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CHRONIC CARBON TETRACHLORIDE INTOXICATION

BY

ALICE STEWART and L. J. WITTS

(From the Nuffield Department of Clinical Medicine, University of Oxford)

Carbon tetrachloride is a non-inflammable, cheapand easily available fat solvent. The majority ofcases of poisoning reported have been isolatedincidents, following temporary exposure to highconcentrations of the vapour or oral administrationof liquid carbon tetrachloride in the treatment ofdisease. In such cases death may result fromnarcosis, hepatic necrosis or acute nephritis but ifthe victim survives, little or no permanent damageensues. There has been little reason to suppose thatworkers in contact with carbon tetrachloride sufferany deterioration in general health, so long as pre-cautions to prevent heavy exposure have been takenin designing the plant. This opinion appeared tobe confirmed by the investigations of Smyth andSmyth (1936) among workers employed in thirty-six factories using carbon tetrachloride. Theymade a careful analysis of air concentrations of thesolvent and carried out a series of blood counts, andliver and kidney function tests, on ninety-six workerswho had been employed over several years. Theyconcluded that their tests showed that no one couldbe considered seriously or even unmistakablyinjured by the solvent vapours.

It was therefore a matter of considerable interestwhen we were asked to carry out an investigationin a chemical factory where large numbers of workerswere said to be suffering from chronic carbon tetra-chloride poisoning. Although only 75 people wereworking at any one time in contact with carbontetrachloride, 122 certificates for compensation hadbeen issued over a period of two-and-a-half yearsand more than 80 people had been dischargedbecause of symptoms attributed to carbon tetra-chloride. The work was acquiring an evil reputa-tion in the district and it was becoming increasinglydifficult to obtain labour to replace the losses. Inaddition the management was perturbed by failureto maintain a satisfactory rate of production. Inwork of this kind efficiency can be measured by theratio between output and input of chemicals. Ina new process it is customary for the ratio to risesharply at first as the technique is mastered, andthereafter to maintain a slight upward trend. Inthis particular process the numerical value forefficiency had actually declined. This was attri-buted to the failure of shift managers and keypersonnel to maintain enthusiasm or even carry on

at all after six to eighteen months in contact withcarbon tetrachloride.

Details of InvestigationThe process consisted in the chlorination of an

aniline derivative in solution in carbon tetrachloride.The factory had been planned for continuous workunder conditions of war, and more attention hadbeen paid to the strength of the walls and the com-pleteness of the black-out than to the state of theatmosphere. Apart from the difficulty of generalventilation, high concentrations of carbon tetra-chloride were liable to occur from spills of materialand from leaks in the piping system which connectedthe separate containers or conveyed the motherliquor from the sump tank back to the still house.Such leaks were inevitable owing to corrosion ofpipes by traces of hydrochloric acid and the solventaction of carbon tetrachloride on the washers ofjoints and pumps. The chlorinated compoundwas eventually separated from the carbon tetra-chloride by centrifuging and vacuum dryingand during these processes an ill-fitting lid or aninefficient draught was enough to contaminate theatmosphere heavily. No useful figures can be givenfor the air concentrations of carbon tetrachloride.Although the chemists used the Halide DetectorLamp over a period of three months, it did notwork satisfactorily and if a serious leak occurred,no one was free to take a reading. At first it wasthought that the high morbidity rate might be dueto some other chemical used in the process. Butan analysis of the air concentration of the varioussubstances and a comparison with other processesin the factory, where they were used without carbontetrachloride, indicated that carbon tetrachloridewas the offending agent. This conclusion was sup-ported by the fact that the symptoms were similarto those described in the literature in mild forms ofcarbon tetrachloridepoisoningand they were differentfrom the known effects of the other chemicals.

Approximately 25 workers per shift were engagedon the plant and work was continued throughoutthe 24 hours on a three-shift basis, so that about75 people were involved each day. Workers wereoften transferred to other parts of the factory sothat the total number of people who had beenexposed exceeded this figure. During the investi-

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BRITISH JOURNAL OF INDUSTRIAL MEDICINE

gation we succeeded in interviewing and examining78 of the factory employees: 51 of these wereworking on the carbon tetrachloride plant at thetime of the examination and 27 were engaged onother processes but had been exposed previously.As many as possible of those examined were per-suaded to have venepuncture and special investi-gations such as test meal, barium meal, gastroscopyand a detailed examination of the eyes by an ophthal-mologist. The tests made on the sample of venousblood included a full blood count, erythrocytesedimentation rate, blood urea, serum bilirubin andphosphatase, plasma proteins and the Takata-aratest for liver efficiency. Technical methods aredescribed in a previous paper (Higgins, O'Brien,Stewart and Witts, 1943).

Another effect of exposure that had attracted theattention of the factory surgeon was a remarkablegain in weight in the women as soon as they beganto work in the plant. When we came to examinethe cases we found several instances of a gain ofover two stone in a few months. This effect wasmost common in the women but was also found ina smaller number of the men.

Gastro-Intestinal EffectsThe severity of the gastro-intestinal symptoms

varied from a mild queasiness to violent and re-peated attacks of nausea, vomiting, colic and diar-rhoea. The more severe symptoms always followeda particularly heavy exposure such as might occurwhile attending to a big leak or spill. It was there-

TABLE 1

Interval-Group Sex | Exposure in months Total Bio- Barium Test Gastro- Eyes

in months since last chemistry meal meal scopyexposed

I Males .. 2-36 0 37 28 16 16 1 1 13

Females . 1-20 0 14 10 3 1 2 2

Males .. 2-24 1-20 10 8 5 3 1 0II l__

Females .. 1-6 1--14 17 14 1 0 1 0

Number and sex of workers examined by various techniques. All were examined clinically. Workers inGroup I were employed on the carbon tetrachloride plant at the time of examination. Those in Group II hadbeen previously exposed but were now employed elsewhere in the factory.

Apart from one case of acute rheumatism, withaortic and mitral disease, two cases of essentialhypertension, four cases of chronic bronchitis andemphysema, together with a fairly high incidence ofminor defects such as gingivitis, dental caries,chloracne and folliculitis, clinical examination ofthe workers was essentially negative. It was astriking thing that despite the severity and durationof their symptoms the subjects had the appearanceof good health. Their appearance almost beliedtheir story. However, a typical history ofsymptomsresulting from exposure to carbon tetrachloride wasobtained in every instance except one. The excep-tion was a woman who had only recently beenrecruited to the work and had as yet experiencedno ill effects. As the histories were related it soonbecame clear that there were two sharply differen-tiated sets of symptoms, one which indicated agastro-intestinal disorder, and the other a cerebraldisturbance. The certificates compiled by thefactory surgeon contained the following list ofcomplaints:NauseaVomiting . .

Anorexia . .Abdominal painDiarrhoea . .HaematemesisHaemorrhage

rectum . .

.

. .

. .

. .

. .

from* .

110 Weakness122 Vertigo64 Collapse78 Confusionf97 Headache5 CoughI Dyspnoean

1 Loss of weight

fore characteristic for the symptoms to be recurrentrather than steadily progressive, though it wascommon for subjects to find that, whereas in theearly weeks or months of exposure they felt wellbetween the severe bouts, sooner or later theydeveloped residual effects such as persistent nausea,alterations of appetite with a perverted sense oftaste and smell, and a vague fullness in the epigas-trium or dull ache in the lower part of the abdomen.Gradually they acquired such a distaste for thesmell of carbon tetrachloride that they experiencedattacks of vomiting in circumstances which hadpreviously had no effect. In some cases sensitivitywas heightened to an amazing degree. One of thefitters declared that he was unable to wear his gas-mask because the smell of it induced vomitingimmediately. A plant chemist volunteered theremark, 'I have now developed a conditioned reflexand the thought of setting about a job which involveshandling the stuff is enough to make me vomit.'Others who had observed the same effect were con-vinced that their vomiting was now psychological,a possibility which was suggested on other grounds.It could not be supported as a total explanation,however, after one had considered the personalityand recoid of many of the people. A few workersbehaved in a different way. They rememberedhaving had nausea and vomiting in the early daysof exposure but in the end became immune and no

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CHRONIC CARBON TETRACHLORIDE INTOXICATION

longer suffered any ill-effects except when heavycontact with the fumes caused temporary giddinessand a feeling of intoxication, a narcotic rather thana gastro-intestinal effect. These workers were ableto work in conditions considered intolerable by theothers.

It was usual for subjects to experience nauseaimmediately after a period of heavy exposure butfrequently vomiting was delayed until after the nextmeal and the attack often reached its climax after24 hours, by which time, in severe cases, there mightbe extreme prostration with salivation, chillinessand shivering. On such occasions the vomit oftencontained streaks of blood and there was usuallysevere colic and diarrhoea.Bowel symptoms were often most conspicuous in

the first serious episode and might not be repeatedin subsequent attacks. In two cases, however, theywere the predominant feature and diarrhoea per-sisted for several weeks after the other symptomshad subsided. A mild recurrent form of diarrhoeawas a very common residual effect, and it wassignificant that no single person working on theplant admitted to being constipated, though severalhad suffered in this respect before taking up theirpresent work. Abdominal pain during the acuteattacks was of two types and a worker might sufferfrom both or only one. Colic was both upper andlower abdominal and was of all grades of severity.The other type of pain was epigastric in situation,aching or burning in character, and persisted forlonger peiiods than did the colic. It was describedby one as grasping pain, by another as like a beltwhich is too tight. Though the liability to attacksincreased, the severity usually did not, and one

gained the impression that in spite of recurrentepisodes there was no continuous deterioration inthe general health. Even the residual symptomsthat stretched from one exacerbation to the nextwere rapidly relieved after a brief period away fromwork.

Certain things accentuated the symptoms bothbetween attacks and at the height of an episode.Many were found to be avoiding fat foods becausethey brought on nausea. Pickles caused pain.Milk, which was supplied freely and in abundance,was soon left untouched. Experienced workersnever had beer before coming on a shift but one

chemist said any long drink had a bad effect.Tobacco often heightened the nausea or the pain,and many experienced dizziness, palpitations, a

feeling of coldness and even collapse when theysmoked immediately after a shift. One intelligentyoung woman commented that the feeling carbontetrachloride gave her was just like the feeling ofbeing pregnant. 'You want to eat, but when you

do, even a cup of tea tastes somehow different.'

Mental EffectsTemporary cerebral effects, such as light-headed-

ness, giddiness and vertigo occurred immediatelyafter exposure to high concentrations of carbontetrachloride vapour, though there was considerable

personal variation in the threshold at whichsymptoms appeared. A few individuals had lostconsciousness whilst attending to leaks or spills.Acute headaches usually followed these events anda more chronic form of headache was found inseveral cases. Alteration of the sleep rhythm wasas universal a complaint as were the gastro-intes-tinal effects. Drowsiness and failure to feel re-freshed on waking were invariably present. Somesaid they could sleep the clock round and still wantmore; others, equally drowsy, had insomnia.Frequently one phase alternated with the other andin such cases temporary insomnia was often asso-ciated with the bouts of sickness. Excessive fatigu-ability as well as drowsiness was commented on byall.The next commonest effect was a loss of mental

agility which showed itself in inability to tacklemore than one problem at a time and impatiencewith anything which demanded spontaneous enthu-siasm. As might be expected, the mental hebetudewhich occurred as a result of exposure was moreclearly described by the plant chemists and skilledworkers than by the process hands. More thanone plant chemist had noticed a time lag betweenthought and decision, and there was a tendency toloss of memory for recent events. Depression andirritability had often been remarked by the subjects.Inertia was such that one had diagnosed his com-plaint as pure idleness. Several said that they usedto be voracious readers but were now liable to fallasleep ovet a book, or had such difficulty in followingthe plot and remembering fresh names, that theyhad given up reading books and only occasionallylooked at the newspapers.The need to clean and cook appeared to help the

women, who were responsible for the care of theirhomes, to throw off the inertia which they felt as aresult of contact with carbon tetrachloride, andseveral of them explained that a sleep of from halfan hour to two hours immediately on returninghome, before attempting to eat, made them feel fitenough to tackle household duties. Almost allworkers interviewed said that they felt too lazybetween shifts to make the effort to go out for airor exercise though they knew it would be good forthem. As one man put it 'The worst of the stuff isthat it stops you doing what you know would do yougood against it; you turn against milk and youcan't be bothered with getting out of doors.' Thiscomment came from a worker who had fished allthe rivers within a radius of 40 or 50 miles andknew in which the fish had survived the by-pro-ducts of industry. After a few months on theplant he had completely dropped a hobby whichhad kept him sane all through the depression.

Other men, who had cultivated allotments duringthe same period, wished to keep them going butsaid they felt too lazy to make the effort after work-ing with carbon tetrachloride. Many of the youngerworkers housed on a new estate had not even begunto get their gardens in order, but there was no meansof knowing whether this neglect was more common

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among these workers than among other residents.The visitors had the impression that in spite of theopinion which most workers expiessed that freshair got rid of the effects of carbon tetrachloride andalso that carbon tetrachloride and beer ' don'tagree,' the workers often spent leisure time in thecinemas and public houses because it required lesseffort to do so than to get out for air and exercise.Nevertheless the speed with which symptoms dis-appeared when workers were removed from theplant was surprising. Almost all reported that aweek-end away, especially if it was spent in exercisein the open air, caused great improvement in bothmental state and gastro-intestinal symptoms. Evena long bicycle ride or a game of golf made a strikingdifference.

Haematological and Biochemical DataVenous blood samples were obtained from 36

men and 24 women. The area from which theworkers were drawn had suffered severely in the

depression. For the ten years preceding the warthere had been a great deal of unemployment andin some cases the unemployed were not reabsorbedinto industry for twelve or eighteen months afterthe outbreak of war. Red cells and haemoglobinin both sexes are some 10 per cent. below the ac-cepted standard of normality (Price-Jones, Vaughanand Goddard, 1935) but they are not significantlydifferent from values obtained in nutrition surveysof comparable areas in 1942. The lowest haemo-globin value in a man was 81 per cent., but four ofthe women had haemoglobin values below 80 percent.-79, 77, 71 and 67 per cent. respectively. Thecolour indices were unity or below. White cells areabove the normal mean for venous blood, whichOsgood, Brownlee, Osgood, Ellis and Cohen (1939)gave as 7410±70. Sedimentation rates also arehigher than Wintrobe and Landsberg's (1935)normals, but they are not very different from agroup of controls from other sections of the factory.There is still a great deal to be learnt about the

TABLE 2

Reticulo-No. Hb, R.B.C., C. .

W.B.C., cytes, E.S.R., Platelets,per cent. millions thousands per cent. mm. thousands

Males .. 37 95±1i14 4-97±O-02 0-97 10-2±0-54 1-07±0-1 9-0±1-22 247±3-21

Females .. 24 86±157 4 6±0 1 0-93 9-1±0-52 1-49±0-11 18 5±2-6 284±17 8

Blood picture in chronic carbon tetrachloride intoxication. In this and subsequent tables the statistical averagesare given ± the standard error of the mean.

TABLE 3

Group Sex No. Mean, Range,mm. mm.

Medical students andnurses (Wintrobe) Males 137 3-7 0-14

Females 100 9-6 0-29

Carbon tetrachloride Males 36 8-5 1-32workers.

Females 24 18-5 3-45

Unexposed workers Males 30 8-2 1-24from same factory.

Females 19 11 0 4-31

Erythrocyte sedimentation rates in workers comparedwith normal men and women controls from the samefactory.

frequency distribution of haematological data infactory populations, but we feel justified in sayingthat there is no pathognomic change in the bloodcount of the carbon tetrachloride workers. Theblood urea, the serum bilirubin and phosphatase,and the plasma proteins were all within normallimits. No individual value was significantlydifferent from the normal, and the Takata Arareaction was negative throughout. The total fats,fatty acids and cholesterol of the plasma were deter-mined in 9 men and 12 women and these also werenormal.

Barium MealsBarium meals were performed on 25 subjects, 19

at present employed and 6 formerly employed onwork with carbon tetrachloride. No one was seenduring an acute attack of sickness but three subjects

TABLE 4

Blood urea, Bilirubin, Phosphatase, Proteins, g. per 100 c.c.No. mg. per mg. per King and g._per_100_c.c. _Takata-ara

100 c.c. 100 c.c. Armstrongunits Total Albumin Globulin

Males .. 37 33-8±0-96 0-43+0-04 9-6+0-49 7-01±0t05 4-5±0-04 2-53±01 NegativeFemales .. 24 300±1-17 0-38±0-08 9-1±0*7 6-99±006 443±004 2-53±0-6 Negative

Biochemical data in carbon tetrachloride workers.

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CHRONIC CARBON TETRACHLORIDE INTOXICATIONTABLE 5

Total fats, Fatty Choles-No. mg. per acids, mg. terol, mg.

100 c.c. per 100 c.c. per 100 c.c.

Males .. 9 608±45 346±40 143+9*8

Females .. 12 564±52 380±63 156±8 4

Total fats, fatty acids and cholesterol in the plasma ofcarbon tetrachloride workers.

had some abdominal pain at the time of the examina-tion and two had had a severe attack of vomiting afew weeks previously. The changes observedunder the screen were similar in all the subjectsexamined. They were present even when there hadnot been any recent exposure, though the changeswere then less marked. The abnormal featureshave been listed in Table 6. They consisted of acharacteristic change in the motility and appearanceof the stomach and intestines, which suggested anunusual state of irritability and was shown chieflyby spasm of various parts of the gut and a rapidpassage of the meal during the first six hours.

In all cases the stomach was of good tone and inthree it was noticeably irregular in the prepyloricarea. Four of these cases were examined with thegastroscope and this examination failed to revealany evidence of ulceration which might have ac-counted for the appearance under the screen.Generally the mucosal folds were normal but in 7cases they were less plastic than usual and therugae appeared unduly prominent. In one of thesethe whole stomach seemed stiffened as though ithad been infiltrated by some process that wasimpairing its normal elasticity. This appearanceof thickening and irregularity of the wall with visiblemucosal pockets was similar to that described withlocalized areas of chronic gastritis, but here againgastroscopy failed to reveal any abnormal surfacechanges.The duodenal bulb was frequently abnormal. In

no less than ten cases it was described as spasticand in six instances it was so exceptionally smallthat it gave the appearance of being in permanenttonic contraction. In addition, the mucosal foldsof the bulb and the duodenal loop were often thickerand more rigid than usual. In spite of these appear-ances there was only one definite duodenal ulcer.This was seen as a small niche in the centre of theposterior wall.

Changes in the small bowel were present in nearlyevery case, for even where there was no irregularityor spasticity of the coils, there was hypermotility.In several cases the head of the meal was in theascending colon at the end of one hour and in twocases it had reached the hepatic flexure. Thechanges in the mucosal pattern were not necessarilypresent throughout the whole of the small bowel.In some cases they were most marked in theduodenum and diminished in intensity towards theproximal coils of the jejunum. In others they weremost severe in the terminal ileum.

Hypermotility was continued through the largeintestine and in several instances the head of themeal had reached either the sigmoid colon or rectumat the end of six hours. Spasm of the colon was aconspicuous feature in all the cases in Group I butwas absent in five of the six cases in Group II andin two of these cases the meal had only reached thehepatic flexure at the end of six hours.

TABLE 6

Group I Group II(19 cases) (6 cases)

STOMACH-Hypertonicity .. .. 3 1Prominent or rigid rugae .. 6 1Excessive secretion .. .. 8 0Pylorospasm .. .. .. 14 3Irregular peristalsis .. .. 5 0

DUODENUM-Spastic cap .. .. .. 8 2Ulcer niche .. .. .. 1 0Irregularity and spasticity of

loop .. .. 7 2

JEJUNUM AND ILEUM-Irregularity and spasticity of

coils .. .. . 11 2

COLON-Spasticity: (1) Severe 14 0

(2) Moderate | 1

HEAD OF THE MEAL AT 6 HOURS-(1) Hepatic flexure .. 0 2(2) Splenic flexure .. 5 2(3) Sigmoid colon .. 10 1(4) Rectum .. .. .. 4 1

Radiographic findings in workers at present employed(Group I) or previously employed (Group II) in contactwith carbon tetrachloride.

Fractional Gastric AnalysisFractional test meals were carried out in 20 cases.

The gastric stimulant was a pint of unsalted grueland the secretion was followed for two-and-a-halfhours. Judged by the standards of Bennet andRyle (1921) hyperchlorhydria was present in 11cases and hypochlorhydria in 3 cases. An excessof mucus was found in 3 cases. The most severehyperchlorhydria was found in a man who had hada heavy exposure with severe nausea and vomitingfive days before. Other examples of hyperchlor-hydria were also associated with recent exposure.The group was comparatively small but it is strikingthat more than 50 per cent. showed excessivesecretion of acid, in contrast to the 10 per cent. thatmight be expected, especially as many of them weremiddle-aged and elderly people. All the subjectswith marked hyperchlorhydria showed considerableradiological changes, but these were also found inthe presence of hypochlorhydria.

Gastroscopic ExaminationGastroscopy was carried out on sixteen workers,

all ofwhom had also had a barium meal and follow-

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through examination. The examination was madewith the Hermon Taylor gastroscope except in oneman who had a slight scoliosis which necessitatedusing the Schindler gastroscope.

In nine cases there were well-marked disturbancesof the musculature. The stomach was very tonicand did not allow easy inflation. The entrance tothe antrum had a mouth-like appearance with themucous membrane thrown into folds at its edge. Itrelaxed very slowly after inflation, and sometimesnot at all. In two cases the mucous membrane ofthe antrum lay in longitudinal folds. Peristalsiswas seen in half the cases, but in one the wavesmoved very slowly and passed only half-way up tothe pylorus. Multiple rings of spasm were some-times seen in the body of the stomach. The finalimpression was that the stomach was tonicallycontracted and unduly liable to intense and pro-longed spasm.

In eleven cases, five of which had shown dis-turbances in tone, the mucous membrane wasnormal. In five the membrane was hyperaemicwith a slight excess of high lights suggesting over-secretion or oedema. In eight cases there was avariable amount of exudate in the body of thestomach. This exudate was usually of the lightfrothy type, but in one case with a hyperaemicmucosa thick adherent mucus was seen in theantrum and lower part of the stomach, and cloudybile-stained mucus was seen pouring back throughthe pylorus, carrying with it lumps of thicker yellow-white mucopus. X-ray examination had revealedconsiderable irregularity of the mucosal pattern inthe duodenum. In one other case, though themucosa was normal in appearance, a small amountof mucopurulent exudate was seen in the region ofthe angulus. The largest amount of the whitefrothy exudate was seen in an individual who hadhad an attack of nausea and vomiting a few dayspreviously and still had slight abdominal pain.Here the mucosa was normal but the angulus andsphincter muscle of the antrum were in intensespasm and the mucous membrane round it wasthrown up into longitudinal folds.The mucosal changes varied in type, occurred only

in a minority, and with one exception were never

severe. They represent minor degrees of gastritisand neither in incidence or severity are they more

than might have been expected in any group of menor women of this age and class. On the other hand,the gastroscopic findings which have reference tothe muscular wall of the stomach were all of thesame type and occurred in over half the cases.

They constitute the positive result of the gastro-scopic investigations and are unusual findings.They support the conclusion that the gastricsymptoms are the direct result of a motor disturb-ance, which may occur without any recognizablegastritis. The discovery of mucopurulent exudatein one case raises the suspicion that where disturb-ances in tone and secretion are continued for longperiods they may eventually exert an irritant effecton the gastric mucosa.

TABLE 7

Examination Group I Group It

TEST MEAL-Number of cases .. .. 19 1Total acid .. .. .. 66±50 12Free HCl .. .. .. 56-5±6-5 0

GASTROSCOPY-Number of cases .. .. 13 3Tone: (I) Normal .. 5 2

(2) Increased .. 8 1Mucosa: (1) Normal .. 9 2

(2) Hyperaemic 4 1Exudate: (1) Nil .. .. 6 2

(2) Frothy 5 1(3) Mucopurulent 2 0

Test meal and gastroscopic findings in carbon tetra-chloride workers.

Examination of the EyesThe fifteen cases examined from the visual point

of view were submitted to the following tests:1. Visual acuity without glasses, and with glasses

when worn. If vision failed to improve to normal,the refraction was checked and vision recorded withan accurate correction.

2. Fields of vision recorded on the Lister Peri-meter with a '-degree white object.

3. Investigation of the central field both forwhite and colours, Bjerrum Screen.

4. Ophthalmoscopic examination.5. Ishihara test for colour vision.The results can be summarized as follows(a) All cases had normal visual acuity, either

without glasses, or with glasses where necessary.(b) In all cases but one the fields of vision were

full.(c) All cases but one showed no scotomata and

no enlargement of the blind spots and no scotomafor colour.

(d) Fundi were normal in all cases.(e) All had normal colour vision save one, who

had partial red-green deficiency. This he hadalways been aware of.The one case who showed on the perimeter test a

loss of field in the lower nasal quadrant of the righteye, on the Bjerrum Screen was found to have anarcuate scotoma arching downwards from the blindspot to the nasal side. Visual acuity was normal,and central colour perception acute. This manwas 41 years of age and had been unaware of anyvisual disturbance. The field defect was rathersuggestive of early chronic glaucoma, althoughthere were no other signs. It was certainly notsuggestive of any toxic condition.

Follow UpExamination of the factory records revealed the

fact that though no deaths had occurred from acutecarbon tetrachloride poisoning, one male workerhad died from a perforated gastric ulcer, one hadbeen operated on for acute pancreatitis, five caseshad developed albuminuria and one case had been

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CHRONIC CARBON TETRACHLORIDE INTOXICATIONfound to have a large liver. In addition 86 indivi-duals had been discharged for gastro-intestinalsymptoms ascribed to carbon tetrachloride. Thenames and addresses of these individuals were ob-tained and an attempt was made to get in touchwith as many as possible. In the end we succeededin tracing three of the cases of albuminuria (twohad left the district), the case of acute pancreatitisand the case of hepatomegaly, and they all attendedfor medical examination. In addition 54 houseswere visited and 30 of the individuals dischargedfor sickness were seen in person by the healthvisitors. A specimen of urine was obtained fromeach. Six houses were empty and no furtherinformation was forthcoming. In 18 cases, thoughthe individual was out at the time of the visit, itwas ascertained from a neighbour or relative thathe was either working full time or had joined theforces. No case of albuminuria was found amongstthe 30 cases successfully visited and only six werenot back at full-time work.

Two of these ascribed their ill-health to carbontetrachloride sickness and were seen by the doctor.One had only left two weeks previously after asevere bout of vomiting and was already recoveringand about to resume work, the other had hadintense diarrhoea and had left the work six weekspreviously. The diarrhoea had persisted for 4 weeks,and in addition he had lost 3 stones in weight andwas extremely weak and breathless. He attendedfor a full examination including blood tests, bariummeal and test meal. An x-ray film of the chestshowed an extreme degree of emphysema and hewas not considered a fit subject for gastroscopy.Of the 4 remaining cases off work for reasons of

health one was pregnant, two were over 60 yearsand had bronchitis and emphysema,'and one wasrecovering from a recent attack of pneumonia.

The majority of the people interviewed had hadgastro-intestinal symptoms for a variable length oftime after leaving the factory. The chief complaintwas nausea with disturbance of appetite and anintense dislike of any smell that reminded them ofthe chemical works. These symptoms had eventu-ally passed off, and apart from the two cases men-tioned above and one other individual who saidthat he had been more chesty since his discharge,no one thought he had suffered any permanent ill-effects. Almost all had returned to full-time workin such strenuous occupations as coal-mining,munitions and aircraft work, a short time aftertheir discharge and had remained in full workingcapacity. The average time interval since dischargewas 10+7 months.The three cases of albuminuria were identical in

that the urine had originally been free of albuminand its presence had been discovered at the routinemedical inspections which were held at the factoryeach month. Though the subjects had experiencedgastro-intestinal effects similar to those described inc

the group as a whole, there had been no other sub-jective evidence of ill-health. A trace of albuminwas still present in the urine of all three but therewas no disturbance of the blood chemistry or bloodpressure. One man was working full time inanother part of the factory, and one woman wasdoing all her housework and looking after hergrandchildren. The other man was less fortunatein that he had developed a compensation neurosisand was rapidly becoming unemployable. He felthe had a financial grudge against the firm anddevoted his whole time and energy to getting hisinsurance company to take legal proceedings.There was nothing on physical examination tosuggest that he was not fit to do full-time work.The only case of enlargement of the liver was

discovered on clinical examination by the factorysurgeon during a bout of diarrhoea and vomitingfollowing carbon tetrachloride exposure. The manwas referred to hospital where the finding was con-firmed. There was no jaundice and he made anuninterrupted recovery from the gastro-intestinaldisturbances. When seen by us he had been backat full-time work for two months. He looked welland his liver was no longer palpable.The man with acute pancreatitis was admitted to

hospital during a bout of vomiting that had begunthree days previously, immediately after exposureto carbon tetrachloride. The vomiting was accom-panied by intense abdominal pain. He was re-garded as a surgical emergency and operationrevealed an intensely congested haemorrhagic pan-creas but no fat necrosis. The abdomen was closedwithout drainage and the patient made an uninter-rupted recovery. When seen by us five monthslater he was back on a light job and felt well exceptthat his appetite was still capricious. Clinicalexamination was essentially negative.

DiscussionAs indicated at the beginning of this paper, the

classical effects of carbon tetrachloride poisoningare narcosis, acute hepatic necrosis and acutenephritis. In our survey of over 170 men andwomen working in heavy contact with carbon tetra-chloride only 1 case of enlarged liver and 5 casesof albuminuria were found, and all six recoveredwithout any sign of progressive hepatic or renaldisease. On the other hand, more than half thetotal 170 had been discharged or transferred fromtheir employment on account of symptoms attri-buted to carbon tetrachloride poisoning. Thissuggests that in the past attention has been tooclosely concentrated on the lethal effects of carbontetrachloride, and disabling symptoms have beenneglected or misinterpreted.Our investigation has shown that the charac-

teristic symptoms of exposure to sublethal concen-trations of carbon tetrachloride vapour are gastro-intestinal distress and mental hebetude. Thealimentary symptoms are associated with hyper-tonicity, irregular peristalsis and spasmodic con-traction of the stomach and intestines, and with

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accelerated passage of the meal. They may besevere enough to simulate an acute abdominalemergency. The mental symptoms are charac-terized by lethargy and loss of mental agility, a sub-narcotic effect. These symptoms are not associatedwith any physical signs of disease. In particular itmay be noted that toxic amblyopia or restriction ofthe visual fields was not found, despite statementsto the contrary (Wirtschafter, 1933).

Elkins (1942) was one of the first to comment onthe occurrence of symptoms such as we have de-scribed in workers exposed to concentrations ofcarbon tetrachloride which had hitherto been con-sidered harmless and which had produced littleobjective evidence of injury. He inclined to theview that they reflected the early stage of liverdamage. The clinical picture revealed in ourinvestigations, however, was not at all suggestive ofhepatic or renal disease and the laboratory data didnot indicate any impairment of function of theseorgans, in spite of prolonged exposure and thepresence of symptoms in some cases for over twelvemonths. It is true that in a single individual normalliver function tests may not mean a great deal, butwe know of no group of proved cases of diffusedisease of the liver in man in which the results ofestimation of the serum bilirubin and phosphatase,the plasma proteins and the Takata-ara reaction,have been consistently negative. Further supportto the view that the gastro-intestinal symptoms ofcarbon tetrachloride poisoning can be divorcedfrom liver damage is given by Minot and Cutler's(1929) observation that in dogs given large doses ofcarbon tetrachloride, symptoms such as vomiting,diarrhoea, weakness and twitching are relieved bythe administration of calcium but the damage to theliver is not reduced.

Studies of the effect of carbon tetrachloride onthe liver in animals provide an explanation for thegreat rarity of chronic liver damage in man andsuggest the reason why no lesions could be demon-strated in our cases. even though exposure mighthave been particularly heavy on occasion (Bollmanand Mann, 1931; Cameron and Karunaratue, 1936).The changes produced in the liver by multipleadministration of carbon tetrachloride depend onthe size of the dose and the interval between succes-sive doses. To bring about permanent liver damagethere must be exposure sufficient to produce animmediate toxic effect and the dose must be repeatedat short intervals. The acute lesion is always afatty degeneration in the cells of the central andmid-zonal regions of the liver lobules. In the rat,repair of central necrosis is complete in fourteendays, and if the intervals between doses of carbontetrachloride are spaced beyond this, the drug canbe administered indefinitely without producing anyalteration in the liver. If each dose of carbon tetra-chloride is too small to produce changes in the liver,no matter how frequently it is repeated, there willbe no hepatic damage. In rats, even though thetoxic dose is repeated often enough to produceextensive fibrous bands round the liver lobules,

together with central necrosis and areas of regene-rating liver tissue, the process may still be reversibleand the liver may revert to normal on discontinuingthe drug. After a certain time however, the cirrhoticchanges become irreversible.We must therefore look beyond the liver and the

kidneys for an explanation of the mechanism ofchronic carbon tetrachloride intoxication. Thesymptoms bear a strong resemblance to post-anaesthetic sickness and recall the chemical rela-tionship between carbon tetrachloride (CC14),chloroform (CHC13) and ethyl chloride (C2H5Cl).It is therefore possible that both the mental hebetudeand the gastro-intestinal upset are due to an effecton the central nervous system and are explicable interms of the narcotic action of carbon tetrachloride.Beattie, Brow and Long (1930) showed that chloro-form exerts quite sharply localized effects on thesympathetic centres in the hypothalamus. We havebeen impressed by the resemblance between carbontetrachloride intoxication and the gastro-intestinaleffects produced by hypothalamic stimulation.Some of the protocols from Cushing's (1932) experi-ments, in which the hypothalamus was stimulatedby the injection of pituitrin and acetyl choline intothe lateral venticles, could be applied withoutalteration to carbon tetrachloride sickness.

" This was accompanied by pylorospasm and anti-peristaltic waves leading to three attacks of vomiting.Each attack was accompanied by vigorous anti-peristalsis. . . . On the cessation of vomiting thetone of the stomach remained increased with promi-nent, apparently swollen rugae. In 20 minutes novisible trace of barium remained in the stomach,most of it being in the lower ileum. In one and one-quarter hours the head of the barium column wasin the hepatic flexure; no stool till followingmorning."

It is therefore suggested that mental hebetude isdue to the effect of carbon tetrachloride on thecerebral cortex, and the gastro-intestinal symptomsare due to stimulation of the parasympathetic orinhibition of the sympathetic centres in the hypo-thalamus. Both effects can be paralleled by theknown actions of chloroform. The fact that theyare not due to hepatic or renal disease does notmean that we can afford to overlook their un-pleasant nature and significance. The differencebetween the concentration of carbon tetrachloridewhich affects the central nervous system and thatwhich affects the liver and kidneys does not seemto be large. If working conditions are such as togive rise to symptoms of chronic intoxication, thedanger of acute lethal effects must be present. Forthis reason we hesitate to suggest any therapeuticindications for the treatment of chronic carbontetrachloride poisoning. It is, in fact, the veryoccurrence and unpleasantness of the symptomswhich has made carbon tetrachloride a relativelysafe solvent, and to palliate them might be as harm-ful as taking the smell out of domestic coal-gas.

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CHRONIC CARBON TETRACHLORIDE INTOXICATIONThe emphasis should therefore be placed on betterdesign of plant, better ventilation, better use ofmasks. Recent experience at the factory underobservation suggests that alternation of work, withsuccessive weeks in and out of exposure to carbontetrachloride, may improve efficiency when con-

ditions of work cannot be made ideal.

Summary1. A detailed examination has been made of

workers at a factory in which exposure to carbontetrachloride was heavy and persistent owing to war-

time difficulties of ventilation.2. Over a period of two-and-a-half years more

than half the workers had been discharged or trans-ferred to other employment on account of symptomsattributed to carbon tetrachloride poisoning.

3. Evidence of hepatic or renal damage was

rarely obtained. The characteristic symptoms were

mental hebetude and gastro-intestinal upset.4. Investigation of the gastro-intestinal tract by

fractional gastric analysis, radiography and gastro-scopy, showed gastric hypersecretion, and hyper-motility with accompanying irritability and irregularcontraction throughout the alimentary tract.

5. No visual effects were detected.6. The symptoms cleared up in a few days or

weeks after removal from exposure, though some

disturbance in the alimentary pattern might remainfor some months.

7. It is suggested that both the mental hebetudeand the gastro-intestinal upset are due to the actionof carbon tetrachloride on the central nervous

system.

This investigation was made possible by theMedical Research Council to whom we are indebted

for a grant for technical assistance. In particularwe wish to acknowledge the help of ProfessorA. W. M. Ellis of the Medical Research Council andDr. A. I. G. McLaughlin of the Home Office. Weshould also like to thank the factory for muchfriendliness and co-operation. The following indi-viduals took part in the investigation:

Miss H. E. Rees and Miss S. Habgood (socialservice) ; Dr. G. Malcolm Brown (gastroscopy);Dr. F. H. Kemp and Dr. J. A. Rose (radiology);Dr. W. J. W. Ferguson (ophthalmology); Miss E.Howes, Mr. G. Higgins, Miss P. E. Quelch and Mr.L. Rawlings (haematology and bio-chemistry).

REFERENCESBeattie, J., Brow, G. R., and Long, C. N. L. (1930).

Proc. roy. Soc., B, 106, 253.Bennett, T. I., and Ryle, J. A. (1921). Guy's Hosp.

Rep., 71, 286.Bollmann, J. L., and Mann, F. G. (1931). Ann. intern.

Med., 5, 699.Cameron, G. R., and Karunaratue, W. A. E. (1936).

J. Path. Bact., 42, 1.Cushing, H. (1932). Papers relating to the pituitary

body, hypothalamus and parasympathetic nervoussystem. Springfield, 111.

Elkins, H. B. (1942). J. industr. Hyg., 24, 233.Higgins, G., O'Brien, J. R. P., Stewart, Alice, and Witts,

L. J. (1943). In publication.Minot, A. S., and Cutler, J. T. (1929). J. clin. Invest.,

6, 369.Osgood, E. E., Brownlee, I. E., Osgood, M. W., Ellis,

D. M., and Cohen, W. (1939). Arch. intern.Med., 64, 105.

Price-Jones, C. I., Vaughan, J. M., and Goddard, H. M.(1935). J. Path. Bact., 40, 503.

Smyth, H. F., and Smyth, H. F. (1936). J. industr.Hyg., 18, 277.

Wintrobe, M. M., and Landsberg, J. W. (1935). Amer.J. med. Sci., 189, 102.

Wirtschafter, Z. T. (1933). Amer. J. publ. Hlth., 23,1035.

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