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FILE NAME: Celanese (CEL) DATE: 1955 Jan DOC#: CEL050 DOCUMENT DESCRIPTION: Laubly Exhibit #3 - Medical Journal .BRITISH j o u r n a l F INDUSTRIAL MEDICINE EDITOR RICHARD SCHILLING ASSISTANT EDITORS GILSON L. G. NORMAN EDITORIAL J. M. Barnes Sir Frederic Bartlett Thomas Bedford G. R. Cameron C. M. Fletcher M. W. Goldblatt A. Bradford Hill COMMITTEE 'T. G. Faulkner Hudsoi Donajuj Hunter R. E. Lane A- Medojuohn J. N. Morris J. R. Squire E d it o r , British Medicai Journal CONTENTS U PAGE . Restarch in Industrial Health in the Chemical Industry. M. W. Goldblatt................... Manganese Poisoning in Moroaan Miners, J. Rodier .. .. ............ Dermatoses in Jute Workers. John Kjnnrar, John Rogers, Owen A. Finn, and Alexander Mair .......................................................................... TaJcosix of Unusually Rapid Development. G. P. Almsatos, A. E. Pontikajos, am B.Tersus .. .. .................... ............................................... Injury to the. Respiratory Trao: by Isocyanates Used in Making Lacquers. Ajce Swensson, Carl-Eric Holmquist, and Kaal-David Lundcren ................... 50 Dimethyl Sulphate Poisoning. T. R. Lsttlerand R. B. McConnell .. ..................... T Vaoadiam Poisoning from Gas Turbines. R. C. Browne .. ................... The Toxicity of Ozone m the Presence of Osddes of Nitrogen. W. M. Diocle and J. C. GaCe The Construction of Critical Orifices Working with Small Pressure Differences and Their Use in Controlling Airflow. H. A. Druett .. ......................................... 65 Miscellanea ' The Health Hazards of the Senior Executive. A. R. COOPER............................................. 71 The Health of the Industrial Worker in Iraq. A. Michael Critchuey ................... 73 Book Reviews .. ................... .. 76 Abstracts ........................ . .................................... 78 C st/si, <S ' ; LONDON BRITISH MEDICAL ASSOCL4TION TAVISTOCK SQUARE. W.C.l U .SA . $7.00 S in g u e N u m b e r 12/6 y JUEZ RT W a tso n -Jones sacrions of the Association RESEARCH IN INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY* BY M. W. GOLDBLATT From the Imperial Chemical Industries, L td., Industrial Hygiene Research Laboratories. H ens original contributions in s for book reviews and ng, Nuffield Department rk Place, Manchester 13. tis Journal, and that they paper only, with double o f x-ray-illustrations is a and photomicro graphs nompanying papers ooth, white paper, htly inserterd m pencil, k is referred to, the place f publication must follow small letter (a, b, c) after 3Qreferences are arranged en as follows : Author's abbreviated according to numerals'), and first page : verbal corrections have per sheet o f sixteen pages rill be responsible for any A limited number of ming proofs. An estimate Association. . nal o f Industrial Medicine seraent Manager, British : ritish Medical Association j The satisfaction 1 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 o f a special kind. Mackenzie was a man with a mission. He also had ,, vocation, and his life was rich in worth. If James Mackenzie sought to bring what might be called " physical" light to the dark and sick lives o f 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 'ffieer in industry requires. The workers and staff of an industry are in a real sense the dock 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 -age of exhortation. The workman was suspicious of the " compo " doctor; the employer might employ a doctor to examine new entrants, for firstaid services, and in compensation cases. Many doctors thus appointed were not permitted to enter the factories at all. The health and well-being of a worker were then of consideration only as they might affect the employer's interests. Then, as now, the appointment of an industrial medical officer and what he was asked to do lay with the employer. * The M ackcnne Jnduitrial H ealth Lecture delivered in M anchester JuU ! J. J9M , at the A nnual ProMnctai M ceuni of the A isoctauon lA -jjU nai M edical Officer, The coming of the second world war ga-.e an impetus to industrial medicine in this country ar.d 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 infarmzgjon with the industrial doctor. To-day the agEloi" 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 m> 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 1 was put in charge of the first industrial hygiene laboratories established by industry in this country, a tangible proof of the awakened realization among industrialists that industrial health is not a question of policy, but one of science, of conscience, and of Civility. Maximum Allowable Concentration of Atmospheric Contaminants in the Working Environment For an industrial environment where harmful elements, compounds, or radiations are known to be actually or potentially present, it has become customary to prescribe an allowable concentration of dust, gas. fume, or vapour which must not be exceeded if an assurance is sought that men and women may work in that environment without harm. Perhaps more customary in the U.S.A. than in Britain, the term " maximum allowable concentra tion " (or variants of it) is becoming more familiar here also. It may be recalled that the conception was foreshadowed in this country by Thomas Leg?: some 45 years ago when he (and Docketing) gave 5 mg.,TO cm. as the atmospheric concentration of ,,T T H fV BRITISH JOURNAL OF INDUSTRIAL MEDICINE lead in which engineers and chemises might work. By prescribing a m axim um intake of lead, how ever, there is the implication that Um harder a man works in the atmosphere containing lead, the shoner 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.TO 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 Hoc. 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 (19451. one of the distin guished workers in the field of maximum allowable concentrations. Cook says : " 1: is to be emphasized that the im em in presenting the m axim um allowable concentrations is to provide a handy yardstick to be used as guidance for the routine industrial control of these health hazards-- not that com pliance wiih 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 industrial atmospheric contaminant could be quickly assessed from the zone in which it falls. Six zones were given as follow s;-- 500-2.000 o.p.m . acetonr, petrol, ether 100- 500 p.p .m . m eihm ol. toluene 20- 100 p.p.m . benzene, butanol. C O .. CO zooo.m .............................. h,s. cs,.c ,h ,c i, . h o . hcn 01- ' p.o.m ....................................CI.COCI,.ASH,.tCH,l,SO. 0 I p .o .m .................................................... radon, n d io a e n v c jisc l . 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 toxicitics 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 0 1 -2 p.p.m. DRINKER AND COOK ZONES (EXPANDED* 0-1 p.o.m. 0-5 p.p.m . H ydroicn selenitic Iodine Stipine Arsine Brommc Cyznojcn chloride Ethyleneglycol m itrate Phosgene Phosphorus tri. chloride K.etenc Nitroglycerin* ! 0 p.p.m. 2 Q p.p.m. Chlorine 1 p*Chior iniltne H yratoie /Chlof-nitrobenzene acid Ethylene chlorohydnn 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 dearly depend IND also on :r.c physical pic Involved. Everyone cor. snous of clinical urgency urgency. The state of m approach to envirortme implied in the table o f my laboratories (Tabie i The actual values g'.ve in the light of expener. emerged from a search, and experimental record: likely. Still, some hav example, in the case ammonia, ethanol. The first three column by certain concentration dangerous symptoms ; concentrations which 3 two columns give cor.ee limit to satisfactory' c: particular substance (de The use of the wc concetiiiation " has besve hold that no cor.ce are worse than others ~ *L Animal For industrial toxical to use animals in expe conditions. Most ir. result of absorption b much more rarely by i: most, acute and chrome Very little is known c substance thus absorbs Factors of safety rr animal experiments ! depending upon mar upon his greater activ-,: can be made of the am absorbed by men a; 1 environmental cond;:: estimated by expostn: estimate. Since she r. many times greater th. fume concentrations without adverse effec: as equally inoffensive concerned. Cutaneous absorpgreat importance ir. and in the field use c and herbicides. Quantitative meas. neous absorption, ir. .VE INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY s or a zone of values i: 'he picture already in hi: cures of the effects o f tl al personnel, however, are! position. They are like); phrases such as " Arsine s bromine, isn't it ? ", o , yes, quite troublesome )ric acid because, in faci t concentration values are] : noted, for very differen should, in general, be con. their own numerical da eir own effects attached to' sc classified into groups fori >memory, but this must be] of toxic effects and not onl ; of maximum allowable] ! and HCN are in the same' : (2-20 p.p.m.) as aniline, tells us nothing of theicj This is even more u. .hlv daneerous zone 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 {merged 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 (wo columns give concentrations which set an upper ',mit to satisfactory conditions in respect of the particular substance (design concentrations). The use of the words " maximum allowable vonesntration " has been avoided because at I.C.I. we hold that no concentration is allowable. Some are vvorse than others but ail are bad. IX Z O N E S 1E X P A N O E D 1 i 0 p-a.m. 2 0 p.s.fn, Wwa.-ataic ^Chlop aniline P'C h lo r nitrobenzene E-.hviene c n io ro n v a rm l| H ydrosen uortce I H O 10 p.p.m . erne of the most fulminating! ustry, and it would be in the] ;ie to bracket them logetheal For, whereas some of the] immediate irritation, others] and others again for eumu-]] pear because of their effects] arucs ; others because of the ; products on haemoglobin cause a dangerous increc .".e pulmonary vessels ; a pttve effects on the envelo: demands different degrees oa hose responsibility it is toil e those prescribed, .y must clearly depent 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, uc'r. more rarely by ingestion and by the eyes, and most, acute and chronic, are to mixtures of substances, kery little is known of the adjuvant effects of one substance thus absorbed on the toxic effects of others. Factors o f 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 o f the amount of a toxic substance daily absorbed by men at work, the acceptability of the environmental conditions in which it occurs can be riiimated 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 S-'eat 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 cutaneousiy than orally. The demonstration of dermatitic effeca in animals which do not perspire in any sense similar to that seen in man is usually impossible although an unicaria-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 or some organic compounds. Erythema and oedema should be measured according to determined scales (Draize, Woodard, and-Ealvcrv. 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 effeca on the skin. Physiological effects (on the circulation, respira tion. blood pigments, tissue and blood enzymes, renal and hepatic function, growth, fertility, centra! nervous system), in the sense of reversible effects, car, be demonstrated by animal experiment with relative ease, and the results in some cases applied to the clinical control of hazards in the factory. Contact dermatitis in man disappears on removal from exposure, but the effect is not truly reversible. A fall in blood pressure, readily demonstrable in animals, is used by some American authorities as a clinical-statistical index of undue absorption of many toxic organic compounds. There are some explosive compounds (made and used both here and in other countries) which are rapidly hypotensive in working conditions: blood pressure determinations are essential for proper medical control in these cases, especially as pseudo-anginal attacks may follow long-term exposure. Many industrial compounds can be shown experimentally to depress the hear:, 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 o f hypertension, perhaps of renal origin, in chronic lead absorption is not resolved. 'LHWJC I BFJT1SH JOURSAL OF 1S D V STR]AL MEDIChVE T able 1 TOXIC C O N C E N T R A T I O N S VA R.OU S G a SES. DUST5, FUM ES. AN D M ETa ES IK THE ATMOSPHERE ___________ , I C X lnu3tnAj PTTKtuctj and H ealih R e ie ire h C o m m ute) Concentrations Causing Severe Toxic Effects m Persons Exposed for the Slated Times (2) ! (3> C oncentraijons which, j Concentrations in I it Exposure Conunues 1 General Atmosphere Tor m ore th an a S hort I o f Plant Greater than O Time, may Lead to Symptoms o f i t h a t belo*- I indicate Unsatit/ocror? Illness Conditions I ! Acetaldehyde Axeiw acid Acetone Acetone cyanohydrin 3 Aeetonyl actione . . 6 Acetophenone 7 Aoetyl chloride I Acrolein 9 10 Acrylonitrile Allyl alcohol 11 Ally! chloride t: Ammonia .. 13 o Am yl acetate .. 14 o Amyl alcohol .. 13 Aniline 16 Arcton 6 (F re o n 12) 2017 (O iftuorodiehloram cthanc) Anxne II Beruene (BenzolI .. 19 Berviine laa H exancl Benzyl acetate Benzyl chloride Bromine Butadiene Butanol (Butyl alcohol) 2'Buianonc (M ethyl ethyl ketone Butyl acetate 'Butyl m ethacrylaic 28 ! Carbon dioxide Caroon disulphide. . 29 C a rto n m ono t id e .. 30 I Cartoon tetrachloride 31 ^ C h lo ra n ih n e 32 t*i<M0) C hlorobenzene 33 34 O tloroQ uudiene Chlorine 35 h^Thtoron itrobenzene 36 Chloroform >7 lo ti p \ lm o o \ ChloroTolu 36 C ytnocen chloride 39 C y elo h eu n e 40 Cyciohcxano) 41 Cyclohexanone 4: C y c io h e x v |a m tnc 4) ^ D ich lo ro b en x en c 44 22'O ichiorodicthvl e th e r. 43 t r u k iranm O ichloroethvlcne 46 D ieycloheiyiam m e 47 Dieihvi carbonate 4g Dfisobutyicne 49 D'-iaobuiyl ketone 50 D im ethyl d io tan e . . 1 (p .p .m . v-v) (mg..cu.* 1 Time of i m etre Exposure 1 (p.p.m. M *C .) (M m .) ; V,) 1.000 I.IJ0 60 200 300 60 4.000 9.630 60 140 i 300 1.424 60 1 1S0 400 3) 60 1 20 46 1 100 120 1 96 1 200 6)6 60 300 1.000 , 3.433)05 1 60 400 1.464 to 312 60 60 500 ; *0 ' 800 ; 20 130 40 i 30 20 1 100 200 300 :oo 1 20 30.000 to ! 231.700 32 ' 60 1 1 20.000 I 1.300 4.800 60 300 3.000 10.728 60 1,000 100 6)6 60 50 20 100 l 3 20 I 1.000 17.968 60 1.000 3.080 60 S et N o. 90 M ethyl ethyl ketone 2.000 9.630 60 800 4 .7 2 4 60 30.000 34.9)0 60 300 1.600 60 400 464 60 2. 12.800 60 10 - 1 5.000 100 300 400 : I.000 130 100 300 8 44 \ 4 400 100 . 1.872 368 60 l 200 30 10 29 10 1 66 1 l 4 4 100Q 9.960 60 500 400 3 . 1106 1) 60 1 2007 2.000 6.990 , 60 800 1.000 4.160 60 400 1.000 4.080 60 300 ' 1.48i)o6 !; 601 100 ] 593 , 1 1 0 0 0 : 1.072 1 60 50 388 60 800 3.92 , 60 4.000 18.640 ! 60 400 | 1.496 , 60 500 ] 1 4 1 2 1 60 200 40 100 30 1.000 40 400 ! :.ooo 200 1 300 Dimethyl Sulphate. . Diotane Ethanol (Ethyl alcohol) . Ether IdtEihyl) 35 36 i fc-Eiho*yethy| methacryla Ethyl acetate 37 Eihyt acctoaceuuc. . 38 i Ethyl benzoate 39 , Ethyl brom ide 60 : Ethyl chloride 6l tl Ethylene chlornydrm Ethylene dichionde 63 Ethylene glycol dinnrate . 15 - 78 1 300 1.830 60 8.000 13.312 1 60 1.000 24.6)4 60 300 3.28 J 60 2.000 7.320 60 200 ; i.o io , 60 200 !.24i ; 60 230 : l .l 35 60 10.000 1 16.830 , 60 20 68 60 300 1 '1 0 5 0 60 20 il 121 60 10 300 1000 2.000 200 800 100 , 00 100 1 5.000 10 100 l becoCmoenaeveamil/aabilteo.n s show n i *tal< are tentative and are issued as a guide. Figures in all colum ns I m g./eu. metre 4-37 x I0-* grairu/cu. ft. (mg. icu.* metre 20'C.I (J.PATI. fr ) I (m f./cu.* I metre I :o*c.) 15 1 DO 1.930 70 712 200 66 116 no 48 1 318 142 1.62) j 71 ! 100,660 j: 1.600 3.376 31J 30 6-6 1 11.230 ; J08 no 400 20 5 {W 00 J00 oo 1 0 ! i1 so no a ; Ui 1 z.so o so JGff i0 0C S 3S J20s c0 J J Jl-C 44 2 339 71 41 J CC J lr SO,2 4(1 C ICO SOJ *4 j' 2.612 1S4 ! i.i: ; us: 1 11.310 480 ii6 : 3.300 o o 1 20(1 : J.000 ] : s S O 9C S 1,2 51 St,U S Si 220 9)6 184 12 26 1490 1.03) 3-2 1796 1.66a n jj j I l vc HU 29 J 12 40 i. m 100 JIG 116 164 612 l 17S 4.036 302 i 1.964 I 9.320 ! 94* \ 1.447 r; in JJ Su i .Otto m SOU 2.01s .96S 32 ji J.098 1 3.128 , 6.136 1.314 ' 1928 ! 340 1i 62 1 434 1 (3.415 ,000 , 5<J`i 400 SO SO i 2.000 2,2 GC >4 410 So 6- :i - ? SOS J'2 1rill be s u b l e t to review as m ore data Continued /XL Eth'icne oxdc 63 ! Ethyl fom iate 66 1 Eihvliflene dichioride 67 Ethvl liiioaic FormaldcnvOe Freon l 2 ( ArCtOn 6 1 69 Hvdrazo.c acid 70 * Hydrogen chloride 71 H 'drogen evanipe. . 72 Hydrogen fluorjac . 7J H 'drcgen selcnide. . 74 H 'drogen sulpnide 75 Iodine 76 lioonorane. . 77 Nctene 78 L aur'l m ercaptan . 79 M ftti'l oue W M eihacroiem II Metnacrylic ac.d . t: MetftaiM aicobol . 83 Methanol (M ethvi cone *4 Mcthvl acetate <5 M u h 'l iy y ia ic 86 M ffltyl p o m jd e 7 . M ethyl rt* -b u iv | ketone 18 Methyl 3<h]oracr>.a:e 89 Methyl chlonde 90 Methyl ethyl ketone '2 3 - 91 . M ethyl iodide 92 Methyl cvciohexancne 93 Methylene chloride 94 Methyl form ate 9? ; M ethyl m cthacrviaie 96 1 N aphtha distillate as C_ 7 j Nickel carDonyl 91 Nurooenzene 99 | Nttrocutane 100 i N itrous fumes (as N O ,; 101 ! N itroglycerine 102 i N itrom ethane 103 j I'-N itropropane ICM : 2-N u ro p ro p a n e 103 o N irro io lu c n e 106 j Pcrchloroetnyicne (Tc:r 107 . > P ro p io ia c io n e U0-Propyl a lc o h o l.. 10* Phosgene Phosphorus trichlor.de 111 Stibine 112 1 Styrene 111 ' Sulphur dioxide 114 . Sulphur m o n ocnionce M3 . Sulphury! chloride . 116 T e tra c h lo rtth x n c .. Tetrachloroethvierse f? T hionv', chloride M l j TH ioonorpnor! nen.'c: M9 , T richloroctnvtcnc .. 120 Toluene (Toluol? . 121 lo. m . S. p) T o iuiC irsi 112 Vinyl ch to n d e 123 Xyiencs ( .\j J oin 124 Xyliduies 123 A ntim onv (dust or sa.; !26 Arsenious ox^ce 127 1 B arium ta l u (as 3 a ; Concentrations shown become available. N THE ATMOSPHERE h ic n . m inus Short ad 10 of U) Concentrations w General Atmosanere O f Plant Greater than rtioxe beto* Indicate L'nsa tisfa cto ry Conditions g. c u ." netre o`c .i 913 too .930 70 712 200 6-6 18 6 no 48 318 42 .623 732 78 .630 ,4rv31-2 o-o 130 308 -4 (2 1.362 1210 480 116 : . 2o o 22 930 IS* 12 26 1490 1353 5-2 1~96 .664 316 164 612 rs *036 502 .' . 9 * 4 ? .::a tu 1*47 V . M 5.323 5.1 56 1.314 1922 3*0 62* 4 5* 34 450 y r) jno 20 4QO 10 20 1 i 20 5 30 00 no jnu 10 20.000 it- > SO J)0 li i i ; J .iO n J0 `200 200 i .000 in it so 2 ri 2 1 I iti ; ; 10 ino jo 2 > /> J Nil JO 200 1.000 IO 200 (m r./cu.* ! metre i W C .) 366 Jo DCS 220 100 32 110 U 12 ISO U 3*1 36a J!t 30.UU TO GO m 4 Oi is 3,613 131 903 U SI ``. l i / Jj 320 11 3-1 'rj j.O 0 6 2 ID :dj 2. i t i Jin 300 ISA 2.01s 131 DSJ 4.600 474 200 1.000 SCO !(jo ino SO Jo JO 2.OOU 2 Jo o- ; l.D li 1.3-Z`j uh -TO 2'2 7 JOS 2 2 i to review as m ore data Canfn INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY Tabu \ continuiti _ i( nI ) Concentrations Causine Severe Ml Toxic Eifecu in Persons ! Concernrat ions, which, : if Exposure Continues Concentration! in Exposed for the Stated Times for more than a Short C in tra i A tm oiBi'ce o f Plant G rta trr man 1 Time, may Lead to those beta* Gas Symptom* o f indicate Unxa/istaerort ; illness Conditions Hi `0 'i `9 >0 85 a 37 33 39 90 91 92 9) 94 95 *6 101 tu: 102 104 103 106 IQ7 IQS I no T T h: ui 1U [ : j ns 117 its 119 120 TIT 122 123 124 Ethylene oxide E:h>i forniate EthvUdene dich lan d e Ethyl silicate Form aldehyde Freon 12 | A rci n 6i H ydruoic acid H ydraten cnlgnde Hydraten cyxm dc., Hydrogen fluoride.. Hydrogen ternde, . Hydrogen sulphide Iodine - Isophorone.. Keiene Lauryt mercaptan ., Mesityl oxide Nlcihacrolem \Iethacrylic acid ., Methailyl alcohol M ethanol (M ethyl alcohol i M ethyl acetate M ethylacrylate M ethyl brom ide Methyl .butyl ketone .. Methyl a<hioracrylate Methyl chlonde Methyl ethyl ketone (2-Butanone) Methyl iodide Methyl cyclohexanone Methylene chloride Methyl formate Methyl methacrylate Naphtha distillate (as Cumenei Nickel carbonyl Nitrobenzene N'itr o e th a n e Nitrous fumes (as N O ,) .. Nitroglycerine Nitromethane I'Nitropropane 2*Nitropropane Nitrotoluene Perchioroethylene {TetraehJoroethvlene 2 - P ra p to la c to n e ........................... Propyl alcohol, . Phosgene ............................................ Phospnorux trichloride Stibine .Styrene Sulphur d i o x i d e ......................... Suiphur m onoehloride (S .C IJ Sulphuryl c h lo n d e .. T e trach lo reth a n e..................................... TetracpIofoethyJene (Perchioroethylene ThionyJ c f t l o n d c ......................... Tluophasphoryl tnchlonde Trichloroethylene .. Toluene (Toluol) .. le. ne, Jk o) Toiuidines Vinyl chloride Xylenes {XyfaU) . . Xytidines 125 A ntim ony (d u st o r salts) (a* 5 b ) . . 126 A n en io u s oxide 127 B arium salts (as Ba l fp.p.m. y/vi (m g..cu." metre 20* C.) Time o f Exposure (M iai fp.p.m *.'V ) 250 1.000 400 400 *50 31..06340 3.464 100 120 See No. 16 Arcin 6. 10 1 [ 20 73 60 100 60 400 60 200 60 i 0 1 JO 60 4 1 :q 40 40 200 0-5 40 1 20 20U 10 34 & 230 5-5 223 3-6 163 816 29 t 20 I i 1 . 0-5 1 50 i 60 0-2 20 I I I >0 I 10Q 1 1.000 3,575 1 400 150 450 l 100 1000 2*560 60 300 500 1.540 60 200 100 356 I 30 250 1.000 1 50 1.000 4 .J 6 0 60 400 4 20 I 2 1.500 3.150 60 500 1000 5.990 60 500 40 300 100 1.000 3.000 JOG 4 200 300 100 236 1.400 7.072 1495 12.480 1.500 28 1.020 1496 190 20 0 150 60 1,000 60 *0Q 60 1000 60 150 1 * 60 4 60 500 1 JO 20 189 60 I 800 1028 60 500 *00 1.480 60 200 *00 1.480 60 200 200 1.140 60 *0 1,000 6.905 60 400 100 300 I 20 10005 j 4.99251 1 601 3001 12 - l I 0-3 1,000 ! :oo 20 10 1 50 See No. 106 20 to ;;1 1000 ,I 1,000 ; Q 4 3,000 1 `54S0 i 13 I 4.330 j 60 520 , 1 112 1 1 56 , l 330 60 Perchloroethykxw. J070 \ > 1 1 10.940 j 60 3.830 60 176 !j M 7,300 4,410 ]1 6S0 200 !S " 0-2 200 20 IQ 4 20 ! 10 i 300 i1 10 !t 1.300 1 303 1 10 Dusts. Fum es, and Metals '.omCoenacveanitlraabtiloe,ns shown in italic are tentative and are iu u j aa a guide. Figures m ail columns I mg,,cu- metre = 4 37 x 10- grura/ea. fc (mg. cu.* m etre 20*0 ISO : 18J2!4 1.732 36 7-2 ! JO 22 85 ' 1-5 ; 70 22 U4 13 8* 408 13 1,4)0 300 640 616 178 200 1.664 10 1.050 1.498 p .p .m . tu :ou JO too 1U 1 to 10J 0-1 JO I 20 fit i so 200 20SO0 00 JS JO 200 1 100 200 (mr. u.1 n e tte W C .) 1; 0 ; II j-; JOS 5 rli no 2id 30 i 39 30 332 S z:o 93 IIS 700 3.536 998 8.320 750 14 204 1.560 37 9-4 1*268 7*0 740 228 1762 60 1.998 4 2 5 8 20 7 S SOU 200 1,000 SO 1 1 200 10 OS 200 m 100 1 200 10 soo on ui ID : so 1.T64 TJ l , 60 JS0 3 1 621 \D V-; 07 3ro 1.331 30 000 : 2 9 1 , 01 866 ! 10O 32 , 10 56 i ** 1 1*0 in 0 ; 422 23 TO jo ! J 23 28 ] 1 * 4.376 ( 400 2.13S 1.149 j I0Q j 333 3,900 i I J 13 50 j SCO 1 S 1,300 Ul 25 O S 03 0 i II be subject :o review as more cata Continued 6 T a O ir I ro n h > `ui"J BRITISH JOURNAL OF INDUSTRI.AL MEDICINE So. Gu (l> Concentration* Causing Severs Toxic Effects in Persons EsexTsed for m e S ta te d Times Cl Concentrations which. if Exposure Commues for m ore than a Short Tim e, may Lead to Symptoms of Illness (J) ConcenlrattoM in Gtne/o! A tm osphar of Plant G /eo irr than Ihair be/ow Jndicait Unsatisfactory Conditions 128 Benzidine 129 Cadm ium ,. no Chlorinated diphenyl ut Chlorinated naphthalene n: Chrom ate* (a* C rO ,) 133 P m itrocrool land w lul . . U-* D m m ophcnol land salts). . 133 Dinitroreionainoi . - 136 D innrotolucne U7 " D ow them A " .. ns Lead (and Lalts) . . ! M e r c u r y .............................. a-haphihylam m e .. I4| Napbthylam tnc .. \*2 " Parath io n ** 143 PcmaGMorphenol . . ]44 ^Phcnyjcnc diamine MS Phosphorus pcnuehlondc )*6 Potam um perm antanaie. . ns Sulphuric acid 148 Sodium cyanide . . 149 T e trjl .............................. ISO T .N .T ........................................ 151 Z inc o x i d e .............................. (p.p-in. v.vj -- _ -- _. -- -- -- ---- --* -- -- __ -- - m etre 20*C.) __ -- -- -- mm. mm mm mm mmm - -- -- -- -- -- - ! Time of i Exposure (Mm.l ; __ -- -- -- -- -- -- B -- -- 1 -- - -- -- ---- -- -- - (p.p.m v-v} --* -- -- -- ---- -- *-- -- -- -- -- -- -- -- -- . (m i.fcu.* . metre 20*C.) | -- -- -- -- ---- *-- -- -- --* -- -- -- -- -- -- --* -- -- -- [fi.pjn. rj -- -- -- -- mm - -- -- -- ~ -- -- -- -- -- -- -- -- 1 (m g .icu metre SO'C. } O-Oti 01 1 I t l I 0 1 | U i \ 1 J-i s ttiz 01 001 00 J If j 0 * ; i * ; a -- 10 Concentration* shown ia italic re tentative and are iuued ai a guide. Fifurn. in all column* win become available. *1 ms.jcu. metre 4-3" x 10"' grains/cu. ft. subject to review as more data Chang in respiration and the respiratory system are usually secondary to irritation of the respiratory tract, to chang 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-isocyanaies are reversible. H 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 invtigation 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.Ch and that N jO , is much less toxic as is also nitric acid vapour (Diggle and Gage. 1954). Any toxic dust is injurious to the lungs although the pneumoconioses, and in particular silicosis, are our most serious and extensive industrial pulmonary diseases. Fig. 1 shows a section of a lung of a rat which, with a group of other rats, was exposed for eight hours a day for many months to an atmosphere of 2 mg. /cm. K.CrO, as a very fine dust. The animals were well enough .'there was a period of coughing and harsh breathing, but nothing serious. They lived on in quietude and sustained the chromate with bored fortitude but the lung shows large and small areas of exsanguinated alveoli crammed with loaded histiocytes in various stages of degeneration. Functionally these areas are out of action. The cell debris in the alveoli contributes further to loss of function until disposed of. Dilated respiratory bron chioles and some emphysema, due partly to the injurious effect of the chromate on the alveolar septa, and partly as compensaiion 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 Jrom 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. FiC. 2.--Oumea-ptw uon of nne is mononuclear r alveolar al:*, boti m tie wi alveoli anc eoa* nil in the pna;; 7 . & ? $ ' \ i f f ^ ./A -* :\_ 7 %7.-3 ^ ,. . . - *' , > ^5 *t *v r ,.^ -r -y 1 * '- . " X '5- V v * x ..; - S *: { y s i * - 4 j f F ic . 3.--R b b n lung Homing c h ro n ic in h alatio n o f fin lead aceiat d u s t. Throe u e a i o f u m lung ih o w in f different lU fc in developmcoi end deain o f lung ohagocytes ; im all alveolus cram m ed w ith dead and dying phagocytes swollen w ith absorbed panicles ; note mulu* nu clear m acro p h ag e. 560, T he cells are later engulfed by the macrophages developed from the septal cells after having acted as dust cells themselves. The macrophages arc 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 O'-f. 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 rnuItnucleate 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 arc mainly found in Industry among those exposed to carbon monoxide, various aromatic nitro- and amino-compounds, and typr:. metallic elements which \ formation. These effects with equal ease ir. all spe The deliberate induc'.ic in the treatment of cyan importance, and recover been obtained by Lloyd depends upon the ultranitrite which, by fom m the circulating cyanide tc toxic cyanmeihaemogloc injection of sodium thit the formation of thiocy liberated cyanide. Renal and hepatic ft many chemical agents ; industrial metallic poise; chlorinated aliphatic hyc vatives of glycols. Re endangered for the char, structural breakdown peculiar position of t: commonly used solver, subtle must be the rr.ee low toxicitt, which is meiabtrtistiL-to the nc (Taylor, 1936 ; Powell, For certain rr.etabc carcinogenicity the use and wider significance, one carbon C1' has members of my depar Amersham (Henson. ' Somerville, 1953). W< establish important me: retention of compound in the body (Henson. 5 Goldblatt, 1954). The toxic compounds ir, : histological sections is The ultimate fate o industrial conditions i known about some of chemical substances a: we are very rarely able or even extraordinary ways in which corr.pi; the body in large p; difficulties and app.-i using labelled ccnpcu in obtaining almost co and output of substar and in discovering ho derivatives are retain; ** Possible to track tr a INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY is a b w rb e d p im c te i; note multi- .mg is paid for in '.he case! ttior. of the precursors oft modified septal cells) and) e occupation o f alveolar; cells and cell debris when.1 arged. The formation of i iso occurs in the chronic! ig. 3). In a universe of >! are inevitable but it is our* -strial dust with other] ents are mainly found in' -o carbon monoxide,! o-compounds, and i iII 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 o f practical importance, and recovery in very severe cases has t n obtained by Lloyd Potter (1930). 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 ovic cyanmethaemoglobin and upon the intravenous uection o f sodium thiosulphate which accelerates ihc 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, noiably 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 Cu 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 Goidblatt. 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 >e are very rarely able to strike a balance by ordinary r 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 o f 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 3 they can take in the body and, if retained for long periods, to leant where they are deposited. Industrial metabolic poisons interfering with phosphorylating processes are dinitroonhocresol (D.N.O.C.). dinitrophenol (D.N.P.), and per.tachlorphenol, the forme 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 induct 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 different 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 orgjtngPr 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. OinJcal and Experimental Aspects of Lead Intoxication Much has been done to elucidate the ciinical picture and pathological processes of lead intoxi cation and poisoning. As the result of 1'2 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 o f workers exposed to any lead hazard is easy and effective by routine determination of fa) haemoglobi n, and (6) 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 readiiy be confirmed by dark-ground examination (Figs. 4 and 5). Haemoglobin determination alone is not sufficient, far 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 aSSS ir r T T ^ ir ^ itf r ii f f i n i r in " 10 BRITISH JOURNAL OF INDUSTRIAL MEDICINE F ig. 4.--R ibbii blood nam ed with alkaline methylene blue and photo* graphed by transmitted lifht showing vanouvsized basophilic (polychromatic) cells due 10 chronic lead exposure. F ig . 3.-- R a b b it b lo o d m in e d with alkaline m cthjrlent blue ani photographed by dark ground illumination bowing c u t ol recognizing nipples (golden granules) and two polychromatic cells : th polychromatic cells art manifestly very find suppled 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, 953). Kehoe (1951) has emphasized that the usual forms of lead intoxication are self-limited, of relative:) short duration, and that there is complete recover; when the exposure has been terminated, and that noirreversible 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 oi picture one would wish to avoid, that of a man who took five years to recover his haemoglobin although removed from contact with lead (see also Fullerton, 1952). Fig. 8 shows the data on a case of some interest. Three months of work on lead were followed by c fairly acute episode from which the patient was allowed to recover while still ai 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 toco's i ss. 6 --RcUlior. bciwetr. l u t r in w o rx e n expo! io i c u m m e d ib o v n win H \ t J J N o. N i m t TL:cf t>:c iyxs l r.G ; vs P. s : 3 G .F k . JC . J.S. I i" i S.F. 16 b k .A V.. ? A W. .'6 < P.N. s 9 T H. fi 10 v; IS I ! F.h.VN. i A  w ith A lkaline m ethylene blue aod Jnd illum ination *howin( ease d granules) a n d two polychromatic cells a re m anifestly very hnelj t turn to work IForeman,' tnap. 1953). ; tsized that the usual forms self-limited, of relatively here is complete recovery-. ;n terminated, and that no i blood-forming tissues is' . The cases to which this y are the now exceedingly muscle palsies. ' f picture one would wish a took five years to recover h removed from contact' on. 1952). i n a case of some interest.' lead were followed by ai n which the patient was! still at the factory doing!] intact with lead. In spite:] r number of stipples andj rmogiobin level recovered! ` on work with lead! as certified. Certi-'j --.a, the patis.n: was again"' INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY 11 J do. b 60 S 20 HbfcS IS V \ 5 IO -- J tS 20 25 lOOOs Stipple+"ft9ychrome, cetls ? --Relation betw een haem oglobin and jtipple-polychfom e count* in vaorxerj exposed to a lead dust hazard. N um bers o f bloods cvim oed shown w uh 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. eii.) and others have described cases of hyper sensitivity and referred to evidence of family susceptibility to lead. A full study of such case's would be of considerable interest. The influence of alcohol must not be forgotten. My fourth proposition is that the changes in p peripheral blood in lead intoxication are due -ro- 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 o f a normoblast in the bone marrow are seen as a corona round the nucleus for mitosis occurs in the stippled nonnoblast apparently normally. There are far more stipple cells in the bone marrow per million erythrocytes than in the circulating biood 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 biood cells were Table 2 LOST TIM E OF TW O CROUPS Year lili No. Name 1 F.G. 2 W ,p. 3 G.F.JC 4 J.S. 3 ; S.F. 6 K.A.M . ? 1 A.W. i : p .N . j 9 j T.H. 10 E-M. 11 ; F.H .W . Certified" .1 U ncertified* Tim Lou Y e a r I No.;. N am e j f j j j Y e a r I No.., N am e Tme Lou Year No. ID6 I9Z9 ! 12 * W .C. 1 3 day* -213 : 10 j 1 . . Nil 23 : 1 16 t dn 13 i a .h .t . ! 1 m lh. -j 111 : L L Nil 17 )0 dayi 13 day* -j 3 w r. Nil u i 2 m ite- 194J -- __ 1 '-- 4 FG. 14 : 101 3 r . x . Nil IS N.l 040 26 day* 194* -- _ :! 4 F K. 7 H.E-W. Mil day* 23 .9 19 20 15 day* 94J (6 day* 2 0 : 11 14 i g s j * . : 1 mt. \ (H b. 73 r . fa u n a * 1941 -- _ [ 2 m uu. j * day* ., 197 ! J* : J i W F. N.l 1941 [ 6 day* 1944 1 3 :3 9 W.F. N.l l 53 day* 17 :4 13 G-F..W. 30 day* h JO F.C. h C J.H . Nil j Nil 94.1 22 :5 21 \ 11 day* 12 J.L. Nil I 23 d a n i 13 R.O. 1 Nil 19U I I m ia. ! 21 day* ;j 14 C.F.H. 1 Nil 19 4i 15 ! W .R. ' N il 26 : l Name C J.H A.S.?. A.W. H.J. G .M . -- H .J. *** H.J. Time Lost .20d>a>'1* , iftvestia'.ion Nil ; n ;i N.l -- . -- N-.l Certifiedrecovery away from factory, f Uncertified-recovery al -o r* . (All c m 60-63 % H b at nme o f o em ficauoo o r acuoo in factory.) : Recurrent cate in i Km* . u aru Jr^ A * BRITISH JOURNAL OF INDUSTRIAL MEDICINE T able 3 PER'.GD OF RECOVERY Or Hb Maintained at i Rem oved to Home ! Vone j or HosptUl f Cases ! 24 1 9 at tim e of 1 tsfer . . j 6.<-70`i 65--7 0% ume to reach | l ^ J month 1 1-66 months 1, or more . (3 w eeiu-T t m onths) ! (16 dayv-2 \ months) licite slight advantage o f grtim * im o l u i y from facxory even gril i n d non-iead work. u u o f Hb 4>~*5% recovered to 80% m 28 day* w hilst at w ork ion-lead. H b% (5 - r f ) lOOO'i 1 0 * R .B .C . w r *6 4g.n r>A$ M b 1 S o p p ie i * P ren rt> in ti S.ow Mb fco*e,y ~ m a in ta in e d Nigh (S*)*) O u rm j h o n - d 100 - w o r k lo r 4 Vj y e a n . r-* - H-- C 80 70 - V v ^ 40 50 20 ~ i 15 - 10 l j , -A 5 ~ v v ^ N 'V ,-P b Non-**} " No plum bum ppled in the stained peripheral blood. Similar .dings were obtained in o u r experiments with bbits. Even in heavy exposure to lead not all the ormoblasts show stipples, many proceeding to ormal haemoglobination. Stipple cells, polyftromatic cells, and reticulocytes all owe the ppearances seen to ribonucleic acid. This can be hown by treating the cells with ribonuclase which .ompletely 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. Ftc. ________ !___ _____i________ !________ ' 0 I2 3 4 yun - -------- ; J4 7 __ Caw o f lead an aem ia th o w ia extrem ely low recovery of haem oglobin whilst, m ain u jn cd i i work. T .H . ACS 29-32 YEARS. R eturned 10 w o rk befor blood re co ve ry-a lter The delivery of " leaded " basophilic cells from the marrow into the circulation is gradual in ordinary circumstances as the peripheral cells arc 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 o f these cells may fail entirely for the others. F ig . 8.---C u e o f certified p lu m b iim considered clinically fii ij return to w ork, b u t th ereafter req u irin g alm ost tw o year u* regain i auble 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 iheir usual form in red blood cells as well as in normoblasts. Reticulocytes stained in dried film and examined in trie dark ground show a finely granular or finely reticular pattern with irregular vacuoles. < r - s> 1000 i 10' s .c . 100 *0 4 . so 70 u SO D IS 10 s 0 M.T. AG; 51-37 TEAIS. Cue of Struiti'iiy ir-4 4iv'fxs, Mh i SuppJ* Nr*r* CaHifwd .1 V- MacFadzean and Davis (1949), Pirrie (lac. cii.), Rimington (1938), Kench, _ane. and Varley (1952), Dustin (1942), and others have gone far to elucidate the nature of the stippling property of the erythrocyte in lead absorption. I FiC. 9 __C u t o f te iu iiiv tiy and of long periods on non-iead Hb ind itvppl values. i run rec u rren t load an aem ia in on work.. D o te correspondence of l Ca a c :r, i- BRITISH JOURNAL OF INDUSTRIAL MEDICINE Lead poisons the later prosumers 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 sa g e and completion o f 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 nan-poisoned normoblasts. Since reticulocytes may increase before lead anaemia and stippling are established we may assume that the stipple and polychrome cells indicate a failure of the normoblast to go on to the reticulo cyte stage. With the failure of the bone marrow in extreme cases of lead poisoning, stipples, polychromes, and reticulocytes ail 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 lit to form haemoglobin, etc.) lead inhibits the full haemoelobination of red cells. (4J Evidence of abnormality of red cells in lead absorption is that they show (a) diminished fragility in being able to withstand lower salt concentrations ; (A) 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 haemoglobmation and (A) greater desiructibility of celts containing lead. Industrial Enzyme Poisons Many industrial poisons are enzyme inhibitors, e.f.. cyanide, organic arsenicals, organo-phospherus 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. U l 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 o f high insecticida! 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 compaTed with the now classical T*au 4 L.D.50. O R G a SO -PH O SP H A T E INSECTICIDES* Compound Orai L.D.SO T .E .P .P . .................... 1 Parioaon Dtmfo* Svito (CornfTxrrcj.il J 5 " >P-C - .. .. 1 i : R.f. 1-0 R.m. J J R.m.r. J R.m. 6 J9-9 7 R.m. 7 3 R.m. I P ..D .J0 0-65 R ? : R.m.f. ; 4 5-837 R.m. i 0 r. > P - S - .* Pesto (O-M .P.A. Schradan) Pam hion .. . E .P .N. * ..............................' M ioafo* M aUihin 1 5 R.m. 9-7-10 0 R.m.f. 6 R.f. 15 R.m. U S R.f. 91-0 R.m. < Parathton 2J2 R.f. 2,160 R.m. g 0 - J R.m.f. * R.f. 7 R.m. SO M. 750 R. "M ed ian lethal & in at o rgan o -p h ajp n ai* m iccticidciR * rats. M mice, m m ale, f * fem ale. Ail values tn m i./K s parathion and tetraethyl pyrophosphate (T-E.P P.). Thus " rnipafox", 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 betn 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 end- plates 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 essentia! that the blood cell cholinesterase of exposed persons should be determined as a routine Q R. C Q . p a r a h ic 2) . T.E.P.P. 3). P E ST O : - 4 ^ PAR AC 5) . E .P. N. 6) . DIM E 7). M i? , 8) SY; 9) .V, ICIO ES- I.P L.D.5Q 0-65 R 12 R.nvf. 4 < -* '3 7 R .m . 4-0 -i 5 R.m.f. 4 R r. 7 R.m . 50 M. ' 750 R. values ft * . Nl- T E.P.P.V propyl l-j ..-.es less on" about 100 ttmisrn enge> ^ the ease of jeaicidal pro;v pathological swered by the p.sc and otUcr crops are : 01 rr.cr of the food :iy answered in pointed by the hich gives llte Investigation of arising from the *y constitute an : ar.sv.er here is precautions are : use of atropine yer. supervisor, tic agent for the arris iGoldblatt. upon the level ot cells, brain, and d at motor endsynapses. Since - - some indt- iptoms. it __ .....esterase of ir.ed as a routine O^GANO-PHOSPHORUS INSECTICIDES I). PARATHION ' CLN S III I / c2h5 O-- P \ dch. 2 5 2) . T.E.P.P. c 2h s \ I | !|/O c 2h5 p- - p C ^o o c ,h. 3). PESTOX jj/C H ^ / - ~ p\ C cH p2N' A). PARAOXON o 2n 5). E.P. N. (U.S.A) 0 2N ,, l/ O -- P^ X3C H 2 S ^)-- 6) DlMEFOX SYSTEMIC 7)- m ip a f o x o = p s - n h .ch(ch^ 2 x n h .ch(ch3) 2 SYSTEMIC ) SYSTOX c2hs s . c2h - ;- l ^ 0 C 2 ^ 5) m a l a t hHION OCH 2 5 CH.OOC.H_C S * ii OCH, C H OOC.HC--~ P --Sv ' OCH, FiC. N -- ro rm a ljc of rsm soundi ,n ortjno^haw fconii iiws:i(lsj. SYSTEMIC LEAST TOXIC BRITISH JOURNAL OF INDUSTRIAL MEDICI SB in o r d e r 10 preclude a Tall 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 Trom single observations. It is so eas> 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 o f 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. Qinlcal observation and experi ments had shown that among organo-phosphorus compounds D.F.P. fdi-isopropyl-phosphoroRuoridaie) and T.O.C.P. (tri-o-crcsyl 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 ,N a. N.O, and repeated doses of barbiturates (Weston Hurst, 1941, 1944), The paralysis which followed "parathion" and mipafox " resembled that described among many people who had absorbed T.O.C.P. in one way or another, and in both these gToups it seems probable that the persistent signs were due to demyelination. Fig. 15 shows a section of the cord of a fowl fl-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-cholinesicrase 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 Den:, 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 arc being synthe sized, it is important not to assume the relative safety of a given compound until acute and chronic FiG. 12.---C ervical cord and ciane nerve o f a fowl tre a te d wiih a preparation o f (ricreivi phosphate calculated to contain 0-1% of th e ortho* isom er. T o tal dote in 16 c a v i J mg./Vtc. by m outh. Firn paralytic tig n i in 21 days followed by p r o j m i i v t worsening o f p a ra ly n t o f )epi. D em yelination in an te rio r a n d lateral colum ns a n d m arkedly on sciatic cord. * 11. M arcili' m eth o d . A -- u p re r. and B -- low er, cervical c o rd -belo1* scem e nerve. experiments hieffect or. the ret variety of animai Occu There are ver have been, shown gens io man. radiations t.v-ra. naphthylamme. pyrene. Of ihe host of which have prod mary gland, lure have been demo: carcinogens. 7h products as tar. established with 3 -t benzpyrene : this compound. Lana-continue lions and work to indubitable r finally to epithet men', has beer, ; animals case of : as well as sever: followed long ; though the turn, sarcomata in a.-., differences are ; reached by the r Neoplastic cr. often highly rr.ii of workers expc and or dust of reported for nea where organic clinical fact has in the U.S.A. a identical bladde b-naphihylamir.: Ciayson. and )_ tumours induci: amine in dete amount of urina excreted. More recent benudinc and r research both lr the demonstra-., benzidine in rats but bladder lu: induced except INDUSTRIAL HEALTH IN THE CHEMICAL INDUSTRY experiments have been carried out. and also the nset on the nervous system studied in detail in a variety of animat 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), 3napltth) amine. benzidine, and probably 3-d benz- p> retie. Of the host of compounds and complex mixtures which have produced tumours o f 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-a benzpyrene from tar casts strong suspicion on this compound. Long-continued therapy with arsenical prepara tions ana work with arsenical compounds have led to indubitable skin changes (hyperkeratosis) and finally to epitheliomata. But no convincing experi ment has been published to demonstrate a similar effect in animals. In the case of certain radiations, neoplastic change as well as severe blood changes have undoubtedly followed long exposure in man and in animals, though the tumours which develop are different-- sarcomata in animals and caicinqmata in man. The differences are attributable to the different tissues reached 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 '-.rashthylamine. It has been suggested by Bonser. Ciavson. and Jull (1951) that the incidence of bladder tumours inducible by treatment with ^-naphthylamine in different species is roughly related to the amount o f urinary conjugates of 2-amino-l-naphiho! excreted. More recently the same suspicion fell upon benzidine and has been amply confirmed. Intensive resea:ch both inside and outside industry has led to the demonstration of the carcinogenic properties of benzidine in rats (rectum, sebaceous ear glands, liver) but bladder tumours had until recently not teen induced except in the case of one dog (Spitz, Maguigan, and Dobriner, 1950). The possibility that here also the o-hydroxyamine is the immediate carcinogen has received much consideration. The contribution made to the elucidation of the problem in this country has been notable and the names of Bridge (1934), Macalpine (1929,) Wigruil (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 wish :the naphthylamines or benzidine is now fully reccgnjed as a carcinogenic hazard, and aniline appears toTe exonerated. Some as yet cryptic factors in the manufacture of magenta and auramme 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 Goldblau. 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 -- amino 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 naphthylamines 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-hydroxyamtr.is 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 hilherto unsuspected aromatic amines and N atives 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 oT examining ail the derivatives of cyclic hydrocarbons and their homologucs 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 fMachie and Gregorius, 1948) but Bidstrup (1951) was not able to draw clear con clusions from her jr-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 limes as great as would be expected among a comparable group of all males in the country (Federal Security Agency. 1955). 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 o f 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 norma! ceil is driving that cell towards excessive, if abnormal, function and, for a lime, 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 afier 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 delectable ai an early stage (sec 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 cystoscopy of v. the Continent a ' U.S.A. Hence t be made and will, with the r a correct pietur; 1 To this end we scope of urine: mining the pic in norma! $ub> colaou's methc hope later, c; malignancy. E ' those hitherto laboratories ha stain, cnaract: the types of ccl urine (Rofe. 1 ; normally inter:' matter and de: I cells in 1 in 1.: they were vos- may thus be urines contain E ujines contain content other two main pa.- sitional. 15u . bladder) ; (i) s from kidney : 15.U and unde in various sta: , A very ir.: counts was t: , more leucccy could be accc < whole blood. is always in a : ' or mechanical By applying F glance ail the h * 0 T * t i Co -;5& 3 r * observation is confirrm hers as other than o ihanical irritation but ot ruled out although it upport for it. It is n' a given material is nol iinarily understood is of carcinogenicity. Fi exercising a toxic efTc^ rt cell in the direction '.e exerting a carcinoge 5 driving that cell towar function and. for a ti: is not to say that a carcin toxic in the ordinary se ;ent in full spate is unlike intent o f carcinogenici duction times for ce: ns are long and :y of exposure, it is to viduals the induction ti n others much longer that| of Vesical Tumou .dical supervision osed in the past to bladde even after exposure ha aving the industry. '.emical industry exfoliativd . to detect early bladde^ rie teaching of Papanicolaou ortance of the recognition i exfoliated cells has been r.ay be exfoliated from the . cervix, and vagina, andj ical and staining character e recognized, there is s neoplastic process should an early stage (see also ^ u's.vpy of workers as it is practised on C o n t in e n t and to some extent in the I 5 A. Hence urinary examinations must S : m a d e and every device used which i l l . w i t h t h e minimum discomfort, give a correct picture of the inside of the organ. To this end we are seeking to enlarge the wopc of urinary examinations by deter mining the picture of vesical exfoliation :n normal subjects, by applying Papani- ki. methods to the urine, and, we `.pu iaicr. by cytochemical tests for malignancy- By methods different from nose hitherto used, Mr. Rofe in my 'aS'ratpries has been able accurately to tain, characterize, separate, and count tne types of cells found in normal human urine (Rote. 1955) after removal of the normally Interfering organic and inorganic nutter and debris and concentrating the ce!!< m I in 1.500 of the volume in which IV: were voided. Certain conclusions may mus be stated : (1) Most normal urines contain blood. (2) Most normal urines contain leucocytes. (3) The cellular content other than these is divisible into two main parts (a) squamous and tran sitional. 15> and over in size (urethra, '. bladder i : |6) small epithelial cells derived from kidney and prostate (in the male) 15 i and under in size. These cells are :n various stages of degeneration. i very interesting feature of these ^ -- - ant> was that there were always far "'ore leucocytes in normal urine than could be accounted for by a simple transudation of wnole blood. This perhaps means that the bladder ;v always n 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 gljnce all the cells exfoliated in a given sample of ^ a-' ^ 4 FtC. lb urine. Having a reliable picture of the normal ceil 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 ceils are concentrated. The character of exfoliaicd bladder tumour cells has been described by Crabce . tumours the early develop ay any disturbance of ihel .'.tonal or non-occupationalj t need to establish routine microscopic blood, which is of bladder irritation, of ties, of a broken frond of of the slow and insidious! rg carcinoma. In a smallj microscopic haematuria is -mour visible in the cv$:o- proportion there may i presence of a tumour. l recommend routine^ t ? ;.d 3. 16 --Smear from urine o f ~ o rk c r m anuiaciure 01 dyeiiuiT im er*n?s.aie. shoeing erM firocyiij. p o ltm jrsM . abnormal and degenerated cpiinsliu. celli, and te le ra i d c rin u e f man-*, nani c:Hi. Papanicolaou's :ecnmuue o f preparation and n am ing. ,4Q1 ^ ft rv * j G -T---1^- - 1 * * 3Sb FiC. I? .--Smear from an o m er J e * w iMorker then, mg e r y in r ''te l. mart' OOljmorpM. and g'.am b in u c 'eaiea malignant c til. pqoanivataa- teennique. 00. u FiC. 17 :o BRITISH JOURNAL OF INDUSTRIAL. MEDICINE U! l rat0nCSr T 1" Vaiuc of chemical industry, and some of the difficulties and cyologicai diagnosis has been amply demonstrated, dilemmas which arise. This kind of work is merely r o T S T S S f - ' Cnrtena,laid dowr! by Papanicolaou [?_'_ . d osis of malignancy include increased sire and bizarre shapes ; enlargement of nuclei in relation to cytoplasm; altered nuclear and chromatin pattern; increased affinity of nuclei the preliminary to the application of the knowledge thereby obtained in the field and the factory. It is there that the ultimate goal set by James Mackenzie must be reached--the prevention of occupational illness. for basic stains ; and variation in nuclear sizes in a group of cells (Figs. 16. 17). In a method of diagnosis of this kind the danger is the false negative. The false positive is less serious, but always of great I am extremely indebted to Mr. Kenneth Cooper and Mr. Leslie H ew itt 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 interest, especially when found in the absence of shanks are due io Mr. Bcrczy. Mr. Croztcr, and Mr. Denies blood cells and cysioscopically visible tumours. for much technical assistance. The cystoscope is not infallible, for we have had R eferences cases in which a positive cytological diagnosis was subsequently confirmed by cystoscopy after initially negative cystoscopic reports. It is becoming clear that the exfoliation of cells from new growths is not a uniformly constant process. One day it may be prolific, another relatively unproductive. Further, the ease of recognition of neoplastic character varies. For these and other reasons we prefer at this stage to base judgment on a combination of the classical search for haematuria and to fortify it with the cytological method. It has thus been possible to assert the presence of a tumour at a stage when a slight microscopic haematuria would have left us in doubt and the patient in delay. Field Experiment Field investigation is properly the domain of the industrial doctor, and it is the most difficult. In the last analysis it is upon field investigation that a final judgment must rest as to the relation between industrial environment and state of health. The difficulty does not lie in the recognition of this proposition, but in obtaining the opportunity and in devising the appropriate methods to establish such relations. To attain results which arc soundly based and generally acceptable is a task requiring the cooperation of many disciplines. In the main, B ik e r. Ft. K . (19331. C a n rrr X . . 13, 117. B afnforth. J. (1953). Practitioner, 171, 2*4. B a n i . J. M-. *nd D eni. F. A. (1953}. J. Path. B a a .. 65. 597. B id stn ip . P L. (1931}. British Journal o f Industrial M edictne. 8. 302- -----. B onnell. J. A.. *nd Beckett. A. G . (1953). Brit. m ed. J,, l . 1068. B o n jer. G . M... C lay to n . D. B-. and Jul!. J. w , (19511. Lancet. 2. 286. --. ---- , and Pyrah. L. N. M952). B m . I. Cancer, 6. *12. B n d tc . J. C. ll9 3 * i. A nnual R eport o f the C h ie f In sp ecto r o f Factories a n d W orkshops for 1933, p . <9. H .M .S .O .. L ondon. C ase. R A. M.. and H osker. M arjorie . (195*). B n t. J. peer. sot. M ed.. I . 39. ---- , ---- . M cD o n ald . D. B., and P c in o n . Jo a n T . 0 9 343. British Journal o f Industrial M edicine. 17. 73. C atch . J- R .. H u fc ill, H. P. W ,, and Som erville, A. R . 0 9 5 3 ) . J. chem. Soc,, p. 3028. , nQ OxizC Iniprcxor o f Factories 0 9 * 9 j, A nnual R ep o rt fo : 1947. 79. C o o k . W. a . 0 9 4 J 1. Induitr. M rd .. 14. 9 )6. C ra h b t. J. G . S. (19J21 B m . m td . J.. 1. 1072. Digglc, W . M .. and G age. J- C. 095*1. British Journal o f Industrial M edicine. 11. 1*0. D r a iz e . J. H .. W oodard. G ., and C alvcry. H . 0 . 0 9 * * ) . J . Pharmacol. I I .177. . D rinker. ? .. and C ook. W. A. (19*91. Proc. IX Int. C o n g r. Induitr. M-ed.. L o n d o n , 19*8. p. 15*. W n fh t, Bristol. D ustin. !>.. Jr. (19*11. Song. 15. 193. Federal Security Agency (1953). Health o f W orkers in Chromate Product** Industry. Public H ealth Service Publication, N o. 192. W ashington. Forem an. H.. H ardy. H. L.. Shipm an. T . L-, and B elknap. E. t~ (19531. Arch, industr. H yp .. 7. 1*8. F u llerto n . J. M. (1952). Brit. m td . J.. 1, 117. G o ld b lau . M. W. ( 19* 7). Brit. m rd. Bull.. 4. *05. ____ {|<J*9i. British Journal o f Industrial M edicine, 6, 63. ------ (1930). Phorm. J., 16*. 229. ..... . ---- 09511. A tti del C onvegno in te m iz ia n a lc d t r M eaicm a del Lavoro. M ilano. 1950, p. 90. H enson. A. F. 0 9 5 5 ) B n t. J. appl. P h yt.. 4. 217. Somerville, A. R., F aro u h an o n , M uriel. E-. and G oldbU t.. M. W . (195*1. Biochrm. J. 58. 383. H u m . E. W eston (19*1). M ed. J. A uit,, 1, 661. , (19*41. Brain. 67. 103. ^ R ch o c. R. A. (19*9) In Industrial Hygiene and To xico lo g y. vol. . p. 6 0 . Edited by F. A. Patty. Iniersctence P u b lish ed , m e.. New York. ---- 09511. Induitr. M ed. S u rg .. 20. 253. . K ench. J. E-. Lane. R. E., and Varley. H, (19321. B io c h tm J. 51. I*. Lane R. .0 9 * 9 ). British Journal at Industrial M e d ia n t. 6, 1-3. therefore, it is in the big organization with gyeat resources that such studies can be made, but it is M calcine J. B. (1929). Brit. med. J., 2. 79*. , M cFadzean. A. J. S.. arid Davia. L. J. ( 19*9). Q uart. J. ** 3.'- SU chie. W ., and G re ta r iu i, F . (19*8). Publ. H>th Hep., M ai a parallel fact that in such organizations the environ mental conditions are likely to be the best. The practical application of the principles which meffcc from field studies requires assiduity on the ppaann oifi mthee iinndouusstirniaail dooocctiuori aainmd uoif 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 content those who are enzaged in research in industrial health in lire Mmistn-* oV A griculture (19331. Toxic C hem icolt in Agriculture^: Residues m Food : Report o f the W orking P o n y , H .M . Stationery Office. London. P ap anicolaou. 0 . N. (19*7). J .U e /.. 57. 375. --pc--i^' (lH19**,o1)9.3fAim. eirt.mJ.. PAurbole.mHmimed..3A1.rb2e0u--uch^ i, 86, fpoWi.. aa. iiio.d (rmisoi. ^>,0, n ,M edicine. 7, 123. pR,,m.?tniip. Dj nw`"fc?. nt`|,9w7i'il!.' (<Su<r. chini.). Zi <* Ror,. t (19551. J. dm. Poi*. TotxoubluheH. S cott. T. S. (1932). flntijA Journal o f Industria M e d i a n i .'9,, U 7 . S om . S.. M iu:,(l. W, H., m d D obnner. K. (19501. C o u re ... T.ylor. H. 119101. J. in d .tir. H jrt. I I . 171. - n5M . w i l p o is . A . U , W U .m i, M. H. C .. 1.0 R o n o . D . C. 119X1. British Journal a f Indu stria l M ed icin e, U . l0 3 - W ignall. T . H. (192). B r u . m e d . J., 2, 2-*8. Bril. J. N] While ihe: criminal or ganese ores rise to a nur The hosier:; already beer and Rodie:. occupations .' when Coupe pamong rive a series of v paraplegia, lean forv-ar salivation. Since the: observation affecting thknown tha: be rare sin; in contact The sympt disablemen occupation problems, partially ir sick rran : M ancon but its m; dioxide r.o Pliny men Stockhclr after three thesis l i ` was final: ce Mom: distir.gu:; Bergman nature u writers c: