Document 7RE86pB55qGkjRZ7jN6Ry4Ojo

FILE NAME: ICI (ICI) DATE: 1955 Jan DOC#: ICI005 DOCUMENT DESCRIPTION: Article from Scientific Journal >ys. J. A. Bonnell. d Urine Proleins in 181 G 198 206 <rkers. and J. C. Gilson .. 217 >f Rats. 228 233 237 Plant with a Report 240 mental Study of the 244 Law rence .. 249 262 M1LEY.......................... 263 279 290 ence to Mines Rescue M. Jones 296 d its Absence when fydrocarbon Vapours. 304 309 Coal-mining Industry. 320 inai Handicap among 322 326 nlth and Disease in 330 335 337 341 7 'OL. 12 No. 1 JANUARY, 1955 BRITISH JOURNAL Industrial medicine EDITOR _____( RICHARD SCHILLING ASSISTANT EDITORS J. C. GILSON L. G. NORMAN EDITORIAL J. M. Barnes Sir F rederic Bartlett Thomas Bedford G. R. Cameron C. M . F letcher M. W. Goldblatt A. Bradford H ill COMMITTEE T. G. F aulkner H udsoi D onald H unter R. E. L ane A. Mekleiohn J. N . Morris J. R. Squire Editor, British Medical Journal /H? CONTENTS K/ pa g e .esearch in Industrial H ealth in the Chemical Industry. M . W. Go l d b l a t t .......................... / y Manganese Poisoning in M oroccan Miners. J. R odier . . ' ............................................... 21 Dermatoses in Jute Workers. John K innear, John Rogers, Owen A . F inn, and" Alexander M air ................................................................................................................ Talcosis o f Unusually Rapid Development. G. P. A uvisatos, A . E. Pr /Irakis, ar: B. Terzis . . ,. . ......................... ........................................................................... Injury to the. Respiratory Tract by Isocyanates Used in M aking Lacquers A ke Swensson, Carl-Eric H olmquist, and Karl-David Lundgren ........................... 50 Dimethyl Sulphate Poisoning. T . R . Littler and R . B. M cConnell . Vanadium Poisoning from G as Turbines. R . C. Browne - . ........................... The Toxicity o f Ozone in the Presence o f O xides of Nitrogen. W. M . D iggle and J. C. Gage The Construction o f Critical Orifices Working with Small Pressure Differences and Their Use in Controlling Airflow. H. A . D ruett ......................................... 65 M iscellanea: . The Health Hazards o f the Senior Executive. A . R . Cooper . . ............................. .. 71 The Health of the Industrial Worker in Iraq. A. M ichael Critchley .......................... 73 Book Reviews - . .................................................................... -7 6 Abstracts ......................................... ." ............................. ; .......................... 78 sz X - 8 /***. LONDON BRITISH MEDICAL ASSOCIATION TAVISTOCK SQUARE, W .C.l Nea r ly Su b s c r ip t io n (4 N u m b e r s) 2 2 s. U.S.A. $7.00 Single N umber 12/6 Brit. J- industr. Med., 1955, 12, 1 . Merewether ORRIS V. Perry 'ND-CLARKE Stewart :nald Watson-Jones he Transactions of the Association ion of original contributions in sections for book reviews and Schilling, Nuffield Department ag, York Place, Manchester 13. ly to this Journal, and that they of the paper only, with double uction of x-ray illustrations is ographs and photomicrographs d graphs accompanying papers or stout, smooth, white paper, be lightly inserted in pencil, a took is referred to, the place year of publication must follow by a small letter (a, b, c) after ribution references are arranged ire given as follows : Author's talics, abbreviated according to abic numerals), and first page 2263. ill but verbal con actions have lings per sheet o f sixteen pages tors will be responsiole for any lutors. A limited number of i returning proofs. An estimate lical Association. Journal o f Industrial Medicine Ivertisement Manager, British : British Medical 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 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 a 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 officer 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 stage 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 ro do lay with the employer. * The M ackenzie Industrial H ealth Lecture delivered in M anchester on July 13, 1954, at the A nnual Provincial M eeting o f the A ssociation o f Industrial 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 byindustry 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. M aximum Allowable Concentration o f 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 of 1 1 BRITISH JOURNAL OF INDUSTRIAL MEDICINE lead in which engineers and chemists might work. By prescribing a maximum intake of lead, however, there is the implication that the harder a man works in the atmosphere containing lead, the shorter time he should be permitted to do so. Thus, merely to ! give a maximum permissible concentration without giving the severity of the work and the time engaged per day in such work, leaves one entirely in the dark as to what a man is absorbing. Lane (1949) and Kehoe (1949) substantially agree that at 1-5 to 2 mg.,/10 cm. " cases of disabling lead intoxication do not occur among men who work regularly in such workrooms, and cases of questionable or mild intoxications are rare But Lane is not slavishly attached to this maximum allowable concentration and insists {loc. cit.) that the final test must be the effect on the workmen and, by implication, that mere analysis of the atmosphere is not enough. This statement is of great general significance and may be considered in conjunction with the views of Cook (1945), one of the distin guished workers in the field of maximum allowable concentrations. Cook says : " It is to be emphasized that the intent in presenting the maximum allowable concentrations is to provide a handy yardstick to be used as guidance for the routine industrial control of these health hazards--not that compliance with the figures listed would guarantee protection against ill-health on the part of exposed workers, nor should the maintenance of the suggested concentrations be considered a substitute for medical control." The use of the words " suggested concentration " is I 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 :-- 500-2,000 p.p.m. 100- 500 p.p.m . 2 0 - 100 p.p.m . 2 - 20 p.p.m . 0-1- 2 p.p.m. 0 1 p.p.m. acetone, petrol, ether methanol, toluene benzene, butanol, CC 14, C O H,,S, C S .,C o H .C l,, HC1, H C N Ci, C O C l2, A s H 3, (C H 3)2S O , radon, radioactive gases, etc. They added : " The zoning scheme is for the classification of information and not for the justifi cation of excessive exposure or misguided legal interpretation." Tables of maximum allowable concentrations must not evoke responses which are entirely unjustified and even dangerous. Classification in zones cannot fail to influence non-medical personnel by suggesting similar toxicities of substances, the effects of which are entirely different. For a doctor the association of a hazard with a value or a zone of values is desirable to supplement the picture already in his mind of one or more features of the effects of the compounds. Non-medical personnel, however, are not as a rule in the same position. They are likely to use, and in fact do use, phrases such as " Arsine-- oh yes, about as toxic as bromine, isn't it ? " , or, " Tetrachloroethane--yes, yes, quite troublesome-- about as bad as hydrochloric acid " , because, in fact, their maximum allowable concentration values are identical, but, it must be noted, for very different reasons. Toxic hazards should, in general, be con sidered as identities with their own numerical data attached to them and their own effects attached to the numerical data. Hazards may have to be classified into groups for convenience or as aids to memory, but this must be on the basis of similarity of toxic effects and not on the fortuitous closeness of maximum allowable concentrations. The fact that both HC1 and HCN are in the same Drinker and Cook zone (2-20 p.p.m.) as aniline, acetic acid, and acrylonitrile tells us nothing of their effects or relative dangers. This is even more strongly illustrated in the highly dangerous zone OT-2 p.p.m. D RINK ER AND COOK ZONES (EXPANDED) 01 p.p.m. 0-5 p.p.m . 1-0 p.p.m . 2-0 p.p.m . H ydrogen selenide Iodine Stibine Arsine Bromine Cyanogen chloride Ethyleneglycol dinitrate Phosgene Phosphorus tri chloride Ketene N itro g ly cerin e Chlorine H y drazoic acid ! p-C hlor aniline /3-Chior-nitrabenzene Ethylene chlorohydrin H ydrogen fluoride N .B .-- H C N 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 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 on the circulatory mechanics ; others because of the 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 of the blood corpuscles. So diverse a picture demands different degrees of urgency in persons whose responsibility it is to prevent concentrations above those prescribed. Moreover, the sense of urgency must clearly depend IND USTI also on the physical properi involved. Everyone concern scious of clinical urgency as urgency. The state of mind approach to environmental implied in the table of cone my laboratories (Table 1). The actual values given m in the light of experience, emerged from a searching < and experimental records, gre likely. Still, some have ah example, in the case of \ ammonia, ethanol. The first three columns inc by certain concentrations to dangerous symptoms ; the concentrations which are r two columns give concentrai limit to satisfactory condr. particular substance (design The use of the words concentration " has been a 1 we hold that no concentra . are worse than others but z Animal Exp For industrial toxicologic;: to use animals in experime conditions. Most industr result of absorption by ini much more rarely by ingest most, acute and chronic, are Very little is known of the substance thus absorbed on Factors of safety must i animal experiments are a depending upon m an's g: upon his greater activity dm can be made of the amount absorbed by men at work, environmental conditions i estimated by exposing anil estimate. Since the metab many times greater than th; fume concentrations at w' without adverse effects ma as equally inoffensive to mt concerned. Cutaneous absorption great importance in the o and in the field use of toxi and herbicides. Quantitative measureme neous absorption in anim zDICIN E INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 3 a value or a zone of values is ament the picture already in his ore features of the effects of the -medical personnel, however, are 3 same position. They are likeh lo use, phrases such as " Arsine--j [oxic as bromine, isn't it ? ", or, le--yes, yes, quite troublesome-- irochloric acid ", because, in fact; lowable concentration values are tust be noted, for very different zards should, in general, be con:s with their own numerical data ind their own effects attached to' ve to be classified into groups for aids to memory, but this must be lilarity of toxic effects and not on seness of maximum allowable th HC1 and HCN are in the samt c zone (2-20 p.p.m.) as aniline, ylonitrile tells us nothing of the) dangers. This is even more i in the highly dangerous zone D COOK ZONES (EXPANDED) loride il 1 0 p.p.m. Chlorine Hydrazoic acid 2 0 p.p.m. p-Chlor aniline p-Chior-nitrobenzene Ethylene chlorohvdrini Hydrogen fluoride , tri- ie M B.-- H C N 10 p.p.m . iave some of the most fulminating n industry, and it would be in the esirable to bracket them together ever. For, whereas some of the 3 for immediate irritation, other1 acts, and others again for cumui ie appear because of their effect: aechanics ; others because of tht abolic products on haemoglobin ; ; they cause a dangerous increase i of the pulmonary vessels ; and disruptive effects on the envelope scles. ture demands different degrees ol is whose responsibility it is tc itions above those prescribed. 3e of urgency must clearly depend also on the physical properties of the compounds involved. Everyone concerned must be made con scious of clinical urgency as well as of quantitative urgency. The state of mind which informs our own approach to environmental contaminants is that implied in the table of concentrations issued from my laboratories (Table 1). The actual values given may require modification in the light of experience, but as each figure has emerged from a searching examination of clinical and experimental records, great modifications are not likely. Still, some have already been made ; for example, in the case of formaldehyde, acetone, ammonia, ethanol. The first three columns indicate the times required by certain concentrations to produce very severe and dangerous symptoms ; the next two columns give concentrations which are not tolerated ; the last two columns give concentrations which set an upper limit to satisfactory conditions in respect of the particular substance (design concentrations). The use of the words " maximum allowable concentration " has been avoided because at J.C.I. we hold that no concentration is allowable. Some are worse than others but all are bad. Animal Experiment For industrial toxicological purposes it is important to use animals in experiments simulating industrial conditions. Most industrial poisonings are the result of absorption by inhalation or by the skin, much more rarely by ingestion and by the eyes, and most, acute and chronic, are to mixtures of substances. Very little is known of the adjuvant effects of one substance thus absorbed on the toxic effects of others. Factors of safety must be assumed if results of animal experiments are applied to man, factors depending upon man's greater susceptibility and upon his greater activity during work. If an estimate can be made of the amount of a toxic substance daily absorbed by men at work, the acceptability of the environmental conditions in which it occurs can be estimated by exposing animals to multiples of that estimate. Since the metabolism of small animals is many times greater than that of man, gas, vapour, or fume concentrations at which animals can subsist without adverse effects may be reasonably regarded as equally inoffensive to man as far as overt signs are concerned. Cutaneous absorption of toxic materials is of great importance in the organic chemical industry and in the field use of toxic insecticides, fungicides, and herbicides. Quantitative measurement of the degree of cuta neous absorption in animals is difficult, but com parative measurements can be made with small animals by time measurements from the onset of symptoms to death, or to measurable biochemical effects after immersion of anatomical appendages, such as paws or tails, in known concentrations of the compounds studied. Many substances are more toxic cutaneously than orally. The demonstration of dermatitic effects in animals which do not perspire in any sense similar to that seen in man is usually impossible although an urticaria-like reaction is sometimes seen. The phenomena of " contact dermatitis ", " sensitization dermatitis ", " allergic dermatitis ", or " eczema " are not reproducible in animals in experimental conditions. Complicated immunological demon strations that some chemical compounds can act in appropriate conditions as skin allergens are possible and such demonstrations have corresponded with the known properties of some organic compounds. Erythema and oedema should be measured according to determined scales (Draize, Woodard, and Calvery, 1944). The skin of laboratory animals does not respond as does human skin to the host of chemical substances which induce dermatitis of the acute variety so frequently seen in industrial conditions. In the case of cutaneous cancer the correspondence is closer. Thus, animal experiment is largely directed to finding whether given chemical com pounds induce direct irritant effects on the skin. Physiological effects (on the circulation, respira tion, blood pigments, tissue and blood enzymes, renal and hepatic function, 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 derm atitis in m an disappears on rem oval from exposure, but the effect is not truly reversible. A fall in blood pressure, readily demonstrable in animals, is used by some American authorities as a clinical-statistical index of undue absorption of many toxic organic compounds. There are some explosive compounds (made and used both here and in other countries) which are rapidly hypotensive in working conditions: blood pressure determinations are essential for proper medical control in these cases, especially as pseudo-anginal attacks may follow long-term exposure. Many industrial compounds can be shown experimentally to depress the heart, dilate the peripheral vessels, or increase vascular permeability. Others, by cholinesterase inhibition, lead to parasympathetic stimulation and vagal effects on the heart. The question of the establishment of hypertension, perhaps of renal origin, in chronic lead absorption is not resolved. 4 BRITISH JOURNAL OF INDUSTRIAL MEDICINE T able 1 TOXIC CONCENTRATIONS OF VARIOUS GASES, DUSTS, FUMES, A N D METALS IN THE ATMOSPHERE (I.C .I. Industrial Products and H ealth R esearch C om m ittee) INDUSTR No. Gas 0) (2) (3) Concentrations Causing Severe Concentrations which, Concentrations in Toxic Effects in Persons if Exposure Continues General Atmosphere No. Gas Exposed for the Stated Times for more than a Short o f Plant Greater than Time, may Lead to those below Symptoms of Indicate U nsatisfactory Illness Conditions (p.p.m. v/v) (mg./cu.* metre 20C.) Time of Exposure (Min.) (p.p.m. v/v) (mg./cu.* metre 2 0 DC. ) (p.p.m . v/v) (m g./cu* m etre 20 C.) 64 Ethylene oxide 65 Ethyl formate 66 Ethylidene dichloride 1 Acetaldehyde Acetic acid . . 3 Acetone 4 Acetone cyanohydrin 5 Acetonyl acetone . . 6 Acetophenone 7 Acetyl chloride 8 Acrolein 9 Acrylonitrile ............................. 10 Ally] alcohol 11 Allyl chloride ............................. 12 Ammonia . . 13 iso Amyl acetate . . 14 iso Amyl alcohol . . 15 Aniline 16 Arcton 6 (Freon 12) (Difluorodichloromethane) 17 Arsine 18 Benzene (Benzol) 19 Benzine (as Hexane) 20 Benzyl acetate 1,000 200 4,000 40 300 80 10 20 100 40 200 500 1,000 400 80 50.000 10 1,500 3,000 100 1,830 500 9,650 140 1,424 400 33 46 220 96 636 355 5,410 1,464 312 251,700 32 4,800 10,728 616 60 500 915 200 3G6 60 40 100 20 50 60 800 1,930 400 965 1 20 70 10 35 60 150 712 75 350 60 40 200 20 100 1 2 6-6 1 3-3 1 8 18-6 11-6 1 50 110 20 44 1 20 48 5 12 -- -- 60 100 318 50 159 1 200 142 100 71 60 300 1,623 100 541 60 200 732 100 366 60 20 78 10 39 60 20,000 100,680 10,000 50,340 1 I 3-2 7-fi 60 500 1,600 50 160 60 1,000 3^576 250 S94 60 50 313 15 94 67 Ethyl silicate 68 Formaldehyde Freon 12 (Arcton 6) 69 Hydrazoic acid 70 Hydrogen chloride 71 l Hydrogen cyanide. . 72 I Hydrogen fluoride. . 73 Hydrogen selenide. . 74 Hydrogen sulphide 75 Iodine 76 Isophorone.. 77 Ketene 78 Lauryl mercaptan . . 79 Mesityl oxide 80 Methacrolein 81 Methacrylic acid 82 Methallyl alcohol S3 Methanol (Methyl alcohol) 84 Methyl acetate 85 Methyl acrylate 86 Methyl bromide 21 Benzyl chloride 22 Bromine 23 Butadiene 24 -Butanol (Butyl alcohol) 2-Butanone (Methyl ethyl ketone) 25 -Butyl acetate 26 -Butyl methacrylate 27 Carbon dioxide 28 Carbon disulphide.. 29 Carbon m onoxide.. 30 Carbon tetrachloride T T p-Chloraniline 32 (mono) Chlorobenzene 33 2-Chlorobutadiene 34 Chlorine 35 p-Chloronitro benzene 36 Chloroform 37 (o & p ) (mono) Chlorotoluene 38 Cyanogen chloride 39 Cyclohexane 40 Cvclohexanol 20 3 8,u00 1,000 See No. 2,000 800 30,000 500 400 2,000 100 20 17,968 3.080 90 Methyl ethyl 9,650 4,724 54,930 1.600 464 I 12,800 1 1 60 60 ketone 60 60 60 60 60 60 8 44 1 400 1,872 60 100 368 1 10 29 1 10 66 1 2,000 9,960 60 400 2,106 60 5 13 2,000 6,990 60 1,000 4,160 60 10 1 5,000 100 500 400 10,000 150 100 500 4 200 50 4 4 500 200 2 800 400 50 6-6 11,230 308 2,412 2,362 18,310 480 116 3,200 22 936 184 12 26 2,490 1,053 5-2 2,796 1,664 5 0-5 2,500 50 200 200 5,000 10 50 50 75 25 1 1 50 75 (H 400 100 25 3-3 5,615 154 965 1,131 9,155 32 53 320 11 351 92 2 9 0-6 249 395 1 3 1,393 410 o / I Methyl iso-butyl ketone 88 Methyl a-chloracrylate 89 Methyl chloride 90 Methyl ethyl ketone (2-Butanc 91 Methyl iodide 92 1 Methyl cyclohexanone 93 Methylene chloride 94 Methyl formate 95 Methv! methacrvlate 96 Naphtha distillate (as Cumene 97 Nickel carbonyl Qfi Nitrobenzene 99 Nitroethane 100 Nitrous fumes (as N O . ) . . 101 Nitroglycerine 102 Nitromethane 103 1-Nitropropane 104 2-Nitropropane I0S o-Nitrotoluene 106 PerchloroethyJene (Tetrachk 107 (-Propiolactone 41 Cyclohexanone 42 Cyclohexylamine . . 43 -Dichlorobenzene 44 3 2 'Dichlorodiethyl ether. 45 (cis & irons) Dichloroethvlenc 46 Dicvclohexylamine 47 Diethyl carbonate 48 Di-isobutylene ! u 49 Di-isobutyl ketone 50 Dimethyl dioxane . . 51 Dimethyl sulphate. . 52 Dioxane 53 Ethanol (Ethvl alcohol) 54 1 Ether (diEthyl) 55 0-Eihoxyethyl methacrylate 56 Ethyl acetate 57 Ethyl acetoacetate. . 58 Ethyl benzoate 59 Ethyl bromide 60 Ethyl chloride 1,000 100 300 100 2,000 50 800 4,000 400 500 15 500 8,000 8,000 500 2,000 200 200 250 10,000 4,080 410 1,836 593 8,072 388 3,928 18,640 1,896 2,412 78 1,830 15,312 24.624 3,285 7,320 1,080 1,248 1,135 26,830 60 200 816 #4 300 40 164 20 S2 60 100 612 25 J 53 1 30 178 n SU 60 1,000 4.036 500 2,013 60 40 302 20 151 60 400 1,964 200 932 60 2,000 9,320 1,000 4,000 60 200 948 100 474 60 300 1,447 200 90 5 1 10 52 26 60 300 1.098 200 * 32 60 2,000 3,828 1,000 1,914 60 2.000 6,156 500 1,539 60 200 1,314 100 657 60 800 2,928 400 1,464 60 100 540 50 270 60 100 624 50 312 60 100 454 50 227 60 5,000 13,415 2,000 5,366 108 uo-Propyl alcohol. . 109 Phosgene .. 110 Phosphorus trichloride 111 Stibine 112 Styrene M3 Sulphur dioxide 114 Sulphur monochloride (S.CK 115 Sulphury] chloride. . 116 Tetrachlorethane . . -- Tetrachloroethylene (Perch! 117 Thionyl chloride 118 Thiophosphoryl trichloride 119 Trichloroethvlene . . 120 Toluene (Toluol) . . 121 (o, m, & p) Toluidines 122 Vinyl chloride 123 Xylenes (Xylols) 124 Xylidines .. 61 Ethylene chlorhydrin 62 Ethylene dichloride 63 Ethylene glycol dinitrate . . 20 68 500 2,050 20 128 60 - 10 60 100 60 1 34 410 6-4 2 50 0~5 7 205 32 125 Antimony (dust or salts) (as 126 Arsenious oxide 127 1 Barium salts (as Ba) become available. 1 mg./cu. metre = 4-37 x I 0 - 4 grains/cu. ft. will be subject to review as more data Continued Concentrations shown in italic a become available. EDICINE ETALS IN THE ATMOSPHERE fee) (2) ntrations which, osure Continues are than a Short may Lead to 'mptoms o f Illness 1 (3) Concentrations in General Atmosphere 8 o f Plant Greater than those below Indicate Unsatisfactory Conditions ! (mg./cu.* n. metre 20C.) {p.p.m . i V v) {mg./cu.* metre 20 C.) 915 200 100 20 1,930 400 70 10 712 75 200 20 6-6 1 18-6 5 110 20 48 5 318 50 142 100 1,623 100 732 100 78 10 366 50 965 ! 35 1 356 i 100 3-3 116 44 51 159 3 73 541 366 li 39 S 100,680 3-2 1,600 3,576 313 10,000 0-5 50 250 15 50,340 l| 1-6 1: 160 Jl 894 I 94 l 50 6-6 11,230 308 5 05 2,500 50 25 I 3-3 ! 5,615 9 154 5 2,412 , 2,362 18,310 480 116 3,200 22 936 184 12 26 2,490 1,053 5-2 2,796 1,664 200 200 5,000 10 50 50 ; 75 25 1 1 50 75 O' 400 100 965 J fisi 9,155 32 58 320 11 351 92 816 164 612 178 4,036 302 1,964 9,320 948 1,447 75 20 25 15 500 20 200 1,000 100 200 300 82 153 80 2,018 151 082 4,000 474 005 52 1,098 3,828 6,156 1,314 2,928 540 624 454 13,415 5 200 1,000 500 100 400 50 50 50 2,000 20 732 1,914 1,539 057 1,464 270 312 ?27 5,366 34 410 6-4 2 50 205 0-5 3 " will be subject to review as more i Continued INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY Table 1 continued No. Gas 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 (3) Concentrations in General Atmosphere o f Plant Greater than those below Indicate Unsatisfactory Conditions (p.p.m. v/v) (mg./cu.* metre 20C.) Time of Exposure (Min.) (p.p.m v/v) (mg./cu.* metre 20C.) {p.p.m. v/v) {meg. lu.* metre 20 C.) <a Ethylene oxide ,< Ethyl formate f(i Ethylidene dichloride h? Ethyl silicate o8 Formaldehyde _ ; Freon 12 (Arcton 6) 69 Hydrazoic acid ^0 Hydrogen chloride 250 450 60 1,000 3,080 60 400 1,648 60 400 3,464 60 100 120 1 See No. 16 Arcton 6. 10 i 18 60 50 75 1 100 180 10 400 1,232 200 200 824 50 200 1,732 100 30 36 10 4 7-2 1 20 30 10 IS 616 206 866 12 IS 15 71 Hydrogen cyanide. . 72 Hvdrogen fluoride. . ij Hvdrogen selenide. . 74 Hydrogen sulphide 75 Iodine 76 Isophorone.. 77 Ketene 78 Lauryl mercaptan . . 79 Mesityl oxide SO Methacrolein M Methacrylic acid 82 Methallyl alcohol . . S3 Methanol (Methyl alcohol) 84 Methyl acetate 85 Methyl acrylate 86 Methyl bromide 87 Methyl iso-butyl ketone . , 88 Methyl a-chloracrylate 89 Methyl chloride 90 Methyl ethyl ketone (2-Butanone) 40 40 2 200 0-5 40 2 20 200 10 44 1 34 1 6 1 280 1 5-5 1 228 60 3-6 1 168 1 816 1 29 1 1,000 3,575 I 150 450 1 2.000 2,560 60 500 1,540 60 100 356 1 250 1,000 1 1,000 4,160 60 20 1 1,500 3,150 60 2,000 ! 5,990 60 20 10 0-5 50 0-2 20 1 10 100 5 400 100 500 200 50 50 400 2 500 500 22 8 5 1-5 70 2-2 114 1-8 84 408 15 1,430 300 640 616 178 200 1,664 10 1,050 1,498 10 01 20 0 1 10 0 5 5 50 i 200 50 200 100 25 20 200 1 100 200 11 17 0 3 28 11 57 0-9 42 204 5-8 715 150 256 308 89 80 832 5 210 599 91 Methyl iodide 92 Methyl cyclohexanone 93 Methylene chloride 94 Methyl formate 95 Methyl methacrylate 96 Naphtha distillate (as Cumene) . . 97 Nickel carbonvl 48 Nitrobenzene 99 Nitroethane 100 Nitrous fumes (as N O .) .. 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 20 118 60 150 I 700 60 1,000 3,536 10 59 75 350 500 1,768 60 400 998 200 409 60 2,000 8,320 1,000 4,160 60 150 750 1 7 14 60 40 204 50 250 1 7 1 5-1 60 500 1,560 200 624 1 30 57 10 19 101 Nitroglycerine 102 Nitromethane 103 I-Nitropropane 104 2-Nitropropane 105 o-Nitrotoluene 106 Perchloroethylene (Tetrachloroethylene) 307 3-PropioIactone 108 1 /so-Propyl alcohol. . 109 Phosgene .. no Phosphorus trichloride in Stibine . . . . 112 Styrene 113 Sulphur dioxide 114 Sulphur monochloride (S-CL) . 115 Suiphuryl chloride.. 116 Tetrachlorethane . . -- Tetrachloroethylene (Perchloroethylene) 117 Thionyl chloride 118 Thiophosphoryl trichloride 119 Trichloroethylene .. 120 Toluene (Toluol) .. 20 189 60 800 2,028 60 400 1,480 60 400 1.480 60 200 1,140 60 1,000 6,905 60 100 300 I 2,000 4,995 60 5 21 1 2 12 1 0-5 1,000 200 20 10 50 See No. 106 20 10 2,000 1,000 2-5 1 4,330 60 520 1 112 1 56 1 350 60 Perchloroethylene. 100 I 70 1 10,940 60 3,830 60 1 500 200 200 40 400 20 800 1 1 0-2 200 20 10 4 20 10 4 800 300 9-4 1,268 740 740 228 2,762 60 1,998 4-2 5-8 I 866 52 56 22 140 50 28 4,376 1,149 0-5 200 100 100 1 200 10 400 0-5 05 0-1 100 10 5 1 10 5 1 400 100 4-7 507 370 370 57 1,381 30 999 2 1 2 9 0-5 433 26 28 5'6 70 25 7 2,188 383 121 (o, m, & p) Toluidines 122 Vinyl chloride 123 Xylenes (Xylols) .. 124 Xylidines 40 176 60 10 44 3,000 7,800 60 1,500 3,900 1,000 4,410 60 300 1,323 40 200 60 10 1 50 5 22 500 1,300 100 441 5 25 Dusts. Fumes, and Metals 125 Antimony (dust or salts) (as Sb). . _ _ _ 0-5 126 Arsenious oxide -- -- -- 0-5 127 Barium salts (as Ba) - -- - -- -- -- 0-5 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 mg./cu. metre = 4-37 x 10" 4 grains/cu. ft. Continued 6 Table 1 continued BRITISH JOURNAL OF INDUSTRIAL MEDICINE I No. Gas . 0) Concentrations Causing Severe T oxic Effects in Persons Exposed for the Stated Times ( 2) C oncentrations which, if E xposure Continues for m ore than a Short Symptom s of Illness (3) Concentrations in Generai Atmosphere o f Plant Greater than those below Indicate U nsatisfactory Conditions 128 Benzidine 129 Cadm ium . . 130 C hlorinated diphenyl 131 Chlorinated naphthalenes 132 C h ro m a tes (as C rO a) 133 D initrocresol (and salts) .. 134 D initrophenol (and sa lts).. 135 D initroresorcinol .. 136 D initrotoluene 137 " Dowthern A " .. 138 Lead (and salts) .. 139 M ercurv 140 a-N aphthylam ine .. * 141 -N aphthylam ine 142 " Parathion " 143 1 P e n ta c h lo rp h e n o l .. 144 /j-Phenylene diam ine 145 Phosphorus pentachloride 146 Potassium perm anganate.. 147 Sulphuric acid 148 Sodium cyanide 149 Tetrvl 150 T .N .T ......................................... 151 Zinc oxide . . (p.p.m . v/v) __ -- -- _ -- _ -- -- -- -- -- --. " -- --- -- -- -- -- -- -- .-- -- -- (m g./cu.* m e tre 20C.) _ __ ,, _ -- .--. -- -- .-- .--. -- -- -- -- -- -- -- -- -- -- -- -- -- - Time of Exposure (M in.) __ -- -- _ -- -- -- .--. -- -- -- -- -- -- -- -- -- -- -- _-- -- -- - (p.p.m . v/v) __ -- -- __ -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- (m g ./cu .* m etre 20C.) __ -- : -- -- -- -- -- -- -- -- -- -- -- -- -- _ -- -- -- -- -- -- -- - (p.p .m . v/v) __ -- __ -- __ -- -- .-- ~ -- -- -- --- ---- -- -- i -- (m g./cu.* m etre 20~C.) 0-015 0-1 1 1 0-1 0-5 1 1 1- ti 0 15 0-2 0-01 0-01 1 0-5 0-.1 1 5 1 1-5 2 10 C o n cen tratio n s show n in italic are tentative and are issued as a guide. Figures in all colum ns will be subject to review as m o re data becom e available. *1 m g ./cu . m e tre = 4-37 X lO " 11g ra in s/c u . 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 form ation 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 o0 5 and that N 20 4 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 2C r 0 4 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 m ono cytic cells undergoing hypertrophy from the capillary blood appear also to be passing into the alveoli. F ig. 2.-- G uinea-pig lung tio n o f fine lead a< m ononuclear phagoc alveolar walls. A ct b o th in the wall and alveoli and coarse gra rial in the phagocytes. ICINE *1 tions which, e Continues han a Short ay Lead to toms of ness (3) Concentrations in General Atmosphere o f Plant Greater than those below Indicate Unsatisfactory Conditions (mg./cu.* metre 20C.) [p.p.m v/v) [mg./cu.* metre 20'- C.) 0-015 - Jo 0-01 0-01 * will be subject to review as more data xtensive industrial pulmonary on of a lung of a rat which, r rats, was exposed for months to an atmosphere of a very fine dust. The 2 was a period of coughing and xhing serious. They lived on ned the chromate with bored shows large and small areas eoli crammed with loaded is stages of degeneration, is are out of action. The cell ontributes further to loss of of. Dilated respiratory bronphysema, due partly to the iromate on the alveolar septa, sation to the loaded alveoli, ;er picture of a portion of a exposure for months to a on of lead acetate (40-50 of the dust cells from the is clearly seen, but monoypertrophy from the capillary be passing into the alveoli. FlG. 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, x 300. Fig. 1.--Rat lung after chronic exposure to fine potassium chromate dust ; many areas of exsanguinated, functionless alveoli filled with histiocytic phagocytes and many ruptured alveoli, x 100. Fig. 2a.--Phagocytosis of blood phagocytes by macrophages deriving from septal cells ; details of coarse pigment granules in guineapig lung. X 1200. .*.H 1 * !uiVwf..,' IN DUSTfi F ig. 3.-- R abbit lung showing chronic inhalation o f fine lead acetate dust. Three areas o f same lung showing different stages in development and death o f lung phagocytes ; small alveolus cram m ed with dead and dying phagocytes swollen w ith absorbed particles ; n o te multinuclear m acrophage. 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 inter formation. These effects cam with equal ease in all species The deliberate induction of in the treatment of cyanide p importance, and recovery in been obtained by Lloyd Potti depends upon the intraveno nitrite which, by forming ms the circulating cyanide to rea; toxic cyanmethaemoglobin a: injection of sodium thiosulr the formation of thiocyanaii liberated cyanide. Renal and hepatic functi many chemical agents ; an industrial metallic poisons, o chlorinated aliphatic hydroci vatives of glycols. Reverse endangered for the change-c structural breakdown is po peculiar position of trichlc commonly used solvents, 1' subtle must be the mechani? low toxicity, which is perhr metabolism to the non-to? (Taylor, 1936 ; Powell, 194: For certain metabolic a carcinogenicity the use of isc and wider significance. A >. one carbon C14 has rece: members of my departmer Amersham (Henson, 1953 Somerville, 1953). We ha: establish important metabol retention of compounds ca> in the body (Henson, Some Goldblatt, 1954). The detc toxic compounds in cells histological sections is alrea The ultimate fate of mo< industrial conditions is uni known about some of the fi: chemical substances are dis we are very rarely able to str or even extraordinary chen ways in which complex sui the body in large part " difficulties and apprehens using labelled compounds a in obtaining almost complei and output of substances c< and in discovering how lonj derivatives are retained in is possible to track them tl B g showing different stages in lien with absorbed particles ; note the lung is paid for in the cast ienudation of the precursors of !s (/.<?. modified septal cells) and by the occupation of alveolar rged cells and cell debris when discharged. The formation ol ;ells also occurs in the chronic :ust (Fig. 3). In a universe of kind are inevitable but it is our industrial dust with other ngs. pigments are mainly found in a exposed to carbon monoxide, o- and amino-compounds, and INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 9 metallic elements which interfere with haemoglobin formation. These effects cannot all be demonstrated with equal ease in all species of laboratory animals. The deliberate induction of methaemoglobinaemia in the treatment of cyanide poisoning is of practical importance, and recovery in very severe cases has been obtained by Lloyd Potter (1950). The method depends upon the intravenous injection of sodium nitrite which, by forming methaemoglobin, permits the circulating cyanide to react to form the much less toxic cyanmethaemoglobin and upon the intravenous injection of sodium thiosulphate which accelerates tire formation of thiocyanate from the now slowly liberated cyanide. Renal and hepatic function can be affected by many chemical agents ; among these are certain industrial metallic poisons, organic solvents, notably chlorinated aliphatic hydrocarbons, explosives, deri vatives of glycols. Reversibility in these cases is endangered for the change-over from dysfunction to structural breakdown is poised precariously. The peculiar position of trichloroethylene among the commonly used solvents, however, indicates how subtle must be the mechanism which determines its low toxicity, which is perhaps related to its ready metabolism to the non-toxic trichloroacetic acid (Taylor, 1936 ; Powell, 1945). For certain metabolic aspects of toxicity and carcinogenicity the use of isotopes is assuming wider and wider significance. A bladder carcinogen with one carbon C14 has recently been prepared by members of my department in collaboration with Amersham (Henson, 1953 ; Catch, Huggill, and Somerville, 1953). We have already been able to establish important metabolic pathways and the long retention of compounds carrying the labelled atom in the body (Henson, Somerville, Farquharson, and Goldblatt, 1954). The detection of the location of toxic compounds in cells by autoradioactivity in histological sections is already a developing method. The ultimate fate of most materials absorbed in industrial conditions is unknown. A great deal is known about some of the final forms in which many chemical substances are disposed of in animals, but we are very rarely able to strike a balance by ordinary or even extraordinary chemical means. The subtle ways in which complex substances introduced into the body in large part " disappear " raise many difficulties and apprehensions. Nevertheless, by using labelled compounds a new era has been opened in obtaining almost complete balance between intake and output of substances containing isotopic atoms, and in discovering how long such substances or their derivatives are retained in the body. In addition it is possible to track them through the various routes they can take in the body and, if retained for long periods, to learn where they are deposited. Industrial metabolic poisons interfering with phosphorylating processes are dinitroorthocresol (D.N.O.C.), dinitrophenol (D.N.P.), and pentachlorphenol, the former two being responsible for both clinical and industrial deaths, and the latter for recent industrial deaths. Dinitro aromatic com pounds require careful study as some may induce cataract. Indirect metabolic effects may arise from interference with normal thyroid function as in the case of some alkyl-nitro-amino derivatives of phenol. The haematopoietic system is one of the first examined in the case of most industrial chemical hazards with chronic effects. Blood counts are some times undertaken on workers in many diffrent branches of the chemical industry, especially where hydrocarbon and chlorinated hydrocarbon solvents, explosives, some metals, radioactive materials, and many other materials are made or used. Animal experiment often gives the appropriate lead as to the nature of the attack on the blood-forming organs or on the blood itself, although there are difficulties from the much greater variability of the blood picture in animals than in man. Reversibility of effects on the blood depends upon removal of the noxa and on the functional recovery of the bone marrow. Clinical and Experimental Aspects o f Lead Intoxication Much has been done to elucidate the clinical picture and pathological processes of lead intoxi cation and poisoning. As the result of 12 years' experience of men in a factory where lead acetate, lead pigments, and paints were manufactured certain clinical and elementary propositions have been formulated. The first is that the control of the health of workers exposed to any lead hazard is easy and effective by routine determination of (a) haemoglobin, and (b) stipple and polychromatic red cells. More complex methods are required in certain of the more highly dangerous lead hazards, e.g., volatile organic lead compounds. The expertise to do this is minimal, and a junior boy or girl can be trained to do it and even interpret the findings in a short time. If the conventional method by transmitted light be used, then it should be realized that the polychromatic cell is a stipple cell with the stipples very closely set, and they should be counted together, and can readily be confirmed by dark-ground examination (Figs. 4 and 5). Haemoglobin determination alone is not sufficient, for many patients are found with 100 to 90% haemo globin who may be presumed to be absorbing lead from the high (stipple and polychrome) counts. Nor B 10 BRITISH JOURNAL OF INDUSTRIAL MEDICINE INDUSTRI F ig , 4.--R abbit blood stained with alkaline methylene blue and ph o to graphed by transm itted light showing various-sized basophilic (polychrom atic) cells due to chronic lead exposure. F ig . 5.-- R a b b it blood stained with alkaline m ethylene b lue and p h o to g ra p h ed by d a rk ground illum ination show ing ease oi recognizing stipples (golden granules) and two polychromatic cells ; the p o lychrom atic cells are m anifestly very1 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 is' concerned. 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 relatively short duration, and that there is complete recover' when the exposure has been terminated, and that no irreversible damage to the blood-forming tissues is associated with plumbism. The cases to which this statement would not apply are the now exceedingly rare encephalopathies and muscle palsies. Fig. 7 shows the kind of picture one would wish to avoid, that of a man who took five years to recover his haemoglobin although removed from contact with lead (see also Fullerton, 1952). Fig. 8 shows the data on a case of some interest. Three months of work on lead were followed by a fairly acute episode from which the patient was allowed to recover while still at the factory doing odd jobs not involving contact with lead. In spite of a very big drop in the number of stipples and polychrome cells, the haemoglobin level recovered poorly. A subsequent period on work with lead again led to an episode which was certified. Certi fied as fit to work after 21 days, the patient was again iiG . 6.--R elation between haem oglol in w orkers exposed to a lead c exam ined show n with H b valu- Ceni Year JUJti IM 7 J9JS No. Name 1 1 F.G. t , W.P. 3 G .F.K . 4 J.S. 5 S.F. 6 K.A.M . 7 AAV. 8 P.N. 1 9 T.H. m s 10 11 -i E.M . F.H.W . Time Lost 8 davs 10 davs 2 mths. 26 davs 15 davs 16 days 2 mths. 6 days 13 davs 18 days 28 days 1 1 mth. i 21 days (All cases 6 OICINE INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 11 Stained w ith alkaline m ethylene blue and ark g ro u n d illu m ination show ing ease oi (golden granules) and two polychromatic o m atic cells are m anifestly very rinelj nd return to work (Foreman, d Belknap, 1953). emphasized that the usual forms i are self-limited, of relatively that there is complete recovery as been terminated, and that no to the blood-forming tissues is ibism. The cases to which this apply are the now exceedingly :s and muscle palsies, ind of picture one would wishin who took five years to recover though removed from contact ullerton, 1952). lata on a case of some interest, irk on lead were followed by a from which the patient was while still at the factory doing ng contact with lead. In spite in the number of stipples ana e haemoglobin level recovered jn t period on work with lead jde which was certified. Certi:r 21 days, the patient was again 5 10 15 20 lOOO's Stipple+"Polychromz"cells i v J . 6 --Relation between haem oglobin and stipple-polychrom e counts in workers exposed to a lead dust hazard. N um bers o f bloods examined shown with H b values. (See text). 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. cit.) 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, irhe 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 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 normoblasts in the marrow showing basophil stippling when only 2-5% of red blood cells were Table 2 LOST TIM E OF TW O GROUPS Year No.i N am e 1936 193? ms mo ! 1 F.G. 2 w .p. 3 G .F.K . 4 J.S. 5 S.F. 6 K.A.M . 7 A.W, 8 P.N. 9 T.H. 10 |E .M . 11 F .H .W . T im e Lost 8 days 10 days 2 mths. 26 days 15 days 16 days 2 mths. 6 days 13 days 18 days 28 days 1 nth. 21 days Year mo N o.| ! 12 13 Name W .C . A .H.T. 1941 -- -- 1943 20 : 11 14 G .F .M .t 1944 17 : 4 15 G .F.M . U ncertified t Time Lost Year | No. Name Time Lost Year No. Name 3 days 1 mth. 13 days -- 1 mth. 4 days 30 days 1936 28 : 10 1 E.E. ! Nil 9 : 12 2 E.E. Nil 4 : 11 3 W.F. Nil 4 F.G. Nil 14 : 10 5 F.K. Nil 28 : 10 6 F.K. Nil 7 H.E.W. S days (Hb. 75% )i gastritis 1937 24 : 3 8 W.F. Nil 5 : 5 9 W.F. N il 10 F.G. N il 11 C .J.H . Nil 12 J.L . N it 13 R.O. Nil 1938 13 : 12 14 C.F.H. N il i 15 \ W .R . N il 1939 23 : 1 1 16 17 18 1940 23 : 9 19 20 1941 -- 1942 -- - 1943 22 : 5 21 1944 -- 1945 26 : 1 22 C .F .H . A .E .P . A .W . H .J. G.M . -- -- H .J. -- H .J. Time Lost N il 20 days* investigation N il Nil Nil -- -- N il -- Certified = recovery away from factory, tU ncertified = recovery at work. (All cases 60-65% H b at time o f certification o r action in factory.) {Recurrent cases in italic. I bVjr aJU * > r 12 BRITISH JOURNAL OF INDUSTRIAL MEDICINE T able 3 PERIO D OF RECOVERY OF Hb W.F. AGE 48-53 YEARS. Hb & Stipples* `Polychromes', Slow Hb recoverymaintained high (StP) during Non-lead No. of Cases H b at time of transfer .. M ean tim e to reach 80% or more M aintained at W ork 24 65-70% 1-93 m onths (3 weeks-7 i m onths) Removed to Home or Hospital 9 65-70% 1-66 m onths (16 days-2 m onths) Indicates slight advantage o f getting m an away from factory even on light and non-lead work. 1 case o f H b 43 -4 5 % recovered to 80% in 28 days w hilst at w ork 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 ribonuclease which completely 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. F ig. years 7.-- Case o f lead anaem ia showing extremely slow recovery of haem oglobin whilst m aintained at work. T.H. AGE 29-32 YEARS. R eturned to w o rk before blood re co ve ry -a fte r 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. F ig . 8.-- Case o f certified plum bism considered clinically fit to return to w ork, b u t thereafter requiring alm ost tw o years to regain a stable H b 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. MacFadzean and Davis (1949), Pirrie (Joe. cit.), 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. F ig . 9.-- Case o f sensitivity and recurrent lead anaem ia in spite o f long periods on non-lead w ork. Close correspondence of H b and stipple values. INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 13 F i g . 10.--R a b b i t blood a f t e r chronic lead inhalation show ing stippled normo blast. Stained with alkaline m e t h y l e n e blue, x 2000. FiG. 11.--Rabbit bone marrow after chronic lead inhalation show ing coarsely stippled nor mobl a s t (R.B.C. # somewhat out of focus), x 2000. * Fig. 12.--Rabbit blood after chronic lead inhalation showing reticulocytes ; ^ supravital staining with brilliant cresyl blue. X 1200. Fig. 13.--Rabbit blood on same occasion as Fig. 12 (dry film stained with brilliant cresyl blue) in which reticu locytes are seen as cells with v a c u o l a te d basophilic material, x 1200. ( i r 14 BRITISH JOURNAL OF INDUSTRIAL MEDICINE Lead poisons the later precursors of the red cell and intoxication manifests itself as (1) retention of basophilic material instead of its almost complete disappearance at the normoblast and reticulocyte stage and completion of maturation. (2) The socalled stipple cell and the polychromatic cell derive from the failure of maturation of the basophil normo blast. The reticulocyte derives from non-poisoned normoblasts. Since reticulocytes may increase before lead anaemia and stippling are established we may assume that the stipple and polychrome cells indicate a failure of the normoblast to go on to the reticulo cyte stage. With the failure of the bone marrow in extreme cases oflead poisoning, stipples, polychromes, and reticulocytes all fail. This is why stipple counts fall in the last stages of very severe lead poisoning. (3) By processes not properly understood (synthesis of porphyrin, incorporation of Fe into coporphyrin III to form haemoglobin, etc.) lead inhibits the full haemoglobination of red cells. (4) Evidence of abnormality of red cells in lead absorption is that they show (a) diminished fragility in being able to withstand lower salt concentrations ; (6) increased brittleness and less durability in the conditions of existence in the circulation. In addition, they are readily taken up and destroyed by the spleen and other reticulo-endothelial cell locations. (5) Lead anaemia is due to (a) poor haemoglobination and (b) greater destructibility of cells containing lead. Industrial Enzyme Poisons Many industrial poisons are enzyme inhibitors, e.g., cyanide, organic arsenicals, organo-phosphorus compounds. The clinical pictures of acute poisoning can sometimes be related more or less specifically to the inhibition of particular enzyme systems. The most important of these has, in recent years, been the large group of organic phosphorus insecti cides (Fig. 14) and potential war gases. Since there is intense competition in this field of manufacture, chemical research is directed towards synthesizing compounds which combine a broad spectrum of high insecticidal activity with low mammalian toxicity. The toxicity of these compounds (Table 4) is attributable to their inhibition of cholinesterase and hence the clinical picture of poisoning is that of poisoning by endogenously produced acetylcholine. But the degree to which they inhibit the enzyme in vitro is in some cases many (even millions of) times less than would be expected from their toxicity in vivo. Transformation into highly potent anti cholinesterases occurs in these cases in the liver. Recently progress has bee made towards evolving organo-phosphorus compounds possessing low mammalian toxicity compa\ d with the now classical Table 4 L.D.50. O R G A N O -PH O SPH A TE INSECTICIDES* Compound Oral L.D.50 l.P. L.D.50 T .E .P .P ......................................... Paraoxon D im efo x Svstox (Commercial) S >P11 -0- .. 12 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. 4-5-8-37 R.m. o ii > P -S - .. Pestox (O.M.P.A. Schradan) Parathion E .P .N . M ipafox M alathion 15 R.m. 9-7-10 0 R.m.f. 6 R.f. 15 R.m. 14 5 R.f. 91 0 R.m. < V-o Parathion 2,420 R.f. 2,860 R.m. 8-0-8-5 R.m.f. 4 R.f. 7 R.m. 50 M. 750 R. *Median lethal doses of organo-phosphate insecticides. R = rats, M -- mice, tn = male, f = female. All values in m g./K g. 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 ORG/ l). PARATHION 2). T.E.P.P. 3). P E S T O X 4). PARAOXO 5). E.P. N. (u ). DIM EFO > 7). M IP A F C 8) . systo ?) M A L A O R G A N O -P H O SP H O R U S INSECTICIDFS I). PARATH ION 0 2N S / c aHs O-- P \ q C2H5 2). T.E.P.P. 3). P E S T O X 4). PARAOXON '2 ' '5 A | c2h50 no c 2h5 & C C H ^ N .] J CCH^N 7 2 N<( ------ ' 1 0 r -y 0 'O C 2H5 5). E .P . N. ( u .S.a ) o 2n < ^ c 2H5 6). D IM E F O X /F o = p Z n (c h 0 2 V ch^ SYSTEM IC % Ml P A F O X / 0 = P s - N H .C H ( C H 3) 2 N m h .c h iJ ^ SYSTEM IC 8). SY S T O X .^s r u c /* u S II /O C H C 2H5'S C2H4 ~ ~ p \ 25 SY ST E M IC c 2h5.o o c .h c S O C 2H5 m a la t h io n C 2H5.OOC.HC -- lPi - s_(/ 0 C H 3 OCK Fig. f4.--Formulae o f active compounds in organo-phosphorus insecticides. LEAST TOXIC 16 BRITISH JOURNAL OF INDUSTRIAL MEDICINE I in order to preclude a fall to dangerous levels ; each subject should be his or her own control. The variance from mean levels in populations is too great to draw conclusions from single observations. It is so easy to ignore the early symptoms which may be no more than a slight tightness in the chest and a sense of mild apprehension. This is the more important since in irreversible inhibition of cholin esterase there is considerable delay before the normal enzyme level is regenerated. In the case of " mipafox " poisoning it may take 50 to 90 days to recover the initial red blood cell level of cholinesterase after an acute severe attack. 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-phosphorofluoridate) 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-(monoisopropyl) phosphorodiamidic fluoride] in this country by Bidstrup, Bonnell, and Beckett (1953), none of which appears to have recovered in some three years. The addition of these agents to the already known diversity of demyelinating agents in man and animals (carbon monoxide, arsenicals, sulphanilamide, spinal anaesthetics, vaccination) tends to turn us from a purely chemical hypothesis to perhaps an enzymatic one. Demyelination has been produced experi mentally with CO, KCN, N 3Na, N,,0, and repeated doses of barbiturates (Weston Hurst, 1941, 1944). The paralysis which followed " parathion" and " mipafox " resembled that described among many people who had absorbed T.O.C.P. in one way or another, and in both these groups it seems probable that the persistent signs were due to demyelination. Fig. 15 shows a section of the cord of a fowl Cl-35 kg.) treated with a single dose of 0-5 g./kg. of tri-o-cresyl phosphate (T.O.C.P.). This and another fowl similarly treated were observed for over 250 days. The phenomena were of the same kind as found with the anti-cholinesterase insecticides. Some recovery was observed, especially in respect of secondary sex characters and egg-laying power, and to some extent in muscular powers, but this was very slow and only partial (see also Barnes and Denz, 1953). The selection of a special tract for attack is puzzling and not less so than in man, in whom the whole picture is of a motor disturbance. In the cases due to insecticide a neuromuscular block due to the breakdown of the normal relation of cholin esterases and their substrates was first seen and later a peripheral neuritis with only those sensory impair ments as are normally associated with polyneuritis. As more and more compounds are being synthe sized, it is important not to assume the relative safety of a given compound until acute and chronic F ig. 15.-- Cervical cord and sciatic nerve o f a fowl treated with a prep aratio n o f tricresy] phosphate calculated to contain 0-1% o f the ortho-isom er. T otal dose in 16 days = 2 m g./kg. by mouth. F irst paralytic signs in 21 days followed by progressive worsening o f paralysis o f legs. D em yelination in anterior an d lateral colum ns and m arkedly on sciatic cord. X 12. M archi's m ethod. A = upper, and B = lower, cervical cord -below sciatic nerve. Ii experiments have be effect on the nervou variety of animal spe Occupatii There are very fe have been shown wit gens to man. The radiations (x-ray, r naphthylamine, benz pyrene. Of the host of con which have producer mary gland, lung, an( have been demonstrs carcinogens. The ac products as tar, lubr established with cert. 3-4 benzpyrene from this compound. Long-continued tl tions and work with to indubitable skin finally to epitheliom; ment has been pub! effect in animals. In the case of certa as well as severe bl< followed long expo though the tumours sarcomata in animal: differences are attril reached by the radia Neoplastic change often highly maligna of workers exposed and/or dust of cert reported for nearly f where organic dyes clinical fact has beei in the U.S.A. and identical bladder tu: (i-naphthylamine. I Clayson. and Jull (IS tumours inducible amine in different s amount of urinary a excreted. More recently t benzidine and has bi research both inside the demonstration c benzidine in rats (rec but bladder tumou induced except in rE i also Barnes and Denz, jcial tract for attack is tan in man, in whom the 'tor disturbance. In the neuromuscular block due tormal relation of cholin;s was first seen and later mly those sensory impairxiated with polyneuritis, pounds are being synthet to assume the relative d until acute and chronic nerve o f a fowl treated with a ate calculated to contain 0 1 % of n 16 days = 2 m g./kg. by m outh, followed by progressive worsening elination in anterior and lateral sciatic cord, x 12. M archi's ? lower, cervical cord below INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 17 experiments have been carried out, and also the effect on the nervous system studied in detail in a variety of animal species. Occupational Carcinogenesis There are very few identifiable agencies which have been shown without any doubt to be carcino gens to man. These are arsenical compounds, radiations (x-ray, radium, ultra-violet light), 3naphthyiamine, benzidine, and probably 3-4 benz pyrene. Of the host of compounds and complex mixtures which have produced tumours of skin, liver, mam mary gland, lung, and bladder in animals, only these have been demonstrated as direct or indirect human carcinogens. The active agents in such carcinogenic products as tar, lubricating oil, soot, pitch, are not established with certainty, although the isolation of 3-4 benzpyrene from tar casts strong suspicion on this compound. Long-continued therapy with arsenical prepara tions and work with arsenical compounds have led to indubitable skin changes (hyperkeratosis) and finally to epitheliomata. But no convincing experi ment has been published to demonstrate a similar effect in animals. In the case of certain radiations, neoplastic change as well as severe blood changes have undoubtedly followed long exposure in man and in animals, though the tumours which develop are different-- sarcomata in animals and carcinomata in man. The ditferences are attributable to the different tissues readied by the radiation. Neoplastic changes, sometimes benign but most often highly malignant and recurrent, in the bladders of workers exposed for varying periods to the fume and, or dust of certain aromatic amines have been reported for nearly 60 years in all parts of the world where organic dyestuffs are manufactured. This clinical fact has been confirmed by experiment both in the U.S.A. and in Britain with dogs in which identical bladder tumours were induced by feeding 'i-naphthylamine. It has been suggested by Bonser, Clayson, and Jull (1951) that the incidence of bladder tumours inducible by treatment with 2-naphthylamine in different species is roughly related to the amount of urinary conjugates of 2-amino-l-naphthol excreted. More recently the same suspicion fell upon benzidine and has been amply confirmed. Intensive research both inside and outside industry has led to the demonstration of the carcinogenic properties of benzidine in rats (rectum, sebaceous ear glands, liver) but bladder tumours had until recently not been induced except in the case of one dog (Spitz, Maguigan, and Dobriner, 1950). The possibility that here also the o-hydroxyamine is the immediate carcinogen has received much consideration. The contribution made to the elucidation of the problem in this country has been notable and the names of Bridge (1934), Macalpine (1929,) Wignall (1929), Walpole, Williams, and Roberts (1954), Scott (1952), Baker (1953), Bonser and others, (1951), Bonser, Clayson, Jull, and Pyrah (1952) and more recently Case and Hosker (1954), and Case, Hosker, McDonald, and Pearson (1954), will always be remembered for the great light shed upon it. The total number of cases which Case and his colleagues (1954) were able to trace in the chemi cal industry between 1900 and 1952 was 455. Case's classical statistical investigations are a model for the future investigation of occupational diseases. Case and others have established on a national scale what others have found in industrial practice both in this country and elsewhere. Contact with the naphthylamines or benzidine is now fully recognized as a carcinogenic hazard, and aniline appears to be exonerated. Some as yet cryptic factors in the manufacture of magenta and auramine appear to throw suspicion on both these processes. The disease was prescribed as an industrial disease in 1953 in this country, just 58 years after the original description by Rehn. It is proper to record the unremitting clinical control by Dr. Charles Cresdee for almost a quarter of a century in one very large centre where these compounds were manufactured, which has been a guide and an inspiration to those who have had to pursue the problem in the quiet of the laboratory (for earlier work and review see Goldblatt, 1947, 1949). More recently, arguing very ingeniously from the fact that these tumours had formerly been attributed to aniline, which until now has not been proven to be a bladder carcinogen, Walpole, Williams, and Roberts (1954) in Manchester came to suspect 4amino diphenyl, which had been found in residues in aniline manufacture 80 years ago, as the probable cause. Experiments on dogs confirmed the presumed bladder carcinogenicity of this compound. Certain condensation compounds of the naph thylamines formerly used in the processing of rubber have already been banned by manufacturers since new knowledge on the previously suspected but uninvestigated incidence of vesical tumours in the rubber industry became available (Case and Hosker, 1954). Both the Leeds and Manchester workers have come to place great emphasis on o-hydroxyamines as the effective bladder carcinogens. This has opened a large speculative field of inquiry, because 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 3-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 (Machie and Gregorius, 1948) but Bidstrup (1951) was not able to draw clear con clusions from her x-ray survey of 724 workers in the industry in this country. Recent statistical data in the U.S.A. show that chromate workers had a mortality rate for respiratory cancer 29 times as great as would be expected among a comparable group of all males in the country (Federal Security Agency, 1953). In 1949 the Senior Medical Inspector of Factories gave. reasons for th 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 EDICINE , if the observation is confirms! process here as other than oi .1 mechanical irritation but I sn is not ruled out although it] find support for it. It is n | that a given material is nof as ordinarily understood is everse of carcinogenicity. F<j ound exercising a toxic effei ng that cell in the direction ith, one exerting a carcinogen 1 cell is driving that cell toward rmal, function and, for a time! . This is not to say that a cartina never toxic in the ordinary sensi oxic agent in full spate is unlikelj stablishment of carcinogenicit an induction times for certain cinogens are long and noi severity of exposure, it is to te individuals the induction tim9 and in others much longer thaif he Diagnosis of Vesical Tumou ontinued medical supervision ol ;n exposed in the past to bladdef inifest even after exposure ha ifter leaving the industry, the chemical industry exfoliative used to detect early bladdeq S.A. the teaching of Papanicolaou le importance of the recognitior iges in exfoliated cells has beer Tells may be exfoliated from th adder, cervix, and vagina, and| hologicai and staining characters .an be recognized, there is nc why a neoplastic process should at an early stage (see alsc c>stoscopv of workers as it is practised on the Continent and to some extent in the L .S.A. Hence urinary examinations must l>: made and every device used which will, with the minimum discomfort, give a correct picture of the inside of the organ. To this end we are seeking to enlarge the scope of urinary examinations by deter mining the picture of vesical exfoliation in normal subjects, by applying Papanicoliou's methods to the urine, and, we hope later, by cytochemical tests for malignancy. By methods different from those hitherto used, Mr. Rofe in my laboratories has been able accurately to stain, characterize, separate, and count the types of cells found in normal human urine (Rofe. 1955) after removal of the normally interfering organic and inorganic matter and debris and concentrating the cells in 1 in 1.500 of the volume in which they were voided. Certain conclusions may thus be stated : (1) M ost normal urines contain blood. (2) Most normal urines contain leucocytes. (3) The cellular content other than these is divisible into two main parts (a) squamous and tran sitional. 15u and over in size (urethra, bladder) ; (b) small epithelial cells derived from kidney and prostate (in the male) 15 x and under in size. These cells are m various stages of degeneration. \ very interesting feature of these counts 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 always in a state of some irritation, either chemical or mechanical, which does not reach consciousness. By applying Rofe's method it is possible to see at a glance all the cells exfoliated in a given sample of F ig . 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 adder tumours the early develop-] ded by any disturbance of the! ccupational or non-occupational[ es the need to establish routine! for microscopic blood, which is] sign of bladder irritation, of ricosities, of a broken frond of , or of the slow and insidiousl trating carcinoma. In a small] ses microscopic haematuria is] a tumour visible in the cysto- I# arger proportion there may be| ' the presence of a tumour, is useless to recommend routine! F ig . 16.-- Sm ear from u rine o f w orker in m anufacture o f dyestuff intermediates showing erythrocytes, polymorphs, abnorm al and degenerated epithelial cells, and several definitely malig nant cells. Papanicolaou's technique o f preparation and staining. \ 500. / % V * G * aS&k i * F ig. 17.--Smear from ano th er dyestuff worker showing erythrocytes, many polym orphs, and giant binucleated m alignant cells. Papanicolaou technique, x 500. F ig . 17 ^ f -3 ' 20 BRITISH JOURNAL OF INDUSTRIAL MEDICINE <1952) working in my laboratories. The value of .cytological diagnosis has been amply demonstrated. The cytological criteria laid down by Papanicolaou for the diagnosis of malignancy include increased size and bizarre shapes ; enlargement of nuclei in relation to cyto p lasm ; altered nuclear and chrom atin pattern ; increased affinity o f nuclei for basic stains ; and variation in nuclear sizes in a group of cells (Figs. 16, 17). In a m ethod of 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 tum ours. T h e cystoscope is not infallible, for we have had cases in which a positive cytological diagnosis was subsequently confirmed by cystoscopy after initially negative cystoscopic reports. It is becoming clear that the exfoliation of cells from new growths is not a uniformly constant process. One day it may be prolific, another relatively unproductive. Further, the ease of recognition of neoplastic character varies. For these and other reasons we prefer at this stage to base judgment on a combination of the classical search for haematuria and to fortify it with the cytological method. It has thus been possible to assert the presence of a tum our at a stage when a slight microscopic haematuria would have left us in doubt and the patient in delay. F ield Experim ent Field investigation is properly the dom ain of the industrial doctor, and it is the most difficult. In the last analysis it is upon field investigation that a final judgment must rest as to the relation between industrial environment and state of health. The difficulty does not lie in the recognition of this proposition, but in obtaining the opportunity and in devising the appropriate methods to establish such relations. To attain results which are soundly based and generally acceptable is a task requiring the cooperation of many disciplines. In the main, therefore, it is in the big organization with great resources that such studies can be made, but it is a parallel fact th at in such organizations the environ mental conditions are likely to be the best. The practical application of the principles which em erge from field studies requires assiduity on the part of the industrial doctor and of those responsible for industrial hygiene, for this requires not only the willingness of employers to make money available, but also the willingness of workers to create it. In conclusion, my object has been to indicate some of the things which concern those who are engaged in research in industrial health in the chemical industry, and some of the difficulties and dilemmas which arise. This kind of work is merely the preliminary to the application of the knowledge thereby obtained in the field and the factory. It is there that the ultim ate goal set by Jam es Mackenzie must be reached--the prevention of occupational illness. I am extremely indebted to Mr. Kenneth Cooper and Mr. Leslie Hewitt for their kind cooperation in the 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. R eferences B ak er, R . K . (1953). C ancer R es., 13, 137. Bam forth, J. (1953). P ractitioner, 171, 244. B arnes, J. M ., and D enz, F . A. (1953). J. Path, B a d ., 65. 597. B idstrup, F. L. (1951). 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