health hazards pharmaceutical industryhealth hazards of the pharmaceutical.industry to0 10 w.c.c.-...

Brit. J. industr. Med., 1947, 4, lii.

HEALTH HAZARDS OF THE PHARMACEUTICALINDUSTRY

BY

R. M. WATROUS

From the Abbott Laboratories, North Chicago, Illinois, U.S.A.

(RECEIVED FOR PUBLICATION, NOVEMBER 25, 1946)

In recent years the pharmaceutical industry hascome to occupy a unique position in regard to prob-lems of industrial hygiene and toxicology; practi-cally no other single commercial enterprise presentssuch a wide variety of potentially toxic exposures orsuch a rapidly-changing advent of new chemicalsubstances. This dynamic situation, which rendersthe work of the plant physician so instructive in thisindustry, has been created by the increasing applica-tion of organic chemical synthesis as a method forproducing therapeutic substances. Around thecore of the old industry, which was chiefly concernedwith extracting active ingredients from medicinalherbs, there has been built up in the past twentyyears a new and highly-complicated fine chemicalmanufacturing enterprise, concerned with intricateorganic syntheses, and dependent for its life on beingable to follow the most advanced techniquesdeveloped in the research laboratory. Such manu-facture, which seldom settles down to the sobermass-production of the heavy chemical industry, isessentially a batch-process and half-experimentalbusiness, full of unexpected occurrences, strangechemical substances, and unusual toxicologicalproblems. It is rarely able to make use of manu-facturing equipment specifically designed for onesynthesis; that is a privilege reserved for heavychemicals. As- a consequence, more versatileequipment must be used-equipment which mustalways fall short of the ideal in either safety or effi-ciency where any specific synthesis is concerned.

This. concretion of the new industry around theold makes a convenient division in the considerationof toxicological hazards: the problem of handlingcrude vegetable drugs and their extracts may beconsidered separately from the more complicated

problems of synthetic chemistry in the factory.Under a third heading certain miscellaneous hazardsto health will be considered.

Hazards from Handling Crude Drugs and TheirExtracts

The hazards of extracting active principles fromcrude drugs are unequally divided between the threeclasses of materials involved; the herbs themselves,the solvents, and the finished active material. Ofthe three, the crude materials offer the least strikingdangers to health. Two exceptions which have beenprominent in my own experience are ipecacUanhaand podophyllum.

Ipecacuanha.-The powdered form of the former mayact as a mild primary irritant on the skin and mucousmembranes, but is especially dangerous to those whohave developed an allergic sensitivity to it; asthmaspecifically caused by this herb has been described(Salter, 1860; Peshkin, 1920). I have seen one nearlyfatal asthmatic seizure provoked by inhalation of verysmall amounts of dust from the powdered drug.Podophyllum.-Podophyllum root is still handled in

large amounts as a source of the benzene extract, podo-phyllin, a time-honoured laxative. The irritant resinwhich constitutes the active principle is present insufficient amounts in the dry powdered root to constitutea hazard. Workers who feed the root into the grindermust be protected by goggles and dust respirators toprevent irritation of the mucous membranes. In excep-tional cases, even the skin may be irritated by the dust.Failure to use protective equipment results in a character-istic, very painful conjunctivitis and keratitis, which isdelayed in its onset for four to six hours after exposureand lasts several days. In its mild form this irritationsubsides spontaneously under treatment with antisepticand local anaesthetic ointments; a more severe form,

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caused by massive exposure to the concentrated podo-phyllin, may produce diffuse infiltration of the cornea, oreven ulceration.

Penicillin.-The extraction of penicillin frommould cultures, though more modem in date,nevertheless properly should be classified with olderprocesses of pharmaceutical manufacturing. It has,in my experience, presented one exposure which,though not toxic, had a sufficient nuisance value torequire medical investigation. The first penicillinwas grown in shallow trays. At one time, many ofthe cultures were being contaminated by Aspergillusniger, which matured and sporulated abundantly.The contaminated cultures were worthless, but hadto be dumped in order to sterilize and re-use thepans. The dumping released dense clouds of blackspores into the air; the workmen inhaling the dustfound their nasal mucus and their sputum stainedblack for many hours thereafter, and were thusthrown into a mild panic. It was difficult to re-assure these men on the grounds that the mould wasprobably non-pathogenic, especially since nothing inthe literature could be found concerning exposuresof similar magnitude. However, the passage oftime and the continued good health of the work-men disposed of all our fears, and the advent ofdeep-tank culture methods rendered this particularnuisance obsolete.

SolventsThe solvents used to extract active principles from

crude drugs are numerous and varied. Methylalcohol is not commonly used. Ethyl alcoholoffers medical hazards only to the extent to which itis denatured with more toxic materials.

12-A. The most available form of anhydrous ethylalcohol in the United States is formula 12-A, which con-tains 5 per cent. of benzene. The hazards of thismaterial arise from the tendency of chemical workers toregard it as alcohol pure and simple, and to handle itwith corresponding carelessness. To the industrialphysician it presents another difficulty: measurementsof its concentration in the air are complicated by thepresence of the alcohol. Instruments based on thecombustible vapour principle give readings which canbe interpreted in terms neither of pure alcohol nor purebenzene, and the colour development in the butanonetest is affected by the presence of the alcohol. However,I am able to report that a group of two or three workerswho were employed for some five years in almost dailycontact with concentrations of 12-A alcohol vapoursufficient to cause stinging of the eyes and an overpower-ing odour failed to show any change in blood counts, orother signs of ill-health. Butanone tests made duringthe heaviest exposure showed concentrations of benzeneranging from 20 to 100 parts per million, as nearly as couldbe estimated with the anomalous colour-development.Benzene.-Benzene itself is, unfortunately, such

an excellent solvent for many active principles, aswell as for numerous important synthetic chemicals,that it constitutes a major problem in the pharma-ceutical industry. This is not the place to describeor discuss the well-known facts about acute andchronic benzene poisoning, except to affirm frommy own experience that these well-established factsare still completely uhknown or disregarded inmore backward works, and that they cry out formore popular diffusion among workmen and fore-men, even in the most progressive organizations.Accordingly, this review will present only thoseobservations on the control of chronic benzenepoisoning which have proved useful or pertinent inmy own experience.

This experience covers eight years' observation ofa group of some 150 workmen in a chemical manu-facturing department, in which benzene is handledin scores of processes, in amounts ranging from afew litres to a thousand gallons, and under condi-tions ranging from the very best closed methods tothe most primitive and dangerous ones. Theexposures are essentially intermittent; grab samplesof air have shown concentrations as high as 3,000parts per million, and as low as 0 parts per million.Shifting men frorm one process to another has beena characteristic feature of this department; conse-quently, though some work periods involve noexposure to benzene for months, each man mustbe observed for signs of poisoning at all times,since all are exposed at one time or another-andto unpredictable degrees.The mainstay of preventive medicine in this

situation continues to be periodic determinationof the blood count of each man every three months.If suspicious or abnormal values are observed, theinterval of examination is shortened, and investiga-tion of the clinical and occupational details of theindividual case is undertaken. The details of thissystem are described in full elsewhere (Watrous,1943a). Suffice it to say here that arbitrary limitshave been set up to define suspicious and abnormalvalues of the blood counts. In fixing these limits,the industrial physician should bear in mind thenormal variation which exists in all biometricdata; this variation can be conveniently visualizedby constructing frequency-distribution curves for thevarious quantities measured. In my opinion, noother method approaches this one in completenessand ease of comprehension, and it should be uni-versally used to describe blood-count statistics forany group. Fig. 1 is a series of frequency-distribu-tion curves for my group of workers, covering theperiod May, 1945, to August, 1946, and representing880 complete blood counts on 200 individuals.

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HEALTH HAZARDS OF THE PHARMACEUTICAL. INDUSTRY

to0

10

W.C.C.- THOUSANDS PER CU. MM.40 50 60

NEUTROPHILES

R.B.C.- MILLIONS PER MM3 EOSINOPHILES PER HAM

100 WBEC.

FIG. 1

Though other investigators (Greenburg andothers, 1939) have found that changes in the sizeof the erythrocytes and very mild anaemia are theearliest haematological signs of benzene poisoning,I have not found these indices reliable. The mostconstant early sign-of poisoning, in my experience,has been a progressive decline in the total whitecount to values below 5,000 per c.mm. I havenot found this to be accompanied by any consistentalteration in the ratio of lymphocytes to granulo-cytes, or any definite trend in the erythrocyte countor haemoglobin content of the blood. Leukopeniapersisting below 5,000 cells per c.mm. has been mycriterion for complete removal of the worker fromthe chemical manufacturing department; suchmeasures have been required seven times in eightyears, and in each case the blood returned to andremained normal. The justification for this methodof detecting benzene poisoning, and for the arbitraryvalues adopted as suspicious and abnormal, rests,therefore, on this limited experience. All that canbe said for the method is that it has apparently pre-vented the occurrence of any case of irreversiblebone-marrow damage over an eight-year period.

In my limited experience, determination of urinarysulphate ratios has not been useful. The fact thatexposure to benzene is present may be determinedby the physician's nose as he walks through theworks, and may be proved quantitatively at any

given time and place by air sampling. Urinarysulphate ratios add nothing to this knowledge,

except to indicate that agiven individual has absorbedbenzeneduringa given period.Because ofthe:enormous vari-ation in sensitivity of individ-uals to benzene exposure,proof of absorption is noindication of damage, just

70 so 90 as a normal sulphate ratioPER 100 W.B.C. is no guarantee of absence

of damage. The conditionof the bone marrow is of thegreatest importance, and thisis most accurately reflected inthe blood count. However,mere passive waiting for signsof bone-marrow damage toappear is no adequate pro-gramme for the prevention of

,s, 90 benzene poisoning; it is,IOGLOBIN GM. PER 1oo cc. rather, an indispensable last

line of defence. If no otherdivision of the industry ischarged with the task of

inspection of the work-place, air sampling, and thedesign of closed or ventilated equipment, the indus-trial physician. must assume these duties. In anycase, he must be fully informed of all activitiesrelating to industrial hygiene and preventiveengineering which take place in the factory, andshould play an active part in furthering such work.

Chloroform and ethykne dichloride.-Chloroform andethylene dichloride (1,2-dichloroethane) are occasionallyused to extract alkaloids and other fat-soluble principles.Both solvents are liver poisons, and men working withthem under ordinary conditions may develop certainvague symptoms which are referable to the gastro-intestinal tract and which suggest very slight liver damage.These consist of anorexia, a heavy feeling in the epi-gastrium, and fatigue. At this time the urine may givea positive test for urobilinogen, and in my experience thisis an indication for transferring the workman temporarilyto other employment. Amyl acetate and ethyl ether areother solvents occasionally encountered in vegetableextractions. Neither has proved especially toxic in myexperience; the former because its strong odour has adeterrent effect on those who are in danger of over-exposure, the latter because of its very low inherenttoxicity.AlkaloidsThe purified extracts of vegetable drugs include

all the alkaloids which are used in therapeutics:atropine, hyoscine, scopolamine, emetine, aconitine-all powerful poisons which may cause illness ifhandled by careless or untrained workers. A com-mon sight in the medical dispensary of a pharma-

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ceutical industry, and a baffling one for the novice,is the single widely-dilated pupil caused by the en-trance of minute particles of one of the belladonnaalkaloids into the worker's eye in the form of dust.This may be seen even in persons who merelywalk through the manufacturing department. Oneapplication of eserine i per cent. ointment to theaffected eye, after thorough irrigation with normalsalt solution, will usually correct the pupillarydilatation within a few hours.

It is quite possible for a workman, if improperly in-structed and protected, tb develop acute poisoning byinhaling the dust of pure alkaloids of the belladonnagroup. One such case which I observed was that of achemical worker 31 years old who had been grindingpure atropine sulphate through a fine-mesh sieve. Hisforeman had failed to impress upon him the necessity ofwearing a dust respirator. He presented himself in amildly inebriated state, complaining of blurred visionand dryness of the mouth. The pupils were widelydilated, the skin was flushed, and the pulse was 132.The patient was persuaded, with some difficulty, torest in bed, where he tossed about, talking incessantlyin a disoriented fashion. It was decided to administereserine or pilocarpine in fractional doses intravenously,and here we encountered a difficulty which all physiciansin charge of pharmaceutical works would be welladvised to keep in mind: there was no preparation ofeserine or pilocarpine at hand in a form suitable forparenteral injection.* The emergency was met by askingthe pharmacologist's laboratory to weigh out anddissolve eserine in the same way as they would do foranimal experiments. Repeated doses of 1 mg. wereinjected intravenously, each injection being followed by aperiod of observation, in which the condition of thepulse and the pupils was the most informative index ofthe patient's condition. After four injections thepulse had slowed to 102 and the patient was out ofdanger. There were no untoward after-effects, and theman was back at work the next day.

Aconitine hydrobromide may also give rise toacute poisoning if handled in the form of the purepowder. In one mild case which I observed, thesymptoms were identical with those produced bya strong cigar in a person not used to smoking:there were pallor, weakness, nausea and vomiting,and cold sweat. The illness subsided in aboutthirty minutes; it was caused by the inhalation ofdust while weighing a small amount of aconitinehydrobromide on an ordinary laboratory balancewithout using protective equipment.

In my experience emetine hydrochloride has neverproduced industrial systemic poisoning, but it isa local irritant; not infrequently, workers fillingampoules with the 6-5 per cent. solution may

splash a drop in one of their eyes. A painfulchemical conjunctivitis results, which requires about48 hours to subside.One unusual toxic exposure which came to my

notice was the result of weighing some 500 g. ofpure desiccated scarlet fever toxin, prepared bythe method of George and Gladys Dick. Thelight, fluffy powder was readily dispersed in theform of dust, but no one had thought to warn thepharmacist about protection against this hazard.He presented himself the next day with a sorethroat, a typical strawberry tongue, and an erythe-matous rash. There was no fever; repeated testsrevealed no albumin in the urine. The symptomshad subsided the next day. The patient had neverhad scarlet fever.

The Hazards of Organic SynthesisOrganic chemical synthesis presents industrial

hazards of three main types. Firstly, the activeagents used to attack and modify the structure oforganic compounds are, by their very nature,exceptionally able to attack and modify the organiccompounds of the human body, thus producinghighly poisonous effects. Secondly, the inter-mediate compounds in most organic syntheses areoften characterized by the readiness with whichthey enter into chemical combination with otherorganic matter; they are active. This often conferstoxic properties ofgreat variety upon them. Thirdly,the final products, though they are medicinesdesigned to be introduced into the human body,may nevertheless produce severe poisoning underconditions of industrial exposure.

Chlorinating AgentsOf the active agents widely used in organic syn-

thesis, the chlorinating agents form a group whichvery commonly produces illness when improperlyused. The common members of this group includechlorine, phosphorus oxychloride (POCI5), carbonylchloride or phosgene (COC12), thionyl chloride(SOC12), and phosphorus pentachloride (PCI5).Chlorine and phosgene are gases, phosphorusoxychloride and thionyl chloride are liquids whichvaporize readily at. normal temperatures, andphosphorus pentachloride is a solid, of which Ihave had no personal experience. The first four arelung irritants and, therefore, may produce pulmonaryoedema if inhaled in sufficient amounts. Theirwarning properties vary. Chlorine gives goodwarning of its presence; thionyl chloride andphosphorus oxychloride cause considerable irrita-tion of the mucous membranes, but may be said tohave only fair warning properties; phosgene gives

* Prostigmine, or prostigmine methyl sulphate, are suitable forthis purpose, and should be kept available wherever belladonnaalkaloids are being handled.

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HEALTH HAZARDS OF THE PHARMACEUTICAL INDUSTRY

very poor warning. The most excellent engineeringis required to prevent accidents when these chemicalsare used in a manufacturing process, since, in addi-tion to being poisons, they are highly corrosive tocommon metals; ordinary ventilating equipment,condensers, pipes, and tanks are apt to be destroyedwithin a few weeks. The leakage which rmay thenresult is extremely dangerous. Ordinary canister-type masks are not safe in such circumstances;repair workers should be equipped with air-supplymasks or closed oxygen systems.

Sulphonating AgentsOf the sulphonating agents, chlorsulphonic acid

(HOSO2CI) is extensively used in the manufactureofp-acetylaminobenzene sulphonyl chloride, a neces-sary intermediate for most sulphonamides. Thefumes of the acid itself are highly irritating, and inmany sulphonation reactions HCI gas and SO2 aregiven off. It is often not economically feasible totrap these irritant by-products in a small synthesis,and they are often vented into the outside air. Thisis a bad practice, which will cause a large amountof bronchitis and conjunctivitis under adverse windand weather conditions. Scrubbing towers ofsimple and cheap design, or very high stacks, areusually required to eliminate the nuisance. Othercommon sulphonating agents, concentrated H2SO4and fuming sulphuric acid (oleum), are too familiarto require much discussion. However, it is well toremember that the heat of reaction of oleum andwater is so great that there is some question as tothe proper method of washing this acid off the skin,if it should be spilled. We recommend liberaldousing with anhydrous ethyl alcohol for the firstwash, to be followed immediately by streams ofwater.

Methylating AgentsA common methylating agent used in the pharma-

ceutical industry is dimethyl sulphate ((CH3)2SO4).It is a highly corrosive, volatile liquid, possessingvesicant and lung-irritant properties. It must behandled with the same care as the liquid chlorinatingagents described in a previous section. Its warningproperties are only fair.The laboratory chemist is sometimes tempted to

use two methylating agents of extreme toxicitybecause they make possible certain very elegantsyntheses. These are nitrosomethyl urethane and

0

diazomethane. (H3C-N-C-OC2H5 and H2CK 1.)

N=O

The latter may be obtained by treating the formerwith alcoholic KOH, and is an extremely poisonous,yellow, odourless gas, described in the Germanliterature of 1895, but having received scant atten-tion since then. Von Pechmann (1895) stated thatnitrosomethyl urethane caused 'red, itching areasand blisters to appear on the skin. Inhalation ofits sweetish vapour causes severe bronchial catarrh,as well as a painful irritation and disturbance ofaccommodation of the eyes. Since these symptomsare not unlike those produced by diazomethane.it seems probable that the toxicity of nitrosomethylurethane is due to its conversion to diazomethane inthe body.'The difficulty which these compounds would present

if used in large-scale production may be imagined byconsidering the effects which I observed in two laboratorychemists who made up a few ounces to use in an experi-ment. In both cases the chemical was spilled on theoperator's hands. There appeared to be a latent periodof five to ten days between the exposure and the appear-ance of the dermatitis. The first symptom was a painlesserythema which, after two to four days, developed into asevere, itching, uniform erythema, with marked swellingof the skin. At this time the skin assumed a peculiardusky, cyanotic appearance, and itching was pronounced,No blisters appeared at any time. In the severe case,the phase of acute swelling lasted about five days andthen subsided, being followed by an extensive desquama-tion of the affected skin.

These two cases, fortunately, represent my onlyexperience with this compound, since it has never beenthought feasible to introduce it into large-scale manu-facture. I was informed, however, by the director ofsynthetic chemistry of another large American chemicalworks, that whenever they manufactured nitrosomethylurethane, reactions occurred in the workers despite allpossible precautions. They were, finally obliged to dis-continue manufacture of the compound for this reason.Expenrments performed by R. K. Richards(personal

communication) demonstrated that nitrosomethylurethane painted on the shaved skin of rats at twenty-four-hour intervals will kill the animals after twoapplications. Purplish discoloration of the skin ap-peared in one of three animals. Death was evidentlydue to haemorrhagic oedema of the lungs, probablycaused4,y inhalationofvapour from the skin. Nitroso-methyl urea (H3CN-C-NH2), another compound

N O11

from which diazomethane may be generated, showedno adverse effects when painted on the skin of ratsin a 10 per cent. alcoholic solution for four succes-sive days, However, one case of severe dermatitisfrom handling this compound has been reported tome (Hager, personal communication).

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116~~BRITISH JO URNAL OF INDUSTRIAL MEDIC-INE

Alkyl Halides chloride produced some conjunctivitis and irritationThe alkyl halides are extensively used in synthetic o h pe eprtr rc nafwisacs

chemistry for the purpose of adding methyl and Hoer,noewhhaWiesdteisiouothealylgouptocompund, b thegenraland deadl action ofmethy bromide, with its delayedreacton:-NaR'X-R-R' NaX.Theyfind effect upon the central nervous system, can regard

extensive use, particularly in the synthesis of barbi- any of the lower alkyl bromides with anything butturic acid derivatives, in which a large variety of distrust, and I believe that closer observation of menalkyl groups are linked to the middle carbon of the chronically exposed to these compounds may' revealmalonic acid or the cyanoacetic molecules: mnild degrees of- damage. In any event, most

members of the alkyl halide series are powerfulo anaesthetic agents, and must be handled with cau-

C-OC25 -O-CIHtion for that, if for no other reason.

I ~~~~~~~~Sodium and potassium cyanide.-Sodium andH-C-Na +RX -+H-C-R +-NaX potassium cyanide are frequently used in organicI ~~~~~~~~~~synthesi's to form nitriles with organic halides:

GO0-C2H6 C-O-C2H5 NaCN + RX-+RCN + NaX

o ~~~~~~~~~~Itis a fact, not peculiar to the pharmaceuticalCommnmebersof tis sriesare thylbromde,industry, that the cyanides themselves, despite their

n-butyl bromide, isopropyl bromide, 1-methyl- great toxicity, seldom are the cause of seriousbutyl bromide, and many others, limited in variety poisoning under ordinary conditions of use. Suchonly by the number of alcohols which may be poisoning as does occur is usually the result of anusefllyubsitutdi thebariturte olecle.accident in which acid is allowed to come in contactusefullysubstitutedinihtheactedcybarbituratehanmolecule.

oMethyl bromide and benzyl chloride find application wihuratdcnde Inshanvn,soefinohersynhess.he iteatue dalig, iththe the largest handlers of cyanide in the United States

toicpophersytiesesofTheslierompunedseaslangrouwishth favour the antidotal measures described by Chenloimie largpelytoieprsofte exoperimnts onanimalps and others (1944), in which 10 c.cm. of 3 per cent.(Flury and Zernik, 1931), but a few of the more soimntteaenjcditrvoul,flwdnoxious members of the series have given sufficient b50cm.o25pe cetI oimthoupaetrouble to cause extensive comment for themselves Boxes containing all.the necessary materials for suchindividually, treatment are sometimes prepared and kept ready

for emergencies in the work-rooms where cyanide isMethyl bromide.-Leading the list is methyl handled. Many of the nitriles have toxic properties

bromide, unquestionably the most toxic, which resembling cyanide itself, and in general they mustmay produce distuirbing symptoms in concentrations be handled, if volatile, with extreme care. In onebelow 35 parts per million (Watrous, 1942). I case of exposure to benzyl cyanide (benzonitrile)have had no experience with this compound in its which I observed, the symptoms consisted of vertigo,capacity as a methylating agent, but at one time faintness, ataxia, pallor, and weak pulse, followedduring the war a number of pharmaceutical manu- by headache and vomiting the next day. Thefacturers in the United States were requested to fill general properties of this compound are describedthe liquid into glass ampoules for military use as by Heifter (1923).a delousing agent. Widespread difficulty was en-countered at that time, not only from inhalation of Acetylating Agentsthe vapour, but especially from the vesicant action Acetylating agents used in organic synthesis areof the liquid, which had -previously been reported in numerous. Glacial acetic 'kcid, acetic anhydride,the literature but was not widely known at that time. monochloracetic acid, and dichloracetic acid are aT'his vesicant property is also present in benzyl few. These compounds, in varying degrees, havechloride, but is absent in ethyl bromide, isopropyl the peculiar property of producing ex'tensive bullousbromide, and 1-methyl-butyl bromide. I have desquamation of the skin, especially on the palms ofobserved a small group of workers exposed inter- the hands, with little or no warning. It is not un-mittently to ethyl bromide vapour in 'concentrations common to see separation of the entire upper layerup to 1,500 parts per millon, to benzylchloride up of the skin on both palms in workmen who spillto 500 parts per million,, and to 1-methyl-butyl these substances on their hands. In most cases thebromide up to 920 parts per million. No systemic victim is unaware of anything except a mild stingingsymptoms were complained of by these men over or itching sensation and, therefore, does not troublea period of years, though the vapour of benzyl to wash off the chemical or take any other action to

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halt its destructive effect. When such accidentsare reported promptly, soaking the affected parts foras long as four hours in sodium bicarbonate solutionwill generally prevent any damage; these veryprotracted soaks are essential to permit the reagentto diffuse out of the skin instead of into it. Theacetylating agents are, of course, also lung irritants,but their warning properties are such that pulmonarycomplications are seldom seen.

Condensing AgentsWhat might be called the condensing agents form

a miscellaneous group of considerable chemicalactivity. Sodium methylate and sodium ethylateare widely used in the chemical synthesis of drugs.They are usually made up just before use by addingsodium to the appropriate alcohol in a closed tankor still; the next step in the reaction is then usuallycarried out without delay in the same container.In this way, the workmen are never directly exposedto the compound except by some unusual accident.The chief danger from the compounds themselvesis their corrosive effect upon tissues. The hazardin making them arises from the presence of sodiummetal and hydrogen, with the possibility of explosionand fire if improper methods are used. Concen-trated sulphuric acid, phosphorus oxychloride,phosphorus pentachloride, and phosphorus pent-oxide are often used as condensing agents becauseof their extreme avidity for water. The sameproperty endows them with corrosive properties inrespect to human tissue, most of which have beenpreviously discussed.

Nitrating AgentsNitrating agents find occasional use in the pharma-

ceutical industry, though in general these reactions aremore common in the heavy chemical industry whichsupplies the basic chemicals from which fine chemicalsare made. The dangers of corrosive action, explosion,and inhalation ofiNO2-the inevitable accompanimentsof any nitration-are so familiar as to need no furthercomment.

Organic ReductionsOrganic reductions are common in the synthesis

of medicinal chemicals, and are most usually broughtabout by the addition of finely-divided iron or zinc,with an acid, to the organic substance. The evolu-tion of hydrogen always creates the hazard of explo-sions, and the storage, handling, and recovery offinely-powdered zinc carries with it certain dangerswhich are not commonly recognized. Dry powderedzinc, if dispersed as a dust in air, is highly explosivewithin certain limits; wet powdered zinc may under-go oxidation and is subject to spontaneous com-bustion (Brown, 1941).

E

Toxic Intermediate CompoundsTo describe all the toxic intermediate compounds

which might be encountered in the organic synthesespeculiar to the pharmaceutical industry wouldrequire much space, and a great deal more un-published knowledge than any one individual islikely to acquire at the present time. I shall, there-fore, limit the following discussion to compounds ofwhich I have personal knowledge or experience, andto those which present especially difficult or little-known properties.

Dichlorethyl acetate.-In one method of synthe-sizing sulphathiazole, the intermediate compoundaminothiazole is made by adding chlorine to vinylacetate and by condensing the resultant dichloro-ethyl acetate with thiourea. Dichloroethyl acetateis an unstable liquid with a sharp odour, possessingvesicant and lung-irritant properties of somewhatlesser degree than mustard gas. It produces con-junctivitis and tracheitis in low concentrations inthe vapour phase. Liquid leaking from the equip-ment may produce blisters; small amounts ofliquid entering the eye will cause corneal ulceration.

Aminothiazole.-Aminothiazole itself is a crystal-line solid with a marked tendency to. sublime atmoderately elevated temperatures. Exposure toits vapour and dust causes dermatitis, some gastro-intestinal symptoms, and a distinctive dark-brownpigmentation of the urine, not due to bile pigmentsor haemoglobin. Deichmann and his co-workershave investigated the toxicity of aminothiazole.They found that aminothiazole repeatedly inhaledat levels of 0-2 mg. per litre had a toxic effect onthe lungs, liver, kidneys, and heart of guinea-pigs.The tissues of rabbits and rats exposed similarlydemonstrated insignificant gross lesions; micro-scopic examination disclosed mild toxic degenerativechanges in the liver and kidney. Two guinea-pigswhich died after four and forty-one seven-hourexposures to an atmosphere containing 0-025 mg.per litre were found to have oedema, congestion, andemphysema of the lungs, and fatty degeneration ofthe liver. Three guinea-pigs which survived forty-two such periods of exposure showed only slighthepato-cellular degeneration.

In workers exposed to the chemical in amountsvarying from 0 1 to 3-0 mg. per cu. ft. (0{0036 to011 mng. per litre), Watrous (1943b) found noevidence of liver damage, but occasionally therewere anorexia, nausea, and vomiting. In threeinstances, a distinctive syndrome of urticaria fol-lowed by arthralgia appeared and ran a course lastingup to five weeks. The disorder closely resembledserum sickness. Further cases were prevented by

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18BRITISH JOURNAL OF INDUSTRIAL MEDICINE

adopting improved method of handling the chemi-cal. The handling of 2-aminopyrimidine, a materialof somewhat similar properties and an intermediatein the synthesis of sulphadiazine, produced no suchsymptoms.Astwood and his co-workers (1945), in their

investigation of compounds possessing anti-thyroideffect, found aminothiazole to be about one-seventh as active on the thyroid gland as thiouracil.This property was discovered independently inFrance by Perrault and his collaborators (1944-5),who observed symptoms of hypothyroidism ina group of aminothiazole workers. The chemicalis now reported (J. Amer. med. Ass., September 28,1946) to be in use in France as a medication forthyrotoxicosis, and some of the side-effects resemblethe symptoms I observed in chemical workers.Three of my patients complained of excessive gainin weight, puffiness of the face and hands, andlassitude, but objective evidence of thyroid hypo-function was not definite enough to attract myattention at the time.

p-acetylaminobenzene sulphonyl chloride.-.p-acetyl-aminobenzene sulphonyl chloride is a necessaryintermediate in the' synthesis of aimost all thesulphonamides. It is prepared by sulphonatingacetanilid with chlorsulphonic acid. The resultingcrude chemical is a light-brown powder, somewhatunstable in the presence of moisture, and having astrong smell of acetic acid. The crude material is

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purified, and must then be thoroughly dried. Thechemical is a moderately powerful primary irritantto the skin and mucous membranes, and may pro-duce conjunctivitis, rhinitis, bronchitis, and derma-titis. In one unusual case, it produced bronchialasthma with a specific wheal formation when thediluted material was applied to a scratch on theskin. This is a very rare phenomenon in connexionwith simple chemical compounds, as it generallyindicates the presence of specific reagins in theblood.

The patient was a man 33 years old, employed for ten:years in chemical synthesis. A few years previously,.he had been exposed to the vapour of thionyl chloride-in sufficient amounts to produce pulmonary oedema.requiring treatment with oxygen. While recovering,from this accident, he was exposed to the dust of p--acetylaminobenzene sulphonyl chloride, and graduallynoticed an increasing susceptibility to this irritant,.which finally provoked typical asthmatic attacks. Hewas shifted to a part of the factory at least 300 yards,from the location where this chemical was prepared anddried, but whenever the wind blew in his direction fromhis former place of work, he would become dyspnoeic.On many occasions he was able to tell within ten minutesafter the mechanical drier in the remote part of the factoryhad been placed in operation. A 1: 100 solution of'p-acetylaminobenzene sulphonyl chloride in acetone wasmixed with equal parts of water and applied to a scratchon the patient's forearm. Within a few minutes, ery--thema, itching, and wheal formation of the extent usuallyspoken of as four plus appeared at the site of the scratch-

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A control scratch not treated with the chemical showedno reaction. The same solution was applied to the skinof four normal subjects after scratching; no erythema orwheal formation occurred. A 1: 10,000 dilution of thechemical produced no reaction on the patient's skin oron the skin of controls.A small series of cases exhibiting specific atophy to

simple chemical compounds, with more elaborateproof of reagin formation, will be referred to inanother section.p-acetylaminobenzene sulphonyl chloride.-p-acetyl-

aminobenzene sulphonyl chloride was claimed to bethe cause of aplastic anaemia in a lawsuit brought inone of the eastern states of the U.S.A., and thereforedata on the blood counts of workers handling thischemical are pertinent. Fig. 2 represents thefrequency-distribution of figures from 43 bloodcounts made on 6 workmen who handled this chemi-cal steadily from May, 1943, to May, 1944. Theywere exposed to the crude material, the acetonesolution, and the dust from the refined product.The concentration in the air was always less than0-066 mg. per cu. ft. * By comparing these curveswith those in fig. 1, it will be seen that no sig-nificant trend indicating depression of a haemato-poietic activity can be detected. In the casementioned, I was informed that the plaintiffhad worked many years in another factory wherethere was exposure to benzene, and had onlyrecently come in contact with p-acetylaminobenzenesulphonyl chloride in working for the companyagainst which he filed suit.

Pentothal sodium.-Thiourea has already beenmentioned as an intermediate in the synthesis ofaminothiazole; it is also used in the manufacture ofpentothal sodium. Thiourea is known to be adepressant of thyroxin formation. However, thedose required to produce this effect clinically is ofthe order of one or more grammes per day, and it isdifficult to conceive of industrial exposure whichwould permit the absorption of this amount; in myexperience, no toxic effect of any kind has occurredin men handling this compound. Organic com-pounds of sulphur in general tend to contain impuri-ties of variable composition, usually foul-smelling,and ofuncertain toxicity. Most of these compoundsspontaneously liberate HaS, and it is difficult toascertain, in any case, whether the symptoms ofintoxication are predominantly caused by this or

* This concentration was present at the exhaust outlet of a rotarydrier, and was too irritating to be tolerated in the air of the work-room. It was determined by collecting the chemical in an impingercontaining strong aqua ammonia, thus forming acetyl sulphanilamide,which was measured, after neutralization and hydrolysis, by Marshall'smethod. About 10 per cent. of the dust appeared to consist ofsulphanilic acid, and thus gave a test by Marshall's method withouthydrolysis.

by other sulphur compounds. In the purificationof crude Pentothal Sodium, H,S, mercaptans, andother disagreeable smelling compounds are present,and may produce headache, nausea, vomiting,faintness, and vertigo if not removed by properventilation.

Carbon monoxide.-Carbon monoxide is anexpected by-product of certain organic syntheses,as in the manufacture of phenylethylmalonic ester.This ester is formed by the condensation of phenylethyl acetate with diethyl oxalate; when the con-densate is distilled, CO is liberated. Since the gasis quite pure and odourless, it gives no warning of itspresence. Points which must be carefully watchedin the design of equipment for such distillations are:discharging condensed steam into sewers, therebycarrying trapped gas to remote points; leaks in theexhaust line of the vacuum pump; and the provisionof water seals on all floor drains communicating withthe chemical sewer. Carbon monoxide is alsoproduced when methyl or ethyl formate are con-densed with ethyl acetate in the preliminary stagesof synthesizing 2-aminopyrimidine. This toxic gasis, of course, also to be reckoned with in hundredsof locations in the pharmaceutical factory in whichilluminating gas is used for fuel. Special problemsarise where many gas flames are used for sealingglass ampoules in rooms which must be kept free offlying dust, or in which the moisture-content of theair must be kept low; in such circumstances,conventional exhaust ventilation may be difficult orimpossible to use.

Arsenic.-All the intermediates of arsphenamineand its derivatives are potentially toxic because theycontain arsenic. All these compounds are solids,and must be handled in the form of dry powders,with the production of dust. I have been unable tofind any study of the toxicity of these materials underthe usual conditions of manufacture, but observa-tions made by Watrous and McCaughey (1945)indicated that -intermittent exposure to the dust ofarsenical intermediates at levels ranging from0-001 to 0 015 mg. per cu. ft. did not give rise toany symptoms of chronic arsenic poisoning overlong periods of time, though the amount of arsenicexcreted in the urine was higher than normal.Enormous amounts of arsenic were found in thehair of some of these workmen who had no symp-toms of poisoning; this was considered tQ consistof settled dust, firmly attached to the hair, but mightprove very misleading in any medico-legal casesbecause of the importance attached to arsenic in thehair by the conventional teachings of toxicology andforensic medicine.

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BRITISH JOURNAL OF INDUSTRIAL MEDICINE

Aniline.-Aniline is an intermediate in the syn-thesis of arsanilic acid; dimethylaniline is used as asolvent in the synthesis of aminopyridine. Thetoxicity ofthe former can hardly be over-exaggerated,since the accepted maximum allowable concentra-tion of the vapour is scarcely more than that forsuch dangerous poisons as HCN, H2S, and CS2.The danger to untrained workers is more likely toconsist of disregarding the presence of small splashesof the oil on their shoes, clothes, or gloves. Fortrained workers, using properly-ventilated equip-ment, the hazard consists chiefly of accidents in themachinery, with sudden massive exposure to the oilor its vapour. In my experience, there have beenonly two cases of marked methaemoglobinaemia,and both recovered with no other treatment thanremoval of contaminated clothing, rest in bed, andoxygen. In the aniline dye industry, I am informed,cases showing cyanosis of the lips are seen almostevery day, and are regarded lightly, except whenaccompanied by some other intoxication, such asthe ingestion of alcohol. In the dye industry, also,-exposure to dimethyl aniline is sufficiently intense toproduce methaemoglobinaemia similar in everyway to that caused by aniline; in my own experiencedimethyl aniline has never caused any symptoms,probably because it was not extensively handled.

Halocrine.-In the manufacture of mepacrine(quinacrine dihydrochloride), many of the inter-mediate products are very active, and may constituteprimary irritants or sensitizers. In my experience,the intermediate halocrine,

Cl

Nhas demonstrated a marked ability to sensitize theskin of susceptible workers. Exposure to thechemical dust in some of these men caused a severecontact dermatitis, necessitating permanent transferto other work.

Final Products of SynthesisMepacrine and acriflavine.-Among the final pro-

ducts of organic synthesis, mepacrine itself deservesmention as an especially troublesome primaryirritant and sensitizer. Rather extensive compress-ing and grinding, thrice repeated, are necessary toprepare'the material in the form of tablets; dustcontrol during these operations is mandatory,but extremely difficult, because of the structure ofthe machines involved. In a study made at theAbbott Laboratories (Watrous, 1944), exposure to

the dust at levels between 035 and 4-2 microgrammesper litre was sufficient to cause conjunctivitis inmore than half of the workmen, and dermatitis,rhinitis, and stomatitis in about a third. Similarsymptoms have recently been described by Barlowa-nd others (1946). Acriflavine, another dye of theacridine series, possesses similar, though weaker,irritant properties; workers bottling tablets of thisdye often suffer from a conjunctivitis of considerableseverity if they transfer the material to their eyes byinjudicious rubbing with dust-stained hands.

Nicotinic acid.-Nicotinic acid and its salts havea peculiar effect upon the skin of certain workerswho handle these chemicals in bulk: this consistsof a diffuse erythema on the exposed parts of theskin, usually not accompanied by itching, andresembling sunburn in appearance. It is usuallytransient, disappearing in from twelve to twenty-four hours, though sometimes it assumes a papularcharacter on the second day and lasts several days.The amide of nicotinic acid has never produced thisrash in my experience (Watrous, 1939).

Powdered penicillin.-Dry powdered penicillinhas proved to be a potent sensitizer and skin irritantin all the American factories where it is handled.It may produce follicular erythema, diffuse; papularrashes on the exposed parts of the body, or, in somecases, severe generalized urticaria which persists fordays or weeks after exposure ceases. In the lattercases it seems probable that a generalized sensitivityhas been created by previous contact with the sub-stance, and that the urticaria results from systemicabsorption of the powdered drug by inhalation. Ina series of four cases showing industrial dermatitisfrom exposure to penicillin, Friedlaender andothers (1946) found the patients to be sensitiveto pure crystalline penicillin rather than to anyparticular impurity in the commercial product.

Local anaesthetics.-The local anaesthetics, pro-caine, butyn (butecaine sulphate), and butesin(n-butyl aminobenzoate), form a group of substancesmore or less prone to cause sensitization and derma-titis upon prolonged contact with the skin. Thetendency for procaine to sensitize the skin of dentistsand others who frequently spilled solutions on theirhands was recognized many years ago, and was oneof the factors which made prepared solutions incartridges so popular with dentists. Womenengaged in filling cartridges with sterile solutions ofprocaine are subject to a characteristic occupationaldermatitis caused by excess solution overflowingfrom the tubes and running down their arms. Thisusually mild, papular dermatitis is specificallylocated along the path taken by the drops as they

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run from the wrist to the elbow on the flexor surfaceof the forearm. It may be prevernted by equippingthe workers with rubber gloves with turned-up cuffsto catch the liquid; it promptly subsides when con-tact with the solution ceases. Some operators maybe returned to their work after the dermatitis sub-sides, and appear to suffer no further inconvenience.Others experience a recurrence of the condition in amore severe form, and are thus classified as per-manently excluded from work with procaine. Butynand butesin have produced much less industrialdermatitis in my experience, possibly because theyare marketed in forms not requiring such intimatecontact with the skin in the process of manufacture.

Neoarsphehamine.-Neoarsphenamine, apart fromits arsenic content, may occasionally provokesensitization of the skin in those who pack it inampoules. In such cases the minute amount ofdust which settles on the skin during the processmay cause papular rashes on the exposed skin areas.In one such case the skin was so sensitive to contactwith the drug that a patch test made with a fewmilligrammes of the powder exhibited vesiculationwithin twelve hours. Such marked reactions,however, are rare; patch tests are usually negative,but many mild dermatoses of this kind subside whencontact with the drug ceases and recur when it isresumed. Neoarsphenamine may also act as aprimary irritant if it is allowed to accumulate underthe nails of those handling it. This is especiallyprone to occur in women who affix labels to thesealed ampoules. Occasionally an ampoule breaksin the machine, and the spilled powder is wiped upwith a damp cloth. The cloth soon becomes staineddeep brown as the wet powder oxidizes. If thisoxidized material accumulates beneath the nails ofthe operators, a deep brown stain is produced, andthe distal edge of the nail becomes exquisitelytender, with signs of inflammation extending a fewmillimetres proximally. Hot soaks of 10 per cent.sodium thiosulphate, with temporary change ofwork, usually bring the condition under control.XTo prevent it the wiping rags should be moistenedwith sodium thiosulphate and should be frequentlychanged.

2-methyl-1,4-naphthoquinone.-2-methyl-1,4-naph-thoquinone, a synthetic form of vitamin K, has theproperty of sensitizing the skin and producing derma-titis. Workers who handle this chemical present adark-brown staining of the skin, and may later showpapular or eczematoid dermatitis. These pheno-mena were noted in the works at the time when thechemical was first being prepared for clinical use,but were not considered significant, since the medica-

tion was to be administered orally. However,Page and Bercovitz (1942), who had been successfulin administering 2-methyl-1,4-naphthoquinone toinfants by percutaneous inunction, encountereddermatitis in five out of nine adults to whom theygave the material by the same route. Itching,erythema, oedema of the skin, and even ulcerationwere observed in some of the subjects.

Sulphonechloramides.-At least two sulphone-chloramides which are used as antiseptics or dis-infectants have rather unusual properties as localirritants and sensitizers. These are chloramine-T

0

(H3C S=NCl)and"Halazone"(p-sulphonedi-

O-Na0

chloramidobenzoic acid, HO-C SO2N/).When these chemicals contaminate the workingenvironment in the form of dust, they may producedermatitis, rhinitis, conjunctivitis, and bronchitis intheir capacity as primary irritants. Their mostremarkable property, however, is their ability toproduce specific atophy in certain individuals. Theseworkers, after rather heavy exposure to the chemicals,gradually become more and more intolerant tothem, and begin to exhibit typical asthmatic symp-toms instead of the initial picture of simple irritativebronchitis. Finally, as the syndrome is fullydeveloped, they are unable to encounter the minutestquantities of the chemicals in the air without suffer-ing an asthmatic attack.A series of fourteen such patients, investigated by

Feinberg and Watrous (1945) all gave whealing responsesto scratch tests performed with chloramine-T solutionsin dilutions ranging from 1: 10 to 1: 10,000. Four ofthe more sensitive patients had reagins in their blood,which were demonstrated by passive transfer. In otherwords, these patients gave every reaction to this simplechemical compound which one finds in typical allergiesof the atophic variety, formerly believed to be provokedexclusively by proteins of high molecular weight. Inview of the serious and permanent disability imposed byasthma, no pharmaceutical workers should ever besubjected to heavy exposure to chemicals of this generaltype.

Mercury poisoning.-The hazard of mercur1poisoning must be considered in the pharmaceuticalindustry in connexion with three occupations: themanufacture of organic mercurial antiseptics, themoulding of mercury bichloride and mercuryoxycyanide tablets, and the use of mercury mano-meters. In making solutions of organic mercurial

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BRITISH JOURNAL OF INDUSTRIAL MEDICINE,

antiseptics, it is often necessary to allow dilute solu-tions to age for several weeks in 1,000-gallon tanksto eliminate precipitation when the product is finallyfilled into bottles. It is not unusual to observe afine film of tiny droplets of metallic mercury on theglass lining of the manholes of such tanks-ampleevidence that the atmosphere above the solutionmust contain mercury vapour. In my experience,no cases of poisoning have ever resulted from thisparticular cause, but under unusual conditionsthere is no doubt that the possibility of mercurialpoisoning would be present.In the moulding of antiseptic tablets of mercury

bichloride or mercury oxycyanide, a moist powder ormass is rubbed into a mould with a spatula. The tabletsare then ejected by means of a male punch-plate, spreadon trays, and dried in an oven. In another method thetablets are punched on a machine, using a dry granulatedform of mercury bichloride. In either case the chiefdanger is systemic absorption of mercury by inhalationof dust; minor symptoms may be caused by the localirritant action of mercury salts on the skin. Tablet-moulders should be carefully selected from a group ofolder, responsible employees who have had enoughexperience to develop a wholesome respect for andknowledge of poisons. They should be supplied withefficient dust masks and rubber gloves, and should carryout their moulding under ventilated hoods. The un-loading of dried tablets should be done in hoods, and anysubsequent counting and bottling must be surroundedwith even more stringent precautions. When suchprecautions are in effect, air levels of mercury are of theorder of 0 002 mg. per cu. ft. Under such conditions nocases of mercurialism have come to my notice.

In the laboratory, or in certain manufacturingoperations, mercury offers peculiar advantages as aliquid of high specific gravity. It finds extensiveuse in manometers, in apparatus for gas analysis,and in simple devices for maintaining inert gasesat a constant positive pressure. The latter instancehas considerable manufacturing importance infilling ampoules which must be protected by a layerof inert gas above the liquid or solid. To obtain aconstant flow of inert gas from high-pressure cylin-ders, some type ofpressure-release must be provided;a tube immersed in a few inches of mercury is effec-tive for this purpose. The constant. bubbling ofthe gas through the liquid must carry some mercuryvapour into the work-room, and there is, of course,the inevitable spillage which occurs when suchdevices are adjusted or moved frequently. Here,as in chemical laboratories, one cannot assume theconcentration of mercury vapour to be insignificant;actual measurement of the air content should bemade periodically to be sure this is so.

Stilboestrol.-The chemical synthesis of diethyl-stilboestrol is hazardous in its final stages,inwhichthe

drug is purified by crystallization from various fatsolvents such as ether and benzene. As Fitzsimons(1944) has-pointed out, spillage of these concen-trated solutions on the skin may lead to directabsorption of toxic amounts of stilboestrol, withthe production of gynaecomastia in male workers.Spilling small amounts of the solution on work-benches leaves a deposit of fine powder which maycontaminate the air as dust.To Fitzsimons's twenty cases I can add two more which

I observed in young men who purified diethylstilboestrol,and several others of similar causation and course havebeen reported to me (Passarelli, personal communication).In these cases the patients complained of moderate tosevere loss of libido. In the two men I observed, amoderate normocytic anaemia developed concomitantlywith the hypertrophy of the breasts; in one case the redcount and haemoglobin fell from 4-4 to 3-7 millionand from 15-6 to 12-6 g. per 100 c.cm., respectively. Inthe other case the fall was from 5 0 to 3 9 million andfrom 16-0 to 14-4 g. This caused alarm in view of thedepressant effect of diethylstilboestrol when large doseswere given to animals (Von Haam and others, 1941;Castrodale and others, 1941). However, when thepatients were removed from contact with the drug,their blood quickly returned to a normal state and theother symptoms gradually subsided.The physical hazard in exposures of this kind,

in factories where good industrial medicine is prac-tised, is probably far less than the psychologicalhazard. The fact that an industrial poison mayhave a feminizing effect is something new under thesun, and its impact upon suggestible young menwith neurotic leanings *can be disastrous. Inindustries where poor relations obtain betweenlabour and management, or where industrial medicalservice is rudimentary, exposure to this chemicalmay be expected to be a rich source of litigation. Iknow of one instance in which the manufactureof diethylstilboestrol was abandoned for this veryreason. It is worthy of note that the mixing andhandling of diethylstilboestrol in the diluted formsin which it is dispensed for clinical use have never,in my experience, given rise to any symptoms; thesole danger seems to arise in the handling of the purechemical.Morphine and codeine.-Tablets of morphine and

codeine intended for hypodermic injection muststill be hand-moulded in the pharmaceutical in-dustry, since machine-made tablets would notdissolve quickly enough to be practical. The hand-moulding process involves much handling of theraw materials, and under certain conditions enoughdust may be created to permit effective doses ofthese drugs to be absorbed. Cases of seriouspoisoning can scarcely occur, because of the rela-tively large amount of material which would have to

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be absorbed by inhalation. However, it is notunusual for tablet workers to complain of drowsi-ness and lethargy if exposed to unusual amountsof dust. The suspicion that effective doses areabsorbed in this way from the respiratory tract isstrengthened by the observation that, when mixturesof morphine and atropine are being handled,pupillary dilatation and dry mouth may be observedin addition to the other complaints. No case ofaddiction, however, has ever come to my notice as aresult of such exposure.

Veterinary preparations.-Many pharmaceuticalmanufacturers make certain products intended forveterinary use, and the physician whose knowledgeis confined to the armamentarium ofhuman medicinewould little suspect what poisons are still in goodrepute in the art of healing animals. A tonicpowder for horses may contain up to 2 5 per cent.of white arsenic; vermifuge capsules for animalsmay contain pure tetrachlorethane. Thus it maycome to pass that packers are inadvertently exposedto dangerous amounts of arsenic, or soft-capsulemakers to toxic vapours, in the innocent belief thatmaterial used as 'medicine' can hardly be dan-gerous! Such errors will be eliminated in thewell-organized pharmaceutical works by seeing thatthe formula department affix special precautionarylabels to all formulae containing poisons, and byincluding in instructions for compounding theformula details of all necessary precautions for hand-ling the ingredients.

Miscellaneous HazardsIn addition to the specific hazards peculiar to the

pharmaceutical industry, workers in this occupationare subjected to a number of other noxious agentscommon to other industries.Radiint Energy

Radiant energy may endanger pharmaceuticalworkers in several different ways.

Ultra-violet light.-Exposure to ultra-violet lightoccurs in the arc-welding incident to the construc-tion and repair of manufacturing equipment as wellas in rooms devoted to the manufacture of syntheticvitamin D from ergosterol. In addition, so-calledgermicidal lamps have found certain applicationsin the packaging of products subject to spoilagefrom air contamination. The prime factor in the-injuries inflicted by these modem devices is ignoranceon the part of well-meaning persons who becomeenthusiastic about 'applying the benefits of modernscience' to their tasks without understanding thefundamental principles involved. All radiant energyof wavelength too short to be perceived by thesenses produces injury not immediately perceived

by the senses, but this is a concept which modernman has not yet appreciated. However, he mustlearn to appreciate it if he is to survive much longeron this planet. In the near future pharmaceuticalindustries will probably be occupied with furnishingradio-active isotopes of chemical elements whichwill localize in specific tissues, such as the thyroidgland and the osseous system, and the safe handlingof these substances can be guided only by rationalprocesses, not by any pre-existing or familiar patternof experience.

Visible light.-In the visual spectrum, an occa-sional source of complaint by industrial workers isthe introduction of fluorescent lighting in work-rooms formerly illuminated by incandescent lamps.Complaints of eye-strain, headache, and many othersubjective symrptoms will arise in suggestible in-dividuals when any change is made in their environ-ment, and such complaints may be disregardedwhen attributed to fluorescent lighting. The onlyjustifiable complaint with respect to this type of illu-mination comes from those who work with rapidly-moving objects under lighting which does not includethe proper ballast and diphasic circuits to eliminatethe stroboscopic effect of fluorescent lamps.

In the pharmaceutical industry, ampoule-sealersare, by virtue of their occupation, specificallyexposed to the effect of visible light. Their occupa-tion involves daily gazing into gas flames used forraising glass to fusion temperature, as well as finediscrimination as to the proper temperature at whichto draw off the fused neck of the ampoule to makea proper seal. These workers are prone to acceptthe belief that such work is hard on their eyes, andtend to attribute any. occular defects which mayarise in their lives to their peculiar occupation. Themajority of sealers elect to wear tinted glasses toreduce the glare from the flames, but the tint cannotbe too deep, because it would then diminish visualacuity necessary for hanqling the ampoules underordinary illumination.

Glass containing praseodymium, and sold underthe trade name didymium glass by the Corning GlassWorks, Corning, New York, U.S.A., makes a veryeffective filter for this particular work. The maincomponent of the glare coming from hot glass in agas flame is due to the practically monochromatic yellowradiation of the sodium D lines. Didymium glassselectively absorbs this light, but passes enough of theother radiations of the visual spectrum to allow goodvision in rather dim surroundings. The elimination ofglare from the flame enables the worker to see the moltenglass more clearly, and thus should reduce eye-strain.To test the truth of the workers' frequent assertions

that sealing was bad for the eyes, two surveys were madein which several visual functions of the entire sealinggroup were tested. An interval of one year separated the

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BPJTISH JO UR4VAL OF INDUSTRIAL MEDICINEsurveys. The instrument used was the Bausch andLomb ortho-rater, by means of which visual acuitymay be measured for far and near objects, phorias maybe detected, depth perception measured, and colour-blindness revealed. The tests were made on each eyeseparately, both with and without the corrective glasses,if any were worn. Twenty-seven of the. employeestested in the'first survey were available for the second.Of these, twenty-six showed either improved performanceor no change in the second test, whereas one showed,poorer performance. The great preponderance of thoseshowing improved vision was attributed to the fact thatmany had become aware of uncorrected visual defects orpoorly-fitting glasses in the first survey, and had takenrernedial steps.

Infra-red light.-The use of banks of incandescentlamps radiating a high percentage of infra-red energywas applied in the automobile inddstry to hastenthe drying of lacquer on rapidly-moving productionlines, and has found at least one application in thepharmaceutical industry for the same purpose.Those who design such devices are rarely aware ofthe fact that intense infra-red radiation may producecataract; therefore the industrial physician mustinspect such installations and assure himself that noworker receives harmful amounts of this radiation.

Bacteria and VirusesA small group of laboratory workers in any large

pharmaceutical industry will necessarily undergoan occupational exposure to virulent bacteria andviruses. Even though such employees have hadextensive professional training which is supposed totender them extremely careful, accidents may occur;this is especially true where virulent cultures arehandled in large quantities, as in the manufactureof vaccines. Several fatal infections with thevirus of equine encephalomyelitis occurred in theUnited States in connexion with large-scale manu-facture of vaccine (Helwig, 1940). As a result,experiments were carried out to determine a suitableimmunization procedure to be applied to laboratoryworkers.

Iii 1939 a small group of laboratory workers at theAbbott Laboratories were given four injections ofAbbott equine encephalomyelitis veterinary vaccine,mixed Eastern and Western types, diluted 1: 1 with

N normal salt solution. Each dose consisted of I c.cm.injected into the gluteal muscle. The doses wererepeated at two- to three-day intervals. Six weeks afterthe vaccination, blood serum from the men in thegroup was tested for neutralizing power against the livingvirus. Only a slight increase in titre was observed.Accordingly, each subject received 05 c.cm. of undilutedvacccine. In 1940, Beard and others described a methodwhich successfully immunized 100 exposed persons;2 c.cm. of full-strength vaccine were injected into thegluteal muscle twice. At present the routine method of

immunization at Lederle Laboratories, where this vaccineis still manufactured is to inject 0-5 c.cm. of Westerntype vaccine into one deltoid muscle, and 05 c.cm. ofEastern type into the other. The same doses arerepeated in a week. Thereafter, one ' booster' dose ofthe same size is given annually (Hardy, personal com-munication).

Reagents, etc.Several toxic hazards arise in large bacteriological

or pharmaceutical laboratories where strong re-agents, illuminating gas, and large amounts ofglassware are used. A popular solution for cleaningglassware is a mixture of sulphuric acid and potas-sium dichromate. A chemist cleaning his ownglassware rarely has enough contact, with thissolution to produce disease, but in large laboratoriesthe division oflabour tends to create exposures whichmay produce severe dermatosis. The hands aremost affected, and tend to become hyperkeratoticand fissured. Extreme cases of this dermatosismay be seen in old photolithographers, who handlechrome etch with their bare hands.One case of erosion of the nasal mucous membranes

arose from the use of this solution as the result of a singleaccident. A well-meaning, but chemically naive workerthought she might prevent contact of the solution and herhands by using a tray for the glassware, which could beimmersed in the concentrated acid. Unfortunately themodel tray which was used to try out the idea was madeof iron galvanized with zinc. The violent evolution ofhydrogen created a mist of acid chromate solution,which was inhaled with painful, though educational,results. Trays were later made of stainless steel.

Another laboratory hazard attends the use ofglass wool, or of cloth made of spun glass fibre.In the preparation of packages for the administra-tion of blood plasma during the war, rolled tapemade of glass cloth was used in the filter assembly.Workers who cut and rolled this tape developedirritation of the skin on the flexor surfaces of theforearms, where their arms rested on the table top.,This was eliminated by providing long cuffs ofcellulose acetate.

Blood-plasma preparation required a few workersto spend almost half their time inside large refrigera-tors. The blood was centrifuged in cold rooms atabout 40° F., and frozen plasma was stored inrooms close to 00 F. From these rooms, --theworkers would emerge into a working area at70 to 800 F., and it was this frequent transition whichcaused all their complaints. Many assertions weremade that this work was bad for the health, and thatit caused frequent colds and coughs. However, thehazard was more mental than physical, and noincrease in respiratory infections could be demon-strated objectively.

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Chemical laboratory research workers are gener-ally considered too well educated to do anything sofoolish as poison themselves with the reagents theyuse. In my experience this assumption is unwar-ranted. Where such workers are exposed to ben-zene vapour, they require just as careful watchingas any chemical labourer. One pharmaceuticalmanufacturer found leukopenia in five out of twentyresearch chemists. Most of these men had Ph.D.degrees, but they had received no instruction or

special warning during their university studies andwere unaware of any particular hazard in handlingbenzene. In reporting this, the Industrial HygieneDivision of the United States Public Health Service(Bloomfield, 1945) calls for adequate instruction inAmerican universities concerning laboratory pre-cautions for chemical research workers.

Miscellaneous hazards are encountered by themechanics who install and repair the great variety ofequipment needed in pharmaceutical works. Manylarge vessels used for chemical reactions must belined with sheet lead, and the fabricating and repairof such linings is a skilled trade. Lead burners,because of this special skill, are likely to be steadilyoccupied handling lead only; they scrape, brush,file, and weld the sheet. The technique employedfor welding lead sheet in the Abbott works requiresthe use of an oxy-hydrogen torch. This burns witha quiet, moderately hot flame, and has no tendencywhatever to produce lead oxide fume; indeed, theflamie seems to possess reducing properties whichprevent any oxidation of lead. The scraping,brushing, and filing of the sheet produce mainlylarge particles which have no tendency to remainsuspended in the air; however, the handling of old,corroded lead sheet would probably involve more

dust. Six urinary lead determinations have beenmade on one lead burner over a period of nineteenmonths. These varied between 0-015 and 0037 mg.

per day. No symptoms ofplumbism have appeared.The use of oxy-acetylene torches in fusing lead givesrise to abundant fume, and would be more hazard-ous. Other fumes encountered by maintenanceworkers include zinc and cadmium oxide, which are

generated when iron pipes plated with these materialsare heated. The very toxic effect of cadmiumfumes, not generally known to the average shopworker, makes it imperative to supervise all use ofcadmium-plated pipe very closely.

ConclusionIt should be apparent from the foregoing that any

pharmaceutical industry, large or small, is particu-larly in need of expert counsel in matters affectingthe health of workmen. A thorough knowledge ofthe literature of known poisons is essential for theindustrial specialist in this field, but he must alsohave an alert readiness to detect and investigatepossible new poisons. In doing so, the process ofuntangling the threads of a new syndrome from theinevitable surrounding mass of subjective symptoms,neurotic complaints, incidental diseases, and otherirrelevancies requires the nicest judgment andscientific balance, together with a most intimateknowledge of all the manufacturing processes. Faras one may be from reaching this goal, the struggletowards it is full of interest and satisfaction.

REFERENCESAstwood, E. B., Bissell, A., and Hughes, A. M. (1945). Endocrino-

logy, 37, 456.Barlow, 0. W., Gorhan, L. W., and Bedell, A. J. (1946). Occup.

Med., 1, 482.Beard, J. W., Beard, D., and Finkelstein, H. (1940). J. Immunol., 38,

117.Bloomfield, J. J. (Ed.) (1945). Industr. Hyg. News Letter (U.S.

Publ. Hlth. Service), vol. 5, No. 10, p. 2.Brown, H. R. (1941). U.S. Bureau of Mines, I. C. No. 7148: Dust

Explosion Hazards in Plants Producing or Handling Alwninium,Magnesium or Zinc Powder.

Castrodale, D., Bierbaum, O., Helwig, E. B., and Macbryde, C. M.(1941). Endocrinology, 29, 363.

Chen, K. K., Rose, C. L., and Clowes, G. H. A. (1944). J. IndianaState med. Assoc., 37, 344.

Deichmann, W B., Kettering Laboratories, Cincinnati. Personalcommunication.

Feinberg, S. M., and Watrous, R. M. (1945). J. Allergy, 16, 209.Fitzsimons, M. P. (1944). Brit. J. industr. Med., 1, 235.Flury, F., and Zernik, F. (1931). 'Schadliche Gase.' Julius

Springer, Berlin.Friedlaender, A. S., Watrous, R. M., and Feinberg, S. M. (1946).

Arch. Derm. Syph., Chicago. 54, 517.Greenburg, L., Mayers, M. R., Goldwater, L., and Smith, A. R. (1939).

J. industr. Hyg., 21, 395.Haam, E. von, Hammel, M. A., Rardin, T. E., and Schoene, R. H.

(1941). Endocrinoloey, 28, 263.Hager, G. P., Eli Lilly and Co. Personal communication.Hardy, S. M., Lederle Laboratories. Personal communication.Heffter, A. (1923). ' Handbuch der experimentellen Pharmakologie.'

Julius Springer, Berlin. Vol. 1, p. 798.Helwig, F. C. (1940). J. Amer. med. Ass., 115, 291.Letter from Paris (1946.) Ibid., 132, 236.Page, R. C., and Bercovitz, Z. (1942). Amer. J. med. Sci., 203, 566.Passarelli, E. W. (Chicago). Personal communication.Pechmann, H. von (1895). Chem. Berichte, 28, 855.Perrault, M., Bovet, D., Droguet, P., and Jeantet. (1944-5). Arch.

Malad. profess., 6, 245.Peshkin, M. M. (1920). J. Amer. med. Ass., 75, 1,133.Richards, R. K. Department ofPharmacology, Abbott Laboratories.

Personal communication.Salter, H. H. (1860). 'On Asthma.' I. and A. Churchill, London.Watrous, R. M. (1939). J. Amer. med. Ass., 112, 2132.- (1942). Industr. Med., 11, 575.

(1943a). Ibid., 12, 721.-(1943b). Ibid., 12, 832.

(1944). Ibid., 13, 887.-, and McCaughey, M. B. (1945). ]bid., 14, 639.

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