Document nNRJ6aJ2kyRokQgB56LovG8Y8

181 198 206 217 22S 233 237 240 244 249 262 263 279 290 296 304 309 320 322 326 330 335 337 341 , 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 Frederic 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. Meuclejohn J. N. Morris J. R. Squire Editor, British Medical Journal /H&7 u. i v-6 CONTENTS Research in Industrial Health in the Chemical Industry. M. W. Goldblatt .. Manganese Poisoning in Moroccan Miners. J. Rodier .. * ................ ... .. PAGE . /9^sr-6 c . 21 Dermatoses in Jute Workers. John Kinnear, John Rogers, Owen A. Finn, and . Alexander Mair ...................................... ................................................... Talcosis of Unusually Rapid Development. G. P. Altvisatos, A. E. Pontulahs, am B. Terzis .. .. .: ........................ .. ............................................................... Injury to. the Respiratory Tract by Isocyanates .Used in Making Lacquers. Axe Swensson, Carl-Eric Holmquist, and Karl-David Lundgren .......................... Dimethyl Sulphate Poisoning. T. R. Littler and R. B. McConnell .. ... .. .1 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 Tbeir Use in Controlling Airflow. H. A. Druett .. ... .. .. .. .. 65 Miscellanea : The Health Hazards of the Senior Executive. A. R. Cooper................................................... The Health of the Industrial Worker in Iraq. A. Michael Crttchley .......................... 71 73 Book Reviews ................................................... .. ........................... -76 Abstracts . ..................................... ' ....................................... v........................ 78 : . LONDON BRITISH MEDICAL ASSOCIATION TAVISTOCK SQUARE, W.C.l 'early Subscription (4 Numbers) 2 2s. U.S.A. $7.00 Single Number 12/6 ftri:. J. indusir. Med., 1955. 12, 1 REWETHER S JLRY ZUJtXX WART d Watson-Jones ransactioos of the Association RESEARCH IN INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY * BY M. W. GOLDBLATT From the Imperial Chemical Industries, Ltd., Industrial Hygiene Research Laboratories, Welwyn. Herts of original.contributions in ions for book reviews and lining, Nuffield Department York Place, Manchester 13. > this Journal, and that they ; the paper only, with double ; on of x-ray-illustrations is mhs and photomicrographs rap|^%ra>mpanying papers stoiMpCmooth, white paper, lightly inserted in pencil. xx>k is referred to, the place x of publication must follow a small letter (a, b, c) after ution references are arranged given as follows : Author's cs, abbreviated according to ic numerals), and first page but verbal corrections have gs per sheet of sixteen pages s will be responsible for any ors. A limited number of stunting proofs. An estimate a.1 Association. . lumal of Industrial Medicine ertisement Manager, British British Medical Association i ;:G- . The satisfaction I feel at the opportunity afforded me to add my homage to that of old colleagues who have preceded me in the commemoration of James Mackenzie and his work is of a special kind. Mackenzie was a man with a mission. He also had _ vocation, and his life was rich in worth. If James Mackenzie sought to bring what might be called " physical " light to the dark and sick lives of the industrial workers of his time, he brought much spiritual light also. To have enlisted the cooperation of some of the most notable and busy men in public health and medicine through his Industrial Health Education Society required qualities which, when they impinge on other men's minds, raise them to heights they would never wish to leave. These qualities of Mackenzie are those which every medical .'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 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 -tage 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. ` The Maclccniie Industrial Health Lecture delivered in Manchester `ti Jul> 13, J954, at the Annual Provincial Meeting of the Association " Incustnal Medical Officers. The coming of the second world war gave an impetus to industrial medicine in this country and in many others for which the workers may be thankful. Practitioners now visit factories, join in lectures and discussions, avail themselves of services provided by industry in the factories, and exchange information with the industrial doctor. To-day the stage of exhortation is almost over. James Mackenzie died in 1944, his society having been wound up at the beginning of the war, but he must have seen the movement towards more and more social realization of responsibility for the health of the nation in a sense more profound than it had ever been. My own satisfaction in paying my tribute to Mackenzie consists in the knowledge that after following with so many of my friends his path 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. 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 some 45 years ago when he (and Duckering) gave 5 mg./lO cm. as the atmospheric concentration ol BRITISH JOURNAL OF INDUSTRIAL MEDICINE INDL lead in which engineers and chemists might work. of a hazard with a value or a zone of values is also on the physical pi By prescribing a maximum intake of lead, however, desirable to supplement the picture already in his involved. Everyone cor there is the implication that the harder a man works mind of one or more features of the effects of the scious of clinical urgenc in the atmosphere containing lead, the shorter time compounds. Non-medical personnel, however, are urgency. The state of it he should be permitted to do so. Thus, merely to not as a rule in the same position. They are likely approach to enviromm give a maximum permissible concentration without to use, and in fact do use, phrases such as " Arsine-- implied in the table of giving the severity of the work and the time engaged oh yes, about as toxic as bromine, isn't it ? ", or, my laboratories (Table per day in such work, leaves one entirely in the dark " Tetrachloroethane--yes, yes, quite troublesome-- The actual values givt as to what a man is absorbing. Lane (1949) and about as bad as hydrochloric acid ", because, in fact, in the light of experiei Kehoe (1949) substantially agree that at 1-5 to their maximum allowable concentration values are emerged from a search 2 mg./10 cm. " cases of disabling lead intoxication identical, but, it must be noted, for very different and experimental record do not occur among men who work regularly in such reasons. Toxic hazards should, in general, be con likely. Still, some ha\ workrooms, and cases of questionable or mild sidered as identities with their own numerical data example, in the case intoxications are rare ". attached to them and their own effects attached to ammonia, ethanol. But Lane is not slavishly attached to this maximum the numerical data. allowable concentration and insists {toe. cit.) that the Hazards may have to be classified into groups for 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 " h 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 pan of exposed effects or relative dangers. This is even more strongly illustrated in the highly dangerous zone 0-1-2 p.p.m. DR1NICER AND COOK ZONES (EXPANDED) The first three coium: by certain concentrator dangerous symptoms ; concentrations which two columns give concc limit to satisfactory c particular substance (d The use of the w concentration " has be we hold that no cono are worse than others Anima For industrial toxico 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 these concentrations when they proposed a zoning system, whereby, it was stated, the toxicity of an industrial atmospheric contaminant could be quickly assessed from the zone in which it falls. Six zones were given as follows 0-1 p.p.m. 0-5 p.p.m. 10 p.p.m. 2-0 p.p.m. Hydrogen Ariine selemde Bromine Iodine Cyanogen chloride Siibine Ethyleneglycol dinitrate Phosgene Phosphorus tri chloride Ketene Nitroglycerine Chlorine S p-Chlor aniline Hydrazoic : /vChlor-mtrobenzene acid Ethylene chlorohydrtn Hydrogen fluoride N.B.--HCN 10 p.p.m. In this table we have some of the most fulminating poisons met with in industry, and it would be in the highest degree undesirable to bracket them together to use animals in exp< conditions. Most in result of absorption 1 much more rarely by i most, acute and chronh Very little is known ( substance thus absorbs Factors of safety r animal experiments depending upon ma: upon his greater activi can be made of the arr absorbed by men at 500-2.000 p.p.m. \ ) 00- 500 p.p.m. 20- 100 p.p.m. 2- 20 p.p.m. 01- 2 p.p.m. 0 1 p.p.m. acetone, petrol, ether methanol, toluene benzene, butanol. CC!. CO Ht$, CS-.CfH.CI,. HCl, HCN Cl. COCls. A*H ,, (CH ,^SO 4 radon, radioactive Stases, etc. 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 environmental condit estimated by exposin estimate. Since the r many times greater th They added : " The zoning scheme is for the on the circulatory mechanics ; others because of the fume concentrations classification of information and not for the justifi effects of their metabolic products on haemoglobin : without adverse effec cation of excessive exposure or misguided legal still others because they cause a dangerous increase as equally inoffensive interpretation.'" of the permeability of the pulmonary vessels ; and concerned. Tables of maximum allowable concentrations must others because of disruptive effects on the envelope Cutaneous absorp not evoke responses which are entirely unjustified of the blood corpuscles. great importance in and even dangerous. Classification in zones cannot So diverse a picture demands different degrees of and in the field use c fail to influence non-medical personnel by suggesting urgency in persons whose responsibility it is to and herbicides. similar toxicities of substances, the effects of which prevent, concentrations above those prescribed. Quantitative meas are entirely different. For a doctor the association Moreover, the sense of urgency must clearly depend neous absorption in :ine INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 3 alue or a zone of values is it the picture already in his features of the effects of thtj iical personnel, however, are ne position. They are likely >e, phrases such as " Arsine-- : as bromine, isn't it ? ", or yes, yes, quite troublesome-- hloric acid ", because, in factj ible concentration values are be noted; for very different is should, in general, be conith their own numerical data their own effects attached to 0 be classified into groups for to memory, but this must be ity of toxic effects and not on ess of maximum allowable -IC1 and HCN are in the same one (2-20 p-.p.m.) as aniline, nitriU^ells us nothing of thein angv^ This is even more 1 ttvs^Rghly dangerous zone .'OOK ZONES 1 EXPANDED' 1 *0 p.p.m. 2 0 p.p.m. Chlorine ^Chlor aniline Hydraioic p-Chlor-nitrobenzene ic acid EihvJene chlorobydrmJ Hydrogen fluoride i* --HCN 10 p.p.m. e some of the most fulminating ndustry, and it would be in the rable to bracket them togethei :r. For, whereas some of the or immediate irritation, others :s, and others again for cumuappear because of their effects chanics ; others because of the olic products on haemoglobin ^ "ley cause a dangerous increase jf the pulmonary vessels ; and ruptive effects on the envelope :es. -e demands different degrees of whose responsibility it is to ons ^\ve those prescribed, of ufijimcy must clearly depend also on the physical properties of the compounds parative measurements can be made with small involved. Everyone concerned must be made con animals by time measurements from the onset of scious of clinical urgency as well as of quantitative symptoms to death, or to measurable biochemical urgency. The state of mind which informs our own effects after immersion of anatomical appendages, approach to environmental contaminants is that such as paws or tails, in known concentrations of implied in the table of concentrations issued from the compounds studied. Many substances are more my laboratories (Table 1). toxic cutaneously than orally. The actual values given may require modification The demonstration of dermatitic effects in animals ia the light of experience, but as each figure has which do not perspire in any sense similar to that emerged from a searching examination of clinical seen in man is usually impossible although an a;td experimental records, great modifications are not urticaria-like reaction is sometimes seen. The likely. Still, some have already been made ; for phenomena of " contact dermatitis ", " sensitization example, in the case of formaldehyde, acetone, dermatitis ", " allergic dermatitis ", or " eczema " ammonia, ethanol. are not reproducible in animals in experimental The first three columns indicate the times required conditions. Complicated immunological demon by certain concentrations to produce very severe and strations that some chemical compounds can act in dangerous symptoms ; the next two columns give appropriate conditions as skin allergens are possible concentrations which are not tolerated ; the las: and such demonstrations have corresponded with the two columns give concentrations which set an upper known properties of some organic compounds. limit to satisfactory conditions in respect of the Erythema and oedema should be measured according c.'.r-.icular substance (design concentrations). to determined scales (Draize, Woodard, and Calvery, The use of the words " maximum allowable 1944). The skin of laboratory animals does not concentration " has been avoided because at l.C.I. respond as does human skin to the host of chemical we hold that no concentration is allowable. Some substances which induce dermatitis of the acute are worse than others but all are bad. variety so frequently seen in industrial conditions. Animal Experiment In the case of cutaneous cancer the correspondence is closer. Thus, animal experiment is largely Forindustrial 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 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, growth, 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 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 animals, is used by some American authorities as a clinical-statistical index of undue absorption of many toxic organic compounds. There are some explosive estimated by exposing animals to multiples of that compounds (made and used both here and in other estimate. Since the metabolism of small animals is countries) which are rapidly hypotensive in working many times greater than that of man, gas, vapour, or conditions: blood pressure determinations are fume concentrations at which animals can subsist essential for proper medical control in these cases, without adverse effects may be reasonably regarded especially as pseudo-anginal attacks may follow as equally inoffensive to man as far as overt signs are long-term exposure. Many industrial compounds concerned. can be shown experimentally to depress the heart, Cutaneous absorption of toxic materials is of dilate the peripheral vessels, or increase vascular great importance in the organic chemical industry permeability. Others, by, cholinesterase inhibition, and in the field use of toxic insecticides, fungicides, lead to parasympathetic stimulation and vagal effects and herbicides. on the heart. The question of the establishment of Quantitative measurement of the degree of cuta hypertension, perhaps of renal origin, in chronic lead neous absorption in animals is difficult, but com absorption is not resolved. C* U o BRITISH JOURNAL OF INDUSTRIAL MEDICINE Table 1 TOXIC CONCENTRATION'S OF VARIOUS CASES, DUSTS. FUMES, AND METALS IN THE ATMOSPHERE (I.CL Industrial Products and Health Research Committee) No. Cas (I) Concentrations Causing Severe Toxic Effects in Persons Exposed for the Stated Times <2) Concentrations which, if Exposure Continues for more than a Short Time, may Lead to Symptoms of illness 1 (3) [ Concentrations in General Atmosphere of Plant Greater than those beto*.' indicate Unsatisfactory Conditions (mg. /cu.* Time of ! (mg./cu.* j (mr./eu.* i v.v) metre 20*C) Exposure (Min.) (p.p.m. j metre v,v) | 20*C.) Ip.pjii. i metre t) 1 2trc.) Acetaldehyde Acetic acid .. 3 Acetone 4 Acetone cyanohydrin 5 Acetonyl acetone . 6 I Acetophenone 7 , Acetyl chloride 8 Acrolein 9 10 Acrylonitrile AIM alcohol oowo 1.000 60 i 500 200 , 500 i 60 40 4.000 ; 9.650 1 60 600 40 1 140 J 20 300 1,424 i 60 150 80 400 ; 60 40 10 33 1 1 2 20 46 1 8 100 220 50 40 < 96 20 915 100 1.930 71702 200 6*6 18-6 n4o8 1 1 ! 1 1 1 I; *00 20 400 10 20 i $ 20 s J66 $0 9C$ 3$ JSC m 3-3 2b0 44 22 i I Ally} chloride .12 Ammonia .. 13 iso Amyl aceute 14 iso Amyl alcohol 15 \ Aniline 16 a,cion 6 (Freon 12) j (Difluorodichioromcthane) 17 j Arane 18 Benzene (Benzol) .. 19 Benzine (a* Hexane) 20 Benzyl aceute 21 Benzyl chloride Bromine Buudtene 24 *-Buunol (Butyl alcohol, 125 2-Butanone (Methyl ethyl ketone r-Butyl aceute rfButyl methacrylate Carbon dioxide Carbon disulphide.. Carbon monoxide.. Carbon tetrachloride 31 p-Chloraniline 32 (mono) Chlorobenzene 33 2-Chiorobuudienc 34 Chlorine 35 P-Chloronitrobenzene 36 Chloroform 37 io Si p) (mono) Chlorotoluei 38 Cyanogen chloride 39 Cyclohexane 40 CycJohexanol 41 Cyclohexanone 42 Cyclohexylamine .. 43 oDichlorobenzene 44 h^Diehlorodiethyl ether. 45 Iris A irons) Dichloroethyl 46 Dtcysriohexylarmne 47 Diethyl carbonate 48 D*-isobutylene 49 Di-isobutyl ketone 50 Dimethyl dioxane .. 51 Dimethyl sulphate.. 32 Dioxane 53 Ethanol (Ethyl alcohol) 54 Ether (diEthylj 55 fe-Ethoxycihyl methacrylate 56 Ethyl aceute 57 Ethyl aeetoaeeuie.. 58 Ethyl benzoate 59 Ethyl bromide 60 Ethyl chloride 200 < 636 ' 500 , 255 I 1,000 ? 5.410 400 1.464 80 ' 312 60 1 60 60 60 50.000 10 1.500 2.000 100 : 251.700 22 4.800 10.728 , 616 ' 60 ! 60 60 60 100 I 3 20 1 B.oOO 17.968 60 1.000 3.080 60 See No. 90 Methv) ethvl ketone 2.000 9.650 60 | 800 4.724 60 . 30.000 54.920 ` 60 500 1.600 60 400 464 60 | 2.000 12.800 i 60 8 400 100 10 10 2.000 400 2.000 1.000 i 1 1 44 1.872 368 29 66 9.960 2,106 13 6.990 4,160 | 1 60 ] 1 1 60 60 1 60 60 1.000 100 300 100 2,000 50 800 4.000 400 500 , 4.080 ! 410 1.S36 ! 593 ; 8,072 388 ! 2.928 18.640 1 1.896 1 2.412 ' ; 1 , 1 i 1 60 1 60 1 60 60 60 60 60 60 15 500 8.000 8.000 500 2.000 22S 20 250 10.000 i 78 1.830 , 15.312 24,624 3.285 7.320 i 1.080 1.248 1 1.135 j 26.830 1 60 60 60 60 60 60 60 60 60 I 100 200 200 i 200 ' 20 1 20.000 iI 500 1,000 50 10 i1 5.000 100 500 400 i io.ooo 150 1 100 i 500 i4 200 50 4 4 500 200 .2 800 i 400 I 200 1 40 ; 100 30 1 1.000 ' 40 , 400 1 2.000 i 200 1 300 10 | 300 2.000 ! 2.000 ! 200 800 100 j 100 100 I 5.000 I 318 142 < 100 1.622 1 100 ! 732 , lvo | 78 1 10 j 100.680 I 3-2 1.600 3.576 ' 313 i 50 6-6 1 11.230 1 308 I1 10,0000. 1 $0 2S0 i IS $0 ! 2.412 2.362 1 18.310 < 480 116 : 3,200 200 200 $.000 10 $(1 $0 936 184 12 26 2.490 1.053 5-2 1 2.796 1.664 ' n 7$ .i t J 1 0$ 400 100 , 816 i 164 612 i 178 4,036 ' 302 i 1.964 1 9.320 ! 948 | 1.447 7$ 20 *$ 1$ $00 20 200 1,000 200 1 200 52 1.098 3.828 6.156 1,314 2.928 540 624 454 13,415 2lHi 1,000 $Ou 100 400 SO SO SO 2,000 ISO 71 $41 3CC 39 $0,340 ICOVC $94 94 2$ J- 1$4 90$ 1,151 9,1$$ 32 $4 320 12 3S1 92 2-9 C-C 24U 39$ 2-3 1.39S 410 30C $2 1S3 SU 2,01s 2$J str* 4,000 474 90S 2ti 732 1,914 1.339 1,4C4 270 312 *.)? $,3CC 61 I Ethylene chlorhydnn 62 ; Ethylene dichlonde 63 . Ethylene glycol duiitrate 20 | 68 . I 500 I ~ 2.050 20 1 128 60 10 60 100 60 j t 34 410 6-4 il 01 , - 20$ Ji' Concentrations shown in become available. iuIic are tentative and are issued as a guide. Figures in all columns will be subject to review as more data I mg./cu. mentas4*J7 x ICM grains/cu. ft. Continued INDUS No. Gas 64 Ethylene oxide 65 Ethyl formate 66 Ethyiidene dichlonde 67 Ethyl silicate 68 Formaldehyde Freon 12 (Arcton 6) 64 Hvdrazotc acid 70 Hvdroscn chloride Hydrogen cyanide. . Hydrogen Auonde.. Hydrogen selemdc.. 74 Hydrogen sulphide 75 Iodine 76 Isophorone 77 Ketenc 78 Lauryl mercaptan .. 79 Mesityl oxide 80 Methacrolem 81 Methacrylic acid 82 Meihatlyi alcohol .. $3 Methanol (Methyl alcohe K4 Methyl aceute 85 Methyl acrylate 86 Methyl bromide 87 i Methyl iso-butyl ketone 88 i Methyl s-chioracrylate 84 Methyl chloride 90 Methyl ethyl ketone (2-5 91 Methyl iodide 92 Methyl cyclohexanone 93 Methylene chloride 94 Methyl formate 9956 i! Methyl methacrylate Naphtha distillate (as C 97 1 Nickel carbonyl Nitrobenzene 99 | Nitroethane 100 1 Nitrous fumes (as N0) ioi ! Nitroglycerine 102 l Nitromethane 103 1 1-Nitropropane 104 : 2-Nttropropane 105 . o-Nitrotoluene 106 i Perchloroethylene (Te 107 i >Propiolactone isoPropyl alcohol.. 109 1 Phosgene no ' Phosphorus trichloride in Stibine 112 ' Styrene 113 ` Sulphur dioxide IU , Sulphur monochioride us : Sulphury! chloride.. 116 ` Tetrachlorethane .. -- 1 Tetrachloroethylene ( III Thionyl chloride .. Thiophosphoryl trichlc 119 Trichloroethylene .. 120 Toluene (Toluol) .. 121 (o, m. Si. p) Toluidincs 122 Vinyl chloride 123 Xylenes (Xyiols) .. 124 XyHtiines 125 Antimony (dust or sa 126 Arsemous oxide 127 I Barium salts (as Ba) Concentration* shown in become available. CINE IS IN THE ATMOSPHERE :> tons which, ? Continues lan a Short y Lead to 3ms of less (3) Concentrations in Central Atmosphere of Plant Greater than those below Indicate Unsatisfactory Conditions (mg./cu.* metre 20*C.) j (.p.p.m. V v) (mg./cu.* metre I Jo'c.) 915 too -1.930 70 712 200 66 18-6 110 48 318 142 1.623 732 78 .no 366 20 SO ton 06S 10 3S 556 20 J00 i 3w 5 11-6 JO 44 i 22 SO iso 100 71 100 541 Itm 360 10 ' 30 100,680 3-: 1.600 SaP 6*6 tl.230 308 19,000 n.y SO 2S0 IS s (is 2,500 so : 40.31V 1-6 ICO 304 94 23 3-5 5,625 154 2-412 2.362 18.310 480 116 3,200 -** 936 184 12 26 2,490 1.053 52 2,796 1,664 200 200 5.000 JO SO so J rs 25 J 1 So 7 it-S 400 100 90S 1.131 32 S3 320 11 3S1 02 *9 i-6 249 52S IS 1,396 416 816 164 612 178 4.036 302 1.964 9.320 948 1,447 75 20 25 IS S00 20 200 1,000 100 20*t SOU yj yj 2,0 IS ISl 232 4,660 474 965 32 1,098 3.828 6.136 1.314 2,928 540 624 454 13.415 M 410 S 200 1,000 , soo 100 400 SO so so 2,000 So 26 732 1,214 1,330 cs: 1,464 270 312 3,360 JOS 3-2 ill t to review os more data Continued INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY Table l continued No. Gas Concentrations Causing Struct Toxic Effects in Persons Exposed for the Stated Times (2> , Concentrations, which, ! if Exposure Continues 1 for more than a Short I Time, may Lead to Symptoms of Illness (3) Concentrations in General Atmosphere of Plant Greater than those below Indicate t/nsa/rj/ae/<v>- Conditions (p.p.m. Vf*l (mg./cu.* metre 20`C.J Time of Exposure (Min.; (p.p.m V/v) (mg..cu.4 metre 20*C.) (p.p.m. r/r) metre 50* C.) E'hylene oxide Ethyl formate Ethylidene dichlonde Ethyl silicate Formaldehyde Freon 12 (Arcton 6) fA Hydraxotc acid "0 Hydrogen chloride 250 ! i.ooo | 400 400 ; too 450 > 60 100 180 3.080 i 60 i 400 ! 1.232 1.648 60 200 824 3.464 60 200 1.732 120 1 30 36 10 200 SO 100 10 1 See No. 16 Arcton 6. 10 > IS 60 4 7-2 ! 1 50 73 20 30 ; 10 IS 6W 206 12 ; IS H ydrogen cyanide.. Hydrogen fluoride.. Hydrogen sclcnide.. Hydrogen sulphide Iodine T6 Isophorone.. 77 Kctene Lauryl mercaptan .. `9 Mesityl oxide <0 Meihacrolein 40 40 2 200 0*5 40 ' ! 20 200 1 10 44 34 2806 5*5 1 228 ! 3-6 1 168 [ 816 1 29 I 1 1 1 1 60 20 10 0*5 50 0*2 20 1 10 100 5 * 8-5 1-5 70 2-2 114 1*8 84 408 15 10 01 20 thi 10 OS so 1 : U J 0 23 ; 57 0 42 204 5 s l Methacryljc acid .. *2 Meihallyi alcohol .. >3 Methanol (Methyl alcohol) $4 Methyl acetate $5 Methyl acrylate 86 Methyl bromide 37 Methyl tr^-butyl ketone .. 48 Methyl a-chloracrylate 89 Methyl chloride 90 Methyl ethyl ketone (2*Butanone) J.000 3,575 i 400 150 450 1 100 2.000 2J60 60 500 500 1 1.540 1 60 200 100 i 356 50 250 ! 1.000 50 1,000 1 4,160 60 400 4 1 , 20 i 12 1.500 ' 3.150 60 500 2.000 1 5,990 i 60 500 1.430 300 640 616 178 200 1,664 10 1.050 1,498 200 J 7IS so 1 150 200 1 256 100 1 SOS js ! 39 20 i so 200 1 332 1' 5 J00 210 200 \ 392 91 92 93 94 9? *6 V9 100 101 IU2 103 104 105 106 J07 108 109 no 111 112 >13 114 115 116 117 118 119 120 oT 122 123 124 Methyl iodide Methyl cyclohexanone Methylene chloride Methyl formate Methyl methacrylate Naphtha distillate (as Cumene) Nickel carbonyl Nitrobenzene Nitroethane Nitrous fumes (as NO,) .. i i i ; i Nitroglycerine Nitromethanc ........................... ........................... 1 1 1-Nitropropane 2-Nitropropane ; o-Nitrotoluene 1 Perchloroethylene (TetrachJoroethylcne) j1 2-Propioiactone 1 uo-Propyi alcohol.. 1 Phosgene Phosphorus trichloride : ' Subme -Styrene Sulphur dioxide Sulphur monochloride (S.CIJ .. Sulphury) chloride.. Tetrachlorethane .. Tctracbloroethyienc (Perchloroethylene) Thionyl chloride .. Thiophosphoryl trschloride Trichloroethylene........................... Toluene (Toluol)........................... (o, m. A p) Toluidines Vinyl chloride Xylenes (Xylols) .. XyJidines 40 300 2.000 1,000 3.000 300 4 200 800 100 236 1.400 7.072 2.495 12.480 1.500 28 1.020 2,496 190 1 ! ' ! 1 ! l 1 60 60 60 60 60 I 60 60 I 20 800 400 400 200 1.000 100 2.000 5 2 : , ! 1 1 189 2.028 1.480 1,480 1.140 6.905 300 4,995 21 12 1 ! ! : 1 60 60 60 60 60 60 1 60 1 l OS 2 5 * 1.000 i 4,330 60 200 ! 520 j ] 20 112 i 10 i 56 ; 50 350 60 t No. 106 Perchloroethylene. 20 10 i! 17000 :i 2.000 i 10.940 1 60 1.000 i 3.830 60 40 3.000 1.000 40 176 7.800 4,410 200 60 60 60 60 20 1 150 1 1.000 400 1 2.000 ' 150 2 40 500 . 30 118 i 700 3.536 998 8,320 750 14 204 1.560 57 j 10 ; 75 soo I 200 ! 1,000 50 J J , 200 1 10 , so 1 ISO 1,763 , 429 4,160 250 624 ! 19 1 9-4 i 500 ' 1.268 200 200 740 1 100 200 740 100 ' 40 228 1 400 . 2.762 I 200 1 20 60 ; 10 j 800 1,998 < 400 ,1 4-2 OS i i ; 5*s | 0-5 4507 370 370 JJ31 30 299 2- 0*2 200 20 10 4 20 1 10 >4 | 800 ' 300 i 10 ! 1.500 300 10 J 866 | QJ i 100 OS 433 52 10 1 26 56 23 22 ;! 5*6* 140 10 70 50 s ! :s 28 1 i| 076 400 j 2,133 1,149 I 100 I 333 44 3,900 1,323 50 5 o 500 1,300 100 441 S 25 Dusts. Fumes, and Metal* ^ Antimony (dust or salts) (as Sb).. Arsemous oxide 1-7 Barium salts (as Ba) OS OS OS Conccnipiioni ihown in italic arc tentative and air taauetf aa a guide. Finns in ail aalumna will be aubiect to review is more data available. ' 1 mg./cu. metre a 4-37 x I0-4 graim|OL ft. Continued n6 Table I continued BRITISH JOURNAL OF INDUSTRIAL MEDICINE No. Gas (U Concentrations Causing Severe Toxic Effects in Persons Exposed for the Stated Times UJ Concentrations which, if Exposure Continues for more than a Short Time, may Lead to Symptoms of Illness (4) Concentration* in General Atmosphere of Plant Greater than those below Indicate Unsatisfactory Conditions i:s 129 130 131 132 133 134 133 - 136 r 137 138 139 140 HI 142 -M3 144 M5 146 147 148 149 150 151 Benzidine .. Cadmium .. Chlorinated diphenyl Chlorinated naphthalenes Chromates (as CrOa) Dtmtrocresoi (and salts) .. Dmiirophenol (and salts).. Dinurorcsoronoi .. Dinitrotoluenc * Dowihem A ** Lead (and salts) Mercurv........................... a-Naphthylamine .. ^-Naphthylimme .. ** Parathton *' Pentachlorphenol .. /^Phenylene diamme Phosphorus pentacbloride Potassium permanganate.. Sulphuric acid Sodium cvanidc Tetr\l ........................... T.N.T..................................... Zinc oxide .. (mc-icu. * j Time or (p-pjn. metre Exposure (p.p.m , metre vl 20*C.) | (Min.) V/V) ! 20-C) _ _.. __ | __ _ -- -- -- , --- ---- -- ---- _ ___ __ __ __ -- -- -- -- _ __ _ -- -- ___ __ __ -- -- ___ _ __ -- -- _ _ ---- ___ -- ---- __ __ -- -- __ -- -- -- -- i-- _ ___ ---- -- __ 1-- ---- __ -- -- -- -- _-- ------ ---- -- ---- -- -- _ -- 1-- ____ _-- ---- -- -- -- _ __ ---- ---- -- ---- _ ____ -- -- (p.pjn. rfr) __ -- -- __ -- -- -- -- -- -- -- -- __ -- -- -- -- -- -- -- -- -- -- 1 (mg.lcu.* . metre \ SO1 c.i Q-02S ti'l 'J )2 0'J 1 vs 11 i1 1 1' -ff-iJ 0-2 0-02 0-02 2 OS 01 1 it 2 *, 10 Concentrations shown is italic are tentative and are issued as a guide. Figures in all columns will be subject to review as more data become available. 1 mg.^cu. metre s 4*37 x I0-* 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 Gage, 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.CrO. 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. uon oi nne if mononuclear p alveolar walls. both in the wa alveoli and eoa rial in the phag< NE which. mtinues a Short sad to of ng.,cu.* metre :o`C.) in(i) Concen:rations General Atmosphere of Plant Greater than those below indicate Unsatisfactory Conditions (p.p.m. *) -, # 1 " i] be subject to review as more data ;nsive industrial pulmonary t of a lung of a rat which, ats, was exposed for eight tonths to an atmosphere of. very fine dust. The animals vas a period of coughing and Ting serious. They lived on d the chromate with bored nows large and small areas >ii crammed with loaded stages of degeneration, are out of action. The cell ntributes further to loss of f. Dilated respiratory bronlysema, due partly to the ornate on the alveolar septa, .tion to the leaded alveoli, r picture of a portion of a exposure for months to a n of lead acetate (40-50 of thedust cells from the cl^j seen, but monopertrejffv from the capillary e passing into the 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 in the phagocytes. 300. Fig. 1.--Rat lung after chronic exposure to fine potassium chroi: many areas of exsanguinated, functionless alveoli filled nh phagocytes and many ruptured alveoli, x 100. FtC. 2j.--Phagocytosis of blood phagoc>ies b> macrophages deriving from septa( cells; details of coarse pigment granule* m guineapig lung. . 1200. eawgr-. Q INDili Fic. 3.--Rabbit lung showing chronic inhalation of fine lead acetate dust. Three areas of same lung showing different stages in development and death of lung phagocytes \ small alveolus crammed with dead and dying phagocytes swollen with absorbed panicles; note multi* nuclear macrophage. - 560. These cells are later 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 {i.e. 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 multinucleate 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 i formation. These effects with equal ease in all spe The deliberate inductio in the treatment of cyani importance, and recover been obtained by Lloyd : depends upon the intrav nitrite which, by formin' the circulating cyanide to toxic cyanmethaemoglob injection of sodium thic the formation of thiocy liberated cyanide. Renal and hepatic ft many chemical agents ; industrial metallic poiso: chlorinated aliphatic hyc vatives of glycols. Re endangered for the chan structural breakdown i: peculiar position of tr commonly used solven subtle must be the mec: low toxicity, which is i metabolism to the no (Taylor, 1936 ; Powell. For certain metabo carcinogenicity the use ( and wider significance, one carbon C14 has members of my depar Amersham (Henson, ! Somerville, 1953). W< establish important met retention of compounc in the body (Henson, E Goldblatt, 1954). The toxic compounds in c histological sections is The ultimate fate o: industrial conditions i known about some of chemical substances at we are very rarely able or even extraordinary ways in which compk the body in large p; difficulties and appp using labelled compou in obtaining almost co and output of substan and in discovering ho^ derivatives are retaint is possible to track th B INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 9 * 3wi.ng different stages in development with absorbed particles ; note multi- : lung is paid for in the case; jdation of the precursors of Jj .e. modified septal cells) and .' the occupation of alveolar;1 d cells and cell debris when! charged. The formation oft . also occurs in the chronic: (Fig. 3). In a universe of' id are inevitable but it is ourij idustrial dust with other jj ^nents are mainly found in ! ;posed to carbon monoxide,! and Jno-compounds, and 5 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 learn where they are deposited. \wth 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 been 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 toxic cyanmethaemoglobin and upon the intravenous interference with normal thyroid function as in the niection of sodium thiosulphate which accelerates case of some alkyl-nitro-amino derivatives of phenol. the formation of thiocyanate from the now slowly The haematopoietic system is one of the first iiberated 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 reculiar 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 Clinical and Experimental Aspects of Lead Intoxication one carbon C14 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 \mersham (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, e<;abl;sh 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 Goldblatt. 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 cells. 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 ''e are very rarely able to strike a balance by ordinary boy or girl can be trained to do it and even interpret r even 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 's possible to track them through the various routes from the high (stipple and polychrome) counts. Nor - 10 n BRITISH JOURNAL OF INDUSTRIAL MEDICINE I INDUS Oo' c a FiC. 4.--Rabbit blood suined with alkaline methylene blue and photo* graphed 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 of recognizing stipples (golden granules) and two polychromatic cells : the polychromatic ceils are manifestly very hnel> stippled cells. is the stipple and polychromatic count sufficient, for a relatively low count is frequently found with a very low haemoglobin fFig. 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 is concerned. Moreover, men kept on at work in spite or evidence of lead intoxication do not develop a proper respect for lead and hence develop recurrent attacks of lead poisoning (see 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 hos pital (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 relativeh 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 c 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. Certi fied as fit to work after 21 days, the patient was again |ic. 6.--Relation between hae in workers exposed 10 a cuumoed shown with Ht ^ ear No. Name Ti: L< J>JC 1927 jyii I9jy 1 F.C. 2 V* ,p. 3 G.F.K. i J.S. S 10 :r 5 S.F. 26 6 k.A.M. 7 A.W . 16 S P.N. 2r 6 9 T.H. n IB 10 E.M. 28 U F.H.NV. 1 (Al !NE INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 11 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. 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 (loc. cir.) 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 changes in the bone marrow. The stippled red cell derives from stipple normo blasts in the marrow, both of which may be seen in ied with alkaline methylene blue aatf ground illumination showing ease of den granules) and two polychromatic tic ceils are manifestly very rtneb ( the circulating blood (Figs. 10 and 11). The stipples 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 during lead intoxication. Pirrie (1952), using guinea- return to work (Foreman,' lelknap. 1953). i shasized that the usual forms re self-limited, of relatively: 3- . r --Relation between haemoglobin and stipple-polychrome counts in * oncers exposed to a lead dust hazard. Numbers of bloods examined shown with Hb values. (See text). pigs, found as many as 55% of haemoglobinating normoblasts in the marrow showing basophil stippling when only 2-5% of red blood cells were ,t there is complete recovery; oeen terminated, and that no; the blood-forming tissues is! ;m. The cases to which this jplv are the now exceedingly nd muscle palsies. j 1 of picture one would wish vho took five years to recover , ugh removed from contact' erton. 1952). i i on a case of some interest.! on lead were followed by at om which the patient was! ile still at the factory doing] contact with lead. In spite! the number of stipples andj haemoglobin level recovered; t on work with lead! : wljgj^was certified. Certi-j 21 days, the patient was again! Table 2 LOST TIME OF TWO GROUPS Certified* Uncertified! Year No.- Name Time Lost Year I1 No.! Name Time Lost Year No.. Time Lost Year ; No.. Name Time Lott 1 F.G. 2 W.P. 3 G.F.K. 4 J.S. S.F. k.a.m. A.W. P.N. 9 I T.H. 8 days 10 days 2 mite. 26 days 15 days 16 days 2 mihs. 6 days 13 days 18 days 1040 13 2941 1 -- J94S -- 1941 20: 11 14 1944 17:4 15 W.C. A.H.T. _ -- ISJ6 3 days l mth. 13 days 28 : 10 I I 94 ::1121 i-- i 14 : 10 1 28 : 10 1 GSM.t 1 1 mth. 1 4 days ] 1SJ7 24 : 3 5:5 C.F.M. 30 days 2'jSO 10 : E.M. i 23 days 11 ! F.H.W. 1 mth. i I 21 days 1933 13 : 12! E.E. j Nil .. ! Nil W.F. ; Nil \ F.C. Nil . F.X. : Nil , F.K. 1 H.E.W. 1 Nil i S day] '(Hb. 75 r.) gastritis IMS 23 : 1 mo 23 :9 mi 16 C.F.H. 17 A.E.P. 18 . A.W, 19 H.J. 20 G.M. i1 -- i ! | 1 Nil 20 days' investigation Nil Nil Nil i W.F. Nil mi ; --; I W.F. 1 F.C. CJ.H. Nil Nil Nil 1913 1 22 : 5 . 21 H.J. Nil J.L. 1 R'' Nil Nil 1944 ! -- -- 1 C.F.H. I W.R. Nil ms ' Nil 26 : I 22 H.J. Certified-recovery away from factory, tUncertified-recovery at work. (All cases 60-65% Hb at time of certificauoo or action in factory.) ;Recurrent cases in italic. If -*---7' r^)\2 BRITISH JOURNAL OF INDUSTRIAL MEDICINE Table 3 PERIOD OF RECOVERY OF Hb W F AGE <1-53 YEARS. Hb 8 Supples 'Polychromes'. Stow Hb recovery-- maintained htjh (Sr P) during Non-lead Maintained at Work Removed to Home or Hospital No. ot Cases 24 9 Hb at time of transfer .. Mean time to reach 80% or more 5-70% 1*93 months (3 weeks-7$ months) 1-66 months (16 days-2} months) Indicates slight advantage of getting man away from factory even on light and non-lead work. 1 ease of Hb 43-45% recovered to 80% m 28 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 corrmle'ely removes the basophilic material and leaves the cells uniformly acidophil. 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. Fjc. 7.--Case of lead anaemia showing extremely slow recovery of haemoglobin whilst maintained at work. T.H. AGE 29-32 YEARS. Returned to 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. Fjc. 8.---Case of certified plumbism considered clinically fit to return to work, but thereafter requiring almost two years to regain a sublc 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. H.T. AGE St-57 YEARS. Cue of Sensitivity end Recurrence. MacFadzean and Davis (1949), Pirrie (loc. cii.), Rimington (1938), Kench, Lane, and Varley (1952), Dustin (1942), and others have gone far to elucidate the nature of the stippling property of the erythrocyte in lead absorption. FtC. 9 --Case of sensitivity and recurrent lead anaemia in spite of long periods on non-lead work. Close correspondence of Hb and stipple values. % v.-.rrr: Q i INI ; 4g-S3 YEARS. iromes . Slow Hb recovery. ) during Non lead ~V ,wwf^_ 34 yean 5 of extremely slow recovery of numed at work. 4. AGE 19-32 YEARS. *ork before blood r*eovry-*Kr recovery in factory. Mr' .It Cert* I days) f t 1 *__ Non-Pb on-Pb 234 years oism considered ciinicaHy fit to r requiring almost two years to d work. H.T. ACE 5-S7 YEARS k of Sen*nv<y tr*4 Recurrence. ls `Polychromes Never Certified. vx 1-- >ry f'Ayr _____Hor~^. 2 3 4 5 6 years nd t lead anaemia in spite ad Close correspondence of Fjc. J1.--Rabbit bone marrow after chronic lead inhalation show ing coarsely stippled normoblast (R.B.C. somewhat out of focus), x 2000. Fic. II.--Rabbit blood fier chronicleai! inhalation jhow.nj reueulocues supra wtal staining wh brilliant cresjl blue. x j 200. Fig. 13.--Rabbit blood on same occasion as Fig. 12 (dry film stained with brilliant crdyl blue) in which reticu locytes are seen as cells with vacuolated basophilic material, x 1200. n 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 of lead 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 (o) 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, ccyanide, 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.50. ORGANO-PHOSPHATE INSECTICIDES* Compound Oral L.D.50 l.P. L.D.S0 T.E.P.P....................................... Paraoxon Dimefox Svtiox (Commercial) S P >P-0- 1-2 R.f. 2*0 R.m. 3-5 R.m.f. 5 R.m. 6-39-9-7 R.m. 0-65 R 1-2 R.m.f. 4 5-8 37 R.m. 7-3 R.m. 0 >pi;-s- .. Pesiox (O.M.P.A. Schradan) Parathion ........................... E.P.N. Mipafox Malathion t-S R.m. $-7-10-0 R.m.f. 6 R.f. 15 R.m. M 5 R.f. 91-0 R.m. < V., Parathion 2.426 R.f. 2.860 R.m. 8-0-6 5 R.m.f. 4 R.f. 7 R.m. 50 M. 750 R. Median lethal doses of organo-phosphate insecticides. R -- nu, M * mice, m male, f -- female. All values in mg./Kg. parathion and tetraethyl pyrophosphate (T.E.P.P.). Thus " mipafox", which is the mono-isopropvl analogue of " dimefox ", is perhaps 25 times less toxic than "parathion", and "malathion" about 200 times less toxic to mammals. The optimism engendered by these facts is tempered in the case of " malathion " 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 1). par; 2). T.E. 3). PES' 4). PAR/ 5). E.P. DIME 7). M I PI 8). SYS 9) M t ORGANO-PHOSPHORUS INSEC TIC IDES l). PARATHION II/c2h \o C2H5 2) . T.E.P.P. 3). PESTOX CCH3')2N. ^ U/NCCH^ CCH^N7 NCCH^ 4). PARAOXON o2n 5). E.P. N. (u.S.a) o2n _!/shs O-- P CH 2S 6). DIMEFOX D- mifPAFOX SYSTEMIC / 0 = P^-NH.CH^H3)a N^H.CH^Hg). SYSTEMIC 8)- SYSTOX cAs'cA-o-"<0C2H5 t malathion oc* CHOOCH.C S ^ I- II .OCH CH_.OOC.HC-- P--S\ 3 NOCH^ ' Fig. M.--Formulae of sclive compounds in organo-phosphorus imcctkcidau SYSTEMIC LEAST TOXIC i Q 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- isopropvl) 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, NjNa. 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 (1-35 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. 15.--Cervical cord and sciatic nerve of a fowl treated with a preparation of iricresyi phosphate calculated to contain 0-1% of the onho-iaomer. Total dose in 16 days -- 2 mg./kg. by mouth. First paralytic signs in 21 days followed by progressive worsening of paralysis of legs. Demyelination in anterior and lateral columns and markedly on sciatic cord. X 12- Marchi's method. A upper, and B -- lower, cervical cord -belo* sciatic nerve. t experiments havt effect on the ner variety of animal Occu There are ver have been showr gens to man. radiations (.v-ra naphthvlamine. pyrene. Of the host of which have proc mary gland, lung have been demor carcinogens. Th products as tar. established with 3-4 benzpyrene : this compound. Long-continue lions and work to indubitable : finally to epithei ment has been ; effect in animals In the case of ( as well as sever, followed long e though the turn sarcomata in ani differences are ; reached by the r Neoplastic ch often highly mal of workers expo and 'Or dust of reported for nea where organic clinical fact has in the U.S.A. t identical bladde b-naphthylaminr Clavson. and Jul tumours inducir amine in differe amount of urina excreted. More recent: benzidine and h research both ir the demonstrati benzidine in rats but bladder tur induced except INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 17 experiments have been carried out, and also the Maguigan, and Dobriner, 1950). The possibility effect on the nervous system studied in detail in a that here also the o-hydroxyamine is the immediate variety of animal species. carcinogen has received much consideration. Occupational Carcinogenesis The contribution made to the elucidation of the problem in this country has been notable and the There are very few identifiable agencies which names of Bridge (1934), Macalpine (1929,) Wignail have been shown without any doubt to be carcino (1929), Walpole, Williams, and Roberts (1954), gens to man. These are arsenical compounds, Scott (1952), Baker (1953), Bonser and others, radiations I'.v-ray. radium, ultra-violet light), {2- (1951), Bonser, Clayson, Jull, and Pyrah naphth> Limine. benzidine, and probably 3-4 benz- (1952) and more recently Case and Hosker (1954), p>rene. and Case, Hosker, McDonald, and Pearson (1954), Of the host of compounds and complex mixtures will always be remembered for the great light shed which have produced tumours of skin, liver, mam upon it. The total number of cases which Case and mary aland, lung, and bladder in animals, only these his colleagues (1954) were able to trace in the chemi have been demonstrated as direct or indirect human cal industry between 1900 and 1952 was 455. Case's carcinogens. The active agents in such carcinogenic classical statistical investigations are a model for products as tar, lubricating oil, soot, pitch, are not the future investigation of occupational diseases. established with certainty, although the isolation of Case and others have established on.a national scale 3-4 benzpyrene from tar casts strong suspicion on what others have found in industrial practice both this compound. in this country and elsewhere. Contact with the Long-continued therapy with arsenical prepara naphthylamines or benzidine is now fully recognized tions ana work with arsenical compounds have led as a carcinogenic hazard, and aniline appears to be to indubitable skin changes (hyperkeratosis) and exonerated. Some as yet cryptic factors in the finally to epitheliomata. But no convincing experi manufacture of magenta and auramine appear to ment has been published to demonstrate a similar throw suspicion on both these processes. The effect in animals. disease was prescribed as an industrial disease in In the case of certain radiations, neoplastic change 1953 in this country, just 58 years after the original as well as severe blood changes have undoubtedly description by Rehn. It is proper to record the followed long exposure in man and in animals, unremitting clinical control by Dr. Charles Cresdee though the tumours which develop are different-- for almost a quarter of a century in one very large sarcomata in animals and carcinomata in man. The centre where these compounds were manufactured, differences are attributable to the different tissues which has been a guide and an inspiration to those reached by the radiation. who have had to pursue the problem in the quiet Neoplastic changes, sometimes benign but most of the laboratory (for earlier work and review see often highly malignant and recurrent, in the bladders Goldblatt, 1947, 1949). of workers exposed for varying periods to the fume More recently, arguing very ingeniously from the and or dust of certain aromatic amines have been fact that these tumours had formerly been attributed reported for nearly 60 years in all parts of the world to aniline, which until now has not been proven to where organic dyestuffs are manufactured. This be a bladder carcinogen, Walpole, Williams, and clinical fact has been confirmed by experiment both Roberts (1954) in Manchester came to suspect 4- in the U.S.A. and in Britain with dogs in which amino diphenyl, which had been found in residues in identical bladder tumours were induced by feeding aniline manufacture 80 years ago, as the probable '--naphthylamine. It has been suggested by Bonser, cause. Experiments on dogs confirmed the presumed Clayson. and Jull (1951) that the incidence of bladder bladder carcinogenicity of this compound. tumours inducible by treatment with ^-naphthyl- Certain condensation compounds of the naph amine in different species is roughly related to the thylamines formerly used in the processing of rubber amount of urinary conjugates of 2-amino-l-naphthol have already been banned by manufacturers since excreted. new knowledge on the previously suspected but More recently the same suspicion fell upon uninvestigated incidence of vesical tumours in the benzidine and has been amply confirmed. Intensive rubber industry became available (Case and Hosker, research both inside and outside industry has led to 1954). the demonstration of the carcinogenic properties of Both the Leeds and Manchester workers have benzidine in rats (rectum, sebaceous ear glands, liver) come to place great emphasis on o-hydroxyamines but bladder tumours had until recently not been as the effective bladder carcinogens. This has induced except in the case of one dog (Spitz, opened a large speculative field of inquiry, because 18 BRITISH JOURNAL OF INDUSTRIAL MEDICINE a considerable number of hitherto unsuspected It will be difficult, if the observation is confirmed, aromatic amines and derivatives of them could to envisage the process here as other than one yield various o-hydroxyamines metabolically. initiated by local mechanical irritation but a The dilemma before industry in this field is chemical carcinogen is not ruled out although it is how to deal with the considerable numbers of more difficult to find support for it. It is not compounds that might carry suspicion. The sufficient to state that a given material is non project of examining all the derivatives of cyclic toxic. Toxicity as ordinarily understood is in hydrocarbons and their homologues which, in some sense the reverse of carcinogenicity. For their metabolism, might yield amines or derivatives whereas a compound exercising a toxic effect of amines of potential carcinogenicity must, how on a cell is driving that cell in the direction of ever, be undertaken. There is no escape from the inanition and death, one exerting a carcinogenic argument that if a compound is carcinogenic in effect on a normal cell is driving that cell towards animals, in whatever location in the body, it must excessive, if abnormal, function and, for a time, be so regarded, at least potentially, in man. In more vigorous life. This is not to say that a carcino some cases it is possible to circumvent carcino genic compound is never toxic in the ordinary sense, genicity chemically. In the case of -naphthylamine but rather that a toxic agent in full spate is unlikely this has been done in this country and in some to permit the establishment of carcinogenicity. continental countries by avoiding liberation of the Although the mean induction times for certain base at any stage of manufacture or use. Certain occupational carcinogens are long and not food azo-dyestuffs have already been rejected dependent on the severity of exposure, it is to be because of the possible metabolic fission of the noted that in some individuals the induction time relatively simple molecules with the liberation of a may be quite short and in others much longer than carcinogenic amine, in the absence of any but the mean. presumptive evidence. A systematic study of food colours on these lines is in progress in my Recent Work in the Diagnosis of Vesical Tumours laboratories. The need for continued medical supervision of In the industrial field the manner of attack must men who have been exposed in the past to bladder be cooperation between statisticians, industrial carcinogens is manifest even after exposure has doctors, and experimentalists. The statistical ceased, and even after leaving the industry. weapon is one which is potent in the hands of In a section of the chemical industry exfoliative specially gifted people, provided all the data are cytology is being used to detect early bladder collected on a pre-determined plan and all in tumours. In the U.S.A. the teaching of Papanicolaou possession of relevant records cooperate fully. (1947, 1948) on the importance of the recognition Before it is prudent to publish the view that a given of neoplastic changes in exfoliated cells has been material is not carcinogenic in any circumstances, much regarded. Cells may be exfoliated from the it is well to remember that experienced investigators lung, stomach, bladder, cervix, and vagina, and, have made such statements and subsequently have provided the morphological and staining characters been proved mistaken. of tumour cells can be recognized, there is no Experiment (in our hands as well as in others') theoretical reason why a neoplastic process should has failed to show carcinogenic properties in not be detectable at an early stage (see also chromates, but in the U.S.A. there is considerable Bamforth, 1953). statistical support that chromate dust can induce In the case of bladder tumours the early develop lung cancer (Machle and Gregorius, 1948) but ment is not attended by any disturbance of the Bidstrup (1951) was not able to draw clear con patient in either occupational or non-occupational clusions from her *-ray survey of 724 workers in cases. Hence arises the need to establish routine the industry in this country. Recent statistical urine examinations for microscopic blood, which is data in the U.S.A. show that chromate workers often the earliest sign of bladder irritation, of had a mortality rate for respiratory cancer 29 times ruptured small varicosities, of a broken frond of as great as would be expected among a comparable a small papilloma, or of the slow and insidious group of all males in the country (Federal Security oozing of an infiltrating carcinoma. In a small Agency, 1953). proportion of cases microscopic haematuria is In 1949 the Senior Medical Inspector of Factories unaccompanied by a tumour visible in the cysto- gave, reasons for the belief that the pulmonary scope, and -in a larger proportion there may be fibrosis in asbestosis is followed by an inordinately no blood in spite of the presence of a tumour. high percentage of cases of pulmonary cancer. In this country it is useless to recommend routine cystoscopy of wc the Continent a U.S.A. Hence u be made and t will, with the rr a correct picture To this end we scope of urinar mining the pict in normal subje colaou's metho hope later, b> malignancy. B those hitherto laboratories ha stain, character the types of cel! urine (Rofe. 15 normally interfe matter and det cells in 1 in 1> they were voic may thus be : urines contain urines contain 1 content other t two main part: sitional, 15u. a bladder); (b) sr from kidney a 15fi and under in various stag A very inte counts was th more leucocyt* could be accou whole blood, is always in a s: or mechanical. By applying R' glance all the * n . %+ *i O ,to^-opv 01'" orkers as it is practised on Continent and to some extent in the { 5 a Hence urinary examinations must be nude and every device used which w;il. with the minimum discomfort, give a correct picture of the inside of the organ. To this end we are seeking to enlarge the wpe of urinary examinations by deter- ntminc the picture of vesical exfoliation :n normal subjects, by applying Papani- '.n'C' methods to the urine, and, we hope iutcr. by cytochemical tests for nuiicnancs. By methods different from tr.osc hitherto used, Mr. Rofe in my laboratories has been able accurately to Ntain, characterize, separate, and count the types of ceils found in normal human urine (Rofe. 1955) after removal of the normally interfering organic and inorganic nutter and debris and concentrating the ceils in ! in 1.500 of the volume in which K- .ne> "ere voided. Certain conclusions ::u;. thus be stated : (1) Most normal urines contain blood. f2) Most normal urines contain leucocytes. (3) The cellular content other than these is divisible into two main parts (a) squamous and tran sitional. 15;u and over in size (urethra, bladder): ib) small epithelial cells derived from kidney and prostate fin the male) .i* Ir-i and under in size. These cells are m various stages of degeneration. \ sery interesting feature of these __> unis "as that there were always far more leucocytes in normal urine than could be accounted for by a simple transudation of "hole blood. This perhaps means that the bladder : always in a state of some irritation, either chemical or mechanical, which does not reach consciousness. applying Rofe's method it is possible to see at a dunce all the celk exfoliated in a given sample of 4 FiG. 16 urine. Having a reliable picture of the norma! 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 oI # Jr FtC. 16.--Smear from urine of worker m manufacture ofdyestuff intermediate; showing m throewej, po/> morphs. abnormal and degenerated epithelial cells, and several definite!* malt;*- nm cells. Papanicolaou's lechmoue of preparation and seaming. 500. Fic. 17.---Smear from another d>esiuif worker shoeing erythrocytes. man> polymorphs, and giant binuclcattd malignant cells. Papanicolaou V technique. 500. Q <1952) working in my laboratories. The value of chemical industry, and some of the difficulties and cytological diagnosis has been amply demonstrated. dilemmas which arise. This kind of work is merely The cytological criteria laid down by Papanicolaou the preliminary to the application of the knowledge for the diagnosis of malignancy include increased thereby obtained in the field and the factory. size and bizarre shapes; enlargement of nuclei It is there that the ultimate goal set by James in relation to cytoplasm; altered nuclear and 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 cystoscopicaliy visible tumours. 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. The cystoscope is not infallible, for we have had References cases in which a positive cytological diagnosis Baker. R. K. (1953). Canerr R'i,, 13, 131. Bamforth, J. (1953). Practitioner, 171, 2*4. was subsequently confirmed by cystoscopy after Barnes. J. M-. and Denz, F. A. (1953). J. Pork. Baa.. 65. 597. initially negative cystoscopic reports. Btdstrup. P. L. (1951). British Journal of Industrial Medicine, 8. 302. ---- , Bonnell, J. A., and Beckett, A. G. (1953). Brtt. med. J., 1. It is becoming clear that the exfoliation of cells from new growths is not a uniformly constant Bonscr, G. M., Oayson. D. B.. and Jull. J. W. (195U. Lancet, 2. 286. --and Pyrah, L. N. (1952). Brit. J. Cancer, 6. 41*. Bridge. J. C. (1934). Annual Report of the Chief Inspector of V'ocess. One day it nay be prolific, another Factories and Workshops for 1933. p. 49. H.M.S.O.. London. Case. R. A. M.. and Hosker, Marjorie E. (1954). Bnt. J. prev. sac, relatively unproductive. Further, the ease of recognition of neoplastic character varies. Med., 8. 39. . McDonald. D. B,, and Pearson. Joan T. (1954). Brtttsh Journal of Industrial Medicine, 11. 75. For these and other reasons we prefer at this Catch, J. R.. Huggill, H. P. W., and Somerville. A. R. (1953). J. chem. Sot.. p. 3028. ,, stage to base judgment on a combination of the Chief Inspector of Factories (1949). Annual Report for 1947. 79. Cook. w. A. (1945). tndustr. Med., 14. 936. classical search for haematuria and to fortify it Crabbe. J. G. S. (1952) Brit. med. J,, 2. 1072. , ., with the cytological method. It has thus been Diggle, W. M., and Gage, J. C. (1954). British Journal of Industrial Medicine. II. 140. possible to assert the presence of a tumour at a Draize. J. H., Woodard. C., and Calvery. H. O. (1944). J. Pharmacol. stage when a slight microscopic haematuria would 82. 377. ,a Drinker. P., and Cook. W. a. (1949). Proc IX lm. Congr. Industr. have left us in doubt and the patient in delay. Med.. London, 1948. p. 154. Wright, Bristol. Dustin. P.. Jr. (1942). Sang, IS. 193. Federal Security Agency (1953). Health of Workers in Chromate Field Experiment Producing Industry. Public Health Service Publication, No. 192. Washington. Field investigation is properly the domain of the Foreman. H., Hardy, H. L., Shipman. T. L., and Belknap, E, L. (1953). Arch, industr. H)f., 7, 148. industrial doctor, and it is the most difficult. In the last analysis it is upon field investigation Fulienon. J. M. (1952). Brit. med. J,, 2. 117. Goldbiau. M. w. (1947). Brit. med. Bull., 4. 405. , (1949). British Journal of Industrial Medicine, 6, 65. that a final judgment must rest as to the relation -------, (1950). Phorm. J., 164, 229. ----. (1951). Aiti del Convegno intemazionale di* Medicine del between industrial environment and state of health. Lavoro. Milano. 1950. p. 90. The difficulty does not lie in the recognition of this Henson. A. F. (1953) Bnt. J. appl. Phvs., 4. 217. --i --, Somerville, A. R.. Farquharson, Muriel, E., and Goldblatt, proposition, but in obtaining the opportunity and M. W. (1954). Btochem. J. 58. 383. Hum. E. Weston (1941). Med. J. Aust., 2, 661. in devising the appropriate methods to establish -------, (1944). Bratn, 67. 103. such relations. To attain results which are soundly Kehoe. R. A. (1949) In Industrial Hjiiene and Toxicology, voi. 2. p. 643. Edited by F. A. Patty. Jmcrsciencc Publishers. Inc., based and generally acceptable is a task requiring New York. -------. (1951). Industr. Med. Surg., 20. 253. the cooperation of many disciplines. In the main, therefore, it is in the big organization with great Kench. I. E, Lane, R. E., and Varley. H. (1952). Biochem. J,. 51, ix. Lane. R. E. (1949). British Journal of Industrial Medicine, 6, 125. Macalpine, J. B. (1929). Brtt. med. J., 2.794. resources that such studies can be made, but it is McFadxean. A. J. S.. and Davis. L. J. (1949). Quart. J. Med., 18. 57. Machle. W,, and Gregorius, F. (1948). Publ. Hlth Rep., Wash., a parallel fact that in such organizations the environ 63. 1114. mental conditions are likely to be the best. Ministry of Agriculture (1953). Toxic Chemicals in Agriculture : Residues in Food : Report of the Working Party. H.M. The practical application of the principles which Stationery Office. London. Papanicolaou, G. N. (1947). J. UroU 57. 375. emerge from field studies requires assiduity on the -------. (t94g). Amer. J. Publ. Hlth, 31. 202. pan of the industrial doctor and of those responsible Petr)', H. (1951). Zent. Arbeltsmed. Arbeussch*, 1, 86. Pirrie. R. (1952). J. Path. Ban., 64. 211. for industrial hygiene, for this requires not only the Potter. A. Lloyd (1950). British Journal of Industrial Medicine, 7, 125. Powell, Joan F. (1945). Ibid., 2. 142. willingness of employers to make money available, but also the willingness of workers to create it. Rimingion. C. (1938). C.R. Lab. Carlsberg (Scr. chits.), 22, 454. Rofe. P. (1955). J. elin. Path. To be published. Scoti. T. S. (1952). British Journal of Industrial Medicine, 9, 127. In conclusion, my object has been to indicate Spitz. S.. Maguigan. W. H. and Dobnner. K. (1950). Cancer, 2. 789, Taylor. H. (1936). /. industr. Hyg. 18. 175. some of the things which concern those who are engaged in research in industrial health in the Walpole. A. L., Williams. M. H. C.. and Roberts. Dm C. (1954). British Journal of Industrial Medicine, 11, 105. WignalU T. H. (1929). Bnt. med. J., I, 258. / ij l ) i