Document Y9kzkmMqNM5DgZzGqonoLgVGn

L'TAy- -v^A':A" - 'MY'TlAT A? aBMHi -!V~ I ......... yWPgg ' ' `ntfjSc LOGY M. tl, no. 1 $ :h some of the terms, old have been well to : in general between Sects, as with many '.tie similarity and the y the more serious. Semen's compensation on industrial health, occupational disease ve been mentioned, i of occupational diere and specific) with r disadvantages are two. rst-Aid Treatment of / the traumatic in-. ken care of in another "rst-aid a few words ul describing what tc . poisoning, cyanide, lere the patient is still ompt fiction is neces- one compact volume 'le much information d health that otherreference to many .nning students of in industrial safety and relations, it should ik. The operating will want more comthe particular expo und the industrial 1 in prevention, will ineering methods of By E. TT. Baader, .E AUF DEM GEBIETE ttek". Adam and ipp. 104-128). eluding the history Leas well known :er are included: the J seen in England in s cancers of genera.nd the liver cancer :he Haff, caused by '.incus.--L. Teleky. THE JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY Volume 21 FEBRUARY, 1939 Number 2 THE SYSTEMIC EFFECTS RESULTING FROM EXPOSURE TO CERTAIN CHLORINATED HYDROCARBONS* Leonard Greenberg, Mat R. Maters and Adelaide Ross Smith Division of Industrial Hygiene, New York Stale Department of Labor, New York City HLORINATED naphthalenes product is present. On the whole, C and diphenyls, because of their electrical, heat and moisture- the higher the chlorination, the more toxic this material becomes. In the resisting properties, and because thmeaynufacture of chlorinated diphenyls, are non-inflammable, are used exten . CeHj is converted into CuHio which, in sively for insulating wire and in the manufacture of electrical condensers. The chlorinated naphthalenes are naphthalenes in which one or more of the hydrogen atoms has been replaced by chlorine. There is, thus, a series of these substances beginning with monochlomaphthalene and going on to the octochlor derivative. In in dustry' they usually occur in mixtures in which more than one chlorinated turn, is chlorinated to CuCIjo; the substitution products range from the monochlor to the decachlor diphenyl. A rather characteristic acneform skin eruption resulting from exposure to these substances has been recog nized for a great many years---indeed, ever since they began to be manu factured about 25 years, ago. These skin eruptions came into some prom inence in Germany during the war and have been attracting sporadic interest * Received for publication September 13, 1938. _ i The chlorinated naphthalenes are some times referred to as "Halowax" by pur chasers and users. While the Halowax Cor poration manufactures these substances, it also manufactures many others. Since the term "Halowax" is merely a trade name for substances manufactured by this Company, it should not be used indis criminate! v. In all instances, substances soouia be designated by their chemical names only. in this country ever since. An in vestigation of this condition, as it ap peared among a group of young work ers engaged in the manufacture of electrical condensers, was reported in a recent issue of this Journal (1). Experience has shown that the medienl practitioner.in otiH-aomcwhnt un-- familiar with the skin eruptions, even 29 63 * ft.-. ' HARTOLDMON0021614 WWSriivMM ilfl Jot t|.j . te Rint.f; f].- mi 30 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY M. tl, no. t though they are by no means uncom- and (C) given off at 192C and 172C -Tgorr-m-tfae -industi ins tvfaei u ibiruhliF" -respectively:--targe doses; approx-- rinated naphthalenes and diphenyls imately 15 mg. per kg, were injected are used. The reason for this is that subcutaneously each day. any one physician is likely to see such Animals receiving compound (A) cases only rarely, unless he happens and the sublimate of compound (B) to be practicing in the immediate vi showed no lesions attributable to these cinity of one of these factories where substances when killed at the end of large numbers of workers are em 2 months. The 30 animals, however, ployed. That the relatively rare sys which had received the higher chlo temic effects resulting from such rinated compounds (B) and (C) and exposure almost invariably go un the sublimate of (C), all died in from recognized is not surprising under the 12 to 26 days. Autopsies uniformly circumstances. It is of the greatest showed extensive damage. importance however, that physicians The next important study to be become acquainted as promptly as pos published was that of Drinker, Warren sible with the clinical and pathological and Bennett (4). These investiga pictures presented by these patients, tors administered chlorinated hydro particularly as regards systemic ef carbons by inhalation, subcutaneously fects, since failure to detect early and by mouth, to white rats. Mix clinical manifestations of toxicity, and tures of (a) tri- and tetrachlomaphtha- to remove ' susceptible individuals lene; (b) penta- and hexachlomaph- promptly from further exposure, may, thalene alone, and (c) with 10% refined on occasion, result fatally. chlorinated diphenyl; and (d) chlori Review of Literature ok Systemic Effects* nated diphenyl were used. Briefly, these experiments showed, that the tri- and tetrachlomaphtha- Experimental studies.--The first lenes produced relatively unimportant mention in the literature of systemic pathological changes in the liver until effects from chlorinated naphthalenes extremely high concentrations were is that of Lehmann in 1919 (2). He used. Animals exposed for 6 weeks to found that animals which were fed or the higher chlorinations, however, in which inhaled these substances lost relatively low concentrations, regularly appetite and at death showed "pecu showed minor degrees of liver damage liar" lesions in the liver. even though, as a group, they gave no In 1936, Flinn and Jarvik (3) ex clinical evidences of such toxicity perimented on rabbits with three dif while alive. Exposed to still higher ferent compounds; (A) a mixture of concentrations, the rats lost weight tri- and tetrachlomaphtbalene, (B) a mixture of tetra- and penta-chlornaphthalene and (C) a mixture of penta- and hexa-chlomaphthalene. They also used sublimates of (B) and appetite, and began dying after 8 days' exposure--many with severe jaundice. Examination of the liver of these animals at autopsy revealed marked central fatty degeneration * A review of the literature on skin mani- with necrosis of liver cells. festations'hppeared in the article by Mayers and Silverberg mentioned above (l). It is of considerable interest that . IS3SJ u. V - the exposec i. cal evidence XS^MIrom acute Pven Mgtetrachlorid control anin . othe 'tjp^^Jjiitmght out ;rats, which marked paliver) no ab ' common in rather 'from acute y I;(2)' even th ;logical chanj these chlorir '' Vl3|v lower co 'very persist* Jxal'months after cases of syst 'X&W& chlorinated : . rare m spite ff^these substa doubt th ports has bee: fact that cas ; Ire . unusual U~;inent of i. -- Yu)appearing to "Important r61e . Vv.f tion--and se< '-w-- part of physic poisoning. I "Jr- been general i ^oncological j 'dnated hydr< . still relatively able regarding "f-x industrial pois The danger "yU- of knowledge : tion that rece HARTOLDMON0021615 1 z rmr proxected 1 (A) l (B) these nd of ever, chlo') and > from jrmly to be 'arren stigahydro:ously MLxphthamaphefined chlori- .owed, jhthaortant t until were ;-eks to ver, in ,-ularly, amage ave no axicity higher weight after 8 severe e liver vealed .ration TWM&g,- t-ys ;i- w*s't' V t!>. I Mi1! SYSTI-.MIC Ll'I-T.CTS 01' CIU-OlUNATi'-H HVDrUK'AHV.ONS 81 ^ the exposed rats, which gave no clini- tion of the Labor Department in New jfi\ cal evidences of disease, promptly died York State, in which a physician had from acute yellow atrophy of the liver been treating a severe case of jaundice Hjc when given a very small dose of carbon in a young woman exposed to chlorin ^tetrachloride--a dose well tolerated by ated naphthalenes. After a long and ^ control animals. serious illness, when the girl was on jSWJv.Two other points of interest were her way to recovery, the physician l&p^rought out by the study: (1) in the expressed the opinion that within a jljvV.rats, which on autopsy showed even few weeks she would be able to return marked pathological lesions of the to her former work. Whatever the n0 abQormalities were found in cause of the jaundice in this case, there the other organs--a finding not un- is good reason to believe, on the basis -^commca in experiments on animals, of the experimental work previously but rather rare in humans who die cited, that further exposure to such, acu^ yelIow atrophy of the liver; substances would have entailed a " even the less important- patho- grave risk to the patient's life. . ~ ''^cpvlogical changes induced in the liver by In 1934, Courtois-Suffit (5) reported : ' -l^lhese chlorinated hydrocrbons in the on the work of Touraine who, with tower concentrations were found to be his associates, examined 60 workers ex -V.-irjg^.yery persistent, being present even 2 posed to trichlornaphthalene and ' -`^rKrihonths after cessation of exposure. found mild digestive disturbances and Clinical Reports.--Clinical reports of dizziness in 13, but nothing of a more HriSwi.c^es of systemic poisoning from the serious nature. ' ''t^P^Wonnated naphthalenes are as yet In 1935, Schwartz suggested the , . V.^^.rare in spite of the length of time that possibility of systemic disease from :-' ^fet&ese substances have been in use. exposure to these substances in a talk .,i^.CNo doubt the infrequency of such re before the American Public Health . uzcfejp ports has been, in part, due first, to the Association (6). _ ^vv.fact that cases of systemic poisoning In 1936, three fatal cases of jaun ' are unusual occurrences--the ele- dice in chlorinated naphthalene work ----- A^V-ment of individual susceptibility ers were recognized in this country. :\k appearing to play an even more im- These were reported by Flinn (3) and ' Prtant r<Me than usual in this situa- Drinker (4) who summarized the cases .^on--second, to failure on the briefly. part of physicians to recognize cases of All three of the men were young and _ poisoning. Until recently there has ..a. been general lack of knowledge of the v.toxicological properties of these chlo nnated hydrocarbons, and there is still relatively little information availa^e regarding the clinical picture of mdustrial poisoning from them. in none could any predisposing cause other than their industrial exposure be found to account for their illness. Two of the men who had worked side by side died within 2 months of each other. Both had been exposed to mixtures of penta- and hexachlornaphthalene, and one had been The danger that lies in such a lack exposed to a mixture of tetra- and of knowledge is exemplified in a situa penta-chlornaphthalene with 10% tion that recently came to the atten chlorinated diphenyl. In both, the pS-v'ffc I.*::-- pi JggSBSral HARTOLDMON0021616 diagnosis of acute yellow atrophy of the liver was made on autopsy. In the third case no autopsy was reported, but death occurred after an acute ill ness characterized by jaundice. In one case dermatitis characteristic of the effect of chlorinated naphthalenes had preceded the jaundice. In addition to these fatal cases, Drinker (4) also mentions four cases of non-fatal jaundice among indi viduals with similar exposure. No details are given. Case Histories Because of the obvious need for more clinical data in regard to the effects of chlorinated naphthalene ex posure, we are reporting 3 cases in persons who, after exposure in the course of their work to these known hepatoxic substances, died of acute yellow atrophy of the liver, and in whose cases no other etiological factors could be discovered even after very careful investigation. The first case was seen in consultation at the Lin coln Hospital in New York City by Adelaide Ross Smith. The second and third cases were seen in consulta tion at the New Haven Hospital by Dr. Leonard Greenburg, (now Execu tive Director of the Division of In dustrial Hygiene of the New York State Department of Labor) when he was Commissioner of Health of New Haven, Conn. The plant conditions under which the patients had worked were carefully investigated. Cass l. H.F.' A 17 year old girl was admitted to the Lincoln Hospital, New York City, on the * Grateful acknowledgement is made of the courtesy extended by the staff of Lin coln Hospital and the Medical Examiner's Office in granting permission to use the records in this case. service of Drs. Kenneth Taylor, Edwin Hauser and Scott Johnson on April 26, 1932 in a semi-comatose condition. She was intensely jaundiced on admission. Her past medical history, obtained from members of the family, was entirely nega tive with the exception of a tonsillectomy in 1930. Until the onset of the present illness she had been unusually healthy and free from symptoms of any kind. The occupational history was as follows: After being graduated from grammar school she attended high school for 1 year and then obtained a job, her only one, with a concern manufacturing electrical condensers for use in radios. She worked at this one place for 7 months and stopped working there 7 days before her admission to the hospital. Her work consisted of soldering and labelling condensers. It is possible, from the information given, that she may also have assisted in the Bealing operations, but this could not be definitely ascertained. In any event, in the soldering of the con densers Bhe was exposed to the fumes of triand tetrachlornaphthalene with which the condensers were originally impregnated. At the same time she was exposed to fumes of the higher chlorinated naphthalenes from the sealing operations conducted in close proximity,to the tables at which the solder ing was done. The present illness began about 5 months before admission to the hospital--or ap proximately 2 months after starting work in the plant--at which time she noticed several pigmented areas on her face. These con tinued to increase in severity and extent, and caused her to visit the outpatient de partment of the Lincoln Hospital. Herej sugar was found in her urine and she was referred to the skin clinic where a diagnosis of acute catarrhal jaundice was made. Her rectal temperature, at that time, was 100. A diffuse papulo-puatular eruption was also present on her face. On being questioned about it, the patient stated that it had been present to her knowledge for about 2 months.f From then on she suffered from t Investigation revealed the fact that some of her co-workers were also suffering from a similar acneform eruption, and one girl discontinued her work because of it. None of these other girls suffered any systemic disease. reading weaknes Jetito-WM poor; h K*ifely more jaundi iffoh Increased. . |i`Abont 6 weeks jotter noticed th. f&bout 3 weeks late ('severe headach ated. This was ^puffiness and swi and abdomen i0he continued ( |;weak before adn admission she 1 f'fidvementa of the |tkry, bobbing of Grith any pain. to develo in mentaJ ithe hospital in th r ^[,_LThis was the fire ~'r^*SjjrciiiTed. She arri ..'^Y^^^^state of prostrati Summary of p. " fy^^t'patient gave th ; Llj^^^eolored girl alth white; ' She look . developed for he l .".^^^puffiness of the f ' She was ! iTi5^:E^quently <fisturtx contractions of t 'I'AWjT'ciated with in\ / xxi^^yhead;' The ten- Vlvip,;. 114, respiration ----first ad: (`iHgEtieot 1* bo jaui More careful ex 'vjiyjvY nteck revealed a vr^':A'tioa beginning ; . mg down to, Besides this g rSf-L were three area: ___ ;&*': rest, appearing --ne on ea one on the cb these black spo o(rev?.'- r aggregation: 'jJfjY did not share ii 'IvY' R was t teristic of jaur - The skin oft the body wa ~'^|kLish subtinge. Ti'j'jV ?; tLfcft;:' 00041 HARTOLDMON0021617 <. '1 mMmxm i, no. X Edwin 26, 1932 he was ed from y negatomy in it illness vnd free follows: tr school And then concern ifor use place for re 7 days al. jig and le, from nay also ons, but rtained. tne con es of trihich the jgnated. to fumes mes from in close e solder- 5 months --or ap5 work in d several ;ese con : extent, -.ient de~ .. Herej she was diagnosis ie. Her srw 100. . was also les'.ioned had been about 2 red from 'set that unering and one _=e of it. .red any - SYSTEMIC EFFECTS OP CUT,OPIN'ATP!) HYPUOCAKISON'S 33 . easing w ealcness and nausea. Her ap- .pnuts \wvtitld ppvor; her bkiu bcuoiiis progres sively more jaundiced, and the pigmenta- on increased. jAbout 6 weeks before admission her Another noticed that her eyes were yellow. ``'About 3 weeks later she began to complain ' o^'severe headaches which continued un bated. This was followed in a few days by ^puffiness and swelling of the face, hands, jjet'and abdomen. !She continued at her regular work until fweek before admission. On the morning il'admiBsion she began to have convulsive Jhadrements of the abdomen with involun- jiiry bobbing of her head, unasaociated jwitli any pain. At the same time there, named to develop memory defects and a ., change-in mental status. On the way to d&teq* the hospital in the ambulance she vomited. &,Thi4 was the first time vomiting had ocIncurred., She arrived in the hospital in a - piSsji state of prostration. of physical examination.--The i 'vm?3patient gave the impression of being f j 'i^S^colored girl although she was, in reality iT.T^^^wiite:'-'- She looked well nourished and well . ..''|5g^fc[eveloped for her age. There was general S' ..... puffiness of the face, hands, feet and abdome'nb'-She was hiccoughing, and was fre* T^S'quently disturbed by a series of tetanic '... .contractions of the abdominal muscles as30 :":ftkhnated with involuntary bobbing of the . '_y^..head. :..The temperature was 100, pulse >r?yll4,' respiration 26. . '1 The first admission note stated, "pa- ...,T,:tient is so jaundiced her face is black." ...u&More careful examination of the face and '.J'ikneck revealed a negroid type of pigmenta- :y.y; tioa beginning at the hair line and extend- Jng' down to, .and including, the neck. ii: Besides this general pigmentation there were three areas somewhat darker than the rest, appearing very much like dab3 of char- ne on eak cheek below the eyes and 'one on the chin. On close examination -tv.these black spots appeared to be the result aggregations of comedones. The scalp ivf ^ Dt 8kare in the general dark pigmenta- Y`C^on" ^ waB a yellowish color charac"'!> _teri8tio of jaundice. ' " The skin of the thorax and the lower part , the body was dark brown with a yellow 'd subtinge. Over the akin of the abdo- V men there was a girdle-like area of deeper pigmentation beginning at the level of the umbilicus and extending to the pelvis. There was also a line of deeper pigmentation in the garter region on the posterior surface of the left thigh about 1 inch above the popliteal fold. . Examination of the eyes revealed deep jaundice of the sclerae and the conjunc- tivae. The pupils were equal and regular, and reacted to light and accommodation. There was no nystagmus or strabismus. The blephoral conjunctivae were redder than normal. The discs were somewhat pale, though well defined. There was no exophthalmus. The normal ratio in width of artery to vein was preserved. The ves sels were not contracted, and did not pre sent the hair-line appearance believed to be associated with arsenic or quinine poi soning. Other positive physical findings were: slight injection of the throat; slight edema of the feet and hands; an apical systolic murmur; abdomen distended and tympani tic; liver on pj-sussion small, with tympany extending to the very costal edge. Laboratory findings: These were as follows: Blood count on admission--White cells, 9,100; Red cells, 4,200,000; Polys., 80%; Lymphs, 20% Hemoglobin, 87%; Bleeding time, 4.5 minutes; Clotting time, 2.5 minutes; Platelets, 220,000. Blood chemistry: Non-protein nitrogen, 35, later 45, mg./lOO cc.;Protein, 6.9 mg./lOO cc.; Urea N. 20.83 mg./lOO cc., Creatinin, 2 mg./lOO cc.; Glucose, 88 mg./lOO cc.; Cho lesterol, 145 mg./lOO cc.; Calcium, 8 mg./lOO cc.; CO combining power,* 52; Albumin, 2.5 mg./lOO cc.; Icteric index, 230; Van den Berg, immediate direct reaction; Wasser- man, negative. Urine--Sp. gr. 1.008: Alkaline. Albu min negative. Sugar, a trace. Acetone, It. Bile pigment present. Urobilinogen a trace. Few red and white cells. Stools--Urobilin present. Spinal fluid--Pressure normal. Cells: 10, Lymphocytes. Clear. Glucose pres ent. Globulin absent. X-ray examination--No evidences of lesions of the heart and lungs; bones of skull, ribs, shoulder joints, clavicles, tibia and fibula. The gastric contents, and later, i(`v. l:mm l iH ' in fePXY V'X: tV iiH'.-V'.; j' --v.J v-" /: ' .y.V1 fc-;; HARTOLDMON0021618 34 JOURNAL OP INDUSTRIAL HYGIENE AND TOXICOLOGY M. 11, not T TsWfj- at autopsy, the organa were analyzed for arsenic, phosphate, lead, tin and antimony. A trace of phosphate was reported, prob ably from inorganic phosphates ingested before admission. Diagnosis--The patient presented a pic ture which was distinctly puzzling to all physicians who saw her and no conclusive diagnosis was reached at the time. The various diagnoses suggested included: ob struction of the common bile duct, toxic jaundice possibly due to some dye, obstruc tion of the inferior Vena Cava, blood dyscraaia, Addison's diabetes, hemochro matosis, industrial poisoning of unknown origin possibly due to arsenic, causing acuteglomerular nephritis and acute hepatitis; and finally acute yellow atrophy of the liver and pancreas "possibly due to an unknown industrial poison. Course--The clinical course was steadily down-hill. At 11 p.m. on April 27th the patient became unconscious and went into a coma. There was Cheyne-Stokes breath ing. . A peculiar odor was present which was variously identified by hospital physicians as ethylene or garlic. The pupils were im mobile to light. Deep reflexes were greatly depressed. There was no Babinski. Ab dominal reflexes disappeared. The skin became dusky throughout. The liver dull ness seemed to diminish. On April 28th the temperature rose to 106; the pulse to 140, and the patient died. Anatomical diagnosis--An autopsy was performed at the Medical Examiner's office on April 29, by Dr. Chas. H. Hocfcman, Assistant Medical Examiner. The report in full was a3 follows: Body is that of a white adult female, well developed and nourished. Cyanosis of lips, ears and fingernails. Marked pigmentation about eyes, lower lips, neck and abdomen. General icteric tinge to entire body. No evidence of violence. Some edema about ankles. Hair is black. Eyebrows black. Brown iris. Conjunctivae and 3clerae ic teric. Rigor mortis present. Postmortem lividity of dependent parts. Scalp incised and reflected, calvarium removed. Brain found congested. Meninges bile tinged. On section, no evidence of intracranial in jury or hemorrhage. Dura stripped and reveals no evidence of fracture. Body opened in usual midline incision. Sternum removed. Some remnants of thy mus still present. Lungs are free. Bron chi contain a bloody mucous. Mucosa injected, has yellowish tinge. Hemor rhagic infarct about siae of hen's egg in left lower lobe. This is airless and dark red in color, firm. There are also similar smaller areas in other lobes. Heart is small and shows some sub-epicardial hemor rhages. Some hypertrophy of left ventri cle. Valves thinned. Arteries natural. All are bile Btained. No significant findings in myocardium or coronary arteries.. - Esophagus is natural. Stomach is dis tended, contains some dark material. The rugae are somewhat hypertrophied. The duodenum contains green chyme. The ampulla is patent. The jejunum, ileum and large gut are natural. Many petechial hemorrhagic areas noted in the mesentery with some enlargement of mesenteric lymph nodes. Liver is small, weight 720 gm. Capsule wrinkled. ' Right lobe on section shows'*' areas of yellow surrounded by red areas. Left lobe much firmer although liver cuts firmly throughout. All ducts patent. Gal' bladder small. Wail thickened throughout. Pancreas is natural in size, somewhat congested. Spleen is natural in size. On section, firm, dark red in color. Follicles are somewhat indistinct. Kidneys show swollen cortex. Evidence of parenchyma tous degeneration of epithelial cells. Capsule strips easily. No granulation. Degenerative changes in cells of glomeruli only. No glomerulitis. Uterus is small. Endometrium bile-stained. Ovaries are natural in size; right contains corpus luteum cyst. Bladder wall is Bomewhat thickened. Mucosa is injected. Microscopic examination--Liver--From size of a through and through transverse section one suspects that the entire liver was about J normal size. Liver segment is very firm and composed of two distinct and peculiar types of tissue: (a) That con stituting major portion of parenchyma is red in color; firm and elastic in consistency; (b) Other areas are light yellow in color and are scattered indiscriminately throughout reddish areas. Yellow areas vary from i to 2 in. in diameter. External surface fSsooth,; '. ' .. . 1 typical p i atrophy is iarea is c ophy" in w appeared, t . normal i to have' ^^^jfood'cells, ee KgfJnd older seal t;umeroua bile ^seem to have t ':rrkr& tjner&ting is! - - offtfca liver c< Sporting, stror ducts. .The 1 ".-jAVpt.-jlh.oso liver . ys-fifegenerated a ieea.in the g ' X<ri been one oi ' "'MS}'inffrom the d : - :rv*.;;r-*Y ' T vV'Yflli^Sba-Sb0' ^orium. whic .-i&Ssr Some. of the V .'.' Xi^'deeper, in cor w-SilrWS't Heart--Sh myocardial c jK;Kidneys-- _,,A'_eratioh invol ' rS'Y'glomeruli. 3 ih: glomeruli, fb Adrenalsdegeneration 'crifPs.' Pancreas'.viT of cells of ac . Summary Tjhdently cause p.volving mos 'Tr liver.. TKe _and. recovert similar nafu oung initted to tl 1934, com . tory given \ He had v * Author I "7r I-*" .g ton. byon:03a mor: in ark nilar .mall aorltriural. lings disTbe The The 1 and ;chial ntery Tnph apsule shows :as. r cuts Gall zhout, :what . On .Hides : 3how nyma- cells. lation. .meruli small. :3 are aus luoewhat --From nsverse .i liver -sgment distinct .at conayma is 'stencv; .lor and -.ughout y from surface t$b. tm\ SYSTEMIC EFFECTS OF CHLORINATED HYDROCARBONS .' ; ' 35 of Uver, judging frotn this portloii, was --^lyrwtrtrrorptrtrT^^ uf smooth. December, 1933. At that time he felt run j A typical picture of clear subacute yel- down and became jaundiced. He was seen J^low atrophy is revealed. Slides show that in the dispensary in January and found to ST'red., area is composed of so-called "red have an enlarged palpable liver. He then atrophy" in which all the liver cells have Bpent several weeks in another hospital with (^/disappeared, their place being occupied by slight improvement in the jaundice. - b.'^heir normal supporting stroma, which In March, 1934, he returned to the job ^`geems to have been spared, great numbers of in the wire factory. Following this, the j.'pZ'blood cells, early fibroblastic proliferation jaundice became quite intense with increase older scar tissue. In these red areas, in general malaise, anorexia, attacks of ".^fe^J'mmnerous bile ducts are seen. These also dizziness and loss of weight. Three days gify teem to have been spared destruction. The before admission vomiting had occurred. & yellow areas are composed of actively re- He had taken no drugs and there had been gjbjj'generating islands of liver cells. no exposure to carbon tetrachloride or - .' The toxin evidently has destroyed most chloroform. ^ydf'the liver cells, leaving intact their sup Summary of physical examination--The porting . stroma, blood vessels and bile temperature was 99", pulse 74, respiration ildncts.' The latter seem to be regenerated. 20, blood pressure 130/74. The patient was _ _ , . JjjhThose liver cells spared destruction have a thin well-developed man who appeared regenerated and havedormed yellow islands moderately ill. There was bright yellow in the gross picture. There evidently jaundice of the entire body. The pupils has been one or more attacks of hepatitis judg- were widely dilated, the nasal septum de from different ages of the pathological viated, causing obstruction on the right, ^^^ftfprpcess in various parts of liver.* the mucous membranes injected and the 4^^?^y/Skin--Shows an increased density of tongue moderately coated. The tonsils '.lYssfewnum which stains deeply with eosin. were enlarged and cryptic. Lungs were >.;?ZrjSg5i='Soine of the epidermal cells are slightly clear, heart normal, radial vessels soft, - ^..MVrT^eepef jn oorium than normal. abdomen tympanitic, soft non-tender. The Heart--Shows, mild parenchymatous liver edge was felt at the costal margin. myocardial degeneration. The organ was soft and non-tender. The ::^^^'I-'Kidneys--Show severe epithelial degen- upper edge of the liver dullness was in the reration involving epithelium of tubules and 6th interspace. - .-.-.vipcp.glomeruli. No inflammatory reaction of Laboratory findings--These were as fol glomeruli. lows: ' Adrenals--Show severe parenchymatous Urine--was dsrk yellow and was nega _ -/Vt;,' degeneration of cells. tive except for the presence of bile and uro Pancreas--Shows intense degeneration bilin. ilhl'..9.(ceUs of acini and of islets. Blood count--red cells, 4,380,000; hemo Summary--An unknown toxin has evi- globin, 85%; white cells, 6,800; Polys., .:p';'dently caused a severe diffuse cytolysis in 65%; Lymphs, 29%; Large Monos., 4%; - -Tr.volving most of organs, predominately the Eos., 2%. Subsequent examinations liver. The latter has evidently undergone showed a slight rise in white cells to 10,000. / and recovered from previous attacks of a Stool--showed bile, considerable undi ' similar nature.* gested food, small amount of fat. Kahn lest--negative. ' Case t--F. D. Liver function tests--Icteric index--30 to ..VL:1.';.: A young man, 24 years of age, was ad- 50. Bromsulfonphthalein showed marked ^^ted to the New Haven Hospital on May . ..Y 2, 1934, complaining of jaundice. The his- V>rY given was as follows: He had worked in a wire factory coating Authors' italics. f The waxes employed in this process are the higher chlorinated naphthalenes. These are used in a molten state in a bath through which the wire to be coated is passed. The process is partially but not entirely enclosed. Exhaust ventilation is in use. ft,', h 1 . , m i:a Illlll ='m. m nEm gfHaS vJ ,J`Vi *(#< 0004 HARTOLDMONQ021620 36 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [vol. SI, no. J impairment: 100% retention in 6 min., pneumonia (bilateral), subpleural hemor __J'three-car 85% retention in 30 min. rhages, cloudy swelling of kidneys. ^p!tion.faiIe( Blood chemistry: Non-protein nitrogen, 28 mg./lpO co.; Urea N, 11 mg./lOO cc.; Serum total proteins, 8.15 mg./lOO cc.; Serum total albumin, 2.68 mg./lOO cc.; Serum total globulin, 3.49 mg./lOO cc. A/G ratio, 0.76; Blood sugar, 68.0 mg./lOO cc.; Blood calcium, 10.32 mg/100 cc.; Blood phosphorus, 4.12 mg./lOO cc.; Serum fatty acids, 11.3 mg./lOO cc.; Serum lipoid phosphorus, 7.5 mg./lOO cc.; Serum total cholesterol, 10.5 mg./lOO cc.; Serum free cholesterol, 63.0 mg./lOO. . Sugar tolerance test was within normal limits. X-ra'y of abdomen showed hepatio flexure of colon unusually high. , Course. The patient was put on a high carbohydrate diet and his general condition improved but the jaundice persisted. He was discharged on May 16, 1934 with the diagnosis of toxic hepatitis. He was admitted again on June 1, 1934 complaining of abdominal swelling of 3 days' duration, weakness, anorexia and edema of the legs which had developed soon after his discharge. The physical exam ination showed deep jaundice, systolic mur mur, abdomen distended and tympanitic with dullness in the flanks, moderate pitting edema of the legs. Examinations of the urine, blood and stool showed no important variations from the original findings with the exception of a drop in white cell count to 6,400 with 74% polys., and a decrease in serum albumin to 1.88%. Serum CO, con tent was 54.54. Serum chloride was 98.0 Case S--C. C. A young man 22 years of age was admitted to the New Haven Hospital on February 28, 1935 with the complaints of jaundice, ab dominal pain, nausea and vomiting of bloody material. The history given was as follows: He had worked in the same wire coating plant as the previous patient (F. D.). The present illness had b n un with jaundice 2 months previously with no other symptoms. This continued for about 1$ months. Two weeks before admission be became more jaundiced and concomitantly de veloped upper abdominal pain, malaise, nausea and finally vomiting--the vomitus becoming bloody in character. He was treated by his family doctor with no relief. His condition became worse and he finally became delirious and incoherent. Hos pitalization was advised. Summery of physical examination--The patient was comatose, irrational and vomit ing bloody material. Positive findings of significance were as follows: Temperature not elevated. Blood pressure 102/68. Generalized jaundice, petechiae over the extensor surfaces of the arms; tenderness over the upper quadrants of the abdomen. No liver dullness percussable. Course--His condition became rapidly worse, coma setting in soon after admission. The vomiting continued. The patient died about 24 hours after admission. Anatomical diagnosis--Extensive necro <^HSBosihg ca ^f&stxar dthy/.yoi Sec absence g.to li gpfctg-.or. folio iiffcubetances ' : t: v>r ear.. ^. .. is 6 in Sd^ie c: sea ap ' leastone ^followed h.l^R^^ghnprpvemer . Tdllip^tarattack a'^'IrL'.view i barren, and __ ^SilirLorgans of ^^experiments such h .threeof lyh^^^Such-.; lesion incase : --^-fothe liver ' etiology. C '^IJaqwledge rafp^say.:'whethe . ..i.'jv^fspl-yn- m. `a- ry .nr ;-^secondary 1 - r^^.Hght of the .iv^/ ever, one w mg./lOO cc. The patient's course after the second admission was rapidly downhill. The dis tention could not be controlled and he soon passed into complete coma. A convulsion occurred on June 8th and on June 10th he died. Anatomical diagnosis.* Extensive nec rosis, fibrosis and regeneration of liver, acute entero-colitis with edema, fibrosis of sis and regeneration of liver; jaundice, acute lymphadenitis of portal nodes; as cites; perienteritis of jejunum; cloudy swelling of heart and kidneys; acute pul monary congestion; healing exanthematous rash of fore-arms. DISCUSSION These three cases show the occur .'^vyiew and s `^played by 1 final pathoh v./;y:v.' ' It. has . ifeaffiDrinker's ( y-g'i-h'o. evidence expose ;^ftthalenes, p: I `i II , pancreas, acute pancreatitis, jaundice, as rence of similar pathological changes in cites, edema of lower extremities, focal the liver in three young adults known . strop hoses of car I j'l.i ! 3'|`i * Autopsies on this and the following case were performed on the pathological service to have been working with chlorinated of the New Haven Hospital by Dr. H. M. naphthalenes and diphenyls--all were 'jlpfi'83 be ha -.'"rvThis protr Zimmerman. Grateful acknowledgement exposed directly or indirectly to the \"whether dt is made of his courtesy in permitting use of the records. higher chlorinated hydrocarbons. In /VUi atrophy of 45./.. .. . /-'LJ.-rr HARTOLDMON0021621 Cl led 23, ab o{ i aa dug The :a 2 ma. itha. ame de use, atua was lief, tally Hoa- -The unit58 of Mure 2/63. : the rnesa ,men. pidly tsion. ; died lecroidice, ; aa'.oudy : pul.atous tccurzes in own nated were o the i. In teb. 19S9] SYSTEMIC EFFECTS OF CHLORINATED HYDROCARBONS 37 ill three cases, a most careful investi gation failed to reveal any other prefdisposing cause for the condition. In first case in particular, that of a ealthy young girl on her first job, absence of any conditions predis ing to liver damage either preced ing or following her exposure to the substances in question is especially ilcar. |.iltis of interest to note that two of ^.the.cases apparently had suffered from ifai least one previous attack of hepatigjitis; followed by a certain ' degree of ^improvement before the onset of the ffatal attack., . In view of the fact that Drinker, fjSVarren and Bennett found no lesions d-d^^imorgans other than the liver in their .''.^^^experimental animals, it is noteworthy 3wpdhat such lesions were conspicuous in .three of the cases here reported, j '.'^^'Such lesions, are, indeed, usual find w:n|pings in cases of acute yellow atrophy '.N^^^of.'.the liver in humans regardless of ;3^$>taology. On'the'basis of present knowledge, it would be impossible to ';^s|isay whether they_ are the result of . .-dug-primary. intoxication or are merely secondary to liver damage. In the '."~rAf''Ifght of the animal experiments, how ... v^ever, one would incline to the latter iew and speculate as to the part played by length of exposure, in the ''/.'final pathological picture. J'fji It has been mentioned that in Drinker's (4) experiments, rats with -q^no-evidence of clinical- disease while -ijS being exposed to the chlorinated naphbL thalenes, promptly died from acute - v&S-yellow atrophy of the liver when given /iff doses of carbon tetrachloride so small .'.has to be harmless to control animals. ' This prompts speculation as to whether death from acute yellow ; atrophy of the liver in workers simi- larly exposed occurs only in those having some pre-existing substratum of liver damage--such as might follow an attack of catarrhal jaundice, for example--and that this .might ac count, in part at least, for the fact that only a very occasional worker out of a large group will suffer from sys temic effects of exposure to these sub stances. In the three cases reported however, no history was given sug gesting that any hepatic disorder prior to exposure had occurred. The presence of a papulo-pustular eruption in two cases is of interest. In one it antedated the systemic symp toms. This type of eruption is char acteristic of the dermatitis caused by chlorinated naphthalenes, and until recently was the only disturbance at tributed to them. The presence of "aggregations of comedones" such as were found in Case I is also characteristic of the skin eruptions produced by these sub stances. The question as to whether or not the skin eruption in such a case is in any way connected with the onsets of systemic effects cannot be answered, since thus far no correlation has been established between skin lesions and systemic disease (1). It is interesting, therefore, that in Case I the skin eruption apparently antedated all evidences of systemic disease. Had the girl been promptly removed from further exposure, when it was first observed, it is possible that her life would have been saved; or had the physicians first called upon to treat the jaundice (of whatever origin) in her case, or in the second case here reported, recognized the danger of continuing exposure to the chlorinated naphthalenes, these dedths might pos sibly have been averted. *' >^-"`5rrw *, .. i / 1 - iH IfX HHBhBhS aSiiBsS|BSSaSB \r- > Ml k * kA X-r> f:. .ami mMol>M< a.4B*. Hm &$* %-? .;Va. HART OLDMON0021622 1 JIT a 5* r,!, m Jou m i* ;;t- incbb; ;M!:r I'M: 'ft 38 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [vol. it, no. t Recommendations for Medical Control 1. The authors wish to stress the need for the conscientious reporting by physicians of all illnesses occur ring among workers exposed to the chlorinated naphthalenes ' and di phenyls, particularly cases v.hich have been carefully worked up, so that the clinical disease entities resulting from such 'exposure can become further clarified and thus mere readily recog nized in the future. Fewer errors in the diagnosis and management of these cases would occur, and workers' lives could undoubtedly be saved in this way. 2. Persons suffering from the typical acneform eruptions should be removed from further exposure. . 3. Persons who have, at any time in the past, had any liver disease--even a mild catarrhal jaundice--should not work with these substances; nor should workers with a history of typhoid fever, malaria, gall-stones or other dis eases known to affect the liver ad versely. - 4. Persons receiving arsphenamine treatment for syphilis; or those who are taking drugs believed to be in jurious to the liver in susceptible persons, should ndl be further exposed-- in their work to potential liver poisons. 5. Persons working with the chlo rinated naphthalenes and diphenyls, if requiring a general anesthetic for an operation, should not be given chloro form or avertin, and vice versa, indi viduals who have recently received such anesthetics should not imme diately thereafter go back to their former work or to work with other substances believed to be potentially toxic to the liver. 6. Pregnant women should not be exposed because the liver, in preg nancy, appears to be peculiarly suscep tible to injury. 7. Experience seems to indicate that by proper attention to ventilation and medical supervision of workers the chlorinated naphthalenes and diphe nyls can be used in industry with safety.1 ' ^ SUMMART The systemic effects resulting from exposure to certain chlorinated naph thalenes are discussed, and the litera ture of the subject briefly' summarized. Three liver deaths in workers handling these substances are presented in some detail, with autopsy findings. Recom mendations for prevention are given. BIBLIOGRAPHY 1. Maters, M. R., and Silverberg, M. G.: Skin conditions resulting from expo sure to certain chlorinated hydro carbons. This J., SO, 2*14 (1938). 2. Lehmann, K. B.: Kurzea Lehrbuch der Arbeits- und Gr.werbehygiene. S. Hirzel, Leipzig, 1919. p. 251. 3. Flinn, F. B., and Jarvik, D. E.: Action of certain chlorinated naphthalenes on the liver. Proc. Soc. Exper. Biol, and Med., 3S, 118 (1936). 4. Drinker, C. K., Warren, M. F., and Bennett, G. A.: rhe problem of pos sible systemic effects from certain chlorinated hydrocarbons. This J., 19, 283 (1937). 5. Coortois-Suffit: fitude sur l'intoxication professior.nelle par le trichloronaphthalene. Ann de med. legale, 14, 422 (1934). Abstr. of paper by Touraine, A., and Mntrel, B.: Der matoses professionnelles par le naphthaline et ses derives. Prat, med. franc., IS, 335 (1934). 6. Schwartz, L.: Dermatitis from synthetic resins and waxes. Am. J. Pub. Health, S6, 5S6 (1936). *mpingent monly use riiSsfeisV dust surv :*#?riumpmger giggby the L' i?iHrx Service a cepted si concentra ,`:jiplg.fteld (2)>3 4 'irpSt cither inv* . YKpwi correlate ' '&r^;'bnpingerr those of pinger. 1 J hivestigal consider? __risk'd, instrumei the dust ] "counts" A*!f; Green lis formatior riij'i.. "the app .. sile st res ffijCr the large cracking .Kr,< - the mate .-IjC; (5) were "X/. any dcfii '.S~ this frac : * Recei . 1933. HARTOLDMON0021623