investigation toxic hazards - a bmj journal · absent. the nervous system only was affected. severe...

THE INVESTIGATION OF TOXIC HAZARDS *

BY

M. W. GOLDBLATT

(Imperial Chemical Industries (Dyestuffs Group)

The purpose of this paper is to draw the attentionof medical officers in industry who are responsiblefor the health of workers engaged in operationsinvolving the use or manufacture of toxic materials,to the importance of a measure of fundamental orelementary knowledge of the measures that must betaken to discover the dangerous properties of suchmaterials.A high proportion of the work of industrial

doctors has to do with matters of organization,routine examination to determine the presence ofevery-day disease, accident surgery, ventilation,lighting and heating, canteens, transfer to and fromparticular work, sickness absence and so on. Whilstall such activities can be regarded as scientificactivities, there is at least some doubt as to how farthe average doctor finds himself in a state of con-fidence when expressing views on matters somewhatoutside the sphere of general doctoring.We have all in recent months seen publications

on so important a matter as sickness absence inwhich conclusions alleged to be based on statisticalanalysis serve merely to show that the basal elementsof scientific observation are all too little appre-ciated. It seems to me that industrial medical menmust realize that in some fields they must startab initio and not assume that an opinion can begiven merely by virtue of the fact that the matterhas something to do with health or sickness.Many of us have been called by the national need

into work which demands an approach of a qualita-tively different kind from that which obtained inthe consulting room or hospital. The view hasfrequently been voiced, and voiced with conviction,or with superciliousness, that the problems of indus-trial medicine are well within the scope and com-petence of any good all-round doctor and that,therefore, the insistence of many of us on the needfor special training was so much vapour.

I hope that, in the course of this paper, it maybecome clear that some measure of training isnecessary at least in the study of toxic materials.

I will close this short introduction by laying downa fundamental principle which must always be keptin mind in work of this kind. It is this: ' Younever find anything unless you know what you arelooking for.'

* From a lecture delivered to the Association of Industrial MedicalOfficers. October, 1943.

Those who have still a recollection of the mentalprocesses which go on when one examines a slideof pathological tissue for diagnosis will know whatis meant. What happens, roughly speaking, is this:first one tries to recognize the organ or tissue andthis is done partly by experienced visual memoryand partly by analysis; when this is satisfactorilyconcluded upon, one then tries to establish thenature of the abnormality by fitting what is seen tovisual pictures of known conditions.The process is one of asking oneself whether such

or such appearance is present. In other words, oneis looking for something which is already in themind.A similar process is gone through in a more reflex

manner when a clinical examination of a patient ismade. So often an abnormality is detected with-out the examiner being able to produce a diagnosis,because he is unable to fit his observation to analready known fact, usually a fact of pathology.This sort ofthing is particularly evident in examiningworkers who are engaged in industrial hazards. Toexamine such subjects with the commendable hopethat the disturbances in structure or function will bedetected by means of the much advertised clinicalsense, is to run the risk of missing most importantcases. The situation is difficult enough when oneknows what to look for; without such knowledgethe likelihood of detecting early clinical changes isvery remote. Indeed, this has been the case in thehistory of the investigation of most industrialhazards. The medical man has had to wait formanifestations of disease, which nobody could miss,before being in a position rightly to attribute themto the relevant agent.

Thus, as it seems to me, the necessity becomesapparent that the medical man must somehowobtain so vivid a picture of the pathological orpathological-physiological properties of the sub-stances he has to deal with that clinical observationscan almost at once be properly correlated.

Simple examples will at once suggest themselves.Thus, if a medical officer is not acquainted with

the fact that exposure to certain chlorinated hydro-carbons may lead to contraction of the field ofvision, it will not in general occur to him to instituteroutine mapping of the fields, and hence he maymiss the early manifestation of toxic changes. Asimilar situation arises in men exposed to carbon

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THE INVESTIGATION OF TOXIC HAZARDS

disulphide when a characteristic central scotomamay arise.

Let us consider another substance for a moment.Ethylene chlorohydrin is a simple derivative ofethyl alcohol-monochlor ethyl alcohol. Verylittle information on the properties of this com-pound exists in the literature, in fact only one properpaper. Men working on its manufacture in care-fully prescribed conditions suffered no apparentharm for years. The advent of war led to a quitedifferent situation, and soon a considerable numberof toxic events occurred, including deaths. Herewas an excellent example of the helplessness of themedical service; not knowing what to look for, itwas not to be expected that the insidious action ofthis material would be detected at a reasonablyearly stage.A vast amount of work has been done on benzol,

both physiological and pathological. Clinicalrecords exist of large numbers of cases. In spite ofthis, medical detection of early cases is still ex-tremely difficult. The old claim that leucopeniawas an early index of toxic effects is certainly nottrue in a sufficient number of cases to make itreliable as a diagnostic test. Abnormalities ofbleeding- and clotting-times are probably lateeffects. The sulphate urine ratio is not sufficientlyprecise and requires massive absorption. Anaemiais probably a very valuable index, but again it is asomewhat late phenomenon. Here is, then, aninstance of a compound on which much moreresearch is still required before the medical super-vision will have the proper thing to look for in itshands.An instance which is topical is that of T.N.T.

The determination of the precise period at whichthe process of liver damage begins is still notpossible. The cry for liver function tests has beengoing on for many years. The precise liver functionto be tested out of the innumerable things the livercan do is not known. Studies are in progress.When the crucial index of liver damage is in ourhands we shall know what to look for, and perhapseliminate the incidence of this occupational diseasein its fatal forms.A notable instance comes to my mind, which was

investigated most ably by Dr. Donald Hunter andhis colleagues. Here the ignorance of the manu-facturers was responsible for dire events. The sub-stance to be manufactured was methyl mercurynitrate (CH3.Hg.N03). The sequence of events isworth mentioning.

Methyl iodide (a most dangerous compound) wasprepared from CH3OH, P and iodine. This wasthen allowed to react with Hg under electric lamps,methyl mercuric iodide being formed. The materialwas broken up by tapping on rubber sheets. Thiswas done in a room 16 feet square, with 4 sky-lights, 2 windows and a large double door-all open.In the next stage the dry methyl mercuric iodidewas mixed with a solution of mercuric nitrate in apower-driven pestel and mortar mill.The insoluble mercuric iodide was filtered off and

an almost saturated solution of methyl mercuricnitrate obtained. This was diluted and mixed withan inert powder, was then dried, ground and packed.

Masks, goggles and elbow gloves were worn:ventilation of the room-40 feet square-was goodas far as windows, skylight and gaps in the wallcould make it, but it was not good enough.Twelve men were involved in the work; 8 showed

mercury in the urine and 4 did not. There was nodoubt that the symptoms of mercury poisoning,which developed in 4 cases, were due to inhalationof dust. With the exception of tremor, the usualsymptoms of poisoning by inorganic mercury wereabsent. The nervous system only was affected.Severe generalized ataxia, dysarthria, gross con-striction of the visual fields were present in all cases.Memory and intelligence were unaffected. Thecases were difficult to handle and much re-educationof movements was required.Here we have an extremely toxic process, on

which men were employed, without the employerapparenttly having any knowledge of the extremehazard of the product. Hunter's investigationsshowed that animals exposed to the vapour of thematerial developed marked lesions in the brain andcord. There was even less excuse than might havebeen advanced on the ground that the toxic pro-perties of methyl mercury nitrate had not beenpublished, for the toxicity of methyl iodide is verywell known.Another example in a large chemical concern

which possessed a considerable medical service isworth a note.The process involved was the manufacture and

distillation of a chlorinated aromatic amine. Thecompound was of great importance, and it wasthought necessary to prepare the base as opposed tothe hydrochlorideThe operation was undertaken in a hot August.

Ventilation was poor and the properties of thematerial had not been studied from a physiologicalpoint of view. In a very short time several of themen had developed an acute haemorrhagic cystitis.I have made a careful study of the compound in-volved and, as a result, it has been possible to showfrom purely physiological experiment that, bymodifying the molecule, these effects could be pre-vented. By adapting the process to the modifiedmolecular structure, it has been possible to manu-facture the material required during several yearswithout any adverse effects on the men.One final example of ignorance leading to severe

toxic results; this time on the part of a worker who,ignoring works instructions, became severely ill,unfortunately an all too common event in chemicalfactories. Working with a liquid-o-toluidine-the worker spilled a cubic centimetre or two into histop-boots. Instruction was that in such a case theworker should immediately report, have himselfstripped, bathed and await orders. This man

ignored all this. A few hours later he felt sick, andon then belatedly reporting he was found to beseverely cyanosed. On return home he was later

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BRITISH JOURNAL OF INDUSTRIAL MEDICINEtaken with an acute haemorrhagic cystitis which hisdoctor was at a loss to understand. He wisely con-tacted my department, and it was possible for us todeal with the situation, but it took several weeks toget the patient quite better. There have been nosequelae after two years. We mention this case toshow that workers must realize the character ofhazards as well as managers and doctors.

I hope it will be clear from these examples thatsome radical attack on the problems of toxichazards is urgent.As the years have passed since the institution of

a Factory Medical Inspectorate, a great deal ofinformation has been accumulated by the Inspectorson the properties of many materials, but this know-ledge has, in the main, been obtained from clinicalcases of actual poisoning. Valuable as this hascertainly been, we have no excuse nowadays, or atany rate in peace-time, for allowing cases of poison-ing to occur if the physiological properties ofchemical products can be determined by experiment.Modern emphasis is on prevention, and I know

of no field in industry in which this is more neededand in which more success can be attained.

I proceed, therefore, to certain aspects of the

investigation of toxic hazards. These will beelementary, but if pursued will amply repay effort.

There are four ways of discovering the physio-logical properties of toxic or suspected materials:(a) Literature search; (b) Physical and chemicalproperties; (c) Experimental study; (d) Clinicalinvestigation.

(a) Literature Search. This is obvious, but notall manufacturers have installed adequate facilitiesfor such a search. Nor is such a search to beregarded as something easy. Language facilityis essential. Membership of proper libraries isneeded.

In addition, a proper filing system for permanentrecord is required, and additions must be made asknowledge increases.

In the chemical industry, particularly the organic,the choice of such a filing system is no easy matter,but in other industries it is perhaps easier. Fromthe doctor's point of view, he must be in a positionto use his accumulated record in such a way thathe can quickly and confidently transmit to theoperating departments what he knows about thecompounds involved.An example of such a report form is here shown.

TOXICOLOGICAL REPORT

Names of Mater-ial.

Chemical ...............................................................

Trade ...........................................................................

Ref.Date

Formula or Composition................... ......

A. Physical and Chemical Colour ..... ,Odour... M. ......... B.P V.P.Data. Reaction.Volatility........................ Particle size.Solid

Liquid Specific Gravity ..Detection.GasDust Solubilities

B. Routes of Absorption.Modes of Excretion.

C. Known effects on man. Central Nervous Cardio- Gastro- OtherSystem and Respiratory Vascular Intestinal Urinary SystemsSpecial Senses

Acute

ChronicD. Toxicological ~~~~Siolid i}L.D.50D. Toxicological Liquid L..5Properties. Gas. Toxic concns. with times ..............................................................

Animals. (p.p.m. (v/v): mins.) ........ ................................................. ...

Pathological ejjects.

E. Probable effects in manin industrial conditions.

F. Recommendations,Pre--Plantt,.vention and Safety. Max. allowable concn. (gas or vapour).

Protective appliances ......................... ................ ...............................................Medical Supervision

G. Treatment of Poisoning.Contra-indications.

FIG. 1.

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THE INVESTIGATION OF TOXIC HAZARDSBy filling up such a report form, the doctor or

any other person will immediately be in a positionto see what is known and what is still required tobe known.

It is clear that literature search alone is very oftennot sufficient. Text-books are rarely of great help,perhaps because there is no space to deal adequatelywith all subjects. The I.L.O. publication ' Occu-pation and Health ' is often useful but badly requiresbringing up to date. Published papers must in thelast resort (or perhaps the first) be the source ofinformation and the medical officer must oftenbuild up his own literature survey.

(b) The second method of understanding thenature of the physiological action of toxic or sus-pected materials is to find out oneself: the firstrequisite being a thorough appreciation of thephysical and chemical properties of the material inquestion to the extent that these may influence theentry into the organism and the toxic effect on thelatter.

Let us, first of all, consider what in general wewant to know.The decisive points must have relation to the

manner in which, so far as can be foretold, theworker is likely to be exposed to the material inquestion. Thus, it might be said in almost everyindustrial problem of this kind that the worker isnot asked to eat the stuff. But it cannot be assumedthat, in fact, he won't ingest it.We are all acquainted with the predatory activities

of workers when faced with the bottle labelled' Alcohol.' A case comes to mind in which aworker took home a quantity of sodium nitritewhich he though was salt: the result of using thisin cooking was to kill the whole family. Anothercase was that of a man who, having an urge toshuffle off his mortal coil, took home a quantity ofsodium cyanide from a works, retired to the cellarand ended his life.Then we have the recorded cases of men who have

drunk deeply of organic solvents.Apart from voluntary ingestion of dangerous

materials, we have the involuntary. rhis sort ofevent is not, in general, a very serious matter, butin certain industries it becomes a matter of firstimportance to forbid eating or chewing on theplant, and in a good many cases, nail-biters mustbe eliminated.

These points are mentioned because the deter-mination of toxicity of substances given by mouthshould not be regarded as of academic interest only.

It is clear that the nature of the material willdetermine in great measure the manner in whichthe organism is likely to meet it, and the route bywhich it is likely to be absorbed.When reference is made to the ' nature of the

material' under consideration, the least that thiscan mean is its chemical identity. Theoreticallythis should always be available, or at any ratedeterminable. In practice we know that veryfrequently the employer himself does not know whathe is using. Products are used for a multitude of

purposes under bizarre and meaningless names,which are no clue to their compositions and whichindeed may obscure them. It is the particularindustrially important property which is emphasizedand not the composition. Nowhere is this moreblatant than in the case of solvents. Time and timeagain cases. have been reported of toxic effectsattributed to exposure to volatile solvents in whichthe offending substance was either not known to bepresent or from which it was specifically stated thatcertain toxic solvents were absent.The ' nature of the material ' must also include a

statement of the degree of purity and the nature ofthe impurities, for the use of completely purechemical individuals in technical processes is un-usual. It will be appreciated that the physicalproperties determine the readiness with which thematerial can enter the organism.A few simple examples may serve to indicate that

the appreciation of physical properties is of greatimportance.

Metallic mercury has a high boiling point, andhence a priori it might be considered likely that inoperations far below the boiling point the hazardto workers would be minimal. That this is not thecase is known to all.

Cases of mercurial tremor among laboratory boysand physicists have occurred, whose contact withmercury was simply that arising from bench work.Mercury strewn in droplets on the surface of alaboratory bench volatilizes and is absorbed by theoperators through the respiratory tract.Again lead, which is used in industry in a multi-

tude of forms, can be absorbed into the organismin the form of most insoluble salts or oxides. Leadchromate, oxides, sulphate, all practically insolublein water, might be held to offer little chance of toxiceffects, but we know perfectly well that inhaled asfine dust the organism is able to transform theminto readily diffusible forms.

In the filling factories, the physical propertypossessed by both T.N.T. and tetryl of being solublein lipoids lies behind the whole theory of poisoningby absorption through the skin. But care must beexercised here lest one overlooks the dust and fumehazard by over-concentrating on the skin absorp-tion.

In general, liquids which are lipoid solventsrequire careful assessment, for it is easy for the un-initiated to raise alarms where none is warranted.Thus, a perusal of the experimental results withdichloro-ethane (ethylene dichloride) might lead oneto expect many industrial casualties. Actually, pre-caution is such that none has, as far as I know,been reported, although symptoms due to narcoticeffects may occur.The precautions laid down for the handling of

trichloro-ethylene are well known to all thoseengaged in de-greasing machinery. This compoundpossesses in an outstanding degree many physicalproperties necessary for good anaesthetic actionand, indeed, has recently found considerable favouramong anaesthetists. But its virtues as an anaes-

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BRITISH JOURNAL OF INDUSTRIAL MEDICINEthetic render it all the more necessary to treat itwith caution. Chronic effects attributed to thissolvent still await explanation, although its grossacute toxicity appears to be not serious.

In the vast field of organic compounds, there is atendency to ignore purely physical properties, par-ticularly when dealing with solids. I always lookwith suspicion at materials of low melting point andhigh or considerable lipoid solubility if in associa-tion with toxic radicles. These are the compoundswhich more or less readily penetrate the skin. Ingeneral, these compounds show little, if any, solu-bility in water.The importance of careful control of temperature

in certain porcesses is illustrated by the cases oftoxic effects arising from the handling of chlorinatednaphthalenes-synthetic waxes largely used in insu-lation work. The process is simple, the danger liesin not realizing or ignoring straightforward instruc-tion. The wax melts at a certain range of tempera-tures, and it is required that the material should bekept molten, but not raised above a certain maximumrange. When this is not done, the material givesoff vapour and this vapour is both irritant to theskin and poisonous to the liver. ' Chloracne 'cases have been described and liver atrophy andnecrosis has occurred too frequently. The coldsolid wax on the dipped articles leads to no troubles,but inhalation of toxic dust may follow processingof the articles. This is a good example of thesignificance of physical form and properties.

Difficulties which may be met with as to workabletemperatures or as to the evolution of fume at pre-scribed temperatures should not be taken withindifference. Satisfaction must be demanded orthe process stopped.

I think it was in a shed where this sort of processwas going on that a certain medical officer, whodeserves great commendation, decided that con-ditions were dangerous. Receiving no satisfactionfrom his management, he printed a notice-ThisPlant is Dangerous, affixed it to the door and clearedall the workers out.One final example of the importance of tempera-

ture. In the rubber industry, it is often necessaryto incorporate a compound which when heatedliberates an inert gas. This gas enmeshed in therubber mass creates the condition of sponging. Thefinal product when cold has no irritant propertiesand is handled daily with impunity. But when it ishot or warm, application to the skin leads to severedermatitis and absorption through the skin maytake place and lead to cyanosis.Another physical property of great importance is

density, especially when dealing with a gas or vapour.In war-time plant which may have been erected ina hurry, the result may sometimes be that units ofplant are rather crammed together and ventilationis unable to cope with local pockets of air. Gasesor vapours greater in density than air tend to collectin such pockets. It then becomes necessary tointroduce local draught, but evidence will always besought by managements as to any higher concen-

tration at these points than in the general air spacein the shed; and the doctor is well advised not tostart talking before he has the data in his hands.

I have considered it desirable to multiply examplesbecause I am by no means convinced that medicalofficers as yet realize the need for inquiring mostmeticulously into the physical properties of materialsbefore examining the more medical aspects of toxicmaterials.The chemical properties of industrial materials

are of importance to us, in so far as they mayinfluence the views of medical officers and the kindof advice which they will be led to give to themanagements.

I take it that a safe, rough definition of a chemicalproperty is that it is a power latent in an elementor compound which permits it, in suitable condi-tions, to interact with other elements or compoundsin a way which results in a change in the interactingmaterials other than change of state or aggregation.From the point of view of the industrial toxi-

cologist, it is evident that merely to apprehend thechemical properties of the interacting materials maybe quite insufficient. He must recognize that theproducts of the interaction or the by-products mayconstitute the important feature for the investigatorof hazards.

Thus, in the manufacture of certain complexdyestuffs of the sulphur colour class the initialmaterials used, whilst not entirely without toxicproperties, are relatively easily handled with safety.But as a result of the reaction H2S is liberated andconstitutes the principal hazard.

Similarly, one may have residual materials after areaction is completed which are potentially oractually dangerous products.Of a potential hazard I shall give one notable

example. In a process where the residual fluidscontained inorganic sulphides, the run-off was intoa sort of gutter. This gutter was also used byanother unit for running off waste acid, but anarrangement had been made whereby the two run-offs were never run together or before water oralkali had cleared all remnants of the last run-offaway. On one unfortunate occasion a misunder-standing arose and the acid met the sulphide. Theresult was a tremendous evolution of H2S and aworker-a woman-collapsed and was trapped inan inaccessible spot. After extrication with greatdifficulty she was brought round sufficiently, in theambulance room, to permit of her transfer tohospital. Here she had respiratory symptoms andgreat restlessness, both common in H2S poisoning,and unfortunately she died within a few hours.Now it cannot be expected by industry that the

medical officer should be a chemist, but it is per-fectly justifiable to expect him to know in detail thevarious stages of the processes and to be in a posi-tion to ask the questions which are relevant to hisunderstanding of the hazards.One aspect of this question of chemical properties

deserves special mention. It is so often the casethat information is required at short notice on the

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hazards of a material that the medical man, failingrelevant literature, may have to make a guess.Although it is always possible to make a guess onthe safe side, one looks a little foolish if laterinformation reveals that his guessed apprehensionswere so much warmed air. We call this sort ofguess toxicity by analogy, but in order to do it inthe organic field with some degree of verisimilitudeit is necessary to comprehend the significance ofstructural formulae.The correlation of chemical structure with phar-

macological or toxic action has never been attainedexcept in isolated cases. I think we should all agreethat there is no obvious reason for quinine to be sopotent against the plasmodium or for Bayer 205against the trypanosome. Some advance is beingmade on the lines of the action of sulphonanilamidein competing for p-aminobenzoic acid against thedemands of the haemolytic streptococcus.But in general, in the field of toxicology, we must

rely on ab initio investigation or on experience,taking into account all the physical and chemicalproperties which appear relevant.The specificity of toxic effects in relation to

chemical structure is sometimes striking. This is avast subject in itself, but I will choose two examples.The following three substances are isomeric:CH3 CH3 CH3

C . ,NH2 ' NH2 Cl/ `NH,

The first of these produces in certain circum-stances rapid and violent haemorrhagic cystitis, bothexperimentally and clinically; the others do not.The following two compounds are also isomeric:

CH3-O-NO and CH3.NO2(CH3.NO)methyl nitrite nitro-methane

B.P. -120C. B.P. 1010 C.All are familiar with the depressor activity of

nitrites, but the nitro-paraffins do not act in a similarway.

Guessing in cases such as these is dangerous.But from our knowledge thatNH.CO.CH3 NH2

is much less toxic than

acetanilide aniline

we can reasonably offer the guess thatCH3 CH3

--NH.CO.CH3 / -NH2will be less toxic than

acetyl-toluidine o-toluidineand CH3 CH3

--NH.CO.CH3 NH2CllX! less toxic than

--chlor acetyl toluidine 5-chlor-o-toluidine.

The important chemical properties of reduction andoxidation should always be kept in mind.Whereas the organism has mechanisms for

buffering extraordinarily large amounts of acid andalkali, it is less endowed for dealing with reducingand oxidizing compounds. It is true that con-siderable concentrations of reducing agents exist inthe blood, but these are not in a position to exertthis property because the reaction conditions arenot suitable.The absorption into the circulation of oxidizing

and reducing agents, which can exert these pro-perties at the reaction of blood, will exert profoundeffects on the blood pigment and lead to all theconsequences of interference with the oxygen-carrying capacity of haemoglobin.

Powerful oxidizing and reducing agents exert adeleterious action on the skin, a fact which shouldalways influence the medical officer in criticizingthe well-known agents used for skin cleansing.On the importance of the acidity or alkalinity of

compounds in aqueous solution all will be informed,but special mention must be made of two materialswhich require the utmost attention at all times:ammonia and lime. These compounds have mostdevastating effects if they enter the eye. Ammonialiquid in the eye, after what has appeared to beadequate irrigation and relief of symptoms, cancontinue to exert a steady effect leading to cloudingof the cornea, penetration into the anterior chamberand disintegration of the lens.

In the case of lime it is usual to attempt neutraliza-tion of the caustic effect by irrigation with ammo-nium chloride or tartrate. Some ammonia isformed, but is soon swept away and the calcium issolubilized. The occurrence of such cases indicateslax safety supervision. Quicklime must never behandled without goggles. The lime burn in the eyeoften leads to an angry, resistant granular con-junctivitis, with a tendency to burrow under thebulb and may produce a permanent ectropion.

In both these cases the utmost speed of action isessential so that appropriate apparatus is requiredwherever the hazards exist.

In considering the chemical properties of amaterial, it is well to keep in mind its possibleaction on some essential constituent in the organism.A simple example is, say, oxalic acid. Apart frombeing an irritant poison it kills by removing ionizedcalcium from the blood, if absorbed.

Similarly the relation of fluorine and hydro-fluoric acid to calcium will come to mind as alsothe use of injection locally of calcium gluconate incases of hydrofluoric acid burns. The relevance ofremembering decomposition products ofcompoundsis shown in the case of phosgene, the effect of whichis almost certainly related to the liberation ofactive HCI.The use of oxygen and of oxygen-carbon dioxide

mixtures is known to all as perhaps our most valu-able stimuli to the cardiac and respiratory systems,but in some cases the value of oxygen is based uponthe chemical properties of the toxic material which

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BRITISH JOURNAL OF INDUSTRIAL MEDICINEled to its use. Carbon monoxide springs to themind. Here by increasing the oxygen tension inthe blood the reaction Hb+CO-÷Hb.CO is morereadily reversed and the CO removed.

Let us examine the case of methaemoglobinaemia.Here the iron in some of the blood pigment is inthe oxidized ferric state and cannot carry oxygen.The use of 02 or 02-CO2 is here dictated by theneed to assure a maximum saturation of suchhaemoglobin as is still functional until such time asa more normal concentration of Hb is reached.The use in such cases of intravenous methylene blueis based upon its property of being a powerfulhydrogen acceptor. Thus, in the tissues a favour-able condition is produced for the liberation ofintramolecular oxygen for the support of tissuesdeprived of normal oxygen supply by the abnormalstate of the blood pigment. The application ofmethylene blue in cyanide poisoning has the samebackground since cyanide inhibits tissue oxidation.The property of protein precipitation possessed

by such agents as tannic acid, tri-chloracetic acid,picric acid, etc., lies behind their use as agents inthe treatment of burns.The deposition of lead in the bony skeleton

depends on the possibility of a double decom-position of calcium phosphates and lead compounds.The formation of the silicotic nodule possibly

depends upon the slow formation of silicic acid atpoints of deposition of silica particles.

These are all elementary points serving to showthat a proper assessment of chemical properties isnecessary to the medical officer who aims to visualizehis hazards as they act and to understand therationale of his therapeutic measures.

(c) Experimental Studies. With all the effortsthe doctor may make to establish the toxic pro-perties of his materials, the time must come whenhe is faced with substances about which little ornothing is known from the toxicological point ofview or about which he feels that extant informationis unsatisfactory.

In such event, apart from the precarious guessmethod, he has no alternative except experimentaland/or clinical investigation.

Experimental investigation involves laboratorystudies on animals.Now it is customary to cast a somewhat dubious

eye at animal work in this and other fields and,indeed, one may perhaps ascribe to this attitude therapid disappearance of animal experiment ordemonstration after the second year or so of medicalstudies. This is a pity, for it is by animal experi-ment that we can develop a grasp of process asopposed to established change in tissues. Theobject of medical investigation is far more to obtainknowledge on the process of attack on and changein the cell than merely to describe the terminal statein which the cell finds itself. The need for this stateof mind will be at once apparent in such a field ascancer investigation. Of course, the appropriatetechniques have to be developed and therein mostoften lie the difficulties.

Animal experiment can give a great deal ofinformation, but its application to the humansubject requires considerable care and experience.The quantitative aspect can be fairly accurate inanimal work, but indiscriminate acceptance ofanimal figures for human subjects would be, inmany cases, unjustified.We have further to remember that, if it were

possible to carry out experiments on men, we shouldstill be faced with the factor of individual variationwhich would prevent a universal application ofresults to all subjects. We all know of cases thatcan take aspirin or quinine and others who cannot.Similarly we have individual variation to skinhazards and even gases. And this individual varia-tion is not, in general, referable to manifest struc-tural signs. An apparently completely uniformpopulation of animals shows marked individualvariations even in the most carefully controlledconditions. The term toxic dose of any materialthus requires careful consideration, for whilst agiven dose may be toxic or lethal to a certain pro-portion of a given group of animals of a particularspecies, it will not necessarily be so to all.We reserve for a later contribution the considera-

tion of aspects of the experimental determination oftoxicity and the interpretation to be applied inindustrial problems.

Reference has been made to individual variationwithin any given species, but variation as betweenspecies may be even greater. Hence the applicationof such findings to man is always a matter only ofsuggestive inference. In pharmacological studiesdetermination of M.L.D. (i.e. median lethal dose=dose which in the long run will kill 50 per cent.of animals) is always a necessary preliminary toutilization of drugs in human subjects. But onehas to be prepared for adverse findings in man. Atopical example will perhaps be of interest.

In research to develop new compounds of thesulphonamide type, a compound was preparedwhich, as far as animals were concerned, possessedadmirably the properties required: it had powerfulbacteriostatic activity, a low toxicity, did not pro-duce cyanosis and so on. But on application inthe ward in therapeutic doses, the degree of cyanosisproduced in man was so great that the substancehad to be abandoned. Clearly there was somedifference between the power to detoxicate thiscompound in the rodent and in man.An industrial hazard with which wrong conclu-

sions might have been drawn is aniline. If thetoxicity of this amine had first been studied in therabbit, a quite false conclusion would have beenreached. For whereas aniline produces severe andeven fatal cyanosis in man, I have never been ableto obtain cyanosis in the rabbit. On the otherhand, the rat or mouse or cat or dog would haveput one on the right path.

Let us take an example where the sensitivity ofthe animal is so great that its reaction is used as amost valuable index of impending danger. Thecase of carbon monoxide is outstanding. Mice

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exposed to a concentration of some 500 parts permillion (v) for 20 minutes will react with unmistake-

able toxic effects, whereas men can support thisconcentration for at least an hour without trouble.But one does not risk this. If the mouse showssymptoms, the working place is cleared.But the mouse or canary are by no means infallible

in detecting hazardous concentrations of all toxicgases.

These are simple examples. Much greater diffi-culties of decision are the daily lot of the doctor inthe chemical industry.An example: For certain complicated processes

cyanuric chloride (CNCl)3-a solid-must be used.Now the toxicity of this material is very high-5 mg./kg. for mice when injected or given by mouth-and one becomes anxious. But the circumstancesin which the compound appears in the processesrender it most unlikely to be absorbed by the worker.On the other hand, a compound like crotonaldehydecyanhydrin-a liquid with a pungent vapour-can-not be used without some degree of transferenceinto different vessels with escape of vapour, andhence its very high toxicity, easily demonstrable onanimals, renders it a hazard of great importance.Thus toxicity in the industrial sense must have

relation to the circumstances of manufacture or use.Hence the significance of the doctor's knowledge ofplant and process. It is this aspect of industrialmedicine on which so much emphasis must be laidif its value to industry is to be established.The intimate knowledge of plant required by the

doctor if he is to pronounce with confidence is suchthat it becomes necessary for him actually to workin the shed with the worker. This is realized insome American factories where the young, or evennot so young, doctor spends several months actuallyas a worker, doing day and shift work and thuslearning not only the nature of chemical plant andprocess but also the worker's terminology.

Every industry has its own ' argot ' and the doctorshould know it.

Moreover, the experienced worker has a know-ledge which, if properly tapped, will open the eyesof the doctor to many things not to be found eitherin text-books or in the literature. Toxicity data inapplication must have relation to the habits ofworkers. It must always be kept in mind that thefactory life of a worker becomes after some time apsychological and physical conditioning to externalrequirements. The result is a more or less uniformpattern of behaviour, and this must be apprehendedand understood by the doctor. Recommendationsbased entirely on laboratory findings as to toxicitywithout regard to such patterns of workers' be-haviour are of little practical value. For, to imple-ment recommendations designed to prevent toxicevents requires the understanding collaboration ofthe worker. If all processes could be carried outin totally enclosed plant, such collaboration mightbe unnecessary, but such an ideal is never likely tobe attained except in a minority of processes.

An example is worth quoting.You will all know that satisfactory germina-

tion in 100 per cent. of seeds is not possiblein most soils unless measures are taken to protectthe seed against certain fungi. Among such pro-tective agents is a group or organic mercurial com-pounds. The early experience in the manufactureof one of these was such that it became clear thatonly if total enclosure were practised could reason-able security of the workers be assured. This com-pound attacks the skin with production of a bullousdermatitis. In the present process, there is abso-lute enclosure from the time of mixture of theprimary reactants until the automatic delivery ofthe final product into the receiving tins. So satis-factory is now the process of manufacture that casesare not met on the plant, but practically only in thedressing of the seed by the seed-dresser and in thesowing by the farmer. Proper precaution by theformer should in general obviate trouble and, in thelatter case, it is only in cases of exceptional sensi-tivity that trouble arises.

This is the more striking when we consider thatthe seed is dressed with a diluted product containingonly from 1 to 15 per cent. of calculated Hg.

I recently saw some cases of distressing characterin a farming area, which are worth mentioning. Ayoung farmer had developed an erythematous-vesicular rash as a result of handling dressed seedwithout proper precaution; he visited his doctorwho diagnosed scabies as the condition was cer-tainly very itchy. The patient was plunged intohot baths and scrubbed and inuncted with sulphurointment. The result was a fearsome mess. WhenI saw the case, it was one of a generalized, oozingsulphur dermatitis, chronic and intractable.The fault here lay partly with the farmer, mainly

with the doctor, but also in part with the manu-facturer who had not sufficiently disseminatedknowledge on this particular hazard. Properlytreated, the condition can be completely cured evenin severe cases in less than three weeks or a month.But the intelligent co-operation of the worker is

essential both in prevention and in treatment.The example just quoted-it was one of three of

varying severity-illustrates another aspect of theresponsibility of the doctor engaged in the chemicalindustry, viz. responsibility to the user of chemicalproducts. He must not only prescribe for the pro-tection of his workers in the factory where theproduct is manufactured, but also be prepared toinform users of its actual or potential dangers andhow best to circumvent or neutralize them. Noamount of academic knowledge will overcome theproblems involved. Such knowledge must be com-bined with an appreciation of working conditionsand the circumstances of exposure. Untowardevents may occur which demand an immediateresponse from the medical officer as to the hazardsof the products of his industry. Two mild examplesin the dyestuffs industry are of interest.The first was a trivial event, but led to great

anxiety. A child in a Midland town was left alone

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at home and proceeded to eat a tablet or bag of thehousewife's material known as Dolly Blue or somesuch name. I surmise that the child looked apretty sight when mother returned. The alarm wasrung, but the dyestuff involved is very soluble andrapidly excreted. Simple diuretics were advised anda mild purge, and in a day or two all appeared tobe well.The second is an amusing case. A certain small

dyeing concern operates in an agricultural regionand was in the habit of liberating not inconsiderableeffluents into a small stream at which the local cowscould drink. The principal dyestuff these peopleused is a black. Now a black dye may containmuch beside black compounds. The local autho-rities raised considerable objections to this. TheM.L.D. of the material was found to be so high asto be negligible, but it was clearly also necessary tofind how the dye was excreted. So metabolismexperiments were set up and on collecting the urineof animals treated with the dye, it was found that ared dye was excreted. Study of this dye in theurine led to its identification as one of the shadingmaterials in the original mixture. Now whilst itcould be concluded that the cows would not suffergrievous harm from taking a drink of this unattrac-tive cock-tail, it was by no means certain that themilk would not be of a somewhat revolutionarycolour if sufficient of the stuff were taken. So thepractice was condemned and the firm had to makesuitable alternative arrangements.

In the days when the Channel Islands were in anon-infected state, we received great quantities oftomatoes from them and certain grades of tomatoeswere made into tomato puree. Now, as in the caseof browned kippers, this country will not eat theproduct unless it is dyed a nice juicy colour. Thedye used is harmless and is added in small amounts.But there must be an assurance that the colour willbe maintained in the can almost indefinitely.A very large quantity was thus prepared during a

period some years ago and canned. When sometime later a few cans were opened by customers whohad bought them at a grocer's, they discovered withalarm that the puree was a jaundiced mess insteadof a juicy red. The canners demanded a veryheavy indemnity for what was going to be a totalloss. Arguments of various kinds were used onboth sides, and it was alleged that there was some-thing wrong with the dye which was now probablya dangerous poison.Now clearly there were three main factors-the

dye, the tomatoes and the can.It was easily demonstrated that the dye was the

same as had always been used, the tomatoes couldbe assumed as the same, so the trouble must havebeen in the can. The can was tinned iron and itwas easy to show that iron reduced the dye to ayellow derivative.An agreement was reached, since it could still be

claimed that the dyestuff makers had not informedthe user as to the effects of ferrous metals on thecolour.

These examples will perhaps serve to show youthat there are aspects of the work of an industrialdoctor engaged with toxicological matters whichcan exercise the mind in manners not usually asso-ciated with doctoring. It is not to be supposed thatindustrial doctoring in general entails work of thiskind. But it is in the highest degree desirable thatmore people should be engaged in it as a constantguard against calamities which occur as a result ofignorance, neglect and indifference in the handlingof industrial materials, many, very many, of whichexert toxic effects.

The SkinNo discussion of industrial hazards can overlook

reference to the skin. As an industrial route ofentry of toxic products into the organism, the skinis second only to the lungs, Reference has beenmade to the rough general criteria of skin absorb-ability-viz. low melting point, lipoid solubility ormiscibility, fat solvents.But it is not only the properties of the material

which determine ease of skin absorption. The con-dition of the skin itself is a determining factor-hot, greasy, perspiring, for example. Experience,often after notable toxic events, has taught us in thepast that certain materials are absorbed through theskin, e.g. aniline, nitrobenzene, toluidine, lead tetra-ethyl, mercury, carbon disulphide, etc.To determine of a new material whether it is

likely to be absorbed in this way, the physicalproperties are a very useful guide. But the demon-stration on the animal is always desirable, particu-larly if the material is toxic.The experimental pathology of the dermatologist

is only exceptionally carried out on animals. Thereasons for this are obvious. But in the matter ofabsorption, provided a dehaired area of skin isused, reasonable conclusions can be drawn. Thereare technical difficulties as, e.g. prevention of lickingboth by the individual animals and by others, themaintenance of the part exposed without exposingto absorption by the respiratory tract, prevention ofremoval of material and so on.

It will be convenient to use my reference to theskin to introduce some notions on the importanceof a competent knowledge of pathology-bothclinical and experimental-in this kind of work.

Let us for a moment consider the place of patho-logy in general medicine. I think it true to saythat it is the science of topographical and histo-logical description of morbid processes. Experi-mental pathology attempts to relate causes to thefindings of topography and histology.Now it seems to me that, if man is to intervene

successfully in the process of disease, some waymust be found to eliminate causes or, if that is notattainable at any stage, to get between the causeand the establishment of the morbid changes. Theimplication is simply that we must not wait for post-mortem material to establish a pathology. It is, inmy submission, a most depressing business to wadethrough the immense contributions of the German

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schools of morbid anatomy and to realize how littlehas emerged which helps us to attack morbid processat a hopeful stage or with hopeful methods.

In the field of work under discussion, immediatecauses are in greater or lesser measure determinableand, as has been pointed out, it is theoreticallypossible completely to eliminate industrial poisoningand disease. As long, however, as man must usehis hands to work so long will we have industrialskin disease. And as long as processes cannot allbe completely enclosed or otherwise made safe whentoxic materials are used, so long will we havepoisoning and disease in industry.When, therefore, the doctor considers the hazards

of his industry, he must be in a position to visualizewhat is going on in and on his workers during theirexposure to the toxic materials.To obtain this view animal experiment in the first

place is a sine qua non, and complete physiologicaland pathological study a necessary preliminary toestablishing the needed control over the health ofthe workers.As to physiology, the effects on respiration,

circulation, nerve transmission, isolated tissues,secretions, reflexes should be studied. The meta-bolism of the material, i.e. the changes it undergoesin the organism and the retention in the tissues,must be dealt with. In certain cases, the absorptionof the material can be gauged by the degree ofexcretion in the urine (and faeces in some cases),and methods must be devised to determine theexcreted products quantitatively. In other cases,studies must be made of the effects on the blood andblood-forming organs, on the composition of theurine, on the pigments of the blood, on the digestiveprocesses and so on.

These things must be done both as acute andchronic experiments.On the pathological side, sections of organs must

be prepared to find changes in structure, both fromminute exposure and massive exposure for shortand long periods. Correlations with physiologicalfindings have to be made so that as far as may beone can visualize what is going on and obtain anindication of the point of necessary interventionwhen dealing with the workman himself.The effects of a host of materials on the skin

present a most difficult problem.Of the direct attackers of the skin little need be

said; strong acids and alkalies, halogen derivativesof sulphur, organic sulphates, certain organicarsenicals, certain chlorinated hydrocarbons, etc.,require little investigation relatively. It is when wecome to those substances to which some people aresensitive, or which set up a sensitivity, that con-siderable difficulty arises in experimental studyThe usual laboratory animals possess skin which isdifferent structurally and functionally from humanskin, and hence response to industrial dermatiticagents is different.

Still, it is possible in a sufficient number of casesto establish what corresponds to dermatitis onanimal skin-rabbit, mouse, rat, guinea-pig, horse

and pig are probably better animals to use, but noteasy to do so.Much has been written on the patch test.The application of this test in industry is, in my

view, impracticable and in general not justifiable.In hospital or at a skin clinic, this sort of test to

determine sensitivity to a specific agent is possible,but in a factory it is a most delicate matter and ifundertaken must have the written acquiescence ofthe worker subject-otherwise unending troublemay arise.Taken all in all, we must rely on clues from

animal work and, where these are not very satis-factory, on analogy and observation in the factory.

Since the acute reactions of human skin to indus-trial dermatitic agents are very similar to those incases of eczema of which the gross pathology isknown, it is possible for the medical officer to drawconclusions at a very early stage, provided the casesare made to report at the onset.But there are many reactions to dermatitic agents

other than the ezcematous, e.g. acneiform, bullous,urticarial, pure oedema of a massive character, etc.And extremely frequently there occurs simulta-

neously with the skin condition, or sometimes pre-ceding it, a marked oedema of the lids and sometimesa conjunctivitis with persistent lachrymation.

(d) Clinical Study of Industrial Hazards. I thinkit will be wise to state at once that the possibility ofclinical study of workers by the factory doctor was,until relatively recently, overshadowed by the busi-ness of compensation. It was natural for theworkman to look askance at a doctor appointed byan employer, since it appeared to him that such anappointment could only be in the interest of theemployer and hence likely to operate against theworker's interests. It is probable that in a goodmany instances there was justification for this view,but things have changed in recent years. As aconsequence, clinical examinations to detect signs orsymptoms of industrial poisoning have becomeeasier to institute. It is difficult except in thosecases where examination is required by law, e.g. forlead, phosphorus and so on. But there are manymaterials which demand that regular examinationsshould be done to detect early signs of diseasewhich are not formally scheduled under Act ofParliament. And, further, it has got to be remem-bered that to examine a man's blood or urine, sayonce a month, is a procedure which produces con-siderable anxiety in his mind and perhaps evenmore in the mind of his wife.

Explanation by the doctor of the need for repeatedexamination is likely to produce quite wrong con-ceptions in a man's mind and even if right ideas areimplanted the reaction will often be-' If the stuffis dangerous I want more money ': this may be ajustifiable position to take up, but since more moneywill not help the doctor in his control of the hazard,it is not of much value from the present point ofview.

It will thus be seen that much tact and under-standing of the worker is called for. In order not

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to produce a scare in a particular department orplant, it is essential very often to spread the examina-tions over a number of sections and thus, willy nilly,one collects control data.The psychological situation as between a doctor

and patient who consults him is quite different fromthat between an industrial doctor and a workerwho feels quite well and has not consulted him.Where objective observations can be made, it isrelatively uncomplicated, but so much depends onthe accurate presentation of subjective symptoms,which the workman may be and often is disinclinedto divulge if they appear minor.A plant was recently inspected where many of the

workers quietly left the shed, went round the backand had a quiet and private vomit several times aweek and never volunteered the information or evenmade complaint. Many other instances in varioustrades could be given.

It has always to be kept in mind that very fewsubstances limit their action to single organs orsystems, e.g.-

Gen7eral Systemic Poisoning. Pb, As, CH30H, CS2.Circulatory Poisons. C6H5NH2, As, C6H4(NO2)2,

Pb, Hg, Va, C6H6, T.N.T., C6H5N02, CO.Respiratory Poisons. Si, NH3, nitrogen oxides,

Cl, S02, H2S, cobalt arsenide.

Gastro-Intestinal Poisons. Zn, Pb, As, Hg, Cd,Sb, C6H6, cyanide, nitro and amido bodies, tetra-chlorethane.

Dermatitic Agents. X-rays, actinic rays, HCHO,tar, benzene, cutting oils, ZnCI2, hexamine, p-phenylene diamine, chromates, petroleum oils, etc.

Action on Sk-eleton and Joints. Pb, P, acids, As,Hg, mesothorium.

Action on Organis of Special Sense. CH30H,actinic rays, intense light, Pb, As, HCN, H2S, CS2,Hg, turpentine, Mn, C6H6.

Action on Genito-Urinary System. Aniline, ben-zene, Pb, As, Hg, x-ray, Va, turpentine, b-naph-thylamine, phenol, nitroglycerine, ether, p-nitro-aniline.

Action on Brain anid Nervous System. Pb, Mn,As, CS2, ether, phenol, cyanide, CH3OH, trichloro-ethylene, nitroglycerine, some chlorinated hydro-carbons.The organization and systematic record of

examination of workers are no easy matters andrequire the most careful study in every case.Record cards are also required for routine

examinations of units of plant: the use of suchcards depends entirely on the doctor knowing whereand how to look for trouble.

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investigation toxic hazards - a bmj journal · absent. the nervous system only was affected. severe...

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