Document Q9eEk7zyYEKaaQqLZp7Bg6v6

PLAINTIFF'S EXHIBIT 181 198 206 217 22S 233 237 240 244 249 262 263 279 290 296 304 309 320 322 326 330 335 337 341 l. 12 No. 1 .BRITISH JOURNAL IF 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. Fauljcnbr Hudsoi Donald Hunter . R. E. Lane A. Meklejohn J. N. Morris J. R. Squire . Editor, British Medical Journal U1T-te CONTENTS Research in Industrial Health in the Chemical Industry. M. W. Goldblatt .. ' .. . page .. __ /9^-SC Manganese Poisoning in Moroccan Miners, J. Rodier ... .. ... 21 Dermatoses in Jute Workers. John Kinnear, John Rogers, Owen A. Finn, and - . .. Alexander Mair ......................... ................................... .. Talcosis of Unusually Rapid Development. G.-P. Auvisatos, A. E. Pontikaeb, B.TER2JS .. ,. .: .-. ' .. ......................... .. .. J&. Injury to. the. .Respiratory Tract by Isocyanates .Used in Making Lacqoers. r Are Swensson, Carl-Eric Holmquist, and Karl-David Lundgren ......................... 50 Dimethyl Sulphate Poisoning. T. R. Ltitler 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 f The Construction of Critical Orifices Working with Small Pressure Differences and Their Use in Controlling Airflow. H. A. Druett .................................................-6-5 Miscellanea: . ' . ~ , **.... The Health Hazards of the Senior Executive. -A. R. Cooper................................................ The Health of the Industrial Worker in Iraq. A. Michael Outchley ........................ 71 73 Bode Reviews -.......................... .. .. .. .' .. ... . -75 Abstracts . ..........................' ...................................... v....................... 78 _ J > 1' * : ; LONDON BRITISH MEDICAL' ASSOCIATION . . TAVISTOCK SQUARE, W.C.l "early Subscription (4 Numbers) 2 2s.' ' -U.S.A.' $7.00 - Single Number 12/6 Bri:. J. industr. Med., 1955. 12, 1 REWETHER S uuiy Jlarke WART d Watson-Jones ransactions 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, Welveyn, Herts of original.contributions in ; ions for book reviews and tilling, Nuffield Department \ York Place, Manchester 13. > this Journal, and that they ; the paper only, with double ' .on of x-ray -illustrations is lpbsand photomicrographs rapljr-jpcompanying papers stouwpflmooth, white paper. . lightly inserted in pencil.. ` xjok is referred to, the place 8 x of publication must follow B a small letter (a, b,- c) after 9 ution references are arranged ] given as follows : Author's | cs, abbreviated according to ic numerals), and 6rst page but verbal corrections have gs per sheet of sixteen pages s will be responsible for any ors. A limited number of -turning proofs. An estimate 2.1 Association. . mmol of Industrial Medicine ertisement' Manager,- British British Medical Association 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 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 u 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 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 workerand 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 -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. 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 **t July 13. 3954. at the Annual Provincial Meeting of the Association *' Industrial' Medical Officers. some 45 years ago when he fand Duckering) gave 5 mg./lO cm. as the atmospheric concentration of 1 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 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 " Axsine-- 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./30 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 (loc. 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 " 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 comrol 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 these concentrations when they proposed a zoning system, whereby, it was stated, the toxicity of an 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. 0-5 p.p.m. 1 *0 p.p.m. 2*0 p.p.m. Hydrogen Arsine selenitic Bromine Iodine Cyanogen chloride Stibine Ethyleneglycol dinitrate Phosgene Phosphorus tri chloride K.eiene Nitroglycerine Chlorine | p-Chlor aniline Hydrazoic ; /vChior-mtrobenzene acid ' Ethylene chlorohydrin ' Hydrogen fluoride 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. JOO- 500 p.p.m. 20- 100 p.p.m. 2- 20 p.p.m. 0*1 -- 2 p.p.m. 01 p.p.m. acetone, petrol, ether methanol, toluene bHe.nsze.cnes,.b.cu,tHan.oal.C.HC1a.. CO hcn Cl. COC1,. AsH ,, (CH)?SO * radon, radioactive gases, etc. in any sense whatever. For, whereas some of thelimits 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 on the circulatory mechanics ; others because of the classification of information and not for the justifi cation of excessive exposure or misguided legal interpretation." Tables of maximum allowable concentrations must effects of their metabolic products on haemoglobin : still others because they cause a dangerous increase of the permeability of the pulmonary vessels ; and 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 also on the physical piinvolved. Everyone cor scious of clinical urgenc urgency. The state of it approach to environmf implied in the table of my laboratories (Table The actual values givt in the light of expcriei emerged from a search and experimental record likely. Still, some ha\ example, in the case ammonia, ethanol. The first three colum: by certain concentrator dangerous symptoms ; concentrations which two columns give conce limit to satisfactory c particular substance (d- The use of the w concentration" has be we hold that no conc< are worse than others Anima For industrial toxico to use animals in expt conditions. Most in result of absorption \ much more rarely by i most, acute and chronii Very little is known c substance thus absorb* Factors of safety r animal experiments depending upon mai upon his greater activi can be made of the arr absorbed by men at environmental condit estimated by exposin estimate. Since the r many times greater th fume concentrations without adverse effec as equally inoffensive concerned. Cutaneous absorp great importance in and in the field use c and herbicides. Quantitative meas 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 the iical personnel, however, are -ne position. They are likely se, phrases such as " Arsine-- : as bromine, isn't it ? ", or; yes, yes, quite troublesome-- hloric acid ", because, in factj lble 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 iess of maximum allowable -IC1 and HCN are in the same one (2-20 p-.p.m.) as aniline, nitril^eils us nothing of their This is even more 1 tfisiaRghly dangerous zone TOOK ZONES (EXPANDED' 1*0 p.p.m. 2 0 p.p.m. Chlorine pChlor aniline Hydratoic p-Chlor-nitroben2ene je acid Ethylene chlorohydrm 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 cuipuappear because of their effects chanics ; others because of the: olic products on haemoglobin ' ney cause a dangerous increasa )f the pulmonary vessels ; and iruptive effects on the envelope :es. re demands different degrees of whoM responsibility it is to ons *^jsve those prescribed, of urgiiHcy 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 infonms 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 in the light of experience, but as each figure has which do not perspire in any sense similar to that imerged from a searching examination of clinical seen in man is usually impossible although an and 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 particular 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 e 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 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, .v.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 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 substance thus absorbed on the toxic effects of others. ease, and the results in some cases applied to the Factors of safety must be assumed if results of clinical control of hazards in the factory. Contact animal experiments are applied to man. factors dermatitis in man disappears on removal from depending upon man's greater susceptibility and exposure, but the effect is not truly reversible. upon his greater activity during work. If an estimate A fall in blood pressure, readily demonstrable in can be made of the amount of a toxic substance daily animals, is used by some American authorities as a absorbed by men at work, the acceptability of the clinical-statistical index of undue absorption of many environmental conditions in which it occurs can be 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. BRITISH JOURNAL OF INDUSTRIAL MEDICINE Table 1 TOXIC concentrations of various gases, dusts, fumes, and metals in the atmosphere (I.GL industrial Products and Health Research Committee) No. Gas 0) 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 r- (3) Concentrations ttt General Atmosphere ofPlant Greater than those beio* Indicate Unsatisfactory Conditions i (mg./cu.* 1 Time of j (p.p.m. ; metre 1 Exposure (p.p.n V/V) 1 20*C.) ij (Min.) ! v/v) Acetaldehyde Acetic acid .. Acetone Acetone cyanohydrin Acetony] acetone .. Acetophenone Acetyi chloride Acrolein 9 Acrylonitrile 10 Ally! alcohol 11 Allyl chloride .12 n Ammonia .. iso Amyl acetate 14 15 tso Amyl alcohol Aniline 16 As-cton 6 (Freon 12) (Diftuorodichloromethane) 17 Arxine ........................... IS Benzene (Benzol) .. 19 Benzine (as Hexane) 20 Benzyl acetate *21 Benzyl chloride........................... Bromine....................................... Butadiene .. 24 n-Butanol (Butyl alcohol) 2-Butanone (Methyl ethyl ketone) 25 />Butyl acetate 26 o-Butyl methacrylate 27 Carbon dioxide 28 Carbon disulphide,. 29 Carbon monoxide.. 30 Carbon tetrachloride 31 p-Cbiorantlinc 32 (mono) Chlorobenzene .. 34 2-Chlorobutadiene Chlorine 35 />*Ch)oronhrobenzene 36 Chloroform 37 (o A p) (motto) Chlorotoluene 3S Cyanogen chloride ,. 39 Cyclohexane 40 Cyclohexano! 4! 42 Cyclohexanone Cyclohexylimine .. 43 o-Dichlorobenzene fcJi'Dtchlorodiethyl ether.. 45 ini ii irons'! Dichlorocthylene 46 Dtcydohexylanune 47 Dpcihyl carbonate 48 DMsobutylene 49 DMsobutyl ketone 50 Dimethyl dioxane.. 51 Dimethyl sulphate.. 52 Dioxane 53 Ethanol (Ethyl alcohol) .. 54 Ether {diEthyl) 55 fc-Ethaxyethyl methacrylate 56 Ethyl acetate 57 Ethyl acetoacetate.. 58 Ethyl benzoate 59 Ethyl bromide 60 Ethyl chloride 1.000 I- 1.830 ;1 200 ! 500 ! 4.000 1 9.650 1 40 1 140 300 1.424 i 80 400 1 )0 33 1 20 46 too I 220 * 40 > 96 t 60 6o 60 1 60 60 1 1 l 1 200 500 1,000 400 ' j so . ' 50.000 . '' 10 1.500 3.000 100 { 636 1 355 S 5.410 1.464 312 : 251.700 32 4,800 10,728 , 616 ! 1 , i : 60 ] 60 60 60 60 1 60 60 60 20 100 . 1 3 20 1 8.u00 1,000 17.968 3.080 60 60 See No. 90 Methyl ethyl ketone 2.000 9,650 60 800 4,724 60 30,000 54,930 60 500 1,600 60 400 464 60 2,000 12.800 60 400 100 10 10 2,000 400 5 2.000 1,000 1,000 100 300 100 2,000 50 800 4.000 400 500 1.872 368 29 66 9,960 2,106 13 6,990 4,160 4.080 4)0 1,836 593 8,072 388 3,928 18.640 1.896 2.412 1 60 1 1 1 60 60 1 60 60 60 I 60 I 60 60 60 60 60 60 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 I 60 60 60 60 60 60 60 60 60 1 500 ; 40 800 20 ! 150 : 40 2 8 ! 50 1 20 | 100 ! 200 300 , 200 I 20 | 20,000 i1 500 1,000 50 10 5,000 100 500 400 i 10.000 150 t 100 ) 500 4 200 50 4 4 500 200 2 800 400 200 40 100 1.03000 40 400 2.000 200 300 10 300 L00O 1000 200 800 100 100 100 5.000 318 142 1.623 732 78 100.680 3-2 1.600 3.576 313 | SO 1 100 1 100 , 100 ! id j 10,000 I 0-5 1 so 250 ; 2* iss 72 542 \ zee 1 30 50,340 1C 200 ' $94 94 50 6-6 11,230 308 5 25 0-5 3-5 s.soo > :.6ic so lil 2,412 2,362 18.310 480 116 3,200 200 200 5,000 10 50 50 9G5 ' 2,2$2 ` 9,255 32 58 320 936 184 12 26 2.490 1.053 5-2 2,796 1.664 ' , ' 2 75 25 J 1 50 75 OS 400 100 n 352 92 2-9 C-C 24U 395 2-3 2,39$ 42V 816 164 612 178 4.036 302 1,964 9.320 948 1,447 75 ! 20 25 25 500 20 200 . 2,0tt0 200 ` 200 300 $2 153 Sit 2,02$ 252 9S2 4,nvo : 474 90S 52 1,098 3.828 6.156 1,314 2.928 540 624 454 13.415 ! 200 . 2,000 ,* 500 200 ! 400 50 : 50 SO , 2,000 iv; 732 \ 2,924 2,539 , 057 . 2,4G4 270 31i *-27 5,3CC 61 I Ethylene chlorhydrin 6632 ! E--Etthh. yyll.eennee diehloride glycol dinimte .. 20 68 500 '2,050 20 128 60 60 60 10 34 7 100 I 410 : 6-* { so 0-5 \ 205 3-2 ,__Concentrations shown in italic arc tentative and are isstted as a guide. Become available. Figures in all columns will be subject to review as more data I mg./cu. metre =-407 x IO-*grains/cu. ft. Continued INDUS No. Gas 64 Ethvlene oxide 65 Ethyl formate 66 Ethylidene diehloride 67 Ethyl silicate 68 Formaldehyde Freon 12 (Arcton 6) 69 Hydrazoic acid ( 70 Hydrogen chloride Hydrogen cyanide.. Hydrogen fluoride.. 73 Hydrogen xelenide.. 74 Hydrogen sulphide 75 iodine 76 Isophorone.. 77 Ketene 78 Lauryl mercaptan .. 79 Mesityl oxide 80 Methacroiein 81 * Mcthacrylic acid .. 82 : Methallyl alcohol .. 83 . Methanol (Methyl alcohc 84 . Methvl acetate 85 1 Methyl acrylate 86 Methyl bromide .. 87 . Methyl iso-butyl ketone 88 Methyl a-chloracrylate 89 i Methyl chloride .. 90 Methyl ethyl ketone (2-B 91 | Methyl iodide 92 Methyl cyclohexanone 9934 :j Methylene ehloride Methyl formate 95 Methyl metbacrvlate 96 { Naphtha distillate (as Ct 97 | Nickel carbonvi 98 Nitrobenzene to99o | ; Nitroethane Nitrous fumes (as NO s) ioi !i NitrogJvceriae 102 1l Nitromethane 103 j| I-Nitropropane JO* ![ 2-Nitropropanc 105 ;i o-Nitrotoluene 106 j| Perchloroethylene (Te* 107 :i ^-Propiolactone .. 108 1 iso-Propyl alcohol.. 109 no ! Phosgene .. Phosphorus trichloride 11! Stibine 112 1 Styrene 113 i Sulphur dioxide .. IW , Sulphur monochloride 115 j Sulphuryl chloride.. 116 Tetrachlorethane .. -- 1 Tetrachloroethvlene ( 117 1 Thionyl chloride .. 118 } Thjophosphoryl trichk 119 Trichloroethvlenc .. 120 ( Toluene (Toluol) .. 121 (o, m. ii. p) Toluidines 122 Vinyl chloride 123 Xylenes (Xylols) .. 124 Xylidincs .. 125 Antimony (dust or s* *126 Arscnious oxide .. t2? 1 Barium salts (as Ba) L _ Concentrations shown in become available. CINE LS IN THE ATMOSPHERE 1) ' ions which. = Continues lan a Shore y Lead to ams of less Concentrations in General Atmosphere ofPlant Greater than those below Indicate Unsatisfactory Conditions (mg./cu.* metre i 20`C.l (p.p.m. V- y) (mg./cu.* metre | 20*C.) 915 , 100 : --1,930 70 712 I 200 1 6-6 18-6 : no 48 1 i 1 200 20 400 10 75 20 1 J 20 S 366 SO 065 35 350 100 3*3 11-6 44 12 318 1 J 1.623 732 78 100.680 3-2 1.600 Sr 6-6 11.230 308 ! SO i 200 200 Km 10 i 10,000 ! 0*5 SO 2S0 IS S OS 2,SOO SO ISO 71 542 366 30 50,34V 1*6 ICO 304 94 25 3*3 5,625 154 2.412 2.362 18.310 480 116 3,200 200 200 3M0 20 SO SO DCS 1.131 !,15S 32 58 320 j 11 936 75 3*si 184 25 02 12 2 2-9 26 1 6*6 2.490 So 249 1,053 i i* 305 5-2 2,796 400 2.395J-5 1.664 200 426 816 164 612 178 4.036 302 1,964 9.320 948 1.447 * 73 'JO 25 IS Soo 20 2V0 1.000 100 200 301: 52 135 SU 2,025 251 982 4,600 474 OHS 52 1,098 3.828 6.156 1.314 2,928 540 624 454 13,415 i -5 200 : i,ooo . 500 I 200 400 SO t 50 50 . i.Oou 26 732 * 2.924 1,539 6S7 ' 1,464 270 322 227 5,366 SO 0< 'JOS 3*2 :t to review as more data Continued INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY Table l continued No. Gas - M> Concentrations Causing Severe Toxic Effects in Peraons Exposed for the Stated Times Concentrations, which, if Exposure Continues for more than a Short Time, may Lead to Symptoms of illness ^ W). Concentrations in General Atmosphere of Plant Greater than those below Indicate Unsatisfactory Conditions Ethylene oxide Ethyl formate Ethylidene dichloride Ethyl silicate Formaldehyde Freon 12 (Arcton 6) 69 Hydrazoic acid '0 Hydrogen chloride Hydrogen cyanide.. Hydrogen fluoride Hydrogen seienide.. 774t Hydrogen sulphide Iodine 76 isophorone 77 Ketene 78 Laut^l mercaptan 79 Mesityl oxide <0 Methacrolem I (p.p.m. ! v/v> (mg./cu.* metre 20*C.) Time of Exposure (Min.) 250 450 60 1.000 3.080 j 60 i 400 1,648 60 400 3.464 ! 60 100 120 ' See No. 16 Arcton 6. 10 18 60 50 75 ; (p.p.m v/v) too 400 200 200 30 4 20 (mg./cu* metre | 20*C.) f 180 ! 1.232 824 1.732 36 1 j 7-2 ! 30 ; (p.p.m. r/*) 10 200 50 200 10 1 20 (mcjt.Su. * metre 20* C.) 2S 616 'JOr, 366 2'J I Methacrylic acid Methallyl alcohol .. Methanol (Methyl alcohol) $4 Methyl acetate 85 Methyl acrylate............................ 86 Methyl bromide .. S7 Methyl iso-butyl ketone .. 88 Methyl a*ch)oracrylate .. 89 Methyl chloride............................ 90 Methyl ethyl ketone (2-Butanone) 1,000 150 2,000 500 100 250 1,000 4 1.500 2,000 ` 3,575 450 2460 1,540 356 1,000 4,160 20 3,150 5.990 i ! ; ; : 1 I 1 60 60 1 1 60 1 60 60 91 Methyl iodide ............................ 92 Methyl cyclohexanone 92 Methylene chloride 94 Methyl formate............................ 95 Methyl methacrylate 96 Naphtha distillate (as Cumene) .. 07 Nickel carbonyl............................ V-89 100 Nitrobenzene ............................ Nitroethane ............................ Nitrous fumes (as NO,) .. 40 i 300 , 2.000 i 1.000 i 3,000 ; 300 .4 I 200 800 100 236 1,400 7,072 2.495 12,480 1,500 28 1,020 1496 190 ! 1 ! ; 1 | 1 1 60 60 60 60 60 1 60 60 t '101 102 103 104 105 106 J 07 108 109 110 Nitroglycerine ............................ Nitromethane ............................ 1-Nitropropane 2-Nitropropane............................ 1 1 i o-Nitrotoluene ............................ ! Perchloroethylene (Tetrachloroethylene) i1 2-Propiolactone........................... i fro-Propyi alcohol.. Phosgene...................................... . Phosphorus trichloride .. 1 ; i 20 800 140202 200 1.000 100 2,000 { 2 ! , ; 189 2,028 1,480 1,480 1.140 6,905 300 *091 21 12 1 1 1 i | I 60 60 60 60 60 60 1 60 1 1 ~ M2 113 114 113 116 Stibine -Styrene Sulphur dioxide............................ Sulphur monochloride (S-Clj) .. Sulphuryl chloride.. I. Tctrxchlorethane .. I 0-5 i1,000 2-5 ; 4.330 ! 200 S 520 J 20 112 i 10 I 56 ; 50 350 1 60 1 1 1 60 17172 118 119 120 perchloroethylene (Perchloroethylene) i See No. 106 PerchJoroethylcoe. Thionyl chloride Thtophosphoryl trichloride 20 . 10 ! 100 70 l 1 Trichloroethylene .. Toluene (Toluol) .. 2,000 I 10,940 1.000 ; 3,830 60 60 uT 122 123 124 (o, m, it p) Toiuidines Vinyl chloride Xylenes (Xylols) .. Xylidines .. 40 3.000 1.000 40 176 7,800 4,410 200 60 60 60 60 Dusts. Fumes, and Metals 400 1,430 200 725 100 300 50 250 ; 500 640 200 210 200 616 200 SOS 50 , 178 2S 39 ! 50 200 20 SO ; 400 ! 1,664 200 832 |2 10 i $ 500 1 1,050 100 220 ! 500 ! 1,498 200 390 20 1 150 > 1.000 400 ! 2.000 ' 150 2 40 500 i 30 118 \ 700 ' 3,536 998 8,320 750 14 204 1.560 57 1 20 I 75 1 500 \ 200 ! 1,000 ; so ;i 2 i 200 i io SO 3SO 1,768 400 4,260 J` S0 624 29 i : 9-4 ! 0'S. 1 4 i 500 200 : 1.724680 1 200 100 507 370 200 40 740 * 100 > 370 228 ! 1 j 400 2,762 I 200 2,331 20 60 10 30 ii 800 1,998 t 300 J 4-2 , 0*5 999 i 1 i 5-8 | 0'S 2* 0-2 200 20 10 4 20 10 4 800 300 1 866 52 56 22 140 50 28 4.376 1,149 0-2 200 20 s 2 20 2 itoo 200 OS 433 26 23 5-6 70 25 2,238 333 i 1,50100 300 10 44 3,900 1,323 50 5 500 2,300 100 442 5 25 j^5 Antimony (dust or salts) (as Sb).. Arsenious oxide .. 1-7 Barium salts (as Ba) O0*S5 0`S xso^T'vaiUbie11* ShOW"iulic "* (enulive and "* iuued a Piidc. Figures in ill columns will be subject 10 review as more data 1 mg./cu. metre s 4*37 x 10"4 grains/cn. ft. Continued 6 Table I continued BRITISH JOURNAL OF INDUSTRIAL MEDICINE No. Gas 0) Concentrations Causing Severe Toxic Effects in Persons Exposed for the Stated Times U) Concentrations which, if Exposure Continues for more than a Short Symptoms of Illness (J> Concentrations in General Atmosphere of Plant Greater than those below Indicate Unsatisfactory Conditions 128 Benzidine .. 129 Cadmium .. 130 Chlorinated diphenyl 13! Chlorinated naphthalenes 132 Chromates (as CrOa) 133 Dinitrocrcso! (and salts) .. 134 Dinitrophenol (and salts).. 135 Diniirorcsorcinol ,. 136 Dinixrotoluenc 137 Dowthcm A ** .. 138 Lead (and salts) .. 139 Mercury........................... 140 a-Naphthylamine .. 141 fc-Naphthylamine .. M2 * Parathion " -143 Pentachlorphenol .. 144 p-Phcnyiene diamine 145 Phosphorus pentaebioride 146 Potassium permanganate.. 147 Sulphuric acid 148 2 Sodium cvanide M9 Tetrjl ............................ 150 T.N.T...................................... 151 Zinc oxide .. (p.pjn. v/v) (ms.,eu.* metre 20*C.) Time of Exposure (Min.) (p.p.m V/V) (mg./cu.* metre 20'C) (p.pjn, r!r) 1 (mg./cu.* i metre \ 50lC.) .. -- __ -- __ -- _ |-- 1TM -- 0-0JJ 0-J -- --; 2 __ __ _i 2 __ -- -- 0-1 -- -- -- -- --1 V'S _ -- -- -- -- --\ 3 __ _ -- --- -- 3 -- | IS __ __ __ __ -- 1-- ---- -- -- 1l -tbJZ __ -- ---- 0*J - -- -- -- -- --! 0-01 -- -- __ O'Ol -- ---- I __ -- -- --' -- -- 0'S -- -- --* -- -- 0-1 -- -- ---- } -- ---- 4/ _-- -- _-- -- ---- 2 -- I *,, ---- -- -- --i -- -- -- --* -- -- -- -- ----- 20 Concentrations shown in italic are tentative and are issued as a guide. Figures in all columns will be subject to review as more data become available. 1 metre ~ 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.Os and that N.04 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;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. NE which, mtinues a Short sad to of 9 Concentrations in -S General A tmosphere 9 of Plant Greater than 9 those below 9 Indicate Unsatisfactory 9 Conditions 9 ng.,cu.* metre 20`C.) _ __ -- (p.p.m. vv) ._ - -- -- -- -- ---- -- __--_ __--_ ---- ---- _-- ---- -- ---- -- 1- ---- (mc. cu.* 9 metre 9 ju-c.) a 0-0K fl u-i 9 9 v-i 0`S j j J-5 i* n-to /)! 0'0l 9 9 0'02 1 U-2 j l s 1-5 - 10 J ii be subject to review as more data insive industrial pulmonary i 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 ling serious. They lived on d the chromate with bored lows large and small areas >li crammed with loaded stages of degeneration, are out of action. The cell ntributes further to loss of f. Dilated respiratory bronivsema, 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 'ead acetate (40-50 of thedust cells from the Q seen, but monopertnspKv 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. Ftc. 1.--Rat lung after chronic exposure to fine potassium chromate ouit many areas of exsanguinated, functionless alveoli filled "ith hi;ioc>tiphagocytes and many ruptured alveoli, x 100. Fig. 2a.--Phagocytosis of blood phagocytes by macrophages deriving from septal cells; details of coarse pigment granules in gutneapig lung. .% 1200. j I I o INDTK Fig. 3.--Rabbii 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 particles; note multinuclear 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 (/.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 metabol carcinogenicity the use < and wider significance, one carbon C14 has members of my depar Amersham (Henson, Somerville, 1953). Wt establish important met retention of compound in the body (Henson, Goldbiatt, 1954). The toxic compounds in c histological sections is The ultimate fate o', industrial conditions i known about some of chemical substances ar we are very rarely able or even extraordinary "avs in which complc the body in large pz difficulties and apprt using labelled compou in obtaining almost co and output of substan and in discovering ho1derivatives are retains is possible to track th 6 mem 35 M1| 1 %* 1 ) with absorbed particles; note multi-* : lung is paid for in the case] tdation of the precursors of! .e. modified septal cells) and! the occupation of alveolar: d cells and cell debris when! charged. The formation of] : also occurs in the chronic! (Fig. 3). In a universe ofj id are inevitable but it is our) ndustrial dust with other: jments are mainly found in! ;posed to carbon monoxide, { and ino-compounds, and i y.. Jt 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. with 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 chlorphcnol, the former two being responsible for bn 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 meihaemoglobin, 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 nieciion 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 '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 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 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 Goidbiatt. 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 t even extraordinary chemical means. The subtle the findings in a short time. If the conventional ''ays 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 i`> possible to track them through the various routes from the high (stipple and polychrome) counts. Nor !i - 10 BRITISH JOURNAL OF INDUSTRIAL MEDICINE I FlG. 4.--Rabbit blood stained with alkaline methylene blue and photographed by transmitted light showing various-sized basophilic (polychromatic) cells due to chronic lead exposure. FiC. 5.--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 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 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 relative!) short duration, and that there is complete recoven 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. Certi fied as fit to work after 21 days, the patient was again led with alkaline methylene blue and ground illumination showing ease oi den granules) and two polychromatic tic cells are manifestly very line!) return to work (Foreman, Selknap. 1953). Dhasized that the usual forms re self-limited, of relatively .t there is complete recovery seen terminated, and that no the blood-forming tissues is ;m. The cases to which this jplv are the now exceedingly-j 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 a' 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! : wljgrjjfwas certified. Certi-'j 21 days, the patient was again! INDUSTRIAL HEALTH IN THE CHEMICAL IND USTR Y 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 20r Hb 85 179 rise in stipples, and who oscillated violently even when on work not involving a lead hazard. Lane (loc. cit.) and others, have described cases of hyper Hb 80 134 IO IS 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. * l\ tMi.H b 60 5 /r - Hb 65 15 A A\ /\ J \A /\ \\f/ ti\V/ S\L IO 15 20 t i i t i i lOOOs Stipple -(-"Polychrome''cells The stippled 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 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 guineapigs, found as many as 55% of haemoglobinating Relation between haemoglobin and stipple*polychrome counts in u'orkers exposed to a lead dust hazard. Numbers of bloods examined shown with Hb values. (See text). normoblasts in the marrow showing basophil stippling when only 2-5% of red blood cells were Table 2 LOST TIME OF TWO GROUPS Certified* ;l Year No.- Name ! r.-.-.o F.G. W.P. G.F.K. J.S. 1 S.F. K.A.M. A.W. I P.N. l'Jli 9 ! T.H. WO : E.M. 1l F.H.W. 8 days 10 days 2 mths. 26 days 15 days 16 days 2 mths. 6 days 13 days 18 days 28 days 1 mth. 21 days Year II No.! Name 1940 jI 12 | W.C. j U A.H.T. ji 1941 1942 1942 20: 11 u GJM.t. 1944 17:4 1J GS.M. Time Lost Year No.i 1936 3 days -[23 : 10 1 mth. j! 9:12 13 days || Name 1937 5 24:3 s 1 W.F. 30 days 1 3:5 9 W.F. 10 F.G. 1 11 CJ.H. 12 J.L. 13 R.O. 1 1938 13 :12 14 C.F.H. 1 13 W.R. Uncertifiedf Time Lost Year ; No.. Name mo : ' ; -1 I I 16 : C.F.H. ; 17 . A.E.P. J Time Lost Nil 20 days' mo .3 A.W, | 23:9:19 H.J. I :i 19U ; --: _ ;J 1943 ` 122:5; 21 , //.y. i | J i j Nil TM _ m 1 Nil : Nil 1944 ! -- ` -- .1 . 194S ` " 126 : 1 22 H.J. . * ! Certified-recovery away from factory, tUncenified-recovery at work. (All easm 60-65% Hb at time of certification or action in factory.) ^Recurrent cases in italic. - <- <./-r-.rr. C^) 12 BRITISH JOURNAL OF INDUSTRIAL MEDICINE Table 3 PERIOD OF RECOVERY OF Hb W.F, AGE <8-53 YEARS. Hb k Supples `Polychrome*'. Slow Hb recovery-- mtmairid hijh (StP) during Non-lead Maintained at Work Removed to Home or Hospital No. of Cases 24 9 Hb at lime of transfer .. Mean time to reach 80% or more 1*93 months (3 weeks-7^ months) 65--70% 1*66 months (16 days-2} months) Indicates slight advantage of getting man away from factory even on light and non-lead work. 1 case of Hb 43-45% recovered to 80% m 28 days whilst at work on non-lead. r.... re J 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 ribonuclease which com^lt'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. Fig. 7.--Case of lead anaemia showing cxxremely slow recovery of haemoglobin whilst maintained at work. T.H. AGE 29-32 TEAKS. Returned to work before blood recovery-liter 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. Fig. S.--Case of certified plumbism considered ciinically fit to return to work, but thereafter requiring almost two years w regain a subie 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 51-57 YEARS. Cue of Sensitivity and Recurrence. MacFadzean and Davis (1949), Pirrie {loc. tit.), 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. Fig. 9.--Case of sensitivity and recurrent lead anaemia in spite of long periods on non-lead work. Close correspondence of Hb and stipple values. Q 1 ; 48-53 YEARS. iromo'. Slow Hb rtcovery) during Non4ead loo-Pb 3 yun 4 f 56 I extremely slow recovery of ntained at work. -I. AGE 19-32 TEARS. .ork before blood recovery--after recovery in factory. . 2ert* I days) 11 t___Non-Pb____I pn-Pb 2 3 4 years Dtsm considered clinically fit to r requiring almost two years to d work. H.T. ACE 51-57 YEARS. ie ot Scnticinty and Recurrence. Polychromes'. Never Certified. /V \ t _Pb_ Non-fo >ry I'Ayurc . NorvPfr. 4 S 6 years nd 'Q' lead anaemia in spite ad Close correspondence of 32^ INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY F10. 10 -R a b b i t blood after chronic lead inhalation show ing stippled normo blast. Stained with alkaline methylene blue, x 2000. Fig. 11.--Rabbit bone marrow after chronic lead inhalation show ing coarsely stippled normoblast (R.B.C. somewhat out of focus), x 2000. Fic. 12.--Rabbit bloodafter chroniciead inhalation showing reticulocytes supravital staining with brilliant cres>l blue, x 1200. FiG. 13.--"Rabbit blood on same occasion as Fig. 12 (dry film stained with brilliant crcayl blue) in which reticu locytes are seen as cells 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 ofthe 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 rextreme 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, c.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.50. OROANO-PHOSPHATE INSECTICIDES* Compound Oral L.D.50 I.P. L.D.50 T.E.P.P....................................... Paraoxoft Dimefox Sv$tox (Commercial) s I! >p-o- .. o i; >p-s- .. 1-2 R.f. 2-0 R.m. 3 5 R.m.f. 5 R.m. 6-39-9-7 R.m. 7*5 R.m. : 0-65 R ; 1-2 R.m.f. 1 I 4-5-8-37 R.m. 1 ; 1-5 R.m. Pestox (O.M.P.A. Schradan) Parathion ............................ E.P.N. Mipafox .. .. .. Malathion .. .. . * ; f 9-7-10-0 R.m.f. i 8-0-8-5 R.m.f. 6 R.f 4 R.f 15 R.m. 7 R.m. 14-5 R.f 971l -'V0 Rtv.m. : 50 M. < */.* Parathion 2,420 R.f. . 750 R. 2,860 R.m. j Median lethal doses of organo-phospbate insecticides. R~ rats, M *- mice, oi male, f -- female. AM 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 "malathion" about 200 times less toxic to mammals. The optimism engen dered 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 CTlClDES* I.P. L-D.JO , 0-6S R 1*2 R.mX i 4-5-807 R.m. f. 8-0-8*5 R.m.r. 4 R.r.. * 7 R.m. . 50 M. 750 R. ' ate insecticides. All values in mg..Kg. ?ha"S-E-p-p-)mqFpfeopropyl ps 25 times less thion" about 200 optimism enge.iin the case of insecticidal proby pathological answered by the these and other crops are : (1) imer of the food sly answered in appointed by the which gives the ids investigation of arising from the hey constitute an answer here is precautions are use of atropine oyer, supervisor, utic agent for the toms (Goldblatt, upon the level of cells, brain, and at motor endsynapses. Since some indimptoms, it cholinesterase of ned as a routine ORGANO-PHOSPHORUS 1NSECTIC IDES l). PARATHiON ' ' 02N 1 C2HS 2). T.E.P.P. C2H5\II ll/0C2^ _ /P'-O-P 3). PESTOX 4). PARAOXON (CF^^N. ^ f/Kcnp, /NP--O P. CCH^N7 o2n o II /OC H, O-------- DP ' \d C2HS 5). E.P. N. (U-S.a) o2n dimefox SYSTEMIC t Ml PAFOX / o=Ps-nh.ch^:fQ2 \ih.ch(^2 SYSTEMIC 8)- SYSTOX 2) malathion '\ ^oc_h_ c^s-c2Hro-p( 25 'O c2th5 c2h5.ooc.h2c s ,OCH,, C H OOC.HC-P-s( 3 ^OCHg Fic. T4.--Formulae of active compounds in organo--phosphorus insecticide!* 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-Iethal 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. fdi-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 Petty (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, NjNa, N:0, and repeated doses of barbiturates (Weston Hurst, 1941, 1944). B 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 (T35 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 Fie. 15.--Cervical cord and Kiatic nerve of a fowl treated with o preparation of trieresy) phosphate calculated to contain 0-1% of the ortho-isomer. Toul dose in 16 days -- 2 mg./kp. by mouth. First paralytic aipns in II 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 -below sciatic nerve. experiments havi effect on the ner variety of animal Occu There are ver have been showr gens to man. radiations f.v-ra; naphthylamine, pyrene. Of the host of which have proc marv gland, lung have been demor carcinogens. Th products as tar. established with 3-4 benzpyrene : this compound. Long-continue tions and work to indubitable : finally to epithel ment has been ; effect in animals In the case of c as well as seven followed long e though the tum> sarcomata in ani differences are i 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. a identical bladde b-naphthylamin; Claysoo. and Jui tumours inducit amine in differe amount of urina excreted. More recent! benzidine and h; research both in the demonstrati, benzidine in rats but bladder tur induced except so Barnes and Denz, 1 tract for attack is in man. in whom the disturbance. In the romuscular block due -nal relation of cholin'as first seen and later those sensory impair ed with polyneuritis, ands are being synthe3 assume the relative infil acute and chronic o % srvc of a fowl treated with a calculated to contain 0*1% of 6 dajs - 2 by mouth, lowed by progressive worsening nation in anterior and lateral >atic MareM's - louS^A-Wcal cord below 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,) Wignall 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 ('x-ray, radium, ultra-violet light), (}- (1951), Bonser, Clayson, Jull, and Pyrah napiuhyiamine. 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 gland, 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 and 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 Crcsdee 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-1-naphtho1 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 arid 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 teen as the effective bladder carcinogens. This has- induced except in the case of one dog (Spitz, 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-hydroxyamines metabolically. The dilemma before industry in this field is how to deal with the considerable numbers of compounds that might carry 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 (Machle 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 monality 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 detect 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 ii ' ' ` ' ' , cystoscopy of w< the Continent a U.S.A. Hence u be made and will, with the rr a correct picture To this end we scope of urinar mining the pict in normal subje colaou's methohope later, by malignancy. B those hitherto laboratories ha: stain, character the types of cel! urine (Rofe. 19 normally interfe matter and deb cells in 1 in 1.5( they were void may thus be s 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 leucocvti could be accou whole blood, is always in a st or mechanical. By applying Rc glance all the : ' * * ** (i -- CINE :he observation is confirme sss here as other than oi icchanical irritation but i ; not ruled out although it! : support for it. It is n| it a given material is noj ordinarily understood is se of carcinogenicity. Ffl d exercising a toxic effe that cell in the direction one exerting a carcinogen 11 is driving that cell toward .1, function and, for a tin us'Is not to say that a carcinc 'er toxic in the ordinary sen : agent in full spate is unlikelj lishment of carcinogenicit induction times for cer jgens are long and no| erity of exposure, it is to ndividuals the induction timl id in others much longer than ; of Vesical Tumot inueaMRedical supervision exposed in the past to bladde est even after exposure ha : leaving the industry, chemical industry exfoliative sed to detect early bladdes .. the teaching of Papanicolaou mportance of the recognitiot ; in exfoliated cells has beer .s may be exfoliated from the ier, cervix, and vagina, andjj logical and staining character be recognized, there is no ;y a neoplastic process should it an early stage (see alsc der tumours the early develop-1 d by any disturbance of the jpational or non-occupational the need to establish routine or microscopic blood, which is ign of bladder irritation, of :osities, of a broken frond of or of the slow and insidious iting carcinoma. In a small: s microscopic haematuria is i tumour visible in the cysto ger proportion there may be he pngence of a tumour, s uscfp^o recommend routine: n U0.,opv of uorkers as it is practised on X continent and to some extent m the A Hence urinary examinations must made and every device used which `vffl with the minimum discomfort, give j correct picture of the inside of the organ. To this end we are seeking to enlarge the s:opc of urinary examinations by deter mine the picture of vesical exfoliation n normal subjects, by applying PapanicX.i'ou's methods to the urine, and, we iatcr. by cytochemical tests for maiicnancy. By methods different from those hitherto used, Mr. Rofe in my laboratories has been able accurately to 1 <uin. characterize, separate, and count the types of cells found in normal human urine (Rofe. 1955) after removal of the normally interfering organic and inorganic nutter and debris and concentrating the ceils in 1 in 1.500 of the volume in which Vi :::e\ were voided. Certain conclusions :v.a>. thus be stated : (1) Most normal y 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. 15;x and over in size (urethra, bladder): (b) small epithelial cells derived from kidney and prostate (in the male) 15-i and under in size. These cells are m various stages of degeneration. \ very interesting feature of these c. -.mis 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 *#- Fig. 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 .'Jr Fig. 16.--Smear from urine of worker m manufacture of dyestuff intermediate*, showing erythrocytes, polymorph*, abnormal and degenerated epithelial cells, and several definitely malig nant calls. Papanicolaou's technioue of preparation and staining. * 500. Fig. l7**""Smear from another dyestuff worker shoeing erythrocytes, many polymorphs, and giant binuefeated malignant cells. Papanicolaou technique. 500. 20 BRITISH JOURNAL OF INDUSTRIAL MEDICINE <1952) working in my laboratories. The value of chemical industry, and some of the difficulties and cvtological 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 cystoscopically 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). Cancer Res., 13, 137. Bamforth, J. (1953). Practitioner. 171, 244. was subsequently confirmed by cystoscopy after Barnes, j. M., and Dcnz, F. A. (1953). J. Path. Bact.. 65. 597. initially negative cystoscopic reports. Bidstrup. P. L_ (1951). British Journal of Industrial Medicine. 8, 302. --. Bonne!!, J. A., and Beckett, A. G. (1953). Brit, med. J., 1. 1068. It is becoming clear that the exfoliation of cells from new growths is not a uniformly constant Bonser, G. M... Clayson. D. B.. and Juil. J. W. (1951). Lancet, 2. 286. --. --, --, and Pyrah, L. N. <1952). Brit. J. Cancer. 6. 412. Bridge. 3. C. (1934). Annual Repon 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). Brit. J. prev. soc. relatively unproductive. Further, the ease of Med.. 8. 39. ., --, McDonald. D. B., and Pearson. Joan T. (1954). British recognition of neoplastic character varies. Journal of Industrial Medicine. 11. 75. For these and other reasons we prefer at this Catch. J. R., Huggitl, H. P. W.. and Somerville, A.'R. (1953). J. chem. Soc.. 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). Industr. Med., 14.936, classical search for haematuria and to fortify it Crabbe. 3. G. S. (1952) Brit, med. J.. 2, 1072. ,, , .. with the cytological method. It has thus been DiggJe, W. M,, and Gage. J. C. (1954). British Journal of Industrial Medicine. 11. 140. possible to assert the presence of a tumour at a Draize, J. H., Woodard, G., and Calvery, H. O. (1944). J. Pharmacol. 82. 377. stage when a slight microscopic haematuria would Drinker. P., and Cook, W. A. (1949). Proc. IX Int. Congr. Industr. have left us in doubt and the patient in delay. Med.. London, 1948, p. 154. Wright, Bristol. Dustin. P.. 3r. (1942). Song. 15. 193. Federal Security Agency (1953). Health of Workers In Chromate Field Experiment Producing Industry. Publie 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. //;., 7, 148. industrial doctor, and it is the most difficult. Fullerton* J. M. (1952). Brit, med. J.. 2.117. In the last analysis it is upon field investigation Goldbiatt. 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). Attt del Convegno intemazionale di'Mcdicina 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) Brit. J. appl. Phys., 4, 217. ----. Somerville, A. R.. Farquharson, Muriel, E., and Goldbiatt, proposition, but in obtaining the opportunity and M. W. (1954). Biochem. J. 58. 383. Hum. E. Weston (194)). Med. J. Aust., 2, 661. in devising the appropriate methods to establish -------, (1944). Brain. 67. 103. such relations. To attain results which are soundly Kehoe. R. A. (1949) In Industrial Hygiene and Toxicology, vol. 2, p. 643. Edited by F. A. Patty. Interscience Publishers, Inc., based and generally acceptable is a task requiring New York. ------- , (19511. Industr. Med. Surg.. 20. 253. the cooperation of many disciplines. In the main, Kench. 3. E., Lane, R. E.. and Varley. H. (1952). Biochem. J.. SI, ix. therefore, it is in the big organization with great Lane. R. E. (1949). British Journal ofIndustrial Medicine, 6, 125. Macalpine. 3. B. (1929). Brit. med. J., 2. 794. resources that such studies can be made, but it is McFadzean. A. J. S.. and Davis. L. 3. (1949). Quart. J. Med., 18. 57. Machle. W,, and Gregorius, F. (1948). Publ. Hith Rep., Wash., a parallel fact that in such organizations the environ 63. 1114. mental conditions are likely to be the best. Ministry of Agriculture (I9S3). 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. t/roL, 57. 375. emerge from field studies requires assiduity on the -------. (1948). Amer. J. Publ. Hith, 38. 202. pan of the industrial doctor and of those responsible Petry. H. (1951). Zent. Arbeltsmed. Arbeitssch^ 1, 86. Pirrie, R. (1952). J. Path. Bact., 64, 211. for industrial hygiene, for this requires not only the Potter. A. Lloyd (1950). British Journal ofIndustrial Medicine, 7, 125. Powell, Joan F. (1945). /bid.. 2, 142. willingness of employers to make money available, Rimington, C. (19383. C.R. Lab. Carlsberg (Ser. chim.), 22, 454. but also the willingness of workers to create it. Rofe. P. (1955). J. din. Path. To be published. Scott. T. S. (1952). British Journal of Industrial Medicine, 9, 127. In conclusion, my object has been to indicate Spitz. S.. Maguigan. W. H,, and Dobrincr. K- (1950). Cancer, 3, 789, Taylor. H. (1936). J. industr. Hyg. 18. 175. some of the things which concern those who are engaged in research in industrial health in the Walpole. A. I_ Williams. M. H. C. and Roberts, D.-~ C. 0954). British Journal of Industrial Medicine, 11, 105. WignaU, T. H. (1929). Brit. med. J., 2, 258.