Document 6bQwg4X83pzZB37qxaKYe6yGE

;D TOXICOLOGY [vol. SI, no. 1 difficulty with some of the terms, chapter it would have been well to the difference in general between nd chronic effects, as with many ces there is little similarity and the effect is usually the more serious, subject of workmen's compensation lace in a book on industrial health, /elopment of occupational disease ion should have been mentioned. 0 general types of occupational dists (all-inclusive and specific) with idvantages or disadvantages are 1 paragraph or two. ffiapter on "First-Aid Treatment of s" treats only the traumatic in Burns are taken care of in another r, but under first-aid a few words have been helpful describing what to acute cases of poisoning, cyanide, spills, etc., where the patient is still ing but where prompt action is neces- >es combine in one compact volume a readable style much information ustrial safety and health that otherivould require reference to many s. For the beginning students of inil engineering, industrial safety and , or personnel relations, it should a helpful book. The operating :er and manager will want more corninformation on the particular expoin his plant and the industrial :ian, if interested in prevention, will more on the engineering methods of )1.--S. W. Ourney. iTRiAL cancer. By E. W. Baader, `NeTJE ERGEBNISSE ATJF DEM GEBIETE i krebskrankheiten". Adam and er, Leipzig, 1937 (pp. 104-128). 'aluable study, including the history idustrial cancer. Less well known i of industrial cancer are included: the and nasal cancers seen in England in 1 workers, the lung cancers of generaorkers in Japan, and the liver cancer hers in the Curische Haff, caused by :ech, Opistorchis felineus.--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 Greenbtjrg, May R. Mayers and Adelaide Ross Smith Division of Industrial Hygiene, New York State Department of Labor, New York City HLORINATED naphthalenes product is present. On the whole, and diphenyls, because of their the higher the chlorination, the more electrical, heat and moistureresisting properties, and because they are non-inflammable, are used exten toxic this material becomes. In the manufacture of chlorinated diphenyls, CeH6 is converted into C H12 10 which, in sively for insulating wire and in the turn, is chlorinated to 'CuCI1o; the manufacture of electrical condensers. substitution products range from the The chlorinated naphthalenes are monochlor to the decachlor diphenyl. naphthalenes in which one or more of A rather characteristic acneform the hydrogen atoms has been replaced skin eruption resulting from exposure 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 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. > 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 criminately. In all instances, substances should 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 (I). Experience has shown that the medi cal practitioner is still somewhat un familiar with the skin eruptions, even 30 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [vol. SI, no. S though they are by no means uncom and (C) given off at 192C and 172C mon in the industries where the chlo respectively. Large 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 tetrachlornaphtha- to remove susceptible individuals lene; (b) penta- and hexachlornaph- promptly from further exposure, may, thalene alone, and (c) with 10% refined on occasion, result fatally. chlorinated diphenyl; and (d) chlori nated diphenyl were used. Review of Literature on Systemic Briefly, these experiments showed, Effects* that the tri- and tetrachlornaphtha- Experimental studies.--The first mention in the literature of systemic effects from chlorinated naphthalenes is that of Lehmann in 1919 (2). He found that animals which were fed or which inhaled these substances lost appetite and at death showed "pecu liar" lesions in the liver. In 1936, Flinn and Jarvik (3) ex perimented on rabbits with three dif ferent compounds; (A) a mixture of tri- and tetraehlornaphthalene, (B) a mixture of tetra- and penta-chlornaphthalene and (C) a mixture of Ienes produced relatively unimportant pathological changes in the liver until extremely high concentrations were used. Animals exposed for 6 weeks to the higher chlorinations, however, in relatively low concentrations, regularly showed minor degrees of liver damage even though, as a group, they gave no clinical evidences of such toxicity while alive. Exposed to still higher concentrations, the rats lost weight and appetite, and began dying after 8 days' exposure--many with severe jaundice. Examination of the liver penta- and hexa-chlornaphthalene. of these animals at autopsy revealed They also used sublimates of (B) marked central fatty degeneration * A review of the literature on skin mani with necrosis of liver cells. festations appeared in the article by Mayers and Silverberg mentioned above (1). It is of considerable interest that : ' ,, j | < ; , ; f : ; ; : ; : i f : ; Feb. 1939} SYSTEMIC EFFI the exposed rats, which gavt cal evidences of disease, pron from acute yellow atrophy oi when given a very small dose tetrachloride--a dose well tol control animals. Two other points of inte brought out by the study: ( rats, which on autopsy shomarked pathological lesion liver, no abnormalities were the other organs--a finding common in experiments on but rather rare in humans from acute yellow atrophy of (2) even the less importar logical changes induced in th these chlorinated hydrocrbo: lower concentrations were foi very persistent, being preser months after cessation of exp Clinical Reports.--Clinical: cases of systemic poisoning chlorinated naphthalenes ar rare in spite of the length of these substances have beer No doubt the infrequency of ports has been, in part, due fii fact that cases of systemic ; are unusual occurrences-- ment of individual susc appearing to play an even : portant r61e than usual in t' tion--and second, to failuri part of physicians to recogniz poisoning. Until recently t been general lack of knowled toxicological properties of th rinated hydrocarbons, and still relatively little informal able regarding the clinical p industrial poisoning from the: The danger that lies in sm of knowledge is exemplified ii tion that recently came to t D TOXICOLOGY [vol. SI, no. S given off at 192C and 172C vely. Large doses, approx15 mg. per kg, were injected neously each day. als receiving compound (A) > sublimate of compound (B) no lesions attributable to these ces when killed at the end of hs. The 30 animals, however, had received the higher chlocompounds (B) and (C) and dimate of (C), all died in from 26 days. Autopsies uniformly extensive damage, next important study to be ied was that of Drinker, Warren ennett (4). These investigaIministered chlorinated hydro s by inhalation, subcutaneously f mouth, to white rats. Mixf (a) tri- and tetrachlornaphtha(b) penta- and hexachlornaph3 alone, and (c) with 10% refined lated diphenyl; and (d) chloridiphenyl were used. ;fly, these experiments showed, .he tri- and tetrachlornaphthaDroduced relatively unimportant logical changes in the liver until lely high concentrations were Animals exposed for 6 weeks to igher chlorinations, however, in mly low concentrations, regularly d minor degrees of liver damage Lough, as a group, they gave no il evidences of such toxicity alive. Exposed to still higher ntrations, the rats lost weight ppetite, and began dying after 8 exposure--many with severe ice. Examination of the liver ;se animals at autopsy revealed 3d central fatty degeneration necrosis of liver cells, is of considerable interest that Feb. 1939] systemic effects of chlorinated hydrocarbons 31 the exposed rats, which gave no clini cal evidences of disease, promptly died tion of the Labor Department in New York State, in which a physician had from acute yellow atrophy of the liver been treating a severe case of jaundice when given a very small dose of carbon tetrachloride--a dose well tolerated by control animals. in a young woman exposed to chlorin ated naphthalenes. After a long and Two other points of interest were brought out by the study: (1) in the rats, which on autopsy showed even serious illness, when the girl was on her way to recovery, the physician expressed the opinion that within a few weeks she would be able to return marked pathological lesions of the to her former work. Whatever the liver, no abnormalities were found in the other organs--a finding not un cause of the jaundice in this case, there is good reason to believe, on the basis common in experiments on animals, but rather rare in humans who die of the experimental work previously cited, that further exposure to such from acute yellow atrophy of the liver; substances would have entailed a (2) even the less important patho grave risk to the patient's life. logical changes induced in the liver by In 1934, Courtois-Suffit (5) reported these chlorinated hydrocrbons in the on the work of Touraine who, with lower concentrations were found to be his associates, examined 60 workers ex very persistent, being present even 2 posed to trichlornaphthalene and months after cessation of exposure. found mild digestive disturbances and Clinical Reports.--Clinical reports of dizziness in 13, but nothing of a more cases of systemic poisoning from the serious nature. chlorinated naphthalenes are as yet rare in spite of the length of time that these substances have been in use. No doubt the infrequency of such re ports has been, in part, due first, to the In 1935, Schwartz suggested the possibility of systemic disease from exposure to these substances in a talk before the American Public Health Association (6). fact that cases of systemic poisoning In 1936, three fatal cases of jaun are unusual occurrences--the ele dice in chlorinated naphthalene work ment of individual susceptibility ers were recognized in this country. appearing to play an even more im These were reported by Flinn (3) and portant r61e than usual in this situa- Drinker (4) who summarized the cases tion--and second, to failure on the briefly. part of physicians to recognize cases of poisoning. Until recently there has been general lack of knowledge of the All three of the men were young and in none could any predisposing cause other than their industrial exposure be toxicological properties of these chlo rinated hydrocarbons, and there is still relatively little information avail able regarding the clinical picture of industrial poisoning from them. The danger that lies in such a lack of knowledge is exemplified in a situa tion that recently came to the atten 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 exposed to a mixture of tetra- and penta-chlornaphthalene with 10% chlorinated diphenyl. In both, the 32 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [vol. 21, no. 2 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. Case 1. 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 sealing operations, but this could not be definitely ascertained. In any event, in the soldering of the con densers she 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-pustular 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. 3 TOXICOLOGY [vol. 21, no. 2 )f Drs. Kenneth Taylor, Edwin nd Scott Johnson on April 26, 1932 ni-comatose condition. She was r jaundiced on admission, ast medical history, obtained from i of the family, was entirely negai the exception of a tonsillectomy in ntil the onset of the present illness been unusually healthy and free nptoms of any kind, ccupational history was as follows: ing graduated from grammar school nded high school for 1 year and then 1 a job, her only one, with a concern ituring electrical condensers for use s. She worked at this one place for is and stopped working there 7 days ler admission to the hospital, work consisted of soldering and g condensers. It is possible, from irmation given, that she may also sisted in the sealing operations, but uld not be definitely ascertained, event, in the soldering of the conshe was exposed to the fumes of tri.rachlornaphthalene with which the sers were originally impregnated, same time she was exposed to fumes ligher chlorinated naphthalenes from ding operations conducted in close ity to the tables at which the solder s done. present illness began about 5 months admission to the hospital--or aplately 2 months after starting work in mt--at which time she noticed several ated areas on her face. These conto increase in severity and extent, msed her to visit the outpatient deent of the Lincoln Hospital. Here| was found in her urine and she was ;d to the skin clinic where a diagnosis te catarrhal jaundice was made. Her temperature, at that time, was 100. ise papulo-pustular eruption was also it on her face. On being questioned it, the patient stated that it had been it to her knowledge for about 2 is.f From then on she suffered from ivestigation revealed the fact that of her co-workers were also suffering a similar acneform eruption, and one iscontinued her work because of it. of these other girls suffered any nic disease. Feh. 1939] SYSTEMIC EFFECTS OF CHLORINATED HYDROCARBONS 33 increasing weakness and nausea. Her ap petite was poor; her skin became progres sively more jaundiced, and the pigmenta tion increased. 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 I About 6 weeks before admission her mother noticed that her eyes were yellow. About 3 weeks later she began to complain popliteal fold. Examination of the eyes revealed deep jaundice of the sclerae and the conjunctivae. 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 of severe headaches which continued un be associated with arsenic or quinine poi abated. This was followed in a few days by soning. a puffiness and swelling of the face, hands, Other positive physical findings were: feet and abdomen. slight injection of the throat; slight edema She continued at her regular work until of the feet and hands; an apical systolic 1 week before admission. On the morning murmur; abdomen distended and tympani of admission she began to have convulsive tic ; liver on percussion small, with tympany movements of the abdomen with involun extending to the very costal edge. tary bobbing of her head, unassociated Laboratory findings: These were as with any pain. At the same time there follows: seemed to develop memory defects and a Blood count on admission--White cells, change in mental status. On the way to 9,100; Red cells, 4,200,000; Polys., 80%; . the hospital in the ambulance she vomited. Lymphs, 20% Hemoglobin, 87%; Bleeding This was the first time vomiting had oc time, 4.5 minutes; Clotting time, 2.5 curred. She arrived in the hospital in a minutes; Platelets, 220,000. i state of prostration. Blood chemistry: Non-protein nitrogen, Summary of physical examination.--The 35, later 45,mg./lOO cc.;Protein, 6.9 mg./lOO patient gave the impression of being a cc.; Urea N. 20.83 mg./lOO cc., Creatinin, colored girl although she was, in reality, 2 mg./lOO cc.; Glucose, 88 mg./lOO cc.; Cho > white. She looked well nourished and well lesterol, 145mg./lOO cc.; Calcium, 8 mg./lOO : developed for her age. There was general cc.; CO combining power, 52; Albumin, i puffiness of the face, hands, feet and abdo- 2.5 mg./lOO cc.; Icteric index, 230; Van den 1 men. She was hiccoughing, and was fre- Berg, immediate direct reaction; Wasser; quently disturbed by a series of tetanic man, negative. contractions of the abdominal muscles asso Urine--Sp. gr. 1.008: Alkaline. Albu ciated with involuntary bobbing of the min negative. Sugar, a trace. Acetone, r head. The temperature was 100, pulse 1+. Bile pigment present. Urobilinogen , I 114, respiration 26. a trace. Few red and white cells. I . The first admission note stated, "paf tient is so jaundiced her face is black." Stools--Urobilin present. Spinal fluid--Pressure normal. Cells: j More careful examination of the face and 10, Lymphocytes. Clear. Glucose pres 5 neck revealed a negroid type of pigmenta- ent. Globulin absent. i | tion beginning at the hair line and extend X-ray examination--No evidences of * ing down to, and including, the neck. lesions of the heart and lungs; bones of | Besides this general pigmentation there skull, ribs, shoulder joints, clavicles, tibia j| were three areas somewhat darker than the and fibula. The gastric contents, and later, R rest, appearing very much like dabs of charH coal--one on each cheek below the eyes and || one on the chin. On close examination ft these black spots appeared to be the result f of aggregations of comedones. The scalp j did not share in the general dark pigmenta- | tion. It was of a yellowish color characteristic of jaundice. The skin of the thorax and the lower part Iof the body was dark brown with a yellow ish subtinge. Over the skin of the abdo 34 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [vol. 21, no. 2 at autopsy, the organs 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 dyscrasia, Addison's diabetes, hemochro matosis, industrial poisoning of unknown origin possibly due to arsenic, causing acute glomerular 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. Hochman, Assistant Medical Examiner. The report in full was as 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. Conjuiictivae and sclerae 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 size 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 stained. 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. Gall bladder small. Wall 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 somewhat thickened. Mucosa is injected. Microscopic examination--Liver--From size of a through and through transverse section one suspects that the entire liver was about i 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 I ; ; ` ' ; j 5 : < i : ; Feb. 1939] SYSTEMIC EFI of liver, judging from this p smooth. A typical picture of clear si low atrophy is revealed. Slide red area is composed of so-' atrophy" in which all the live disappeared, their place being i their normal supporting strc seems to have been spared, great blood cells, early fibroblastic p and older scar tissue. In thesi numerous bile ducts are seen, seem to have been spared destru yellow areas are composed of : generating islands of liver cells The toxin evidently has dest of the liver cells, leaving intae porting stroma, blood vessel: ducts. The latter seem to be r Those liver cells spared destri regenerated and have formed ye seen in the gross picture. The has been one or more attacks of he\ ing from the different ages of the process in various parts of liver. Skin--Shows an increased corium which stains deeply ' Some of the epidermal cells i deeper in corium than normal. Heart--Shows mild parei myocardial degeneration. Kidneys--Show severe epithi eration involving epithelium of glomeruli. No inflammatory : glomeruli. Adrenals--Show severe parer degeneration of cells. Pancreas--Shows intense <4 of cells of acini and of islets. Summary--An unknown tox dently caused a severe diffuse c volving most of organs, predom liver. The latter has evidently and recovered from previous a similar nature.* Case 2--F. D. A. young man, 24 years of af nutted to the New Haven Hospi 2, 1934, complaining of jaundice tory given was as follows: He had worked in a wire fact * Authors' italics. D TOXICOLOGY [vol. SI, no. S | opened in usual midline incision. I removed. Some remnants of thyII present. Lungs are free. Bronltain a bloody mucous. Mucosa 1, has yellowish tinge. Hemorinfarct about size of hen's egg in rer lobe. This is airless and dark jolor, firm. There are also similar areas in other lobes. Heart is small lows some sub-epicardial hemor- Some hypertrophy of left ventrialves thinned. Arteries natural, bile stained. No significant findings cardium or coronary arteries, ihagus is natural. Stomach is dis, contains some dark material. The are somewhat hypertrophied. The mm contains green chyme. The aispatent. The jejunum, ileum and gut are natural. Many petechial hagic areas noted in the mesentery ime enlargement of mesenteric lymph I t ; } fi er is Bmall, weight 720 gm. Capsule ed. Right lobe on section shows }f yellow surrounded by red areas, t lobe much firmer although liver cuts throughout. All ducts patent. Gall ;r small. Wall thickened throughout, lcreas is natural in size, somewhat Jted. Spleen is natural in size. On n, firm, dark red in color. Follicles omewhat indistinct. Kidneys show n cortex. Evidence of parenchymadegeneration of epithelial cells, de strips easily. No granulation, lerative changes in cells of glomeruli No glomerulitis. Uterus is small, metrium bile-stained. Ovaries are al in size; right contains corpus lu- cyst. Bladder wall is somewhat Bned. Mucosa is injected. croscopic examination--Liver--From if a through and through transverse >n one suspects that the entire liver ibout $ normal size. Liver segment y firm and composed of two distinct leeuliar types of tissue: (a) That coning major portion of parenchyma is 1 color; firm and elastic in consistency; ther areas are light yellow in color and cattered indiscriminately throughout sh areas. Yellow areas vary from 2 in. in diameter. External surface jj it i jS if Feb. m9] SYSTEMIC EFFECTS OF CHLORINATED HYDROCARBONS 35 of liver, judging from this portion, was wire with waxf from July to the middle of smooth. December, 1933. At that time he felt run A typical picture of clear subacute yel down and became jaundiced. He was seen low atrophy is revealed. Slides show that in the dispensary in January and found to red area is composed of so-called "red have an enlarged palpable liver. He then atrophy" in which all the liver cells have spent several weeks in another hospital with disappeared, their place being occupied by slight improvement in the jaundice. their normal supporting stroma, which In March, 1934, he returned to the job seems to have been spared, great numbers of in the wire factory. Following this, the blood cells, early fibroblastic proliferation jaundice became quite intense with increase end older scar tissue. In these red areas, in general malaise, anorexia, attacks of numerous bile ducts are seen. These also dizziness and loss of weight. Three days seem 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 generating islands of liver cells, no exposure to carbon tetrachloride or The toxin evidently has destroyed most chloroform. of the liver cells, leaving intact their sup Summary of physical examination--The porting stroma, blood vessels and bile temperature was 99, pulse 74, respiration ducts. The latter seem to be regenerated. 20, blood pressure 130/74. The patient was Those liver cells spared destruction have a thin well-developed man who appeared regenerated and have formed yellow islands moderately ill. There was bright yellow seen 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 ing from the different ages of the pathological viated, causing obstruction on the right, process in various parts of liver.* the mucous membranes injected and the Skin--Shows an increased density of tongue moderately coated. The tonsils corium which stains deeply with eosin. were enlarged and cryptic. Lungs were Some of the epidermal cells are slightly clear, heart normal, radial vessels soft, deeper in corium 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 Kidneys--Show severe epithelial degen upper edge of the liver dullness was in the eration involving epithelium of tubules and 6th interspace. glomeruli. No inflammatory reaction of Laboratory findings--These were as fol glomeruli. lows: Adrenals--Show severe parenchymatous degeneration of cells. Pancreas--Shows intense degeneration Urine--was dark yellow and was nega tive except for the presence of bile and uro bilin. of cells of acini and of islets. Summary--An unknown toxin has evi dently caused a severe diffuse cytolysis in Blood count--red cells, 4,380,000; hemo globin, 85%; white cells, 6,800; Polys., 65%; Lymphs, 29%; Large Monos., 4%; 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. Case S--F. D. Kahn test--negative. Liver function tests--Icteric index--30 to A young man, 24 years of age, was ad 50. Bromsulfonphthalein showed marked mitted to the New Haven Hospital on May 2, 1934, complaining of jaundice. The history given was as follows: f The waxes employed in this process are the higher chlorinated naphthalenes. These are used in a molten state in a bath He had worked in a wire factory coating through which the wire to be coated is passed. The process is partially but not Authors' italics. entirely enclosed. Exhaust ventilation is in use. 36 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [vol. SI, no. S ' Feb. 1939] SYSTEMIC EFI impairment: 100% retention in 5 min., pneumonia (bilateral), subpleural hemor 85% retention in 30 min. rhages, cloudy swelling of kidneys. f all three cases, a most care gation failed to reveal any Blood chemistry: Non-protein nitrogen, 28 mg./lOO cc.; Urea N, 11 mg./lOO cc.; Serum total proteins, 6.15 mg./lOO cc.; Serum total albumin, 2.66 mg./lOO cc.; Serum total globulin, 3.49 mg./lOO cc. A/G ratio, 0.76; Blood sugar, 68.0 mg./lOO 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 , .. ( * disposing cause for the com the first case in particular, healthy young girl on her the absence of any conditic posing to liver damage eith cc.; Blood calcium, 10.32 mg/100 cc.; bloody material. The history given was as i ing or following her expose 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. follows: He had worked in the same wire coating plant as the previous patient (F. D.). The present illness had begun with jaundice 2 months previously with no other symptoms. p 1 substances in question is clear. It is of interest to note tl the cases apparently had sufl Sugar tolerance test was within normal This continued for about 1$ months. at least one previous attack limits. X-ray of abdomen showed hepatic flexure of colon unusually high. Course. The patient was put on a high carbohydrate diet and his general condition 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 tis followed by a certain improvement before the on: ; fatal attack. In view of the fact that improved but the jaundice persisted. He treated by his family doctor with no relief. Warren and Bennett found was discharged on May 16, 1934 with the His condition became worse and he finally in organs other than the livi diagnosis of toxic hepatitis. He was admitted again on June 1, 1934 complaining of abdominal swelling of 3 days' duration, weakness, anorexia and became delirious and incoherent. Hos pitalization was advised. Summary of physical examination--The patient was comatose, irrational and vomit experimental animals, it is m that such lesions were consj ' ` all three of the cases here edema of the legs which had developed soon ing bloody material. Positive findings of Such lesions, are, indeed, u 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 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. l ings in cases of acute yellor of the liver in humans reg etiology. On the basis o knowledge, it would be imp urine, blood and stool showed no important No liver dullness percussable. a say whether they are the variations from the original findings with Course--His condition became rapidly primary intoxication or ai 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 C02 con tent was 54.54. Serum chloride was 98.0 worse, coma setting in soon after admission. The vomiting continued. The patient died about 24 hours after admission. Anatomical diagnosis--Extensive necro i secondary to liver damage light of the animal experime ever, one would incline to mg./lOO cc. sis and regeneration of liver; jaundice, view and speculate as to, 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 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. \ j i > played by length of exposu final pathological picture. It has been mentioned Drinker's (4) experiments, died. no evidence of clinical dise Anatomical diagnosis.* Extensive nec DISCUSSION | being exposed to the chlorina rosis, fibrosis and regeneration of liver, acute entero-colitis with edema, fibrosis of pancreas, acute pancreatitis, jaundice, as cites, edema of lower extremities, focal * Autopsies on this and the following case were performed on the pathological service of the New Haven Hospital by Dr. H. M. Zimmerman. Grateful acknowledgement is made of his courtesy in permitting use of the records. These three cases show the occur rence of similar pathological changes in the liver in three young adults known to have been working with chlorinated naphthalenes and diphenyls--all were exposed directly or indirectly to the higher chlprinated hydrocarbons. In ! i s I 1 | thalenes, promptly died fr< yellow atrophy of the liver w doses of carbon tetrachloridt as to be harmless to control This prompts speculation whether death from acul . atrophy of the liver in worl J TOXICOLOGY [vol. 21, no. 2 ia (bilateral), subpleural hemorloudy swelling of kidneys. Case S--C. C. g man 22 years of age was admitted !W Haven Hospital on February 28, i the complaints of jaundice, abpain, nausea and vomiting of laterial. The history given was as d worked in the same wire coating the previous patient (F. D.). The illness had begun with jaundice 2 previously with no other symptoms, ntinued for about 1) months, eks before admission be became lundiced and concomitantly de upper abdominal pain, malaise, ind finally vomiting--the vomitus g bloody in character. He was by his family doctor with no relief, iition became worse and he finally delirious and incoherent. Hostion was advised, wry of physical examination--The was comatose, irrational and vomit>dy material. Positive findings of tnce were as follows: Temperature evated. Blood pressure 102/68. ized jaundice, petechiae over the r surfaces of the arms; tenderness e upper quadrants of the abdomen, r dullness percussable. se--His condition became rapidly :oma setting in soon after admission, niting continued. The patient died 4 hours after admission. omical diagnosis--Extensive necro. regeneration of liver; jaundice, ymphadenitis of portal nodes; asperienteritis of jejunum; cloudy ; of heart and kidneys; acute pulcongestion; healing exanthematous fore-arms. DISCUSSION ie three cases show the occurif similar pathological changes in er in three young adults known e been working with chlorinated lalenes and diphenyls--all were d directly or indirectly to the chlprinated hydrocarbons. In Feb. 1939] SYSTEMIC EFFECTS OF CHLORINATED HYDROCARBONS 37 all three cases, a most careful investi larly exposed occurs only in those gation failed to reveal any other pre having some pre-existing substratum disposing cause for the condition. In of liver damage--such as might follow the first case in particular, that of a healthy young girl on her first job, the absence of any conditions predis an attack of catarrhal jaundice, for example--and that this might ac count, in part at least, for the fact posing to liver damage either preced that only a very occasional worker out ing or following her exposure to the of a large group will suffer from sys substances in question is especially temic effects of exposure to these sub clear. stances. In the three cases reported It is of interest to note that two of however, no history was given sug the cases apparently had suffered from gesting that any hepatic disorder prior at least one previous attack of hepati to exposure had occurred. tis followed by a certain degree of improvement before the onset of the fatal attack. The presence of a papulo-pustular eruption in two cases is of interest. In one it antedated the systemic symp In view of the fact that Drinker, toms. This type of eruption is char Warren and Bennett found no lesions acteristic of the dermatitis caused by in organs other than the liver in their chlorinated naphthalenes, and until experimental animals, it is noteworthy recently was the only disturbance at that such lesions were conspicuous in tributed to them. all three of the cases here reported. The presence of "aggregations of Such lesions, are, indeed, usual find comedones" such as were found in ings in cases of acute yellow atrophy Case I is also characteristic of the of the liver in humans regardless of skin eruptions produced by these sub etiology. On the basis of present stances. The question as to whether knowledge, it would be impossible to or not the skin eruption in such a case say whether they are the result of is in any way connected with the onset primary intoxication or are merely of systemic effects cannot be answered, secondary to liver damage. In the since thus far no correlation has been light of the animal experiments, how established between skin lesions and ever, one would incline to the latter systemic disease (1). view and speculate as to, the part It is interesting, therefore, that in played by length of exposure, in the Case I the skin eruption apparently final pathological picture. antedated all evidences of systemic It has been mentioned that in disease. Had the girl been promptly Drinker's (4) experiments, rats with removed from further exposure, when no evidence of clinical disease while it was first observed, it is possible that being exposed to the chlorinated naph her life would have been saved; or had thalenes, promptly died from acute the physicians first called upon to yellow atrophy of the liver when given treat the jaundice (of whatever origin) doses of carbon tetrachloride so small in her case, or in the second case here as to be harmless to control animals. reported, recognized the danger of This prompts speculation as to continuing exposure to the chlorinated whether death from acute yellow naphthalenes, these deaths might pos atrophy of the liver in workers simi sibly have been averted. 38 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY [vol. 21, no. 2 Recommendations foe 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 which have been carefully worked up, so that the clinical disease entities resulting from such exposure can become further clarified and thus more 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 not 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. Summary 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. Mayers, M. R., and Silverberg, M. G.: Skin conditions resulting from expo sure to certain chlorinated hydro carbons. This J., 20, 244 (1938). 2. Lehmann, K. B.: Kurzes Lehrbuch der Arbeits- und Gewerbehygiene. 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., SB, 118 (1936). 4. Drinker, C. K., Warren, M. F., and Bennett, G. A.: The problem of pos sible systemic effects from certain chlorinated hydrocarbons. This J., 19, 283 (1937). 5. Courtois-Suffit: Etude sur l'intoxication professionnelle par le trichloronaphthalene. Ann de med. legale, 1/,, 422 (1934). Abstr. of paper by Touhaine, A., and Men^trel, B.: Der matoses professionnelles par le naphthaline et ses derives. Prat, med. franc., IB, 335 (1934). 6. Schwartz, L.: Dermatitis from synthetic resins and waxes. Am. J. Pub. Health, 26, 586 (1936).