Brit. J. industr. Med., 1955, 12, - oem.bmj.com · Esbach's picric acid test was carried out on 15 cases in which proteinuria had been demon-strated by testing with trichloracetic

Brit. J. industr. Med., 1955, 12, 181.

EMPHYSEMA AND PROTEINURIA IN MEN CASTINGCOPPER-CADMIUM ALLOYS

BY

J. A. BONNELLFrom the Department for Research in Industrial Medicine (Medical Research Council), London Hospital

(RECEIVED FOR PUBLICATION DECEMBER 7, 1954)

Diseases of occupational origin occur as acute orchronic illnesses. The former are usually dramaticand the connexion between symptoms and occupa-tion is obvious. An insidious illness developing overmany years and due to long exposure to smallquantities of a poisonous substance may long gounrecognized as being of occupational origin.

Since all the recorded cases of chronic cadmiumpoisoning had occurred among men employed in thealkaline accumulator industry, it was decided toinvestigate other industries where cadmium is used.This paper describes five cases of chronic cadmiumpoisoning and reports the results of an investigationof men employed at two factories in England wherean alloy of copper and cadmium is manufactured.

Because cadmium increases the wear and dura-bility of copper without reducing significantly itselectrical conductivity the alloy is used to replacepure copper for certain purposes. These includepost-office telephone wires, high-tension electricalconductor cables, and overhead contact wire forelectrically powered omnibuses and trains.

Review of the LiteratureCadmium and its salts have been known to be

acutely toxic substances since 1858. The first casesof acute cadmium poisoning were recorded bySovet in 1858 (quoted by Prodan, 1932) followingthe inhalation of fine particles of cadmium carbonatewhich had been used as a silver polish. Numerousreports of acute cadmium poisoning have beenpublished since that time (Frant and Kleeman,1941: Huck, 1947).

Stephens (1920) first drew attention to the factthat cadmium might cause chronic ill health. Hedescribed the case of a man who had been exposedto small quantities of cadmium in the atmosphere ofa zinc spelter works. The symptoms were recurrentbronchitis, loss of weight, and weakness, and theman had been receiving compensation for sometime for suspected lead poisoning. At necropsy he

was found to have chronic interstitial nephritis andhypertrophy of the heart muscle. The liver wasfound to contain 0-91 grain of cadmium per poundweight and 0-77 grain of zinc per pound, despitethe fact that calamine the zinc ore contained only05to 1 5%ofcadmiumand 35to40Oofzinc. Stephenssuggested that the symptoms were due to cadmiumand stated that he had seen six similar cases over aperiod of eight years. Chronic illness due to cad-mium was not mentioned in the medical literatureagain until Mancioli (1940) described chronicrhinitis and pharyngitis in men plating metals withcadmium by an electrolytic process. Mancioli'spatients complained of dryness and irritation of thepharynx, a burning sensation in the nose withepistaxis, and were found to have ulcers in thecartilaginous parts of the nose and in the naso-pharynx.

In 1942 Nicaud, Lafitte, and Gros investigated agroup of workers in an alkaline accumulator factoryin France. No details are given about the number ofpeople employed in the factory or the number ofpeople taking part in the investigation. Theydescribe impairment of general health with markedloss of weight, an iron-deficiency anaemia, andsevere osteoporosis with pseudo-fractures of thelong bones such as are seen in osteomalacia orrickets. They state that chronic bronchitis andemphysema were occasionally seen in their patientsbut they were of the opinion that the exposure tocadmium was in no way connected with the condi-tion of the lungs. The skeletal changes were curedby administration of calcium and vitamin D,suggesting that nutritional deficiencies, perhapsconnected with the Second World War, may haveplayed some part in their production.

Barthelemy and Moline (1946) and Princi (1947)found that men who had been exposed to cadmiumfor two or more years developed a golden-yellowring at the alveolar margin of the teeth. Apart fromthis discoloration of the teeth, Princi found no

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BRITISH JOURNAL OF INDUSTRIAL MEDICINE

evidence of chronic ill health among a group of 20men who had worked as cadmium smelters for sixmonths to 22 years. The average concentration ofcadmium in the atmosphere was found to be as

high as 31-30 mg. per cu. m. and the men were

found to be excreting between 11 and 125 ,ug. ofcadmium per litre of urine. Princi concluded thatexposure to cadmium in these conditions did notcause chronic ill health. Hardy and Skinner (1947)investigated a group of five men who had beenexposed to cadmium fume for from four to eightyears. These men complained of chronic cough andgastro-intestinal symptoms. Although no definiteconclusion could be drawn from such a smallgroup, it was suggested that these symptoms were

due to cadmium and that further investigation was

necessary to confirm this opinion.In 1946 frequent complaints of tiredness and

shortness of breath among men employed in an

alkaline accumulator factory in Sweden led to an

investigation by Friberg (1948, 1950). The men

made small briquettes of cadmium and iron whichcompose the negative electrode of the accumulator.During manufacture finely divided cadmium oxidedust passed into the working atmosphere andsettled on the floor, machines, and benches and on

the clothes, hands, and faces of the workers. Of 58men investigated, 43 had done this work for more

than nine years and complained of symptoms. Inorder of frequency these were dyspnoea, excessivetiredness, impairment of the sense of smell, cough,and a sensation of dryness of the mouth. Onexamination the abnormal findings were emphysemafor the group as a whole compared with a controlgroup, proteinuria in 35 of the 43, impairment oftenal function in nine cases, a raised E.S.R. in 31,and anosmia in 14. The average haemoglobin valuein this group was lower than normal. Fifteen menwho had worked in the same factory for less thanfour years were free from symptoms and no abnor-mality was detected on examination.The urinary protein could not be demonstrated

unequivocally by the boiling test, but a positiveresult was obtained by testing with trichloraceticacid. Esbach's picric acid test was carried out on

15 cases in which proteinuria had been demon-strated by testing with trichloracetic acid. TheEsbach test was negative in 12 cases but an opales-cence was observed in seven. The protein was

precipitated with full saturation of the urine withammonium sulphate but not with 50% saturation.The electrophoretic mobility was lower than ordinaryalbumin at the protein concentration studied, andcorresponded more closely to that of alpha-globulin.Electrophoretic analysis was also carried out on

five cases after concentrating the urinary proteinand this showed three or four components, thelargest of which was similar to the protein men-tioned above. Examination by ultracentrifugeindicated that the molecular weight of this proteinwas about 20,000 to 30,000.

Administration of cadmium dust to rabbits byinhalation for two to three hours daily for sevenand nine months resulted in the appearance ofproteinuria in the majority of the animals. Thisprotein had similar characteristics to the proteinfound in the urine of the workmen. All the rabbitsdeveloped emphysema, and inflammatory foci werefound in the kidneys of the majority. In a laterpaper Friberg (1952) describes animal experimentsusing radioactive cadmium. It was found that onlysmall amounts of cadmium were excreted in theurine until the proteinuria appeared. There wasthen a striking increase in the quantity of cadmiumexcreted, and the concentration of cadmium in theurine was found to bear a direct relationship to theamount of protein in the urine. Friberg suggeststhat cadmium excreted in the urine is bound to theprotein.Baader (1951) investigated a group of 11 workers

in an alkaline accumulator factory' in Germany.Eight of these, seven men and one woman, werefound to have emphysema, proteinuria, and loss ofweight. Baader considers that a watery dischargefrom the nose, which he calls " cadmium snuffles ",is an important early sign. He gives a detaileddescription of a young man aged 39 in whom thiswas the first symptom. Eight years later he was sodisabled by dyspnoea that he was forced to give upwork and he died after three years. Necropsyshowed severe emphysema, fatty infiltration of theliver, and toxic nephrosis. The renal lesion is notdescribed in detail, but it is important to note that aprotein was excreted in the urine which gave similarreactions to that described by Friberg. Althoughthe man had not been working with cadmium forfour years before death, there were large deposits ofcadmium in the liver and kidneys.

Friberg and Nystrom (1952) report the results ofre-examination of the men exposed to cadmium formore than nine years in the alkaline accumulatorindustry in Sweden. There had been no furtherexposure to cadmium. Five of these 43 men haddied. In two cases death was due to emphysema.Two others had died of coronary thrombosis; severerenal damage attributed to cadmium was found atnecropsy. One man died from acute pancreatitis;the lungs were found to be emphysematous.

In nine of the remaining 38 men there wasevidence to suggest that the disease had progressed.

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EMPHYSEMA AND PROTEINURIA IN CADMIUM WORKERS

Increased dyspnoea was complained of by five,proteinuria had developed in four, and in threethere was deterioration of renal function assessedby testing the maximum specific gravity of the urine.The symptoms and signs in 25 men were unchanged,whereas in four other men there was a distinctimprovement in the performance of tests ofrespiratory function.

In Friberg's opinion the prognosis for mensuffering from emphysema was favourable providedthey were removed from exposure to cadmiumbefore the symptoms became severe. Consideringthat four new cases of proteinuria had occurred andthe renal function tests in three men showed greaterimpairment, Friberg suggests that the renal lesionmay eventually become a more important cause ofdisability than emphysema in many of his cases.Two fatal cases of emphysema in men casting

copper-cadmium alloys were reported by Lane andCampbell (1954). The emphysema developedrapidly over a period of two years without precedingchronic bronchitis or asthma. In one case thediagnosis was confirmed at necropsy. There waswidespread emphysema affecting both lungs. Inmany places the lung substance had been reducedto a coarse spongework but a narrow zone of lung0 5 to 2 cm. wide under the pleura had been spared.There were therefore no emphysematous bullae onthe surface of the lungs. There was little evidence ofchronic bronchitis. The cadmium content of thelung was 277 ,ug./100 g. of tissue, of the kidney233 ,ug./100 g., and of the liver 25 tlg./100 g.

Manufacture of Copper-Cadmium AlloysThe two factories at which the investigations were

made will be referred to as factory A and factory B.Both factories produce alloys of copper containing 0 5to 1% of cadmium. The details of the process and thetypes of furnace used in the two factories differ but themethod is the same in principle. A master alloy con-taining up to 50% cadmium is manufactured at bothfactories by a process which will be described, andknown amounts of this alloy are added to molten copper.

Process at Factory A.-The master alloy is made in acoke-fired pit-fire furnace and contains 33XO% cadmium.Pure cadmium is placed in a crucible which is loweredinto the pit fire. When the cadmium is molten, purecopper in the form of copper wire is added. Exhaustventilation through a flue at the upper half of the pitremoves the cadmium fume. As the metals in thecrucible become molten they are stirred by the furnace-man to ensure thorough mixing. When the mixing iscompleted a cover is placed over the crucible before it isremoved from the furnace. The molten metal is pouredinto moulds under exhaust ventilation.At one time the low-percentage cadmium alloys were

produced in this type of furnace. Copper was placed inthe crucible and lowered into the pit fire; when the

copper was molten the master alloy was added and themix stirred. Since the stirring was performed manuallyand there was no exhaust ventilation over the pit themen were exposed to a high concentration of cadmiumfume.The pit-fire furnace is now used only for the manu-

facture of the master alloy. The present method ofmanufacture of the low-percentage alloys is by means ofan electrically heated, mechanically controlled furnacecalled a rocker resistor furnace situated in the sameworkshop. This furnace is barrel shaped and balancedat each end on rockers (Fig. 1). It is heated by a carbonelectrode which passes through the centre of the furnace.Bars of pure copper are introduced into the furnacethrough a door on the long side. The door is closed andthe tap-hole is plugged with fireclay. The copper meltsin approximately 50 minutes, and at this stage a knownamount of the master alloy is added through the door,which is quickly closed. The total charge is 4 cwt. Thefurnace is rocked to and fro in its long axis by mechanicalmeans to ensure thorough mixing. Since the boilingpoint of cadmium is 767° C., and the temperature of themolten copper in the furnace is 1000 to 11000 C., a largeamount of finely divided cadmium oxide fume is pro-duced each time cadmium is added to molten copper.This can be seen as a dark yellow cloud similar inappearance to nitrous fumes.

Process in Factory B.-The master alloy is manu-factured in an oil-fired pit-fire furnace (Fig. 2) andcontains 50,' cadmium. The process is different fromthat in factory A in that the copper is placed in thecrucible first and when it becomes molten pure cadmiumis introduced. Clouds of cadmium fume are produced,and there are no ventilation hoods to remove the fumefrom the atmosphere. The mix is stirred manuallyduring and after addition of the cadmium and it is thenpoured into moulds. The workmen wear cotton-woolpads over the nose and mouth.The low-percentage copper-cadmium alloy is produced

in oil-fired tilting furnaces (Fig. 3) in a different workshop.The furnace stands upright and consists of an outershell lined by fire brick. A crucible containing thecopper is placed inside this shell and a space of 2 to 3 in.remains between the crucible and the furnace wall toallow the flames of the burning oil to heat the crucible.When the copper becomes molten the master alloy isadded, the mixture is stirred manually, and the alloy ispoured into moulds. Hoods with powerful exhaustventilation are placed over these furnaces by the workmenduring casting operations.The working conditions in both factories are likely to

have been very much worse during the Second WorldWar when the black-out interfered with ventilation.

Method of InvestigationIn each of the factories there was a small group of men

who were working on the manufacture of copper-cadmium at the time of the investigation or who haddone so at some time in the past. There was also alarger group of men in each factory who worked in thevicinity of the copper-cadmium furnaces. Control

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184 BRITISH JOURNAL OF INDUSTRIAL MEDICINE

_ . . _ , _ §.°... .... ~~~~~~~~~~~~~~~~~~~~.

FIG. 1.-Rocker furnace in factory A.

FIG. 2.-Oil-fired pit- fire furnace in factory B.

FIG. 3.-Oil-fired tilting furnace in factory B.



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groups of men of comparable ages who did similar workbut had never at any time been exposed to cadmiumwere examined at each factory.The men were asked to volunteer to take part in the

survey. Each man was interviewed and a clinical exami-nation made. The occupational history, the past medicalhistory, and the family history were obtained, andspecific inquiry was made about suggestive symptomssuch as a watery discharge from the nose, loss of senseof smell, yellow discoloration of the teeth, shortness ofbreath, abdominal pain, and episodes of metal fumefever. At the clinical examination the height, weight,and blood pressure of each man were recorded. Bloodwas taken by venepuncture for estimation of the haemo-globin concentration, erythrocyte sedimentation rate(Wintrobe), haematocrit, and the plasma proteins. Eachman was asked to provide an early morning specimen ofurine and 24-hour specimens were obtained from asmany of the workmen as possible. They were asked tocollect the specimens away from the factory and pre-ferably at week-ends. The early morning specimens ofurine were tested for protein, blood, and sugar. Intesting for the protein, an equal volume of 250' tri-chloracetic acid was added to the urine in a test-tube andallowed to stand for 10 to 15 minutes. The urine wastested with 30' sulphosalicylic acid in a similar way.The heat test for protein and Esbach's test were done onall urines which gave a positive reaction with trichlor-acetic and sulphosalicylic acids. The urine was testedfor sugar by Benedict's test and for blood by the benzidinetest. The cadmium content of the 24-hour specimens ofurine was estimated.The respiratory function was tested in all the men who

attended for examination by measuring the vital capacity,the maximum ventilatory capacity at controlled rates ofbreathing, and the expiratory fast vital capacity Theseare tests of the ventilatory capacity of the lungs. Fromthe data obtained by measuring the vital capacity andmaximum ventilatory capacities, the swept fractions atgiven respiratory rates were calculated. These tests andthe detailed results are described separately (Kazantzis,1955). In order to assess the significance cf these tests,the results obtained from the study of control groups ateach factory are considered as normal for the populationinvestigated. The outer limits of normal represent themean plus or minus twice the standard deviation for eachof the control groups.

All men taking part in the investigation were asked toattend for chest radiographs. At factory A four radio-graphs of the chest were taken in each case. These werepostero-anterior views in deep inspiration and deepexpiration, and corresponding left lateral views followingthe recommendation of Knott and Christie (1951). Infact it was found that the opinion of the radiologist,based on seeing only postero-anterior views, was notinfluenced by the appearances in the lateral views(Simon, 1953). It was decided therefore to omit takinglateral chest radiographs of the men examined atfactory B.The cadmium content of the working atmosphere was

estimated at both factories. The methods employed and

the results obtained are discussed in detail by King(1955).

In factory A brass, bronze and copper-cadmium alloysare manufactured in the same workshop. Although only14 men were casting copper-cadmium, 38 others wereengaged in the manufacture of brass and bronze. Theyhad worked in the casting shop for from two to 25 years.Since the workshop was comparatively small (150 ft. by75 ft.) it was considered that all these men were at riskand they have therefore been included in the exposedgroup (Group IA). In addition, six men had worked inthis workshop in the past, three manufacturing copper-cadmium and three on the brass furnaces. They havealso been included. The total number in Group 1A istherefore 58 men (Table 1). Seven other men working

TABLE 1ANALYSIS INTO AGE GROUPS OF MEN EXPOSED TO

CADMIUM AND CONTROLS

Factory A Factory BAge inYears Exposed Control Exposed Control

Group (IA) Group (CA) Group (IB) Group (CB)25 - 1 1 425-34 4 3 11 1035-44 13 12 15 1645-54 21 25 9 955-64 17 18 5 465+ 3 1 1 I

Total i 58 60 42 44

as brass founders in the alloy casting shop refused to takepart in the investigation. Early morning specimens ofurine were obtained from these men, however, and allwere found to be normal. Four men who had workedcasting the copper-cadmium alloy were absent fromwork owing to sickness. They have not been includedin Group IA but they have been investigated in hospitaland their case histories are recorded.The control group was made up of 60 men in the same

age distribution who volunteered for examination(Group CA, Table 1). They had all worked in differentdepartments of the same factory, but they had never atany time been exposed to cadmium.At factory B the low-percentage copper-cadmium alloy

was manufactured at one end of a large workshop(440 ft. by 180 ft.). There were 15 men employed at thetime of the investigation. Four men manufactured themaster alloy in a separate department in another part ofthe works. There were therefore 19 men employedcasting copper-cadmium. They had worked with cad-mium for from three to 27 years. A further 23 men hadbeen engaged in the manufacture of the alloy for periodsvarying from 18 months to 28 years, but at the time of thesurvey were employed in other departments of thefactory. These men were included in the exposed group(Group 1B, Table 1) making a total of 42. The controlgroup was made up of 44 men in the same age distribu-tion who had worked in either the brass or the ironfoundry for up to 30 years but who had never beenexposed to cadmium (Group CB, Table 1).One hundred and eighty-seven men worked in other

sections of the main workshop refining pure copper and

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casting arsenical copper, bronze and silver bronze, orsorting, inspecting, and cutting the ingots and bars whichwere cast in the workshop. Of these 187 men, 130 hadbeen employed for more than 12 months and 21 othershad at some time in the past been employed in thisworkshop but at the time of the survey were working inother departments of the factory.

It was estimated that the exposure to cadmium ofthese 151 men was less than that of men doing similarwork in factory A because of the different lay-out inthe two factories and the much larger workshop atfactory B. They were therefore considered as a separategroup in whom the extent of exposure to cadmium wasdifficult or impossible to assess. Since it was obvious,however, that all were at risk of absorbing some cadmiumfume, they were examined. There were no cases in thisgroup in whom the findings were consistent with thediagnosis of chronic cadmium poisoning, and theresults of investigation of this group will not be discussed.

Results

In the two factories 100 men, who had beenexposed to cadmium fume were examined. Of these,nine had emphysema and proteinuria, three hademphysema without proteinuria, and seven hadproteinuria without emphysema (Tables 2 and 3).In addition four men at factory A had been forced togive up work because of disabling shortness ofbreath. They were admitted to hospital for investi-gation and their case histories are reported separatelytogether with that of one man from factory Bwho though seriously disabled was still at work atthe time of the survey (Table 7). One of the fourmen from factory A has since died and the necropsyfindings are described.

In this investigation independent assessments ofthe respiratory system were made by clinical andradiological examination and by respiratory functiontests. The clinical diagnosis of emphysema wasmade only when there was a definite history ofdyspnoea on effort in a man who had on examina-tion poor chest movement with hyper-resonance on

percussion and reduction in the areas of liver andcardiac dullness. The presence or absence ofbronchospasm was noted. Heart disease and otherlung disease were excluded as far as this is possibleby clinical examination alone. The diagnosis ofemphysema by clinical examination and radiographyis notoriously difficult and there is much disagree-ment about the specificity of various tests of respira-tory function. For the purpose of this investigationthe diagnosis of emphysema was made by clinical or

radiological examination supported by evidence ofimpairment of respiratory function assessed as a

result of tests referred to above : unless two ofthese criteria have been satisfied a diagnosis ofemphysema has not been made in any man takingpart in the survey.

The demonstration of protein in the urine bytesting with trichloracetic or sulphosalicylic acids isan objective test which can be confirmed by testingrepeated specimens of urine. This type of proteinuriahas been taken to indicate absorption of toxicamounts of cadmium and to support the diagnosisof chronic cadmium poisoning.

Factory A.-Nine of the 58 men in Group lAwere considered to be abnormal. Four had emphy-sema and proteinuria (Table 2). Two had emphy-sema without proteinuria. Three had proteinuriaalone. Case Al1 had clinical evidence of emphysemaonly, respiratory function tests and chest radio-graphs were normal: for the purpose of thisinvestigation he is not considered as a case ofemphysema. Six of these men had worked on thecopper-cadmium furnaces for a minimum of 17years. The other three cases (All, A12, and A13)had worked in the vicinity of these furnaces for40, 10, and eight years respectively (Table 4).

TABLE 4EXPOSURE TO CADMIUM IN YEARS

Years of Factory A Factory BExposure (Group 1A) (Group IB)

5 4 185_9 4 (1)* 11 (3)*10-14 12 7 (2)*15-19 12 (3)* 2 (2)*20+ 26 (5)* 4 (3)*

*Numbers of men affected.

One man out of the 60 in Group CA had pro-teinuria. The protein gave the normal reactions ofurinary protein to heat and picric acid and the manwas found to have hypertension. No cadmium wasfound in a 24-hour specimen of urine. There wereno cases of emphysema in this group. Chronicbronchitis was diagnosed on clinical examination infour men but respiratory function tests and x-rayexamination of the chest were normal. In five othermen localized areas of emphysema were diagnosedby the radiologist but these men were free ofsymptoms and the respiratory function tests werenormal.The results of the respiratory function tests are

discussed in full by Kazantzis (1955). It was foundthat there was a significant difference in the per-formance of the tests between the exposed andcontrol groups (Groups IA and CA).The vital capacities (V.C.) and the maximum

ventilatory capacities (M.V.C.) are similar in thetwo groups, but the mean swept fractions at 30, 50and 70 respirations per minute are significantlylower in Group IA than in Group CA. The samesignificant difference is found between these groupsfor the mean time constant of the expiratory fastvital capacity curve (p<001).

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TABLE 5

RESULTS OF BLOOD EXAMINATION

189

ErythrocyteSedimentation Rate(Wintrobe, mm./hr.)

S.D. Range±6-64+5 89±5-16±4-11

1-391-251-212-23

The mean and standard deviations of the bloodexaminations are summarized in Table 5. Therewas no significant difference in the plasma proteinlevels.

Eight of the men from Group IA who hadworked on the copper-cadmium furnaces hadnoticed soreness of the nasal mucous membraneaccompanied by a thin watery discharge from thenose, but this ceased shortly after leaving work atthe end of the day. None admitted to an impairmentof the sense of smell. Because the dental hygiene ofthese men was so poor it was quite impossible todiscover whether the characteristic yellow discolora-tion of the teeth ascribed to cadmium was presentor not.

Seventeen men in Group IA had worked on thecopper-cadmium furnaces and 10 had sufferedfrom metal fume fever while working with cadmium.The majority of the men in Group IA had experi-enced similar symptoms at some time following theinhalation of zinc fume during brass casting.The results of the analysis of the 24-hour speci-

mens of urine are summarized in Table 6. A sampleof 200 ml. of urine was wet ashed by boiling witha mixture of concentrated sulphuric and nitricacids. A polarograph was used to measure thequantity of cadmium present.

TABLE 6CADMIUM EXCRETION IN 24-HOUR SPECIMENS OF

URINE

24-Hour No Greater thanGroup Specimens Cadmium Cadmium 30 gg.

Received Found per Day

IA 44 30 14 15CA 49 7 42 1lB 39 32 7 26CB 40 6 34 2

Twenty-four hour specimens were obtained from44 of the 58 men in Group IA. Thirty of these menwere excreting cadmium in the urine and 15 ofthese were excreting more than 30 ltg. in 24 hours.Forty-nine of the 60 men in Group CA provided24-hour specimens. Seven of these men wereexcreting cadmium in the urine but only one wasexcreting more than 30 pLg. in 24 hours (Table 6).

Factory B.-Ten of the 42 men in Group lB wereconsidered to be abnormal. Five had emphysemaand proteinuria (see Table 3 and Case Bl in Table 7),four had proteinuria alone, and one had emphysemawithout proteinuria. Case B2 did not complain ofsymptoms but a diagnosis of emphysema was madeon chest radiographs and abnormal respiratoryfunction tests. All 10 men had been exposed tocadmium for over five years (Table 4).

Proteinuria was not demonstrated in any of the44 men in Group CB. Two men were considered tohave x-ray changes characteristic of emphysema.Although both were symptom-free, one showedimpaired respiratory function.The results of the respiratory function tests are

discussed in detail by Kazantzis (1955). It wasfound that there was no significant differencebetween the vital capacities, the maximum ventila-tory capacities and the mean swept fractions of themen in the exposed and control groups (Groups lBand CB). The mean time constant for the expiratoryfast vital capacity curve of the men in Group lBwas, however, significantly different from that of themen in Group CB (0-025 >p >001). When the menin Group lB who had been exposed to cadmiumfor more than ten years were compared with GroupCB, the difference between the mean time constantfor the expiratory fast vital capacity curves shows ahigher level of significance (p<0 01).The results of estimating the total lung volume

and its subdivisions are discussed by Buxton (1955).Thirty-seven men from Group lB were examined.The men with more than 10 years' exposure showeda significant increase in the mean value of theresidual air expressed as a percentage of the totallung volume (p< 0-005). None of the control group(Group CB) were abnormal. There was no signifi-cant difference in the mean value for the total lungvolume nor in the efficiency of intrapulmonarymixing between Groups lB and CB.As in factory A there were differences in the mean

haemoglobin, erythrocyte sedimentation rates, andhaematocrit readings in the two groups. Theresults are given in Table 5, but since these differences

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are slight and are the result of single observations,no conclusions can be drawn from them. Theplasma protein levels were in close approximation.

Specific inquiries failed to reveal evidence of lossof sense of smell, yellow discoloration of the teeth,or abdominal pains, and none had experienced thesymptoms of metal fume fever.The results of the analysis of the 24-hour speci-

mens of urine are summarized in Table 6. Twenty-four hour specimens were obtained from 39 of the42 men in Group lB. Thirty-two of these men wereexcreting cadmium in the urine and 26 of these wereexcreting more than 30 ,ug. in 24 hours. Forty menout of the 44 in Group CB provided 24-hourspecimens. Six of these men were excreting cadmiumin the urine but only two were excreting more than30 Vg. in the 24 hours. The output of cadmium inthe urine from the men in Group lB was found tobe greater than that of the men in Group IA.

DiscussionCadmium oxide in the form of dust or fume is

extremely toxic. Inhalation of high concentrationsgives rise to acute chemical pneumonitis. Stephens(1920), Mancioli (1940), and Hardy and Skinner(1947) suggested that the presence of small amountsof cadmium in the working atmosphere might giverise to chronic poisoning. Friberg (1950), as theresult of an investigation ofmen exposed to cadmiumdust in the manufacture of alkaline accumulators inSweden, described a chronic illness characterizedby emphysema and the excretion of a protein of lowmolecular weight in the urine. Baader (1951)described a similar syndrome in men manufacturingthis type of accumulator in Germany.The results of the present investigation provide

further evidence that repeated exposure to cadmiumfume does cause chronic ill health. The illness ischaracterized by progressive shortness of breath andby the excretion in the urine of a protein complex oflow molecular weight. Death occurs as the resultof pulmonary heart disease or renal failure. In suchcases where the occupational history reveals that thepatient has been at risk of absorbing cadmium fumeor dust the diagnosis of chronic cadmium poisoningis justified.

Tests of the ventilatory capacity of the lungswhich were carried out at both factories showedthat there was a definite impairment of respiratoryfunction in the groups of men exposed to cadmiumwhen compared with control groups from the samefactories.The clinical examination and chest radiographs

of the men who complained of shortness of breathsuggested that the disability was due to emphysema.

The development of the symptoms and the course ofthe disease in these cases are unlike the chronichypertrophic emphysema which follows long-standing chronic bronchitis or bronchial asthma,where cough precedes by many years the onset ofdyspnoea on exertion. In only a few of the casesfound in this investigation was a history of chroniccough obtained. Dyspnoea uisually developedgradually over a period of months or years with thedevelopment of a cough in the later stages. In somecases cough and dyspnoea followed immediatelyafter a severe upper respiratory tract infection.Whitfield (1952) reviewed the aetiological factors in103 cases of emphysema and found that 69 gave ahistory of long-standing chronic bronchitis orbronchial asthma. Only four cases occurred in hisseries in which the emphysema had developedwithout a history of preceding pulmonary symptoms.

In studying the men in Group lB who had beenexposed to cadmium for more than 10 years.Buxton found that the volume of the residual airand the residual air expressed as a percentage ofthe total lung volume were both significantlyincreased. This is often found in emphysema,When, however, the mean value for the total lungvolume of this group was compared with that of thecontrol group (Group CB) it was found to beunaltered and the range was not increased. Further-more, the mixing coefficients were within normallimits. These results suggest that there are certaindifferences between the emphysema which developsin men exposed to cadmium fume and the chronichypertrophic emphysema which follows long-standing chronic bronchitis. In the latter theintrapulmonary mixing coefficient is low and thetotal lung volume is increased.Lane and Campbell (1954) describe the necropsy

findings in a man who worked on the copper-cadmium furnaces at factory B. In their case notonly were there no emphysematous bullae at theperiphery of the lungs but there was a narrow zoneof normal lung tissue under the pleura and chronicbronchitis was neither widespread nor severe.Thus, the mode of onset, the results of respiratoryfunction tests, and the findings at necropsy in onecase support the view that the emphysema whichdevelops in men who have been exposed to cadmiumfume is different from the chronic hypertrophicemphysema which follows upon chronic bronchitis.Chronic bronchitis, however, may develop as acomplication in men whose lungs have alreadybeen damaged by the repeated inhalation ofcadmium.Knowledge of the pathological process and the

morbid anatomy of chronic cadmium poisoning

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will be fully understood only when more cases havebeen studied at necropsy.

Friberg (1950) found that the majority of men

who had been exposed to cadmium oxide dust inthe alkaline accumulator industry for more thaneight years excreted a protein in the urine whichdid not give the usual reactions of urinary proteinor Bence-Jones protein. Electrophoretic analysisand examination with the ultracentrifuge suggestedthat this protein was a globulin and that the mole-cular weight was in the region of 20,000 to 30,000.

In the present investigation 19 men were found tohave proteinuria which gave reactions to routineclinical laboratory tests similar to those of theprotein described by Friberg. The boiling test forprotein was unreliable; in some cases it wasnegative and in others a slight cloudiness only was

apparent. It was found that non-specific proteinprecipitants such as 25% trichloracetic acid and3% sulphosalicylic acid gave positive reactions whenthe boiling test was negative or doubtful. Esbach'spicric acid reagent produced a general cloudiness on

standing but the protein did not settle in the tube sothat quantitative determinations by this methodwere unreliable. Kekwick (1955) describes theresults of physico-chemical examination of theserum and of the protein excreted in the urine offour men chosen at random from these 19 cases.The electrQphoretic analyses of the sera showedthat the proportion of gamma globulin was abnor-mally high in two cases and that the alpha globulinproportion was slightly above the normal value inall four cases (Kekwick, Table). There did notappear to be a uniformly consistent deviation fromthe normal which could be attributed unequivocallyto cadmium poisoning. Except for one case theelectrophoretic pattern of the urinary proteinswas similar to those shown in Fig. IA (Kekwick),where there appears to be a large number of ill-defined components covering a mobility rangesimilar to that of the serum proteins. In Case A3(Fig. IB, Kekwick), four relatively well definedcomponents were present but the total proteincontent of the urine was much higher than in theother cases. Inthe ultracentrifuge the urinary proteinssedimented as a single component in all four cases.The sedimentation constants correspond with amolecular weight in the range 20,000 to 30,000.Further work is necessary to determine the natureof this protein and to establish whether it is excretedin some form linked to cadmium.Baader (1952), reporting the case of a man who

died as the result of chronic cadmium poisoning,describes the kidney lesion as a toxic nephrosis. Inthe fatal case reported in this paper (Case Al), the

man died as the result of chronic renal failure. Hewas under observation for 18 months before deathand tests confirmed that the proteinuria was quiteunlike that usually associated with chronic glomer-ulonephritis. The electrophoretic pattern of theprotein was non-specific but it was found to have alow molecular weight (Kekwick). On microscopicexamination of the kidneys Professor DorothyRussell was of the opinion that the changes wereindistinguishable from the nephritis repens ofBright's disease. Further evidence that cadmiumcauses renal damage is provided by Friberg andNystrom (1952) who re-examined the workmen inthe alkaline accumulator industry after five years.There was no evidence to suggest that these men

had any impaired sense of smell, but this may bedue to the fact that they were exposed to cadmiumoxide fume whereas men who were found to havethis complaint in the alkaline accumulator industrywere exposed to cadmium oxide dust.The importance of the presence of cadmium in the

urine, except as a confirmation of absorption, isdifficult to assess. The quantity of cadmiumexcreted does not appear to bear any relationshipto the severity of poisoning. Workmen exposed tocadmium excreted between 0 and 800 gag. of cadmiumper day. Forty-one were excreting more than 30 ,ug.daily. It was of interest that men who had ceasedto work with cadmium for as long as 10 years werestill excreting measurable quantities of cadmium inthe urine.

All 19 men showing symptoms or signs of chroniccadmium poisoning in this investigation had beenexposed to cadmium for more than five years and13 had been exposed for more than 15 years. Ofsix men in Group lB who had worked on thecopper-cadmium furnaces for more than 15 years,five were affected (Table 4). All the cases of chroniccadmium poisoning described by Friberg (1950)had more than eight years' exposure to cadmiumoxide dust.The maximum allowable concentration ofcadmium

in the working atmosphere has been set at 100 jig.per cu. m. (American Conference of GovernmentalIndustrial Hygienists, 1954). In this investigationthe average concentration of cadmium in theatmosphere of the workshop over 12-hour periodsdid not exceed 270 jig. per cu. m. in either factory,but for periods of 15 to 20 minutes every hourduring casting the concentration was much higher(King, 1955). These findings are unlikely to be atrue reflexion of the working conditions at the timewhen the majority of the men affected started work.To comply with black-out regulations during theSecond World War all windows and doors had to

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be closed and covered at night, and the naturalventilation of the workshops was consequentlyreduced. The average concentration of cadmium inthe atmosphere is likely to have been much greaterthan that found in this investigation. Because therewas no evidence in the medical literature to suggestthat cadmium could produce chronic ill health, fewprecautions were taken to remove cadmium fromthe atmosphere during the war years and in theimmediate post-war period. All the men who wereaffected had worked for at least seven years. Since1948 conditions have been greatly improved andprecautionary measures have been introduced ineach factory.

SummaryThe results are reported of an investigation of

men employed at two factories in England wherealloys of copper and cadmium are manufactured.

Five cases of chronic cadmium poisoning in-cluding the necropsy findings in one fatal case aredescribed. The findings in a further 18 cases aresummarized.

Chronic cadmium poisoning is characterized by(a) the development of emphysema, in which thereis some evidence to suggest that the emphysema isnot the same as chronic hypertrophic emphysemawhich follows chronic bronchitis or bronchialasthma; (b) renal disease which is accompanied bythe excretion in the urine of a protein with a mole-cular weight of 20,000 to 30,000. The urinaryprotein does not give the same reactions to routineclinical laboratory tests as the proteinuria whichoccurs in glomerulonephritis, cardiovascular-renaldisease, or Bence-Jones protein.Emphysema and proteinuria may both be present

or may occur separately in a particular case.In the fatal case death was due to chronic renal

failure.Twenty-four hour specimens of urine were

obtained from 83 men exposed to cadmium.

Cadmium was present in 62 cases and 41 of thesewere excreting more than 30 ,l.g. per day.The cadmium concentration of the working

atmosphere was estimated under the present workingconditions and the significance of these findings inrelation to conditions of work in time of war arediscussed.

I am indebted to the management of the two factoriesconcerned, particularly the medical and personneldepartments without whose wholehearted cooperationthe investigation could never have been made.

I wish to thank Dr. Donald Hunter and Dr. P. L.Bidstrup for their encouragement and helpful criticism;Professor J. L. D'Silva for his ready assistance inarranging for the respiratory function tests to be carriedout; Dr. George Simon for reading the chest radio-graphs; Professor Dorothy Russell for the pathologicaland histological report on Case Al ; Professor MelvilleArnott for permission to publish Case A4; ProfessorR. V. Christie for his opinion and arranging furtherrespiratory function tests on Cases B1 and B3; MissJean Peal and Messrs. D. Lawford, E. Palmer, and T.Emerson, for valuable technical assistance. I shouldalso like to thank Dr. D. G. Harvey, Dr. E. H. Evison,and Dr. G. Webster.

REFERENCESBaader, E. W. (1951). Dtsch. med. Wschr., 76, 484.

(1952). Industr. Med. Surg., 21, 427.Barrett, H. M., and Card, B. Y. (1947). J. industr. Hyg., 29, 286.Barthelemy, P., and Moline, R. (1946). Paris med., 36 (1), 7.Buxton, R. St. J. (1955). To be publishedCangelosi, J. T. (1941). Nav. med. Bull., Wash., 39, 408.Frant, S., and Kleeman, I. (1941). Amer. med. Ass., 117, 86.Friberg, L. (1948). J. industr. Hyg., 30, 32.-(1950). Acta med. scand., Suppl. 240.-(1952). Arch. industr. Hyg., 5, 30.

, and Nystrom, A. (1952). Svenska LdkT., 49, 2629.Hardy, H. L., and Skinner, J. B. (1947). J. industr. Hyg., 29, 321.Huck, F. F. (1947). Occup. Med., 3, 411.Kazantzis, G. (1955). To be published.Kekwick, R. A., (1955). British Journal ofIndustrial Medicine, 12, 196.King, E. (1955). Ibid., 12,198.Knott, J. M. S., and Christie, R. V. (1951). Lancet, 1, 881.Lane, R. E., and Campbell, A. C. P. (1954). British Journal of

Industrial Medicine, 11, 118.Mancioli, G. (1940). Rass. Med. industr., 11, 632.Nicaud, P., Lafitte, A., and Gros, A. (1942). Arch. Mal. prof.,

4, 192.Princi, F. (1947). J. industr. Hyg., 29, 315.Prodan, L. (1932). Ibid., 14, 132 and 174.Simon, G. (1953). Personal communication.Stephens, G. A. (1920). J. indusitr. Hyg., 2, 129.Whitfield, A. G. W. (1952). Brit. med. J., 2, 1227.

APPENDIX ICase Histories

Case No. Al (L.H. Record No. 12133/53).-This wasa man aged 54 years suffering from chronic renal failurewithout hypertension and a moderate degree of emphy-sema. On repeated examination of the urine, the onlyprotein demonstrated was one of low molecular weightwhich differed from the proteins usually found in theurine in chronic renal disease (Kekwick, Fig. 1). Heserved in the Armed Forces until 1920 and from 1920 to1952 he had worked casting an alloy of copper andcadmium. He had also cast brass and bronze duringthis time. He had always worked on the pit-fire furnace

and for the greater part of this time was responsible forcasting the " master alloy " containing 33% cadmiumwith copper. He had not worked since November, 1952.He was admitted to the North Staffordshire Royal

Infirmary in March, 1953, and transferred to the LondonHospital in April, 1953, for further investigation. Hewas readmitted in uraemic coma on May 20, 1954, anddied on May 22.He was perfectly well until 1948 when he began to get

attacks of unproductive cough. These attacks persisteduntil he stopped work in November, 1952. For 18months before admission to hospital he had been short

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TABLE 7

SUMMARY OF CLINICAL DETAILS OF MEN SERIOUSLY DISABLED BY CADMIUM POISONING

Renal Function Urine Respiratory FunctionTests Tests

UreaE.S.R. Concen- Chest

Case Date Hb (Wester- trestn Mid- Cd in Radio- Other Datag9. grmm.n (mg./100 (maxi- stream 24 V.C. S.F.30 S.F.70 M.V.C. T.C. graphmm./ |ml-) umrmum Speci- Hours (1.) (%) (%) (./min. (sec.)hr.) Ml.) urine men- (~±g.)

ureamg./

100 ml.)Al 8. 4.53 41 80 144 r 900 Protein- 30-40 -_ - - Normal Liver function tests

6-1 uria normal, normo-blastic bone marrow,

9.11.531 30 25 141 - , - 2-83 58 43 74 0 79 Emphy- plasma proteins, seesema Table 1, Kekwick

20. 5.54 26 - 454 . . . _- Died on 22.5.54A2 3. 2.53 111 50 39 1800 290-980 2-46 42 24 42 2-39 Emphy- Liver function tests

16-5 sema normal, plasma pro-teins, 6-45. (albumin3-22 g. per 100 ml.,globulin 3-23 g. per100 ml.), urea clear-ance test, 62% 1 hr.P.S.P. excretion,33-5% 1 hr.

A3 26.10.53 94 34 42 2500 Protein- 46 245 30 17 31 2P45Emphy- -

uria sema0-55

g./100 ml.A4 18. 3.52 104 3 - - No pro- 112 - - - - - Emphy- 8.4.52. The results of

tein sema cardiac catheteriza-6. 8.53 110 3 38 2400 No pro- - 2-08 30 17 25 4(0 Emphy- tion were compatible

tein sema with emphysema

Bi 25. 3.54 103 2 45 1920 Protein- 59 2-8 31 17 32 3-27 Emphy- The mixing efficiency,uria sema pulmonary diffusing

capacity (carbon mon-oxide technique), andintra - oesophageal

ipressure studies werecarried out at St.Bartholomew's Hos-pital, London. It wasconcluded that thedisability was due toa moderate degree ofemphysema associ-ated with broncho-

_ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _lspasm

of breath on exertion. This was accompanied by a dull,aching pain in the left upper chest which was relieved byresting. There was no past history of haematuria orrenal disease.On examination in April, 1953, there was pallor of the

skin and mucous membranes but no obvious loss ofweight. There was a pronounced uraemic odour in thebreath. He was not dyspnoeic at rest. There was noclinical evidence of cardiac enlargement, but a softsystolic murmur was audible in all areas. The bloodpressure was 165/85 mm. Hg on admission to hospitalbut later fell to and remained at 130/60 mm. Hg. Thechest was barrel-shaped and there was increased reson-ance on percussion with diminution in the area of liverdullness. The breath sounds were vesicular and therewere no adventitious sounds. There was no abnormalityon examination of the abdomen and the central nervoussystem.He was treated with a low-protein diet and un-

restricted fluids, but on discharge from hospital hiscondition was unchanged.

He was readmitted to hospital on November 9, 1953,owing to increasing pallor, shortness of breath, andoedema.There were purpuric spots scattered over the chest

and legs with marked oedema of the legs and back.He was treated by rest in bed, digitalis folia gr. 1

twice daily, abundant fluids by mouth, and a low-proteindiet. He was cautiously transfused with the packed cellsof 14 pints of blood over six weeks with marked improve-ment. On discharge from hospital, haemoglobin was96% and the blood urea was 165 mg./100 ml.He was readmitted on May 20, 1954. He had become

increasingly drowsy and breathless on exertion forseveral weeks. On examination he was very pale andalmost comatose. There were purpuric haemorrhages ofthe buccal mucous membranes. There was a pericardialfriction rub and the blood pressure was 140/100 mm. Hg.Haemoglobin was 26% (3 8 g.%) and the blood urea

was 454 mg. per 100 ml.The results of laboratory and other investigations are

summarized in Table 7.

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Necropsy Findings.-The lungs were oedematous andthere was a moderate, diffuse emphysema, with occasionalbullae measuring up to 2 by 1 cm. There was a smallarea, 6 by 3 cm., of focal bronchiectasis in theinferior and posteromedial aspect of the left lung.There was a sero-fibrinous pericarditis, the pericardial

sac containing about 30 ml. of free fluid. The leftventricle was hypertrophied and slightly dilated, andthere was slight general atheroma with a few flecks inthe main pulmonary arteries.

There was considerable reduction in the size of thekidneys, which weighed only 99 g. The subcapsularsurfaces were smooth and grey. The renal cortex wasnarrow and had an indistinct pattern but contained afew small cysts measuring up to 0-3 cm. in diameter.The liver was pale and oedematous, weighing 1,829 g.

It showed a strong iron reaction as did the otherwisenormal spleen. There was mucous catarrh of thestomach and intestines. The endocrine glands andbrain were normal.

There was osteoporosis of the sternum, ribs, femora,right radius and ulna, and thinning of the vault of theskull. The sternum and ribs were easily cut with a knife.The sternal marrow was partly adipose and there wereislands of bright pink marrow in the upper 8 cm. of theshaft of the right femur. The corticalis of the femur waswhite and dense.

CADMIUM IN TISSUES

Wet Cd in Cd/100 g.Tissue Weight Sample Tissue

(g.) (mg.) (mg.)Muscle .. . 50 0-560 1-120Lung . . 125 2-53 2-024Kidney .. . 20 1-23 6-15Liver . . 75 24-76 33-01Spleen .. . 50 1-94 3-88Small intestine 150 1-15 0 764Rib...40 0-290 0-725Long bone 30 0150 0-50

Both lobes of the left lung and the lower lobe of theright lung showed great but uneven emphysema. Thesubpleural zone was not spared. There was moderateanthracosis, and occasional dust-macrophages occupiedalveolar spaces. There was no fibrosis and no inflam-matory interstitial infiltration apart from a few foci oflymphocytes which were usually adjacent to arteries.In the less emphysematous parts there was extensiveoedematous exudate in the alveolar spaces with earlystages of purulent bronchopneumonia. The bronchioleselsewhere showed mucous catarrh only. No structuralchanges were present in the arteries and arterioles.The pericardium, in sections from both ventricles, bore

a few superficial deposits of fibrin. There was oedema ofthe epicardium which was sparsely infiltrated withpolymorphonuclear leucocytes and round cells. Thisinfiltration extended into the adjacent intermuscularsepta. The muscle fibres of the right ventricle wereslightly hypertrophied, and in the left ventricle thischange was more pronounced. In the latter a few smallfoci of fibrosis were found in the deeper parts of themyocardium. The associated blood-vessels were normal.The cortex of the kidneys was uniformly reduced in

depth and was diffusely affected by interstitial fibrosis.

Many of the glomeruli had undergone ischaemic atrophyin association with fatty-hyaline degeneration of thesmaller arterioles. Residual glomeruli frequentlyappeared unchanged, but some showed degenerativechanges in the tuft best demonstrated by the presence offocal sudanophil deposits in the lobules. In suchglomeruli there were sometimes adhesions between thetuft and Bowman's capsule. This degenerative changewas evidently of a progressive character because a goodmany glomeruli could be identified in advanced stagesof non-ischaemic atrophy, that is, a shrinkage withcomplete loss of cells in the tuft without the hyalinecollagenous thickening of Bowman's capsule thatcharacterizes ischaemic atrophy.The tubules were often grossly atrophied, containing

hyaline casts. Other tubules were dilated, containingbrightly eosinophil granular casts mingled with leuco-cytes, or aggregates of leucocytes alone. In such tubulesthe epithelium was flattened and the distinctive featuresof the proximal and distal parts of the nephron were lost.Casts were very conspicuous in the collecting tubules ofthe medulla. The density of the collagen fibres in theinterstitial tissue was variable. Where this was leastdense the tissue was more cellular and contained spindlefibroblasts. There was a good deal of lymphocyticinfiltration, especially beneath the capsule and near thejunction of cortex and medulla. No sudanophil materialwas present either in the tubules or interstitial tissue.

In addition to fatty-hyaline changes in the arterioles,the larger arteries showed moderate hypertrophy.

Sections from the sternum, a rib, and the right femurshowed advanced osteoporosis. The marrow in all waspartly adipose; haemopoiesis appeared normal.No structural changes were present in the liver. The

Kupffer cells contained free iron-pigment. Only slightfatty change affected the parenchyma and this was ofirregular distribution.The pulp of the spleen was congested and considerable

amounts of free iron-pigment occupied groups ofmacrophages.The pituitary, parathyroids, adrenal, and thyroid were

normal, apart from discrete colloidal adenomata in thelast-mentioned.

In the testis there was diffuse atrophy of the semini-ferous tubules without inflammatory infiltration. In afew foci atrophy was complete.No abnormality was found in sections of the hypo-

thalamus, basal ganglia, and cerebellum.Case No. A2 (L.H. Record No. 3919/53).-A man

aged 52 years suffered from severe emphysema withslight impairment of renal function. The characteristicprotein was present in the urine. He had worked all hislife in the non-ferrous metal industry but from 1937 to1950 he had been casting an alloy ofcopper and cadmium,the first three years on the pit-fire furnace and the latter10 years on the rocker resistor furnace. He was admittedto the London Hospital in February, 1953.He was quite well until 1945. Dyspnoea developed at

this time and by 1949 he was unable to do his usual job.There was no wheezing and no seasonal variationof the dyspnoea. He developed a persistent cough in

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1949 producing 2 to 3 oz. sputum daily. In 1950 he wasgiven a light job in another department in the factoryand since 1951 he has been unable to work at all. Hehad lost 2 to 3 st. in weight since 1948, appetite waspoor, and he complained of slight epigastric pain.On examination in February, 1953, there was obvious

muscle wasting and he was short of breath on theslightest exertion. The cardiovascular system wasnormal with a blood pressure of 115/75 mm. Hg. Thechest was barrel-shaped and chest movements weremuch diminished. There was increased resonance onpercussion of the chest and cardiac and liver dullnesscould not be elicited. Heart sounds were distant, thebreath sounds were vesicular, and scattered rhonchi wereaudible over both lungs. The spleen was palpable twofingerbreadths below the left costal margin and the liveredge was just palpable below the right costal margin.There was no abnormality of the nervous system.The results of laboratory and other investigations are


Case No. A3 (L.H. Record No. 38128/53).-A managed 58 years suffered from severe emphysema. Thecharacteristic protein was present in the urine. Exceptfor service in the army in 1914-18 he had always workedin the same factory, and from 1935 to 1946 had beencasting alloys of copper and cadmium. He had beenemployed on the rocker resistor furnace during thewhole of this time. In 1946 he was forced to take a lightjob and since that time he has been unable to resume hisformer occupation.He was admitted to the London Hospital in October,

1953. He was quite well until 1943 when he developedcough and dyspnoea. The cough has persisted and thedyspnoea has gradually become more severe. At thepresent time he can walk only 20 to 30 yards. Duringthe past four years he has complained of a sensation oftightness in the left upper chest which is relieved by rest.Since 1940 he has noticed a clear, watery discharge fromthe nose which is unrelated to upper respiratory tractinfection. He has lost almost 2 st. in weight since 1946.On examination in October, 1953, there was evidence

of marked loss of weight, and he was short of breath onslight exertion. There was cyanosis of the lips. Theheart was not enlarged clinically, pulse was regular at90 beats per minute, and the blood pressure was 130/75mm. Hg. The chest was barrel shaped with increasedresonance on percussion and diminution of cardiac andliver dullness. Breath sounds were present over bothlungs, with many high-pitched expiratory rhonchi andbasal crepitations.The results of laboratory and other investigations are


Case No. A4 (L.H. Record No. 25498/53).-A managed 49 years suffered from severe emphysema. He hadalways worked at the same factory except for four yearsin the Potteries where he had been employed grindingclay in a water mill. From 1935 to 1947 he was casting

copper alloys: bronze and brass only from 1935 to 1939but from 1939 to 1947 he had been employed on thepit-fire furnace casting the copper-cadmium masteralloy. Because of his symptoms he changed to a lightjob in 1947 and has been unable to work since 1950. Hewas admitted to the Queen Elizabeth Hospital, Birming-ham, in March, 1952, and to the London Hospital inAugust, 1953.He suffered from a cough from 1942 but there was no

disability until 1947, when he noticed that he wasgetting short of breath on exertion. The dyspnoeabecame steadily more severe and at present he is able towalk only 25 to 30 yards on level ground. There has beenmarked loss of weight, amounting to 3 st. in six years.He has suffered from nasal catarrh with a clear mucousdischarge since 1940, and he complains of right subcostalpain aggravated by exercise since 1947.On examination in March, 1952, he was thin, orthop-

noeic, and the lips were cyanosed. The cardiovascularsystem was normal with a blood pressure of 140/90mm. Hg. The cardiac apex was not palpable and theheart sounds were faint. The chest was barrel shapedwith gross diminution of movement on respiration.The expansion of the chest was 1 in. There was increasedresonance on percussion of the chest, and cardiac andliver dullness were absent. The breath sounds wereaudible in both lungs with generalized, high-pitchedexpiratory rhonchi. Neither the liver nor the spleen waspalpable and palpation of the abdomen showed noabnormality. There was no oedema of the ankles.The results of laboratory and other investigations are

summarized in Table 7.Case No. Bi (L.H. Record No. 9954/54).-This man

aged 52 years was suffering from emphysema with slightimpairment of renal function. The characteristic proteinwas present in the urine. He had worked from 1930 to1940 casting alloys of copper and cadmium in a pitfurnace.He was admitted to the London Hospital in March,

1954.He first noticed dyspnoea on exertion in 1939. He

changed his job in 1940 on the advice of his doctor andsince this time has worked in another department of thefactory. Since 1951 he has become increasingly dyspnoeicon exertion and he has lost 21 st. in weight. He hascomplained of epigastric pain, relieved by alkalinepowders, since 1950.On examination in March, 1954, there was evidence

of marked loss of weight and he was dyspnoeic at rest.There was no cyanosis, finger clubbing, or pallor. Thecardiovascular system was normal and the bloodpressure was 140/90 mm. Hg. The thoracic cage wasfixed in inspiration, movement was poor, and there washyper-resonance on percussion of the chest with absentcardiac and liver dullness. Air entry was good, breathsounds were vesicular with occasional scattered rhonchi.The results of laboratory and other investigations are


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APPENDIX II

Physico-chemical Examination of the Serum and Urine Proteins in SomeCases of Cadmium Poisoning

BY

R. A. KEKWICKFrom the Lister Institute, London

Although Friberg (1950) in his monograph oncadmium poisoning gives some data concerning theelectrophoretic and ultracentrifugal behaviour of theserum and urine proteins from such cases, theprovision of further data in connexion with thepresent series described by Bonnell (1955) seemedadvantageous.

MethodsTreatment of Urine and Serum.-In general the con-

centration of protein in the urine was too low to permita satisfactory physico-chemical examination to be madein the usual manner, that is, after simple dialysis toequilibrium against a suitable buffer.

Initially 24-hour samples, but later ovemight samples,of urine were dialysed at 2 to 40 immediately after voidingagainst phosphate buffer pH 8-0 I = 0-02 in orderespecially to remove urea. Following repeated changesof buffer during 48 hours, the dialysed material, aftercentrifuging off any slight precipitate which formed, wasfreeze-dried in 10 ml. quantities in a centrifugal freeze-drying plant. The dry residue was reconstituted in 0-1of the initial urine volume of distilled water to providea solution of urinary proteins in phosphate bufferpH 8-0 I = 0-2. This solution was immediately dialysedfor 24 hours at 2 to 4° against a large volume ofphosphatebuffer pH 8-0 I = 0-2 before electrophoretic and ultra-centrifugal examination.Serum samples were dialysed to equilibrium-against

phosphate buffer pH 8-0 I = 0-2 at 2 to 40, and dilutedwith buffer to give a suitable protein concentration forsubsequent examination.

Protein concentrations were determined refracto-metrically on the dialysed solutions of serum or urineproteins.

Electrophoresis Measurements.-These were made inphosphate buffer pH 8-0 I = 0-2 in the Tiselius (1937)apparatus at 00 and a potential gradient of 6. V/cm.Optical observations by the diagonal Schlieren method(Philpot, 1938) were photographically recorded onIlford half-tone panchromatic plates, using a highpressure Hg arc as a light source from which mono-chromatic light X = 546 m,u. was isolated by a suitablefilter.For the analysis of sera the total protein concentration

was 2 g./100 ml. in each instance. For the urine proteinanalysis the total protein concentration was between1-1 and 1 5 g./100 ml.

Ultracentrifuge Measurements.-The urine proteinswere examined at concentration of 1 g./100 ml. inphosphate buffer pH 8-0 I = 0-2 + 0-15M NaCI. Thesolutions were subjected to 250,000 g. in the Svedbergoil-turbine ultracentrifuge using a 12-mm. cell, theoptical recording being as described under electro-phoresis.

Results and DiscussionIn the Table the electrophoretic analyses of the

sera from four cases of cadmium poisoning arepresented together with the values for normalhuman serum obtained under the same experimentalconditions. In two instances the proportion ofgamma globulin is abnormally high and in all casesthe alpha globulin proportion is slightly above thenormal value. There seems, however, to be nouniformly consistent deviation from the normalattributable unequivocally to the effects of cadmiumpoisoning.

TABLETHE ELECTROPHORETIC ANALYSIS OF SOME SERA FROM

PATIENTS WITH CADMIUM POISONING

Total Electrophoretic AnalysisSerum ProteinSample (g./l0O Globulins

ml.) Albumin Alpha Beta Gamma

A3 7-25 53-8 9-2 16-6 20-5B3 6-94 56-9 9 5 10-8 22-9Al 6-84 65-7 9 9 12-0 12-4B2 6-26 67-8 70 13-1 12-2

Normalvalues 6-75 65-1 6-4 15-1 13-6

In Fig. 1 electrophoresis and ultracentrifugediagrams of the urinary proteins are given. Exceptin one instance the electrophoretic characteristicsof the urinary proteins were similar to those shownin Fig. la, where there appears to be a very largenumber of ill-defined components covering amobility range similar to that of the serum proteins.In the divergent case (A3, Fig. lb) four relativelywell defined components were present but in thispatient the total urine proteins at about 0-5 g./100ml. were very much higher than in any otherinstance.

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ElectrophoresisAnode

U Itracentrifuge

(b)

Migration Direction

FIG. l.-Electrophoresis and ultracentrifuge diagrams of urine proteins (a) Patient B3: electrophoresis afterthree hours at 15 mA., pH 8-0 I = 0-2. (b) Patient A3: ultracentrifuge after 80 minutes at 54,000 rev./min.

The urine proteins sedimented in the ultra-centrifuge as a single component (Fig. 1), which issomewhat surprising in view of the complexity ofthe electrophoretic behaviour. Values for thesedimentation constant determined on solutionscontaining 1 g. protein/100 ml. varied from 2 to2*2 S. These would correspond with a molecularweight in the range 20,000-30,000 which is verymuch lower than that of any known serum protein.The data for the sera are similar in some instances

to those given by Friberg (1950): the sedimentationcoefficients obtained for the urine proteins are ofthe same order as the values quoted by him. Ingeneral a more complex electrophoretic behaviourwas observed for the urinary proteins, but this mayhave been due to the fact that Friberg in many casesconcentrated the urinary proteins by precipitationwith ammonium sulphate. This procedure may not

have provided such representative preparations aswould be obtained by freeze drying the total urinaryprotein.

Summary

The serum and urinary proteins from patientssuffering from cadmium poisoning have beenexamined physico-chemically.

While the serum proteins show divergencies fromthe normal electrophoretic distribution, no charac-teristic deviation appears consistently.The urinary proteins show a large number of

electrophoretic components but sediment as asingle component of a molecular weight in therange 20,000-30,000.

REFERENCESFriberg, L. (1950). Acta med. scand., Suppl. 240.Philpot, J. St. L. (1938). Nature, Lond., 141, 283.Tiselius, A. (1937). Trans. Faraday Soc., 33, 524.

Cathode

(a)

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Documents

Brit. J. industr. Med., 1955, 12, - oem.bmj.com · Esbach's picric acid test was carried out on 15 cases in which proteinuria had been demon-strated by testing with trichloracetic