Document OOKK4RJV2jN3VpMV6RyBjn01

FILE NAME: Celanese (CEL) DATE: 1957 DOC#: CEL052 DOCUMENT DESCRIPTION: Laubly Exhibit #5 - Medical Journal i i ti ' Ih itish Postgraduale M edical Federation University o j London LECTURES ON THE SCIENTIFIC BASIS OF MEDICINE j Volume V in P1 ' U N IVER SITY OF LONDON THE ATM LONE PRESS 1957 X CONTENTS vHi. The Steering of Metabolic Processes >26 II. A . K r e b s , m.d ., f.r .s. Department of Biochemistry, University of Oxford ix. Vitamin A H3 R. A . M o r t o n , d .s c ., f . r .s. Department of Biochemistry, University of Liverpool x. Primary Protein Deficiencies with.special reference to the specific PlasmaAproleinacmias 165 N, II. M a r t i n , b .m ., b .c i l , m.r .c .p ., f .r .i .c . Department of Chemical Pathology, St. Ceorge's Hospital Medical School, London xi. Metabolism o f Collagen 183 R. D. H arkjjess, b .s c ., m .b ., b .s. Department of Physiology, University College, London xii. Protein Ribbons and Sheets 217 K. M R u d a l l , d .s c . Department of Biamslccular Research, University of Leeds xin. Observations on the Structure of Connective Tissue Fibres 231 R. E. T u n b r id g e ; m .d ., m.sc., f .r .c . p . Department of Medicine, The General Infirmary, Leeds xtv. The Elucidation o f Toxicity 244 J . M. B a r n e s , m .b ., b .c ih r . Toxicology Research Unit, Cqrskahon xv. Industrial Toxicology 262 M. W . G o l d b l a t t , m. d ., m.r.c .p ., b .sc. Industrial Hygiene laboratories, Imperial Chemical Industries Ltd., Welwyn xvt. The Nutrition o f Micro-Organisms 285 W. F. J . C u t iib e r t s o n , p h .d ., b .sC., f . r .i.c . Biochemistry Unit, Glaxo laboratories Ltd., Greenford xvii. Living Muscle 2177 D. R. W i l k i e , m .d ., m.r .c .p . Department o f Physiology, University College, London CONTENT! * xvm. Proteins in Muscular Contraction S. V . Perry, ph.d. Department of Biochemistry, University of Cambridge XDC. Observations on the Excitable Cortex in M an J. A. V. B ates, m.b., b.ciiir. Neurological Research Unit, National Hospital for Nervous Diseases, London xx. The Investigation of Gastric Digestive Function in Man J . N. H u n t , d .s c ., m.b., b.s. Physiological Laboratory, Guy's Hospital, London xxi. The Treatment of Hepatic Coma J. F. S t o k e s, m .d ., f . r .g .p . Department of Medicine, University College Hospital Medical School, London xxn. The Physiology o f the Lower Oesophagus and Cardia A . C. DORNfiORST, M.D., P.R.C.P. Department of Medicine, St. Thomas's Hospital Medical School, London xxiii. Renal Control of Acid-base Balance M . D. M iln e , m.d ., m.r .c .p . Department of Medicine, Postgraduate Medical School of London xxiv. Some Anomalies in EndocrineCarcinogenesis E. S. H o r n in o , d .sc. Institute of Cancer Research, University of London xxv. Recovery from the Lethal EfTccts o f Radiation J. F. L o im r, d .m ., m.r . c .p . Radiobiological Research Unit, Atomic Energy Research Establishment, Harwell xxvi. Physiology of Nasal Circulation D. A. S lome, ph.d., m.b., cii.n. Institute of Basic Medical Sciences, University of London Complete List of Lectures 314 333 . 348 j 380 338 404 421 439 451 489 tu XV Industrial Toxicology M. W. G O L D B L A T T he object of industrial toxicology is to obtain knowledge of the possible dangerous effects o f industrial materials before they are made or used, and thereby to be fore warned as to the nature and degree of precaution, protection and supervision which are called for if the health o f workpeople is not to be affected. This is the pure meaning o f our subject. In an extended mean ing it includes also the toxicology of materials in the interest of those who, neither making nor using them in industry, may yet consume them, use them in the home, come into close contact with them in apparel, use them in their hobbies, use them as a weapon against pests o f many kinds, and in other ways demand protection or foreknowledge. On this occasion I am concerned with industrial toxicology in the pure sense. The assumption is that industrial toxicology has a scientific basis. Inasmuch as it engages chemists, physicists, physio logists, pathologists, and medical men, it may claim to have science in its body in greater or less measure. The pursuit o f industrial toxicology is, as I have said on another occasion, `not a question of Industrial Policy, but one o f science, o f conscience and o f civility*. We may recall some notable words uttered by Einstein in 1938: It is not enough that you should understand about applied science in order that your work may increase man's blessings. Concern for man and his late must always form the chief interest of all technical endeavours, concern for the great unsolved problems of the organ ization of labour and the distribution of gootls-- in order that the INDUSTRIAL TOXICOLOGY creations of our mind shall be a blessing and not a curse to mankind. Never forget ibis in the midst of your diagrams anti equations. This quotation contains the crux or tbe aim o f industrial toxi cology, since it is first and above all concerned that the creations of the ingenuity o f men although, in the issue, directed to be a blessing, shall not at any stage be a curse to men at however humble a level. What kind of science is it, then, which embraces such diverse activities as those of the persons directly engaged in it? We may here quote a useful definition o f science given by Conanj (1951): `Science is an interconnected series o f concepts and conceptual schemes that have developed as a result of experimentation and observation and arc fruitful of further experimentation anil observation.' A great encouragement to the young, anil a chastcncr to the conservative not so young. The two processes of experiment and observation embrace everything that takes place in industrial toxicology, but in a sense somewhat different From that implied in the definition. For, whereas in the definition observation is a process which follows upon controlled experiment, in our science there is also observation which follows upon uncontrolled experiment. In asmuch as uncontrolled experiment is not truly science, our science is a combination o f something which is not science and something which is. Industrial toxicology is an activity which, in all its aspects, whether clinical or experimental, whether theoretical or practi cal, is directed toward the frustration of thoughtless people and noxious things. The frustration of thoughtless people, workers or employers, is the more difficult by far. U ncontrolled Experiment When a workman is placed in a particular kind o f work, a kind o f uncontrolled experiment is being started. Except in rare situa tions there is little or no knowledge of how the man will respond physically or psychologically to the work and to the environ ment in which he will be required to spend one-third or more o f his life. The concept man is a variable; the work may be a constant, In H i'" 2G4 M. W . O O L D B I . A T T but tlie environment is rarely controlled, ami except in those minima laid down by law, most rarely measured. From these facts many of the dilemmas of industrial medicine arise. In our field the environment may be measured in respect of contami nants (dusts, fumes, gases, vapours), and may even, in the issue, be controlled by appropriate measures, but the criteria whereby a judgement can be made that one or more workers are being adversely affected rest upon a mixture or the clinical art and clinical science. The variability of response and interpretation in the cases of different human subjects rests in part upon: 1. the varying tolerance and detoxicating powers; 2. the variable symptoms and objective signs for a given toxic agent; 3. the variable subjective responses to signs and symptoms; 4. the difficulty in measuring significance of small deflections from the normal; 5. the difficulty of measuring exposure in anything like abso lute terms; 6. the fears of many workpeople that complaint or confirmed symptoms may prejudice their job; 7. the fear of the employer that he may be subjected to criticism or penalty; B. the not infrequent difficulty of attribution when many sub stances are involved, and 9. the identity of a symptom-and-sign-complex with others known to occur in the non-industrial population. By no stretch of the imagination could an activity involving these and kindred factors be called a science. It may be that a scientist could pursue some aspects of it with more success than others with less training, but it is fair to say that the gift of interpretation often resides in men and women who would scarcely claim to be scientific. But, unlike the clinician, medical observers in the field possess certain advantages which mitigate the usual charges against purely observational medicine. By constant or nearly constant contact with persons exposed to industrial materials, the fre quent post hoc fallacy avoided. Secondly, from the very existence INDUSTRIAL TOXICOLOGY QG of numerous people thus exposed, the range of observation more nearly approaches that o f the experimental method. Thirdly, intuition and authoritarian experience arc less called upon in industry than by the clinical observer-- objective demonstration is more frequently attainable. Nevertheless, it remains certain that for the individual worker as a patient the need for clinical intuition and experience remains, especially in the diagnosis ofindustrial as against non industrial conditions. Writing of the diagnosis of fatigue (one of the most difficult of all things to evaluate in industry) Patrici o f Modcnal says: 'The symptoms are not bound together like links in a chain so that the failure o f one link breaks the chain, but rather like the thousands of fine strands o f an electric wire, the rupture of which still permits the lamp to glow and the experienced man still sees clearly*, anti this dictum may well be applied to the diagnosis o f many industrial maladies. N otifiable and P rescribed I ndustrial D iseases The law in ibis country lays down iwo sets of industrial poisonings known respectively as notifiable industrial diseases (to which one may conveniently add gassing accidents) and prescribed industrial diseases. The Ministry of Labour and National Service is the responsible Government department in the former case; the Ministry o f Pensions administers the provi sions o f the Industrial Injuries Act relative to the latter. These lists have been drawn up from data derived exclusively from human crises of poisoning and disease occurring in industry and attributed to specific substances in most cases. Almost all the notifiable diseases arc included in the much larger list of prescribed diseases. The words accident and disease have been the subjects o f much discussion, but it will perhaps be sufficient to say that they arc distinguishable by the fact that an industrial accident is not foreseen whereas an industrial disease is foresee able once it is agreed that it can arise in more or less defined circumstances. In no case, as far as we know, has a disease been put into these lists as a result of experimental effects with particular In n at M. W. G O L D n I, A T T T a b l e 1. Notifiable diseases (Section 66 of the Factor! Act, 1937) I'li, I*. A, Mg, Anthrax, C S ,, Aniline, Clnntne, llenzrnc, Mil 'toxic jaiimtice (tctiacldoroclliane, nitro or amino derivatives of benzene nr its homolngoes) Ivpithclinmatmu ulceration (pitch, tar, bitumen, mineral oil, paraffin, or any product or residue of them) Chrome ulceration (chromic acid, K ,C r ,0 ,, Na, or (N il,),, or preparation of) Compressed-air illness Toxic anaemia Carien; AcciJin li CO co. . II,s so , Cl Nitrous fume N il, C.H , Naphtha Petrol and benzine Trichloroethylene Nickel carbonyl COCI, MCI 1ICN bitumen, lar, creosote, oil Others Total: 1953: 254 (23 fatal) 1954: 237 (21 fatal) CO, 1953: 121 (19 fatal) CO, 1954: 113 (14 fatai) T a b l e 2. Prescribed diseases (causes or nature of) l'b Mn I* As Hk CS, He Ni process a-, f)-naphthylamine (auramine, magenta) Benzene or homologues Nitro or amino dcriva- tvcs of benzene or homologues Diiiilrophcnol or homo logues Tetrachlorelhane Dioxan Methyl bromide Chlorinated naph thalene Nickel carbonyl Nitrous fume Conioma katnassi Anthrax Glanders l.cptospira ictero-- hacmorrhagica Ankylostomiasis Trirresyi*) l>lloiP*,a,e3 X-rays, ionizing ' particles, lla, etc., or other forms of radiant energy Skin, subcuta neous tissues, boors, leukaemia, aplastic anaemia, etc. Infra-red radiation or 1 glare from molten glass | Cataract or molten red-hot metal j Compressed-air illness Telegraphists1 cramp Wireless cramp Twisters' cramp Subcutaneous cellulitis (beat hand) Heat knee and elbow Synovitis Miners' nystagmus Tuberculosis--nurses and research Pneumoconioses llyssinosis T ar, pitch, bitumen, mineral 1 (a) Corneal ulceration oil, paraffin, soot or I (4) Skin papilloma compound or residue j (r) Kpithclioma of skin Chrome: (a) Ulceration due to chrome compounds. (4) Nasal, upper respiratory passages, mouth, ulceration due to dust, liquid nr vapour. INDUSTRIAL TOXICOLOCIY substances. Laboratory evidence that a material or a process is dangerous is o f no moment as far as notification or prescription is concerned unless workers have been demonstrably affected by them. Laboratory evidence may fortify a contention, but in itself is unacceptable as a means of defining a notifiable or industrial disease. Experimental evidence obtained in animal experiment is so often dilferent from that obtained from observation of human subjects that it is rarely adduced even in a claim of damage against an employer. This latter fact is also in part due to the common attitude toward animal experimentation :uul to the judicial profundity which may observe that neither a rat nor a dog is a man. Now the object of compulsory notification is to maintain an effective watch on what is going on in industry in respect of certain compounds. Gassing accidents are reportable under accidents-- an acci dent being defined as not an accident if there is not a loss of three days' working time. As to gases or vapours which do not appear as causes of notifiable diseases, it may be concluded that it is held officially that they do not give rise to disease. That is, that repealed absorption at suhcllnical levels of the material in question docs not lead to a foreseeable disease. For example, C O and most chlorinated hydrocarbon solvents may give rise to gassing accidents but arc not admitted as causes o f notifiable disease or prescribable disease. Only tctrachlorcthane is in cluded in the notifiable list. On the other hand, aniline poison ing is included as a cause of notifiable disease, but must lie held to cover much more than aniline. The presumed tlisctise would include; anaemia, hacinaturia, dysuria, frequency, mrtlincmnglobinacmia. There is no doubt that severe cases of absorption of aniline or its homologues can lead to acute haemorrhagic cystitis which is sometimes severe but responds to treatment. Notification is rendered powerful by the duty of notification having been laid not only on the medical practitioner who sees the case, but also on the employer. As a true research tool ii could give the most complete picture of every kind of industrial toxic event if its scope were enlarged. It is highly probable that tu |'H ' 2 61 M. W . O O L D D I . A T T as it is this country may with justice claim its records to be the most complete in the world. Nevertheless, the Chief Inspector of Factories has indicated in at least one industrial disease that notification is incomplete. He stated in his report for 1953: It is evident that the notifications in compliance with Section 66 of the Factories Act, 1937, are only a partial indication of the inci dence o f this disease [F.pitlicliomatons Ulceration due to I'itch, Tar and Mineral Oils.) The duties of the medical practitioner and of the employer as regards notification are of prime importance for pre vention, since the application of preventive measures to new pro cesses anti their intensification in recognized hazards are the immediate sequelae. Having regard to the manifold difficulties already referred to, it is no criticism of the law or the Factory Department to say that we do not consider the figures presented in the annual reports o f the chief inspector as giving a fu ll picture o f what is happening. Some two years ago I made the .following statement at a vr^jvji,,nr_c i--i_ i _~ ur t . /u i-t . > v_/ _t ._i ,_u_| 7_a .u:u_t_t _< u1 i j : o u u u - i y ^i nu u. ui u iu. ii a. .u. , 1954): ' people who are absent for three days or more are notified, but how many people are from day to day absorbing compounds o f greater or less toxic powers, without anybody knowing what ultimate effects they may have, or indeed, what immediate effects they are having?' At the same conference, I referred to workers having been found in factories who were without doubt suffering from chronic plumbism and iiad never been notified at all, and in my Mackenzie Lecture of 1954 made reference also to the excellent observations of Dr. M ary Fullerton on such cases (Coldblatt, 1955; Fullerton, 195a). It is therefore interesting to note the remarks ofH .M . Inspector o f Factories, R. Murray ( 1955): there is no doubt that the data available at present are inadequate to assess fully the true incidence of industrial disease and to recognize the part played by working conditions in the causation of disease.' INDUSTRIAL T O X IC O L O G Y F ie l d W o r k in I n d u s t r ia l T o x ic o l o g y The work done in this context by industrial doctors, appointed factory doctors and the very highly skilled members of the Fac tory Department, is industrial toxicology in its most difficult asfiict. That it is not science as ordinarily understood is rallier praise than blame. Inevitably the methods of clinical science are enlisted to fortify a diagnosis (blood, urine, X -ray, E .C .G ., blood pressure, eyes, etc.), but in the issue it is the nature and degree oHoss of faculty which must be concluded upon, and the strongest evi dence derives from the clinical art and the occupational history. The frequent absence of the toxic agent from the body fluids is no evidence against its having been the cause; e.g., recog nizable occupational cancer may be first established long after all vestige of the agent has disappeared; the inability to demon strate chemically the presence on the skin o f any agent which might have caused a dermatitis leads to the need for indirect evidence o f its culpability; in respiratory disease induced by the chronic inhalation of certain metallic oxides it may be impos sible to show the presence of the metal in the body; irreversible effects on the kidneys and the circulation o f a former lead worker may be attributed to that metal long after the blood, urine or tissue levels are indistinguishable from normal; the attribution o f a blood disease to benzene in most cases rests on no chemical confirmation. The experimental demonstration of the length o f time a material or its metabolites may be retained in the body invokes the use o f labelled compounds. Thus, working with my col leagues Henson and Somerville and using a-[8-" Gjnaphthylaminc, it was possible to show that radioactivity was detect able in rats and rabbits for some nine to ten weeks after a single intraperitoneal injection of i mg. (i.e. 5 mg./kg. for rats and '5 mg./kg. for rabbits (Henson el al., 1954). The significance or such findings when considering cumula tion is manifest. Workmen may replenish the remnants o f a day's absorption by the absorption o f the following day and thus maintain residues for years in their blood or tissues. The tu H 370 M. W. G O L D ! ! 1- A T T mobilization of such residues varies with ibe individual, with the material, with the nutrition and fluid balance. In a con siderable number of deaths reported recently among Dyaks engaged in the treatment of wood with pentaehlorophenol there was without doubt a build-up of this compound by per cutem absorption, low state of nutrition and probably a poor water-balance. The enormous fund of data on clinical signs and symptoms combined with the records of pathological changes in the organs and fluids constitutes the background from which the results of exposure to known hazard can be recognized. Where, however, no certainly as to the effects of new materials is extant, their recognition rests upon the clinical acumen of the men in the field. That this recognition can be greatly facilitated by the results of laboratory experiment is part of the case for scientific industrial toxicology. T he I ndustrial. D octor in t iie Fa c to r y There is little doubt in my mind after over twenty years in the field that industrial doctors are regarded witli dubiety by their medical colleagues in what are held to be more exalted fields. This dubiety arises from ignorance and from a conservatism which reflects no glory on its adherents. My own view is that the profession of industrial doctor is being developed on lines which may be criticized and the man himself may sufTer as a result. But the work to which he directs himself is vital to the development o f the industrial society to which we are committed. He has to contend with the vagaries o f employers, workers, engineers, administrators, departments of welfare, both in his factories and in the trade unions, and has to maintain a balanced calm and impartiality in lire midst of conflicting interests. Me has to deal with minds and bodies. Me has to think of bis people not in the brief period of a consulta tion, but throughout the day and night of their work. His wounded in the field have to be sent to other parts of the field or back to the same sector; bis preoccupation is not ended by his cure of them.'Tills is the man who must know about all the activities in bis factories and be able to make a judgement INDUSTRIAL TOXICOLOGY on the impacts of them on Ins human subjects. The condemned paternalism o f the industrial past has changed into his benefi cent paternalism of the present. This man must he as know ledgeable about things and methods as he is about the signs and symptoms of deflections from the normal. lie is the link with the industrial toxicologist and the inter preter to his managements. He poses problems, utters doubts, expresses impressions, hopes for interpretable measurement, carries clinical pictures in his mind which he may be unable to describe, looks in perplexity at the statistician's esoteries antics, begs for antidotes and effective therapies, prays that las firstaid teams will not let him down, pursues the often tedious path o f maintenance of efficiency and readiness in services which may have only the rarest opportunity to show their prowess, and is often expected to know about and pronounce on the most varied matters which may appear irrelevant to his defined function. This is the man who was regarded as the Cinderella o f medi cal art and science. The picture is perhaps overdrawn, since many part-time doctors may also be busy practitioners, or may even not be permitted to enter the factories at all. Hut it cer tainly applies to the now large body of men who are wholly engaged in industrial medicine, and especially those who spend their days in hazardous industries. The kind ofobservation and record lie can make on tiie effects of toxic materials on human subjects is the essential basis o f legislation and the protective measures that may be expected to follow upon it. T he W o r k e r and th e A nim al in I n d u str ia l T o x ic o l o g y Whereas in experimental toxicology the animal is a passive instrument, this is far from the case in industrial toxicology in the field, and I therefore summarize briefly how the worker is different. He should be told what the hazards are which he may en counter and what untoward event may follow. As 1 have advo cated this course for many years, it is a satisfaction to note that Smith (ig/jG) of the engineering and chemical branch of the in I* -- 272 M. W . O O L U B I . A T T Factory Department made the following statement to the Insti tution of Chemical Engineers: We have not in Great Britain done very much so far to teach the ordinary workman the dangers of the materials and plant with which he is concerned, and the reasons that lie behind precautions to prevent injury or poisoning. We ought to do more [he continues) and we can learn a great deal from American authorities and from some o f the big American companies. It would be absurd to suppose that all workpeople are equally susceptible to information o f this kind. In fact, it may very well be that those workers who are susceptible to such education are, on the whole, in little need of it, and vice versa. Workpeople must be taugiit by methods adapted to a practical level of comprehension by a combination of concrete illustration drawn from life and industry and positive action directed against the hazard under consideration. I consider exhortation o f little value. One grain o f positive action, well understood and ap proved by the man's common sense, is worth more than a granary full c f exhortation introduced by biblical negatives. If the information is absorbed, understood and approved, the workman will see the sense of medical and biochemical examinations which are often necessary to measure the extent to which protective measures are defective or deficient. He will, moreover, be more willing to disclose symptoms which arc relevant and less likely to trump up imaginary complaints attri buted to his work. Let us admit that the often wilfully misleading attribution by workers o f subjective symptoms to industrial products or processes is not more irritating than the humiliating obscurant ism which so often attaches to terms which the doctor appa rently authoritatively uses in his daily dilemma of having some how to placate his patients or their relatives; Human subjects vary to a much greater extent than do mem bers o f the same animal species, especially laboratory animals. For a population of humans, the scatter of doses (symptomatic, lethal, producing a measurable biochemical lesion, or patho logical lesion) will be very great and much less so for animals. And hence, even were the mean values identical for men and INDUSTRIAL TOXICOLOGY animals, the application of data from animals to men must have regard to the relatively high standard deviation from the mean in human subjects. If we can assume a normal distribution, the loss at the lower doses will, as far as the whole population is concerned, be regained at the higher doses. Qualitative evi dence for this proposition in the matter o f toxic doses in in dustry is an everyday experience in factories and is often a source o f both danger and dilemma. Men, whose sensitivity cannot be anticipated, enter sheds, or take part in processes under conditions not hitherto suspect and rapidly feo down with a variety of symptoms depending upon the toxic agents involved. Rapid reaction to lead, aromatic amines and nitro compounds, chlorinated hydrocarbons, chlorinated aromatic amines, aromatic diamines, aromatic diisocyanates, chlorinated phenols, nitro derivatives o f aliphatic polyhydric alcohols, phosphorus insecticides, etc., is a commonplace at levels of exposure or absorption regarded as tolerably satisfactory. This is, in part, the result o f the unavoidable employment of r.Qn-se!ected individuals. Experimental animals in numbers permitting statistical interpretation of results are a selected population usually bred for uniformity, and hence will show a much smaller concentration o f individuals at both ends of die distribution curve. It is difficult, perhaps impossible, to simulate with animals the conditions in which a worker may find himself. Injection or feeding experiments arc o f great value in elucidating the pathology and biochemistry o f toxic effects (acute and chronic) and in obtaining the relative toxicides o f different substances with similar actions, but their application to human subjects in industrial conditions or in everyday life calls for much addi tional evidence. Intraperitoncal injection, although with no counterpart in human situations, is o f value as in some sense simulating in halation. But if injected in oily media, the rate o f entry o f the water-insoluble material into the circulation may be so slowed as to be misleading. In the circumstances in which the effect o f oral ingestion of substances by human subjects is at issue, the assumption must ti i I'M Q74 M. W . G O L D 11 L A T T be made that man is much more susceptible than animals, perhaps tenfold or even a hundredfold more. Inhalation experiments are more likely to have direct applica tion to man, but animals arc exposed usually in quiescence and bored fortitude, whereas man is exposed in conditions that entail differences in respiratory rates, energy expenditure, anti varia tions in concentrations. The ingestion of alcohol and many other incalculable factors also affect his response. Per cutem absorption experiments on animals arc the easiest to interpret when positive, but considerable precaution is necessary to obviate per os absorption by licking. Negative or relatively negative results may be misleading unless tempera ture effects {of skin and o f the material itself) arc studied. Simu lation of industrial conditions is closer ir the materials used arc rubbed in, but quantitation inay be prejudiced if this is done. The importance o f temperature was well shown in a factory some years ago, where the handling of a low-melting chlorinated aromatic amine had proceeded for many years without anxiety. This continued until a normal batch was made and handled during an extremely hot August. The almost immediate consccpicnce was an outbreak of violent haemorrhagic cystitis, without doubt following a greatly increased rate of absorption through the skin. Similarly, but more dangerously, the passage through a burnt skin surface is greatly accelerated. This was a factor in the recent death o f a man following a not very extensive burn with hot chlorinated phenol. The divergence of animal susceptibilities and metabolism from those o f man is rendered less significant from our present point of view if several different species are used, rodent and non-rodent. The myth of the monkey need not be pursued if there is some consistency in the reactions or non-anthropoids. The rat is still the most useful animal for our purpose-- relatively cheaply maintained, it lives healthily in laboratory conditions, is easily multiplied, easily handled, gives consistent data, is readily used for metabolic and blood studies, is excel lently adapted to inhalation, insufflation and all manner of injection experiments, consumes artificial diets at foreseeable INDUSTRIAL TOXICOLOGY levels, etc., etc. The great value of the rat lies in the fact i... i for a given breed a body, of knowledge o f their `normal pathol ogy' can be built up, which helps to prevent misleading con clusions. Animal experiment is essential to discover ultimate effects which may follow apparently unharmful exposures to and ad ministrations of industrial materials since the animal can be observed for any desired time, or until death. Such discovery is incomparably more difficult for man. The recent classic statistical studies of Case and his col leagues (1954) on the incidence o f vesical tumodrs in the chemical industry illustrate the immense amount o f work that may be necessary to establish a full statistical picture o f an in dustrial disease and to make justifiable attributions. A work man is often mobile and what has resulted from one or more kinds o f industrial exposure may never become known at all as he moves from place to place in the course of his working life. This adds immensely to the labour o f collecting statistics. In my own experience certificates o f natural causes have been given by practitioners who could have no inkling of the significance of studying the prior occupational history o f the deceased and did not, of course, associate the diseases with it. It is not, in general, a subject o f investigation to discover the effect on immunity reactions of industrial toxic materials in animals or man. That certain industrial poisons can affect complement, agglutinins, haemolysins and bacteriolysins has been shown in respect of CO , C ,1I,, H g C l,, C a C N ,, I'b, P, As, Mn, C C I., K ,C r l O ,I fluoride and thallium compounds. Hut much more work is required. That one kind of industrial lesion may predispose to infection is well recognized in the silicosis(ubcrculosis relation, and evidence is accumulating that an asbestosis lung carcinoma relation exists. Recent work on the effects on mitochondria o f chlorinated hydrocarbons appears to show that these widely used industrial compounds act physically on these complex intracellular struc tures, detaching essential cellular coenzymes arid thus breaking the Krebs cycle. Although mitochondria disintegrate in patho logical conditions, it is not at present possible to say how in [! a7v U. W. O O L D B L A T T far maintained absorption of industrial poisons may lead to irreversible deflections from normal function, not necessarily inconsonant with working capacity for a long time. Without necessarily subscribing to the dark forebodings of the late Sir Edward Mellanby and, more recently, Sinclair (1956) as to the possible relation of food processing and food additives to the many diseases o f unknown etiology, one can still consider it desirable to inquire more closely into the effect of industrial exposure on subsequent health. There are many conflicts of evidence and it is exceptional to find an unequivocal case. Thus, in the matter of the so-called Alkali Welding Rad1 which produces the best weld for many vital national purposes and which has been used for a good many years in other countries without undesirable effects, it is still claimed by operatives in this country that their health is somehow affected. The impossibility of proof of a negative needs no emphasis here, but it may be said to those who are attracted to our field of work that this dilemma is one they will meet at every turn. C hronic Effects of Industrial T ox ic A oents The proof that in industrial conditions a substance or process will have no deleterious effects on workpeople (and it may be permissible to say that work is not the exclusive prerogative of members o f trade unions) rests either upon long experience in the field combined with extensive clinical record or upon the inferences which can be drawn from experiment. From what criteria can the observer in the field draw the necessary conclusion as to the cfTects of chronic absorption? His conclusions, as we have already said, arc the determinants o f official or industrial action and, with the authority of medi cal responsibility, will exert greatest influence on the apprehen sions of workers in a given case. The classification of workers into groups according to significant hazard may be more difficult than at first sight appears. Where many chemical hazards exist many men may belong to several 1 Buie coated low-hydrogen electrodes. in d u str ial t o x ic o l o g y groups. M any may be exposed even if their jobs are etsewncrc than where the hazard exists. Workers in factory laundries may be exposed. Thus, it may become necessary to create sub-groups according to the estimated degree of potential hazard. I may recall, in passing, the cases o f two young women who died from organic mercurial poisoning after having worked as typists in a room adjacent to a packing department, and o f men who devel oped occupational cancer through exposure to fume from an adjacent building. It is an old dictum o f pathologists that on the whole you find what you are looking for. That is to say, as one Examines a tissue or organ or histological slide, one must be constantly repeating in the mind: `Is there this present or that present?' In industrial problems it is necessary to establish not only that this or that is present, but that it is related to a particular substance or process, and that it occurs very significantly more frequently among particular groups than among others. Medical record should include not only the clinical examina tion o f the various systems, circulatory, respiratory, blood, ner vous, excretory, digestive, muscular, etc., but also the diflicult questions o f fatigue, working capacity and efficiency, sleep, zest, interest, appetite and gastric content, memory, emotion, and other elements in the psycho-organic field; i.e. symptoms and signs simulating organic disease but deriving from mental disturbances of function with an as yet unknown pathologicalphysiological basis. I am concerned here to emphasize that the common practice of dismissing many of the subjective com plaints of workers should be discouraged. This practice is dis cernible even where blatant industrial poisoning is foreseeable. On a recent visit to a lead mill, for instance, I asked the manager whether his men complained o f anything. His reply was that some o f them had occasionally complained o f `belly-ache', but there was nothing to it. Shortly thereafter two men went down with all the signs and 65 per cent Hb. Some twenty years ago it was proposed by Smyth, Smyth and Carpenter (1936) in the U.S.A. that for C C 1, a concentra tion of 100 p.p.m. in the working environment was permissible. Six years later Elkins (1942) found in various kinds of operation 27ft M. VV. G O L D I , A T T involving C C 14 that such symptoms ;ts nausea, belching, drowsiness, tiredness, headache, might each or ail occur at average concentrations between 20 and (bj p.p.m. The impor tant point was the frequency of entirely subjective symptoms, nausea and headache, with `little objective evidence of injury'. Two years later Stewart and Wilts (1944) described cases of C C I4 absorption among workers engaged in the chlorination of an aromatic amine dissolved in C CIt. The remarkable thing about these cases was that in spite of a variable gaslro-intcstinal and cerebral symptom-complex (nausea, anorexia, abdominal pain, diarrhoea, sometimes vomiting, liaematemcsis and even rectal bleeding, weakness, dizziness, confusion, headache, dys pnoea, cough, loss of weight) it was, the authors stated, difficult to believe that they were ill at all. In my own experience of factories where, during the war, ethylene chlorhydHn was manufactured in large quantities, and where the machinery and reaction vessels were so closely crowded together that pockets of considerable concentrations were built up, men and women workers without complaint would periodically leave the sheds and have a quiet, secluded and furtive vomit. It was only when one worker made a mild complaint of nausea that the situation was exposed, but unfor tunately not before another worker had suffered long enough to develop a chronic nephritis which killed him. It was manifest that the workers for reasons which might have related to the high rates of pay were loath to report what appeared to them to be minor symptoms. A recent comment by investigators in Holland (Frant and Westcndorp, 1950) on the significance of the urinary concen tration of trichloracetic acid in workers exposed to trichloro ethylene was that `continuous contact may familiarize a work man with the symptoms of drowsiness, dizziness, etc., and this may cause him to neglect them'. Very recently (GrandjcanW a/., 955) a BrilP of Swiss workers submitted men exposed to tri chloroethylene to a detailed psychiatric examination (fixation memory, attention, comprehension, ideation, aifectivity) and claimed that elements something akin to the Korsakow psycho sis could be established in increasing frequency among workers INDUSTRIAL TOXICOLOfiY ns the concentrations in which they had worked rose from 14 p.p.in. to 34 p.p.in. to 40 p.p.m .1 11 is too early to be sure about this work, but it seems desirable to consider where psychiatric tests stand in the routine of indus trial toxicology. Our present criticism ofthc above observations rests upon the inadequate control data, the fact that the inci dence and intensity of subjective symptoms were not greater among men exposed to the higher concentration for longer periods than among those exposed to much milder conditions. The third criterion to which particular attcntionl is now drawn is the degree o f contamination o f the enviror^ment in which the affected persons worked. By the time adverse effects have become manifest it is possible only to try to prevent further trouble. This is the domain of what has been called the maximum allowable concentration. It is well to realize the following facts and queries: (1) A maximum allowable concentration has no legal sanc tion. Where legal sanction has been tried, either methods of determination were found inadequate or the circumvention of the enactment was child's play. (2) The maximum allowable concentration values are thus referred to by Cook, a noted worker in this field: It is to be emphasized that the intent in presenting these maxi mum allowable concentrations is to provide a bandy yardstick to be used as guidance for the routine industrial control of these health hazards-- not that compliance with the figures listed would guaran tee protection against ill-health on the part of exposed workers, nor should the maintenance of the suggested concentrations lie con sidered a substitute for medical control. This is a very cautious statement. Annual review of the `maximum average atmospheric con centration of contaminants to which workers may be exposed for an eigbt-hour working day without injury to health' by the American Conference of Governmental Industrial Hygienists assures the most up-to-date values, from `industrial experience, 1The classic Korsakow syndrome in alcoholism may also he simulated in chrome lead and mercury poisoning. Irritability, forgetfulness, change in moral character, impaired judgement, enfeebled will, false ideas of |>osition in lime anti space, fabulous explanations of real occurrences, peripheral neuritis. in I*" 1 Co Vf. W . O O I . D D L A T T from experimental studies and, when possible, from a combina tion of the two'. 1 No such review by a responsible official body in this country is available. This is in accordance with the British tradition of avoidance o f permissive clauses. (3) Speaking of the American use of maximum allowable concentration values, Smith (loc. cit.) says: These figures, based partly on animal experiments and partly on industrial data obtained from animal experiments, cannot always be interpreted accurately in terms of human response because the quantitative industrial experience is'incomplete. The misuse of the maximum allowable concentration lies in the fact that there seems to be a tendency for some of the industrial hygienists to take samples which may or may not be truly represen tative of the air breathed, to analyse these samples, and, if the results are below the arbitrary maximum allowable concentration, to assume that no further action is required. This may occur even where further improvement in a process, from the aspect of the health of the operatives, could be secured fairly easily. (4) O f the enormous numbers o f places where chemical com- r1s..A...t.i..r.w..i<* si imrvuosSua * Ua s j u n c i o j u i r 5v/ iiisn y re ret analyses carried out? Very few, wc may be sure. And how futile arc the hysterical efforts to establish the atmospheric concentra tion after a case of poisoning or disease has occurred! (5) What is the relation between the universal preoccupation with small amounts of food additives (apart altogether from those which arc banned because they might obscure bacterial decomposition) and that with the maintained absorption for perhaps 30 or 40 hours a week by workers of small amounts of substances ofincomparably greater potency? Men who would be much concerned by the disclosure that if their whole diet consisted o f lollipops they would ingest a few milligrams of a synthetic dyestufT, would hardly be worried at all by a much more significant disclosure relating to their work, where entry into the circulation through the skin or respiratory tract may be extremely rapid. We seem to have a long way to go before the strictures applied to the one should at the very least apply to the other. 1 For 1955 lu ir cc Procttdingi o f *7*A Annual Meeting o f the American Conference o f Coi-ernmenlal nJuihutl UjrgienisU, DulFalo, 24-38 April 1955. INDUSTRIAL TOXICOLOOY v. (6) Sickness absence records in factories are not, in general, a sufficiently sensitive index o f the kind of signs and symptoms to which reference has already been made. A man goes ofTsick almost invariably because he is too ill to work. T h e effects we must seek to recognize are those which reflect upon well-being, efficiency and perhaps on accident incidence, rather than on the grosser criteria of manifest illness. It will, perhaps, be best to seek in the realm o f social relations for evidence of home contentment, zest and interest in both work and leisure, vague discomforts and dysfunction, disturbance o f normal sleep and difficulties called psychological. It will depend a good deal upon the kind of industry being studied as to the effects of predominantly subjective complaints on efficiency and productivity. Some recent studies in the accumulator industry led to the observation that: *. . . neither psychological handicap nor mental ability affected productivity in all groups as much as social background in the home and in the factory' ; and again 'the assumption that workers who have a psychological handi cap such as neurosis produce less than the average worker was not confirmed in this limited study of Bo workers' (Markowe and Barber, 195a). The same observers also found in the same industry that in comparing two groups o f workers as to productivity, it was the more mentally healthy and more effective group which had by far the greater sickness absenteeism (5:1). It may be that ability and efficiency go hand in hand with a measure of hypochon driasis and, if so, confusions would arise in factories possessing toxic hazards. R equirements if P r e ven tio n of C hronic T o x ic E ffects is t o be A tta in ed There are so many chemical elements and compounds which in sufficient concentration produce manifest effects on physio logical, metabolic, enzyme, hormone and other systems that the least we must ask for those exposed repeatedly to any con centrations includes: (a) determination o f the atmospheric concentrations at ap propriate points and as a routine; In P 2fl'- M. W , O O I . D D L A T T (b) development ofsimple but suflicicntly reliable methods of analysis suitable for field application; (c) recognition by industrialists, small or big, that such work is part of industrial processes; (d) routine examination of workers for relevant signs, symp toms or biochemical changes; (c) in appropriate cases, chemical examination of urine for metabolites, metals, or cellular abnormalities; (f) institution at appropriate centres of investigations into the toxicological and pathological effects of new or old materials; (g) recent developments in other countries indicate that a more drastic approach is being made to the dilemma of apply ing experimental results to man. In at least four cases data are being sought by: (i) exposing working volunteers to atmospheres containing organic phosphorus insecticide; (ii) exposing working men in specially enclosed workshops for eight hours a day five days a week to controllable concen trations or lead or fluoride; (iii) volunteers are also being fed diets containing lead or fluorides or other known toxic substances; (iv) the toxicology section of the United States Public Health Service has reported experiments on 51 volunteers who con sumed D D T (35 mg. per man per day) for from one month to one year (Hayes el al., American Association for the Advance ment o f Science, quoted in Chemical Trade Journal, 1956). This kind o f work will, o f course, provide data on normal tolerances, normal metabolic or detoxicating mechanisms, rates o f excretion or retention, rates of recovery of inhibited enzyme systems, effects o f therapeutic agents of the chelate type and, no doubt, much else, but it cannot replace the field work already mentioned. This list is bound to be regarded as formidable to the small employer or even to the not so small man but, in fact, trade organizations are becoming more and more conscious o f the need ibr such work. Even government departments (e.g. D.S.I.R.) arc considering establishing laboratories for these purposes in collaboration with industry. INDUSTRIAL TOXICOLOGY At llie moment in this country only two or three laboratm ics exist for this purpose, the Medical Research Council labora tories under Dr. John Barnes, where there is a strong and im pressive pharmacological rather than industrial predilection; the Medical Research Council unit under Dr. Hunter, where there is a strong clinical (but perhaps less marked pharmaco logical and industrial) activity; and the laboratory o f Dr. Edson who exerts a most careful scrutiny o f insecticidal and fungicidal products. University departments on occasion undertake ad hoc studies for particular industries and naturally have an jtcademic approach. ^ Imperial Chemical Industries have established laboratories employing between thirty and forty persons and the points I have indicated arc dealt with not only in the laboratory, but in the field in close collaboration with the many medical officers in the numerous factories o f the company. A large body o f litera ture, experimental, clinical and industrial information has been built up. The accumulated experience and knowledge of our scientific staff is frequently consulted by government and indus trial bodies and our willingness to discuss and help is dictated solely by their earnestness in the promotion o f health and safety in the factory. Increasing knowledge o f the manifold subtle effects of indus trial toxic materials has brought to light much that was un known or obscure even a short time ago. The constant review o f maximum allowable concentration values which is practised in the United States of America is indication enough that in respect o f atmospheric contaminants doubts may enter at any time as clinical field-experience increases. The nuclear age is calling for the use o f more and more o f the rarer elements, the toxicological properties o f which arc still unknown. T h e organic chemist produces new compounds more quickly than they can be studied and the urge for rapidly delivered toxicological information may induce a tendency to be satisfied with insufficient and superficial experiment. More over, the toxicological data must be combined with the manner of use of materials, the place of use and the working conditions in order to enable a reasonable course to be steered in the factory. 30 M. W. O O L D D L A T T A bove all, the hazard of applying data from animal experi ment to men must be reduced to a minimum. This hazard is variable and should induce a respect for Dclloc's bright couplet: Let us never, never doubt What nobody is sure about. REFERENCES A n nu al Report o f C h ie f Inspector o f Factories, 1953. H .M .S .O . C ase, R . A . M ., M cD onald, D. B. anti Pearson, J oan T . (1954). Bril. J . indtutr. Mid. 1 1 , 75. Chemical Trade Journal (1956). 138, 144. C onant.J . B. (1951), Science and Common Strut. Oxford University Press. C ook, W . A . (1945)\Iad. Mid. 14 , 936. E in s t b in , A . (193B). Address to Student Body, California Institute o f Technology. E lk in s, H . B. {19 4 2 }.^ . iWwlr. Hyg. *4 , 233. F RANT, R . and W esteWdorp, J . (1950). Arch, indtutr. Hyg. 1, 308. F ullerton, J. M . (195a). Bril. mid. J . il, 117. G old Bl a t t , M . W. ( >954)- Proc. B ril. occ. H ilft. Soc. G o l d b l a t t , M . W . (1955). Brit. J . ind. Med. 13, 1. C randjean, E., MDncihhqer, R ., T urrlan, V ., Haas, P. A ., K noepfel, M. K . and R osenuund, H . (1955). Brit. J . indtutr. Med. 13, 131. I U nion, A . F., S omerville, A . R-, Farquharson, M uriel E. and C old- b l a t t , M . W . (1954). Biochem. J . 58 , 383. M a r k o w e , M . and B ar b e r , L. E. D . (195a). B r il.J . indoelr. Med. 9, a a t. M urray, S inclair, R. H. (M19. 5(51)9.5B6r)i.t.LJa.ncientd, t1u, t3r.8M1. ed. 13. 33 t. S mith, J . H . F. (Jan. 1956). Joint meeting o f the Institution of C hem ical Engineers and the Chemical Engineering Group, Society of Chem ical Industry. S u Y n r, H . F., S m y t h , H. F .,J r, and C arpen te r, C. P. (1936). J . indtutr. Hyg. 1 8 , 277. S t e w a r t , A . and W r m , L .J . (1944). Brit. J . induslr. Med. r, 11. XVI The Nutrition of Micro-Organisms W. F. J. C U T H B E R T S O N E ffect or P hysiological S t a t e an d Environment on N utrjent N eeds l living organisms require water, an assimilable source o f energy and sources o f organic compounds and of minerals for growth. Most investigations into the nutrient needs o f micro-organisms have been concerned with requirements for growth and reproduction, i.c. completion o f the whole life cycle, but it is important to remember that the needs may often vary with physiological state and metabolic activity; e.g. the requirements o f the germinating spore differ from those oT the vegetative phase. Similarly the medium constituents necessary for most rapid growth of Pnicillium species can be very dif ferent from those that may stimulate the productive organism to maximum penicillin production. Environmental factors, such as light, temperature, osmotic pressure, pH, redox potential and oxygen supply, are frequently important not only for growth rate but also for nutrient needs. For instance the absence of light may drastically modify the requirements o f photsynthetic organisms, oxygenation may modify vitamin B ,, requirements and changes in temperature can abolish the adenine dependence o f certain mutant strains of Neurospora. U tility of N utritional Studies Knowledge o f the requirements o f micro-organisms simplifies their maintenance in controlled populations under precisely defined conditions. At the same time nutritional information