Document VJda3GDEXjq2pN7qzk3gqw48

ol. 12 No. 1 JANUARY, 1955 .BRITISH JOURNAL F INDUSTRIAL MEDICINE EDITOR RICHARD SCHILLING ASSISTANT EDITORS J. C. GILSON L. G. NORMAN EDITORIAL COMMITTEE J. M. Barnes Sir Frjederic Bartlett Thomas Bedford G. R. Cameron C. M. Fletcher M. W. Goldblatt A. Bradford Hill T. G. Faulkner Hudsoi Donald Hunter R. E Lane A. Mexklejohn J. N. Morris J. R. Squire Editor, British Medical Journal /H&i1 U) W3 CONTENTS PAGE . ' Research in Industrial Health in the Chemical Industry. M. W. Goldblatt .. ................. Manganese Poisoning in Moroccan Miners. J. Rodder .. Dermatoses in Jute Workers. John Kinnear, John Rogers, Owen A. Finn, and .. Alexander Mair ................................ ................................................ ............................. .. Talcosis of Unusually Rapid Development. G.P. Auvisatos, A. E. Pontikaxs, ancf B.Terzis .. .. .: .............................. .. ............................................................................. Injury to. the. Respiratory Tract by Isocyanates .Used in Making Lacquers. Ajce Swensson, Carl-Eric Holmqujst, and Karl-David Lundgren ................................ Dimethyl Sulphate Poisoning. T. R. Littler and R. B. McConnell .............................................T" Vanadium Poisoning from Gas Turbines. R. C. Browne - The Toxicity of Ozone in the Presence of Oxides of Nitrogen. W. M. Diggle and J. C. Gage The Construction of Critical Orifices Working with Small Pressure Differences and Their Use in Controlling Airflow. H. A. Druett .. ............................................................... Miscellanea ' The Health Hazards of the Senior Executire. A. R. Cooper................................................. The Health of the Industrial Worker in Iraq. A. Michael Qutchley ................................ Book Reviews ...................................................... Abstracts .......................... - ........................... ........................ 65#--25^2^ 71 73 76 78 : , LONDON BRITISH MEDICAL ASSOCIATION TAVISTOCK SQUARE, W.C.l early Subscription (4 Numbers) 2 2s. U.SA. $7.00 Single Number 12/6 Bri:. J. industr. Med., 1955. 12, 1 RESEARCH IN INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY * BY M. W. GOLDBLATT From the Imperial Chemical Industries, Ltd., Industrial H)-giene Research Laboratories, Welwyn. Herts original.contributions in os for book reviews and ling, Nuffield Department ark Place, Manchester 13. his Journal, and that they e paper only, with double i of x-ray-illustrations is hs and photomicrographs ^ycompanying papers jmooth, white paper, ghtiy inserted in pencil, ok is referred to, the place of publication must follow small letter (a, b, c) after ion references are arranged ven as foLlows : Author's , abbreviated according to numerals), and first page it verbal corrections have per sheet of sixteen pages will be responsible for any s. A limited number of lrning proofs. An estimate 1 Association. . mol of Industrial Medicine dsement Manager, British Jritish Medical Association j * The satisfaction I feel at the opportunity afforded The coming of the second world war gave an me to add my homage to that of old colleagues who impetus to industrial medicine in this country and in have preceded me in the commemoration of James many others for which the workers may be thankful. Mackenzie and his work is of a special kind. Practitioners now visit factories, join in lectures and Mackenzie was a man with a mission. He also had discussions, avail themselves of services provided by u vocation, and his life was rich in worth. If James industry in the factories, and exchange information Mackenzie sought to bring what might be called with the industrial doctor. To-day the stage of " physical " light to the dark and sick lives of the exhortation is almost over. industrial workers of his time, he brought much James Mackenzie died in 1944, his society having spiritual light also. To have enlisted the cooperation been wound up at the beginning of the war, but he of some of the most notable and busy men in public must have seen the movement towards more and health and medicine through his Industrial Health more social realization of responsibility for the Education Society required qualities which, when health of the nation in a sense more profound than they impinge on other men's minds, raise them to it had ever been. My own satisfaction in paying my heights they would never wish to leave. These tribute to Mackenzie consists in the knowledge that qualities of Mackenzie are those which every medical after following with so many of my friends his path 'nicer in industry requires. The workers and staff of an industry are in a real sense the flock of the industrial doctor, and he should be as preoccupied about their physical and mental well-being as the parson is presumed to be about the spiritual life of his flock. His factory is his industrial health education society, but there the people to be in the health education of the worker and his employer I was put in charge of the first industrial hygiene laboratories established by industry in this country, a tangible proof of the awakened realization among industrialists that industrial health is not a question of policy, but one of science, of conscience, and of civility. taught are not only the workers but the employers also. Thirty years ago, when James Mackenzie was founding his society, industrial medicine was in the >;age of exhortation. The workman was suspicious of the " compo " doctor; the employer might employ a doctor to examine new entrants, for firstaid services, and in compensation cases. Many doctors thus appointed were not permitted to enter the factories at all. The health and well-being of a worker were then of consideration only as they might affect the employer's interests. Then, as now, the appointment of an industrial medical officer and what he was asked to do lay with the employer. Maximum Allowable Concentration of Atmospheric Contaminants in the Working Environment For an industrial environment where harmful elements, compounds, or radiations are known to be actually or potentially present, it has become customary to prescribe an allowable concentration of dust, gas, fume, or vapour which must not be exceeded if an assurance is sought that men and women may work in that environment without harm. Perhaps more customary in the U.S.A. than in Britain, the term " maximum allowable concentra tion " (or variants of it) is becoming more familiar here also. It may be recalled that the conception was foreshadowed in this country by Thomas Legge * The Mackenzie Industrial Health Lecture delivered in Manchester "1 July II. J954. at the Annuel Provincial Meeting of the Association InUustnaJ Medical Officers. some 45 years ago when he (and Duckering) gave 5 mg./lO cm. as the atmospheric concentration oi 1 BRITISH JOURNAL OF INDUSTRIAL MEDICINE lead in which engineers and chemists might work. of a hazard with a value or a zone of values is By prescribing a maximum intake of lead, however, desirable to supplement the picture already in his there is the implication that the harder a man works mind of one or more features of the effects of the in the atmosphere containing lead, the shorter time compounds. Non-medical personnel, however, are he should be permitted to do so. Thus, merely to not as a rule in the same position. They are likely give a maximum permissible concentration without to use, and in fact do use, phrases such as " Arsine-- giving the severity of the work and the time engaged oh yes, about as toxic as bromine, isn't it ? ", or, per day in such work, leaves one entirely in the dark " Tetrachloroethane--yes, yes, quite troublesome-- as to what a man is absorbing. Lane (1949) and about as bad as hydrochloric acid ", because, in fact, Kehoe (1949) substantially agree that at 1-5 to their maximum allowable concentration values are 2 mg./'lO cm. " cases of disabling lead intoxication identical, but, it must be noted, for very different do not occur among men who work regularly in such reasons. Toxic hazards should, in general, be con workrooms, and cases of questionable or mild sidered as identities with their own numerical data intoxications are rare ". attached to them and their own effects attached to But Lane is not slavishly attached to this maximum the numerical data. allowable concentration and insists (/or. cit.) that the Hazards may have to be classified into groups lot final test must be the effect on the workmen and, by convenience or as aids to memory, but this must be implication, that mere analysis of the atmosphere is on the basis of similarity of toxic effects and not on not enough. This statement is of great general the fortuitous closeness of maximum allowable significance and may be considered in conjunction concentrations. with the views of Cook (1945), one of the distin The fact that both HC1 and HCN are in the same guished workers in the field of maximum allowable Drinker and Cook zone (2-20 p.p.m.) as aniline, concentrations. Cook says: acetic acid, and acrylonitrile tells us nothing of their " It is to be emphasized that the intent in presenting the maximum allowable concentrations is to provide a handy yardstick to be used as guidance for the routine industrial control of these health hazards--not that compliance with the figures listed would guarantee protection against ill-health- on the part of exposed workers, nor should the maintenance of the suggested concentrations be considered a substitute for medical control." The use of the words " suggested concentration " is a sufficient indication that the conception is not precise. Drinker and Cook (1949) in a later contribution emphasized, by implication, the imprecise nature of effects or relative dangers. This is even more strongly illustrated in the highly dangerous zone 0-1-2 p.p.m. DRINKER AND COOK ZONES (EXPANDED) 0-1 p.p.m. 0-3 p.p.m. 1 -0 p.p.m. 2-0 p.p.m. Hydrogen Anine selemdc Bromine Iodine Cyanogen chloride Stibine Ethyleneglycol dinitraie Phosgene Phosphorus tri chloride Keiene Nitroglycerine Chlorine | ^Chlor aniline Hydrazoic : p-Chlor-nitrobenzene acid Ethylene chlorobydnn Hydrogen fluoride these concentrations when they proposed a zoning system, whereby, it was stated, the toxicity of an N.B.--HCN 10 p.p.m. industrial atmospheric contaminant could be quickly In this table we have some of the most fulminating assessed from the zone in which it falls. Six zones poisons met with in industry, and it would be in the were given as follows : highest degree undesirable to bracket them together 500- 2.000 p.p.m. 100- 300 p.p.m. 20- 100 p.p.m. 2_ 20 p.p.m. 0*1 - 2 p.p.m. 0t acetone, petrol, ether methanol, toluene bensene, butanol. CCI. CO .. H,S.CS,.C,H,CI,.HC1. HCN .. Ct.COClf.AH,.tCH,)^0, in any sense whatever. For, whereas some of the limits set are those for immediate irritation, others are for delayed effects, and others again for cumu lative effects. Some appear because of their effects They added : " The zoning scheme is for the classification of information and not for the justifi cation of excessive exposure or misguided legal on the circulatory mechanics ; others because of the effects of their metabolic products on haemoglobin : still others because they cause a dangerous increase interpretation." of the permeability of the pulmonary vessels ; and Tables of maximum allowable concentrations must others because of disruptive effects on the envelope not evoke responses which are entirely unjustified of the blood corpuscles. and even dangerous. Classification in zones cannot So diverse a picture demands different degrees of fail to influence non-medical personnel by suggesting urgency in persons whose responsibility it is to similar toxicities of substances, the effects of which prevent, concentrations above those prescribed. are entirely different. For a doctor the association Moreover, the sense of urgency must clearly depend INDUI also on the physical pio involved. Everyone cone scious of clinical urgencyurgency. The state of mi approach to environme: implied in the table of c my laboratories (Table 1 The actual values givei in the light of experienc emerged from a searchi and experimental records likely. Still, some have example, in the case / ammonia, ethanol. The first three column: by certain concentration.' dangerous symptoms ; ' concentrations which a. two columns give concer limit to satisfactory co particular substance (de: The use of the wo concentration " has bee we hold that no concer are worse than others b Animal For industrial toxicolc to use animals in exper conditions. Most ind result of absorption by much more rarely by in most, acute and chronic. Very little is known of substance thus absorbec Factors of safety rr,. animal experiments ar depending upon man' upon his greater activity can be made of the amc absorbed by men at w environmental conditic estimated by exposing estimate. Since the m many times greater tha fume concentrations a without adverse effects as equally inoffensive V concerned. Cutaneous absorpti great importance in t and in the field use of and herbicides. Quantitative measur neous absorption in t 'NE INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 3 ue or a zone of values is the picture already in his atures of the effects of th^ ;al personnel, however, are : position. They are like!) . phrases such as " Arsine-- is bromine, isn't it ? ", or s, yes, quite troublesome-- oric acid ", because, in factj ie concentration values are e noted^ for very different should, in general, be coni their own numerical data leir own effects attached to be classified into groups for o memory, but this must be / of toxic effects and not on s of maximum allowable 31 and HCN are in the same e (2-20 p-.p.m.) as aniline, tril^ells us nothing of thein This is even more Ighly dangerous zone OK ZONES (EXPANDED) l -0 p.p.m. Chlorine Hvdraxoic acid Z 0 p.p.m. ^-Chlor aniline />-Chlor-mtro6enzene Ethvicne chlorohvorm Hydrogen fluoride HCN 10 p.p.m. some of the most fulminating ustry, and it would be in thq b!e to bracket them togethei For, whereas some of the immediate irritation, others and others again for cumuspear because of their effects lanics ; others because of the ic products on haemoglobin j y cause a dangerous increase the pulmonary vessels; and jptive effects on the envelope demands different degrees ol vho* responsibility it is to '*"%ve those prescribed Mcy must clearly depenc also on the physical properties of the compounds involved. Everyone concerned must be made con scious of clinical urgency as well as of quantitative urgency. The state of mind which informs our own approach to environmental contaminants is that implied in the table of concentrations issued from my laboratories (Table 1). The actual values given may require modification i:i the light of experience, but as each figure has emerged from a searching examination of clinical md experimental records, great modifications are not likely. Still, some have already been made ; for example, in the case of formaldehyde, acetone, ammonia, ethanol. The first three columns indicate the times required by certain concentrations to produce very severe and dangerous symptoms ; the next two columns give concentrations which are not tolerated ; the last two columns give concentrations which set an upper limit to satisfactory conditions in respect of the .'.'.rticular substance (design concentrations). The use of the words " maximum allowable concentration " has been avoided because at l.C.I. e hold that no concentration is allowable. Some are worse than others but all are bad. Animal Experiment For industrial toxicological purposes it is important to use animals in experiments simulating industrial conditions. Most industrial poisonings are the result of absorption by inhalation or by the skin, ."uch more rarely by ingestion and by the eyes, and most, acute and chronic, are to mixtures of substances. Very little is known of the adjuvant effects of one substance thus absorbed on the toxic effects of others. Factors of safety must be assumed if results of animal experiments are applied to man, factors depending upon man's greater susceptibility and upon his greater activity during work. If an estimate can be made of the amount of a toxic substance daily absorbed by men at work, the acceptability of the environmental conditions in which it occurs can be citimated by exposing animals to multiples of that estimate. Since the metabolism of small animals is many times greater than that of man, gas, vapour, or fume concentrations at which animals can subsist without adverse effects may be reasonably regarded as equally inoffensive to man as far as overt signs are concerned. Cutaneous absorption of toxic materials is of great importance in the organic chemical industry and in the field use of toxic insecticides, fungicides, and herbicides. Quantitative measurement of the degree of cuta neous absorption in animals is difficult, but com parative measurements can be made with small animals by time measurements from the onset of symptoms to death, or to measurable biochemical effects after immersion of anatomical appendages, such as paws or tails, in known concentrations of the compounds studied. Many substances are more toxic cutaneously than orally. The demonstration of dermatitic effects in animals which do not perspire in any sense similar to that seen in man is usually impossible although an urticaria-like reaction is sometimes seen. The phenomena of " contact dermatitis ", " sensitization dermatitis ", " allergic dermatitis ", or " eczema " are not reproducible in animals in experimental conditions. Complicated immunological demon strations that some chemical compounds can act in appropriate conditions as skin allergens are possible and such demonstrations have corresponded with the known properties of some organic compounds. Erythema and oedema should be measured according to determined scales (Draize, Woodard, and Calvery, 1944). The skin of laboratory animals does not respond as does human skin to the host of chemical substances which induce dermatitis of the acute variety so frequently seen in industrial conditions. In the case of cutaneous cancer the correspondence is closer. Thus, animal experiment is largely directed to finding whether given chemical com pounds induce direct irritant effects on the skin. Physiological effects (on the circulation, respira tion, blood pigments, tissue and blood enzymes, renal and hepatic function, groxvth. fertility, central nervous system), in the sense of reversible effects, can be demonstrated by animal experiment with relative ease, and the results in some cases applied to the clinical control of hazards in the factory. Contact dermatitis in man disappears on removal from exposure, but the effect is not truly reversible. A fall in blood pressure, readily demonstrable in animals, is used by some American authorities as a clinical-statistical index of undue absorption of many toxic organic compounds. There are some explosive compounds (made and used both here and in other countries) which are rapidly hypotensive in working conditions: blood pressure determinations are essential for proper medical control in these cases, especially as pseudo-anginal attacks may follow long-term exposure. Many industrial compounds can be shown experimentally to depress the heart, dilate the peripheral vessels, or increase vascular permeability. Others, by. cholinesterase inhibition, lead to parasympathetic stimulation and vagal effects on the heart. The question of the establishment of hypertension, perhaps of renal origin, in chronic lead absorption is not resolved. BRITISH JOURNAL OF INDUSTRIAL MEDICINE Table 1 toxic concentrations of various gases, dusts, fumes, and metals in the atmosphere (I.C.I. Industrial Products and Health Research Committee) No. Gas 0) Concentrations Causing Severe Toxic Effects in Persons (2) Concentrations which, if Exposure Continues Exposed for the Stated Times for more than a Short Time, may Lead to Symptoms of illness -J. i (rngwcu.* Time of (p.p.m. metre Exposure (p.p.m. (mg./cu.* metre vv) I 20*C.) (Min.) v,v) 20*C.) Concentration in General Atmosphere of Plan/ Greater than those belo* Indicate Unsatisfactory Conditions 1 I Acetaldehyde 2 Acetic acid 3 Acetone 4 Acetone cyanohydrin 5 Aoetortyl acetone .. 6 | Acetophenone 7 Acetyl chloride 8 Acrolein 9 Acrylonitrile 10 Ally! alcohol II Allyl chloride .12 Ammonia .. 13 iso Amyl acetate .. 14 iso Amyl alcohol .. 15 Aniline Id Arcton 6 (Freon 12) (Difluorodtehloromethane) 17 Arsine .......................... II Benzene (Benzol) .. 19 Benzine (as Hexane) 20 Benzyl acetate 21 Benzyl chloride Bromine Butadiene .. -Buunoi (Butyl alcohol > 2-Butanone (Methyl ethv| ketone 25 *-Bufyi acetate 26 "Butyl methacrylate 27 21 Carbon dioxide Carbon disulphide.. 29 Carbon monoxide.. 30 Carbon tetrachloride 1,000 200 I 1.830 500 4,000 9.650 40 140 300 1.424 80 400 10 33 20 46 100 , 220 40 j 96 60 60 60 1 60 60 I l 1 1 200 500 1,000 400 80 ' , ! 656 555 5,410 1.464 312 ! 1 60 1 60 60 60 50.000 10 1.500 5,000 100 : 251.700 52 4,800 10,728 , 616 i : ' 60 1 60 60 60 20 J00 l 5 20 l l.uOO 17.968 60 1.000 5.080 60 See No. 90 Methvi ethvl ketone 2.000 9.650 60 800 4.724 60 , 50.000 54,950 1 60 500 1.600 60 400 464 60 I 2.000 12.800 i 60 500 40 600 20 150 40 2 8 ! 50 1 20 1 100 ! 200 500 , 200 1 20 | 20.000 11 500 1.000 1 50 10 11 5.000 100 500 400 ; 10,000 150 1 100 1 500 9(5 500 506 100 20 50 1.930 70 712 200 6-6 400 10 n 20 1 964 45 J5C 300 33 18-6 ! 1 no I 1 20 5 I " 1 518 142 1.625 ! 752 i 7` 1100,680 5-2 : 1.600 3,576 : 313 1 ** j 200 1 100 1 200 I 10 ! j,m 1 1 50 250 35 359 72 HI j 360 !" ! 50,340 16 160 S94 94 >' 50 6-6 1 1U50 i 508 5 05 :,x>o 50 25 3- i.Sli 154 | 2.412 2J62 18.510 i 480 tl6 : 5.200 200 SO# s.m in 50 50 965 2,131 9,155 3! 53 320 31 pOrioranilinc 32 (mono) Chlorobenzene 3354 2-Chlorobuudicne Chlorine 35 P-Chloronitrobenzene 36 Chloroform 37 io 4c (i*l (mono) Chlorofol 36 Cyanogen chloride 39 Cyclohexane 40 CycJohcxanol 41 Cyclohexanone 42 Cydohexytaminc .. 43 o-Dtchlorobenxcnc 44 &'DichJorodietbyl ether 4454 In* it irons) Dichloroeth lene Dtcydohexylamine 47 Diethyl carbonate 46 Di-isobutylene 49 Di-oobutyl ketone 50 Dimethyl dioxane .. 8 44 1i 4 400 1.872 60 200 956 100 > 368 1 50 184 10 29 1 4 12 10 1 66 1 4 26 2.000 9.960 60 500 2.490 400 < 2,106 60 200 1,055 ' si 13 1, 2 5-2 i J-000 6.990 | 60 800 i 2.796 I 1,000 | 4.160 60 , 400 ' 1.664 a 75 25 2 J 3* 7* 05 400 100 1.000 100 500 100 2,000 50 800 4.000 400 500 4.080 410 1.856 595 6,072 388 5.928 18.640 1.896 2.412 > I | 1 | 1 1 1 60 1 60 60 60 60 60 60 60 200 40 100 30 1.000 40 400 2.000 200 500 ; 816 164 612 i 178 : 4.056 1 502 1 1,964 1 9.520 948 1,447 Z5 2 25 15 500 2U 200 ' 1,000 100 1 200 21 341 92 *9 C-C 249 395 13 I.J9S 410 300 32 153 39 2,015 151 9S2 4,000 474 90S 51 Dimethyl sulphate., 52 Dioxane 53 Ethanol (Ethyl alcohol) 54 | Ether (diEthyO 55 h-Ethoxycihyl methacrylat 56 j Ethyl acetate 57 : Ethyl aoetoacetate.. 58 Ethyl benzoate 59 { Ethyl bromide 60 | Ethyl ehloride 15 500 8.000 8.000 500 2.000 200 200 250 10.000 78 1.830 15.312 24.624 3.285 7.320 1.080 1.248 1.135 26.830 1 10 52 26 60 300 1.096 200 732 60 2,000 3.828 2,000 1,934 60 2.000 6.156 ; soo 1,539 60 200 1,314 100 657 60 800 2.928 : 400 . 2,464 60 60 100 100 540 624 50 270 5tt 322 60 100 454 50 227 60 5.000 13.415 i 2,000 5J6C 61 Ethylene chtorhydrin 62 Ethylene dichloride 63 Ethylene glycol dinitrate 20 1 68 500 1 *2.050 | 20 1 128 ! 60 -! 10 j 34 60 too 1 410 60 , 1 ! 6*4 i m 50 * , 205 J? Concentrations shown in italic arc tentative and are become available. * I mg./cu. as a guide. Figures in all columns will be subject to review as move data 4-37 x I0*4grains/cu. ft. Continued INDUS! Gas 64 Ethylene oxide 65 66 Ethyl formate Ethylidene dichlonde 67 Ethyl silicate Formaldehyde 69 Hvdraxoic acid 70 ! Hydrogen chloride 71 Hydrogen cyanide. . T" Hydrogen fluoride.. 73 H'drogen selenide. . 74 : H'drogen sulphide Iodine 76 ! lsophorone.. 77 Ketene 78 . Laurvi mercapun .. 79 Mesitvl oxide 80 Methacrolein II Methacrylic acid .. 82 MethaJlyl alcohol .. 65 Methanol (Methyl alcohol IU Methyl acetate 85 Methyl acrylate 86 Methyl bromide 87 Methyl rj^butyl ketone . 88 i Methyl a-chlormcryiate 89 : Methyl chlonde 90 Methyl ethyl ketone (2-Bu 91 Methyl iodide 92 Methyl cyclohexanone 93 Methylene chloride *4 Methyl formate 95 Methyl methacrylate 96 Naphtha distillate (as Cur 97 Nickel carbonyl 98 Nitrobenzene 99 Nitrocthanc 100 Nitrous fumes (as NO,l 101 ! Nitroglycerine 102 I Nttromethane 103 1 1-Nitropropanc 104 ! 2-Nitropropane 105 i o-Nitrotoluenc 106 I Perchlorocthylene (Tetr. 107 , ~Propiolactone 108 uo-Propyl alcohol.. 109 ! Phosgene 110 ' Phosphorus trichloride til Stibine 112 ! Styrene 113 ! Sulphur dioxide 1U , SuJpbur monochloride (l !2 i Sulphury! chloride.. 116 * Tetrachlorethanc .. Tetrechloroethylene (P117 Thionyl chloride .. 118 j Thiophosphoryl trichlor 119 i Trichloroethylene.. 120 I Toluene (Toiuol) .. 121 <o. m, 4: p) Toluidines 122 Vinyl chloride 123 Xylenes (Xylols) .. 124 Xylidines 125 ' Antimony (dust or salt: -126 Anenious oxide 127 1 Banum saJu (as Ba) Concentrations shown in u. available. WE INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY IN THE ATMOSPHERE I <:> V which. I Concentrations in Tonunucs General Atmosphere i a Short I of P/ant Greater than Lead to those beio** u of indicate Unsatisfactory 1 Conditions mg. ,cu.* metre 20*0 . {.p.pjn. v r) 915 too 1,930 70 713 200 &i 116 110 .no 20 400 to 20 .i 5 10 i 318 142 1.623 733 78 so 100 m 100 10 (mr.jcu.' metre \ xrc.) 366 SO 90S -JS 330 100 33 u-c 44 12 i 139 71 341 360 ' 30 X.680 3-3 1.600 111,000 0-) SO 2SO IS : 40.340 1*1 260 394 94 . j*6 11.230 308 4 0-3 2,300 so 23 3-3 3,613 134 2.412 2.362 18.3)0 480 116 3.200 936 184 12 26 2.490 1.053 52 2,796 1.664 200 200 SM0 10 40 SO j 74 23 1 l SO 73 if.; 400 100 963 1.131 v.iss 32 S3 320 11 331 02 29 h-6 249 393 1-3 1.39.y 416 1 816 164 612 178 4.036 302 1.964 9.320 948 1.447 74 20 24 IS SOU 20 200 1,000 100 200 son 32 133 30 -.013 131 932 4,660 474 963 . 52 1.098 3.838 6.156 1.314 2.923 540 624 454 13.415 4 20*1 1 tQOO 300 100 400 SO SO SO 2.000 26 732 1.31S 1,330 637 2,464 270 312 3,366 34 410 a i SO 04 7 203 32 :t to review as more data Continued Table { continued ^ (I) Concemntions Causing Severe Toxic Effects in Fenons Exposed for the Stated Times I n (2) [ Concentrations, which. : if Exposure Continues 1 for more than a Short Concentrations in General Atmosphere of Plant Greater than I Time, may Lead to those below Gas Symptoms of Indicate Unsatisfactory Illness Conditions f* "0 ?6 T7 78 79 <0 $4 si 86 87 St 89 90 91 92 9934 95 a6t Vo9 100 101 102 103 104 105 106 107 108 109 110 Ml 112 113 114 115 116 117 lit 119 120 nr 122 123 124 Ethylene oxide Ethyl formate Eihylidene dichlonde Ethyl silicate Formaldehyde Freon 12 (Arcton 6) H ydraxoic acid Hydrogen chloride Hydrogen cyanide.. Hydrogen Ruoridc.. Hydrogen seienide.. Hydrogen sulphide Iodine tsophorone.. Ketene Lauryl mercaptan .. Mesityl oxide Ntethacrolem Methaerytic acid .. Methallyl alcohol .. Methanol (Methyl alcohol) Methyl acetate Methyl acrylate Methyl bromide Methyl iso-butyl ketone Methyl s-chloracrylate Methyl chloride Methyl ethyl ketone (2-Butanone Methyl iodide Methyl cyclohexanone Methylene chlonde Methyl formate ,. Methyl methacrylate Naphtha distillate (as Cumene) . Nickel carbonyl .. Nitrobenzene Nitrocthane Nitrous fumes (as NO a) .. Nitroglycerine Nitromcthane 1-Nitropropane 2-Nttropropane o-Nitrotolucne ........................... Perchloroethyiene (Tetrachlorocthylenc) 2-Propiolactone Iso-Propyl alcohol.. Phosgene ....................................... Phosphorus trichloride Stibinc -Styrene Sulphur dioxide........................... Sulphur monochloride (StC]f) .. Sulphury! chloride........................... Tctnchlorethane........................... Tctrachloroethykae (Perehloroctbylcnc) Thionyl chloride........................... Thiophotphoryl trichloride Trichloroethylene........................... Toluene (Toluol)........................... (o, m. k p) Tolutdincs Vinyl chloride Xylenes (Xylols) .. Xylidincs (p.p.m. V/V) (mg./cu.* metre 20*C.) Time of Exposure (Min.) 250 450 60 1.000 3.080 1 60 400 1.648 60 400 3.464 60 . 100 120 l ! See No. 16 Arcton 6. 10 i 18 i 40 1 50 75 ; i 40 ` 40 200 ! 0-5 40 20 | 200 1 10 44 ! 34 1 | 6 280 5-5 1 1, 1 1 228 3-6 1 60 t 168 | 816 I 1 | 29 1 11 1,000 ISO 2.000 500 100 250 1.000 4 1,500 2,000 ! ` < ' 1 3.575 650 2460 U40 356 1.000 4.160 . 20 3.150 5490 * ! 1 < i ; 1 1 1 60 60 1 1 60 1 60 60 40 300 2.000 1.000 3,000 300 4 200 800 100 236 1.400 7.072 2.495 12.480 1.500 21 1.020 2,496 190 I ` 1 ! i 1 : 1 20 800 400 400 200 1,000 100 2.000 3 2 1 , | 189 2.028 1.480 1,480 1.140 6,905 300 *.995 21 12 1 ! 1 1 1 1 60 60 60 60 60 l 60 60 1 60 60 60 60 <0 60 1 60 1 1 0*5 2*5 1.000 i 4.330 200 520 20 112 10 I 50 56 350 I _ See No. 106 Perchloroethylen*. 20 ; 100 | i 10 ! 70 ! | 2.000 | 10.940 I 40 1.000 ; 3430 40 1 > ! 1 | 1 l j 1 j ! 1 40 3.000 1.000 40 ; 176 7,800 4,410 200 <0 i 60 60 60 (p.p.m v/v) 100 400 200 300 30 4 20 20 10 0*5 50 0*2 20 1 10 100 J 400 100 500 200 50 50 400 2 500 500 20 150 2,000 400 2.000 150V 40 500 30 1 500 200 200 40 400 20 800 i ' 0*2 200 20 10 4 20 10 4 800 300 10 1400 300 10 (mg..cu.* | imetre i 20*C.) 180 I 1432 824 1,732 36 7-2 i 30 ! 85 ! 1-3 i 70 1 2-2 114 1-8 1 1 84 41038 i! ' 1.430 300 640 616 . 178 200 ! 1,664 10 || 118 700 3436 998 8.320 750 14 204 1,560 57 1! * 1 1 9*4 : 1.268 740 1 740 228 2,762 i 60 j > 1,998 4-2 i 5-8 | 866 i 32 56 22 140 50 28 4476 1.149 44 3.900 423 50 (p.p.m. r, r) It) 200 SO 100 It) 1 10 JO o-l 20 0-1 JO o-s 3 so 200 30 200 100 IS 20 200 1 100 200 7150 500 200 1,000 so J 1 200 10 200 101) 100 1 200 10 400 0-5 os 0-1 100 10 5 1 10 s 1 400 100 s 500 100 3 (mry. . metre 20'C.) JS HUi son sun 12 /; 11 J-7 03 23 11 S7 o-o 42 204 5-6 713 ISO 256 301 39 so 332 4 220 599 so 1 3S0 > 1,763 i 499 4,160 230 ! *9 4-7 * 407 370 370 ! 5-7 I 1,331 I 30 ; 909 21 | ! 433 ' 1 IS 1 23 ! 3-6 TO ! 23 17 i 2,133 333 40 1,300 441 25 Dusts, Fumes, and Metals Antimony (dust or salts) (as Sb).. j- Anenious oxide 1.7 Barium salts (as Ba) Concemntions shown in italic are tentative and are issued as a guide. Fn ocomc available. l mg./cu. metre m 4*37 x 10-4 OS OS I OS in all columns will be subject to review as more data >/OL ft. Continued 6 BRITISH JOURNAL OF INDUSTRIAL MEDICINE Table 1 continued No. Gas 128 Benudme 129 Cadmium.......................... 130 Chlorinated diphenyl 131 Chlorinated naphthalenes 132 Chromates (as CrO,) 133 Dmjirocrrsol (and salts) 1> Dinitrophenol (and salts).. 135 Dmiiroresorcinol .. 136 Dimtrotoluene 137 ** Dowthem A " 13 Lead (and salts) 139 Mercurv........................... 140 s*Naphihylamine .. ML h-Naphthylamine .. M2 Pamhion " M3 Pentachiorpheno! .. 144 p-Phenylene diamine 145 Phosphorus pcnucbloridc 146 Potassium permanganic 147 Sulphuric acid 148 Sodium cyanide 149 Tetr>l ........................... 150 T.N.T.................................... 131 Zinc oxide .. i (I> Concentrations Causing Severe Toxic Effects in Persons Exposed for the Stated Times 1 I ! (p.pjn. i V*V) 1 -- -- -- .. i _ _ __ 1 _ - __ -- -- _ _ i-- _ (mg.,cu." metre 20*C.) Time of Exposure (Min.) _ ---- ---- __ __ ---- ---- ---- ---- ---- -- ------ -- - _ __ '-- ---- ---- ---- ---- __-- -- -- ---- ---- _-- (2) Concentrations which, if Exposure Continues for more than a Short Time, may Lead to Symptoms of illness ' (mt/cu.* (p.p.m. , metre V.v) ! 20*C) __ 1 -- -- ---- __ -- ---- ---- ---- ---- ---- ---- ---- -- --- ---- ---- ---- ---- -- ( ------ ---- ---- ---- ---- ---- (J) Concentrations in General Atmosphere of Plant Greater than those below Indicate Unsatisfactory Conditions (f.fjn. rlr) -- -- __ -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- 1 (mg.lcu.* , metre \ SO'C.) 0012 0-2 ;/ I2 O'l ) OS 11 j 11 \ IS 1 0-12 0-1 ! 0-01 O'Ol 3 65 61 J 2 1 *, \ Is 10 Concentrations shown in italic are tentative and are issued as a guide. Figures in ail columns will be subject to review as more data become available. *1 mg./cu. metre m 4-37 x I0-4 grains/cu. ft. Changes in respiration and the respiratory system are usually secondary to irritation of the respiratory tract, to changes in blood pigment, to central depres sion, and to direct damage of the alveolar network. Less direct effects are produced by cholinesterase inhibitors, which lead to powerful parasympathetic stimulation, and by inhibitors of oxidative enzymes. The asthma-like attacks induced by some aromatic diamines and di-isocyanates are reversible. It is unusual for the lungs to be the seat of trans formation of compounds. But in the case of ethylene oxide, which has a wide application in the present-day chemical industry and in the fumigation, of food, combination with water in the lung can yield toxic glycols which may easily have long-term effects. Delayed effects on the lung itself (oedema, haemorrhage, emphysema) can be foreseen by animal experiment. Recent investigation in my laboratories of the notorious " nitrous fumes ", which have been responsible for many deaths from pulmonary oedema, shows that the potent agent is N.Oj and that N.O, is much less toxic as is also nitric acid vapour (Diggle and Gase, 1954). Any toxic dust is injurious to the lungs although the pneumoconioses, and in particular silicosis, are our most serious and extensive industrial pulmonary diseases. Fig. 1 shows a section of a lung of a rat which, with a group of other rats, was exposed for eight hours a day for many months to an atmosphere of 2 mg./cm. K.Cr04 as a very fine dust. The animals were well enough: there was a period of coughing and harsh breathing, but nothing serious. They lived on in quietude and sustained the chromate with bored fortitude but the lung shows large and small areas of exsanguinated alveoli crammed with loaded histiocytes in various stages of degeneration. Functionally these areas are out of action. The cell debris in the alveoli contributes further to loss of function until disposed of. Dilated respiratory bron chioles and some emphysema, due partly to the injurious effect of the chromate on the alveolar septa, and partly as compensation to the loaded alveoli, are also seen. Fig. 2 is a high-power picture of a portion of a guinea-pig's lung after exposure for months to a very high concentration of lead acetate (40-50 mg./cm.). The origin of the dust cells from the alveolar septal cells is clearly seen, but mono cytic cells undergoing hypertrophy from the capillary blood appear also to be passing into the alveoli. FiG. 2.-"Gumea*pii; tion of fine le: mononuclear pr alveolar wails, both tn the war alveoli and coin rial in the phago< 'E *hich. mues short i to f H) Concentrations in Central Atmosphere of Plant Greater than those belo<* Indicate Unsatisfactory Contritions cu. * etre ;C.) - - (p.p.m. r-v) -- (mg- cu* metre -'fl-C.J I ll i i s ec> c. sc tubjec: to review as more data sive industrial pulmonary 3f a lung of a rat which, :s, was exposed for eight nths to an atmosphere of. ry fine dust. The animals s a period of coughing and ig serious. They lived on the chromate with bored 'ws large and small areas crammed with loaded stages of degeneration, re out of action. The cell ributes further to loss of Dilated respiratory bronsema. due partly to the nate on the alveolar septa, on to the loaded alveoli, picture of a portion of a tposure for months to a of >ead acetate (40-50 thedust cells from the 1 seen, but mono- *y from the capillary \ pafsing into ihe alveoli. FiC. 2.--Guinea-pig lung after chronic inhala tion of fine lead acetate dust--origin of mononuclear phagocytes from blood and alveolar walls. Active phagocytosis seen both in the wall and in the lumen of the alveoli and coarse granular pigmented mate rial m the phagocytes. \ 300. FiC. 1.--Rat lung after chronic exposure to Ane potassium chro ::a:e -u>i . many areas of exsanguinated, function less alveoli nlled uh hi'tioc-' nc phagocytes and many ruptured alveoli. x 100. Fig. 2a.--Phagocytosis of blood phagoc'ies bv macrophages deriving from Seoul cells: details of coarse pigment granules in guineapig lung. .* 1200. INDUS Fig. 3.--Rabbit June showing chronic inhaiation of fine lead acetate dust. Three areas of same lung showing different stages in devetopmeet and death of lung phagocytes : small alveolus crammed with dead and dying phagocytes swollen with absorbed panicles; note mulunuclear macrophage. 560. These cells are laier engulfed by the macrophages developed from the septal cells after having acted as dust cells themselves. The macrophages are seen to contain dark pigmented granules and nuclei in various stages of degeneration (Fig. 2a). In Fig. 2a the extent of phagocytic activity is striking. In Fig. 3 we see the progressive changes from the well stained cell in the alveolar wall to the dead dust cells in the alveolar spaces. The effectiveness of the lung barrier to a toxic dust must depend upon the availability of phagocytes to act as a brake on absorption. At so high a concen tration as that used in these experiments blood cells evidently enter as an additional defence. The barrier to dusts presented by the lung is paid for in the case of toxic dusts by a denudation of the precursors of the so-called dust cells (/.?. modified septal cells) and in oxygen capacity by the occupation of alveolar spaces by highly charged cells and cell debris when the toxic material is discharged. The formation of giant multinudeate cells also occurs in the chronic inhalation of toxic dust (Fig. 3). In a universe of dust processes of this kind are inevitable but it is our business to combat industrial dust with other weapons than our lungs. Changes in blood pigments are mainly found in industry among those exposed to carbon monoxide, various aromatic nitro- and amino-compounds, and metallic elements which ir formation. These effects c with equal ease in all spec The deliberate inductior in the treatment of cyanic importance, and recover? been obtained by Lloyd F depends upon the intrav. nitrite which, by forming the circulating cyanide to toxic cyanmethaemoglobi injection of sodium thio the formation of thiocya liberated cyanide. Renal and hepatic fu: many chemical agents ; industrial metallic poison chlorinated aliphatic hyd vatives of glycols. Rev endangered for the chant structural breakdown is peculiar position of tri commonly used solvent subtle must be the mech low toxicity, which is p metabolism to the nor (Taylor, 1936 ; Powell, For certain metaboli carcinogenicity the use o and wider significance, one carbon C14 has r members of my depart: Amersham (Henson, 1` Somerville, 1953). We establish important met2 retention of compounds in the body (Henson, Sc Goldblatt, 1954). The toxic compounds in a histological sections is a The ultimate fate of industrial conditions is known about some of tl chemical substances are we are very rarely able t< or even extraordinary c ways in which comp!e> the body in large pai difficulties and appre! using labelled compoun in obtaining almost con and output of substanc and in discovering how derivatives are retainec *s possible to track the B INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 9 y 'ing different stages in deveJopmcar itb absorbed particles; note multi- lung is paid for in the case*, iation of the precursors ofl . modified septal cells) and! ie occupation of alveolar; cells and cell debris when! larged. The formation of j also occurs in the chronic! Fig. 3). In a universe of j I are inevitable but it is ourt lustrial dust with other icnts are mainly found in iosed to carbon monoxide, id yio-compounds, and j| metallic elements which interfere with haemoglobin they can take in the body and, if retained for long formation. These effects cannot all be demonstrated periods, to leant where they are deposited. uith equal ease in all species of laboratory animals. Industrial metabolic poisons interfering with phos- The deliberate induction of methaemoglobinaemia phorylating processes are dinitroorthocresol in the treatment of cyanide poisoning is of practical (D.N.O.C.), dinitrophenol (D.N.P.), and penta- importance, and recovery in very severe cases has chlorphenol, the former two being responsible for ten obtained by Lloyd Potter (1950). The method both clinical and industrial deaths, and the latter for depends upon the intravenous injection of sodium recent industrial deaths. Dinitro aromatic com nitrite which, by forming methaemoglobin, permits pounds require careful study as some may induce the circulating cyanide to react to form the much less cataract. Indirect metabolic effects may arise from :o\ic cyanmethaemoglobin and upon the intravenous interference with normal thyroid function as in the Election of sodium thiosulphate which accelerates case of some alkyl-nitro-amino derivatives of phenol. the formation of thiocyanate from the now slowiy The haematopoietic system is one of the first liberated cyanide. examined in the case of most industrial chemical Renal and hepatic function can be affected by hazards with chronic effects. Blood counts are some many chemical agents ; among these are certain times undertaken on workers in many different industrial metallic poisons, organic solvents, notably branches of the chemical industry, especially where chlorinated aliphatic hydrocarbons, explosives, deri hydrocarbon and chlorinated hydrocarbon solvents, vatives of glycols. Reversibility in these cases is explosives, some metals, radioactive materials, and endangered for the change-over from dysfunction to many other materials are made or used. Animal structural breakdown is poised precariously. The experiment often gives the appropriate lead as to the peculiar position of trichloroethylene among the nature of the attack on the blood-forming organs or commonly used solvents, however, indicates how on the blood itself, although there are difficulties subtle must be the mechanism which determines its from the much greater variability of the blood picture low toxicity, which is perhaps related to its ready in animals than in man. Reversibility of effects on metabolism to the non-toxic trichloroacetic acid the blood depends upon removal of the noxa and on (Taylor, 1936 ; Powell, 1945). the functional recovery of the bone marrow. For certain metabolic aspects of toxicity and carcinogenicity the use of isotopes is assuming wider and wider significance. A bladder carcinogen with Ginical and Experimental Aspects of Lead Intoxication one carbon C1J has recently been prepared by Much has been done to elucidate the clinical members of my department in collaboration with picture and pathological processes of lead intoxi Amersham (Henson, 1953 ; Catch, Huggill, and cation and poisoning. As the result of 12 years' Somerville, 1953). We have already been able to experience of men in a factory where lead acetate, establish important metabolic pathways and the long lead pigments, and paints were manufactured certain retention of compounds carrying the labelled atom clinical and elementary propositions have been in the body (Henson. Somerville, Farquharson, and formulated. The first is that the control of the health Coldblatt. 1954). The detection of the location of of workers exposed to any lead hazard is easy and toxic compounds in cells by autoradioactivity in effective by routine determination of(a) haemoglobin, histological sections is already a developing method. and (b) stipple and polychromatic red ceils. More The ultimate fate of most materials absorbed in complex methods are required in certain of the more industrial conditions is unknown. A great deal is highly dangerous lead hazards, e.g., volatile organic known about some of the final forms in which many lead compounds. chemical substances are disposed of in animals, but The expertise to do this is minimal, and a junior are very rarely able to strike a balance by ordinary boy or girl can be trained to do it and even interpret *r <ven extraordinary chemical means. The subtle the findings in a short time. If the conventional ways in which complex substances introduced into method by transmitted light be used, then it should the body in large part " disappear" raise many be realized that the polychromatic cell is a stipple difficulties and apprehensions. Nevertheless, by cell with the stipples very closely set. and they should using labelled compounds a new era has been opened be counted together, and can readily be confirmed in obtaining almost complete balance between intake by dark-ground examination (Figs. 4 and 5). and output of substances containing isotopic atoms, Haemoglobin determination alone is not sufficient, and in discovering how long such substances or their for many patients are found-with 100 to 90% haemo derivatives are retained in the body. In addition it globin who may be presumed to be absorbing lead *' Possible to track them through the various routes from the high (stipple and polychrome) counts. Nor 10 BRITISH JOURNAL OF INDUSTRIAL MEDICINE X- Q INDUS'. *^ f%ife* 1 * f 1 'it O' # 0 ^. g 31 t FiC. 4.--Rabbit blood sunned with alkaline methylene blue and photographed by transmitted light showing various-sized basophilic (polychromatic) cells due to chronic lead exposure. Fig. 3.--Rabbit blood stained with alkaline methylene blue and photographed by dark ground illumination showing ease o( recognizing stipples (golden granules) and two polychromatic cells; the 'polychromatic cells are manifestly very finely stippled cells. is the stipple and polychromatic count sufficient, for a relatively low count is frequently found with a very low haemoglobin (Fig. 6). The second proposition is that it is not difficult to prevent the notification of cases of lead poisoning by removing men from exposure at a critical moment and giving them other work. This is, in fact, what happens in most factories with a hazard from lead, Since in most cases rapid recovery is the rule, the statistics of lead intoxication can be kept low, and the national returns become valueless as far as a national industrial picture of lead absorption isconcerned. Moreover, men kept on at work in spite of evidence of lead intoxication do not develop a proper respect for lead and hence develop recurrent attacks of lead poisoningjsee also Fullerton 1952) (Table 2). As a rule (this is my third proposition) no man at work makes as good or as quick a recovery from lead intoxication as he does at home or in hospital (Table 3), so the importunities of men to be kept at work in spite of evident lead intoxication should be resisted and they should not be allowed to return to work until the normal blood picture is re-established, The recent introduction of chelating agents may expedite recovery and return to work (Foreman, Hardy. Shipman, and Belknap, 1953). Kehoe (1951) has emphasized that the usual forms of lead intoxication are self-limited, of relative^ short duration, and that there is complete recover' when the exposure has been terminated, and that no irreversible damage to the blood-forming tissues is associated with plumbism. The cases to which this statement would not apply are the now exceedingly rare encephalopathies and muscle palsies, Fig. 7 shows the kind of picture one would wish to avoid, that of a man who took five years to recover his haemoglobin although removed from contact with lead (see also Fullerton, 1952). Fig. 8 shows the data on a case of some interest, Three months of work on lead were followed by a fairly acute episode from which the patient was allowed to recover while still at the factory doing odd jobs not involving contact with lead. In spite of a very big drop in the number of stipples and polychrome cells, the haemoglobin level recovered poorly. A subsequent period on work with lead again led to an episode which was certified. Certified as fit to work after 21 days, the patient was again g c. 6.--Relation between haerr in worker* exposed to x ) examined shown with Hb \ car No. Name l>iC i*z: JM1 nj 1 F.C. 2 vs.p. 2 G.F.k. 4 J.S. < S.F. 6 K..A.M. 7 A.w . 8 P.N. 9 T.H. 10 E.M. It F.H.W. Tirr Lo- 8 <2 10 c 2m 26 C 1J c 16 c 2 rr 6c 12 c IE ( 28 ( 1t (All VE INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY maintained-in the factory on work involving no contact with lead till the haemoglobin was about 85%. A period on lead again threatened an episode, and subsequently a change to permanent work else where led to a slow and unsatisfactory recovery to almost 90% haemoglobin in about two years. 20r Hb as 179 IO 20r Hb7S )Oqj A-6 7-5) 37 Hdao 134 IS finally, it is important to remember that there are men who are remarkably reactive to even small amounts of lead. This is seen well in Fig. 9 which shows the blood findings in a worker who reacted at once when given work on a lead process, showed great falls in haemoglobin without a simultaneous rise in stipples, and who oscillated violently even when on work not involving a lead hazard. Lane (foe. cfr.) and others have described cases of hyper sensitivity and referred to evidence of family susceptibility to lead. A full study of such cases would be of considerable interest. The influence of alcohol must not be forgotten. My fourth proposition is that the changes in the peripheral blood in lead intoxication are due to 20 changes in the bone marrow. The stippied red cell derives from stipple normo* blasts in the marrow, both of which may be seen in the circulating blood (Figs. 10 and 11). The stipples . with alkaline methylene blue serf aund illumination showing esse rf. n granules) and two polychromatic! ceils art manifestly very fineb \ of a normoblast in the bone marrow are seen as a corona round the nucleus for mitosis occurs in the stippled normoblast apparently normally. There are far more stipple cells in the bone marrow per million erythrocytes than in the circulating blood :turn to work (Foreman,' (knap. 1953). asized that the usual forms self-limited, of relatively .* ? Relation between haemoglobin and stippk*polychrome counts m workers exposed to a lead dust hazard. Numbers of bloods cMimiDed shown with Hb values. (See text). during lead intoxication. Pirrie (1952), using guineapigs, found as many as 55% of haemoglobinating normoblasts in the marrow showing basophil stippling when only 2-5% of red blood cells were there is complete recovery; en terminated, and that no. Table 2 le blood-forming tissues is! l. The cases to which this ly are the now exceedingly Certified* LOST TIME OF TWO GROUPS Uncertified f i muscle palsies. j of picture one would wish to took five years to recover , zh removed from contact' ton. 1952). t an a case of some interest! >n lead were followed by a m which the patient was! : still at the factory doing! :ontact with lead. In spite! te number of stipples and! temoglobin level recovered! pjf^| on work with lead) *was certified. Certi-j Year 1'Jii l'J19 No-; | list Tear F.G. w.p. 8 day* J G.F.K. , 10 day* 4 J4. 1 2 mth*. :J 1 S.F. 6 K.A.M. 7 ! A.w. 8 I P.N. 26 day* 15 day* 16 day* 2 mth*. 6 day* 9 I T.H. 13 day* II day* 2940 2941 1943 1943 20:11 1944 17:4 10 ! E.M. 11 I F.H.W. 28 day* I mth. 21 day* No. Name 1? w.c A.H.T. -- --- 14 CSM.t is GSM. Time Lost Year No. Name 1 1 Time Lou Year No.. Name | 1936 3 day* 2S : 10 l mth. P 9 : 12 11 days 1 4 : II -- 14 : 10 21:10 1 mth. j 4 days ! 30 days 1937 24:3 3:3 1933 13:12 mo 1 . 2 . I Nil ! Nil 23 : 1 48 W.F. F.G. ; Nil : Nil 3 F.X. j Nil 1940 F.K. 1 Nil 23 :9 7 H.E.W. i I days (Hb. 73 % )' fastntii 1941 1 W.F. 9 W.F. 10 F.G. U CJ.H. 12 J.l_ 13 R.O. 14 C.F.H. IS W.R. 1 Nil Nil Nil 1 Nil Nil 1 Nil 1 ! Nil : Nil 1943 1943 22:3 2944 . 1944 26: I , 16 : C.F.H. 8 A.E.P. 18 A.W. 19 H.J. 20 . G.M. 1 _j 21, H.J. _ 22 H.J Time Lost Nil investigation Nil Nil Nil Nil ___ the patient was again! Certified-recovery away from factory, tUncenified-recovery at work. (All cases 60--63 % Hb at time of certification or actioo in factory.) ; Recurrent case* in italic. ^12 BRITISH JOURNAL OF INDUSTRIAL MEDICINE Table 3 PERIOD OF RECOVERY OF Hb W.F AGE <-5I YEARS. Hb & Supple* * 'Polychrome*'. Stow Hb reeovcrymunaind high (S*P) durmj Non-lead Maintained at Work Removed to Home or Hospital No. of Cases 2* 9 Hb at time of transfer .. Mean time to reach 10% or more S5-70*; 1-93 months (3 weck*-7i montbs) 65-70% 1-66 months (16 day*-2} months) Indicates slight adventsft of getting men aiy from factory even on light and non-lead work. I ease of Hb 43-45% recovered to K)% m 23 days whilst at work on non-lead. stippled in the stained peripheral blood. Similar findings were obtained in our experiments with rabbits. Even in heavy exposure to lead not all the normoblasts show stipples, many proceeding to normal haemoglobination. Stipple cells, poly chromatic cells, and reticulocytes all owe the appearances seen to ribonucleic acid. This can be shown by treating the cells with ribonudease which completely removes the basophilic material and leaves the cells uniformly aridophil. In the normal maturation of the erythrocyte, the basophilic sub stance in the cytoplasm practically disappears at the reticulocyte stage, and haemoglobination is com pleted without a hitch. years Fic. 7 --Titf of lend attaemia showing extremely slow recovery of haemoglobin whilst maintained at work. T.H. AGE 2M2 TEARS. Returned te work before blood recovery-after The delivery of " leaded " basophilic cells from the marrow into the circulation is gradual in ordinary circumstances as the peripheral cells are removed. This statement applies to reticulocytes, polychro matic cells, and stipple cells, and it must be clearly understood that the particular appearance associated with these cells is not preformed, but depends upon the method of staining and upon the amount and state of the basophilic substance. Conditions suit able for staining one kind of these cells may fail entirely for the others. Fic. S.--Case of certified plumbism considered clinically fit to return to work, but thereafter requiring almost two years k regain a stable Hb on non-lead work. If blood rich in reticulocytes is stained supravitally with brilliant cresyl blue the usual picture is obtained of a filamentous-granular network but if a dried film is stained with the same dye the reticulo cytes are seen as cells with vacuolated basophilic material (Figs. 12 and 13). Stained supravitally or in dried film stipples are readily seen in their usual form in red blood cells as well as in normoblasts. Reticulocytes stained in dried film and examined in the dark ground show a finely granular or finely reticular pattern with irregular vacuoles. MacFadzean and Davis (1949), Pirrie (be. cit.), Rimington (1938), Kench, Lane, and Varley (1952), Dustin (1942), and others have gone far to elucidate the nature of the stippling property ofthe erythrocyte in lead absorption. 100 , H.T. AGE St-57 YEARS. Cm* of hiwiwcy and Recurrence. Hb g Stipple*`NyOrowei1. Never Certified. To: to 50 20 <F-i-S) S A /k.1000`s 10 10* R.B.C. s 0 / VS JVM-O- ___tt-H____ _ 1 mth*. tafc hoary fAyeert I 2 3 4 S * r-n Fig. 9.--Case of sensitivity and recurrent lead anaemia in spit* of long periods on non-lead work. Close correspondence of Hb and stipple values. IND .V 2 3 4 year* m considered clinically fit to requiring almost two years to work. t.T. AGE St-57 TEAKS. af SfwttrMC7 11*4 Recurrence. > KtycAremci Never CcrtiAed. ___ 1*4 yun ___ _ t 3 4 5 6 years t lead anaemia in spite Close correspondence of Fic. I2.-Rabbii blood after ehronieJead inhalation jhowm* retieulocvies supravital staining with brilliant cresvj blue. * 1200. Fic. 13.--Rabbit blood on same occasion as Fig. 12 (dry film stained with brilliant cresyl blue) in which reticu locytes are seen as ceils with vacuolated basophilic material, x 1200. 14 BRITISH JOURNAL OF INDUSTRIAL MEDICINE Lead poisons the later precursors of the red cell and intoxication manifests itself as (1) retention of basophilic material instead of its almost complete disappearance at the normoblast and reticulocyte stage and completion of maturation. (2) The socalled stipple cell and the polychromatic cell derive from the failure of maturation of the basophil normo blast. The reticulocyte derives from non-poisoned normoblasts. Since reticulocytes may increase before lead anaemia and stippling are established we may assume that the stipple and polychrome cells indicate a failure of the normoblast to go on to the reticulo cyte stage. With the failure of the bone marrow in "extreme cases oflead poisoning, stipples, polychromes, and reticulocytes all fail. This is why stipple counts fall in the last stages of very severe lead poisoning. (3) By processes not properly understood (synthesis of porphyrin, incorporation of Fe into coporphyrin III to form haemoglobin, etc.) lead inhibits the full haemoglobination of red cells. (4) Evidence of abnormality of red cells in lead absorption is that they show (a) diminished fragility in being able to withstand lower salt concentrations ; (b) increased brittleness and less durability in the conditions of existence in the circulation. In addition, they are readily taken up and destroyed by the spleen and other reticulo-endothelial cell locations. (5) Lead anaemia is due to (a) poor haemoglobination and (b) greater destructibility of cells containing lead. Industrial Enzyme Poisons Many industrial poisons are enzyme inhibitors, e.g., cyanide, organic arsenicals, organo-phosphorus compounds. The clinical pictures of acute poisoning can sometimes be related more or less specifically to the inhibition of particular enzyme systems. The most important of these has, in recent years, been the large group of organic phosphorus insecti cides (Fig. 14) and potential war gases. Since there is intense competition in this field of manufacture, chemical research is directed towards synthesizing compounds which combine a broad spectrum of high insecticidal activity with low mammalian toxicity. The toxicity of these compounds (Table 4) is attributable to their inhibition of cholinesterase and hence the clinical picture of poisoning is that of poisoning by endogenously produced acetylcholine. But the degree to which they inhibit the enzyme in vitro is in some cases many (even millions of) times less than would be expected from their toxicity in vivo. Transformation into highly potent anti cholinesterases occurs in these cases in the liver. Recently progress has been-made towards evolving organo-phosphorus compounds possessing low mammalian toxicity compared with the now classical Table 4 L.D.30. ORGANO-PHOSPHATE INSECTICIDES* Compound Orl L.D.30 I.P. L.D.30 T.E.P.P...................................... Paraoxon ........................... Oitnofox $vsiox (Commercial} s f >r-o- .. 1-2 R.f. 20 R.m. 3-5 5 R.m. 6-39-9-7 R.m. 0-63 R 1-2 R.m.f. 4-5-4-37 R.m. 7-3 R.m. 0 >P-$- .. Pestox (O.M.P.A, Schradan) Parathion E.P.N. Mipafox ........................... Maiathion 1-5 R.m. 9-7-10-0 R.mX & R.f. IS R.m. 14*5 R.f. 910 R.m. < *i., Parathion 2.426 R.f 2.360 R.m. 84-6 5 R.m.f. 4 R.f. 7 R.m. 30 M. 750 R. Medan lethal dova of organo-phoiphate insecticides. R -- rtb. M "> mice, tn -- male, f * female. AU values in mg./Kg. parathion and tetraethyl pyrophosphate (T.E.P.P.). Thus " mipafox ", which is the mono-isopropyl analogue of " dimefox ", is perhaps 25 times less toxic than "parathion", and "maiathion" about 200 times less toxic to mammals. The optimism engen dered by these facts is tempered in the case of " maiathion " by its less potent insecticidal pro perties and in that of " mipafox " by pathological considerations. The questions which must be answered by the industrial investigator in respect of these and other agents which are applied to food or crops are : (1) Do they constitute a risk to the consumer of the food products? This has been adequately answered in the report of the working party appointed by the Ministry of Agriculture (1953) which gives the necessary assurance but recommends investigation of the maximum permissible residues arising from the use of toxic substances. (2) Do they constitute an unjustifiable risk to the user ? The answer here is no. provided that the necessary precautions are implemented, and. in addition, if the use of atropine is properly understood by employer, supervisor, and doctor as the specific therapeutic agent for the parasympathetic signs and symptoms (Goldblatt. 1950, 1951). The onset of symptoms depends upon the level of true cholinesterase in the blood cells, brain, and nervous tissues, in nerve fibres and at motor endplates and, of course, at ganglionic synapses. Since a great fall in the enzyme may occur in some indi viduals without any manifest signs or symptoms, it is essential that the blood cell cholinesterase of exposed persons should be determined as a routine |). PARATH 2). T.E.P.P 3). PESTO 4). PARAO> 5). E.P. N. DIMEF 7)- MIPA 8). SYS' $ MA R.m.f. 4 R.f. . 7 R.m. : insecticides, il values in mu. - Kfc. aUJ.E.P.P.). jsopropyl , limes less ,ion" about 200 ptimism enge v in the case of nsecticidal proby pathological nswered by the these and other r crops are : (1) umer of the food .ely answered in ppoinied by the which gives the s investigation of arising from the icy constitute an ie answer here is precautions are ie use of atropine oyer, supervisor, utic agent for the toms (Goldblatt, ; upon the level of cells, brain, and nd at motor end- ,c synapses. Since ct^fe some indi- fymptoms. it _>linesterase of mined as a routine o=p^-nh.ch^:h3)2 \^h.ch(J:h5; systemic ^oc H W-SH4--p< 2s 91= C,H..OOC.H,C S 2 5 2|- || .OCH C,,Hc.OOC.HC--P-S( \>CH, ' Fic. [4.--Formulae of active compound* in organo-ehospbonu mxcticide SYSTEMIC LEAST TOXIC 16 BRITISH JOURNAL OF INDUSTRIAL MEDICINE in order to preclude a fall to dangerous levels ; each slow and only partial (see also Barnes and Denz, subject should be his or her own control. The 1953). variance from mean levels in populations is too The selection of a special tract for attack is great to draw conclusions from single observations. puzzling and not less so than in man, in whom the It is so easy to ignore the early symptoms which may whole picture is of a motor disturbance. In the be no more than a slight tightness in the chest and a cases due to insecticide a neuromuscular block due sense of mild apprehension. This is the more to the breakdown of the normal relation of cholin important since in irreversible inhibition of cholin esterases and their substrates was first seen and later esterase there is considerable delay before the normal a peripheral neuritis with only those sensory impair enzyme level is regenerated. In the case of " mipa ments as are normally associated with polyneuritis. fox " poisoning it may take 50 to 90 days to recover As more and more compounds are being synthe the initial red blood cell level of cholinesterase after sized, it is important not to assume the relative an acute severe attack. safety of a given compound until acute and chronic Until very recently it would have been held that the organo-phosphorus insecticides did not produce chronic effects, acute non-lethal attacks passing off without sequelae and long-term administration of sub-lethal doses to animals giving rise to no chronic toxic phenomena. Clinical observation and experi ments had shown that among organo-phosphorus compounds D.F.P. (di-isopropyl-phosphorofluori- date) and T.O.C.P. (tri-o-cresyl phosphate) both in man and in animals could induce demyelination in the cord and in the brain, and although suspicion was cast, by analogy, on the phosphorous insecticides, it was not till 1951 that a case of paralysis due to * parathion" was described in Germany by Petry (1951) and two cases due to "mipafox" [bis-(mono- isopropyl) phosphorodiamidic fluoride] in this country by Bidstrup, Bonnell, and Beckett (1953), none of which appears to have recovered in some three years. The addition of these agents to the already known diversity of demyelinating agents in man and animals (carbon monoxide, arsenicals, sulphanilamide. spinal anaesthetics, vaccination) tends to turn us from a purely chemical hypothesis to perhaps an enzymatic one. Demyelination has been produced experi mentally with CO, KCN, N,Na, N.O, and repeated doses of barbiturates (Weston Hurst, 1941, 1944). The paralysis which followed "parathion" and " mipafox " resembled that described among many people who had absorbed T.O.C.P. in one way or another, and in both these groups it seems probable that the persistent signs were due to demyelination. Fig. 15 shows a section of the cord of a fowl Cl-35 kg.) treated with a'single dose of 0-5 g./kg. of tri-o-cresyl phosphate (T.O.C.P.). This and another fowl similarly treated were observed for over 250 days. The phenomena were of the same kind as found with the anti-cholinesterase insecticides. Some recovery was observed, especially in respect of secondary sex characters and egg-laying power, and to some extent in muscular powers, but this was very Fig. U.--Cervical cord and viatic nerve of fowl treated with a preparation of tricrayl phosphate calculated to contain 0*1% of the ortho-iftomer. Tout dose in 16 days -- 2 by mouth. First paralytic sipm in 21 days followed by progressive worsening of paralysis of tegs. Demyelination in anterior and lateral columns and markedly on sciatic cord, x 12. Marchi's method. A - upper, and B - lower, cervical cord -below sciatic nerve. I experiments have effect on the nen variety of animal Occur There are ver> have been shown gens to man. radiations f.v-ra> naphthvlamine. t pyrene. Of the host of which have prod mary gland, lung, have been demon carcinogens. Tht products as tar. '. established with c 3-4 benzpyrene f this compound. Long-continuec lions and work v to indubitable s finally to epitheli ment has been p effect in animals. In the case of o as well as severe followed long e though the tunic sarcomata in anir differences are a reached by the ra Neoplastic cha often highly mali; of workers expos and'Or dust of c reported for near where organic c clinical fact has t in the U.S.A. a identical bladder b-naphthyiamine Clayson.andJull tumours inducib amine in differer amount of urinar excreted. More recentl; benzidine and ha research both ins the demonstratic benzidine in rats but bladder turr induced except  Barnes and Denz, tract for attack is i man. in whom the :isturbance. In the muscular block due il relation of cholin; first seen and later nose sensory impair- d with polyneuritis, ds are being syntheassume the relative il acute and chronic c o* a fowl treated with a iJcuJated to contain 0*1% of da>s 2 mg./kg. by mouth, ved by profmsive worsening ioann iinr^ aanntteerior and lateral x 12. Marchj's al cord below INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 17 experiments have been carried out, and also the eiTeet on the nervous system studied in detail in a v ariety of animal species. Occupational Carcinogenesis There are very few identifiable agencies which have been shown without any doubt to be carcino gens to man. These are arsenical compounds, radiations f.t-ray, radium, ultra-violet light), (3napiuh> iainine. benzidine, and probably 3-4 benz- pv rene. Of the host of compounds and complex mixtures which have produced tumours of skin, liver, mam mary gland, lung, and bladder in animals, only these have been demonstrated as direct or indirect human carcinogens. The active agents in such carcinogenic products as tar, lubricating oil, soot, pitch, are not established with certainty, although the isolation of 3 4 benzpyrene from tar casts strong suspicion on this compound. Long-continued therapy with arsenical prepara tions ana work with arsenical compounds have led to indubitable skin changes (hyperkeratosis) and finally to epitheliomata. But no convincing experi ment has been published to demonstrate a similar effect in animals. In the case of certain radiations, neoplastic change as well as severe blood changes have undoubtedly followed long exposure in man and in animals, though the tumours which develop are different-- sarcomata in animals and carcinomata in man. The differences are attributable to the different tissues readied by the radiation. Neoplastic changes, sometimes benign but most often highly malignant and recurrent, in the bladders of workers exposed for varying periods to the fume and or dust of certain aromatic amines have been reported for nearly 60 years in all parts of the world where organic dyestuffs are manufactured. This clinical fact has been confirmed by experiment both in the U.S.A. and in Britain with dogs in which identical bladder tumours were induced by feeding '--naphthvlamine. It has been suggested by Bonser, Clayson, and Jull (1951) that the incidence of bladder tumours inducible by treatment with "-naphthylamine in different species is roughly related to the amount of urinary conjugates of 2-amino- 1-naphthol excreted. More recently the same suspicion fell upon benzidine and has been amply confirmed. Intensive research both inside and outside industry has led to the demonstration of the carcinogenic properties of benzidine in rats (rectum, sebaceous ear glands, liver) but bladder tumours had until recently not teen induced except in the case of one dog (Spitz, Maguigan, and Dobriner, 1950). The possibility that here also the o-hydroxyamine is the immediate carcinogen has received much consideration. The contribution made to the elucidation of the problem in this country has been notable and the names of Bridge (1934), Macalpine (1929,) Wignall (1929), Walpole, Williams, and Roberts (1954), Scott (1952), Baker (1953), Bonser and others, (1951), Bonser, Clayson, Jull, and Pyrah (1952) and more recently Case and Hosker (1954), and Case, Hosker, McDonald, and Pearson (1954), will always be remembered for the great light shed upon it. The total number of cases which Case and his colleagues (1954) were able to trace in the chemi cal industry between 1900 and 1952 was 455. Case s classical statistical investigations are a model for the future investigation of occupational diseases. Case and others have established on a national scale what others have found in industrial practice both in this country and elsewhere. Contact with the naphthylamines or benzidine is now fully recognized as a carcinogenic hazard, and aniline appears to be exonerated. Some as yet cryptic factors in the manufacture of magenta and auramine appear to throw suspicion on both these processes. The disease was prescribed as an industrial disease in 1953 in this country, just 58 years after the original description by Rehn. It is proper to record the unremitting clinical control by Dr. Charles Cresdee for almost a quarter of a century in one very large centre where these compounds were manufactured, which has been a guide and an inspiration to those who have had to pursue the problem in the quiet of the laboratory (for earlier work and review see Goldblatt, 1947, 1949). More recently, arguing very ingeniously from the fact that these tumours had formerly been attributed to aniline, which until now has not been proven to be a bladder carcinogen, Walpole, Williams, and Roberts (1954) in Manchester came to suspect 4amino diphenyl, which had been found in residues in aniline manufacture 80 years ago, as the probable cause. Experiments on dogs confirmed the presumed bladder carcinogenicity of this compound. Certain condensation compounds of the naph thylamines formerly used in the processing of rubber have already been banned by manufacturers since new knowledge on the previously suspected but uninvestigated incidence of vesical tumours in the rubber industry became available (Case and Hosker, 1954). Both the Leeds apd Manchester workers have come to place great emphasis on o-hydroxyamines as the effective bladder carcinogens. This has opened a large speculative field of inquiry, because r 18 BRITISH JOURNAL OF INDUSTRIAL MEDICINE a considerable number of hitherto unsuspected aromatic amines and derivatives of them could yield various o-hvdroxyamines metabolically. The dilemma before industry in this field is how to deal with the considerable numbers of compounds that might cany suspicion. The project of examining all the derivatives of cyclic hydrocarbons and their homologues which, in their metabolism, might yield amines or derivatives of amines of potential carcinogenicity must, how ever, be undertaken. There is no escape from the argument that if a compound is carcinogenic in animals, in whatever location in the body, it must be so regarded, at least potentially, in man. In some cases it is possible to circumvent carcino genicity chemically. In the case of Ji-naphthylamine this has been done in this country and in some continental countries by avoiding liberation of the base at any stage of manufacture or use. Certain food azo-dyestuffs have already been rejected because of the possible metabolic fission of the relatively simple molecules with the liberation of a carcinogenic amine, in the absence of any but presumptive evidence. A systematic study of food colours on these lines is in progress in my laboratories. In the industrial field the manner of attack must be cooperation between statisticians, industrial doctors, and experimentalists. The statistical weapon is one which is potent in the hands of specially gifted people, provided all the data are collected on a pre-determined plan and all in possession of relevant records cooperate fully. Before it is prudent to publish the view that a given material is not carcinogenic in any circumstances, it is well to remember that experienced investigators have made such statements and subsequently have been proved mistaken. Experiment (in our hands as well as in others') has failed to show carcinogenic properties in chromates, but in the U.S.A there is considerable statistical support that chromate dust can induce lung cancer fMachle and Gregorius, 1948) but Bidstrup (1951) was not able to draw clear con clusions from her x-ray survey of 724 workers in the industry in this country. Recent statistical data in the U.S.A show that chromate workers had a mortality rate for respiratory cancer 29 times as great as would be expected among a comparable group of all males in the country (Federal Security Agency, 1953). In 1949 the Senior Medical Inspector of Factories gave, reasons for the belief that the pulmonary fibrosis in asbestosis is followed by an inordinately high percentage of cases of pulmonary cancer. It will be difficult, if the observation is confirmed, to envisage the process here as other than one initiated by local mechanical irritation but a chemical carcinogen is not ruled out although it is more difficult to find support for it. It is not sufficient to state that a given material is non toxic. Toxicity as ordinarily understood is in some sense the reverse of carcinogenicity. For whereas a compound exercising a toxic effect on a cell is driving that cell in the direction of inanition and death, one exerting a carcinogenic effect on a normal cell is driving that cell towards excessive, if abnormal, function and, for a time, more vigorous life. This is not to say that a carcino genic compound is never toxic in the ordinary sense, but rather that a toxic agent in full spate is unlikely to permit the establishment of carcinogenicity. Although the mean induction times for certain occupational carcinogens are long and not dependent on the severity of exposure, it is to be noted that in some individuals the induction time may be quite short and in others much longer than the mean. Recent Work in the Diagnosis of Vesical Tumours The need for continued medical supervision of men who have been exposed in the past to bladder carcinogens is manifest even after exposure has ceased, and even after leaving the industry. In a section of the chemical industry exfoliative cytology is being used to detea early bladder tumours. In the U.S.A. the teaching of Papanicolaou (1947, 1948) on the importance of the recognition of neoplastic changes in exfoliated cells has been much regarded. Cells may be exfoliated from the lung, stomach, bladder, cervix, and vagina, and, provided the morphological and staining characters of tumour cells can be recognized, there is no theoretical reason why a neoplastic process should not be detectable at an early stage (see also Bamforth, 1953). In the case of bladder tumours the early develop ment is not attended by any disturbance of the patient in either occupational or non-occupational cases. Hence arises the need to establish routine urine examinations for microscopic blood, which is often the earliest sign of bladder irritation, of ruptured small varicosities, of a broken frond of a small papilloma, or of the slow and insidious oozing of an infiltrating carcinoma. In a small proportion of cases microscopic haematuria is unaccompanied by a tumour visible in the cystoscope, and -in a larger proportion there may be no blood in spite of the presence of a tumour. In this country it is useless to recommend routine I i ' ' , cystoscopy of wc the Continent ar U.S.A. Hence u. be made and e will, with the m a correct picture To this end we ; scope of urinar; mining the pier in normal subje colaou's methoc hope later, by malignancy. B; those hitherto laboratories hat stain, character the types of cell urine (Rofe. 19 normally interfe matter and deb cells in 1 in 1.5C they were void may thus be s urines contain urines contain k content other t: two main parts sitional, 15u a: bladder); (b) sr from kidney ar 15^ and under in various stage A very inte counts was tht more leucocyte could be accou; whole blood, is always in a st. or mechanical. By applying Rc glance all the c # r\ . su-copv ot workers as it is practised on X Continent and to some extent m the s A Hence urinary examinations must J.' n`,adc and every device used which ^ill with the minimum discomfort, give , picture of the inside of the organ. To this end we are seeking to enlarge the Jopc of urinary examinations by deter- mminc the picture of vesical exfoliation ,n :vr`nul subjects, by applying Papam- methods to the urine, and, we K.pe'uicr. by cytochemical tests for ri-Liiiunancy. By methods different from ;'.o hitherto used, Mr. Rofe in my laboratories has been able accurately to Ntain. characterize, separate, and count V-.* the tvpes of cells found in normal human urine (Rofe. 1955) after removal of the normally interfering organic and inorganic nutter and debris and concentrating the cells in 1 in. 1.500 of the volume in which were voided. Certain conclusions ::u. thus be stated : (1) Most normal urines contain blood. (2) Most normal urines contain leucocytes. (3) The cellular content other than these is divisible into two main parts (a) squamous and tran sitional. 15u and over in size (urethra, bladder): (b) small epithelial cells derived from kidney and prostate fin the male) 15-i and under in size. These cells are m various stages of degeneration. \ \<ry interesting feature of these =*--> c. ants was that there were always far more leucocytes in normal urine than could be accounted for by a simple transudation of whole blood. This perhaps means that the bladder is alwavs in a state of some irritation, either chemical or mechanical, which does not reach consciousness. Bv applying Rofe's method it is possible to see at a glance all the cells exfoliated in a given sample of :p-r s % FtC. 16 urine. Having a reliable picture of the normal cell content, deviations from it can the more readily be recognized and the detection of exfoliated tumour cells is facilitated by the small volume into which the cells are concentrated. The character of exfoliated bladder tumour cells has been described by Crabbe * FiG. 16.--Smear from urine of worker m N 4 manufacture of dyestuff intermediate) showing erythrocytes. polymorphs, abnormal and degenerated epithelial ceils, and several definitely malig. nam cells. Papanicolaou's tcchmouc of preparation and staining. * 500. FtC. l7*~"Smcar from another dycstutl worker showing erythrocytes, many polymorphs, and giam binucteaied V malignant cells. Papamcolaoj technique, x 500. I <1952) working in my laboratories. The value of chemical industry, and some of the difficulties and cytological diagnosis has been amply demonstrated. The cytological criteria laid down by Papanicolaou for the diagnosis of malignancy include increased size and bizarre shapes; enlargement of nuclei in relation to cytoplasm; altered nuclear and dilemmas which arise. This kind of work is merely the preliminary to the application of the knowledge thereby obtained in the field and the factory. It is there that rite ultimate goal set by James Mackenzie must be reached--the prevention of chromatin pattern; increased affinity of nuclei occupational illness. for basic stains ; and variation in nuclear sizes I am extremely indebted to Mr. Kenneth Cooper and in a group of cells (Figs. 16, 17). In a method of Mr. Leslie Hewitt for their kind cooperation in the diagnosis of this kind the danger is the false negative. The false positive is less serious, but always of great interest, especially when found in the absence of blood cells and cystoscopically visible tumours. The cystoscope is not infallible, for we have had preparation of the photomicrographs, and to my colleague Dr. J. G. S. Crabbe for Figs. 16 and 17. My thanks are due to Mr. Berczy, Mr. Crozier, and Mr. Denks for much technical assistance. References cases in which a positive cytological diagnosis was subsequently confirmed by cystoscopy after initially negative cystoscopic reports. It is becoming clear that the exfoliation of cells from new growths is not a uniformly constant process. One day it may be prolific, another relatively unproductive. Further, the ease of recognition of neoplastic character varies. For these and other reasons we prefer at this stage to base judgment on a combination of the classical search for haematuria and to fortify it with the cytological method. It has thus been possible to assert the presence of a tumour at a stage when a slight microscopic haematuria would have left us in doubt and the patient in delay. Field Experiment Field investigation is properly the domain of the industrial doctor, and it is the most difficult. In the last analysis it is upon field investigation that a final judgment must rest as to the relation between industrial environment and state of health. The difficulty does not lie in the recognition of this proposition, but in obtaining the opportunity and in devising the appropriate methods to establish such relations. To attain results which are soundly based and generally acceptable is a task requiring the cooperation of many disciplines. In the main, therefore, it is in the big organization with great resources that such studies can be made, but it is a parallel fact that in such organizations the environ mental conditions are likely to be the best. The practical application of the principles which emerge from field studies requires assiduity on the pan of the industrial doctor and of those responsible for industrial hygiene, for this requires not only the willingness of employers to make money available, but also the willingness of workers to create it. in conclusion, my object has been to indicate some of the things which concern those who are engaged in research in industrial health in the Baker. R. K. (1931). Cancer Mrs.. IS. IS7. Bamforth. J. (1953). Practitioner, 171, 244. Barnes. J. M_. and Dent. F. A. (1933). J. Path. Boct.. 65. 597. Bidstrup, P. L_ 1951). British Journal of industrial Mediant, I. 302. -------. Bonncll, J. A., end Bcckcu, A. O. (19531. Bril. med. J.. 1. 1068. Bonier. C. M.. Clarion. D. B.. and Jull. J. W. (1951). Lanea. 2. 286. -------.-------,-------, end Pyrsh. L. N. ((952). Bril. J. Cancer, 6. 412. Bridge. 3. C. (i934). Annual Report of the Chief Inspector of Factories end Workshops for 1933, p. 49. H.M.S.O., London. Case. R. A. M- and Hoskcr, Marjorie E. (1954). Bril. J. prtt. soc. Mrd,, 8. 39. ----.-------. McDonald. D. B- end Pearson, Joan T. (1954). British Journo! of Industrial Medicine, 11. 75. Catch. J. R., Huggill, H. P. W., and Somcrvilk, A. R. (1953). J. ehem. Soc.. p. 3028. Chief Inspector of Factories (1949). Annual Report for 1947, 79. Cook. W. A. (1945). Industr. Med.. 14. 936. Crabbe. J. C. S. (1952) Brit. med. J.. 2. 1072. Dink. w. M~ and Cage. J. C (1954). British Journal of Industrial Mtdicine. 11. 140. Drain. J. H.. Woodard, G, and Calvary. H. O. (1944). J. Pharmacol. 82 377. Drinker. P.. and Cook. W. A. (1949). Proc. IX Int. Congr. Industr. Med.. London, i94g, p. 154. Wright, Bristol. Dustin. P.. Jr. (1942). Sant. IS. I9J. Federal Security Agency (1953). Health of Workers in Chromate Producing Industry. Public Health Service Publication, No. 192 Washington. Foreman. H,, Hardy. H. L., Shipman. T. L-, and Belknap, E. L. (1953). Arch, industr. Hyt~ 7. 148. Fullerton. J. M. (1952). Brit. med. J.. 2 117. Goldbian, M. W. (1947). Bril. med. Bull., 4. 405. ------ . (1949). British Journal of Industrial Medicine, 6, 63. -------. (1950). Pharm. J., 164. 229. ----, (1951). Atti del Convegno imemaaionak di'Medicine del Lavoro. Milano. 1950. p. 90. Henson. A. F. (1953) Brit. J. oral. Phys.. 4. 217. --, Somervilk, A. R.. Farquharsoa, Muriel. E.. and Goldblatt. M. W. (19541. Biochem. J. 58. 383. Hurst. E. Weston (1941). Med. J. Ausl., 2 661. -------. (1944). Brain. 67. 103. Kehoc. R. A. (1949) In Industrial Hygiene and Toxicology. ol. 2 p. 643. Edited by F. A. Petty. Jniencicnce Publishers, Inc., Nr* York. -------. (19311. Industr. Med. Burg.. 20. 253. Ranch, J. E.. Lane. R. .. end Varfey. H. (1952). Biochem. J.. 51, is. Lanc. R. E. (1949). British Journal of' Industrial Medicine, 6, 123. Macalptne. J. B. (1929). Brit. med. 2 794. MsFadxcan. A. J. S.. and Davis. L. J. (1949). Quart. J. Med., It, S7. Machk, W,, and Gregorius, F. (I94S). Publ. Hlth Rrp., Wash., 63. 1114. Ministry or Agriculture (1953). Toxic Chemicals In Agriculture : Residues in Food: Report of the Working Party. H.M. Stationery Office. London. Papanicolaou, d. N. (1947). J. Ural S7. 373. -------. (1941). Amor. J. Fubt. Hlth. 38. 202 Petry. H. (19312 Zent. Arbeilsmed. Arheitssch., 1, 86. Pirrie. R. (19521. J. Path. Baa., 64,211. Potter. A. Lloyd (1950). British Journal ofIndustrial Medicine, 7, 125. PoweU. Joan F. (1945). /*, 2 142 Rimmgton. C. (19382 C.R. Lah. Carlsberg (Scr. chim.), 22 454. Role, P. (1935). J. din. Path. To be published. Scott. T. S. (19522 British Journal of Industrial Medicine. 9. 127.___ Spin. S. Maguigan. W. H,, and Dobrincr. K_ (1950). Cancer, 3,789. Taylor. H. (1936). J. industr. Hyg. It. 175. Walpok. A. 1_, Williams. M. H. C. and Roberts. D.- C. (1954). British Journal of Industrial Medicine, 11, 105. WignalL T. H. (1929). Bril. med. J* 2 251. ML While there criminal or a ganese ores ; rise to a numi The histories already been and Rodier, i occupational when Couper among five rr a series of net paraplegia, tr lean forward salivation. Since then observations affecting the known than be rare since in contact v The symptoi disablement, occupational problems, a' partially inc; sick man an Mangane: but its min= dioxide has Pliny mentit Stockholm, after three 1 thesis (1774 was finally i de Morveai distinguish Bergman, nature und writers con: