in the tank for several minutes before he could be removed, was saved. That such an anomaly should give rise to controversy in compen sation cases is inevitable. Tn one of the great steel works of Penn sylvania, two workmen were sent into a benzene tank to change the coils after the tank had been thoroughly blown out with steam. One of them was quite unaffected by the benzene vapor, while the oilier died from its effects. The statement of the company doctor that there was something in the man's constitution which caused his tine irutho same sense in which it Is something in a man's constitution causes him to succumb to tvnhoid infection i* ' . VS 400 INDUSTRIAL POISONS IN THE UNITED STATES \f he drinks polluted water while another inau, drinking the same water, remains quite well. As a usual thing men recover completely, if they recover at all, from such accidents; but there are a'few instances of sequela re corded. Robert described the case of a man who was painting the inside of a reservoir with bitumen and crude benzene and who suffered an attack similar to alcoholic intoxication from which he recovered; but later, without further exposure, developed pleurisy and apical catarrh of the lung, and was never restored to complete health. One of Lewin's cases, with relatively slight symptoms, had persistent after-effects. This man had an acute attack of dizziness, n drunken feeling, pressure in the head, dyspnea, oppression of the heart; and when these passed over, a blowing heart murmur, yellow pallor, and general nervous exhaustion. A rather unusual history is given in the report of the British factory inspectors for 1918. The man was employed on the night shift in a benzene distillery and on a certain night the volume of vapor was greater than the condenser could deal with, some of it escaped, and he was overcome. He was revived with oxygen and the next night returned to work; but although at that time the still waa working well he was again overcome and this time he died without regaining consciousness.* Irritation of the skin, or inflammation with swelling and itching, is noted in some cases of acute benzene poisoning (Simonin (15)). A strange story, possible only in Cz&rUt Russia, was told by Dworctzky (1G) in the spring of 1914. Ifc deals with an epidemic of mysterious illness in the factory population of St. Petersburg, beginning in a large rubber works and extending to chocolate and tobacco factories. It waa the cause of widespread excitement, strikes, lockouts, riots, a heated controversy between two schools of doctors, interpellations in the Duma, and ended in the complete suppression of all discussion and inquiry by the-chief of police. * The follo'Tjotf regulation* have teen fanniilatd by the British Fsclnry Inspection Department to govern work in tanka or oilier receptacle* which Imre containcj benssetie or toluene; 1. The period of siring the tank must tnat-ak <5*ya. .2. The tank must be filled with wafer and then steam introduced till Ue water boils. The steam pipe must reach to the bottom of the tank and either by stirring or in some other wy the sludge must be mixed with valor. 3. If a tank has remained empty for some lime it must be filled with water and emptied before anyone goes into it. 4. Entering a tank and working inside must te permitted only to men wearing a helmet or mask which is connected by a rubber pipe to fresh or provided with a breaking sppsralm which will allow the man to breathe normal air or a mixture of oxygen and air. 5. Evrrv man who enters a tank must wear a safety belt with a rope attached and Hit other end of the rope must be held by a man outside 6. An oxygen flssk with face mask and proper connections must always he available. An excellent precaution )* used by the United States Steel Company in their plant at Gary, Indiana. After emptying, washing wit. and steaming out (!<e lank, they lower Into it a cage of white mice, and if the mice are overcome'diy tho /report the process of flooding andi* repeated until the little animals can he lowered into the tank witiav.ii, ihowing any effect. INDUSTRIAL POISONS IN THE UNITED STATES 4G1 The starting poiut wits die rubber glove department of a great nihlier factory where hundreds of women were employed in cementing gloves. The solvent for the cement bed recently been changed from an ill-smeUisg, colored fluid to a. colorless one with a pleasanter odor; and following this change an acute illness developed among these women, consisting of headache, dizziness, excitement, in many oases fainting or cpileptoid convulsions, and involving, in four days' time, no less than 2.31 of them. Physicians were divided be tween those who maintained that there was a toxic substance Iti the cement, and those who held that it was pure hysteria, the latter group being led by von Bcchterew. Color was lent to the hysteria theory by the enormous excitement which the discussion had aroused in the working population who believed there was a con spiracy among the employers to poison them, and by an outbreak of similar symptoms among the women in the tobacco and the cboolate factories. The real nature of the trouble could not he known; for before sny investigation could be made, the manufac turers declared a lockout until the workers would promise to be quiet, and the police forbade any inquiry into die nature of the trouble or any discussion of the occurrences, maintaining that it was all the work of agitators and revolutionists.* Pathology of Acule Benzene Poisoning.--The earliest autopsy record I have found is that published by Sury-Bienz in 1883. Ho found conspicuous bright red spots on the body; the blood fluid and dark red; small hemorrhages in the pleura and intestinal mucosa; general venous congestion and reddened lining of tho air passages which contained blood and mucus. Bainbaucr (33), in 1890, de scribed the findings in the body of a man dying of acute poisoning after exposure to fumes in a benzene extraction apparatus, The blood in heart and vessels waa fluid, the veins of the abdomen en gorged, there was hemorrhage in the gastric mucosa, and bloody foatttsin the air passages. Bcinbauer says that the blood was lake red; weakly -acid, and there waa evidence of destruction of the red cells; but this is contrary to the great weight of evidence, (See Robert, on absence of blood destruction in experimental animals, also Lehmann.) There was a curious aromatic odor from the body, hut no benzene odor in the blood, and no benzene could he demon strated chemically. Heffter, in 1910, reviewed the 21 cases of acute benzene poison ing which had been reported in Germany up to that date. He says that the most characteristic change noted in animals is found also * White in Motcow in October, 1924,1 made Inquiries about tint occurrence and vri* told, that similar trouble bed developed among the 'women employed in rubber factories In Rips ind In Moscow st about the same time at in St. Peters burg. Alt these factories were using a solvent from Baku which was supposed to bo pctrAtaum naphtha. After the excitement down, a quid investigation was permitted and the fact established that the toxic substance was benzene. 4G2 INDUSTRIAL POISONS IN THE UNITED STATES in mvn. The blood remains fluid a long time, dark rod; but there is no evidence of destruction of the red corpuscles. Hemorrhages, usually punctate, arc found in lungs, pancreas, gastric and intes tinal mucous membranes. Tire abdominal organs show unusual congestion, and there is bloody mucus in the air passages. There are numerous cadaveric bright red spots, there is no odor of benzene and it cannot be detected chemically. Buckman'a (17) case was in a man using benzene as crystallizing material in the production of coal-tar drugs, antipyrin and pyram ided He was found, dead on the floor near- a leaking apparatus. There were many wine-red spots on the skin, pronounced hyperemia of the internal organs, and small hemorrhages in the pancreas. Two of the men who died of benzene poisoning in our munition industry during the war came to autopsy, and I am indebted to Dr. K. S. itartland of New Jersey for the notes of bis findings which may be condensed as follows: Case 1. Cyanosis of the mucous membranes and finger tips: cyanosis of the liver, spleen and kidneys*, dilatation of the right heart which was filled with dark fluid blood: pleural ecchymosea and small areas of acute interstitial emphysema in the lungs. Case 2. Cyanosis of mouth, of lips, and of finger tips*, small amount of frothy fluid escaping from the mouth; cyanosis of brain, heart, liver, and kidneys; petechial hemorrhages in pleura and pericardium; reddened and irritated bronchi. On section of the lungs a decided odor of benzene was given off. There was an abnor mal quantity of phenol in the urine, but no benzene. . The same statement as to the presence of phenol bodies in the urine is made by Kefftcr and by Beiselo, wbo failed to find blood ir albumin or hetnatoporphyrir.and by. Simonin who found in addition urobilin, diminished urea, and diminished chlorids. The -riienol is excreted as conjugated sulphuric oraglycuronic acid, but his change is fairly slow and does not occur in rapidly fatal cases (Hefftcr (14)). .. * Qhronie Benzene Poisoning.--The earliest and probably the most "nmoiis cases of chronic benzene poisoning in the literature are '^ntosson's (Id), from a velocipede tire factory in Upsala. These vere twelve young 'women, 15 to 20 years of age, employed in the ire department and recently they bad been working overtime. All f thorn developed more or less severe hemorrhages, nine of them \tiving purpuric spots on the akin, one, cpist&xis and hemorrhage rom the gums and vomiting of blood, one, uterine hemorrhage, nd another, prolonged menstruation. Four of them died after xpasuro of Uatco .weeks to four months. A typical history is that f a girl of 10 who bad wotkcd'fbr three to~fouf months* and had uffered from dizziness and excitement followed by drowsiness. .Jhe lost weight and color and left-'^Tkctory; blit instead of rc^over- /is INDUSTRIAL POISONS TN THE UNITED STATES 463 ing she grew worse, ecchyinoscs appeared on the akin, the nuiulr of red corpuscles fell to 3,704,000 with 80 per com hemoglobin, there were almost no leucocytes to bo seen; she grew gradually weaker, and died after a period of feverishness. Another girl, also 19 years old, wbo bad tuberculosis, worked for eleven to twelve weeks, ten to twelve hours a day, when alio was discharged. Throe weeks later she had profuse menstrual hemorrhage, purpuric spots appeared over the skin, she bad vomiting and dyspnea, and profound anemia. The red cell count foil to 000,000 with beraogtobiu 20 per cent just before death. This same year, 1397, Lenoir and Claude (19) reported a case of purpura hemorrhagica in a man who had been employed for several years in & dyo house where be was exposed every day to fumes of benzene. He had bleeding from nose and gums, purpuric spots on the skin, increasing cachexia, and then died suddenly. At autopsy they found bloody effusion into the pleural cavity, hemorrhages into the mucosa of stomach and intestines and under the endocardium, and myocardial infarcts. If 'S'cmaincd for-Selling(20) in_T9l0 to declare that the most characteristic feature of Tronic benzene poisoning is not the hem* on-hages or the Anemia but the profound leucopeoia, and that the lesions are essentially those of aplastic anemia with destruction of homoplastic tissues- Selling's patients, three in number, were employed in the coating room of a tin can works where a sealing mixture was used consisting of pure rubber and min, dissolved in commercial benzene. Twenty-throe persona were employed in this department, 5 men machinists, 4 girl inspectors, and. 14 girls at the coating machines. These last were between 14 and 16 years of age, and they suffered most severely. Not only were the Cana coated hero but they were also dried, and ton gallons of benzene a day evaporated in. that room. The windows were open, but it was very hot midsummer weather. Case l entered the hospital in fairly good condition, complaining only of **spols on the body and dizziness." She bid worked about four months, and a month before she came to the hospital she had noticed blue spots on arms and lege; then, shortly afterwards, she began to have bleeding from the gums, nose and throat, one nose bleed lasting two days. A few days .before admission there was a severe hemorrhage from the throat, controlled only with difficulty by local applications. For a weofc she had been in bed because of weakness and dizziness. Examination showed only extreme pallor, purpuric spots, bleeding gums, a hemic murmur over the heart. Examination of the fundi showed a number of retinal hemorrhages. For the first few days the patient was in fair condition, but on the sixth day she suddenly develcr Lrigna of profound toxemia and r~it la*' imiIm email etui qmI. TttTiffiutAn rtf blood 464 INDUSTRIAL POISONS IN THE UNITED STATES was followed by decided improvement in symptoms, but not in the blood count, and a relapse occurred two days lator from which she did not rally, dying on Juno Oth, the ninth day after admission. Her temperature ranged from 99.6 to 104.6 F., her pulse from 108 to 165. There was no evidence of hemolysis in the urine nor did jaundice appear. The blood smear showed the red cells smaller and paler than normal, but no poikilocytoais and no extremely largo or small formaThe counts were as follows: Juno SStb. on antraivv*. July let ..................... . . July 3d........................ July 4th........................... Bods i non ivin fUfinn/i Whites 1260 Eemcg'Jobln 28% (Ss'hli) 11% 8% Platelets were practically absent; blood clotting wu delayed and incomplete. A differential count showed: polymorphonuclear* 43 per coot, lymphocytes 41 per cent, large mononuclears 14 per cent, unclassified 2 per cent. Only one. myeloblast was sees, hut no normoblasts. . Case 2 was also 14 years old, bad worked fire months, and com plained of illness for only one week. Her history, physical examina tion, and the course of the disease were very similar to those of Case 1. Her blood counts fell from. 2,100,000 redfl to 1,150,000; iroin 0G0 whites to 140; and the hemoglobin fell from 37 per cent to 15 per cent. The lymphocytes constituted 7l per cent of the whiten, with 10 per cent large mononuclears and only 16 per cent polymorphonuclear*. A platelet count (Pratt's method) yielded, only 2,500 per cubic centimeter, and the blood aftejh standing 46 hours in i tube showed no expression of serum. t Case 3, a girl of 14 years, had worked for about throe months and ad Buffered for two months from anorexia, abdominal pain, vomit- ng aud headache, and one or two fainting spells. She had a much lighter purpuric eruption than, the others and her blood count was 1.900,000 reds, 4,400 whites, hemoglobin 54 per cent, platelets 104,000. Clotting of blood was incomplete, as in the other casos. Bha was discharged after six days. The autopsy of Selling's first case, made by W. O. MacCallum, hewed: hemorrhages in skin, viscera and seroue surfaces; pallor of lie organs; blood pale and watery; muscles a deep red oolor; some atty degeneration, of heart muscle, slighter in liver; bone marrow rf femur fairly consistent, of & dull ochre color, with abundance of >1ood supply. Smears from the marrow anggeBtesdraplaaia, showing :r'rOw cells" of any kind, the most numerous being aortnftl red INDUSTRIAL POISONS IN THE UNITED STATES W cells slightly paler, extremely leucocytes, chiefly of lympUu- eytic oc myclohlaatic ty|vc, with reduced chromatin. The second autopsy was made l>y WinlerniU who found much tlu: same changes except in tho bone marrow which was markedly hyper plastic, but a deeper, darker red than is usual in hyperplasia; and smears showed aplasia, although rot of quite so marked a grade as in Case. 1. Selling lays stress on three facts: the cases were in young girls, the course was essentially clvromc, although in tho end tho serious symptoms developed suddenly; and the disease progressed in spite of withdrawal from the poison. These features were also true in S&ntesson's cases and are noted in many of the subsequent reports. Following Selling's article came a number of reports of similar poisoning, several of them from the same industry and the same city as kia. Thus McClure (21) in 1916 described a case of purpura hemorrhagica in a woman 31 years old who bad been working in i Baltimore can factory. She had bleeding from the nose and mouth, and secondary anemia with black and blue spots over the body, and dyspnea- Tho red blood cel! count was 1,460,000, white cells 1,110, hemoglobin 25 per cent, polynuclcars 40 per cent, mononuclears 37 per cent, transitional* 15 per cent, no nucleated red blood cells,. w> myelocytes, and platelets almost absent. This patient was saved by tho persistent use of transfusion; aplenoctomy was also performed. After the 13th transfusion, the red cell count rose to 5,280,000; ami sonic fourteen weeks later the count was still 4,270,000. A year or so later a boy of 17 employed in the aamo sort of work was treated in tho Johns Hopkins Hospital for purpura hemorrhagica and nosebleed. His blood count was as follows: reds, 2,272,000; Hb. 59 per cent; white cells 3200, of which 46 per cent were polynuclears, 34 per cent mononuclears, platelets greatly diminished. He wqs given five transfusions in the hospital and improved slowly, the improvement being very slow in beginning. He was discharge! after two months with a red cell count of 4,030,000 * and while colls 7800, the platelets still reduced and the lymphocytosis still present. In that same year, a woman of 57, also employed in a can factory, died in the Johns Hopkins Hospital with bleeding from the nose, purple spots on the skin, bloody stools, hematuria, hemorrhage into the ear. At autopsy, erythroblastic hyperplasia was found and myeloblasUc aplasia. Tho red cells were 4,784,090 and hemoglobin 100 per cent, while the white cells were 5480. The bleeding time was twenty minutes. Hogan and Schrader's (22) three cases, with two deaths, are * In tlieec two eaaes the blood count wu Hill low, after two rtumllu and alter 316 avy'fV. It it atill a question whether the damage toJ) b>n marrow i penb&fcfnl As ia shown taler, sahna! experiment* point . I .... w- /Q. W.<*lrAl*i. I to eocdpletc 4GC INDUSTRIAL POISONS IN THE UNITED STATES also to be credited to Baltimore can manufacture. These occurred in the spring of 1922 and were reported in detail soon after. I give only the salient features of the cases,. All were employed in the same can factory and all developed within loss than four weeks time. They formed part of a force of 58 who worked in the room where the bottoms are fastened to the enna by a rubber cement thinned with benzene. It ia in the evaporation of the benzene by steam heat that the benzene vapors arc formed, and in the factory in question the removal of those vapors was `Hamentably insufficient." Case 1 was a girl of 17 years who was admitted to the University of Maryland Hospital March 14, 1923, and died five days later. She had worked only six weeks in the "dope room." About March 4 th she began to feel weak and lost her appetite, and on the 10th she had a headache and noticed bluish spots on arms and legs. By March 13th her mouth bad become very sore so that she could hardly swallow, and the next day she was dizzy and spat blood. At the hospital she was found to be pale, undernourished, weak; and purpuric spots were found, on arms and legs. She had shortness of breath, a hemic murmur over the heart, her mouth was sore, and there was bleeding from the vagina. Her blood. examination on admission was; red cells, 1,240,000, anisocytoais and poikilocytosis, hemoglobin 39 per cent, white cells 600. Transfusion of blood was practiced only once, and was followed by improvement, but on. the fifth day after it the patient suddenly grew worse and died. Case 2, a woman of 25 years, was admitted to fee Maryland General Hospital March 7th with a diagnosis of placenta .praevia and died on the 24th. An attempt was made to deliver her and a macerated fetus was obtained. No history ja given, aside from the statement aa to her employment in a can factory; but it ia evident that there was a hemorrhage from the vaginf. The blood count was as follows t March 16th............... 44 17th............... " 20U>............... Rod Celia 470,000 14 24th............... 900,000 Hemoglobin 19% 22% 12% White Cells 1400 538 434 (following transfusion) 104 peer- A differential white cell count on March 24th showed polyuuclaars 42 par cent, small mononuclears 56 pc*'large Q*pcr cent. Oann 3. a rnrl nf 1 5 v^nrn won ndrrnHdd t/\ fi# Ua.k.:!*! INDUSTRIAL POISONS IN THE UNITED STATES 467 April 9lh, with a complaint of bleeding from the vagina and weak* ness. She had worked in the can factory five weeks and after three days sho had a nosebleed. At the end of the first week, bleed ing began from mucous membranes and she lost her appetite and felt tired after work. By the end of fee socond week her pallor was commented ou by her friends. In another week, bleeding began from fee vagina, which she took to be a menstrual flow, but it per sisted till she came to the hospital, aud for several days after. She vomited twice during the first day of this supposed menstruation, was so weak that she was obliged to give up work, suffered from headache, and her stools were tinged with blood. Physical examiu* ation was unimportant except for pallor of skin and mucous mem branes, weakness, shortness of breath, and a hemic murmur over the heart Repeated blood examinations were made with these results: Date 4-12-22 4-13-22 4-14-22 4-15-22 4*16-22 W.B.C. 250 1200 1950 4700 3050 R.B.C. 880,000 930,000 1,544,000 1,985,000 2,184,000 Hemo globin 10% 17% 38% 42% 44% Small Large Lympho Mono* cytes nucleate 52% 3B% 46% 16% 40% 8% 4% % 4% fl% Polynu*. dcara 38% SS% 46% 76% 50% Transfusions were done on April 11th, 13th, and 15th. Her tem perature ranged from normal to I02-103 while in the hospital. This last case is at once the most rapidly developing instance of chronic benzene poisoning in the literature and the most remarkable instance of recovery. Hogau and Schrader's cases also illustrate the peculiar danger of benzene in youth and in pregnancy.* Ih a personal communication the following history came to me of a death from benzene poisoning in an employee of a can factory; but this time on the Pacific Coast. The victim was a woman, 41 years`old, described as "always skinny and more or less sallowoomplccted" and with a goitre about the aize of an orange. February 1st, 1922, she was put to work at the discharge of the retort where cans are heated after the ends have been coated with a rubberbenzene cement to drive oft the solvent and dry the cement. She removed the warm cans and placed them in boxes. A down-suction draft provided by a fan had been placed here, and just above It was a pipe bringing in fresh air. Nevertheless, about March 16th she began to fed ill, was listless, complained of headache, then of "One of the Industrial insurance companies haa aent me a elatenwnl concern* fv; ;**' ing a jy| case of chronic benzene poisoning **.gnel w<r?*a, 2 jeara of age, who elM worked in * can factory. 40S INDUSTRIAL POISONS IN THE UNITED STATES nausea, and kujr oi blooding from nose and gums. She would feel fairly well in the -morning, but es the day wore oa (there was an eight-hour day) she would grow drowsy and at uight she would suffer from severe headache and nausea. On .May 11th a physician.waa called and found her suffering from nosebleed, bleeding from the gums, unusually profuse menstruation, and over the legs there was a heavy rash with hero and there purpuric spots. She was taken to a hospital where examination showed hemoglobin 35 per cent, red cells 2,512;000, white cells 2,000* By May 24lh the hemoglobin had fallen to 20 per cent, rod cells to 1,000,000, and whites to 2,000. No young red rails were found. The rash had disappeared but purpuric spots appeared on the back. Transfusion of blood was practiced only twice, as her condition was considered hopeless. The exact date of her death is not given. The rubber industry has contributed cases from many lands. The Austrian factory inspectors' report for 1911 describes two deaths from an unusual illness in rubber workers characterised by purpuric spots on the body and found to be caused by fumes of benzene. In 1909 the French Ministry of Labor issued a warning to rubber manufacturers against "benzene" fumes which, in a factory using rubber cement to fasten together rubber fabric and leather, had given rise to a number of serious accidents. The symptoms in these cases are described as pains in the liver region and a tendency to b;ee<ling from the nose aud mouth. ' In 1921 in a French automobile factory the use of benzene rubber cement by six persons, in a hot unventiiated room, was the cause of four cases of purpura hemorrhagica which developed in six mouths' time, aud two of the victims died. The history of one of these, a woman, shows that she suffered atNfirat from headache and dizziness. She became strikingly pale, then purpuric spots appeared over the body followed by acute anemia, lever, and death, within two months of the beginning of her exposure. (Flandin and Robcrti (23).) The late Dr. T. F. Harrington (24) of the Massachusetts Board of Labor and Industry published in 1937, the first American eases from rubber works. There were five cases of chronic benzene poi nting, all in. men, and three of the men died. All had been using benzene cement in building auto tires, applying it by means of a cloth to the rubber. They would do this about eighteen times during sm eiglit-hour day. Case 1, 33 years old, had worked eleven months. I lo soon began to suffer from severe headache, then he spat blood from his spongy blooding gums, and spots like bruises appeared o bis legs and arms and body. He bad to give up work becau& of extreme weakness and breatW.;j;??.sas on slight exertion. After two t Irritation of the akla or **** {`~ks-------- ------------------ irV :\J INDUSTRIAL POISONS IN THE UNITED STATES 469 severe nosebleeds, lie came to the hospital with a pulse of 124; his rod cells were 2,800,000, hemoglobiu GO per rant, white cells 000. Transfusion of eight ounces of blood was followed by uncontrollable nosebleed which recurred daily. He had headache, vertigo, restless ness, delirium, and loss of power in arms and legs. Coma, convul sions, and death occurred on the eleventh day after ho entered the hospital, .,,At this time bis hemoglobin bad fallen to 35 per cent, red cells 1,616,000, white cells 850, of which 62 per cent were small mononuclears aud 14 per cent polynuclear^ The second patient had much the same history, and in addition hemorrhage from the bowels. He had worked for six to seven months. The third was more resistant, working for two years before ho was severely poi soned. His first symptom was the appearance of red spots on (he skin* At dentil his red cells had fallen to 944,000. After the factory had substituted naphtha for benzene they had no further trouble of this sort. Recently a statement was made to me by an insurance man to the effect (bat seventy eases of benzene poisoning developed in a rubber works and three of them were fatal. According to J-cgge (25), the first known esses of chronic benzene poisoning in Great Britain occurred in rubber work and came to light in January, 1918. Two men, both healthy and young, 29 and 30 years old, were employed in spread lug balloon fabric with rubber dissolved in pure ciystallizable benzene. Formerly coal-tar naphtha, i.e., a mixture of benzene, toluene, xylene, etc., had liecn used. Both men sickened after about three mouths' exposure, one dying a week after, the other in three weeks. Their clinical history was practically identical, beginning with malaise and auernia, followed by hemorrhages under the akiu and from the mucous membranes, and later from the nose, gums, and bowels. At autopsy the chief findings were submueous hemorrhages throughout the intestinal tract and hemorrhages under the endothelium of the heart. In one case the characteristic changes of aplastic anemia were found in microscopic examination of the marrow of the long bones. Esti mation of the benzene content of the air in the factory showed that it contained at various places in that room from 2.1 to 10.5 parts per 10,000 of air. Two recent eases in German rubber manufacture are, accord ing to Briickcn (26), the first`instances of chronic benzene poison ing Doted in that country. They were young women using benzene rubber cement to fasten together the two halves of rubber balls, -working in a room kept hot and draftless for fear of injury to the product. After working about two and a half years, No. 1, a woman 22 years old, began to feel ill, found it hard to climb stairs, suffered from headache and somnolence. Six mouths later, >\ftien Briicken first saw her, she winplained oi violent headache, 4 70 INDUSTRIAL POISONS IN THE UNITED STATES (cinpcrsitnrc of 101 F. and a weak, rapid pulse, 100 per minute. A diagnosis of grippe was made, but while the cough and headache subsided, fever and rapid heart action persisted, exhaustion in* creased, sod her pallor was striking, lie then elicited a history of excessive menstruation, coming' on every three weeks and lasting 8 to 10 days; and the fact that the lightest blow produced big black and blue marks on the skin; while bleeding from the gums was frequent, and occasionally blood came with the stool9. A blood examination showed Kb. 26 per cent (Sahli), very striking leucopenio-, few platelets, striking anemia, polychromaaia and anisocyto&is, imt no normoblasts. Bleeding time was very prolonged, the drops continuing to flow without any diminution for 16 minutes, when the observation was broken oft. Treatment brought about no improve ment for some time, temperature persisted at 100-101, bleeding from gums and intestines and two periods of excessive menstrual flow brought great exhaustion, the patient sleeping practically all the time. At the end of four weeks in bed improvement began, and at the end of two months more, convalescence was well established. The blood counts at the beginning and end were as follows: Hb. Fb. U ... % AprU t* ... 81% Color Index a.a WAO Ftiie- UU BleedInc tfest X*tropUI 1,615,090 1.02 1,680,909 t,d 14,140 11 ln. ts% 1 Bln. % tVU* pbo- 41% 14% Xw- Keelns- ON dan pbiit * The second case, in a woman 23 years old also employed at this work for three years, was much less severe; The symptoms were similar, malaise, frequent headache, bruised spots on slight injury, menstruation at shortened intervals. Examination showed mottling of the skin of the arm. The blood findings were: Kb. 43 per cent, slight polychromatophilia and anisocytoaia; differential count of whites, neutrophils, 47 per cent, lymphocytes 36 per cent, mononu clears 12 per cent, eosinophils 3 per cent The city of Milan, which is the center of the rubber industry in I Laly, has been the scene of serious benzene poisoning among young women employed in cementing the seams of rubber raincoats. Ac cording to Mcda (27), in one factory in the winter of 1921 throe women died from this form of industrial poisoning and the follow ing March a number of cases developed in another factory and four girls died, with "very severe anemia hemorrhagica of the aplastic type," the rest recovering after a fairly long period. Fugliese (10) says that in the latter factory the air contained one part of benzene per thousand. Meda describes the factory as being modern in con struction, operating for only one year and supposedly beyond*.criti cism so far as factory hygiene is concerned. The best commercial Ixmzcnc was used. s- INDUSTRIAL POISONS IN THE UNITED STATES 471 One hundred women, mostly young, wurc employed in one room cementing scams with a soluLiou of rubber and benzene aud wiping off the excess with pure benzene, cadi having therefore two beuzeue receptacles on her bench. Many of these women had done the work for several years and no trouble had been experienced but, either bccauso of some change in the composition of the commercial benzene, or perhaps an increase in the density of the vapors (all the Milan cases occurred in winter), poisoning developed. Mcda notes that benzene poisoning seems always to appear in sporadic, sudden epi demics, according to the literature. The victims in. these factories were probably predisposed to poiBOuing by something which lowered their resistance and such factors are chlorosis in young girls, tuber culosis aud pregnancy. Women are certainly far more susceptible than men. Of the seven severe cases in 1922, four died and three slowly recovered. The history of one of these latter is given in detail. This was a married woman 25 years old, unusually vigorous and well nourished, who had done similar work for seven years. She was, however, pregnant at this time. In February, 1922, she began to have headache, dizziness, somnolence, nausea, aud pain in the epigastrium which she attributed to a change in the cement, for she had noticed that it had a different odor. She grew very pale and thin; she had bleeding from the gums, and finally hemorrhagic spots over the body. She was now in tho eighth month of pregnancy, she left the factory, had repeated nosebleeds before delivery, and after her delivery which was normal, she had an outburst of purpuric spots and of hemorrhages, with great weakness. She then came to the hospital with a temperature of 37.6 C., pulse 120, small, soft and regular, respirations 24. Tho urine contained albumin, indican and a few granular casts and epithelial cells; the red blood cells numbered 1,700,000, whites 1,700, hemoglobin 29 (Elcischl), and there was a marked loss of platelets. The differential count of whites gave polynudears 54, mononuclears 13, lymphocytes 33; the blood coagulated slowly and without contraction of the clot. Ten days later, the red count was only 600,000 and the hemoglobin down to 15 per cent, but the whites numbered 3,000; there were no platelets and no youthful forms. The patient then developed a pyelonephritis, with a typical temperature curve, the white cell count rose to 7,300 and suppuration was abundant. Meda emphasizes this fact and thinks that the suppurative process was favored by tbo lowered resistance of the patient but that it also acted, as a stimulant to the Mood-building tissues. As the temperature fell, the patient passed into a condition of profound weakness, delirium or stupor, and the white cell count fell.+o 2,000. Injection of autoge- vaccines-cleared up the nvclitis and vounr blood <*1l* nrwvwrftd. IW A 472 INDUSTRIAL POISONS IN THE UNITED STATES Tecovory bad set in, the red cell count was 3,000,000, the white cells 5,500, with a norma] leucocytic formula, the hemoglobin was 00 per cent and there were many platelets. Meda considers that the striking facts in this history are the vulnerability to benzene which is caused by the condition of pregnancy, breaking down the resist ance of an unusually vigorous woman who had been exposed to it for seven years; the lowered resistance to infection brought about by the benzene poisoning as shown in the infection of the pelvis of the kidneys. He emphasizes the fact that the literature of chronic benzene poisoning consists of single observations on the clinical history and pathological anatomy of individual cases and that there is as yet no comprehensive study of the etiology and prevention of industrial benzene poisoning. Puglicse (10) studied these same cases in Milan. He says that serious cases of poisoning with loss of consciousness occurred in workers exposed to two or three parts of benzene in tea thousand of air. The symptoms in slight cases were headache, nausea, abdominal pains, dizziness, sensations of chilliness and formication, rapid fatigue, loss of appetite, loss of strength, and breathlessness. Lesions of the skin consist of dryness or an itching erythema or oczema, conjunctivitis, blepharitis, or even keratitis. There may be a poly neuritis, and sometimes a retrobulbar neuritis. Ia the urine he has found albumin, casts, droplets of fat, hemoglobin and conjugated sulpho bodies. The anemia may continue to increase after the woman ia removed from. work. Two cases of fatal purpura hemorrhagica caused by benzene fumes were brought before the New York State "Workman's Com pensation Commission in 1920. The men bad been employed on a machine for coating fabrikoid, which is thus described: the fabric is fed in from the front to an endless traveling apron, which carries it over heated pipes. The coating mixture runs down from a can euspendod above a 4-inch (10 cm.) hole in* front, and the whole is encased in a wooden box. The temperature inside the machine is sufficient to volatilize all the solvent. The coating mixture consisted at that time of nitrocellulose, pigment, castor oil, grain alcohol, Ixjnzeno, and ethyl acetate. Fumes escaped from the hole in front, but still more at the back, whore the hot, coated fabric left the ma chine. From evidence given at the hearing, it seems that nosebleed among the men in this department was of fairly frequent occurrence, and that the labor turnover was great. They worked on right-hour shifts, sometimes, but "not very often," sixteen hours. Both of the men who died were young and bad always been strong and vigorous up to the time of their last illness. The first one worked for about nine months before he began to have bleeding from Lho gums, and noticed small, red blotches on the skis botween the ankles and the knees. Tliree^ecks later, March 21, be bad a INDUSTRIAL POISONS IN THE UNITED STATES 473 severe nosebleed. He was taken to the hospital, March 24, and died April 7, after repeated nosebleeds, bleeding from the month, temperaturn over 101 F. and the appearance of purpuric spots all over the legs up to the waist The second man worked for less than six months, sickened February 17, and died March 9. He had been feeling ill, complaining of the poor ventilation in the shop and of loss of appetite, and was very pale. Then, on the night shift of February 17, be had wbat one fellow workman called a chill and another a convulsion, his nose began to bleed, and the blood oozed from bis gums. Evidence given by bis physician was that from then up to his death, he had continual bleeding from tbe nose and month, bruise like blotches appeared on tbe legs and body, and the temperature ranged from 102 F. to over 104. In neither case was any blood examination made, and tbe medical details are very scanty. Tbe company bad made teats of the air around the coating ma chines; for it waa anxious to prevent the escape of the solvent, which it was desirable to recover for use again. Something less than 5 per cent was reported to be the highest concentration of benzene found in tbe air, and it is evident that the officials considered this amount too little to cause any anxiety. A personal communica tion from Canada informed me of a death from benzene poisoning which occurred in s fabrikoid factory, in a man of 50 years. Newton (28) of Akron, Ohio, and Starr (29) of Columbus, Ohio, have given voy valuable data concerning the early stages of slow benzene poisoning. Newton examined three chemists who bad been exposed to benzene vapors for about two weeks. Only one complained of ill health, headache, lassitude, anorexia and loss of weight, and then of a sudden attack of pain in the abdomen, nausea and vomiting. Newton found the pulse and temperature normal; but there was a marked leukopenia, 1200 whites, with 39 per cent of them large mononuclears. The erythrocyte count was 5,760,000, but tbe hemo globin, only 80 per cent. He then examined tbe blood of the other two and found while counts of 1250 and 1700, and a low red count, from 3.G to 4 million. Appropriate treatment resulted in a decides! increase in the while cell count, which shows the value of periodic examinations of the blood in workers exposed to benzene. In this connection it may be noted that Selling (20) examined the other employees in the room from which his cases had cornc, 5 men and 15 girls, and found purpuric spots on the skin in four, two men and two girls, none of .whom complained of illness. Their blood showed a slight grade of anemia and a leucocyte count varying from 3,900 to 5,200 which was somewhat lower than the average (5,200 to 6,000) for those working iu other parts of the factory. An investigation made by the late E. B. Starr (29) of the Ohio -tyrfjr* - State Department of Health brought to'"chl a new source of benzene nnicAnSnir Jn itwlucfr.. fl.A f m INDUSTRIAL POISONS IN THE UNITED SPATES linery establishments. Starr bad an unusual opportunity to study tlto early symptoms of benzene poisoning among some 31 girls who were employed in spreading cement on cloth and pasting it on buckram hat crowns. Up to eight years ago such pieces were always sewed together, then cement waa introduced, but it was only in the fall of 1921 that any trouble from its use was observed, and' then it was found that a change bad been made in August in the com position of the cement. Analysis carried out by the Uepanmnet of Health showed the following constituents in the solvent, the pet centages being given by volume: Carbon tetrachlorid ........... Benzene ................................... Carton dieuipbid ..................... Sample A 70percent 80 " 0 41 w Sample B .66 percent 34 0.05M 0 Twenty-seven of the women employed handled cement, and of these twenty-two bad definite symptoms, and in addition, two out of the four who worked near by were somewhat affected by the fumes. The symptoms consisted in soreness and burning in the throat,' sometimes in the eyes; burning in the epigastrium; nausea; -vomit ing; frequent urination; giddiness; slight air hunger; and a feeling of weakness. It is noteworthy that the symptoms usually increased during tie evening after leaving the factory. An itching inflamma tion over the forearms was sometimes present Starr was not able, to elicit any history of disturbance of menstruation and only one woman bad purpuric spots, which disappeared after a month's time. Pulse and heart action seemed normal. A conspicuous symptom was burning in the epigastrium with tenderness on pressure. One of the women in this group had recently died and benzene poisoning was suspected but investigation showed that death was. due to a perforating gastric ulcer. Starr, howeve^, calls attention to some experiments of `Weiskotteu and his colleagues who found in three animals exposed to benzene vapors, hemorrhages into the gastric imicosa and in ono of them small ulcers. (Sec also Chasscvcnt and Gamier (5), page 478.) A review of all these instances of chronic benzene poisoning in industry fails to throw much light on tho danger limits of benzene vapor io the air of a working room. The men in tho American fabrikoid factory died after several months' esposuro to air con taining, according, to the company chemist, something under 50 pans per 1,000. Puglieso found.only one part per 1,000 in an Italian factory where fatal cases had occurred, and symptoms of poisoning appeared in an atmosphere of 0.2 to 0.3 parte per 1,000. Ix^ggo tells us that as little aa 0.2 to 1.0 part per 1,000 was present in the English WHooivA-. ,;ory where two men contracted fata] ben INt TSTRIAL POISONS IN THE UNITED STATES 4T5 zene poisoning. There is need of a great deal of close observation with analysis of air and probably periodical, examinations of the blood of the men and women employed, before this question is definitely settled. There are certain very puzzling features about benzene poisoning in industry. Some factories use large quantities apparently without any damage, others have deplorable results from much slighter quantities. For instance, I know of one factory employing from 60 to 80 men in on atmosphere heavy with benzene fumes. These men spread a benzene dope over wide surfaces, leasing over the table as they work and using the dope lavishly. They then stand the painted material at one end of the room to dry, and the temperature is kept high to hasten, drying. The men have been for two years under the observation of an unusually alert and scientifically trained physician, yet he has never been, able to detect one case of poisoning. In all the epidemics of benzene purpura in the literature there bavo been some puzzling features. Individual susceptibility of course varies greatly. Lehmann, Weiskotten, Drinker and Hurwitz, and others and that animals show very different degrees of sensitiveness to benzene, from a slight leucopenia to complete disappearance of white cells. Yet this is not enough to explain a sudden outbreak of poisoning in certain individuals of a group which has boon exposed a long time to the fumes, without any increase of exposure. It may be that closer study of such occurrences may reveal decided altera tions in the composition of commercial benzenes, variations unsus pected by the purchaser. The women in Dworelslcy's Russian fac tory had noticed such a change, as bad also those in the Ohio factory investigated by Starr, and the Italian women in Meda'a raincoat works. Benzene has an effect on the skin which probably is traceable to its solvent action on the natural fats of the akin. Painters often suffer from it and, in a recent, report from Germany, the men engaged in painting agricultural machinery suffered from a painful itching and burning rash which was traced to the benzene used ae a sub stitute for turpentine and linseed oil. The most widespread trouble of this sort that I have seen was in a factory making leather uphol stery and automobile tops by coating leather with a solution of nitro cellulose in benzene, amyl acetate, and butyl acetate, Of the 60 men employed, not one had escaped. Some suffered from severe furunculosis, others from redness and tiny blebs which sometimes became infected, forming small ulcers. Anointing with an animal fat before and after work seemed to be the best preventive. Pathology of Chronic Benzene Poisoning.---Selling's cases and the animal experiments performed by him in confirmation of hia findings led to a long scries of experimental studies on the action of benzene, partly because of Jibfanyis1 suggestion that its bematoxic 476 INDUSTRIAL POISONS IN THE UNITED STATES action might bo utilised in tbo treatment of leukemia, partly be cause the direct action of benzene on the blood-forming tissues makes it a useful agent for the student of blood pathology and of immunology. - Selling's'ahim'al'`erpetimbhis*b'ad shown that benzene is a power ful leuootorin, destroying the white cells of the circulating blood and the parenchymal cells of the blood-forming organs--bone-marrow, spleen, lymphatic glands, and the lymph follicles in the appendix-- the myeloid tissue suffering more damage than the lymphadenoid ond the polynuclear cells more than the lymphocytes. The erythro blastic tissue of the bone-marrow is destroyed, but the circulating erythrocytes are injured relatively little. The pathology of benzene poisoning is essentially an aplastic anemia. No nucleated reds or abnormal reds are found, platelets are absent or scanty, and. there is polymorphonuclear leucopenia. Selling found that while benzene destroys the specific cells of the bone-marrow, causing extreme aplasia, there is at the same time an irritant action, and, for a while, tbo two actions go on simultaneously. Jf the injections are stopped at a point when the blood-forming organa are almost, wholly Aplastic, regenerative changes begin within a few days and are complete in ten days to throe weeks, the blood picture also approaching the normal. Some of. the work of Weiskotten (30) and his colleagues has a decided bearing on industrial benzene poisoning, although it was done in connection with the therapeutic use of benzone. His first experiments were carried on with subcutaneous injections of ben zene in olive oil. A fall in the leucocyte curve occurred and at this stage the rabbit might die; but if it survived, there was a rise of leucocytes to the normal level, then a secondary fall almost always ns tow as the first, sometimes lower; and this was followed by a secondary rise if the animal did not die, byt the mortality was as great during the secondary fall as during the primary. A single dose of benzene brought about this series iff reactions. A return to normal would occur even after a high degree of leucopenia. This had been noted also by Selling who reduced .the leucocytes in rabbits almost to the vanishing point, yet saw them return to normal count. Weiskotton (31) has also found that the results of exposure of rab bits to benzene vapor arc of the same general nature as those pro duced by subcutaneous injection of olive oil-benzene mixture. Maxi mal subletlial dosage causes leucopenia, hemorrhages, and slight anemia. After discontinuance of the exposure, the total leucocyte curve rises to a permanent general level, lower than that existing before exposure. This relative leucopenia is permanent. The per centage and absolute decrease of the small mononuclears is greater than that of the polynucleare, not rise to its former'lev#. and . the small mononuclear curve does ratti'- INDUSTRIAL POISONS IN THE UNITED STATES 477 Experiments with guinea-pigs made by Fontana (32) showed that a daily injection of 1 c.c. per kilogram for four to ten days resulted in death with almost complete disappearance of the leucocytes, reduc tion of hemoglobin to about one-tenth, and a fall in the red coll count to about 3,000,000. He found that the lymphocytes survived long est except in the most rapidly developing cases when this inversion of the leucocytic formula did not occur. The irritant action of benzene noted by Selling, probably accounts for the findings of several investigators who used very small quan tities of benzene. Thus Langlois and Dcsbouis (33) experimenting with small quantities of benzene administered in vapor form pro voked a leuoocytoais in guinea-pigs and pigeons, less marked in rabbits and dogs, lacking in cats. There was also a slighter increase of the red cells. This result was doc to stimulation of blood forma tion, not to loss of plasma, and the effect lasted only two days after discontinuance of the exposure. In some cases they observed a slight diminution in the white cells, which they considered accidental. Eosmopbilia, as the only pathological change in the blood, was noted in benzene workers fay Agassc-Lafont and Heim (3). They examined workmen who had been exposed to commercial benzene from a few months to six years and found no change in the Wood except eosinophilia which was present in 80 per cent and appeared \n the early months of exposure, disappoaring soon after exposure ceased and hearing no relation to the intensity of the clinical symptoms. The same thing was found by Simonin (15) in a case of acute intoxication with fever, eruption, and bronchial catarrh. There was an enormous eosinophilia, of 25 per cent, on the fifth day, dropping to 2.5 on the thirteenth. The hemorrhagic features of benzene poisoning were studied by Duke (34) who brought about a rapid rise is tie platelet count by injection of bonzene in rabbits, followed by a rapid fall. When threq dosea only were given, the riae was gradual and did not fall subsequently below normal; hut in animals' receiving five doses the fall was marked, and purpura hemorrhagica and severe anemia, with aplasia of the bone-morrow developed. Fontana (32) noted a marked fall in platelets in About half of his animals (guinea-pigs). Hurwitz and Drinker (35), following up the work of Selling and of Duke, produced aplasia of the bone-marrow in rabbits by injecting 2 c.c. of pure benzene per kilo daily. Not only were all (he formed elements of the blond markedly reduced, but also the factors of blood coagulation, the circulating prothrombin being con siderably less than normal. The fact- that Selling's experiments show a selective action of benzene on the tissues and colls that arc concerned in the produc tion of antilmdics and in defense against infection, led Hcktoen(ft) to investigate its influence on the course of infection in animals. 478 INDUSTRIAL POISONS IN THE UNITED STATES Ho found in rabbi La a depression of antibody formation, a reduc tion of precipitin and lyaia, together with grave lesions in the marrow, Icucopcnis, and reduction in the phagocytic power of tho leucocytes. He concludes that ``benzene may lower the resistance to infection by reduction (1) of antibody production, (2) of the number of leucocytes, and (3) of leucocytic activity." Two years before, Rusk (36) had found that rabbits, when poisoned with ben zene, produced hemolysins and preeipiiins much less efficiently than normal animals. Weiskottcn (37) made some observations in the course of one of his series of experiments, which go to confirm the findings of Rusk and of Hektoen. During daily subcutaneous injections of olive oil-benzene mixture, in four rabbits, he noticed the development of active acute infection and in at least two of these it seemed that infections present- before the injections began were "lighted up" as a result of the injections. In these animals a polymorphonuclear leucopenia did not appear, in fact there was the usual leucocytoeis of acute infection and the animals died at the height of their leucocytosis. Weiskotten concludes that the leucocyte count cannot bo safely depended upon in connection with the administration of benzene. As for organic changes, Cbassevent and Gamier (5) found in the guinea-pig congestion of the peritoneum and of the abdominal organs, ecchymosea or ulcerations in tbe gastric mucosa, at the niveau along the artery. Klemperer and Hirschfeld (36) found more or less severe marrow destruction and severe and extensive necrosis of liver and kidneys. Selling found fatty changes in liver and kidneys, and hemorrhage into lungs, pleura, sad stomach. Neumann (39) found in rabbits dying within 21 to 33 days after repeated injec tions of benzene-olive oil, hyperemia and pigmentation of the liver; spleen very hyperemic, aplastic, rich in pigment; marked hypoplasia of the bone-marrow which was also hyperemia and rich in pigment. Like all observers ho found a marked vacation in the lesions in different animals. Fontana noted diminished volume of the spleen in nil animals dying of chronic benzene poisoning. . Two more suggestive observations on benzene deserve mention. Schiff (40), working in Heffteris laboratory in Berlin on the nature of anaphylactic shock, found that small doses of benzene which caused only a slight leucocytosis would increase sensitivity to an aphylaxis toward sheep scrum, while large doses, causing leucopenta, would lower sensitivity. Jaffe (41) isolated an N-froo acid from the urine of dogs and rabbits after feeding them a long time with licnzcnc, which he identifies with the "Muconsaure" of Rnpe and which has the formula CaH0,. The amount found is small, repyo- eenting only a fraction of the benzene administered, as for instance 0.2 mg. in after 60 gm. of benzene bed been adraiLlOhsied. INDUSTRIAL POISONS IN THE UNITED STATES 470 The erriuo has the characteristics of carbolic acid urine,--dark, almost black in color. The changes caused by toluene axe far less marked and character istic than those of benzene. Hektoen (9) found that the effect of toluene in repeated doses of about 1 e.c. per kilo lessens antibody output in the earlier stages of antibody production, but under certain conditions causes prolonged persistence of antibody in the blood. The feffect produced by benzene on the white blood cells is absent in toluene poisoning, and there is no immediate change as to number, proportion, or phagocytic activity of these cells. Mary W. Brown, in Hektoon's laboratory, found that repeated injections of toluene in rabbits cause a hyperplasia of the myoloid cells of the bone-marrow and a phagocytosis of leucocytes by the giant cells, without a coinci dent increase in the cells of the circulating blood or changes in liver, spleen or appendix. To summarize briefly: the effect of chronic benzene poisoning is to cause a loss of red Hood corpuscles, resulting in profound anemia; a loss of tho elements and substances in the blood which are concerned in blood clotting, resulting in hemorrhage; and a loss of white blood oelH and of the substances in the blood serum which are concerned in defending the body against bacterial infection. A very valuable report has .recently been returned by a special committee of the National Safely Council which was appointed in 1923 to study benzene (benzol) poisoning in industry. Their first report has already been mentioned in this chapter, and the manu script of the 1924 report is now at hand, covering the work done in 1924 with the cooperation of the Hood Rubber Company and the Massachusetts State Department of Labor and Industry. The Committee has collected records of 96 cases of benzene poisoning. 15 of them fatal. Of these, six were of acute poisoning with four deaths, 92 were of chronic poisoning with 11 deaths. In addition two firms reported "several cases of illness.'* The Committee studied the methods of use of benzeue in industry, of fume removal, and of the actual concentration in the air of tho plant and the effect of benzene vapor on the workers as determined by symptoms and physical findings, particularly the findings in the blood. For estimation of the benzene content of the sir they util ized Activated charcoal prepared according to the standard procedure recommended by the U. & Bureau of Mines, a method which is claimed to be the most accurate one in use for field work, yielding amounts about 8 to 10 per cent lower than the existing condition. The benzene-using industries studied fall into two classes. In the first large amounts are used hut in & closed apparatus so that except through an accident to the piping system there is no escape of fumes. In this group chronic poisoning will probably not occur, but th&rtfls' 480 INDUSTRIAL POISONS IN THE UNITED STATES always danger of acuta poisoning which may take place with little warning. Such industries are the production of beozone and motor fuels by distillation of ooal and coal tar, and the chemical .indus tries such as oil extraction, dye and dye intermediates, making paints, varnishes and stains and varnish and paint removers. The second group is much more important, for benzene is used as a solvent or vehicle and as a part of the process the benzene must be removed by evaporation, sometimes hastened by heat. In this class come: the rubber industry, making artificial leather, making sanitary cans, dry cleaning, and the use of paints, varnish and stains and paint and varnish removers. Seventy-eight plants were inspected by field investigators, and in 14 conditions were found satisfactory for an intensive investigation as outlined above. Five were rubber works, three making artificial leather, two making sanitary cans, and one each making paint and varnish remover, insulating electric wires, recovering benzene, and dry cleaning. Twenty-three clinical cases of benzene poisoning bad already been recognized in these plants. _ Eighty-four workers were examined for signs of early benzene poisoning, the blood count being accepted aa the moet important early diagnostic sign. They took as a standard a count of 7,500 white cells and a loss of 25 per cent as probably suggestive of poison ing. On this basis 13 suspicious cases were revealed, 12 with a low white count and one whose white count was only slightly low ered but the hemoglobin was far below normal. The tabulation of these cases show hemoglobin running from 23 per cent to $5 per cent, no less than four being as low as 30 per cent; red blood colls, from 800,000 to 5,424,000; white counts from 1,450 to 6,140. Of the latter, one was between 2,000, and 3,000, five between 3,000 and 4,000, four between 4,000 and 5,000, two between 5,000 and 6,000, and one between 6,000 and 6,500. The Loss was most marked in the polynucleara. "It eeems to us somewhat significant tha* out of 84 men employed in processes involving more or less continuous exposure to benzene fumes, 13, or about 15 per cent, should have shown & blood pictnro strongly suggestive of benzene poisoning. This would appear to con firm the conclusion of our previous report that the benzene hazard in industry is a real, but not a sensational, one. In one dry cleaning plant, however, two out of the three men examined showed this con dition, and in an electric insulating plant four out of nine were thus affected." The physical findings and symptoms were very slight, as in Newton's cases, showing that marked changes in the blood cells may occur before subjective symptoms begin to appear. Only four out of nino suffered from dizziness, yet that was the most frequent complaint one had nosebleed, and six showed pallor. Headache and '-`ioss of appetite were complained of m. two cases. . m r INDUSTRIAL POISONS IN THE UNITED STATES 481 The committee found a distinct relation between exposure to ben zone fumes and symptoms of early poisoning. Determination o) the amount of benzene gave values ranging from 28 to 4,140 part per million. The variations which occur from time to time ir the same plant, especially in summer with the windows open, an very great, but as a general thing where an efficient system of loca exhaust ventilation was at work less than 200 parts of benzene vapoi per million of air was found, and no abnormal blood counts were observed in workrooms provided with efficient local exhaust ventila tion.* BtBUOCOAPHT (1) Hehde*80x, Yahdell, Haggard, H. W., Teague, 1L O., Paixce, A. L., and Wukoeiujch, K. H. "Physiological Effects of Automobile Exhaust Gas.* J. Ini Hyp., 1821-22, 3.131. (2) Robert. Lekrbtich der Intomkationen, 134. (3) Staeheum. Froe. Fop, hf. and Chir. 8o0., London, 1904, 73-78: also Chenw Neies, 1904, 89, 74. (4) Lbwim, L. Jfunchen, med, TPchnschr., 1900, 48, 2377. (5) Ciussetekt and Garmies. "Benzene et ses drirs," Arch, Internet do pharmacol1905, 14, 93. (6) Lebmanm, E. B., Weissbnbebo, t. Wojctecrowsoi, Lerio, and Gunbkr mam. Arch. f. Egg., 1912, 75,1; also Kuntt Lehrbuch der Arbeite ixnd Qevterbehygiene, Leipzig, 1939, 249. (7) RaMBOUSEK, H. 'Die gewerbliche Benzolvergiflung,'' Concordia 1910, 17, 448. (8) Agasse-Lafont, and Heim. Recherche* sar VEyg, du Travail Indust. Paris, 1912, 83. - (9) Hektoch, Ludwio. "The Effect of Benzene on the Production o Antibodies* Jour. Infeel. Du., 1915, 19, 737; also Ibid. 19, 89, (10) PuaumsE, A. Aend. let, Lombardo, 1922, 55, 404 and 443. (CAem Abstr.f April 20, 1923, 17, 516.) . (11) Bcissle, Paul. *Ein Beitrog zur Ksauistik A Benxoldampfvergif tung," UUnchen. mod, Wchmchr., 1912, 59i 2266. (12) Surt-Biemz. Vrtljtchr. f. gerichtL hfed., 1888, 49, 139. (13) Bexmhatob. Kvnhen.,rveA WcJmsehr., 1896, 43, 915. (14) Heftter, A <#Vergiftung dorch Benzol* Devtseh. tned. Wehnsehr 1915, 41, 182. (15) Simomim. "Intoxication par ingestion accideoteJle de benzene," Full et tnem. Boo. med. d. hop. de Paris, Peb. 20,1903, 20,199. (16) Dwohetzkt, A. "Ilithselhafio MaesenvergiRung in ruasicltei Fabrlken," Ifunchen. med. IFchnseAr., 1914, 61. I, 1306. (17) BucbmaH, E. "Zur Frage der akuten Beozolvcrgi flung," Btrl. Klin WeknaeAr., 1911, 47, 936. (18) Samtesson. "Chronisdhe VeTgiftung rnit Stciukohlenthcerbeoziii.' Arch. f. Uyg., 1897, 31, 33G. (19) Lenoir and Claude. Dull. et. mem. Soc. med. d. hop. de Paris, Oct 20, 1897. The report U tigned by C.-E. A. Winilow, Chairman, L. Creeaburg, Vice J. W. 6 Undy, L. E. Weber, W. S. Paine, C. P-.Hfrf**1, Brad^h** and S. !. We:a. 482 INDUSTRIAL FOISONS IK THE UNITED STATES (20) Selltnc, L. Bcitr. z. path. An<xL u. x. alls- FaiA., 1911, SI, 576; also: John* Hopkins Sosp. Bv.lL, 1910,*221, 33. Johns Hopkins Hotp. Rep., 1910, 17, 183. (21) UcCtURz. Pernicious Anemia," J. A. M. A., Sept 9,1916. (22) Hoqax and Schrader, im, J. Pul. Health, 1923,18,279. - (23) FuuflW, O., and Robert!, X Aistr. fr. Bull, el nUm. Boc. mid, A hSp. it Paris, 1921, 45; in J. A. U. A., 1922, 76, B49. (24) Har&chqtoh, T. F, "Industrial Benzol Poisoning in Massachusetts," Boston M. und 8. Aug. 16, 1917, 203. (25) Legos, T. M. /. 7ful Hyp., 1919-20, 1, 689. (26) Brocken. Dsvisch. med. IFchnsehr., 1923, 49, 34, 1120. (27) Hrda, Qiclio. "H Benxolinmo Professional*" 12 Lavoro, 1922, 13, 264, 297, 326, and 363. (26) Newtoh, C. R. "Industrial Blood Poisoning," J. A. 21, A^ 1920, 74,1149. (29) Starr, E. B. "Poisoning by Benzol-Carbon Tetrachloride-Cement with Special Reference to the Early Symptoms of Benzol Poison ing" J. Ind. Hyp., 1922, 5, 203. (30) Wzisxotteh, Sob-warts, and Stxkmslakd. "The Action of Benzol," J. M. 1916-17, 35, 63. (31) Weiskottzh, H. G., .Grass, C. B. F., Boggs, E. O., and Tekpletoh, E. R. "Benzol Vapor XeucopeniaJ. 21* Res., Kay, 1920, 41, 4, 425-488. . (82) Poxtaha, G. Otomole dt dm. Bed., 1921, No. 3. Abstr. in '72 taooro,' 1921, 11, 329; No. 3. (83) Laholois and Desbotjis. "Dea effete dea vapours hydrocarbontee sur le sang," J, is FAprioJ. sxpir., 1907, 9, 268. (34) DokZ, W. VI. "Causes in Variation of Platelet Count," Arch. Ini. Bed., 1913, 11, 100. (35) IIuRvmz, S. H., and Drinker, C.-K. "The Factors of Coagulation in the Experimental Aplastic Anemia of Benxol Poisoning" j. 21. Res., 1915, 21, 421. . (3$) Rusk. "The Eect of Benxol Intoxication and Consequent Leuco- penia on tlie Formation of Artificial Hemalysina and Precipitins," 17, of Calif. Pull. Pail., 1914, 2, 139. (37) Weiskottem, H. G. J. AT. Res., 1917, 37, 215. (38) Klbupereb and Hirscbtelo. Therap. d. (\eptnw., 1913, 57. (36) Neuuakn, W. "Experim. sur Wirkung der Benzol," DmUch. med. Wcknschr1915, 41, 394. J (40) Scarrr, P. "Einfiure dea Bentola auf die A&apbylaxie dea Heer- Bchweincbena," Ztschr. f. Immunitatsforsck. u. *per. Tierap., 1614, 23, 61. (41) JAFffc, If. "Ueber dAufhfttt. d. Benaol im Orgamemus," Zischi. /. physiol. Chsm.. 1909, 62, 6B. CHAPTER 24 BENZENE DERIVATIVES Derivatives of the Coal Tar Series The chemistry of this group is complicated and yet it is impos Bible to understand the physiological effects of the different com pounds without some knowledge of their chemical structure. I have therefore arranged as simply and briefly as possible the essen tials of the organic chemistry of the coal tar aeries. Structure of the Benzene Ring and tic Principal Derivatives, Isomeric Forms, Etc.--The benzene molecule is for convenience represented by a "ring" or hexagon which, if unmodified, stands for CftH, or CH Usually the carbon and hydrogen elements in a graphic formuU arc not written out, for it is understood that all replacements foi the formation of new compounds take place at the expense of th< hydrogen atoms and that no matter how complicated a series o; sueli replacements may be, the original 6 carbon atoms of the rin; remain unaltered. To illustrate, the formula for picric acid, trim iTOphenol, is usually written thus, HO and the unoccupied angles of the hexagon are understood to bt taken by the orl0`--l hydrogen atoms, iM --rtf.*:* 4S4 INDUSTRIAL POISONS IN THE UNITED STATES . Benzene is CH. Tolueno is methyl-benzene, CcHaCHv Xylene is dimethyl benzene, OjH^CH,),. The graphic formulas are these: OH* / OH, In naphthalene, two benzene rings are joined directly together at the expense of two hydrogen atoms, which results in the formula C,H, ot Anthracene is three such rings joined together, or C14Hia. Phenantbreno has the same number of atoms as anthracene and its formula is also CuHi, but the throe rings are differently grouped. When the hydrogen of the benzene ring is displaced by HO, phenols result: CaHtHO, hydroxybeuzenc, or phenol or carbolic acid. C4H4(HO)2j dihydrosybenzene or resorcin. CaH$(HO)a, triliydroxybenzene or pyrogallic acid. C^H^CHjlIO, hydroxytoluenc or oread. The introduction of the nitro group into the ring produces nitro ^-wmpounda, such as nitrobenzene, CaH8No% and dinitrobenzene, INDUSTRIAL POISONS IN THE UNITED STATES 485 CgH^NO,),: nitrotoluenc, CaH4CHaNO,, and trinitrotoluene, C*HCHS (NO,),; nitronaphthalene, CiqHfNO,, and dinitronapbthol,'ClDHsHO (NO,),- Reduction of a nitro compound changes the NO, radical to NH, and produces amido compounds. From nitrobenzene comes amidobenzene or anilin, CaHjNH2. From nitrotoluene comes lmidotoluene or toluidin, CH0II,NH2. From nitroxylene comes amido* xylerie or xylidin, CaH,(CHa),NH,. The reduction may be partial, as when dinitrobenzene is reduced to uitraoiliu, thus: NO, NH, and this may be further hydrolyzed to uitropbenol: HO NOi and then reduced to amidopheaol: HO NH, For convenience the angles of the benzene hexagon have been numbored in the order of the figures on the face of the clock. 1 /\ 5^ n 4 When only one hydrogen atom is replaced by a new atom or radical it is of no importance which of the six is replaced, but 466 INDUSTRIAL POISONS IN THE UNITED STATES when more than one is substituted, several ao-called isomers or isomeric forms are produced, bodies wbicli have the same number of the same atoms, but are differently grouped and differ decidedly from each other in physical properties and in toxicity. For instance there are three xylenes, or dimethylbenzen.es, CH4(CH,),. CH* CHa CH, Orthoxylehe. hletaxylene. Paraxylene. There are three dihydroxybenzenes, C^H^CHO)* Ortbotoluidin, CH, ' X|NHJ is r.n oily liquid nt a temperature at which parntoluidin CH3 /\ NHa is crystalline. ^ Tbe presses commonly used; ortho, meta, and para, refer, theD, to the ditiercht-fonns which result from the dUplacemeat'of two of INDUSTRIAL POISONS IN THE UNITED STATES 487 the hydrogen atoms of the ring. When there are more than two substitutions, a much greater number of isomeric forme is possible, and these are designated by the numbers of the angles, 1-2-3, 1-2-4, 1-3-5, etc. Dinitrophenol 1-2-4 is this: HO . /\ / Vo, NO, It differs toxicologically from all the other isomers. When two or more benzene rings are joined, as in naphthalene, two mono-substitution products are formed, according as the sub stithting atom or radical is combined with jl carbon atom, which h in direct union with one of the common carbon atoms, or not These two forms, known as alpha and beta, may be illustrated a: follows: SOaH 490 INDUSTRIAL POISONS IN THE UNITED STATES pound ia Handled. A study o th sickness records in a. dye works would show that the compounds responsible for the greatest amount of industrial sickness are not necessarily the most toxic, but are those whose use requires more exposure of the workman to contact or to fumes. For instance, mononitrobenrene does not give rise to nearly so much poisoning as dinitrobonzene, yet it is a fluid, while the latter is a solid, but dinitrobenzene has to be transported much more and handled in the open and therefore it always causes much more poisoning. Following is a brief statement of what is known as to the relation of chemical constitution to physiological action in the coal-tar or aromatic series (I). The phenola axe hydroxy (HO) derivatives; carbolic acid is hydroxy-benzene; crcsol is hydroxy-toluene; naph- thpj is hydroxy-naphthalene. The entrance of this hydroxy nucleus renders the two napbthols, alpha and beta, more irritating in their effect than is naphthalene. An increase in the number of hydros groups increases toxicity. Thus, pyrogfrilol, commonly called pyro- gallic acid, trihydroxybenzene, is more toxic than phenol, commonly called carbolic acid, which is monohydroxybenzene. The former is used in at least one plant in the United States to produce gallocys- nin, hut no case of poisoning has as yet been reported here, although such cases are known to have occurred in Germany. Theoretically, phenol or hydroxybenrene should-be more toxic than benzene, but as a matter of fact its use in industry is attended with nothing more serious Chau bums, except in very rare instances in which ah acci dent has caused an overwhelming exposure. The entraoco of the nitroao group (NO) and the nitro group (N02) increase toxicity always, whether they enter the ringer a side chain, but it is not necessarily true that an increasing number of NO, groups increases toxicity. For instance, the French experi ence during the war when they used nittbphenals for explosives, showed that picric acid, trinitropbenol. wasj not nearly so poisonous as one of the dinitrophenoW. Reduction of the NO, group to NH*, as in changing monoaitro- Ikmixoho to anilin, mononitrotolueno to*toluidin, lessens toxicity, and when these axnido compounds arc sulphonatcd they arc appar ently rendered harmless. The entrance of the sulpbonic group (SO/nO) into any benzene derivative removes its toxicity, aa is proo also in the eulphoaation of phenol. The entranco of OOOH may have the aaxno effect. Nitrobenzoic acid is hermlefis, although mtrobenzeno ia very poisonous. The acetyl group (COCH,) makes jiootanilin less poisonous than anilin, and the same is true of the introduction of an alkyl group such as methyl (CHa), for dimethyl- uni Tin less poisonous than anilin. * Chlorin an aromatic compound changes it vc^V/T-Ule, ami certainly does not increase its toxicity, for r.hInrlwi*AT>. { \ INDUSTRIAL POISONS IN THE UNITED STATES 401 to bo leas toxic than benzene: There is no rule as to the toxicity of different isomers, but usually, according to Fracnkcl (1), the pan, position is moro toxic than tho ortho. Practically, paratoluidia seems to cause more trouble than ortho, and paranitT&nilin more trouble than meta, but animal experiments made by Lewis (2) showed that for rabbits meUnitr&niHn was more toxic than para. Among the nitrochlorbenzenes, the ortho isomer seems to be the moat toxic,'next para, and last meta. Usually paraphenylendiarcun is regarded as worse than mcU, but some dye workers believe the reverse to be true. ECydroxy Compounds.--Phenol and the two napbthols, alpha and beta, are the only ones of this group which are of importance indus trially. None of them gives rise to much trouble, in spite of their decidedly dangerous nature.* They are readily and easily absorbed from any surface, including the unbroken akin, and within the body they, are partly oxidized, partly excreted in the urine in combina tion with sulphuric and glycuronic acids and also unchanged. The urine of phenol poisoning is dark or "smoky." The symptoms caused by the absorption of phenol through the skin--the only form in which industrial poisoning occurs--come cm rapidly. In severe cases there is great muscular weakness, then loss of consciousness and death from respiratory failure, sometimes preceded by muscular twitchinga or convulsions. Leas severe poisoning causes headache, dizziness, some excitement and mild delirium, pallor, clammy sweat, irregular respirations and a small pulse (3). A fatal case was reported to me by the late Dr. T. F, Harrington of the Massachusetts State Board of labor, of a young chemist who stepped into a pool of phenol waste arid soaked Iris leg in it. Soon after he began to complain of ringing in the ears, dyspnea and dizziness. Then he became dazed, excited and almost hysterical He was allowed to leave the building in this condition, but evidently he soon lost consciousness, for the next morning he was found dead on the road. The leg was then greenish black up to the knee. Two other fatal cases of industrial phenol poisoning cumc also from tlic accidental souking of the clothing with this liquid. They were reported to me by Dr. F. G. Patterson, formerly Medical Director of the Pennsylvania Department of Labor. The first wus that of a workman who was unscrewing a cap on a phenol drum when some of the contents splashed out over him. A fellow work man immediately turned a hose of runing water on him but, accord ing to his statement, the man "became limp almost at once," col lapsed, and was dead when the doctor reached him. The second * This ia became in the tbKittt oi an iccideat there is no contact with plwel on the part ot the w<*$mca. SnUebinc drop* over the akin ia a poaeible ri%!k,.., and most factories Wap auppiy oi alcohol near at hand so that the ph^aoT may l*> washed off imwediaWv.' ` *r \ I 488 INDUSTRIAL POISONS IN THE UNITED SPATES Tic compounds thus far described are all substitution products formed by replacement of the hydrogen of the ring. They differ in chemical and physical properties and in their effect on human beings from the substitution products which are formed by displace ment of hydrogen from a side chain, such as the radical CH* Thus, if the hydrogen of the ring in toluene is displaced by NHa, atnidotoluonc or toluidin, is formed, while if the replacement takes place in the CH, radical, we hare bwuylamin. A third compound, with the same elementary composition, results when the replacement is in the NHa group of amidobenzene, or anilin, and a CH, radical enters. This last is methyl anilin. These three compounds are very different in action and in properties. CH, CH, CH2NH, NHCH, Toluene. K> Hethyl anilin. This distinction is Tery important, for the ring substitutions have in general the physiological action of benzene, while many of the products formed by replacement of hydrogen in the methyl group act like the alcohols. The following are some instances of these two kinds of products: * Orthocresol. Benzyl alcohol. Chlcrtoluenc, formed by clilorin gas in toluene with heat, is CH, ( >C1 * Substitution product, of toluene ere ueutliy called idyl or toluyfr corn- pound*. Toluylendiimin ie C*HClIt<NIl,), Side-ebaie product, are called iun^.j' Jea**lddiyc is C,li*CHO. '' ** r INDUSTRIAL POISONS IN THE UNITED STATES 48! Benzyl chlorid, formed by clilorin gas in toluene with cold, i CH,CI Bodies similar to benzene substitution products may be forme< from ammonia, H4N, by substitution of one of the hydrogen atom* Anilin is C,H,NH,. Diphenylamin is NH (C,H,) These ammonia substitution products are slightly toxic if at all An instance of a body which is both a substitution and an add! tion product is nitTOSodimetbylanilin N(CH,)S /\ NO When an ami^o compound of the benzene ring is acted on b nitrous acid, HNOa, there results a series of intermediate compoun< known as diazo compounds, which contain two nuclei bound togethi by--N,--. Diazoamidobenzone is c*h>\n NHC,H5/ 1 Anilin, para- and meta-plienylcndiamin, etc., yield these dia: compounds and the latter unite with other amido compounds or wii phenols to form azo coloring matters. For instance, the dia; compound of benzidin acting on alphanaphlhylamin and sulphur acid forms Congo red. The diazo compounds are not poisonous. For industrial use the most important derivatives of benzene ar toluene are the nitro, amido, diamino, and chlor compounds; f< these ere the so-called intermediates used in the production of cot tar dyes, drugs, and perfumes, and some of them are also used : accelerators in the vulcanization of crude rubber. The danger a companying their use in industry depends not only on their clicn cal structure, their actual toxicity, but on tbeir. physical str-uctur solids being leas dangerous to handle than fluids, and those tli volatili2j^t<i.djly being, attended with much more danger,,t^an. tho which do not. Another important factor ia the way a'given coi 492 INDUSTRIAL POISONS IN THE UNITED STATES case was the result of carelessness on the part of a man wbo had charge of bloving weak phenol into a measuring tank. 'Without looking to seo -whether a former charge had been removed from the tank, he blew in another charge.'. His fellow workman saw the tank overflowing, went up to shut the water off, and got his clothes saturated with 10 per cent phenol. He seemed to be all right, but was sent to the medical department for treatment and when he reached there fell unconscious and died. - The physiological action of the naphthola is similar to that of phenol, and there is also a destructive action on the blood and an injurious effect on the kidney (3). Acute nephritis, even hemor rhagic, has followed the medicinal application of n&phthol to the skin. AlpKa^naphihol is said to -be more toxic than beta. The use of btl&naphthol in industry seems to be almost without danger, except from irritation to the skin. In plants where beta uaphthol is produced the steam is said to he irritating aa well as the dust, but in these same departments caustic soda gives more trouble than uaphthol. Nitro and Amide Compounds.---Poisoning from the nitro and amldo derivatives produces in general much the same clinical picture, differing in some details and with a few striking exceptions. According to Curschmann (4), there is an important difference Ixstwccn the nitro and amido compounds, iu that the latter are simply blood poisons and all of the symptoms produced by them may be referred to their action on the blood, while the nitro compounds have in addition a direct action on the central nervous system. That this is true, with regard to the nitro compounds, is undisputed, but Heubner (5) believes that it is true of the amido derivatives of benzene sa well as of the nitro. Heubner succeeded, in his experi ments on rabbits, in producing a narcotic effect, with collapse and paralysis, before blood changes had had time to take place, and he believes that not only nitrobenzene, bjit anilin and phenol, exert a direct action on the lower centers, those of respiration, vasomotor control, and heat regulation. In a light case of poisoning from one of these aromatic com pounds, the faco flushes, the man experiences a sense of fullness and throbbing in the head, burning in. the throat, tightness in the chest, and then a violent throbbing headache may come on with dizziness, roaring in the cars, and some disturbance of sight. Tho flushed face now become* livid, with bluish lips and tongue, and there is a sensation of weakness in the kuccs, & staggering gait. If prompt treatment ie given; that is, if tho man is removed from all contact! with the poison, which iu practice usually means having him strip off his clothes and take a full bath, the attack may last only a few hours, and the man k,..Vo'to return to work on the following day. n ... ork pJlso ftS thk tjlc bluish color of- tho lips siit/*' INDUSTRIAL POISONS IN THE UNITED STATES 4&3 tongue may persist for several days. In severer cases, the color of the face is gray-blue, the Ups and tongue are more deeply cyanosed, tho muscles tremble, the msn staggers and feels as if his koees were caving in. He is nauseated and may vomit and complains of cramps in the abdomen and of extreme weakness. Sometimes, usu ally a few hours after the onset of the attack, consciousness is lost. The respiration is shallow and quick; the pulse is small, fluttering, irregular, and enormously accelerated; the skin is cold, and the blood pressuro is usually low. If coma persists, the respiration and pulse grow slower and slower, there is involuntary defecation and urination, and convulsions usually come on just before death. It is a characteristic feature of all these poisons that the attack seldom takes place while the man is at work, but almost always while he is on his way home, or even some hours later. Many studies have been made of the blood iu poisoning from benzene derivatives, and the changes in acute intoxication seem to occur in the following order. Wetbemoglobin is formed early in the course of intoxication, and probably coincideotally with it is a destruction of red blood cells. (Curschmann (4), Lehmann.(6), Mobr(Y).) The blood count and the hemoglobin fall. Microscopic examination shows that the red cells are altered in size, shape, and staining properties. The cells are pale, and there isuome fragmen tation and polychromatophilia. Early in the attack the blood be comes chocolate colored and thicker than normal, and spectroscopic examination may reveal lines which are said to be those of methemoglobin (Mohr), or rather, lines situated between the mcthcmoglobin and the oxyhemoglobin, and therefore not quite typical (Price- Jones and Boycott (8), Brat (9).) If* however, the spectroscopic test is not made till later in the attack, it is usually impossible to detect these lines. Indeed, Curschmann says that by the time cyanosis ia fully developed methemoglobin can no longer be demonstrated. Tho evidence of the destruction of red corpuscles is succeeded in a few days, from the second to the fifth, by evidence of activo regeneration, and the blood picture then may be very much like that of pernicious anemia, with variations in staining and in size and with the appearance of stippled cells and nucleated cells. Tho changes in the white cells are not so characteristic, but during Ah acute attack there is usually a polymorphonuclear leuoocytosis. Later, as also in chronic poisoning, there is a lessened number of these cells and a relative increase of lymphocytes (Hudson (10)). In tbe slower forms of poisoning, the destruction of red colls acts as a stimulus to further cell production on tbe part of the bone marrow, and an increased red cell count may be found. Malden (11) examined the blood of 13 men employed in an English factor? 'where anilin and nitrobenzene vtt;e:made. Six of the 13 had a - ' 494 INDUSTRIAL POISONS IN THE UNITED STATES high rod cell count with a low hemoglobin, end many imperfectly developed red colls. Loss of hemoglobin ran from 5 to 50 per cent. The cells showed great variations iu size, the large pre dominating, but more noteworthy- was the appearance of stippled cells, which Malden considers quite as characteristic of the early stages of anilin poisoning as it is of lead poisoning. Malden sum2nari2.es the changes in the blood caused by small repeated doses of anilin, thus: Red cells increased in number with loss of hemoglobin; low color index; degeneration and imperfect regeneration of red cells; increase of lymphocytes, decrease of polymorphonuclear leucocytes. Very varying results are reported from the analysis of the urine in cases of acute poisoning. Hay (22) produced in himself .symp toms of intoxication with marked cyanosis, but his urine showed no abnormality. Sugar and caste are commonly absent in tbe urine, although there are occasional instances of reduction of Fehting'a solution. Albumin is usually not found, except perhaps a trace, in acute.intoxication of moderate degree, even when the urine is a dark brown color. This brown color is very common and is often tbe first warning the workman baa that he is beginning to experience tbe effects of tbe poison- A chemist who once had bad a severe attack of anilin poisoning from drawing a quantity into bis mouth while siphoning, told me that always after that if he came in contact with anilin he would notice tbia change in the color of his urine, although he might feel no subjective symptoms at all. In severe poisoning the uriue may be a dark brown or the color of port wine, or a smoky red, and in such cases metkemogtobin or unchanged hemoglobin or blood pigment, bile pigment, bematoporphyrin may be detected. Albumin can sometimes be demonstrated, but not always, even in severe cases (Mohr). Some observers insist that bile pigment is never found in tbe urine; others, that bilirubin can bo detected in the majority of cases. .Mohr found hydrobiliru bin frequently after dinitrobenaene and ealorbenzene poisoning. No thorough study has as yet been made of the reduction of Folding's solution, although the occurrence of this phenomenon is reported fairly frequently. Six such cases were described in a per sonal communication by Dr. Kessler, of Marcus Hook, in men who had been working with dinitrobenzene and anilin.* Their urine was dark brown, contained bile pigment, and had reducing properties, A seventh case was ono of fairly severe poisoning from mononitrohciuonc. Dr. Sutherland, of the Du Pont Company, who has some 1200 men under bis care, says that he finds not infrequently urines reducing Fcblir.g's in men who show signs of poisoning from nitto or amido compounds. According to von jHksdi(L3), a substance which reduces copper sulpliato and is also laavo-rotatory was found in .Sec Ir' ;':ral Poi*on!.;g in Malting Coal-Tar. Dye*'and Dye *Mwino41aieB. Hull. `ZKO, tj. S. liviTCuw ot tabor Stalurtic*. Anril 1Q91 INDUSTRIAL POISONS IN THE UNITED STATES 495 the uriue of a man suffering from nitrobenzene poisoning. This urine amdl strongly of oil of mirb&ne, and contained a trace of sugar and an iucreaae of ammonia and acetone. Neubauer (14) says that in severe anilin poisoning, anilin may be found unchanged in the urine, but this is rare. Usually it is changed by oxidation and conjugation to para-amidophenol--sul phuric ester. Nitrobenzene and the nitranilina are also excreted as para-amidophenol, while, the reduction product of dinitrophenol, winch appears in the urine after poisoning from tbia substance, is araido-2-nitro-4*pbenol. P. A. Davis (15) of Akron examined over one hundred urines of men in all stages of anilin poisoning, from the early, acute, to the persistent, chronic. He summarizes his findings as follows: specific gravity, 1005 to 1030; reaction usually acid; a large amount of uric acid being present; albumin negative except in extreme anemia; testa for anilin, anilin radicals, phenol, acetone, negative; diacetic arid positive only in severe cases. Nearly all showed traces of bematin if 24 hour specimens were evaporated. Microscopically, there were large quantities of uric arid crystals, urates and oxalates. One specimen had diacetic acid with a trace of sugar, two had in volvement of the bladder which improved on change of work and on treatment In the early years of the present century the phyaiciaus attached to the great color works at Jloochat noticed that workmen in this plant were to an unusual degree victims of tumors of the bladder, sometimes cancerous, sometimes benign. In 1904 they began to ask information from 18 other German dye works concerning the occurrence of bladder tumors and of inflammation of the bladder, cystitis; and tbo responses to these inquiries brought to light 38 cases, 18 of which were fatal. This report attracted great atten tion and was followed by others from time to time until, in 1920, the number of known instances of bladder tumor in German dyo works readied 177. At a meeting of industrial physicians in Germany in 1913 Leuonberger (10) spoke on ibis subject, pointed out the fact that it whs undoubtedly an amido, not a nitre body, which must be held respon sible for bladder tumor formation, and urged the physicians atinched to dye works to tabulate their casus and to discover which were the dangerous departments and what was the compound eliminated in the urine that acted as an irritant to the bladder. The answers to these questions arc now appearing iu the ZtnlruiblaU fur Gewerhthygitnc. Industrial poisoning from these compounds, especially from the airiido compounds, is rarely fatal. I have records of two cases of fatal poisoning frgm absorption of nitrobenzene which was apVRcd on the clothes,4aim also of two deaths from anilin poisoning, hut a 406 INDUSTRIAL POISONS IN THE UNITED STATES of the poisons in question was not understood and prompt measures for thoroughly cleansing the akin were not taken. Death is preceded by coma, increasing paralysis of the heart and respiration, consul* siooB, and usually by edema of-the lungs. Usually there are do characteristic changes in the organs, except in the case of a few compounds, sudb, for instance, as trinitrotoluene, which during the war caused & number of cases of very characteristic acute yellow atrophy of the liver. The usual findings consist of slight degenera tive changes in liver, heart, and kidneys, sometimes of pneumonia or edema of the lungs, or of hemorrhages into the lungs and stomach and intestines. The benzene derivatives may be inhaled as fumes or fine dust, but the most important mode of entrance into the body is through tho skin. Hay (12) experimented on himself, applying to the akin 0.1 gm, of dinitrobenneue in ointment. A few hours afterwards his lips turned a vivid blue, hia akin a leaden color; his pulse was 120 with high tension; and there was a sense of fullness and throb bing in his head. Ourschmann produced fatal poisoning in cats by rubbing a few grama of paranitranilm on the akin, and the same result was obtained with phenylendiamin. Observations made on an extensive scale in British munition works during the war showed that contact with such substances as trinitrotoluene and tetryl was not only the chief cause of poisoning but was responsible for all the more serious cases (17). This was confirmed by observations made in American munition plants and American dye works (38, 19, 20;. Nevertheless, fumes, especially when mixed with steam, gave nae to unmistakable absorption of TNT, and several instances have been reported to me of undoubted fume poisoning from anilin and other compounds in dye works. For instance, a case of poisoning occurred on the second story of an aniUn reduction building from the fumes which passed through the cracks in the wooden floor. The reduction apparatus was very defective and it was often neces sary to open up the reducers and to emjAy them, during which time anilin fumes would escape. In anotbor plant, a man who did not come in contact with anilin at all but worked a machine like a cream separator for separating anilin from water, was taken ill and was under treatment for eight days. The installation of a suc tion fan to draw away tho fumes made it possible for him to go back to his work with no furthor trouble. From still another plant came the bistory of a man who was sent to repair pipes in the ceiling above a reducer where monocblor&nilin was being made from nitrochlorbcnzene. Reduction was over and fumes were rising from tho open, steaming reducer. After 45 min utes the man was overcome by tho fnmes and had to bo oarried down. He was dangerously ill for several days and could not return ..work for some weeks. Cases of fume poise:... j'.also Ofcc*. among INDUSTRIAL POISONS IN THE UNITED STATES 491 men oigagcd in centrifuging (called "wringing*' or "spinning") mixed toluidins to separate die para crystals from tho oily ortho Even when tho centrifuges are out of doors very heavy fumea art given off during the process, and it seems that severe poisoning maj occur without any direct contact Although the description given above is typical of this group o: poisons they differ from one another more or less with regard b the prominence of certain symptoms, the degree of toxicity and in at least one instance (dinitiophenol 1-2-4), there is a decide divergence from the usual type. The NUto Compontids.--Mononitrobenzene and meta-dinitroben zene are very important dye intermediates, and the latter is al one of the most important of the high explosives. Mon&nUrobtn sene, known as oil of mirb&ne, is a yellow, oily fluid smelling lik oil of bitter almonds, insoluble in water, but readily soluble i> fata. It passes* easily through the skin and when spilled or splasher on the akin gives rise to rapid severe Intoxication, the blood turning chocolate-colored and the urine dark within a. few hours after evci a slight accident of this sorb If the clothing is soaked with nitre benzene, the resulting collapse may be very sudden and severe. There is the history of a fatal case of nitrobenzene mtoxicatioi in tho records of the Massachusetts General Hospital for July 1916. The patient, an elderly man employed in a soap factory was carrying a five-gallon can of oil of mirbane, some of which h seems to bavo spilled on Lis trousers. He suddenly staggered anthen collapsed, spilling more of the fluid on himself. It is eviden from the record that his imrb&ne-soaked clothing was not removed but that be was sent to the hospital ss he was, practically in poultice of nitrobenzene. When he reached there he was uncos scions, respirations were slow and irregular, his akin was of dark gray-blue color, his pupils were small, irregular, and did nc react to light The heart, however, was regular with good actiountil just before death which occurred an hour after he reache the hospital, preceded by increasing respiratory failure. Sotn blood was witlidawn from the vein of the arm before death and i was chocolate-colored. A similar ease of profound cyanosis an collapse, but not ending in death, occurred in a man who was usin a brass polishing mixture which contained nitrobenzene, and wb spilled it on his overalls and went on working till he auddenl collapsed. Dinitrobtnzzne (tncta) is s solid which volatilizes slightly room temperature. By general agreement it ia pronounced to be tb most troublesome compound that is used in coal-tar dye manufactun This docs not mean that it is Use most toxic of the intermediate: for it is not, but that the requirements of manufacture ate such the men i`;U Necessarily brought in contact with it in sticu a way as t 498 INDUSTRIAL POISONS IN THE UNITED STATES make it difficult to protect them. A chronic form of dinitrobenzene poisoning has been described by the British and the Germans, both of whom have had ample opportunity to observe it among the work ers in roburite, a mixture of dinitrobenzene and ammonium nitrate much used before the war, and in Gorman munition plants where dinitrobenzene was the chief explosive used during the war. Prosser White (21) describes a severo form of anemia in dinitrobenzenc workers, with dusky yellow akin, jaundiced sclera, an appearance of partial asphyxia, wasted muscles, dulled sensibility, partial paralysis of the hand, defective vision. Gorman articles, appearing since the war, emphasize the injurious action of dinitrobenzene on the optic nerve and on the auditory nerve. Cords (22) describes four varieties of optic nerve injury' ranging from light temporary disturbances to the moat severe progressive disorders. The cases in the third group wore moat numer ous. Ilcre was found a more or less pronounced papillitis, fol lowed by a temporal paling of the optic disk. In all these was an advanced central scotoma with loss of color sense for red and green, and frequently complete loss of color sense. There was often pro* nounced contraction of the pupils with inactivity toward light and accommodation. (See also Reis (23).) The reports of the German factory inspectors for the war years show that the principal explosive used was dinitrobenzenc and that the susceptibility to poisoning from this compound is practically universal. In Bavaria from 1915 to the end of the war there were fully 1000 cases of DNB poisoning and many of the victims had from two to tivc attacks. The proportion of cases was greater among women than among men, and the proportion for both sexes increased with the tightening of the food blockade. In 1916 the rate was 66 per cent for women, 56.7 per cent for men; ia 1918, 119 per cent for women, 100.1 per ceht for men. Apparently there were about 113 deaths from DNB poisoning. The British record fqr TNT is 96 deaths. In American dye works DNB is often the only substance that causes real alarm. There is much more exhaustion, depression of the heart, than in poisoning from anilin, and the effects of an acute attack Inst much longer, dragging on sometimes for days or weeks, while in anilin poisoning a man usually recovers in 48 hours. The anemia of DNB poisoning may be profound and persistent Severe poisoning from a Urge dose is always the result of an accident or follows some unusual piece of work, such aa tearing out bricks and rafters in an old room one used for the production, of DNB. Sixteen men engaged on this work were poisoned, several of them remaining unconscious for six or eight hours, and ono having con* vulsions at intervals for twelve hours. * It is not only in the production' of DNB,''but in its jiae as an INDUSTRIAL POISONS IN THE UNITED STATES 499 intermediate, especially for reduction to metapUeoyieodianiin and to roctanitranilia, that the danger occurs. Sometimes molten DNB is run out into open pans, and when it is caked men chop up the cake and shovel the fragments into trucks. In one plant in which this method was used, it was found that no less than 50 per cent of sll the sickness was among the DNB men, although they num bered only 24 in a force of 1500. In consequence, this method has been largely abandoned and the hot DNB is now usually .run out to meet a stream of cold water which granulates it or pellets it. How ever, shoveling and dumping the pelleted DNB and conveying it in trucks causes poisoning; for fumes are given off and it is almost impossible to avoid skin contact. A history of 27 cases of DNB poisoning in men engaged in such work showed that the duration of incapacity was from one to 12-days. The nitrotoluenes, ortho and para mononitrotoluene, are used to produce by reduction the important intermediates, ortho and para toluidin. During the war dinitxotoluene was produced at a stage in the manufacture of TNT, and in the dye industry it is used fot\ the production of toluylendismin. None of these is so toxic as the corresponding benzene derivatives: they act more slowly, and many men can handle them with seeming impunity. Their pathology and symptoms, however, are the same. The effects of trinitrotolu ene were closely studied during the war and it was found to bo a poison with slow action to which about on-third of those exposed were susceptible. Its action was chiefly on the bone marrow, caus ing a great destruction of red blood cells and a resulting hematog enous jaundice. There were 360 notified cases of toxic jaundice from TNT poisoning among the British munition workers, with 96 deaths. Much less common was an aplastic anemia of extreme type without typical degeneration of the liver. Both forma occurred also in American munition works. Trinitrotoluene is not used in dye manufacture,* hut the literature with regard to it is of great value because it enables us to picture the action of similar compounds which have not been tested on human beings so thoroughly as has TNT. The same thing is true of one of the dinitropbenols which is not in itself important since it is used only to a limited extent in dye manufacture, but, like TNT, its physiological action was tested on great numbers of human beings during the war, and it is safe to suppose that the discoveries made with regard to it may prove to apply to other nitro derivatives of benzene. Before the war dinitr(b phenol 1-2-4 was not known to differ in any way from the other I hare been toUl Uuit a peace-time uae for TNT la in making "Cordu,'1 a fuse for dynamite, and tliat "TNT oil" Ia added to aotne kind* of dynamite. Ttii* oil ia removed by wringing from the product* c^.Miefuwl ct*n of nitration o! ^ teJaene'7 *nd it 1# (lie odor of nit roUrnrmv n<$ produces aeriotu yatetnic poiwmtne. 500 INDUSTRIAL POISONS IN THE UNITED fsTATES isomeric forma of this compound, hut its manufacture on a large scale tor the favorite explosive of the French, melinite, a mixture of picric acid and DNP, revealed a very peculiar and characteristic toxic action on men. Perkins (24) says that acute intoxication comes on suddenly, with a sensation of extreme weariness in the limbs, of painful constriction at the base of the chest, a burning thirst, abundant sweat, and aa agitation and anxiety which is quite characteristic. Other very characteristic signs are a dyspnea with especially difficult inspiration, and scanty urine containing a reduc tion product of dinitrephenoL In severer cases death may take placo in a few hours, after a rise of temperature to 104 F. or over, abundant sweats, intense thirst, contraction of the pupils, and some times colic and diarrhea. Excitement and terror are followed by coma, convulsions, and death. Temperatures as high as 100.4 F. have been recorded, and in some cases there was a rise of several degrees after death. Autopsy revealed no characteristic lesions. The French experimenters found that the action of DNP 1-2-4 is highly specific, quite different from the action of the mononitrophenols, except para, which produces similar results, hut only in heavy doses and for a transient period. The same thing is true of the 1-3-4 isomer of DNP. The other isomers resemble the nitre compounds in general, causing formation of methemoglobin. The toxic action of DNP 1-2-4 consists in the production of an increased cellular combustion, oxidation, which has no relation to muscular work nor to any action on any special organ nor to a stimulation of nerve centers, for it occurs even, in cold-blooded animals. The symptoms are explained as showing an exaggeration of the heat radiation activities caused by the progressive elevation of the tem perature, which, in animals, may rise to 113 F. at death. There were four deaths during the war in the two American fac tories which manufactured melinite foT te French. Three men who were handling dry DNP died within 24 hours after the first symptoms occurred. From the meager rcjfert obtainable it seemed that these cases were like those described by the French. The fourth died after an illness lasting several days, which was apparently the typical toxic jaundice as seen in TNT workers. It is possible that in this factory the DNP handled was not the 1-2-4 isomer. Leymiuin (25), in 1002, described threo cases of sudden and severe poisoning which developed in a dye works from the dinitrophcnol used in making sulphur black. The nitrochl4>rbt.nzen&$ are used as intermediates for the produc tion of sulphur dyes, especially sulphur black. They arc volatile and very toxic, but it is their irritating action on the skin which attracts the most attention and which probably protects the jmen from severe general poisoning. Dinilrochlorbenzene, used in the manufacture of suin'1;:;- Hacks, b"s probably caused more dermatL', *\ INDUSTRIAL POISONS IN THE UNITED STATES 501 than any other compound used in coal-tar dye manufacture. Id one Brooklyn plant, every man employed was more or less affected in this way, and during the summer months the place had to close down for lack of labor. One of the men described to me the course of the disease, as follows: it begins with itching behind the knees and at the bend, of the elbow and along the inner surface of tbe thighs, then little red points appear over these areas enlarging and coalescing to form a swollen mass which itches and burns unbearably and which is relieved only by prolonged soaking in alkaline water. Sometimes the face is involved and the eyes swollen shut. Of the three isomers of nitranilin, two are important--meta and para. Kbbert (26) and Rambousek (27) both think that paranitr- anilin is more toxic than meta. Gibbs and Hare (28) confirmed thia and find, ortho more toxic than meta, but Lewis (2), experi menting on animals in H. G. Wells' laboratory, found .meta more toxic than para. Both, according to Gibhs end Hare, cause forma tion of methemoglobin and laming of the central nervous system and of the heart Poromiranxlin is the more important of the two in dye manu facture, being used not only as an intermediate for sulphur dyes and for are dyes, but also with beta* naphtbol for tbe production on the fabric of a bright red dye called para red. The most con spicuous action is on the skin, for it vauses a very distressing, burn ing, itching, eruption, but it is also capable of producing serious and even fatal systemic poisoning. Bachfeld (29) reported nine cases, four of which were serious with scanty and very painful micturi tion, but with no blood or albumin in the urine. A fatal case was reported from the German dye works at Hoecbst in a man who had been working for five hours in paranitranilin dust Another oc curred in an American color works. This was in a white man of 2? years who bad been employed for only twelve days in the paranitranilin department He is said to have been poisoned by dost which resulted from an accident in tho drying room, perhaps in tipping over a tray of the powder. The foreman sent him at once to the bath house and be took a bath and remained there for about an hour. Then he went to the works doctor, but after he had been in tbe waiting room about 20 minutes he lost consciousness and although given stimulants and artificial respiration by means of a lung motor, he died, about two and a half hours after the accident. , MetanUnuulirv is made from dinitrobenzeno by reduction, and poisoning which occurs in such a department may be due to the DNB. I have one instance, however, of a clear case of metanitran- i!in poisoning in a young workman who was sent to clean out a tub in which mctanitranilin had *wcn "processed." Soon afterwards be complained of acute fronUi headache, then be vomited, and then t. * 502 INDUSTRIAL POISONS IN THE UNITED STATES fainted away. He was taken to the hospital and the record reads "vomiting, faintiDg attacks, headache, rapid heart,, veiy profound cyanosis, with lips and mucous membranes almost black." A simi lar case is in the records of the New York Department of Labor. The man was sent to clean out a munjer in which met&nitranilin had been made. He worked of? and on from nine in the evening until midnight, when he went off for half an hour for supper, and when he came back he told the foreman that he felt faint and sick at- his stomach, but nevertheless he was told to go back to work. At half past four in the morning he was found lying on the floor unconscious and was taken to the hospital. He was deeply cyanosed, respirations were rapid and shallow, pulse was rapid and of poor quality. Eight ounces of venous blood were removed; the color was dark and coagulated slowly. The man did not regain con sciousness dll 6:30 in the evening and his convalescence was very slow.* Amido Compounds.--The symptoms set up by the amido deriva tives of the benzene ring are less serious than those caused by bodies which contain the NO or NOz group, although the cyanosis is deeper. A case of dinitrobenzene poisoning does not present as alarming an appearance as one of anilin poisoning, but the involvement of tho central nervous system, the changes in pulse, respiration, and body temperature, are much more grave; convalescence is also slower. Usually a case of anilin poisoning does not incapacitate a man for more than a day or two, although British physicians hold that he should not be allowed to return to work if hia hemoglobin is much below normal. But after dinitrobenzene poisoning, a workman ia likely to be ill for a fortnight or more. The earliest cases of aniliti poisoning in American literature are, so far S9 I can discover, two reported by Apfelbach (30) of Chicago in 1013. These men were referred to .him by factory inspectors, not because they complained of illness, out because of the lividity of tlicir color. Lips and tongue were ,1 a deep blue, but the only discomfort the men experienced was alight headache, dizziness and difficulty ir. swallowing. The first was a press feeder in a printing shop who had been using a new non-inflammable roller wash to clean the ink off press rollers and this proved to contain anilin. The other was mixing alpha-naphthylamin in an open chaser in a paint :incl color works. Both liad methemoglobin in tho blood, os shown by spectroscope. The next cases were Birge's (31) published in 1014. Two men * Various nitroeo compounds sre used as dy< intermediates and also used in ml.ter compounding. Tl.ey seem always to be irritating to the skin and "nUrq*. itcl." is a common expression in plants making intermediatea The committee Appointed by the American Chemical Society to investigate the newer*organic jurulcralors used in rubber compounding reported that para-nitrnso^iniethvl- aintiu V`R .wive of tt' 4e eczema. ( INDUSTRIAL POISONS IN THE UNITED STATES 50; were using ouilin black paint, applying it willi a brush and tboi washing the surface with hot suds, work which naturally encourage* skin absorption. They were seized with nausea and general weak ness, palpitation of the heart, than violent headache and vomiting the skin was veiy pale, the lips blue and they passed dark-colore* urine. In 1915, Hayburst in the course of a survey of the healt) hazards of Ohio industry found many cases of anilin poisoning in the large rubber centers, where it bad recently been introduce* as an accelerator of vulcanization and, after the outbreak of th< war shut off the German supply, the production of anilin also bac begun. R. V. Luce of Akron and I (32) made a study of anilir poisoning in that rubber city in 1916, and found that the conditior was fairly common, the victims bring known as "the blue boys,' from the color of lips and face. In 1217 Lintz (33) described e case which came under hia care at the Brooklyn Jewish Hospital. There was marked cyanosis, great restlessness and pulmonary edema which subsided under venesoction, projectile vomiting, involuntary micturition and expulsion of dark fluid from the Tectum. The color of the blood was very dark. The systolic pressure was down tc 100, the diastolic was 80. By the fifth day the man was discharge*] entirely recovered. Newton (34), in 1920, described four cases of anilin poisoning and one of mixed benzene and anilin, in which, added to the symp toms typical of anilin, there wa9 a benzene lctioopenia. The white count fell from 10,600 whem the poisoning began, to 1,440 some 1C hours later, and then rose to 6,640 after 72 hours. The fonr cases of aniliu poisoning were in employees of an anilin department One Was working inside an anilin-reducing apparatus, the second washed some clothes with anilin, the third and fourth poured anilin into a receptacle and breathed the fumes. The first case is the most interesting. This man, 49 yean old, climbed into a reducer on Jline 26th to dean it out by flushing with a hose. In a short timo he began to fed dizzy and nauseated and he bad a "warm, sweet taste" in his mouth. He climbed out at once and went to the hospital where he did not lose consciousness but was overcome by mental confusion and bodily weakness. Newton saw him aflcr an hour, in collapse, intensely cyanosed, complaining of chilliness, Although liis temperature was 101 P. His pulse was week, dicrotic, 110; the systolic blood pressure was 110, diastolic, 60, but after a hypodermic injection of camphorated oil it rose to 130 and 85. The blood was chocolate colored and flowed freely, the red cells numbered 3,500,000, whites 10,600, hemoglobin 95 per cent. There was strangury at first and when urine was obtained it was dark, sp. g. 1020, acid, negative for sugar, albumin and bile. On June 30th he was still ,.^,,*T*'sod aqd complaining of headache and blood count had fallen half a million; the pressure waa 115 systolic 504 INDUSTRIAL POISONS IN THE UNITED STATES uiid 00 diastolic. The cyanosis was still evident on July 7th but by the 13th it bad disappeared and he could be discharged although lie still was somewhat nervous and sleepless. This was a case of moderate severity. More serious poisoning, occurred in an Akron man engaged in experiments in connection with rubber compounding, work which involved exposure to con tact and fumes ( 32). One morning he went to work at seven feeling perfectly well in every way, but after about an hour and forty min utes he began to have throbbing in the head and increasing nausea which he attributed to tbe July weather and to the poorly ventilated room. He next noticed palpitation of the heart, and then a violent headache came on, increasing in intensity and accompanied by vertigo. As be said, "I felt as if I had been standing on my head for a long time and every ounce of blood in my body had rushed to my brain." Tbe dizziness increased, and about 45 minutes after the onset of the first symptoms he lost consciousness. He was hurried to the hospital where oxygen and heart stimulants were administered, but .apparently with little effect; for tbe cyanosis persisted, tbe heart action was very feeble for* more than 16 hours, and he did not regain consciousness till the following morning, a period of about 22 hours. A cathetemed specimen of urine ob tained on admission showed no abnormality, but a specimen 18 hours later was smoky, with specific gravity 1022, a trace of albumin, no sugar, but hemoglobin was demonstrated by the Heller test and the Scbonbcin-Alinen turpcnUoe-guaiac test. This hemoglobinuria persisted for five days. A blood examination made on entranoe gave normal finding? in all respects except for a slight cosinophilia, lmt four days later there were stipplod red cells-and some irregu larity iu the size and shape of the red cells. The hemoglobin was 75 per cent (Sahli). The patient suffered from severe headache for five days and complained of weakness^and exhaustion some two weeks longer, after which he slowly improved. "Friedlander (35) reported from the Municipal Insane Hospital in Frankfort a case of acute maniacal delirium in a man who had loosed a rubber pipe leading into an anilin receptacle and bad re ceived a splash in the face and mouth, swallowing about a mouthful. About four hours later he became delirious and was brought to the hospital in a strait jacket and deeply cyanosed. The nest day he was rational but excited, and by the third day the cyanosis had cleared up, but he was still restless aud irritable and liia heart was still weak find rapid. By the fourth day his mentality was normal. A somewhat similar history was related to me in an American dye works. The man was a pipe fitter making repairs in the ceiling over the anjlui reducers. Suddenly be became maniacal and ran gmuck over the plant, and it was six bourn before ho came to himself. Tji^-^funan .thought this was an instance of f",,~ poisoning; but INDUSTRIAL POISONS IN THE UNITED STATES 505 it seemed to me possible that the steam from the reducers carrying anilin with it had gradually soaked the ceiling and in working there the man's bauds had become saturated with anilin. Chronic anilinism was described by Hirt as characterized by disturbances of sensibility and of the motor nerves, inertia, head ache, digestive disorders, skin eruptions, and roaring in the ears. In the early days of rubber compounding with anilin just prior to the <var, workmen in Akron who were exposed to anilin were not infrequently treated by their physicians for chronic valvular heart disease with failing compensation, because the cyanosis, the altered pulse, the complaint of palpitation of the heart, breathlessness on exertion, weakness and easy fatigue, and indigestion, all seemed to point to such a diagnosis. A typical case of th& sort came to my attention in 1014. Tbe man had worked with anilin for nine months. He complained especially of muscular weakness and fatigue; palpitation of the heart came on when bo had any unusual exertion, and almost always at the end of the day's work; and he had frequent headaches while at work, sometimes severe and accompanied fay nausea and dizziness. He was never cyanosed, and while examination showed a rapid pulse, 94, there was no abnor mality of the heart. His blood examination showed the condition described by Malden (see page 494); namely, a red cell count of 5,400,000, ^ith only 68 per cent hemoglobin. Davis(15) baa seen men in the rubber industry who "seem to acquire a tolerance for anilin, in that they remain cyanotic for years without the development of any apparent serious symptoms. . . . These patients have some blood changes, of course, yet they fed no ill effects except for a slight tired feeling at the end of tho day's work. .The body attempts to maintain an equilibrium between intake and output of anilin but there is a surplus amount which is absorbed and which causes blood changes that are responsible for the marked cyanotic condition." It is generally recognized in American anilin plants that long exposure to anilin ia likely to make the men irritable, hard to get along with, '`grouchy." The foremen say that such men are not really up to a full day's work and if they try to push them it ouly makes things worse. They arc likely to have a poor appetite and complain a good deal of headache. Sometimes eczematous rashes appear, or pustular eruptions, particularly on covered parts of the akin, the scrotum, arm pits, and inguinal regions. CurscJmiaim (4) lays great stress on & slowly developing form of poisoning, not only from anilin but even more from solid aruido compounds, lie says that in such cases the carlieet sign of chronic poisoning is a loss of hemoglobin, and therefore blood examinations are of greiii^n.jpctical importance, because any workman :> bas lost from iu to 20 per cant of his faemoriohin is f R/Mih' fix'* r>u\." 50G INDUSTRIAL POISONS IN THE UNITED STATES of an aciHo attack of poisoning and should be temporarily suspended from work. At tins stag be may be slightly cy&noscd, but typical microscopic changes in th blood ore not found till & later stage. He bad a case of almost typical neurastbeuia and the only thing that pointed to anilin poisoning was the loss of hemoglobin and the riso i:i blood pressure, which last he considers a valuable diagnostic sign. The average blood pressure (Htva-lfocci) in 100 workmen not exposed to anilin, Curschmann found to be between 110 and 120, but in men intoxicated with anilin it ran from 135 to 165. In cases of pronounced anemia with cyuiosis there may be a rise of 40 in pressure, and at the same time the pulse is always alow, down to 48. In these cases the urine is brown and there is slight jaundice. In the foreign literature there are frequent references to dis turbances of vision in the course of aniiin poisoning; as, for instance, among the dyers in a Swiss factory as described by Sena (86). This consisted in a loosening of the epithelial covering of the cornea followed by inflammation, cloudiness, and consequent dimness of vision. The men were working over vats of steaming anilin black, containing free anilin, and Seen attributed the trouble to the action of oxidation products of anilin, the quinones, which cause painful smarting of the eyes so that the victim rubs them vigorously and detaches the surface cells, leaving the cornea -exposed to -further cauterization. Very few fatalities have occurred from anilin poisoning, and those chiefly in the years before 1917, when its manufacture was still largely experimental in this country. The most recent death of which I have heard took place in a small, poorly managed works iu New England. On the afternoon of August 7th, 1922, a work man was overcome by what was said to be anilin poisoning, while making phenyl 1-8 acid. In this process anilin is driven by cornpressed air from drums to an autoclave, where naphthalene and sul . phuric acid are added. The temperature is raised to 160 C. and kept there for some 24 hours, then the mixture is pumped to a still and the remnant of anilin not used in the reaction is distilled off and returned to the drum. The man who suffered from the fumes from this process recovered, but the following night the foreman in charge who was working alone iu the room, somehow spilled anilin on his trousers and was found at half past three in the morning in a semi-conscious condition, from which he never recovered. The ioluidins, ortho and para., are considered by some to be more toxic than anilin, although toluene is much less toxic than benzene. Trcitenfcld (37) found that thqy worked very much aa anilin does, with the same effect on the central nervous system, but causing rather less cyanosis Kambousek says that they act like anilin/'but produce more injury to the urinary system, mote, strangury and hc '_A-.iu thau Joes anilin, and this statement is confirmed by / '' INDUSTRIAL POISONS IN THE UNITED STATES 507 Kessler of the Anilin Products Co. Gibbs and Ihire tested the throe isomers, para, ortho, and met* toluidin, on animals and found that all destroy red blood cells, lower the body temperature, and lame the spinal cord. The fatal dose per kilogram of body weight is: for pnra, 0.1 gm.; for ineia, 0.125 gra.; and for ortho, 0.208 gm. Melfttoluidin is not used in dye manufacture, and experience in American dye works usually show's that para is more toxic than ortho, although it is crystalline, while ortho is an oily liquid. The tobridins are often said fo give more trouble than anilin, but this is not necessarily because they are mere poisonous, but rather be cause no process in /Connection with anilin, except repairing and cleaning apparatus, necessitates so much exposure to fumes and contact as docs the centrifuging or "spinning" of the two toluidina. Friedlander (35) and Stark (38) have both reported cases of severe poisoning with coma, maniacal delirium, end great prostration, following the splashing of toluidin on the Ain. In both cases there was scanty, bloody urine passed with agonizing pain. Very little is written of the action of the xylidins, but they are undoubtedly much less poisonous than anilin and toluidin. The diamins are well known poisons. Indeed, toluylcrdi&ttwn. has long been regarded aa a typical blood poison causing extensive destruc tion of red blood corpuscles, methcmoglobin, severe hematogenous jaundice with destruction of liver cells. (St&delmann (39), Dragondorff (40).) The two phetu/lendiamins, meta and para, are very important dye intermediates, and para is also used for dyeing furs under the trade name of Ursol. Formerly, before its dangerous nature was discovered, it was used as a hair dye, and sooording to Knowles (41) was responsible for not only a do- matitis but severe symptoms of nervous disturbance, sleeplessness, dizziness, weakness of the legs, and even epileptiform convulsions, coma and death.4 According to Blaschko (42) and also Olson (43), the irritating, effect of hair dyes and fur dyes contain ing parapheoylendiamin la not caused by this compound but by the presence of a mid-product, quinonc dichlordiamin, which is much more irritating to the skin. Very interesting reports have been published lately of (he occurrence of attacks of bronchial asthma In furriers using Ursol, attacks which resemble anaphylaxis. (See Olson (43).) ^ H&nzlik (44), however, rejects the theory that anaphylaxis is A report waa made by a committee appointed by the Rubber Section of the American Chemical Society to inquire into the toxicity of the organic aecelera- tore of vulcanisation (see p. 524), and the one wbieb u pronounced moot dangerous urea pare-phcaylendiamin. It was said to produce, when inhaled a duel, symptoms of a common cold with sneering and extreme depression. A large dose effwee,.death with symptoms of ptomaine poisoning. is the only refem.-- ^ each an street which I have seen jo the literature. The report of OwWOtniU#* m* h < *l- *<* '* * "" ' 508 INDUSTRIAL 1*0ISONS IN THE UNITED STATES the basis of the asthmatic symptoms which develop in consequence of exposure to phcnylcndiamin and its oxidation product, qninonedifimia. Tlic irritation is the direct result of tho inherent chemical properties of these bodies and is independent of precipitation in the tissues. Hamlik found that all the plicnylendiatnins are toxic compounds, dimthylparaphcnylendic,nU7i being the moat ao, then diethyl, then paraphenylendiamin and metapbenylendiamin is probably the least so. The diethyl and dimethyl compounds are absorbed through the akin with extraordinary ease, in fact the dose required for this mode of poisoning is no larger than for poisoning by hypodermic injection, a property due to their marked Tolatility and lipoid solubility. He estimates that about a teaspoonful of dimethyl'p-phenylcndiamin held in tho palm of the hand would be enough to kill an adult man. The vapors also may cause death. The two alkyl compounds are very irritating to the skin, the others are not or are very slightly so in animal experiments. All of them stimulate the circulation and respiration, cause fall of body temperature, tremors, increased reflex excitability, convulsions, coma, death. The hypodermic and gastric administration of para* phcnylcndiatnin produces in rabbits an edema of the face, nose, conjunctiva and neck, while meta-phcnylecdiaram causes hydro thorax, and therefore it seems probable that the asthma and other respiratory symptoms which have been observed in workers in the fnr*dye industry are due to direct irritation and bronchial stimula tion and not to anaphylaxis. Paraphenylendiamin is used as an intermediate for sulphur dyes; meta, as an intermediate for Bis marck brown, Manchester brown, and many azo dyes. It is often looked on as more dangerous than para, but .this may be because it is made by the reduction of dinitrobenzenc, and it is quite possible that this last is responsible for some of the trouble. Paraphenylen* diamin, on the oilier hand, la made by the reduction of para-amidophenol, which is comparatively non-toxic. Other compounds belonging to this group site the methyl and ethyl derivatives of anilin, which are distinctly less poisonous than anilin. In the early days of American dye manufacture, 1916, two severe cases of poisoning by dimdhylcnUin were reported to tho Hew York State Department of Labor, but aucb cases are exceptional. One of them was caused by direct contact with dimcthyl&nilin, but the other seems to have been caused by fumes. A man of 22 years bad liecn employed for two weeks on the night shift One night at half past ten ho climbed a ladder to inspect a vat of dye which was said to be crude violet made from dimcthyUnilm, phenol, and other substances. He lifted the lid, breathed the fumes, and fainted, and the doctor who was summoned thought ho Had fallen into the violet dye, he was so deeply cyano9cd. He did not recover consciousness, for eight hours, and then lie was taken*!?# hospital INDUSTRIAL POISONS IN THE UNITED STATES 509 complaining of impaired vision, rearing in the car*, and intense pain in tho abdomen. Ho was in the hospital for seven days. Anilin kydrocklorid produces exactly the same symptoms as anilin, and there may be a good deal of poisoning in the course of its production, although the work is usually carried on in au open shod to allow the fumes to cscajKj. A fatal case of anilin poisoning reported by While and Sellers (45) at the Brussels Congress of Industrial Hygiene in 3010 was in a man who splashed anilin over himself while making anilin hydrochlorid and died within 24 hours. Price-Jones and Boycott (8) used this compound in their animal experiments and brought about all the blood changes characteristic of anilin. SvlfatuUc acid is produced in the same way by the use of sulphuric instead of hydrochloric arid. The same risks attend., its production, but there is no proof of its toxicity. A very slightly toxic compound is anlknuitlic add (ortho-amido-benzoic acid) which is used for lake colon and for the pigment, scarlet B, the dye used for two-cent postage stamps. Bcnsaldekyd, or oil of bitter almonds, is, according to Robert, quite harmless. More or less severe trade dermatitis is caused by pam-amidophenol, an important intermediate, especially for sulphur dyes. It is produced by the reduction of paranitraniUn, which is much more poisonous. The excretion of both nitro and amido derivatives of ben zene from the body is preceded by their reduction to para-amidophcnol, which is found in tbc urine as an alkaline salt of para-amidopbenol-etheivaulphuric acid. Frequent cases of dermatitis ore reported from a German jiienyl' hydrazin plant among the men wlto wrap the product in cloths for the filter. An explosion of a distilling kettle full of this com pound resulted in the death some days later of one workman and inflammation of the eyes of.a large number of others. Avwdoaxotoluene, or scarlet red, is derived from orthotoluidin and is used in alizarin coIot manufacture: It is known to physicians as a stimulant for tissue growth, useful to hasten healing after severe burns. Two cases arc recorded of cyanosis, dizziness, head ache, slight fover, rapid pulse, and albuminuria after such an appli cation of scarlet red. The napbthalcno derivatives are far less toxic than benzene or toluene derivatives, as would naturally be expected. The napbthols, which bear tbc samo relation to naphthalene as phenol docs to ben zene, resemble phenol, but are less soluble and Ices corrosive. Alpha^napfUhol is more strongly antiseptic than beta and probably more poisonous. The use of betamaphthol in industry, especially in making para reds, seems to give rise to little if any trouble, except for ita^eflfe*^. on the skin, and even the fumes are r ' V v lv irritating to inekkin, but the caustic soda used in preducinc beta 510 INDUSTRIAL POISONS IN THE UNITED STATES wo plit)iol is much worse in this respect than the bcU-naphthol itself. X ilrusc-bctornapfUhol, formed at one stage in the production of H ncio. gives rise to dermatitis, as do all the nitroso compounds; while dinilro-naphikot, or Martins yellow .or Manchester yellow, baa the usual action of a nitro derivative, but is one of the weaker members of the group. The no.phihylam.ins, alpha and beta, are capable of producing symptoms characteristic of amido compounds, although, according to the testimony of practical men, alpha never causes severe poison ing. Beta-naphthylamin seems to be distinctly more toxic, and in one large American plant where there is no trouble at all with the alpha compound the men in the crude naphthionic department who come in contact with beta-naphthylamin suffer not only from cyanosis but from frequent micturition, apparently from over-acidity of the urine. . The pyridine., used in the making of anthraquinone and in other processes for indanthrene dyes, are said to make the men "dopey," to give them headache, dimness, dulling of the intelligence. They have al&o a curious effect on the skin similar to that which has been described in English briquette factories as a result of handling of tarry substances. The skin is raw and sensitive as if from sunburn, and the man suffers moat after washing his face and hands and fore arms and going out into the open air. Bjbuocrapht (1) FfUEKKEL, S. DU ArzncimUlel Synthese auf Orundlage der Betis- hung twischtn chtmUchcr Aufbou und Wirfcunp, Berlin, 1912. (2) Lewis, J, H-, with Wells, H. G., Sansum, W. D., McClure, W. B, and Lussky, H. O. J. 2nd. Hyg., 1920-21, 2, 249. (3) Hunt, Reid, and Gettler, 0. O. In Legal Medicine and TcxUoUgy, by Peterson, Haines, and Webster, Phils*, 1923, Vol. 2, 701. (4) CursChmank, F. DtvUch. VriliUKr. f. ofitnl. Qetvnd., 1911, (5) Heubner. Zentralbl. f. OevtcrbehygUne, 1114, 2, 409. (6) Lehmann, "K. B. Arch. f. Hyg., 1912, 75, 1. (7) Mohr. Deuitch. med. Wcfcnschr., 1902, 29, 73. (8) Trice-Jokes and Boycott. Guy's Rasp. Rep., 3901, 63, 300. (0) Brat. Deutech. rned. Wchiischr., 1901, Nos. 16 tod 20. (30) Hudson, W. G. M. Rcc., 1917, 91, 8. (11) Malden. J. Hyg., 1907, 7, 072. (12) White and Hat. Lancet, 1901, 2, 682. (13) Yon Jaksch, K. DiagnotlUc innerer Kranhheiten, ed. 6, Berlin* Vienna, 1907. (14) Neubauer.' Analyte dee Hems, ed. 11, Huppertfe Lehrbuch, Wies baden, 1913, toI, 2, 1479. (15) Davis, P. A* wAnil in Poisoning in the Rubber Industry," J. 2nd. Hyp., 1921-22, 3, 63. . (16) Leuenbercer, 8. G. "Die tinter dem Einfluss der aynthetiSchen Farbeninduatrie beobachteie Geachwiilstentwiddung/' Beiir. t. Win. , .. Chir., 1912, 80, 316. -*gs'W t INDUSTRIAL POISONS IN THE UNITED STATES 611 (17) Moore, B. "The Causation and Prevention of Tri-Nitro-Tolucue (T.N.T.) Poisoning." Nau Health Insurance lied. Research Com., Spec. Rep. Series No. 31, London, 1919. _ (18) Voronin, Caul, Hoofer, C. VT., and Johnson, J. M. "TTi*Nitro- Totuene Poisoning, its Nature^ Diagnosis and Prevention," J. Ind. Hyg,, 1921-22, 3,23. . (19) Hamilton, Alice, "Trinitrotoluene as an Industrial Poison," Ibid., 1921-22, 3,102. t (SO) Haytborn, 8. K. "Experimental Trinitrotoluene Poisoning," Ibid., ~ 1920, 2, 298. (21) White, Prosser. In Oliver's Dangerous Trades, London, 1902, 475. (22) Cords, It. ZtrUd. /. Qstocrbehyg., 1919, 7, 6. ` (23) Has. "Sehnerreuerkrankungen durch T.N.T^" Ztschfi. /. Augen- KeUk^ 1922,47, 199. .' (24) Peanuta, R.G. 17. 8. Public Health Rep., 1919, VoL 344, 233$. X26) LetManh. Vrtljschr, /. periefcil. Med, 1902, Suppl. 311. (26) .Kobeat. Lehrbuch der Inlexikaiicnen, Stuttgart, 1900, 801. (27) RaMBOU8EK, J. Industrie! Poisoning Tr. hy-T. M.Legge, London, ' _ 1913, 215. ... ' ' (26) Gibbs-and Haw. Quoted by Kobert, .Lehrbuch der Jnloxihalienen, ' Stuttgart, 1911, 790. - (29) BaOH/eld/ Vriljsekr. f. gtricktl. Med., 1898, 15, 390. (30) AyreLBAOH. G. L. BuU. P. J. Rep. 1U., 1913. (31) Baas, E. G. J. A. U. A., 1914, 62, 314. (32) Luce, R. V. and Hamilton, A. J. A. M. 4., 1916, 66, 1441. (33) Lentz, W. "Anilin Poisoning,1' J. A. M. A., 1917, 68, 692. (34) Nbwton, C. R. J. A. M. A., 1920, 74, U49. (35) Fueolandcb. Neurol, CentrolW., 1900, 19, 155 and 295. (36) Sehx. Cor.-Bl. /. schweit. Aerxte., 1897, 161. (37) TaarrENrcU). Quoted by Kobert, Lehrbuch der Intoxikaiionen, Stutt gart, 1911, '790. (36) Stabck. Thtrap, ilcnaith., 3892, 6, 376. (39) Stadelmann. Quoted fay Malden, eee (11). (40) DragENdoREF, Quoted' by Kobert, Lehrbuch der IntaxilzHionen, Stuttgart, 1911, 782. (41) Knowles, F. C. M. Rtc^ 1916, 217. (42) Blabchxo, Deulsch. med. Wchnschr., 1913, 2, 2106. (43) Olson, aV. J. A. U. A., 1916, 66,864. (44) HiynJ*, P. J. "The Pharmacology of Some Phenylenediaminea /. IndnsL Hyg., 1928, Vol 5,386 and 448. . (45) Won and Sellers. Inti. Congress ef Industrial Hygiene, Brussels, 1910