TOXIC POLYNEURITIS ARISING DURING THEMANUFACTURE OF TRICRESYL PHOSPHATE

BY

DONALD HUNTER, KENNETH M. A. PERRY, AND R. BYRON EVANS

From the Department for Research in Industrial Medicine (Medical Resear-ch Council), The London Hospital

This communication records the toxic effects-aused by tri-ortho-cresyl phosphate in three menemployed in its manufacture. Tricresyl phosphateis used in the recovery of phenol residues from gasplant effluents and also as a plasticizer in theplastics industry. A plasticizer is a substance usedto render a plastic material more pliable, and byalteration of the amount of the plasticizer added,such characteristics as flexibility, hardness, waterresistance and inflammability can be varied betweenwide limits. In this industry it is being used inincreasing quantities, for example, as much as50 per cent. oftricresyl phosphate is sometimes addedto polyvinyl chloride. Tricresyl phosphate used inindustry is an oil with a slightly pungent odour:of the three isomerides the ortho- and meta- areliquids, and the para- is a crystalline solid. Indus-trial tricresyl phosphate is prepared by treatingcresols with phosphorus oxychloride in the presenceof an aluminium catalyst. It has been the boastof industry in the United States of America thatin a plant manufacturing 100,000 lb. of this materiala day without any special precautions no cases ofpoisoning have occurred. However, since 1939black-out regulations in Great Britain, imposed as aprecaution against air attack, have led to a lessfortunate state of affairs, and three workmenemployed in a manufacturing plant have developedpolyneuritis. As a result of these cases poisoningby tricresyl and triphenyl phosphate resulting fromthe manufacture or use of these products in industrywas scheduled under the Workmen's Compensation(Industrial Diseases) Order, 1942, No. 1326.

Environmental ConditionsAll three of these men worked in a room about

25 feet long, 12 feet wide, and 12 feet high which,owing to black-out regulations, was totally enclosedduring the hours of darkness, although it was pro-vided with a roof vent. During daylight doorsand windows were open. The men worked atwash tanks which were roughly cubic vessels ofabout 5 feet high, with a partially open top. Theclosed-in portion of the top supported the variousfittings, one of these being a 6 inch vent pipeextending through the roof to the open air. Crudetricresyl phosphate entered these tanks at a tem-perature of approximately 600 C. At this stage itcontained hydrochloric acid which gave it anunpleasant irritating odour. However, it wasimmediately cooled by treatment with an equalvolume of cold water, this operation being carriedout by opening a valve and shutting it at the appro-priate moment. The washing was automatic, but

it was nevertheless possible for the men to inhalevapour from the tanks. The cold tricresyl phosphateis of low volatility, having a low vapour pressure atordinary temperature. The ortho-isomer contentof the finished product was about 60 per cent. Thethree affected men also handled triphenyl phosphate.

It was not possible at the time the men werepoisoned to determine the concentration of tri-cresyl phosphate which was present in the atmos-phere. This, however, was estimated at a laterdate when conditions were arranged to reproducethose in operation at the time. The injectors, fansand air conditioning plant were shut off, the coversof the washing vats left open, and the water drainedfrom the cooler. The determinations were carriedout during daytime, and also during simulated andactual black-out conditions. The highest con-centration of tricresyl phosphate was found in theroom containing the washing vats after the hotliquid had been blown over from the reaction vesselsinto the washing vats. Twenty litres of atmospherewere aspirated through an absorption train for16 to 30 minutes, commencing 5-10 minutes beforethe end of the delivery of hot liquid. The absorp-tion train consisted of 2 bubblers, each containing100 mls. of alcohol, followed by 2 tubes packedwith glass wool and cotton wool respectively. Over90 per cent. of the tricresyl phosphate was found inthe first bubbler, the remainder in the second, andnone in the wools. The tricresyl phosphate wasdetermined by estimating colorimetrically the P205produced by its decomposition.

TABLE 1

SAMPLES OF ATMOSPHERE FROM A POINTINSIDE THE WASHING VAT 6-9 INCHESABOVE THE FINAL LEVEL OF THE LIQUID.

Tricresyl phosphateMgs. per 20 litres . .

Mgs. per cu.m. . .

Parts per million wt/wt. . .

Parts per million vol/vol.

DaytimeA B

0-2 0-210 108 806 06

C0-15403

TABLE 2SAMPLES OF ATMOSPHERE FROM A POINT

9 INCHES ABOVE THE TOP OF THE WASHINGVAT AND OVER THE CENTRE OF THEOPENING.

Tricresyl phosphateMgs. per 20 litresMgs. per cu.m. ..Parts per million wt/wt. . .

Parts per million vol/vol.

Simulatedblack-out<005<2-5<2<0-15

Actualblack-out<0 05<2-5<2<0-15

227

on January 12, 2020 by guest. Protected by copyright.

http://oem.bm

j.com/

Br J Ind M

ed: first published as 10.1136/oem.1.4.227 on 1 O

ctober 1944. Dow

nloaded from

BRITISH JOURNAL OF INDUSTRIAL MEDICINETABL

SAMPLES OF ATMOSPEAT SHOULDER HEIGAND 2 FEET IN FRCVAT.

Tricresyl PhosphateMgs. per 20 litresMgs. per cu.m.Parts per million wt/wt.Parts per million vol/vol.

Finally, samples of the arooms containing washingperiod of 24 hours on thexperiments the alcohol in tby 20 mls. of ethylene gly4the first and 25 mls. of watsamples were drawn fromabove the lower step, 3 incland 3 inches along the ope:end. Black-out conditionsblack-out times in the mon

TABLI

Volume of atmospheretested . .Tricresyl phosphate

Mgs. in volume under testMgs. per cu.m. ..Parts per million wt/wt.Parts per million vol/vol.

1

The method of estimating tas follows:-1 ml. of a dilutephate (0-1 mg.) in alcohol wadish with 25 mls. of alcoholsolution. The dish was plaheated until dry. The dishusing a low flame until charristrongly to remove the bulkand contents were allowed tcand 2 drops of nitric acid w4this stage the solution waswas transferred to a water bporated to dryness. The relittle water and transferred tc1 ml of MM11 mar -aint T-Ja T-Tl

E 3 sion the process was speeded up for Government contractIERE FROM A POINT and the plant production rose by 30 per cent. He workediHT FROM THE FLOOR every Sunday instead of one in four. Two weeks before)NT OF THE WASHING he was seen he complained of slight stiffness of the neck.For two days before he had had lower abdominal painSimulated Actual accompanied by diarrhoea, passing three pale watery-black-out black-out stools per day. Five days later he suddenly found he<0-02 <0 02 could not walk properly. He was unable to lift his toes<1-0 <1 0 and his feet dragged. The disability progressed until<10 <10 eventually he was unable to stand without the help of a<0-06 <0-06 stick. He then found that he had weakness of the<0-06 <0*06 fingers of both hands and he was unable to do up buttons.

There were occasional tingling sensations and numbnessLtmosphere in one of the in the calves of both legs. Previous history.-Bronchitisvats were taken over a during the last year. Family history.-Father and

iree occasions. In these mother dead. Three brothers and two sisters alivethe bubblers was replaced and well. There was no familial nervous disease.col monomethyl ether in Condition on admission.-Robust man. Afebrile. Noter in the second. These abnormality in respiratory, cardiovascular or gastro-a point 4 feet 9 inches intestinal systems. Nervous system: no mental abnor-

hes in front of the washer mality; no abnormality detected in cranial nerves;*ning from theright-hand fundi normal. Upper limbs: weakness of hand gripning from the right-hand and of dorsi-flexion of both wrists: slight symmetricalwere in operation during wasting of thenar, hypothenar and first dorsal interosseousth of April. muscles. Reflexes all present and equal. No sensory

loss. Lower limbs: great weakness of dorsiflexors andE 4 plantar flexors of ankles; slight symmetrical wasting ofA B c calves; flail ankle joints; knee jerks brisk and equal;AB C ankle jerks absent; plantar responses flexor. Slow,

6cu.ft. 30 cu.ft.26cu.ft high-stepping, rather stamping gait. Two-point dis-6cu. ft.0 cu.ft. 26cu. ft. crimination normal; appreciation of pin-prick, cotton

wool touch, vibration and posture normal. Special0175 0-47 0-67 examinations.-Blood count: Haemoglobin (Sahli) 921266 0455 0-91 per cent., white cells 8200 per cmm., differential count-128 0042 0-70 normal; no abnormality seen in stained film. Blood0-10 0 03 0-06 Wassermann reaction negative. Lumbar puncture:

pressure 95 mm. of cerebro-spinal fluid; Queckenstedt's;he tricresylphosphate was test normal; fluid clear and colourless; no excess of whitesolution of tricresyl phos- cells; protein 18 mg. per 100 cc., Wassermann reactions transferred to a platinum negative. Fractional test meal: no free hydrochloricand 2 mls. of N/10 KOH acid for 2j hours, later rose to 0-08 per cent. Urine: noced on a water bath and albumin or sugar. Progress.-He was treated withLgwas then gently heated, vitamin E by mouth and vitamin B intra-muscularly.ng finished, and then more His muscles were treated first by rest and then withof the carbon. The dish massage and galvanism. After the third week he begancool and 5 mis. of water to show slow but steady improvement and six months

ere added and mixed. At after admission he was discharged. He then walkeddefinitely acid. The dish with a high-steppage gait. Uplifting toe springs fitted)ath and the solution eva- to his boots helped him. One year after admission heasidue was dissolved in a had completely recovered and was able to return to

a test tube (6 in.x 1 in.). work.1 mi1. v1 vJ-vi per cent. iNa211r%J41/H2V r2(J5:-U'l mg.tricresyl phosphate), 2 mls. of N/10 KOH and 2 drops ofnitric acid were placed in a control tube. The level ofliquids in both tubes were adjusted to the same heightand to both tubes were added, with shaking, 0-5 mls. ofmolybdate reagent (5 gms. of ammonium molybdatedissolved in 100 mls. of cold water and poured into35 mls. of nitric acid (d= 1-2)) followed by 05 mls. ofbenzidine reagent (0 05 gms. of benzidine hydrochloridedissolved in 10 mls. of glacial acetic acid and dilutedwith water to 100 mls.). Ammonia was then added toboth tubes approximately simultaneously to developalkalinity and the blue colour. Both solutions gavecolours of the same intensity and the results can beregarded as quantitative.

It is important that contact with any glass, includingstirring rods, be avoided when the solutions are hot andalkaline as traces of silica are absorbed and nullify theresults.

Case HistoriesCase 1. E.R., a man aged 41 years. For three years

before admission to hospital the patient had beenemployed in a chemical factory, at first working onnitrating processes. Six months later he began tohandle cresol, phenol, phosphorous oxychloride, causticsoda and sulphuric acid making tri-ortho-cresyl phosphateand triphenyl phosphate. For six months before admis-

Case 2. G.M., a man aged 30 years (L.H. Reg. No.M.168/1941). For 8 months previous to admission thepatient had been employed in the manufacture of tri-cresyl phosphate and was in contact with the samesubstances as case 1. He worked for 63 hours per week.Five months later he began to complain of cramp-likepains in the thighs, calf muscles and toes. About thesame time he noticed that he had recurrent attacks ofhiccup. One month before admission he had an attackof diarrhoea, unaccompanied by abdominal pain orvomiting, which lasted one day, and soon afterwardshe noticed that his feet were weak and found that hehad to lift up his legs to prevent his toes dragging alongthe ground. He found that he could only walk withdifficulty and consequently took to bicycling. Morerecently he complained of ' fluttering ' of various musclesall over his body, chiefly forearms, neck and thighs.Previous history.-He had scarlet fever with acutenephritis as a child. At the age of 15 he was employedin the production of lead arsenate and had several attacksof abdominal colic. Five years before admission hedeveloped a secondary anaemia which responded well toiron. Family history.-Father died of pneumonia at theage of 50. Mother and one brother and four sisters alive,and well. There was no familial nervous disease.Condition on admission.-Intelligent, slightly pale man.Weight 10 st. 5 lb. Afebrile. Yellow stain on hands

228

on January 12, 2020 by guest. Protected by copyright.

http://oem.bm

j.com/

Br J Ind M

ed: first published as 10.1136/oem.1.4.227 on 1 O

ctober 1944. Dow

nloaded from

TOXIC POLYNEURITIS FROM TRICRESYL PHOSPHATEand particularly around finger nails. Caustic sodaulcer on one finger. Cold, moist hands and feet. Noabnormality discovered in the respiratory, cardio-vascular or gastro-intestinal systems. Nervous system:no mental abnormality; concomitant strabismus; con-genital nystagmus; fundi and pupils normal. Upperlimbs: weakness of flexors and extensors of wrists andfingers, of dorsal and palmar interossei and lumbricals;wasting of thenar and hypothenar eminences and of firstdorsal interosseous muscle, some hypotonus of musclesof the wrists; reflexes all present and equal; no sensoryloss. Abdominal reflexes present and equal. Lowerlimbs: gross weakness of dorsi-flexors and plantarflexors of both feet; he was unable to move his toes;wasting and hypotonus of both calves, the left is half aninch smaller than the right; wasting and hypotonus oftibialis anticus on both sides; flail ankle joints; sensationunimpaired; calves and tendo-Achilles very tender onpressure; fibrillation of muscles of thighs and forearms;knee jerks exaggerated; ankle jerks absent; plantarresponses flexor. Slow, high-stepping gait with draggingof feet. Special examinations.-Blood count: red cells4,500,000 per cmm., haemoglobin (Sahli) 88 per cent.,colour index 09, white cells 13,400 per cmm., differentialcount normal; no abnormality seen in stained films.Blood Wassermann reaction negative. Lumbar punc-ture: pressure 100 mm. of cerebro-spinal fluid; Quecken-stedt's test normal;sfluid clear and colourless; no excessof white cells; protein 20 mg. per 100 cc., Wassermannreaction negative. Urine: no albumin or sugar. Pro-gress.-For six weeks after admission the weakness ofthe feet became worse. After three months, however,there were signs of improvement, the patient being ableto move some of his toes. The flexors and extensorsof the wrists were improVed. Fibrillary tremors ofthighs were particularly marked. Plantar responsesunobtainable. He was treated with vitamin B1 intramuscularly and with massage and movements. Hecontinued to make progress and regained power in theupper limbs which returned to normal. There wasgreat improvement in dorsi-flexion and plantar flexionof the foot, and he was discharged from hospital after19 months, wearing uplifting toe springs. He con-tinued to make slow progress and after 34 years therewere only slight residual signs, and he returned to work.

Case 3. G.S., a man aged 38 years. (L.H. Reg. No.M.252/1941). For six months before admission thepatient had been employed in the manufacture of tri-ortho-cresyl phosphate, and he did exactly the same jobas the other two men. During this time he had com-plained of cramp-like pains in the hands which came onafter he had been lifting heavy drums. Ten days beforeadmission he had diarrhoea, passing 5 stools per dayfor 2 days unaccompanied by abdominal pain, and 1day later he noticed that his toes dragged along the groundand that his feet slapped down as he walked. At thesame time there was a severe aching pain in his calfmuscles, particularly on standing or walking, and atintervals severe stabbing, shooting pains in the samegroup of muscles. He also had severe pains in hishands radiating upwards into the forearms and he foundhe was unable to extend his fingers which became fixedin a position of semi-flexion. As this pain graduallywore off so also was he able to straighten his fingers.The weakness of his legs gradually became worse.Previous history.-At the age of 33 he was admitted tohospital with a history of having drunk spirits of salts.Family history.-Wife died by suicide. Three childrenalive and well. Two brothers and one sister alive andwell. There was no familial nervous disease. Con-dition on admission.-Well nourished man. Afebrile.Quantities of yellow material around nail beds. Noabnormality in cardiovascular, respiratory or gastro-intestinal systems. Harrison's sulcus. Scoliosis. Ner-vous system: no mental abnormality; no abnormalityin cranial nerves ; fundi normal. Upper limbs: slightweakness ofextension of wrists, especially left; no wastingor alteration in tone; reflexes all present and equal; no

sensory loss. Abdominal reflexes present and equalLower limbs: weakness of dorsi-flexors and less of plantarflexors of feet; slight wasting of calf muscles, more oftibialis anticus; general slight flaccidity of plantar anddorsi-flexors of feet; fibrillary tremors of thigh muscles;no impairment of sensation marked tenderness ofcalves and tendo-Achilles; knee jerks present and equal;absent ankle jerks; plantar responses flexor. Gait slowand high-stepping. Special examinations.-Blood count:red cells 4,700,000 per c.mm., haemoglobin (Sahli)92 per cent., colour index 0 9, white cells 8000 per c.mm.,differential count normal; no abnormality seen in stainedfilms. Blood Wassermann reaction negative. Lumbarpuncture: pressure 100 mm. of cerebro-spinal fluid;Queckenstedt's test normal; fluid clear and colourless;no excess of white cells; protein 100 mg. per 100 cc.;Wassermann reaction negative. Urine: no albumin orsugar. Progress.-He was treated with vitamin B1intramuscularly and with massage and movements. Hemade steady progress and the power in the legs returnedwith increased ability to dorsi-flex his feet. Movementreturned in both big toes after four months, but fibrillarytremors of thigh muscles persisted. He was dischargedafter ten months in hospital, able to walk with no evidenceof foot-drop, and he returned to work.

The clinical picture of tri-ortho-cresyl phosphatepoisoning is that of a polyneuritis with flaccidparalysis of the distal muscles of the upper andlower extremities. Slow but complete recoveryusually occurs. These three cases were of menengaged in the manufacture of tricresyl phosphate.Up to the present time no case has been reported inmen using the substance as a plasticiser or in thosemoulding plastics. As is shown later, however,plastic materials containing tricresyl phosphatehave given rise to symptoms in experimental animals.

Opportunities to study this clinical picture occurredduring a period of 40 years prior to the discoveryof the first victim of industrial poisoning. It wasencountered in patients treated for pulmonarytuberculosis with phospho-creosote, in people whohad partaken of an alcoholic beverage known asJamaica ginger or jake, in women who had takenapiol as an abortifacient, and in certain victims fedon a soya bean cooking oil adulterated by accident.

Previous Outbreaks of Poisoning with TricresylPhosphate

In 1899 Lorot reported six cases of multipleneuritis out of 41 cases of pulmonary tuberculosistreated with phospho-creosote. This substancewas discovered in 1894. Later it was shown tocontain 15 per cent. of tri-ortho-cresyl phosphate.In the next 35 years 53 additional cases were recordedin various parts of Continental Europe (Roger andRecordier, 1934).

In the spring of 1930 there appeared suddenly, inthe mid-western and south-western states of theUnited States of America, an outbreak of paralysischaracterized by bilateral foot- and wrist-drop.During March and April of that year almost 4,000cases were reported in the press throughout theUnited States of America. During the whole year15,000 people were affected, and of these 10 died.A connexion was immediately recognized betweenthis paralysis and the ingestion of adulteratedsamples of the popular alcoholic drink alreadymentioned-Jamaica ginger or jake. The quantityof ginger fluid consumed was not the determiningfactor in the severity of the symptoms which fol-lowed; a single drink is known to have produced

229

on January 12, 2020 by guest. Protected by copyright.

http://oem.bm

j.com/

Br J Ind M

ed: first published as 10.1136/oem.1.4.227 on 1 O

ctober 1944. Dow

nloaded from

BRITISH JOURNAL OF INDUSTRIAL MEDICINE

the same result as that following the use of thebeverage for many days.The clinical picture develops by three stages. In

some cases there are early transient gastro-intestinalsymptoms including nausea, vomiting, diarrhoea,and abdominal pain. These clear up and a symp-tom-free interval follows lasting from 5 to 21 days,the average being 10 days. This interval is followedby soreness of the muscles below the knees andnumbness of the toes and fingers lasting severaldays and followed by weakness of the toes andbilateral foot-drop. After another interval of about10 days weakness of the fingers and wrist-dropfollows. This paralysis is not usually as severe asthat in the feet and legs. In the upper extremitiesparalysis does not extend above the elbows. Thethigh muscles may be involved in advanced cases.There are neither sensory changes nor loss ofsphincter control.By July, 1930, Smith and Elvove proved that the

adulterated beverage contained about two per cent.of tri-ortho-cresyl phosphate and that this causedthe paralysis. The reason for including this sub-stance as one of the ingredients will probablynever be known. It may have been used on accountof its physical properties.. By subcutaneous in-jection of samples of the adulterated drink, as wellas of pure synthetic tri-ortho-cresyl phosphate,Smith and Elvove succeeded in producing a paralysiscomparable to that seen in human beings in avariety of laboratory animals including -hens,rabbits, calves, dogs and monkeys.

Zeligs (1938) had the opportunity to follow up316 cases of jake paralysis during 6 years. Hisdescription of the clinical picture in 1930 andlater in 1936 shows that the poison may attack theanterior horn cells and the pyramidal tracts, inaddition to the peripheral motor nerves. In 1930all the patients had typical foot-drop, the degree ofparalysis varying from slight muscular weakness tocomplete flaccid paralysis of all the muscles of thefeet and legs. In about three-fourths of the casesthe upper extremities became similarly involved,wrist-drop being common. The ankle jerks wereabsent, the knee jerks present and in many casesover-active. There were no abnormal plantarresponses and no ankle clonus. Sensory changeswere absent. During the next six years many of thepatients recovered completely and others improvedsufficiently to be able to use their hands and feetadequately. Out of 316 patients admitted to theCincinnati General Hospital in 1930 a group of 60were found still in institutions in 1936. Theyhobbled about with the aid of sticks. Physicalexamination showed spastic paralysis with adductorspasm, paralytic talipes, exaggerated tendon re-flexes, and extensor plantar responses. In the upperextremities there was marked atrophy of theextensors of the wrists and of the interossei, withbilateral claw hands.The initial conception of tri-ortho-cresyl phosphate

poisoning as being a peripheral neuritis is thereforeno longer tenable. The anterior horn cells andpyramidal tracts may sometimes be affected too, butthe extreme muscular wasting tends to mask theinvolvement of the upper motor neurone. Whenmuscular activity is partially restored the spasticsigns of the previously hidden upper motor neuronelesion become clinically apparent. In such casesthe end result resembles amyotrophic lateral sclerosis.

In 1931 ter Braak reported in Holland an outbreakof some 40 cases of paralysis from the use of apiolas an abortifacient. During 1931 and 1932 50 morecases were published from Germany, France,Switzerland, and Jugoslavia. Samples of apiolwere found to be adulterated with tri-ortho-cresylphosphate to the extent of 28 to 50 per cent. (Ger-mon, 1932). Nobody knows why this substancewas chosen as an adulterant. Neither in colour,taste, nor odour do the two oils resemble eachother. In the women affected there was a lowermotor neurone paralysis of the distal muscles ofthe extremities, without sensory loss.

In April, 1937, there occurred an outbreak affect-ing 68 people who had partaken of soya bean oilused for salads and for cooking. Forty-one ofthese people lived in Natal and the other 27 travelledin a ship which had been provisioned in Durban(Sampson, 1938, 1942). This oil was found tocontain 0 4 per cent. of tri-ortho-cresyl phosphate.The victims first had gastro-intestinal symptoms and7 to 14 days later developed cramps in the calvesof their legs. Ultimately lower motor neuroneparalysis of the feet and hands supervened, butsensation was unimpaired. I

Cases of tri-ortho-cresyl phosphate poisoninghave recently occurred in Miinster owing to shortageof fats in Germany. The patients were factoryworkers who had obtained a fat substitute from theirplace of work. They had taken it home and,because of the shortage of natural animal andvegetable fats, had used it to fry potato pancakes.They developed nausea, vomiting, abdominalcramps, and diarrhoea, followed in 10 days byrapidly increasing weakness of the feet, legs, andthen arms. There was progressive atrophy of themuscles. As a result of this outbreak, a warningwas issued to factory medical officers in Germany,who were instructed to prevent recurrences byeducation and propaganda (Humpe, 1942).

Portal of EntryHamilton (1934) suggested that dangerous ex-

posure to tri-ortho-cresyl phosphate might occurin the mixing of lacquers containing this materialas a plasticizer, particularly if the ingredients wereheated.Hodge and Sterner (1943) estimated the amount

of tri-ortho-cresyl phosphate that can be absorbedthrough unbroken skin, and how rapidly the absorp-tion occurs. Tri-ortho-cresyl phosphate containingradio-active phosphorus was used and the absorptionmeasured in two human subjects and one dog. Thehuman subjects applied 0-22 g. and 0-11 g. of thetri-ortho-cresyl phosphate with radio-activity of395,000 counts/mm./0 1 g. The first had thirteenmicrograms of tri-ortho-cresyl phosphate per 100 cc.of blood at the end of one hour, and he excretedseven micrograms in the urine in the first hour, andcontinued at 35 micrograms an hour for the next24 hours. He excreted 797 micrograms or 0-36per cent. of the amount applied. The second hadfour micrograms per 100 cc. of blood at the end ofone hour, and excreted 143 micrograms or 013per cent. of the amount applied.

2-094 g. of the tri-ortho-cresyl phosphate wasapplied to the abdomen of a bitch and the bloodlevel quickly established itself at 8 micrograms/100 cc., and maintained this for 24 hours. Theurinary excretion began equally promptly, being

230

on January 12, 2020 by guest. Protected by copyright.

http://oem.bm

j.com/

Br J Ind M

ed: first published as 10.1136/oem.1.4.227 on 1 O

ctober 1944. Dow

nloaded from

TOXIC POLYNEURITIS FROM TRICRESYL PHOSPHATE44 micrograms in the first hour, rising after sevenhours to a maximum of 1312 micrograms. Theradio-active phosphate was distributed in the varioustissues of the dog 24 hours after its application tothe abdominal surface. Retention was in the fol-lowing order:-visceral organs, muscle, brain, bone.The authors consider that the magnitude of

absorption of tri-ortho-cresyl phosphate throughhuman skin is such that a real hazard exists inindustrial operations permitting a considerable orrepeated exposure to this compound. A safeindustrial hygiene control requires that measures betaken to prevent. such skin contact, and that allworkmen exposed to the compound be instructedas to the hazard, and the necessity for preventingskin contamination.

Because of the low volatility of tri-ortho-cresylphosphate and the low vapour pressure at ordinarytemperature, it has been argued that poisoningcannot occur from inhalation. However, the factthat in our cases the symptoms were precipitatedby the introduction of black-out conditions sug-gested that poisoning may arise in this way. Further,in order to try to prevent recurrence, the firmemploying the men fitted the wash tank room withventilators and a fan. The tanks were closed inand the vents fitted with injectors, so that thevapours might be quickly transferred to the openair. Since these precautions no further cases ofpoisoning have occurred, and it is therefore possiblethat the lungs were the portal of entry of the poisonin our cases. However, the black-out conditionsin the plant raised the temperature: and the intro-duction of a more elaborate ventilating systemsubstantially lowered this temperature. In view ofthe atmosphere concentrations a more probableexplanation is that increased sweating caused greaterabsorption through the skin.

Experimental Evidence of ToxicitySmith and Elvove (1930) showed that the specific

toxicity of tri-ortho-cresyl phosphate for the motornerves is not shared by the meta or para cresyl estersor by the phenyl ester. The dosage of tri-orthocresyl phosphate was approximately 30 times lessthan that of triphenyl phosphate. Flinn (1943)was able to produce paralysis in 28 days in domesticfowls fed with cellophane, containing 11 per cent.of tri-ortho-cresyl phosphate, in amounts of 1 gm.per kilo of body weight.

Attempts were made to confirm these experi-mental observations. Twelve twelve-week old henswere obtained and fed with gelatin coated capsulescontaining 0 5 g. of one of the pure isomers oftricresyl phosphate or triphenyl phosphate. Fourhens were used as controls, and two each were fedwith tri-meta, tri-para, and tri-ortho-cresyl phosphateand triphenyl phosphate. Unfortunately two of thecontrols developed fowl paralysis after the othershad had 2 g. of the drug. It was noticed, however,that the two hens which received the tri-ortho-cresylphosphate became completely paralysed in the wingsand legs. The fowl paralysis in the controls renderedthis experiment unsatisfactory, and it was thereforerepeated with 12 twelve-week old cockerels. Afterreceiving 3 g. of tri-ortho-cresyl phosphate twocockerels became paralysed and died four daysafter receiving 3-5 g. After 12-5 g. the two cockerelsfed with tri-meta-cresyl phosphate showed con-

siderable weakness of the legs, and after 15-5 g. theydeveloped respiratory paralysis. They were grosslyemaciated and were then killed. The cockerelswhich were fed with tri-para-cresyl phosphate andtriphenyl phosphate showed no evidence of ill-health after they had received 25 g.

Measures for Prevention of PoisoningSince there is experimental evidence that tri-

ortho-cresyl phosphate can be absorbed throughthe skin, it is important, as a measure of prevention,that workers with these compounds should wearelbow length gloves to protect their hands and arms,and should change into special clothing duringtheir working hours. This will prevent the pos-sibility of smoking and food being eaten and thuscontaminated with dirty hands. Bathing facilitiesfor use at the end of the work period are alsodesirable. In the cases described in this paper theportal of entry may have been the respiratory tract,and therefore all rooms where the substances areused should be provided with exhaust ventilation.Tanks should be closed in and the vents fitted withejectors so that the vapours may be quickly trans-ferred to the open air.

SummaryThe literature of the toxicity of tricresyl and

triphenyl phosphate is reviewed. An account isgiven of the cases of three men who developed atoxic polyneuritis while working in industry in themanufacture of tricresyl phosphate. Experimentson domestic fowls confirm that tri-ortho-cresylphosphate is toxic. 3 5 g. of tri-ortho-cresyl phos-phate killed two twelve-week old cockerels. 12-5 g.of tri-meta-cresyl phosphate produced weakness ofthe legs, and 15-5 g. respiratory paralysis, whereas25 g. of tri-para-cresyl phosphate and triphenylphosphate produced no effect. Measures for theprevention of poisoning are discussed.

We are much indebted to Mr. R. Milton andDr. J. Graham for help with the animal experiments,and to the research chemists of Messrs. A. Boake,Roberts & Co., Ltd., for preparing the isomers oftricresyl phosphate in pure form for these experi-ments.

REFERENCESter Braak, J. W. G. (1931). Nederi. Tijdschr. Geneesk,

75, 2329.Flinn, F. B. (1943). Personal communication.Germon, G. (1932). Intoxication Mortelle par l'Apiol.

These de Paris.Hamilton, A. (1934). Industrial Toxicology, New York,

Harper and Brothers; p. 195.Hodge, H. C. and Sterner, J. H. (1943). J. Pharm.

exper. Ther., 79, 225.Humpe, F. (1942). Munch med. Wschr., 89, 448.Lorot, C. (1899). Les combinaisons de la crdsote dans

le traitement de la tuberculose pulmonaire. Thbsede Paris.

Roger, H., and Recordier, M. (1934). Ann. de Med.,35, 44.

Sampson, B. F. (1938). Bull. Off. int. Hyg. publ., 30,2601.

(1942). S. Afr. med. J., 16, 1.Smith, M. I., Elvove, E., et al. (1930). Publ. Hlth. Rept.,

Wash., 45, 1703, 2509.Zeligs, M. A. (1938). J. nerv. ment. Dis., 87, 464.

231

on January 12, 2020 by guest. Protected by copyright.

http://oem.bm

j.com/

Br J Ind M

ed: first published as 10.1136/oem.1.4.227 on 1 O

ctober 1944. Dow

nloaded from