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R&S 112045 SlO-KEDICAL RESEARCH DOCUMENT DESCRIPTION FORM 63 68 69 000035ft 'uplicate in all cards:--> /-7/^ year as-1961- File lumber [Right justify [Numeric only] Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by.one blank space 1 -20-21 . 40 41 / fca ' 7 ----------------------- . s r?- 77 78 ;/c_ Sub-Index Code 60 61 62 11 12 13 Title of Report: end with space-hyphen-hyphen-space. Follow with Index Tartu separated from each other with .comma-space. Avoid other punctuation; do not abbreviate. 12 *' /'///? v / ---i f/. /'C/i. t-e>.,^. ^^_ ---------- " ------------------------ 3^------------ ---------- ^------ 61 '62 21 22 SIf rr>^j J (/ 23 24 Source (Journal, Vol., Number, Pages, Date) J ^ oir ^'C7^ 0 --=rr: / / /-i.3 <Jn /' ^.7 y' 61 62. 31 32 2rief Summary' 61 62 61 62 63 64 4* O) TREAT REP it 103 irss, and weed 107 Pimentel 111 d 115 ttc 1 976 the Tncbn; Treattton..........................941 Etfftr Cawed by True Yaa................................. 941 m. Berry & Horn 6s of the eneral Hospital t Dyspnea in a 19...................................944 *t 7". ,lf(Du^ rials thesis ........................ 932 .^Lunp? 954 iag Board ...................................... 934 mdcncc <> Due to IdovuridiM , 956 nt Syuem 957 c5oiu(iom 957 ......................................... 957 ......................................... 959 caftook* 959 4 Heart Failure with IHyper|lyretttU .... 962 be Quality of Mvdka) .............. ;....................... 962 Public Affairs A New Inquiry .... 90S RRENT CONTENTS 0 1976 by ISI wt?vs_i r.-ma Proceedings of 0000350 the Royal Society of Medicine VOL. 69 NO. A , APRIL 1976 Sectioaof Proctology 237 Rectal Cancer: The Spectrum ofSelective Surgery 4 President's Address by A York Mason Section ofthe History ofMedicine 245 The Politics of Anatomy: Dr Robert Knox and Victorian Racism MDBtddiss United Services Section 251 Human Factor Problems in Helicopter*- Research and Development JR Allan 252 Human Factor Aspects of Army Helicopter Operations KEdgington 255 Human Factor Problem of Operating Helicopters at Sea A PSteeie-Perkins Section ofSurgery 257 Trial and Error m Gastric Surgery President's Address by Andrew M Desmond Clinical Section 263 Sderodermatomyositis with Mcgaoolon, Small-bowel Involvement and Impaired Lung Function VSrlnivas (for V WJohnson) 264 Calcinosis in Scleroderma JN Rosenberg (forJGLewis) 264 Menetrier's Disease and Carcinoma ofStomach J D Stamatakis (for A P Wyatt) 265 Severe Intra-abdominal Sepsis CHBrowne andEGross (for Gillian C Hanson) 266 Ileocolitis Responding to Bowel Sterilization Stephen P Kane (for Graham Neale) Section atOphthalmology 267 Cataracts in Early Childhood The Scope of the Problem Brian Hareourt 268 Etiology and Genetic Aspects Barrie Jay 270 Cataracts in Early Life: Biochemistry Anthony F Winder 272 The Surgery of Cataracts in Children NSC Rice 275 Vinyl Chloride: Introduction to the problem Suzette Gauraln 277 Vinyl Chloride and the Production of PVC A W Barnes 280 MD Kipling. A WBarnes, CSDarke 281 USeUkofT 281 Review of Animal Studies K S Williamson 283 L Magas, HEStokinger 284 Clinical-Aspects of Vinyl Chloride Disease 284 Acro-osteolysis BJPreston, KUaydJones and R G Grainger 286 L Magos, BJPreston, K LloydJones 286 Clinical Aspects ofVinyl Chloride Disease: Skin Anne E Walker 288 Leo DJerassL Anne Walker, MarcusMKey 289 Prtmysl VPelnar, Anne Walker 289 Evidence ofan Immune Complex Disorder in Vinyl Chloride Workers A Milford Ward 290 Leo D/erassi, Margaret Turner-Warwick, A Milford Ward, L Magos, E Vtgliani, RuthUlis 290 Chromosomal Effects in Peripheral Lymphocytes fFHPurchase, CRichardson and D Anderson 291 Sylvia D Lawler, l FHPurchase 292 L de Boer, IFHPurchase, D G South 292 Preliminary Results of Grey-scale Ultrasonography in the Detection of Vinyl Chloride Related Liver and Spleen Disease KJWTaylor, JJBarrett, DMJ Williams, P M Smith and B W Duck 295 Collagen Studies in Acro-osteolysis M l VJayson, A J Bailey, C Black and K LloydJones 297 Epidemiological Studies ofPVC Manufacturers and Fabricators, and Primary Angiosarcoma of the Liver PJ Baxter 299 A J Fox. L Magos 299 Histopathology of Liver Lesions Associated with Exposure to Vinyl Chloride Monomer K Weinbren CONTENTS CONTINUED V i CURRENT CONTENTS 1976 by ISI njnvuuqjmgwww ,UMJ C-13 ,n " If , ,1 1 ^ .^ ^ aw .i.r ie i!w m s w m - l 4 . w |x|j ! 9 ' >i| urnw n u ' i l lJ r w TU W M M WW g " .1 w '` 'tw ' w " ,ie p y rw 1  * % \ V 5 t r r t 5 ! n--enjmmiiiiiinmenr.......... far Ji ---------- ^Ti i, i 33 (/) CONTENTS CONTINUED 303 Epidemiological Studies orVinyl Chloride Health Effects in the United States Henry Falk and RichardJ Waxweiltr 306 Mitchell R Zuvon, H Falk, RI McCollum, AJ Fox,J A Bannell, IJSelikoff 307 Medical Surveillance of Vinyl Chloride Workers BWDuck 309 A John Robertson, B W Duck, Robert Murray, L Magos PROC ROY SOC MED 309 Environmental Monitoring HF Henning Section of Dermatology 311 Acanthosis Nigricans and Eruptive Xanthoma R W Emmerson 312 Juvenile Bullous Disease Roger Clayton (for M Feiwef) 313 lsoniazid>induced Pellagra WADGriffiths (for M WGreaves andR H Meara) Fortschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin Articles in German-Each Abstract in English and German VOL. 124 NO. 3 MARCH 1976 Naainnsira Demonstration of Wall Movement Bare Anomaly of Cerebral Vemeta (Unilateral and Stroke Volume Distribution of Left Venbi- Aplasia of Internal Carotid Artery, Persistent dm stiet Myocardial Infarction. HypoglomalArtery). F. Wiedner, N.Sehad201 a Sehrejw------------------------------------- 243 dintnal end Experimental Investigations with It- Unusual Catebral Artatiovenou* Malformation 201 far Non-fnvssive Myocardial Sdntigte- G- Stampiel .250,,.,i, ..-- pby. H. Uchlo. H. Illegal. H. Sabening, Atypical Termination of Vertebral Artery end of a Hoi, H.W. Pal*. J. Dre-let, Inferior Posterior Cerebellar Artery. Sauer .................--,--.--206 P. DistelgMier, J. Wappenaehmidl --........ 253 Reliability of Myocardial Scintigraphy inth Thalli nCD-Meoileetation end Clinical findings. um-201 a Comparison with Lonvocatdiogrm- H. SeyfeddiaipBr, G. Ditsea---- ,------- --2S6 phy and Perfusion Scintigraphy. fi, Felix, W. Peosky, J. Wagner, P. Thurn, G. Neumann, IP. Hadda, H. Simon, C. Winkler.....-...........--........210 Radiogenic Carotid Stenosis - Probiam of Radia tion Induced Arteriosclerosis. B. Woldorff, U. San, B. Hairing, 1LS. Simon. G3. Bredac_____ _______ --2S9 Cinemstogrspbic god Clinical Findings from Angiographic Diagnosis of Trophoblastic Tu Simultaneous 2-Plans Coronary Angiography. mours. G- Schwarx, G. Techeme----,, --...264 G. Friedmann, HJLHilget. D.W.Behianback214 Effectivenem of Vasopressors end Vasodilators for Phaimaeo-Dynomic Panel Angiography. S-Veein216 Undoairabla Pbsrmeco-Angio-Gtsphic Effects of Adrenaline in Malignant Renal Tumours. LLelek, V.Guttonyi226 Catheter Embolisation of Metastamting Banal Car- tintmaa Using Butyle-2-Cysno-Acryiate M. Thales. P. BruM. F. Gerlach. HJ. Bienack232 Supra-Ronal Venography in Patient* with Suspect Value oflutensifiei PholopneumopeJngraphy in Diagnosis of Gynaecologies! Diseases L. Diaakow, A. Saikaniat*_----...268 Accuracy ofPlacental Scintigraphy, B. Botha, M. Motxkn, F. Bowlins, HGHeuue271 Comparison ofIsotope Nephrographic Examina tions during Pregnancy and Hormonal Con- deception. B. Voigt G. dinger, J. Arndt W. Stoll27S Bacteriological Invontigatiana In Radiological Clinic (Radiographic Apparatus, Rooms and Personnel). W. Frik. W. Scbiek, H-Zmhlsdorff278 ed Endocrine Hypertension. H- Weimleder, S. Ahdelliemid. Pmoutanmnra, Trans-Vascular Foreign Rody Ex tinction. H. Bitter............. ........ ....... ...... ,284 H. defer, B. Schaenow_______-23S Coeiioc Angiography with High Contrast Plow Salas. J. Schroder------------------------------- 239 Angiographic Demonstration of Arterial Compo nent of Large Meningioma* in Cerebral Cor tex end Medulla. S. Bochenhehaar, H. Aachayeri. Voigt_______ 242 Inroiremeni ofEntire GastroJntaatinal Canal by Chronic Lymphadenosis HID. Geistner, B. Jacob* --___ _____ ______________ 287 Csnadidissis ofStomach J. Vitoeec________ 289 Unusual Peh-Pslvic and Peri-Ureteric Reflux As sociated with a Hypernephroma. M. Ikonen, L Panto, P. Eemppainen____ 290 C-14 ay ' spsupw. CURRENT CONTENTS 1976 by !SI$ J JllUPJ'i BM445 VOL. 55 N A TECHNIC OF GENERAL ANESI Katz, Machida, Wootton and CARDIOVASCULAR DYNAMICS , PLUS N.0 IN THE DOG--Lit ANESTHETIC CONSIDERATIONS ORIGIN--Dalai, Bennett Gn, "PENTAZEPAM" (PENTAZOCINE FOR LAPAROSCOPIC STERl SURVIVAL FOLLOWING MASSIV MONARY EMB0LECT0MY: A BACTERIOLOGIC ASPECTS OF White .............................. RESECTION OF STENOTIC TRAC FACTORS INFLUENCING CH0: TRANSLARYNGEAL INTUBA CARDIOVASCULAR EFFECTS 0 Campbell, Levin and Elliott MANAGEMENT OF A PARTURlEN A POTENTIAL IGNITION SOURCI THE INTERACTION BETWEEN dNEOSTIGMINE ON NEUR0M INCIDENCE OF PROLONGED PAl Andersen and Saga.......... CIRCULATORY CHANGES IN PAl ING THIAMYLAL-SUCCINYLC Peterson .................................. FAILURE TO INDUCE HEPATIC THANE METABOLITE AND f Reves and McCracken ... ATYPICAL PSEUD0CH0LINE5TEF Fernandez .......................... awFCTHFTie CONSIDERATIONS THEORETIC SIGNIFICANCE OF ANTAGONISTS IN CLINICAL . MANAGEMENT OF INTRACTABLE ADMINISTRATION OF LIDOC, THOUGHTS ABOUT MEDICAL WR A COMPARATIVE STUDY OF ENF INTERVALS--Kaplan. Miller a EFFECT OF Paco. ON 0. CONSl MAN--Patterson ................. THE EFFECTS OF DOXAPRAM ON DYNAMICS IN THE ANESTF tvankovich, Albrecht, Bonnet ETOMIDATE: AN ULTRASHORT-AC INDUCTION--Gooding and Co THE INFLUENCE OF SUCTION TRAUMA AND FLUID ASPIRA Glover CASE HISTORY NUMBER *3: A LIF MEMBRANE PUNCTURE--Po< CURRENT CONTENTS 1976 by ISI 1 -<3SS2& Volume 69 Number 4 April 1976 6>3-` ^J-X. y^w^c //^^-rc, fcJUi Svu./ H Proceedings ofthe Royal Society of Medicine !t u R&S 112048 Vinyl Chloride page 275 Published by The Royal Society of Medicine 1 Wimpole Street London wIm 8ae * t- 'J1 17 ' Volume 69 April 1976 275 * .5 Section of Occupational Medicine President Suzette Gauvain mrcp i , Meeting 12 September 1975 Vinyl Chloride \. i` !' DrSuzette Ganvatn (Medical Advisory Service, Health and Safety Executive, Baynards House, 1 Chepstow Place, Westbourne Grove, London IV24TF) Vinyl Chloride: Introduction to the Problem The story of vinyl chloride, when it comes to be written, will be seen as a watershed in the history of occupational medicine, forcing us to take a new attitude to occupational hazards and react quickly to first evidence of harm. The polymerization process of vinyl chloride to polyvinyl chloride was first discovered in Germany in tbc mid 1930s. The fire and explosion risks and the narcotic effect were quickly appreci ated. Acro-osteolysis, a condition mainly affecting the terminal phalanges of the fingers, sometimes the toes, and to a lesser extent the other bones of the body, was first recognized in autoclave cleaners in Belgium (Gordier et al. 1966) and subsequently confirmed in a number of investiga tions of autoclave workers in Canada, England and the USA. Soft tissue changes, coldness and numbness of the hands and fingertips, resembltng Raynaud's phenomenon, were also described. Lilis et al. (1975), summarizing the findings in the world literature in relation to the prevalence of disease among vinyl chloride and polyvinyl chloride workers, make the point that hepatitis like liver changes were reported by Tribukh, from Russia, in 1949. However, until Viola reported (Viola et al. 1971) that he had failed in an attempt to produce acro-osteolvsis tn rats exposed to 30 000 parts/104 of vinyl chloride, but demon strated carcinogenic effects, little attention was paid to this earlier finding. The level of exposure of the rats was so high that its significance to humans was not dear and further testing was necessary. Maltoni, commissioned by a consor tium of European chemical interests, including Imperial Chemical Industries, to undertake further studies, confirmed cancer in animals at . exposures as low as 250 parts/104 (Maltoni et al. 1973). As a result of Maltoni's work an epidemio logical study was undertaken in the USA on men who had previously worked as cleaners of auto claves (reactors) in a polyvinyl chloride poly merization plant. Creech & Johnson published this work in 1974, but their findings of a cluster of cases of angiosarcoma of the liver in one factory were transmitted to the National Institute of Occupational Safety and Health (United States) on 22 January 1974 (United States Senate 1974), to the Department of Employment (HM Chief Inspector of Factories) on 23 January, and to the Acting Chief Employment Medical Adviser on the following day. On 29 January 1974 Imperial Chemical Industries put out a press statement announcing that it was taking steps to inform government departments, the TUC, its own workers and its customers, of the facts available so far; and that a single suspected death in the United Kingdom was under urgent investigation. Subsequently this 70-year-old retired autoclave worker, who had died at the end of 1972 after twenty years of ex posure, was confirmed to have died of angio sarcoma of the liver. Since 1974 intensive investigations have taken place in this and many other countries. The United States government have published an account of the hearing before the Subcommittee on Environment of the Senate Committee on Commerce, on the dangers of vinyl chloride (United States Senate 1974). Senator Tunney, in !? 33 CO to o 40 5 < i '"r" if" 276 JVoc. ro 5oo. Med, Volume 69 April 1976 IS his opening statement, said: This hearing will be additional information shows this to be necessary focusing on ways to mitigate the problems in ... The success of the Code depends primarily on volved with vinyl chloride as well as ways to the united efforts of management, supervisors and avoid crises of this type in the future.' Previously, employees. This is very much a first edition of the on 10 and 11 May 1974, the New York Academy Code in temporary format; I hope that those who of Sciences, the American Cancer Society, the have suggestions for improving it will put them National Institute for Occupational Safety and forward via the joint consultative machinery Health and the Society of Occupational Environ required by the Code.' mental Health hcid a workshop entitled Toxicity of Vinyl Chloride - Polyvinyl Chloride (Selikoff & Hammond 1975). Medical Subgroup The medical subgroup defined its terms of refer The International Agency for Research on ence as being: `To examine the medical aspects of Cancer (1974, 1975) published technical reports exposure to vinyl chloride; to decide in the light of a working group on vinyl chloride held in June of existing clinical, pathological, toxicological 1974 and of a succeeding meeting in January and epidemiological information the examina 1975. The International Chemical Workers tions which should be included in the Code of Federation published for its members a handbook Practice; and to indicate those which require on vinyl chloride and its hazards (Levinson further research before inclusion in the Code'. I 1974). The Environmental Protection Agency in Washington, DC published in September 1974 a The subgroup consulted and gratefully acknow preliminary assessment of the environmental ledged the help given oy experts on diseases of the problems associated with vinyl chloride and poly liver and relevant diagnostic ptocedures. Because vinyl chloride, in which it set forth recommenda of the difficulty of determining which medical m tionsto clarify and reduce the associated risks. tests indicate the effects of vinyl chloride on the liver preceding the development of angiosarcoma, Meanwhile, the Department of Employment they `concluded that insufficient experience wi: staff in the United Kingdom had been taking liver function tests or screening tests is as 3 active part in consultations in Europe and in the available to enable firm recommendations to be J United Stales. As soon as the information was made regarding them in this Code of Practice. communicated in January 1974, HM Inspectors Liver function tests for this purpose are however of Factories and Employment Medical Advisers in use in factories making PVC ... *. As a result throughout the United Kingdom were notified, of experience gained from these tests and from and industry on its own initiative set out to ensure other information, `formal recommendations that no person would be exposed to amounts of may be issued as a supplement to the Code in due vinyl chloride vapour that were above a con course'. centration of50 parts/10*. The medical aspects of the code are contained The TUC and the CBI accepted an invitation in parts 12,13 and 14. Part 12 defines `supervised from HM Chief Inspector of Factories to form a workers'. Part 13 is concerned with their medical joint working group with representatives of supervision. Supervised workers should undergo government departments. The first meeting took pre-employment medical examinations. Those place on 14 June 1974. An interim hygiene already employed should be examined, if this has standard was adopted and two subgroups were not been previously done, within twelve months. *: set up to draft the environmental and medical The examinations should be repeated annually, sections of a code of practice; these were pub and should include: (1) a full medical and occupa lished in February 1975 in temporary format by tional history; (2) a clinical examination with the Health and Safety Executive (1975). In the particular reference to the abdomen, skin and introduction Mr Bryan Harvey, Deputy Director extremities; (3) X-ray examination of the hands; of the Health and Safety Executive, states that the (4) such further tests as may be indicated by the code sets out to (a) define an interim hygiene above procedures or may be recommended in standard that must not be exceeded; (b) require supplements to the Code. The leaflet describing regular monitoring to measure the concentrations the early effects of vinyl chloride monomer should 33 of vinyl chloride in the atmosphere; (e) outline be given to the supervised workers at this exami CO '3kro 4 methods of achieving (a); (d) provide for medical nation unless issued previously. 'J>3 '.4 supervision; (e) provide for joint consultation and education and training. He further states: `... the Code as now published is based on our The physician engaged to provide medii supervision for the workers should see a su 0 existing knowledge and wilt be improved where vised worker who reports symptoms which m; o01 L J '- ' t V im in* 111111 _ in Iilfi'itr^riflmirt /-? 19 Section ofOccupational Medicine 277 ssary ly on sand >f the jwho them inery be due to exposure; he or she should see a super vised worker who has been absent from work more than two weeks owing to illness. These absences should be reviewed on a group and individual basis. If indicated, medical examination should be undertaken at any time. Section 16 provides for the keeping of confidential medical records of all supervised workers; these must not be destroyed without the agreement of the Chief Employment Medical Adviser. tnteneatittoal Agency for Research oo Cancer (1974) Internal Technical Report No. 74/005. tARC. Lyon (1975) Internal Technical Report No. 75/001.1ARC, Lyon Leriasoo C (1974) Work Hazard: Vinyl Chloride. International Chemical Worker* Federation. Switzerland Lille R. Aoderaon H. Nicholson W J, Daw* $ Fkehbeio A S dtSelikaff IJ (1973) Armais ofthe New York Academy of Sciences 244* 22-41 Maltoai C, Crespi M ft Burch P J R 4 (1975) Excerpta Afedica International Congress Scries No. 275 Stiikafi IJ ft Hammond C ed (1975) Annals ofthe Sew York Academy ofSciences vol244 Tribakh S L Tikhomirova N P. Levma S V ft Kotlov L A (1949) GlgienaSattit 10,58 Vailed Scatea Senate Committee on Caawutt, Subcommittee Eaviropmeof (1974) Second Session on Danger* of Vinyl Chloride. ,-cfercts of light The purpose of the present symposium is to review British experience of the environmental, clinical, epidemiological and pathological effects Serial No. 93-110. US Government printing Office. Washington, DC Viola P L, Bigotti A ft Caputo A (1971) Cancer Research 31,516 >gical of exposure to vinyl chloride arising in the course niru of polymerization of vinyl chloride monomer to le of polyvinyl chloride, and to exchange information. quire The implications of the association of angio nowjfthe ausc dical sarcoma of the liver with exposure of workers to vinyl chloride monomer have had such a pro found effect on industry, .workers and govern ments that these effects must be seen in the wider context of occupational carcinogenesis generally. Mr A W Barnes (ICIPlastics Division, Welwyn Garden City, Hertfordshire) t the jma, I think it is necessary to consider what the future may hold in the way of carcinogenic risks. We can, I believe, regard the experience we have Vinyl Chloride and the Production of PVC gained throughout the world with vinyl chloride as a pilot study on a newly discovered occupa Polymerization Characteristics cticc. vever esult from tions i due tional carcinogen. Frank and open discussion between government departments and both sides of industry is indispensable to the achievement of success. Postscript of Vinyl Chloride Vinyl chloride has a boiling point of -- I3.5C; under normal pressures and temperatures it is a gas. In its liquefied form under pressure, it can be readily polymerized at temperatures in the range 40-70C to give polyvinyl chloride (PVC), a white solid material. The addition polymerization The Working Group on Vinyl Chloride Code of of about 500-1500 molecules of vinyl chloride ained Practice for Health Precautions met on 8 October produces one molecule of PVC and the poly-' vised dical iergo 11050 1975 and adopted a new hygiene standard agreed by the Working Group as 'a ceiling value of 30 ppm and a time weighted average of 10 ppm, allowing that wherever practicable exposure mcrization reaction is strongly exothermic. The polymer itself is insoluble in the liquid monomer and so precipitates out as it is produced. The polymer is, however, capable of absorbing high s has should be brought as near as possible to zero con proportions of monomer (40% by weight) so that nths. jally, centrations.' The figures of 30 parts/10* and 10 as the polymerization reaction proceeds and more parts/10* replace the original figures of 50parts/10* polymer is precipitated, so equally is more xipa- and 25 parts/10*. monomer absorbed by the polymer to the point with at about 70% conversion where monomer as a and Other requirements of the Code, including separate liquid phase disappears and the remain tnds; medical supervision, arc currently being re ing monomer must be polymerized in its dis y the viewed. solved state within the swollen polymer. As this d in phase of the polymerization proceeds, the con ibing centration of monomer in the polymer decreases lOUld unu- dical upei ma REFERENCES CorditeJM,FfcvezC,MJ &Srrri*A (196$) Copiers de Afedectne du Travail 4, J4*J9 and the rate of reaction correspondingly dimin ishes until at about 92-95 % total conversion the CniehJ L jr ft Johnson M N speed of polymerization becomes uneconomical!/ (191A) JournalofOccupononoJ Aledieine 14,509-518 Earfraoiftcotsl Protection Agency (1974) Preliminary Assmment oftb* EmrirortmeniaJ Problem* Associated with Vinyl Chloride slow. These are the fundamental characteristics of vinyl chloride and its polymerization mechan ! and Polyvinyl Chloride. Washington* DC Health ft Safety Executive (1975) Vinyl Chlcmde Code of Practice ism which decide the principal features of indus for Health Precautions (Temporary Format). London trial processes for the production of PVC. 30 l f (/> * V t to o. i - t r S 1 t 1 'P. I :% nm w> mui mjtMui.ja"'nxmiyfwiisuiiMgjl-1 i <j muism. wi iw.mw 2 % % i \ *1 ;; 30 </) rotrnoo / * 4 1 i t 1 i'i niit iii~Miimir'ii i~-- 278 Proc. roy. Soc. Med. Volume 69 April 1976 TheProduction Processfor P VC Because it. must be polymerized in liquefied form at temperatures above its boiling point, the industrial process must be carried out in pressure vessels (at 5CFC the vapour pressure of vinyl chloride is --7 atmospheres). Because the reaction is exothermic, means must be found for removal of the heat produced so thar the temperature of reaction (and thus the pressure, and the properties of the end>product) may be kept under control. In the most widely used process, this control is achieved by dispersing the liquid monomer into tiny droplets (about 100 pm in diameter) in ap proximately equal quantities of water, by means of mechanical agitation together with the-addition of small quantities of surface-active agents which facilitate the breakdown of the monomer into droplets and stabilize it in this form. This finesubdivision of liquid monomer enables the heat evolved from the polymerizing monomer to be rapidly transferred to the surrounding water and then removed by a cooling jacket on the reactor, the proerss being aided by agitation. The sub division of the monomer into droplets has also the vital property of ensuring that the polymer, which is produced within each droplet, is pre sented at the end of the reaction in finely divided, powder form, and not as an intractable horny tna conversion and solving some of the problems connected with vinyl chloride toxicity in this way. At the termination point of the reaction, there fore, the 5-6% residual monomer (still at a pres sure of 4-5 atmospheres) is vented back to a gasholder and a sluny of PVC particles (100-150 pm diameter), suspended by stirring in water, is left in the reactor. Now to a description of the process in engineer ing rather than chemical terms: polymerization is carried out in cylindrical, stirred, jacketed pressure vessels. To begin, water, surfactive agents and free radical catalyst are added to the reactor: the air space above this liquid phase is purged of oxygen (which inhibits polymerization) and liquid vinyl chloride is then injected into the reactor. (In the UK, reactor sizes range from 10m3 to 40m3 and the monomer charge per batch ranges up to about 15 tons.) The reactor contents are then heated to and maintained at reaction temperature. After a reaction time of the order of eight hones, excess monomer is vented to a gas holder <for recycling) and the reactor is evacuated, at elevated temperature, to strip as much mono mer as possible from the polymer on which it is absorbed. The polymer slurry is then trans ferred to closed tanks prior to the next stage the process. As polymerization proceeds, the two phase Meanwhile the empty autoclave, which still system of monomer dispersed in water becomes a contains vinyl chloride gas at a low partial pres three phase system of solid polymer precipitated - sure is further evacuated before opening to within liquid monomer droplets which are in turn atmosphere; and automatic high pressure water dispersed in a continuous water phase. A great cleaning jets are activated to remove polymer deal of research has been devoted in the past scale from the walls. At this stage, the cycle is thirty years to the control and stabilization of complete. this rather delicate colloidal system but, even so, small quantities of polymer are still thrown out Vinyl chloride monomer has a strong affinity for from it and form a thin continuous film of PVC PVC and the last traces of it are difficult to remove on the walls of the reactor. If left, this will in from the polymer; the polymer in the slurry after'' crease in thickness and, since PVC is a poor stripping therefore still contains around 500 thermal conductor, will reduce the heat transfer parts/10* of vinyl chloride. This slurry is centri characteristics of the vessel and make temperature fuged. to remove the water phase and the wet control impossible. At the end of the reaction it is powder is then dried in continuous driers; during therefore essential that this film should be cleaned this process further vinyl chloride is removed in away. This is one of the basic reasons why a truly the drier gases and the final dried powder cur continuous process has never yet been developed rently contains about 50 parts/10* of monomer. for making PVC and why the polymer, the world ' over, is still made by a batch process in relatively Interfaces between small reactors. This, as we shall see, has a signifi Vinyl Chloride andPeople cant influence on the ease of controlling fugitive This description of the production process gives monomer in a PVC plant. some indication of the relative potentials of different parts of the process for creating signifi As polymerization nears 90-92% conversion, cant exposures of people to vinyl chloride. If we the rate of reaction slows down markedly and at take a plant capable of making 100 000 tons per about 95% conversion has become so slow as to annum (tpa) of PVC then the polymerization be quite uneconomic. There is no possibility building will, during the course of a year, have therefore of continuing polymerization to 100% handled over 100 000 tons of vinyl chloride inJ i '* V \*.k 20 roblems his way. t. there* ; a pres* ck to a 100-150 water, is ngmeersrization jacketed jrfactive d to the phase is fixation) into the ge from r batch contentsreaction order of 0 a gasacuated, 1 monc whiq stage in tich still tial pres sing to .re water polymer . cycle is Unity for o remove my after und 500 is centrithe wet s; during moved in -'der cursomer. tess gives ntials of tg signifide. If we tonsj >eriz| ear, doride in 21 Section ofOccupational Medicine 279 liquefied form under pressure. Into the drying section will have passed 50 tons of vinyl chloride in a form strongly absorbed on the polymer and at a concentration on polymer of about 0.05%. In the finished product, 5 tons of vinyl chloride will leave the factory, each year, still absorbed on the polymer at a concentration of 0.005%. Although strictly outside the scope of this paper it is wonh proceeding further and pointing out that in further fabrication operations on the polymer, some of this small residual concentration of monomer is driven off so that in the final fabri. catcd article only --5 parts/10* of monomer remain or 0.5 tons out of the original annual total of 100 000 tons. In fabricated articles which are used for foodstuffs packaging (bottles, film and foil), and which represent about 10% of total UK production, the monomer concentration is still lower, and the pro rata amount absorbed on foodstuff containers from a 100 000 tpa plant would be 50. lb. Of this quantity 31 lb might migrate into the foodstuff where its average con centration is unlikely to exceed 10 parts per thousand million. Since total UK production is about 400000 tpa this means that the annual ingestion by the average UK citizen cannot exceed 0.0001 g, a figure which agrees well with calculations based on diet analysis. A final potential interface arises because at points in the production process, vinyl chloride is exhausted to atmosphere. On a typical PVC plant and with current levels of achievement, 0.3% of the monomer is lost to atmosphere; with this performance ground level concentrations at the factory boundary are well below 0.1 parts/10* and even these low amounts decay very rapidly with distance. In the band i-1 mile (0.4-1.6 km) around one factory, for instance, the concentra tions determined are in the range 0.01-0.0001 parts/10*. These figures should make dear that by far the biggest potential for exposure exists in the poly merization section of the plant, since here 100 000 tons per year of a liquefied gas under pressure are handled in a confined space, in contrast to other parts of the process and to the later down stream operations of the plastics industry. In these downstream operations the corresponding quantities, this time in the form of absorbed vapour at a low partial pressure and not confined to a single geographic situation, range from 5 tons down to 3 lb per year. That the polymerization section is in fact the area where hazard has existed in the past is confirmed by the fact that all the authenticated cases of vinyl chloride-relared angiosarcoma of the liver throughout the world have been of workers engaged in plants where liquid vinyl chloride under pressure was used in large quantities. The nature of the polymerization process, as described above, illustrates why exposures in the past could have been large. The plants are com posed of a large number of batch reactors of small capacity per batch, relative to the total annual throughout. In each reactor, two complete cycles per day are carried out and each cycle requires vinyl chloride to be injected under pressure, heated, contained, stirred and polymerized almost completely; at the end of the cycle un polymerized monomer has to be removed and the rea-tor opened and cleaned. The possibilities of small leakages from pumps, valves, stirrer glands and from the opened reactor at the end of the cycle were obviously significant: and the manual cleaning of reactors gave further opportunity for high exposures. This was particularly true during the long period in the 1940s to 1960s when vinyl chloride was thought to be harmless and when a recommended exposure limit did not exist or, late in the 1950s, was set by regulatory authorities, industrial hygienists, &c., at a level of 500 parts/ 10*. The general consensus of opinion throughout the world, today, is that average atmospheric exposure for polymerization workers between 1940 and 1970 might have been of the following orders: 1945-55, --1000 parts/lC*; 1955-60, -400-500; 1960-70, --31XW00; mid-1973, --150; 1975, --5 parts/10*. Across the world, there will have been variations around these figures because of differences in plant design or process operation. Even the way in which jobs were organized can have caused variations. In some countries or on some plants workmen were employed specifically to clean out autoclaves (where exposures could have been very high) while in others autoclave cleaning was part only of a whole range ofjobs Carried out by individual work people. Some spokesmen have suggested, . perhaps for full-time cleaners, exposure levels as high as 3000 parts/10* in the early days of the industry. With these very high figures as background, the progress made by the PVC industry in the UK in reducing atmospheric concentrations sines the carcinogenic hazard of vinyl chloride became known in early 1974 is shown in Table 1, which, also shows improvements made at all the other interfaces described earlier in this paper. Al though. as we have seen, the exposure levels in these other places are many orders of magnitude lower than on the polymerization plants, industry has aimed to reduce fugitive vinyl chloride levels ..................'m.'whsjwsu 3 A>.. <4.-4^'^.. - >--''..-'--^''-w -- .... ^-'K.-.'--- --^>4,---- r 280 Free. roy. Sot. Med. Volume 69 April 1976 <! -j at every point in order to eliminate concern some areas almost incomprehensibly lower - levels wherever it might exist. With work still in pro which prevail today. For it is on this, quite, gress, all these figures will be reduced further properly, that industry, and society generally, though, in view of the effort already put in, it is have focused their attention in the past eighteen likely that the polymerization plant atmospheres months. are approaching a limiting value of 2-5 parts/10*. : Table 1 1 3 f Vtarl cHatM* mom Inals ia UK iadwor iWjmtiJmrfiw VCM in plant atmmphen (weekly avenge) Mmmrj 1974 {pcrulUn -ISO My1975 (jarttfJQ*) --5 DISCUSSION Dr M D Kipling (Employment Medical Advisory Service, Birmingham) said that it was known that workers bagging the PVC powder were sometimes covered with the dust and that this powder contained mVCMemmiora VCM product 3QQ-5QQ0.7J% ofoutput 0J%ofoutput <50 formost a percentage of vinyl chloride monomer. He asked whether any information was available on the panicle- size ofthe dust produced in differing processes through fmbHcrnttemmnd list VCM ia plant atmotphewa 3-15 VVCCMM iian PbaVrCerbaoctotle* -50 0.1 <2 ~z 001 out the world and the incidence of vinyl chloride Mr A W Barnes replied that the particle sizes of PVC powder did vary very widely, depending on the application for which the PVC powder was made. Finally a few rough calculations of the daily However, most manufacturers produced all grades of dosages at the current exposure levels and at the polymer so that it was unlikely that any medical higher atmospheric levels which previously could conditions peculiar to a particular manufacturing site have existed on PVC plants may be helpful in could be explained in terms of the polymer and its putting current plant performance and present particle size. Moreover, it should be remembered thut, 3 downstream exposures into perspective, one with another, and in comparison with earlier figures (Table 2). all the significant medical effects under discussion at this conference (angiosarcoma, acro-osteolysis &c.) had, throughout the world, been observed exclusively in workers on polymerization plants or, in two cdflk Table 2 Pily <mi(iiattrad and aariiampiiaura krtb Daily dot* (likebed? plants handling liquid vinyl chloride under prcs^^y Features common to all these workers were that they were exposed to vinyl chloride vapour in the atmo sphere but were not exposed to PVC dust since the polymer was maintained in aqueous suspension throughout this stage of the process. Potymcrixation plant operator at 1000parts/10* 0.36 It was in the drying and bagging sections of the FolymariiationplantopaatoruSOOpans/IO* Ol)S, PVC-producing process that exposure to soiid PVC PotyntttitaUon plant operator now mi particles could arise but, despite extensive medical --J parts/10*. Fabrication plant operator at I patt/lO* Awznm UK citizen through ingestion in food OlOOIS 0.0004 0.000000004 investigation, no significant abnormalities had been found among drier operators or packers. It was u1 perhaps worth noting, too, that the greater proportion of PVC powder was of a particle size similar to sand 0) 3 i In later papers to this conference, a wide range of diseases or symptoms which have been associated with or attributed to exposure to vinyl so it did not generally pose an airborne dust problem. For those powders which might cause true dust ex posures it had been customary in industry, because of N> O U1 3 chloride will be discussed. It is important to note the nuisance and discomfort factors alone, to provide that most, if not all, of these have been contracted some form ofrespiratory protection. by people who worked under conditions repre Dr C S Darke (Royal Infirmary, Sheffield) said that he i sented by the highest figures in the above table. had investigated 14 cases of breathlessness in workers Today no one is exposed to doses at this level. The exposed to vinyl chloride monomer. The findings were: exposure of workers in industry is now at least no abnormal physical signs; chest radiographs two orders of magnitude lower, while the general normal; routine respiratory function tests difficult to public in the UK absorbs, through foodstuffs, a evaluate but some results slightly below predicted JS quantity which is some fifty million times lower. values, especially impaired CO diffusion in 6 indi viduals; perfusion and ventilation scans showed w i While the conference will be concentrating striking abnormalities as illustrated by one slide re vealing marked perfusion defects of uoper lobes. One primarily on problems which have occurred in the patient underwent open biopsy of each of the thrps past, I hope it may find some time to consider lobes of the right lung. Histology revealed focal whether there remains any possibility of similar alveoiar wall thickening with macrophages in the effects occurring at the markedly lower - and in alveolar spaces and increased reticulin and collagen ^*'ArtHiiiigrnfirrrttilttft*-'--^*^^*^^**^*-*- ',>>a^>^--^..>.i ., ~=-.MiNfftH*w 22 wer-levels this, quite generally, !$t eighteen al Advisory known that j sometimes sr contained He asked - the particle' -ses throughayl chloride aresofPVC ing on the was made, ill grades of my medical acturing site mer and its inhered that liscussioc at eoh-stf^.) iexflpiy j> two Eases, ler pressure. se that they a the atmoat since the suspension tions of the > solid PVC five medical es had been ers. It was r proportion iilar to sand jst problem, rue dust exr, because of 5, to provide isaid that he s in workers tidings were: radiographs s difficult to w predicted l in 6 indiins showed me slide ret lobes. One of the three vealed focal jges^fethe ind ^^Ken 23 Section ofOccupational Medicine 281 formation seen on electron microscopy. No obvious Dr KS Williamson vascular abnormality except on fluorescent examina (ICILtd, Central Medical Group, tion. It might be of importance that some of the worst. Fulshaw Hall, Wilmslow, affected men were concerned in a polymerization Cheshire, SK9IQB) process that yielded `plastisol', a very fine PVC powder with particle size around 0.5 fun. These particles, containing vinyl chloride monomer, could be carried to the alveolar walls where they might be retained and thus set up a reaction of the type seen on light microscopy. ReviewofAnimal Studies Since vinyl chloride is a gas at norma) -temperature and pressure, inhalation is the important route of exposure in industry, and most animal studies have used this method of dosing. Many experi Professor IJ Setikivff{Mount Sinai School ofMedicine, City University of New York) said that pulmonary abnormalities had been unexpectedly common findings among some 1200 vinyl chloride- polymerization workers in his studies. Obstructive pulmonary function defects were noted in approximately 50%. Neither age nor cigarette smoking served to explain the findings. For those under age 40, obstructive findings were predominantly among cigarette smokers, mental studies have demonstrated the very low acute toxicity of the compound. The acute in halation toxicity was studied by Masrromatteo et al. (1960), who found that the lethal concentra tion for mice, rats and guinea-pigs exposed for 30 minutes was between 200 and 300 000 parts/10*. In long-term studies few toxic effects were re ported, though Torkelson et al. (1961) found that as expected. After that age, however, the prevalence inhalation of vinyl chloride resulted in minimal of changes was very much the same among smokers and nonsmokers. Of course, age correlated strongly with duration of employment. These two factors were analysed separately and it was found that the changes were generally among smokers with less than 20 years from onset of exposure, but that thereafter they were present in both smokers and nonsmokers. Radio- microscopic changes in the liver and kidneys of several species of experimental animals exposed seven hoars a day to 500-200 pans/10* for sixmonth periods. No significant changes were . found in any species exposed to 50 parts/10* for six months. graphic changes were less common. Overall. 13.3% of 985 chest films showed linear, reticular or nodular In 1971, however, Viola et aL reported that changes characterized as 1/0 or 1/1 in the ILO U/C while attempting to produce acro-osteolysis in Classification. Dyspnrea was uncommon and signs or symptoms of chronic bronchitis were. hot striking (Milleretal. 1975. Miller 1975). The pathogenesis of these abnormalities was not clear. It was not known, for example, whether they reflected another biological change associated with exposure to vinyl chloride monomer, or another factor. Mr A W Barnes had noted that manufactured PVC might currently contain 5 parts/10* of retained rats, they had found tumours of the ceruminous glands, lungs and bones in animals exposed for 4 hours a day, 5-days a week, for 12 months to 30 000 parts/10* of vinyl chloride. Viola's findings, which are the earliest to be published describing the oncogenic effect of vinyl chloride, caused considerable concern throughout the world and led to further epjdemiological and animal studies, vinyl chloride monomer, as well as other agents added many of which are still incomplete. The most In the polymerization process. Inhalation of such PVC complete series of animal studies available to' us particles might be associated with adverse effect Frongia and his colleagues (1974) had reported significant histopathological changes in the lungs of guinea-pigs exposed to PVC powder in a PVC plant. In- the polymerization facilities investigated by Professor Seiikoff, there had usually been opportunity for PVC dust exposure as well as vinyl chloride are those conducted by Maltoni and his coworkers (Maltoni 1973, Maltoni & Lefemine 1974). In these experiments groups of rats were exposed to vinyl chloride vapour concentrations ranging from 10 000 to 50 parts/10* for 4 hours a day, 5 days a week, for 12 months. The animals exposure, either by a period of work with the polymer were then maintained for the rest of their Jives during the employment span and/or as the result of incomplete separation of the various parts of the production process. PVC dust was often to be found in several parts of the plants. It would seem of interest to study further the in fluence of vinyl chloride and PVC in the experimental animal, as well as the pulmonary status of workers producing vinyl chloride monomer but not exposed to PVC during or after the polymerization process. unless they became ill. Tumours of the cerumi nous glands, angiosarcomata of liver and other organs, nephroblastomata and a variety of other tumours were found in animals exposed to vinyl chloride. In animals exposed to 50, 250 and 500 parts/10* the logarithms of the numbers of animals having angiosarcomata and the total tumour-bearing animals are linearly related to the dose of vinyl chloride, but in animals exposed to REFERENCES Fnwtia N, SpiitAZzoU A A BaeartUi A (1974) MedicUtg del Lavoro 65* 321-342 Miller A (1975) Environmental Health Perspective 11* 247-250 Miller A, Ttirvtein A S, Chuimc M it Seiikoff IJ (1975) AttmUsa/the New York Academy ofSciences 246* 42-52 higher concentrations, this relationship is not found. Tumours have also been found in mice and hamsters by Maltoni and by Kcplinger et al. (1975), who reported the findings of angio sarcomata and lung adenomata in mice exposed r 282 Proe. ray. See. Med. Volume 69 April 1976 24 by inhalation to 2500, 200 and 50 parts/10* of vinyl chloride. More recently brii Maltoni et al. (1975) and Purchase (1975, personal communica tion) and his co-workers have- found liver tumours in rats given high daily oral doses of vinyl chloride in oil. Neither investigation is completed yet. Maltoni et al. dosed Sprague Dawley rats daily by gavage at 50, 16.6 and 3.3 mg/kg for 12 months. They reported the occur rence of one angiosarcoma of the thymus in the 50 mg/kg group and one angiosarcoma of the liver in the 16.6 mg/kg group in an interim report approximately 13 months after the start of the experiment Purchase and his co-workers dosed Wistar rats daily by gavage at 300, 30 and 3 mg/kg for 6 months. Fourteen months from the start of the experiment, a large proportion of the animals in the 300 mg/kg group and several of those in the 30 mg/kg group have been found to have liver tumours. Preliminary histopathological work suggests that some of these tumours are hepato cellular carcinomata, though further work is necessary before this can be confirmed. To facilitate comparison between the dosage of vinyl chloride received by the animals in thesevery different long-term experiments, I have made some simple calculations which are presented in Tables 1 and 2. These calculated doses make no allowances for possible differences in the amount of vinyl chloride retained in inhalation and oral dosing experiments, and because of their low inherent accuracy are no more than rough guides to the doses involved. Tablel Katmbnltthnttaiiet (data ofMaltoni) Ventilation--100 ml air/min 6 litia/hour 24 Uucx per4-hotir expoiure period--0.024 m* Waiyht ofrata auumed lo be 300 ( Parts//O* 300 230 30 ^ Atwtoldost Dallydot* (my) Doily dot <glkgHdaily mg/nd(0D24 x mg/m1} (mg/kg) dose x 250) 1230 30 625 13 123 3 SO 13 30 7.3 S US Table 2 Rat ont doaiat radian It is of some interest to compare the do" received by animals in long-term studies with calculated theoretical doses for men exposed to various shift-average concentrations of vinyl chloride at work (Table 3). Again the calculated figures are no more than very rough indications of dose, but they do give a useful measure for assessing the animal data. Table 3 Mf* tt work Ventilation -- I0m*air per I-'hour shift Weight usuto be 70 kg Panel IIP 500 loo 3p 10 1 Daily dote mg/m* (my/m* x. 10} 1230 230 123 23 ZJ 12 500 2300 1230 250 23 DeUydcsc Imglkg) 180 40 18 4 0l4 AmmtoldoSw (?lk*)(*cUy dose x 250) 44.6 1.9 4eS OS 0.1 Green & Hathway (1975) and Watanabe et at. (1975) have studied the pharmacodynamics and metabolism of vinyl chloride using UC-la belled material given by different dosing methods to rats. Both groups have shown that the proportion of the dose retained and metabolized is greater following smail doses than large, though the absolute amount metabolized falls with diminish ing dose (Table 4). Table 4 AiROttiti(*iiy) chhrid* mitabalLfd ittir differing tingle doee* giwt orally in cwni oil (Green Jt Hathway !975) Das* (mg/kg) 430 300 30 3 1 0.23 Percentage natabollxed * 12 46 <9 86 ML3 metabolised (my/icy) 36 36 1U 2.1 OX6 0L24 Three principal eliminative routes have been identified by both groups: expiration of un changed vinyl chloride by the lungs, expiration as CO, by the lungs, and excretion of metabolites in the urine. The proportion of vinyl chloride eliminated by these different routes varies with dose (Table 5). Study Maltoni (230doles) Dailydan (m*/kg) SO 16.6 3.3 Total dose (t/kg) 12.39 4.09 0-8 Tables Proportion of a ainyie oral do of riayt dtloridt eliminated by tarioai route* (Green & Hathway 1973) PuictUM 300 <123 doses) 30 3 ) tumours found 37.39 3.79 0.4 Date Proportion eliminated (TO lyng/kg) Unchanged Co, Owe metaaalites 0.23 4 430 92 12 73 IS doses with sed to vinyl tilated ations tre for tetal. as and. shelled to rats, cion of greater gh nir r been of unpiration abolttes chloride ies with ill 25 Section ofOccupational Medicine 223 Major metabolites identified in the urine are: (I) thiodiglycolic acid; (2) S-(2-chlorethyl) cysteine and N-acetyl-S-(2-chlorethyl) cysteine: (3) urea. Thiodiglycolic acid is derived from monochloracetic acid (this can itself be detected in small amounts in the urine) which in turn might reasonably be supposed to derive from cyclic chlorethylene peroxide or epoxide, powerful un stable alkylating agents which..though likely to have a very short life within the body, must have high potential biological activity. The cysteine containing metabolites may be presumed to arise by the reaction of vinyl chloride with cysteine derived from glutathione. Since the size of the glutathione pool may well be limited, vinyl chloride could cause significant depletion, so . reducing the available protective mechanisms within the liver cells. Watanabe et ai. (1975) have reported progressive depletion of the hepatic nonprotein .sulphydryi content (equivalent to gluta thione in this context) in rats exposed to 1000 and 250 parts/10* vinyl chloride by inhalation. No such depletion was found following exposure of rats to 10 parts/!0* for 7 hours. Hathway (1975, personal communication) considers that the ethyl cysteines themselves may well be mutagens. Thus work on the metabolism of vinyl chloride has already begun to identify several interesting areas for further investigation. Though many important animal studies are still incomplete, there is already a substantial body of evidence to show that vinyl chloride is oncogenic, and there are some intriguing indica tions of the possible mechanisms of this action. The further studies which will be available in the near future may well help us to define working conditions which will not present health hazards to men exposed to vinyl chloride, and may perhaps allow us some insight into the fundamental mechanisms of the oncogenic effect. REFERENCES GnnTtHulmyDE (1975) Chemleo-biologiealInteractions II, 545*562 KtplliiccrML.Good*J W Gordo*DC&OtiiminJC (1975) Annals 0/the Hew York Academy ofSciences 246* 219-224 MoitooiC (1973) Excerpta Medico International Congress Series 275.4 Mfltow C CUiberti A, Giunt L Sl Chioeo P (1975) Cll Ospedati della Vita 2.65-46 Maho*iC&LtfcmmeG {1974) Uneei-Jtendiconti drila Classe dl * ScienceFlsiche, Matematichee Natumii56.1-II Mwiwttto . Fisher A M. Christie H & Dantiftr H (1960) American Industrial Hyeten* AssociationJournal21* 394-398 Terkehon T R, 0>n F Si R<nv V' K (1961) American Industrial Hygiene Association Journal 22.35^*361 VioU P L, Bitottj A & Capufo 4 ' (1971) Cancer ArtrarcA 31. 516*522 Wgtuabt P G, Hefner R E ir McGowan G R St Gthrift* P J (1975) Progress Report to Manufacturing Chemists Association Task Group on Vinyl Chloride Research. Washington DISCUSSION Dr L Magos (MRC Toxicology Unit, Carsholton) said that the dose plotted against the log of the number of malignancies gave a straight line, making it very difficult to draw any conclusion about the threshold or no-effect level, as the zero-effect level could theoreti cally never be reached. Secondly, Dr Williamson's data on the metabolism of vinyl chloride depending on dose indicated that at low exposure levels a high proportion of vinyl chloride was metabolized and less was exhaled un changed. This might mean that increasing exposure above a certain level would exhaust the biochemical ability of the organism to convert vinyl chloride to a toxic metabolite responsible for the carcinogenic effect. These considerations indicated that experimental data must be interpreted with the utmost care. Dr H Stokinger (Toxicology .Brancft, National Institutefor OccupationalSafety and Health. Cincinatti, Ohio) said, in amplification of Dr Williamson's remarks on metabolism of vinyl chloride, that two metabolites had been identified in the liver of rats exposed to vinyl chloridc: N-acetyl-S-(2-hydroxyethyl) cysteine and thiodiglycolic acid. The importance of knowing the nature of these endogenously supplied moieties was that they represented free, available sul phydryl (SH) groups that acted as 'scavengers' of the vinyl free radical, thus removing its oncogenic poten tial. In a series ofdecreasing exposures of rats the find ings were:at 1000 parts/10*, rapid and complete satu ration of available free SH groups (liver); at 200 and 100 pans' 10*, fairly rapid saturation of available free SH groups: at 50 parts/] 0*. a plateau of the saturation curve; at 10 pans/10*. no disturbance in the amounts of free SH. Inferences and conclusions: (I) From the fact that hsemangiomas occurred in the liver, and not in the lung (the primary site of entry), it could be inferred either that little or no vinyl chloride metabolism to free radical occurred in the lung, or that there was ample free SH to scavenge the vinyl radical. 12) Most important, the liver had a built-in antagonist to the vinyl free radical that provided the basis for a threshold for the carcinogenic response, in this case a threshold for an occupational carcinogen demonstrated by a specific biochemical constituent reaction. This finding explained the fact that among the tens of thousands of workers exposed only a small handful of hemangiomas had been found. (3) Finding an oncogenic threshold of appreciable magnitude (between 50 and 10 parts/10*) removed concern about general exposure of the public to small amounts (see Barnes, p 2S0) of vinyl chloride in PVC plastic wrappings of foods: the. United States FDA could forget it! (4) To bolster resistance to effects of vinyl chloride, vegetables of the Brassica family should be eaten. Factors reducing free SH were: certain industrial exposures that were detoxified by cysteine, e.g. brombenzene; substances or condi tions, e.g. certain chronic diseases. 4 fTiirrp .... 284 Proc. roy, Soc. Med. Volume 69 April 1976 26 Clinical Aspects of Vinyl Chloride Disease Methods All patients had the following regions exam by plain film radiography: hands, feet, shoulders, elbows, knees, ankles, pelvis, chest, skull, man Dr B J Preston, Dr K Lloyd Jones ' dible and spine. Case 1 (AD) also underwent a barium swallow, meal and follow-through, angio and Dr R G Grainger graphy of the hands and serial films of the hands (Departments of Radiology and Rheumatology, at 6 months and 2 years after presentation, and a Harlow Wood Orthoptrdic Hospital, film of the pelvis at 2 years. near Mansfield, and Department of Radiology, Northern General Hospital, Case Reports Casel Sheffield) , A D presented at the age of 35 years with symptoms of severe Raynaud's phenomenon, pain in many joints, Aero-osteolysis The word acro-osteolysis means dissolution of the extremity of a bone and it is applied to the distal phalanges of the hands and feet. There are many causes, e.g. scleroderma, psoriasis, hyper parathyroidism, sarcoidosis, ergotism, diabetes, tabes, syringomyelia, familial and idiopathic acro-osteolysis. A similar appearance may occur trismus, and thickening and tightness of the skin. He had been engaged in the polymerization processes of vinyl chloride for 5) years. A radiograph of the hands (Ftg 1) showed dissolution of the central parts of all the terminal phalanges except for the little fingers, erosion of all the terminal tufts, thinning of the central parts of all the middle phalanges but particularlythose of the little fingers where there is extension into the base, thinning of the middle and distal parts of the as"a result of trauma. Recently, acro-osteolysis proximal phalanges of the ring and little fingers and of the hands of workmen associated with vinyl erosions with a well-defined sclerotic margin at the chloride polymerization processes has been re base of the right first metacarpal and at the tips of 33 corded by Cordier et al. (1966), Wilson et at. (1967), Harris & Adams (1967), Dinman et al. both ulnar, styloid processes. In addition, seft tissue thickening was present over the wrist .and the whole of the hand. A film of the feet showed acro-osteolysis of (1971), and Langee/tf/. (1974). the terminal phalanges of both big toes, a large <D erosion in the head of the left first metatarsal bone We would' like to present' the radiological and small erosions in the head of the right first - findings in four patients who had been involved metatarsal bone and the right medial and intermedjMc oro in the production of polyvinyl chloride. cuneiform bones. The radiograph of the cn 00 ; Fig 1 Case I Hands (U.73), showing transverse defects in distal phalanges, osteolysis, erosions andsoft tissue thickening ^WviJlJUU' isjsvxm -WW'I Al ------ 26 9ving; reeggTioonr s examined hands, feet, shoulders, vis, chest, skull, man^D) also underwent a follow-through, angiptrial films of the hands ter presentation, and a 5 years with symptoms of on, pain in many joints, tightness of the skin. He /merization processes of radiograph of the hands f the central parts of all pt for the little fingers, a, thinning of the central ilanges but particularly x there is extension into Icand distal parts of the eg and little fingers and sclerotic margin at the irpal and at the tips of In addition, soft tissue ie wrist and the whole of .sowed aero-osteolysis of both big toes, a large :ft lint metatarsal bone head of the right first medi^fcd intermediate iograHKsf the pelvis 5S a 3 27 Section ofOccupational Medicine 285 some healing as there was new bone formation at the tip of the distal phalanx of the left big toe. However, the erosion at the head of the right first metatarsal bone had progressed in size over the 2-year period. The film of the pelvis two years after presentation showed a slight increase in the size of the erosions of the ischial tuberosities. In view of the patient's persistent and increasing symptoms and signs in the hands, arteriography of the hands was performed and it was done under general anesthesia. The large vessels were patent but in the left hand there were occlusions in the digital artery on the ulnar side of the thumb and radialis indicis artery of the index finger, and narrowing of the digital artery on the ulnar side of the little finger. In the right hand. Slight narrowing and tortuosity of the radiafis i indicis artery and medial digital artery of the little finger was shown. In both hands, hypervascularity of the terminal tufts was recorded. i -I i Case 2 .1 F P, aged 38 years, had been engaged for two years in the manufacture of polyvinyl chloride. Acro-osteoiysis was recorded in both index fingers and the right thumb. Erosions with a well-corticated margin were visualized at the base of the right first metacarpal bone, medial epicondyle cr the left humerus and inferior poles of the left patella. Some increase in the soft tissues was noted and this is best assessed by observing the region over the radial and ulnar styloid processes.' revealed large erosions around both sacroiliac joints. Case 3 i li / at the tips of the greater trochanters and along both ischial tuberosities. The radiographic survey of the peripheral joints recorded erosions at the lateral end of the left clavicle, left upper humerus, medial and lateral epicondyles of the right humerus, medial D D, aged 28 years, had been involved for 2 years in the processes of polymerization of vinyl chloride. Th; skeletal survey revealed no evidence of acro-osteofysis or any other significant abnormality. I condyles of the left humerus, both olecranon pno- , cesses, inferior parts of the patella, both lateral femoral condyles and anterior aspects of the tibia, both medial malleoli and posterior aspect of the left calcaneum. . Films of the mandible (Fig 2) revealed considerable erosion of both ascending rami, causing marked thinning of the bone; on the left side this extended up wards to involve the condyle. Films of the skull and spine and barium swallow, meal and follow-through examination showed no abnormalities. Monitoring films of the hands and feet were taken at six months and 2 years after presentation and these showed interesting changes. At 6 months, the films of 3J the hands recorded the following changes: (a) central defects in the distal phalanges of the little finger; (6) S (/) further osteolysis, particularly of the, bases of the distal phalanges; (c) periosteal reaction along the proximal phalanges of the left thumb and index finger, and right ring finger; (d) shortening of the distal part of the finger. Radiographs of the hands taken 2 years after presentation showed even further ro oin CD resorption of the bony fragments of the distal pha langes, and the proximal fragments appeared dense thus suggesting avascular necrosis. Serial films of the feet showed extension of the acro- osteolysis of the big toes in the first 6-month period (Fig 3) but on the 2-year film there appeared to be wg.fHW.iw n ficje,, n. i'i ,.j ' 'j f 236 Proc. roy. Soc. Med. Volume 69 April 1976 28 Case 4 D W, aged 44 years, had been working at the factory for five years. The skeletal survey did not show aeroosteolysis or any other significant abnormality. Discussion These 4 cases show the wide radiological spectrum that may be encountered in men complaining of symptoms which could be related to their work in the polymerization of vinyl chloride. In Cases 3 and 4, no specific changes were encountered: in Case 2 only moderate changes were recorded whilst in Case 1, extensive bony changes were documented. Indeed, in Case I, most regions of the body were involved and a review of the litera ture revealed that no previously reported case had such extensive bony changes. It has been suggested that personal idiosyncrasy , may be an important factor in the wide variation of the radiological findings (Wilson etal. 1967). The changes in the mandible in Case 1 have not been previously described in occupational acro-osteolysis but it is interesting to note that atrophy of the mandible in idiopathic and familial acro-osteolysis has been recorded by Greenberg & Street (1957), Papavasiiiou et al, (1960), and Cheney (IS65). Ross (1970) stated that the bone changes regress after the sufferer is removed from the hazard but in our Case I the serial films of the hands, feet and pelvis indicated that the acroosteolysis was extending. Fragmentation of the remaining tufts has been described as part of the healing stage by Wilson et al. (1967), but in our Case 1 it was only in the distal phalanx of the left big toe that there was any definite evidence on the 2-year film to indicate bony regeneration, ' The stenoses and occlusions of the digital arterics-and increased vascularity in the pulps of the fingers recorded on the arteriograms in the first case have also been reported by Lange et al. (1974). Narrowing and occlusions of the digital arteries are known to occur in Raynaud's phenomenon (Marshall et al. 1966). Certainly, the disability due to the Raynaud's phenomenon in our case seemed out of proportion to abnor malities in the vascular tree. Lange et al. (1974) suggested that the dense vascular rete of the terminal pulps of the fingers was due to stasis of contrast in the vessels secondary to the shortening of the phalanges. This may be partly the case but Laws et al. (1967) have observed hypereemta of the pulps of the fingers in a case of clubbing due to bronchial carcinoma and a similar mechanism may apply in our case, as there is a strong dinical resemblance to clubbing. REFERENCES Cheat? W D (1965) American Journal of Roenttenoloey M, 595-617 Cottficf J M* Fiem C, Ltfttrt .\1 J & Stvmi A (1966)Cahitrsde Mcdecmettu Travail 4, 14*19 Dirasii B D, Cook W A* \> huthous* W M, Magneton HJ4 DUcktkT(l97l) Archives of Environmental Health 12, 61*73 Greenberg B & Strati D M (1957) Radiology 69* 259*262 HarmDK1 Adams WCF (1967) British Medical Journal iii, 712*7f4 Lance C E* Jlih* 5, Sinn G & Veltman G (1974) internationolrt Arcmvfur Arhcitsmeditin 32, 1--32 bft J W, Cl Sallab R A & Scott J T (1967) British Journalof Baatr.logy 40,740-747 MarshallTR,Neestadt D, Chwmley WF4 KasdanM L ()966> Radiology 86,299*303 PapavasiiiouCG,Garcano Wallis W L (I960) American Journal of Roentgenology 92, 637-691 Ross J A (1970) In: Symposium Ossium. Ed. A M Jelliffc & B Strickland. Livingstone, Edinburgh 4 London; pp 321-324 * Wilson R H, McCormick W E, Tatum. C F & Creech J L (1967) Journal ofthe American Medical Association 291,577-581 DISCUSSION Dr L Magos said that Dr Preston's Case 1 might be idiopathic acro-osteolysis aggravated by exposure to vinyl chloride. In the two-year follow-up study Dr Preston had found improvement in the fingers, which were usually involved in occupational vinyl chloride acro-osteolysis, and deterioration in the pelvis. Dr B J Preston replied that idiopathic acro-osteolysis was considered in the differential diagnosis of Case 1 but the distribution of the bony abnormalities other than those in the hands was different from those recorded in idiopathic acro-osteolysis. Dr K Lloyd Jones added that Dr Preston's Case 1 all had severe involvement of the skin by the sderodermS tike condition seen in vinyl chloride workers together with, evidence of other multisystem involvement. It was most unlikely that this combination in a vinyl chloride production worker (autoclave floor worker) would be due to idiopathic acro-osteolysis. It was not considered reasonable to submit this patient to biopsy of the defects in the distal phalanges. Biopsy of the lesion in the mandible had been unrewarding. He was employed as a production worker in a PVC plant and had never been exposed to vibration or the use of power tools. Dr Anne E Walker {Royal Hospital, Chesterfield. Derbyshire) Clinical Aspects ofVinyl Chloride Disease: Skin Industrial acro-osteolysis, a triad of Raynaud's phenomenon, sclerodermatous skin change and lytic bone lesions, has been well documented as occurring in workers engaged in the poly- i.l| iMfjwjijP.1 rmnjUSJ. 28 it *a -T-.-n -am u L iffeA M -3J4 " L I.-377-SS1 ,,_ 1 might be xposure to study Dr gen, which yl chloride .,`s. o-osteolysis s of Case 1 il**U other from those :leroderma;rs together '.vement. It in a vinyl jor worker) . It was not if to biopsy opsy of the mg. He was C plant and the use of kaynaud's change and umented as the poly- 29 Section ofOccupational Medicine 287 mcrizatioti of vinyl chloride monomer (VCM) to `rubbery-legged', and this suggested that the men polyvinyl chloride (PVC). Medical surveys of had been intermittently exposed to very high large numbers of employees have shown an levels of VCM, which in experimental studies incidence of approximately 3 % (Wilson et al. produces anesthesia. These symptomsuvere most 1967, Dinman etal. 1971). Both these.studies.nlso frequently experienced when men,were hosing suggested that the disorder was largely confined down the reactors during emptying, but also by to reactor cleaners. men when inside cleaning the empty reactor, and by maintenance men when unblocking pipes In 1974 Lange et at. described a more general carrying VCM. ized disorder affecting men engaged in the manu t facture of PVC. They observed splenomegaly, None of the 37 men had evidence of sclero thrombocytopenia, liver damage and impaired dermatous skin change. One man previously respiratory function, and these changes occurred employed at the plant had extensive sclero both in the presence and absence of clinical and dermatous skin change affecting the hands, fore- radiological evidenceofacw-ostecdysri. -.aeons, face, trunk, thighs and .dorsum of the feet; . additionally he had-extensive lytic-lesions of the " CuiUnalStudy Atones, phalanges, feet, pelvis.and jaw (K Lloyd- In. February 1974 I saw one man with severe Jones, personal communication). In 5 men there Raynaud's phenoavt.... ; :*-;s ^ r-C: ~ ^"tagmenon; in die fingers but ncv`cv.u-.i: '`osjiimsf Iv.-? 4 r. -.4, ;\------ v..... ">' '. occur was employed as a reactor operator at a local ring colour changes from blue black to blanched firm which manufactures PVC. Between February white to a flushed pink. Individual fingers on the 1974 and February 1975, 36 of the men employed same hand might show a different colour change at this plant were referred with symptoms thought at any one time; on one occasion I observed a to be due to exposure to VCM. harlequin effect: the index finger was blanched white on the radial side and blue black on the The study covers 37 men aged between 26 and ulnar side. Eight other men described symptoms 59 years (average 40 years 2 months). Length of of Raynaud's phenomenon but at .examination employment at the plant ranged from 9 months only had rather cold hands. Coldness of the feet to 5J years (average 2 years 8 months). Thirty was a common complaint, but difficult to evaluate workers had at some time been reactor operators, clinically. 4 were maintenance men, 2 worked as `baggers' and 1 wasa warehouseman. During the last year 4 men have shown some thickening of the skin with limitation of extension The presenting symptoms arc shown in Table 1. of the fingers and mild `clawing' of the hands. The commonest complaint was of excessive These changes become more marked when the fatigue: men claimed to be excessively fatigued hands are cold. after minimal exertion and also reported somno lence. Coldness of the hands was also a frequent Of the 37,4 developed a curious swelling of the complaint. face, largely periorbital and tending to improve in .warmer conditions; the swelling ^vas firm, and Obviously these subjective symptoms were suggestive ofsdercedema rather than scleroderma. difficult to evaluate or measure. However, one MmLj&atv&Mi.noteworthy: 36 of the 37 stated that Skin biopsies were obtained from the dorsum r - on?ar-teast one occasion they had felt overcome of the hand in 15 men. Thtk-ejudermis and by the vinyl chloride fumes, describing them adnexal structures showed no abnormality. In the selves variously as `unsteady', `slightly drunk' and dermis there was some destruction of elastic tissue, but it was probably a normal age change. Tablel Pm*otb| irwtosain 37 mn In one man with severe Raynaud's-phenomenon the dermal arteries showed some'niedial thicken ing. Symptom So. ofcasts Cold hands hnsltm Impaired grip powtf Cold feet Achcsinbom Achcv ia nuiadt* Dyspnoa Eiccuiv* fuieue Louoflibido 30 16 IS 16 30 IS 17 32 |) Arteriography of the brachial arteries was ,, carried out on 4 men. In the one man with severe sclerodermatous skin change the digital vessels in all the fingers were almost totally occluded. In the other 3 men there was patchy occlusion of the digital vessels, mainly in the ring and little fingers. 33 (/> ro o CT> i t .7 j l f- m. i i y- t r | rJ & % lt i 'I :sj I 4 I $<6 $ *? 30 C C/> to o o IO -S i j `A i \ v3 i ; :| M -/ < f^nWi-iifcfctafcw; witi ifirimki* *4 238 proc.roy.5Soc. Med. Volume 69 April 1976 30 Blood flow measurements assessing total Anger blood flow and capillary flow were performed on a small number of men. In 5 men capillary flow fell abnormally on cooling and was slower in returning to normal on rewarming. In 3 men total finger blood flow was also abnormally reduced on cooling and slower to return to normal. Immunological studies have shown a high level of cryoprecipitate in the symptomatically affected men (A Milford Ward). REFERENCES Cordier JM,Firtfi C,LdtvnMJft Srma A (1966) Carters de MJdecine du Travail 4, 6 Diomid BD, Cook W A* Whittbovt* WM4 Mitwign H J (1971) Archives ofEnvironmental Heaith 22, 61*73 Harris DK6 Adimt WCP (1967) British MedicalJournals* 712-714 Line* C E, Jvhf S, Stein G it Veilmin G (1974) Internationales Arehtvfur Arbettsmedixin 32, 1 Markowitz S S, McDonild C J, Fethiere W it. Ktnatr M S (1972) Archives of Dermatology 106,219 Sarin I, Drcjmirt 1 it Viiiski M (1963) Medicine Interna (Bucharest) 15,967 Tikondii Y it Mabuchi C (1973) Japanese Journal ofIndustrial Health 15,385 Wilson H, McCormick W E, Tatum C F & Creech J L (1967)Journalofthe American Medical Association 201,577 Discussion In the survey of 37 men, of whom at least 36 appeared to have been exposed to high levels of vinyl chloride monomer on at least one occasion, DISCUSSION sclerodermatous skin change was not observed. Dr Leo Djerassi (Department of Occupational Medi However, 5 had severe Raynaud's phenomenon cine, Haifa, Israel) said that in one patient in his series and at least 3 others had abnormally cold hands the presenting syndrome of vinyl chloride disease was which interfered with their normal dexterity. These circulatory changes are only a part of a generalized disorder which may result in dyspnoea, cramp-like pains in the limbs, paresthesia, exces a pals moonlike face. This particular type of sdercedema (not scleroderma) had already persisted for five years after exposure had ceased. In one case of scleroderma-like syndrome a skin biopsy showed no change in elastic or fibrous tissue sive fatigue and, in some cases, impaired liver i but several areas of perivascular infiltration, small function. The symptoms may be severe enough to round nuclear cells, mostly lymphocytes and larger limit normal activity and may occur without mononuclear elements. changes in the hands. In one case of Raynaud-like phenomenon which started about eight months after initial exposure, the The relative sparsity of clinical change in the skin or evidence of pathology on biopsy contrasts with the marked sclerodermatous and plaque-like changes described by others (Cordier et al. 1966, Harris & Adams 1967. Wilson et al. 1967). Perhaps the early recognition and removal from manifestations usually appeared two or three hours after work began, and the full-blown phenomenon could be observed on the shop floor. This same pati$egt left the factory because of loss of libido, and Djerassi wondered whether this was an immed transient complaint due to the narcotic effect of vinnyvT! chloride monomer, or a prolonged disturbance con exposure prevented more severe skid change in nected with the vinyl chloride disease as stated by the men under observation. Most of the above Dr Anne Walker. authors observed improvement in the sclero dermatous skin change on preventing further exposure. However, in one case described by Harris the skin change appeared to resolve spontaneously whilst the man continued working. Dr Anne Walker, in reply, said that the sclercedemalike change observed in 4 of the men varied consider ably from day to day but in two men had persisted for at least eighteen months after the last exposure. In 13 biopsies from 13 patients an excess of inflam In my series there has been little improvement in the vascular signs during the period of ob servation, and this is in accord with the findings matory cells in a perivascular distribution were present in 4 of the specimens. The cells were largely lympho cytes. Loss of libido was the presenting complaint in one of others (Adams 1974, personal communication and M N Johnson 1973, personal communica tion). However, Sudu describes the disappear ance of Raynaud's phenomenon within one year (Sudu et al. 1963). In two instances cervical sympathectomy is recorded as produdng clinical patient and had persisted since the man left the firm approximately three years ago. In 3 of the workers complaining of impotence, unnary excretion cf androsterone and dihydroepiandrosterone were very low. These measurements were made approximately twelve months after the last exposure to vinyl chloride. improvement (Takouchi &. Mabuchi 1973, Dr Marcus M Key (University of Texas School of Markowitz //. 1972). Public Health, Houston, Texas) asked if baggers and At the present time it is not known whether the peripheral vascular disorder is directly warehousemen had previously worked as reactor cleaners. related to the presence of circulating immune Dr Anne Walker replied that they had not. Usually complexes or to some other alteration in the men started as baggers and later became reactor sensitivity of the vessels to exposure to cold. operatives and cleaners. The one warehouseman had 30 mKJ (MS .'L M.J77 tonal Medi na his series disease was i of scleraled for five ie & skin jtous tissue tion, small and larger non which posure, the.. hree hours senomenon, unengkf a, aJ^Br unmeante* set of vinyt'1 bance con-; stated by - derademad considermisted for are. s of inflamere present Jy lympho- aint in one eft the firm .'.e workers a of andro- very low. roximately /l chloride. School of ^aggers and as reactor JL Usually me reactor aeman had iTtfttiniAiiiir 'i*rf >vfi'W>iiritfVyi. ItfUtfS f "* if 31 Section ofOccupational Medicine 289 never been in a reactor. One of the baggers had spent an initial training period as a reactor cleaner but had felt nauseated whilst in the reactor. After the first two weeks he had worked entirely in the dry building for four years. The other bagger was an epileptic and had never been in a reactor. Dr Prenrysl V Pelnar (Montreal, Canada) asked what blood flow measurements were done ? Dr Anne Walker said that blood flow measurements were made on 10 men. The subjects were kept in an ambient temperature of 2TC for one hour, then the room was cooled to I0'C for the next hour ana finally the room temperature was raised to 27'C for the final hour. During the three hours total finger flow in the index finger was measured by means of a pletfiysmograph and capillary flow in the middle finger by electrical impedance. Additionally, the skin temperature on the back of the hand was measured. Dr A Milford Ward (Department ofImmunology, Hallamshire Hospital Medical School, Sheffield, S1G 2RX) Evidence of an Immune Complex Disorder in Vinyl Chloride Workers The occurrence of Raynaud's phenomenon and loss of bone density in association with dermal thickening which constitutes the syndrome of acro-osteoiysis (AOL) has been recognized in the vinyl ghloride industry since the mid 1950s. but the overall frequency of the syndrome has been low and no series have been subjected to thorough immunological investigation. Recent studies have indicated that the disease process is not confined to the skip and skeletal tissues, but is a multi system one with involvement of many organs and tissues. Immunological and immunochemical investiga tion of 58 workers from a single factory has revealed evidence of a chronic soluble complex disorder in 21 individuals. The extent and severity of the immunological abnormalities parallels the clinical features to a large extent, but some indivi duals show laboratory evidence of an active disease process at a stage when the clinical features are minimal or absent. Circulating immune complexes were demonstrated in 9 out of 10 individuals who were severely affected clinically; in 7 out of 15 individuals who were symptomatic to a degree that they were incapable of active employment; and in 5 out of 28 indivi duals who were symptomatic but able to work. Immune complexes were not detected in 5 individuals from the factory who were completely asymptomatic. The major features of the disorder include hyperimmunogiobulinremia, cryoglobulinemia and cryofibrinogenasmia, and in vivo complement activation via the classic pathway with C4 and C3 conversion. There is, in addition, evidence for a reduced T cell population, with low spontaneous sheep cell rosette counts, and an increased B-cell population, as evidenced by an absolute increase in lymphocytes showing membrane bound immunoglobulins. The total lymphocyte counts are usually normal or slightly increased. Some patients show non-organ-specific antitissue anti bodies of low time but rheumatoid factor is univemlly negative. Immunofiuorescent examination of biopsy material from skin (8 patients), muscle fl patient) and lung (1 patient) has shown the presence of circulating immune complexes, with deposition on vascular endothelium and occlusion of small vessels. In those vessels which show subintimai proliferation and luminal occlusion, immuno globulin, complement and fibrinogen are present in the subintimai regions of the vessel wall. Experimental evidence on the metabolism of vinyl chloride suggests that at least part may be taken up by the liver and become incorporated into aminoacid synthesis/ The incorporation of the chloride radical into protein synthesis could result in a structurally abnormal protein which would react as antigsnicaliy 'foreign' material. The association of these experimental data with the observed immunological profile allows the construction of a theoretical model of the disease process. The initiating sequence is at present speculative and remains to be proven by further study, but the later sequence of events can be adequately explained by the immunological abnormalities. Structurally abnormal or antigenically `foreign' protein escapes tolerance and incites an immune response with B-cell prolifera tion and hyperimmunoglobulinamia. The immune complex formed by interaction of the antigen and antibody is cryoprecipitable and will activate the complement sequence. The cryoprecipitate and the reactions secondary to complement activation will produce vascular occlusion and fibrinogen/ fibrin conversion and polymerization. The frequency with which abnormalities have been detected in this series, especially in that group in whom there were no overt clinical signs, suggests that the disease process may be more common than generally supposed. The theoreti- fJ l 3, i 3t -3 30 CD o o> CO ISWSf 290 Proc. ray. Soc. Med. Volume 69 April 1976 cal, and at present speculative, initiating sequence of reactions in this disease process also raises the question whether other unsaturated halogenated hydrocarbons may also be involved in a similar chain of events. Further studies are in progress in an attempt to clarify the initiating reaction sequence and to define the precise relationship between vinyl chloride and the observed immunological anoma lies. DISCUSSION Dr Leo Djerassi said that fatty liver might be the early histological change in liver caused by vinyl chloride. In one Of his cases which began with splenomegaly, liver biopsy showed a fatty liver. The patient did not consume alcohol habitually. The finding was not surprising, as chlorinated hydrocarbons were known to cause fatty liver. The clinical development of this case brings us to the evidence of immunological phenomena in those exposed to vinyl chloride, and to the possibility of another target organ-the spleen. Splenomegaly was the first deviation in this case, and increased progressively. Hypersplenism followed.. Splenectomy and splenorenal <hunt were indicated because of (esophageal bleeding. The patient's condi tion improved sufficiently to enable him to work full time on a nonstrenuous job. Dr A Milford Ward replied that the classification used in this study was a clinical one, based on history, physical examination, and an assessment of the patient's ability to continue his employment. 1: therefore included such aspects as spienomegai ,. aero--osteolysis, and scleroderma. t Dr E Vigliani (Milan. Italy) asked whether the presence of B and T in the tissues could be detected by im munofluorescence. ; 1 Dr A Milford Ward replied that iymphoreticular tissue was not examined histologically or immuno- logically so the presence of T and B cells could not be assessed in tissues. T and B cell counts were per formed on peripheral blood. Dr Ruth Lilis (Mount Sinai School of Medicine, New York) asked whether immune complexes were found in the kidney. There were in the literature a number of cases of Goodpasture's syndrome in persons exposed to chlorinated hydrocarbons. Dr A Milford Ward said that renal tissue was not examined. None of the patients showed clinical evidence of renal disease, and it was not considered ethically justified to biopsy the kidney in the absence of proteinuria or luematuria. Antibodies to renai glomerular basement membrane were not detected. Professor Margaret Tutner-Wsrwick (Cardiothoracic Institute, Brampton Hospital. London SW3) asked what was the cause of the T cell depression mentioned, Dr IF H Purchase, Mr C Richardson and Dr D Anderson (IC1 Central Toxicology Laboratory, and whether the spontaneous sheep rosette T cell Alderley Park, near Macclesfield, Cheshire) counts were confirmed by other in vitro tests such as PHA transformation. Chromosomal Effects DO Was there evidence whether C3 conversion was in Peripheral Lymphocytes B triggered by the classical or by the alternative path Vinyl chloride produces liver tumours in animals </> way? Was evidence found of immune complex deposition in capillaries of the skin and lung as well as in the exposed by inhalation (Maltoni Sc Lefemine 1974) or dosed by the oral route (Maltoni et al. ro o larger vessels mentioned ? 1975, Purchase 1975, unpublished). Epidemio logical studies demonstrated that workmen O) Dr A Milford Ward replied that the cause of the T cell exposed to vinyl chloride had an increased risk depression was not clear, but it was a feature often of developing certain tumours, particularly seen in circulating immune complex disorders and in autoimmune states. The low rosette counts were partially confirmed by a mild depression of the PHA reactivity of the peripheral blood lymphocytes. Complement activation in vinyl chloride disease was by the classic pathway with conversion of C4 as well as C3, as would be expected with IgG class antibody directed against the antigenic groupings. hepatic angiosarcomas (Creech Sc Johnson 1974). In common with other carcinogenic chemicals, such as benzene, recent studies have demonstrated that workmen exposed to vinyl chioride have an increase in the percentage of lymphocytes with chromosomal abnormalities (Funes-Cravioto et al. 1975, Ducatman et al. 1975, Purchase et al. Immune complex deposition was found in capil 1975) . Studies of this type carried out on lympho laries and small vessels in skin, muscle and lung. cytes recovered from peripheral biood provide an Dr L Magos said he would like to see the patients classified by grade, since it was always frustrating to read of `severely affected* people without knowing what `severely affected' meant. The grading could be based on degree of splenomegaly, acro-osteolysis. scleroderma <c. easy clinically applicable method of assessing damage to living ceils caused by carcinogenic chemicals. If there is a quantitative relationship between the percentage of chromosome abnor malities and the amount of exposure to the chemi cal, the estimation of chromosome abnormalities *4 ion c$ed history, of the nent. ': amegal , presence i by im- reticular mmunoouid cot /ere per- ne. New e found Tiber of exposed * was not clinical <nsidercd ssenceof a renal cted. ) animals .efemine mi et al. lidemio'orkmen -sed risk ticularly n 1974). icmicals, 'nstrated have an tes with vioto et .se et al. lymphoovide an assessing inogenic itionship t abnortc cheminnalities '33 - Section ofOccupational Medicine 291 may provide a useful tool for determining levels of exposure which do not produce this mutagenic effect. We have studied a population of 80 workers including exposed workers, nonexposed workers from the same industrial site, and nonexposed control subjects from another environment. The exposed population has been divided into groups based on the type of work carried out: Group 1 are autoclave operators; Group 2 are maintenance workers who have worked in the polymerization plant; Group 3 are those who work in polyvinyl chloride (PVQ production but not with auto claves; Group 4 are maintenance workers in the same area as Group 3. It is virtually impossible to define exposure of these groups of workers to VCM apart from saying that the autoclave workers have the highest exposure and Groups 3 and 4 the lowest. One worker, who was employed as an autoclave worker for 11 years and sub sequently as a maintenance worker for 14 years, has been included in Group 1. Blood samples were taken and lymphocyte cultures were prepared using standard Difco kits (Difco Laboratories, Detroit, Michigan, USA). Lymphocytes were cultured for 48 or 72 hours. All slides were coded before scoring, to ensure unbiased analysis. One hundred cells per indi vidual were analysed (except for one individual where 200 cells were analysed), using the classifi cation of Buckton & Pike (1964). Workers who had been exposed to X-rays or prolonged drug treatment were excluded from the study. The results of the chromosome analysis are given in Table 1. All individuals were found to have normal male karyotype, except for one who had a 46, XY karyotype with inversion of No. 3 chromosome. There was no significant difference between 48- and 72-hour cultures so these data have been pooled. When the percentage of B and C cells in various groups is compared, it is seen that Groups 1 and 2 had higher percentages than Group 3 and the control group. The difference between the com bined results from the exposed groups and the control group is statistically significant. These results -confirm the findings of Funes-Cravioto Table 1 Ronlti (idq analyte* of ehnwoioiw abnormalities in worker* onployod la PVC aiottfacnrt IB and C cells classified aocordiAf to Buckton A Pike 1964) Croup I Group! Group 3 Croup a Controls on site Controls off site No. of BCtlb Worker* <%> . IS 21 3 6.4 6.9 6-6 12 3.1 19 34 5 24 CUCtlh CSCtlb <:*> <%) 1.72 1.48 1.20 M0 0.44 0.30 0.20 0.41 0.53 0.30 0.10 0.00 et al. (1975) and Ducatman et al. (1975) that workmen exposed to vinyl chloride have an in creased percentage ofchromosomal abnormalities. There is also some incomplete evidence that higher exposure results in larger increases in abnormalities. This relationship still requires to be studied in more detail. The induction of chromosomal abnormalities is indicative'of a mutagenic effect of vinyl chloride. It is important to know whether vinyl chloride is capable of inducing mutagenic effects in other test systems and particularly whether such an effect is produced on germ cells. Accordingly vinyl chloride was examined for dominant lethal effects in mice. Groups of 15 male mice were exposed to 3000, 10 000 or 30 000 parts/10* of vinyl chloride for 6 hours per day for 5 consecu tive days. Each male was mated with 2 virgin females per week for 8 weeks and the females were killed at 13 days and examined for dominant lethal effects. There was no significant increase in any of the parameters (early deaths per implanta tion, early deaths per pregnancy). Vinyl chloride, therefore, did not produce dominant lethal effects in mice, indicating that it did not produce a mutagenic effect in germ cells even at these high levels. REFERENCES Buckton K E & Pike M C (1964) InternationalJournal ofRadiation Blolozy 4,439 Crwdi J L A Johnson M N l\?H)Journal ofOccupational Medicine 16,150 bmunu A, Hiisehhon X A SelikofT IJ (1975) Mutation Research 31,163 Fmet'Cravioto F, Lambert 8, Undstea J, hrenb*rt L. Natarajoa A T A Ositrman-GoJkor S (t975)Juzifcef i. 459 Maltoai C, Ciliberti A, Gianni L A Chieco P ((975) Ospedalidelta Vita 2,65-66 Mahout C A Lefemine G (1974) Environmental Research 7,337 Purriuat IFH, Richardson CR A AarfcrvoaD (1975) Latteel ii, 410 DISCUSSION Dr Sylvia D Lawler (Royal Xfarsden Hospital, London SJV3) asked were the chromosome breaks distri buted at random? Was a banding technique used? Were the people who actually had symptoms separated out? Genetic effects on human gonads were not absolutely excluded by negative results in a dominant lethal experiment in mice. Was there any evidence of lower fertility? Dr I F H Purchase replied that the chromosome breaks were distributed randomly. No banding tech nique was used. The people selected to take part in the study were randomly selected and had not been separated into those with and without symptoms. The only evidence that had been produced experimentally suggested that genetic effects did not occur in the gonads and no effect on fertility was seen. i $ i C. T t r. < t r ro o 5 r O) U1 -if a I- m^jpm IP.'tJ*" r"' TilI"*' ft f^firLr`rn' i 292 Proc.roy. Sac. Med. Volume 69 April 1976 Dr Lde Boer (The Hague, Netherlands) said that Mrs I Fteig had reported (Mcdichem Conference on Chromo some Aberrations, Milan, October 1974, in press) on chromosome studies in which there were not more > abnormalities in the exposed group compared with a control group. *sis, portal hypertension, (esophageal varices splenomegaly may-be common results of VCM toxicity (Marsteller et al. 1973, Smith & Williams 1974, Makk et al. 1974, Thomas et al. 1975, Lange etal. 1974). Dr f F H Purchase said that his was the third study which had described such abnormalities, the other being those by Funes-Cravioto et al. (1975, Lancet i, 459) and Ducatman et al. (1975, Mutation Research 31, (63). Dr D C Smith (Zerolit Ltd, hleworth, Middlesex) asked whether Dr Purchase's results showed a statistically significant difference between categories 1-4 of exposed workers, i.e. those working on the autoclave (1 and 2) and those away from the antoclave (3 and A), assuming that the autoclave area was the one of maximum exposure. Dr IF H Purchase replied that there was a statistically significant difference between the results from auto clave workers and controls, and between the results from all exposed workers and controls. Dr K J W Taylor (Department ofDiagnostic Radiology, Yale University School ofMedicine, New Haven, Connecticut, USA), Dr JJ Barrett (Department ofNuclear Medicine, King's College Hospital. London SES), DrDMJ Williams (BP Chemicals International Ltd, Sully, Penarrh, South Glamorgan), DrPMSmith .. (Department ofMedicine, Welsh National School ofMedicine, Uandough Hospital, Penarth, South Glamorgan), and Dr BW Duck (Occupational Health Unit, BP Research Centre, Sunbury on Thames) In view of these adverse reports, a survey was undertaken of487 workers with varying exposures to VCM by two of the authors (Williams et al. 1975). Full blood pictures were obtained and standard liver function tests were done. Two patients identified by a thrombocytopenia of 72 000 and 45 000/mm1, and slightly raised G-glutamyl trarspeptidase G-GT levels, were' subsequently found to have periportal fibrosis, portal hypertension, splenomegaly and oesopha geal varices on barium swallow, plain abdominal radiography, splenic venography and needle biopsy of liver. It was clearly unacceptable to carry out these invasive investigations on all exposed workers, but the less invasive techniques seemed relatively insensitive. Thus, a pilot project was carried out to ascertain whether ultrasound offered a possible noninvasive method for visualizing the liver and spleen in workers exposed to hepatotoxic agents. Initial results proved encouraging (Taylor et aL 1975, Williams etal. 1976). Although ultrasound has been used as a d<j nostic tool in obstetrics for many years, the inssttrrip mentation* was comparatively crude since the relevant echoes to be displayed were of large magnitude and did not require sophisticated instrumentation. Kossofff1974) developed greatly improved equipment which was clinically applied to obstetrics, the eye, breast and thyroid. Using similar instrumentation, the technique was evalu ated for the investigation of liver and splenic pathology (Taylor et al. 1973, Taylor & Milan Preliminary Results of Grey-scale Ultrasonography lathe Detection of Vinyl Chloride Related Liver and Spleen Disease A number of cases of angiosarcoma of the liver in workers exposed to vinyl chloride monomer (VCM) led to the recognition of the potential hazards of such exposure (Creech & Johnson 1974, Block 1974, Lee * Harry 1974). To date, there are only 47 such cases described in world literature, so angiosarcoma can be regarded as a rare manifestation of VCM toxicity. However, Znfmtitrf vIU Fig 1 Schema to show movement oftransducer to display the anatomicalfeatures shown in Fig 2. The portal vein is shown anterior to the less dramatic changes including periportal fibro inferior vena cava J} V) TO o CT> x O) *>* XKifa L:w4aLtntwJfa.- .fW.tiJi. # 34 ageai!! varnicees and results of VCM imith A. Williams mas et al. 1975, rts, a survey was varying exposures , (Williams et at. re obtained and were done. Two nbocytopenia of slightly raised jT levels, were .riportal fibrosis, aly and cesophaptain abdominal jhy and needle > cany out these xposed workers, seemed relatively vas carried out to ftered a possible ing the liver and oatotoxic agents, ig (Taylor et al. . usAVa diagycars.The instracrude since the i .were of large re sophisticated -.eveloped greatly clinically applied 1 thyroid. Using nique was evalu* ver and splenic Taylor & Milan ntn ev msducer to in Fig 2. 33 Section ofOccupational Medicine 293 i f | | Fig 2 Parasagittalscan ofliver 2 cm to right of midlineshowing normal liver consistency, portal vein andinferior vena cava, (Reproducedfrom Taylor ct al. 1975, by kindpermission) 1976). This technical development was called grey-scale ultrasound, and the major difference between this and older instrumentation is the ability to display the normal tissue parenchyma. Thus, whereas the liver was previously found to" be a relatively echo-free area in which only con tour and size could be distinguished, the display of the normal parenchyma allowed diffuse patho logy to be recognized due to an abnormal pattern. Small space-occupying lesions appear now as small defects of the normal parenchyma. The liver is scanned in a series of paramedian sections illustrated in the schema shown in Fig 1. The resulting ultrasound scan is shown in Fig 2. Ultrasound is a fast means of acquiring data. Using this single pass technique through the liver Fig 3 Parasagittal section ofliverfrom patient with, vinyl chloride-relatedportal hypertension. The portal vein-is dilated and highly tortuous. Note that there are very large echoesfrom the deep surface ofthe liver which is consistent with capsularfibrosis (arrowed). (Reproducedfrom Tayloret al. 1975, by kindpermission) as shown in the diagram, good resolution is obtained without degradation by respiratory or cardiac excursions. This ultrasound technique involves no ionizing radiation nor other known hazards, no discomfort, and no need for contrast media. It does require considerable operator expertise and high quality instrumentation, which has only recently become commercially.availablc. Machines which do not display the consistency of the liver are unsuited for examination of it. Nineteen volunteers were selected from the factory workforce, with varying exposures to vinyl chloride monomer which are summarized ir Table 1. Only 2 patients had no exposure at all, but 7 were normal on standard testing (Table 2). Table! Pwtl--n4 Itwhtf VCM txiHwtfn i (from William* </. 1976) Chm exposure Gate i 2 3 4 3 6 7 9 10 11 12 13 1is4 1C 17 IS 19 At* 41 40 32 45 4S 45 36 47 30 45 36 39 41 42 so 55 32 43 46 Low Medium riifh (No nwuo) (No exposure) ty Cm ly 3m 10m 2y 3m ly lm 3y 9m I5y Cm 3jr 10m Cy Sm 2y Sm 12y 9m 6y 6m 7y 4a 7y 2y 3m 2y Cm ly im Intermittent exposure low Medium High (No exposure) (Noexpoturt) Cy 4m ly Jm 15/ 4m lOy 5m 3y 7m 3y 4m , ly 10m 8y 4m 7y 5m Cy Cm lOm 2y 4m Im Jy 3m Ira 3y 3m 3y 2m 17yllm 3y 2m 3y 6m 6y 5m 6y 3m I4y 3m ly 4m ly 7m Low capowre, 0-25 pam/104: medium. 25-200 piru/10*; high. > 200p*rts/I0* Tim* fines is yean and months * \ / `' ~ ji ..^ijna ion,iijLjyj,ui;w m iprjfi -*' w f X Q ? ><, 30 (/> ro o o) -4 p r-' .--s 4 * JS s atiililiAMuitote *~T tn^lil U Ti ^iI wi Ti I -V.. iifrtliMiMuaaaNi MCbuMWaSSl- 294 Proc. roy. Soc. Med, Volume 69 April 1976 36 The ultrasound examinations were carried out by the same operator (KJWT), who had no know ledge of the results of the screening tests carried out at that time nor of the exposure of any par ticular worker. Abnormal findings included in creased size and tortuosity of the portal vein associated with portal hypertension, probable capsular fibrosis (Fig 3) and splenomegaly (Fig 4). The results of routine screening and ultrasound are shown and compared in Table 2. Routine screening consisted of clinical examination, full blood picture, urinalysis and standard liver function tests. Repeated abnormality in any in vestigation led to further investigation including barium swallow, plain abdominal- radiography. Table 2 CMp*tftsdit of fc*ormftlifit* detected by ttandifd methods *ttd hr iltmanofruhy (from Williams et a/. 1976) Cm* Standard mtihods Utttmontftraphjr 1 Normal Normcl 2 Normal Normal 3 Normal Normal 4 Liver 6 cm enlarged Slightly enlarged liver but norm*! consistency 3 Normal Normal 6 ^ Normal Technically difficult /obesity)* Enlarged portal vein. 50% increase in spieen size .7 Normal Enlarged portal vein, splenomegaly (12 cm) t Normal Enlarged liver with a decree ofabnormal fibrosis - t Afkafioe phosphatase Portal vein not shown. 3lhi/l .. Spieen twice normal Mze. Liver consistency slightly abnormal 10 Wedge liver biopsy: portal Enlarged liver with tract fibrosis in pluo possible atty infiltration extending into parenchyma 11 Bilirubin 31 pmol/l Portal vein slightly enlarged. SGOT60iu/l ' Marked splenomegaly(18cm). Liver technically difficult to see 12 Needle Over biopsy: slight Normal fibrosis and fatty change 13 SGOT60iu/l,GGT95ui/I. Portal vein and spleen Needle liver biopsy: normal. Liverdifficult moderate (attydegeneration to see (obesity) and mild porul fibrosis 14 Platelets 106 000/mm* Large portal vein and spleen (12 an). Liver enlarged, slight change in consistency 13. SGPT 62 iu/L Needle Portal vein and spleen liver biopey: fatty change normal, but possible cirrhotic changes in liver 16 SCOT 60 iu/t Normal lCT59iu/l 17 Bilirubin 21 tunol/l, GGT Marked enlargement of portal 66 iufl, platelets 99 000/mm*. vein and solcen. Slight change Splenomegaly, oesophageal m liver consistency varices, periportal fibrosis It GGT 82 iu/i, platelets Splenomegaly. Marked 43000/mm*. BSP 19% cin-hotic changes (43 min). Splenomegaly, and fatty infiltration ersophageal variem. Fatty degeneration with minimal periportal fibrosis 17 Bilirubin 43 mol/I, Marked splenomegaly and SCOT 50 iu/I, platelets severe cirrhosis 80 000 mm*. BSP 21% (43 min). Splenomegaly. (Portacaval shunt 1968) Fig 4 Ultrasonogram ofspleen scannedalong tenth left interspace. When the spleen is enlarged due to portal hypertension, low-level echoes are returned and so appear dark. The gridsquares are 2 cm apart, and the spleen is thus 17 cm in length. This enlargement was not apparent on a plain abdominal radiograph cesophagoscopy, splenic venography and liver biopsy. Comparison of the results of ultrasound and routine methods in Table 2 shows that known pathology in Cases 4, 9, 10, 11, 14, 15 and 17-19 were confirmed on ultrasound examination. Cases 1, 2, 3 and 5 were confirmed to be normai. Cases 12 and 13 were known 10 have liver abnor mality on histological examination but this was not detected by ultrasound examination. ever, additional information was obtained ultrasound in Cases 6, 7, 9 and 11. In all these workers, the ultrasound findings led to a review of the radiological results and these are sum marized in Table 3. The ultrasound results were confirmed in 3 patients and were not contradicted in Case 6, in whom obesity prevented adequate assessment of spleen size on a plain abdominal radiograph. These volunteers were taken from a workforce of 487 of whom 20.9% had abnormal biochemical or hsematologic results on initial testing. Further, intensive investigation failed to reveal the early pathology which was demon strated by grey-scale ultrasound and was con firmed retrospectively by radiological examina tion. The main advantage of ultrasound lies in its potential as a noninvasive technique for monitor ing populations at risk. The lack of ionizing radiation is a great advantage in this respect. These preliminary results suggest that ultra sound will result in a small incidence of false negatives (2 out of 19), so that the method is complementary rather than a replacement for current techniques. Both acquiring the ultrasound scans and interpreting them requires operator expertise, but automated scanners should become available within the next year, while experience Blww ' '-) >. 4 %*s l^a th 0 land and the vasnot J liver id and known ` 17-1? ' ration, ormal. abnaootar^ isHoW' ed by * these ? xview sum- s were dieted equate MninaJ rom a tormal initial led to emon* conunina> in its >nitornizing ultra' false lod is it for sound erator some rience T rif i lilifir-^--v'-'; *:&--.ffiitin.mr 37 Section ofOccupational Medicine 295 Table 3 F--faa-fa Hi. hmdat Cm* 6 Normal 7 Normal * Nonal 11 Normal Ultrasonography Further assessment SpliooQJtcaly Barium swallow normal. Spieen not wen on X-ray abdomen. Spfaionii ,ly Barium *wallow normal. Spleen wide innsvcndy but did not extend below kvd of 12th rib Spknocnipiy Barium swallow after Bbscopan. Showed passible Grade 1 varices. Splenomegaly conArmed on review ofstraight X-ray of abdomen Splenomegaly Possible Grade 1 varices can be gained if the potential of the method is sufficiently, promising. Preparations are currently being made for a more extensive investigation of the application of grcy*scale ultrasonography to detect any liver pathology in a community in the United States which has been heavily exposed to air pollution with VCtvf, as well as in workmen exposed during the course of their employment. This further study should allow a more detailed assessment of the relative, value of this new tech nique. Acknowledgment: We would like to acknowledge the cooperation of the Working Party on Vinyl Chloride Toxicity of the Chemical Industries Association. REFERENCES Block JB (1974)Journal oflht Amtria* MtdicaiAntciotion 229,53-54 CnKbJ Lie JoImmM N (1974) Journal ofOccupational Medicine 16,130-151 KmffG (1974) JournalofClinical tf/mametd2,61-72 Lane* C L Job* S, Stein G * Veltman G (1974) Internationales Archiv/Ur ArbcitsmcdlxUt 32, 1-32 Lee FI * Harry D S (1974) Zorn*!,1316-1318 Makk U Crab J L, WhelanJ G it Johnson M N (1974) Journalofthe America* Medical Association 230,64-68 Manttller H J, Letbath W K, Moiler R. Jut* S, Lance C E.. Rolocr H G it Vdt<nu G (1973) Deutsche Meditimsche Wochensenri/t 48,2311-2314 Smith PM* William* 0 M J (1974) Digestion 10,321-322 Taylor K JW, Carpenter DA* MeCrendy V R (1973) Journal ofClinical Ultrasound 1,2S4-287 Taylor K J W * Milan J (1976) Proceeding of J975 Conference on Tissue Signature*. National Bureau of Standards, Washington. Ed. M Linzer(in press) Taylor K J W, WiUiams D M J, Smith PM* Dock B W (1975) Lancet i, 1222-1224 Thomas L B, Popper H. Berk P D, Selikoff I * Falk H (1975) New EnglandJournal ofMedicine 292, 17*22 Williams D M J, Smith P M, Taylor KJW, Crvisley I R * Duek B W (1976) British Journal ofIndusmol Medicine (in press) Williams D M J, Taylor KJW, Crowley I R, Smith PM* Dock B W (1975) Digestion 12,362 Dr MIV Jayson {Department ofMedicine, University ofBristol) Dr A J Bailey {ARC Meat Research Institute, Langford, Bristol) Dr C Black ( Department ofMedicine, University ofBristol) Dr K Lloyd Jones {Harlow Wood Orthoptedic Hospital, Mansfield) Collagen Studies in Acro-osteolysis Collagen is a fibrous protein present in most con nective tissues and it is the nature and arrangement of collagen fibres that are principally responsible for the mechanical properties of these tissues. The collagen molecule consists of three chains of amino acids formed into a triple helix, and these molecules are aligned in the fibre in.a parallel and quarter-stagger arrangement giving rise to the characteristic banded appearance of collagen seen on electron microscopy. This quarterstagger arrangement is maintained by specific lysine-derived intramolecular crosslinks and it is these crosslinks which are responsible for the strength ofcollagen. When collagen is newly fanned, the intra molecular crosslinks are labile aldimine bonds, and can be detected by reduction with tritiated potassium borohydride (Bailey et al. 1970). How ever, as the collagen matures these crosslinks become stable and nonreducible andare therefore no longer readily detectable. Studies of the collagen crosslink patterns in normal human skin will therefore show the highest levels in infancy and during the rapid growth period, but will fall to virtually baseline levels by adulthood. If excess labile aldimine bonds are detectable in adult human skin, then proliferation of new collagen is occurring. Collagen Studies in Scleroderma The skin changes of acro-qsteolysis (AOL) are in many respects analogous of those of scleroderma. In both conditions there is severe rigidity and thickening of large areas of skin, suggesting qualitative or quantitative changes in the collagen. In a study of skin biopsies from adult patients with scleroderma (Herbert et al. 19741 we found an increased proportion of labile aldimine cross links in 9 of 11 patients with active progressing disease. In contrast, in patients with longstanding nonprogressive scleroderma there was no excess of the labile bonds. Analysis of the centre and the growing edge of a plaque of morphoea demon strated the maximum level of crosslinks at the V 1 3 I - ! t f f si l R&S 112069 ^. `^^V^nnA -HfrtiflVl--rr i**i^-^rfrTriVfr;i.iri! 296 Proc. roy. Sue. ,`Aed. Volume 69 April 1976 * 38 edge of the plaque and much lower levels towards the centre where the collagen has matured. This provides a direct confirmation of increased col lagen synthesis in the skin in scleroderma. Collagen Studies in Acro-osteolysis Case 1 A D. aged 36 years, was a plasterer until six years before we saw him. He then started as a reactor cleaner and a `B' operator in a plant manufacturing polyvinyl chloride, scraping the inside of the reactor with a chisel, wearing gloves and overalls but no' mask. Following this initial three-week period he became an `A' operator, working outside the reactor, and was involved in charging and recovery from the reactor and controlling the flow of chemicals including vinyl chloride through various valves. There was no direct contact with the chemicals, but he frequently - noticed fumes escaping from the valves. After three years he noticed the onset of Raynaud's * * phenomenon which progressed with gradual shorten 3 ing and instability of the tips of the fingers. There was a gradual thickening and coarsening of the skin I t <i Ii c A; spreading up his arms on to the face and a little on the * chest wail and axilla. Two years later he gave up work with marked weakness of his hands and arms, which Fig 1 Rate ofsynthesis ofhydroxyproline relatedto the originalhydroxyproline content ofnormal and AOL skins banal) caused great difficulty in gripping and lifting heavy Iweights. Examination confirmed the features of aeroosteolysis with gross thickening of the skin, but with the following differences from scleroderma: (1) No ulceration of the fingertips. (2) Instability of the tips of the fingers. (3) Hair follicles and hair preserved. (4)No puckering around the mouth. (5) No telangei. ectasia. (6) General coarsening of the features. (7) No samples of skin from the patient with AOL and also at surgery from patients with other conditions not thought to involve any abnormality of collagen metabolism. They were cultured a^a stainless steel raft at the interface betw^Hk culture medium containing 3H-proline an^^n tightening of the skin across the nose. atmosphere of 20% oxygen, 5/,, carbon dioxide, Investigations showed slightly raised plasma 75% nitrogen in a modified Macintosh Fildes jar ! viscosity of 1.80 cP, and positive antinuclear factor at 37C for 24 hours. Following culture the (1:10). Skin histology showed distinct sclerosis of the deep layers of the skin without epidermal atrophy. On radiography there was gross lysis of the central parts of the terminal phalanges, the sacroiliac joints, certain costovertebral joints, the left condyle of the temporo- specimen was homogenized, dialysed to remove excess JH-proline, hydrolysed and separated in an amino acid analyser and the quantity of synthesized *H-hydroxyproline was determined. , mandibular joint, and loss of definition of the right This was related to the hydroxyproline content of mandibular vertical ramus. the original biopsy. The results are presented in Fig 1 and show that the rate of collagen synthesis Skin Crosslink Studies in Acro-osteoiysis in the patient with AOL was considerably A skin biopsy was obtained from this patient. greater than that of the normal controls. Reduction with potassium borohydride revealed a high proportion of the hydroxylysinonorleucine Discussion crosslink typical of new collagen formation in By both crosslink analysis and by measurement scleroderma. There was also a second redureable of 3H-proline incorporation into hydroxyproline, component present in significant amounts but we have confirmed excess new collagen synthesis further studies will be required in order to in the skin of a patient With AOL. These results I identify its nature. are analogous to the findings in the skin in scleroderma (Laitinen et al. 1969, Herbert et at. Quantification ofCollagen Synthesis 1974), and account for the thickening of the skin. Hydroxyproline is an amino acid that is unique It is possible that the effect is generalized, and to collagen and is formed from proline. By grow- excess collagen proliferation in the blood vessels ' ing tissue in a culture medium containing radio could lead to chronic ischsmia with ulceration of active-labelled proline and measuring the syn the fingertips and further local collagen produc thesis of hydroxyproline, an index of the rate of tion. Isehxmic necrosis could similarly occur in collagen formation can be obtained. We obtained AOL and so produce the typical bone lesions. ''5 WUJH.W tedto the AOL VOL and ediItIUioPnIIsS ialit)^ xd sweeceil^ra and an dioxide, -ildes jar ture the remove .rated in entity of ermined. ontent of sented in synthesis siderably surement yproline, synthesis results skin in ett et al. the skin, zed, and d vessels ration of producoccur in ' lesions. 1 Section ofOccupational Medicine 297 However, the AOL bone lesions differ in appearance from those ofsystemic sclerpsis. The cause of increased collagen synthesis in scleroderma has not been elucidated. Leroy (1974) studied the rate of collagen synthesis by individual fibroblasts from scleroderma and control patients. He found that, when first cultured, scleroderma fibroblasts synthesize new collagen much more rapidly than controls. This implies that cellular factors are of greater im portance in causing excess, new collagen forma tion. In addition Johnson & Ziff (1974) reported that lymphokine from normal human donors can increase the rate of collagen synthesis. Several chemicals are known to induce ab normal fibrosis. Practolol (Brown et al. 1974) can lead to peritoneal fibrosis. Methysergide can cause retroperitoneal fibrosis and ergotamine can lead to peripheral ischtemia and has been used in the rat as an experimental model for scleroderma (Harris & Robinson 1974). Epidemiological in vestigations strongly implicate vinyl chloride in the pathogenesis of aero-osteolysis, and therefore as a further possible chemical cause of increased collagen synthesis, opcnicillamine is a useful agent in the treatment of scleroderma, but only when.the disease is active and progressive, that is whilst the crosslinks are labile and can be cleaved by the drug. When the collagen has matured, the crosslinks become stable and the drug is no longer effective (Herbert et al. 1974). It may be that D-penicillamine will be of value for treating AOL, but only for active disease. It is of fundamental interest to determine the manner by which vinyl chloride leads to excess collagen proliferation. This should lead to a better understanding of the processes of collagen synthesis and could well act as a useful modelfor the study ofscleroderma. REFERENCES BniJeyA J.pMch CM Fowler L<J (1970) BiochemicalJournal 117, $!9 Brown P, Baddeley H, Read A E, Dari** J D A McGarry J {1974) Lancet it, 1477 Mania E D jr & Robtafotf M S (l974)/oi*fwfl/ ofRbewnaialofy I, Suppt. 1* 149 Herbert C M, Undberg K A, Jtywa MIV A Bailey A J (1974) Lancer i. 187 Johnson R L A Ziff M (t974)Jouma/offiMfumatofofyltS*ippL l,33 LaiiiArfl O, Uitte J. JaimoKaein M A MutteJcallio K K (1969) Anna's ofClinical Research 1,64 Leroy EC (1974) Journal ofClinical Jntnstifatiott 54, ISO ' Dr Robin Walker (Walton GeneralHospital, Liverpool, 9) spoke on the subject of Clinical Aspects of Vinyl Chloride Disease: Liver Epidemiological Studies Dr P J Baxter {Employment Medical Advisory Service, . Health and Safety Executive, Baynards House, 1 Chepstow Place, London W24TF) Epidemiological Studies of PVC Manufacturers and Fabricators, and Primary Angiosarcoma of the Liver The Joint Working Group on the Vinyl Chloride Code of Practice decided from the outset that epidemiological studies would be necessary to evaluate the extent of the risk to workers engaged in the manufacture and fabrication of PVC. The Employment Medical Advisory Service (EMAS) proposed three studies: a prospective study of PVC manufacturers, a prospective study of PVC fabricators, and a retrospective study of primary angiosarcoma of the liver. As these studies were intended to be as comprehensive as possible they could only be accomplished by drawing on the cooperation and expertise of a number of bodies: the industry, HM Factory Inspectorate, the Registrars General for England and Wales, 3nd Scotland, the Royal College of Pathologists and experts from university departments and else where. Prospective Study of P VC Manufacturers In the past, workers engaged in PVC manufacture were exposed to vinyl chloride as a result of work ing inside autoclaves or from leaks occurring at various stages of the process. The main aim of this survey is to evaluate the effects of this exposure in terms of mortality and cancer registration rates according to certified causes by including a/I past workers at every factory manu facturing PVC in Great Britain. Present and future workers are also to be incorporated. Identification details of the workers, including duration of employment and details of past exposure, are entered by the factory personnel departments onto individual survey cards accord ing to instructions provided by EMAS. Past exposure had been graded into high (>200 parts/ 10*), medium (>25 parts/10*), and low (<25 parts/] 0*), with `constant' and 'intermittent' categories. The cards are updated annually and sent to EMAS headquarters. Under the new Code of Practice all present and future exposures will be `low'. Identification detaiis of the workers are sent through EMAS to the National Health Service Central Registries in England and Wales, and Scotland. Death certificates for these persons h - wvr. milf-'.UV trar-- I 00 (/) to o -4 J,*' 5* 3 3 * '3 `i { uaiira.'d fTliiTItf Hi rrmMi t 298 Ptoc. roy. Soc. Med, Volume 69 April 1976 1 *are coded according to the International Classifi liver between 1963 and 1973. The results of 1 cation of .Diseases (1967) by the Registrars study have been reported elsewhere (Baxter &. General. Workers alive at the start of the survey Fox 1975) and showed that, on average, oniy 3 "3 are flagged, a procedure which results- in the adult cases were certified a year in England andi coded death certificates being picked out and Wales. One case reported in 1972 had previously notified to EMAS at the time of death. been employed as a PVC worker, (The only other angiosarcoma death in Great Britain known to This procedure should result in an almost com have occurred in a PVC worker was in 1974. 33 plete follow up of workers. The total number of Both workers had been engaged on the manufac 8 males and females identified as having worked in turing side.) 03 the manufacture of PVC is 7746 of whom only 84 (1 %) have not been traced, 72 (1 %) have missing The main aim of this study is to identify and 3 Information, and 147 (2%) have emigrated. verify all diagnosed cases ofprimary angiosarcoma N> O Workers entered into the present analysis number of the liver occurring from 1974 onwards, and to -r>o4 7410, over half of whom are current employees; evaluate their association with occupational 8S% were exposed to `low' or `medium' con exposure to vinyl chloride. From 1974 onwards, centrations, only 12% having worked in `high' the Registrars' General Offices are sending all concentrations; 46% had constant exposures. death certificates with an underlying cause of death stated as being liver cancer (including Statistical comparisons will be made between primary, secondary and unspecified categories) to observed and expected deaths, calculated using the EMAS headquarters, where diagnoses likely to England and Wales sex-age-standardized .rates be angiosarcoma are selected. Angiosarcomas supplied by the Registrar General. are also notified to EMAS from cancer registries, hospital pathologists and hospital discharges PVC Fabricators (Scotland only). A sample will be taken from Exposure to vinyl chloride during the manufac amongst the other liver cancers, and for both ture of the finished articles from raw PVC occurs these and the angiosarcoma cases the hospitals as the vinyl chloride trapped in PVC synthesis is where they were treated will be contacted in order released during the further handling and process to request the loan of available histological ing of the PVC. This survey aims to study the material. Sections will be submitted for diaigsnfllk mortality and cancer registration rates for all to a panel of expert histopathologists whhoo! ^P causes in each sector of the industry and to deter not know the history or identity of the casseess. ,3An mine whether these rates arc related to vinyl estimate will then be made of how many angio chloride exposure. There are at least seventeen sarcomas are misdiagnosed or miscertified as different types of industry and twenty types of other liver cancers. With the permission and operation, and the size of the work staff varies assistance of the hospital consultants and_ general from a handful to hundreds of men. Records of practitioners concerned, the next of kin of the employment and exposures are likely to be poor deceased angiosarcoma cases will be traced and or nonexistent in some of the smaller factories an interview requested with one of our Employ and for this reason a sample will be taken of ment Nursing Advisers trained in interviewing workers employed at, or near to, the present techniques. The nurse will seek to obtain a fuil time, over a wide range of the industry, the names occupational history of the deceased. of the factories making up the sampling frame being provided by HM Factory Inspectorate and The controls, matched for age. sex and death trade organizations. As many as 20 000 workers register (locality), will be chosen from the other may be involved. The procedure for the follow up liver cancer deaths and also from deaths from of workers and the analysis of the results will be all causes. Four liver cancer controls for each similar to that described for the study of manu angiosarcoma case will be randomly selected by facturers. EMAS. The controls of deaths from all causes will be selected by the Registrar General's Office Retrospective Study from the same death register as an angiosarcoma ofAngiosarcoma case. The next of kin of both sets of controls will The significance of cases of angiosarcoma of the be interviewed in an identical manner to the liver occurring in vinyl chloride workers relates angiosarcoma cases. As far as possible the inter to the rarity of the tumour in the general popula viewers will not know the cause of death of the tion. To assess its rarity and to look for any time deceased. Finally, our Employment Medical trends, EMAS asked the Registrar General for Advisers will investigate the places where the England and Wales to collect all death certificates cases and controls worked and record details of with a possible diagnosis of angiosarcoma of the occupational exposure to vinyl chloride and other WH 41 Section ofOccupational Medicine 299 us chemicals. They will also attempt to obtain photo Professor K Weinbrcn ' & copies of all hospital and general practitioner (Department ofHistopatkology, 3 records for the verified cases of angiosarcoma. Royal Postgraduate Medical School, 3d Du Cane Road, London W12 OHS) sly The verified cases of angiosarcoma will be ier entered into a register which will include occupa Histopathology of Liver Lesions Associated - to tional histories and the copies of the medical with Exposure to Vinyl Chloride Monomer H. records, and an estimate of the true incidence of So far only 2 cases of angiosarcoma of the liver x- angiosarcoma will be obtained. Finally, the have been reported in British workers exposed to frequency of occupational exposure to vinyl vinyl chioride monomer (Lee St, Harry 1974) but chloride will be compared between the angio more material has been studied in the United ad sarcoma cases and thecontrols. States by Bradford Block (1974) and by Thomas na et al. (1975). The lesions encountered in this last to In conclusion, prospective and retrospective publication included 15 angiosarcomas and the- *1 studies are being carried out to provide a compre structural changes are clearly presented by these Is. hensive assessment of the risk of occupational authors. At the same time, angiosarcomas have ill - exposure to vinyl chloride and the development been described in other circumstances, which of of primary angiosarcoma of the liver. The pro included prolonged exposure to arsenical medica *S spective mortality and cancer registration studies tion for psoriasis (Regelson et al. 1968) arsenic to* will also permit the testing of hypotheses con toxicity in vineyard workers (Roth 1957) and after to cerning the carcinogenicity of vinyl chloride in exposure to thorium dioxide for arteriography as ther sites, such as the lung and brain. And in the (Visfeldt Sc Poulson 1972). The lesion has been ts, absence of a satisfactory objective test for use in encountered also in patients with no evidence of ,es morbidity surveys, mortality data should enable exposure to a particular toxin (Baker et al. 1956). m the more serious complications of periportal The characteristics of the tumour are for the most th fibrosis due to vinyl chloride to be assessed. ils er REFERENCE BaxtcrPJ it Fox A J (I97J1 Lanctt ii, 37-2S in o- as DISCUSSION ad Dr A' J Fox (Employment Medical Advisory Service, :al London) said that in the prospective study of PVC lie od manufacturers described by Dr Baxter great care had been taken to elucidate the role of (1) year of entry into the industry, (2) level ofexposure as estimated by jy- people who had worked in the individual plants, (3) ng length of exposure in the industry, and (4J length of ull follow up. These studies, coupled with those of 'healthy population effect* and `survivor population effect' were of fundamental importance in the evalua ith tion of the results of exposure to vinyl chloride ier monomer. im .ch by Dr L Magos (MRC Toxicology Unit, Carshnlton) said SCS that in the retrospective epidemiological study re ice viewed by Dr Baxter vinyl chloride workers were ~na divided according to exposure time and level of ex Wll posure. How could data be obtained on the level of he exposure of a worker who had had twenty years' ex rr- posure? he In the German literature there were many cases of cal splenomegaly, fibrosis of the liver, and thrombo ihe cytopenia. Dr Magos was surprised that no similar Fig 1 Angiosarcoma showing dilatedsinusoidalspaces of cases had been reported from the U1C during the containing red blood cells and linedby tumour cells. meeting. H&E.XI50 i li t i i j -f V f J 3 * 3 J I 1. . : .........* * * * kUH 300 ^roc. roy. Soc. Med. Volume 69 April 1976 .................................................... Fig 2 Papillaryformations oftumour cells are borne on a core ofconnective tissue andhepctocytes. Hi. E. ye. 600 Fig 3 Well-differentiatedfattened tumour cells. resembling endothelial cells on connective tissue cores and linirig vascular spaces. H i E. x 400 Fig 4 Bizarre giant tumour cell in papillary angio sarcoma. Hi E. x 600 part agreed by these various workers and I pro pose to outline them. I shall also briefly discuss some of the other changes which have been noted in the livers of patients suffering from angio sarcoma and those of patients who had been exposed to vinyl chloride monomer but did not show evidence of the development of tumours. The tumour consists of cells which vary con siderably in appearance but seem to have enough common features, particularly in their mode of growth, relationship to vascular spaces and stromal changes, to support the view that they are derived essentially from one celi type. In general the tumours show a gross appearance of dark haemorrhagic nodules in the liver; there is a variable distortion and apparent fibrosis in the intervening liver tissue. Sometimes foci are macroscopically less hemorrhagic. There is often frank necrosis. The microscopical appearances at first glance are variable, but analysis suggests a consistency. Thomas et al. (1975) have delineated 3 main types depending really on the relationship of the tumour cells to' the vascular spaces; (1) The sinusoid;! pattern, in which dilated hepatic sinusoids are lined by enlarged and proliferating tumour cells. *tt *"'ll*?.*w-*? _ ... . . . . .'  r>v 1 prorcuss oted giobeen d not rs. r connough >de of . and c they .ranee lere is in the i are often dance ency. types mour / oidal s are cells. MMa 43 satii rnimtl i JmmAJM Section ofOccupational Medicine 301 hepatocytes, resembles cells normally associated with vessel walls and appears to be closely related to vascular spaces with variable degrees of abnormality. There are changes in other elements, both in tumour-bearing regions and in parts of the liver which appear to be free of tumour. These changes seem to involve mostly the supporting stroma. In the regions of the tumour, the perisinusoidal reticulin fibres are prominent, obviously in creased and appear to run between the tumourbearing sinusoid and the hcpatocyte plate, apparently causing reticulin increase in the space of Disse, which exists between liver cell and normal sinusoidal wall. The alteration varies from a minor inconspicuous (as the authors abroad put it) increase in reticulin fibres which may not be seen without the use of special stains (and in fact, both special stains and special optical manoeuvres may be employed to highlight this change) to massive increase of collagen fibres which surround the hepatocyte plates, clearly obstructing the lumen, sometimes apparently en- Fig 5 Solidarea oftumour resembling solidspindle-cell sarcoma. H&E.'X. 400 with hepatocyte plates clearly recognizable between the tumour cells. This appearance is found most often (Fig I). (2) The second most common is termed the papillary type, in which papillary formations of tumour cells are borne on a core of connective tissue, which may include recognizable surviving hepatocytes, often with canaliculi containing inspissated bile pigment (Fig 2). (3) The cavernous type, in which the blood-filled spaces appear even larger and are surrounded by thick fibrous walls which seem to be lined by the tumour cells. In addition there are several variables. The tumour cells may be welldifferentiated in that they simulate endothelial cells of liver sinusoids (Fig 3) and it may be difficult to distinguish tumour cells from reactive ceils, or they may be quite unusual, showing irregular bizarre and giant-cell forms (Fig 4). They may also present as solid box-like polygonal cells, suggesting an appearance similar to carci noid or epithelial tumour cells. The helpful diagnostic feature may well be the close relation ship to hepatocyte plates or obvious blood-filled spaces. The poor differentiation may be seen also in the frequently found solid areas in which the ceils look like solid spindle-cell sarcoma, without evidence in many foci of vascular spaces (Fig 5). In sum, the tumour ceil is distinguishable from Fig 6 Fibrosis associated with obliteration ofsinusoids and disappearance or atrophy ofhepatocytes in angiosarcoma. H &.E. x 150 l|.,, m. JgtJJIWBWWlf^^W yiWJ! nKTT JO 03 to o -M $ CJl % % % 302 Free. roy. 5<kt. A/w/. Volume 69 April 1976 trapping single hepatocytes. and sometimes with _ no hepatocytes appearing to survive t Fig 61, It is, of course, not dear whether the fibrosis precedes hepatocyte loss or not, but appearances suggest that it does. Such hepatocyte survival occurs even in the middle of very poorly differentiated tumour, a phenomenon which is quite unusual in the case of other tumours. Remote from the tumour-bearing areas, such perisinusoidal reticulin increase is recognized and again it varies from the minor inconspicuous form to quite striking fibrosis (Fig 7). There is also conspicuous fibrosis in portal tracts with .a patchy, sometimes marked, peri vascular and periductal fibrosis. The venous iumina which are thought sometimes to be com promised in other forms of fibrosis, such as the Indian noncirrhotic portal fibrosis, arc not regularly affected in this way and would be unlikely to provoke the portal hypertension some times described. Subcapsular fibrosis has been . *-;*** ^*^ L, (------------------ 44 Fig 8 Hepatic capsularfibrosis in patient exposedto vinyl chloride monomer andpresenting with portal hypertension. H A E. x 1SO \ repeatedly observed in the cases from the United States and this seems sometimes to be continuous with the fibrosis in the portal tracts. The relevance of such nontumourous changes to the subsequent development of angiosarcoma is of course one of the major practical issues at present. Such changes are sometimes found in the livers of workers exposed to vinyl chloride monomer and we have had an opportunity to see sections referred by several clinicians concerned with this problem, including Dr F Lee, Dr Robin Walker, and Dr IF H Purchase. The findings will JJ probably be incorporated in their own reports fio but, in summary, several liver biopsy sections cn have been looked at for the nontumour changes described. It happens that both controls and exposed patients have quite a content bf fat and N> that several of the exposed personnel do show O -J sinusoidal thickening, difficult to make out, but o> easier in dark-ground preparations. One particu lar case, which I hope Dr Frank Lee will report, ! I Fig 7 Liver biopsy sections showing variations in intralobular sinusoidalreticulin. Upper, slight increase. Lower, much increase. Cordon A. Sweet silver presented with portal hypertension and had quite striking capsular thickening, diffuse sinusoidal reticulin increase, hypertrophy and possibly impregnation: Dark-groundillumination. x36Q hyperplasia of endothelial cells, and what seems nited -UOUS ingcs toma .es at >n the aride 0 see rned .obin 1 will sorts tions nges and . and show , but ticuport; quite oidal .sibly sems 4M-- i Section ofOccupational Medicinc 303 t Dr Henry Falk (Cancer and Birth Defects Division, Bureau of Epidemiology. Centerfor Disease Control, United Slates Public Health Service. Department of Health, Education, and Welfare, Atlanta. Georgia 30333, USA) and Mr Richard J Waxweiier (Division of Field Studies and Clinical Investigations. National Institute far Occupational Safety and Health, Centerfor Disease Control, United States Public Health Service. Department ofHealth, Education, and Welfare, US Post Office Building, Cincinnati, Ohio 45202, USA) Epidemiological Studies of Vinyl Chloride Health Effects in the United States The vinyl chloride (VC) problem has had a con siderable impact in the United States during the past year and a half. Perhaps related to the age i and conditions of the VC industry, or simply to the sheer size of it, the United States has so far i had the largest share of cases of VC-induced hepatic angiosarcoma (HAS); at the present time there have been 17 known cases in polymerization Fig 9 Bizarre andenlargedsinusoidal lining cells and hepatocyte mitotic abnormality in same patient as Fig8.H6E.x6QQ workers (Lloyd 1975). The finding of the initial cases was a dramatic event, and unlike what has occurred with many other proven or suspect carcinogens, the confirmatory experimental evi to be striking hepatocyte involvement, even with dence arrived almost simultaneously with the mitotic abnormalities (Figs 8-9). epidemiologic results (Maltoni & Lefemine 1974). The widespread industrial applications and uses The question whether these lesions are signifi by the consumer were instantly appreciated, and cant as prcmalignant changes is unanswered, as since the VC oroblem also arrived at a time of many of the alterations can be found in other growing awareness and concern among workers conditions such as congestive cardiac failure, and consumers about environmental and occupa endothelial cell hyperplasia in cases of lymphoma, tional hazards, it served to focus these concerns. and of hepatocyte and other changes in many drug toxicity situations! Other pathogenetic Within the first few months after the initial questions also have to be posed, such as what is cases were described a number of worrisome the primary lesion, which cell is involved in the reports appeared. Investigators in Louisville, formation of the tumour, what is responsible for Kentucky, and also at Mount Sinai Hospital in the curious fibrosis and survival of the hepato- New York demonstrated a high percentage of cytes. Understanding these processes would liver function abnormalities in polymerization probably enable us to make a Detier assessment workers, suggesting a broad problem < Makk et at. of individual risk factors and perhaps to work out 1974, Lilis etal. 1975), and, in addition to this, the whether there is a tolerable exposure. earliest mortality studies (Monson et al. 1974. Tabershaw & Gaffey 1974) suggested increased REFERENCES Biker H De C, Facet G E Ac Diwxi J (!956)Journal ofPatholojf end Bacteriology 72,173-182 Block JB (1974) Journo/0/the American Medical Association 229,53-54 Boyer J L, Sea Gupta K P, Biswas S K. Pal N C, Bai Mallick K C, Bar F L it Baiu A K (1967) Annals ofInternal Medicine 66,41-67 rates for nonhepatic tumours, parallelling the multiplicity of tumour types seen in experimental studies (Maltoni & Lefemine 1974). Review of records at the Connecticut Tumor Registry, started in 1935, revealed 5 definite cases of HAS; Lao FI & Hany D S (1974) Lonrrfi, 1316 Rcgebon W, Kin V. Otpim J it. Hollaad J F (1968) Cancer(Philadelphia) 21* 514-522 RoffcF (1957) ZeitschriflfAr Krebsfonchunt 61,468-503 Tbonu* L B. Popper H, Berk P D, Salikolt 1J Si Falk II (1975) S'ew Engtana Journal ofMedicine 292, J 7-22 Vttfcfdt J & Pouisoa H (1972) Acta Potho'cricaet MievotHoiofica Scandiaarica Section A 80,97-108 4 cases were clustered in one industrialized area and had occurred since 1967; 3 of these (and possibly a fourth case where the diagnosis was uncertain after review of slides) occurred in workers at two polyvinyl chloride (PVC) fabricat ing plants or in residents living nearby (Landrigan & Heath 1976). Further concern was generated by $ T F r t 37 f CO CO I l ro o N N 1 f 1 4 I : 6 e % 41 .>1 $ \ ,J 4^ - ( 3 S i'l ji 1 1 i ^Y*-1 r - ---^*-3- vdW Ml* an 304 Proc. toy. Soc. Med. Volume 69 April 1976 ' 46 reports of the potential carcinogenicity of chemi cals structurally related to VC, e.g. chloroprene (Lloyd era/. 1975) and trichloroethylene (National Cancer Institute 1975, unpublished data), and by the knowledge that VC workers in many instances have been exposed to multiple related chemicals, including vinylidcne chloride and acrylonitrile (vinyl cyanide). As part of the United States Public Health Service response to the VC problem, the NationalInstitute of Occupational Safety and Health (NIOSH) and the Bureau of Epidemiology, Center for Disease Control (CDC), have worked on a number of VC-related epidemiologic projects during the past year and a half; in this paper we will briefly review some of'the early results of three of these studies. Table 2' Hepatic angiosarcoma m the United States # by age at death and sex. 1966-1973 A ft at death (ytari) 0-9 10*19 20-29 30-39 40-49 JO-39 60-69 70-79 80+ Mat* 2 1 1 3 7 13 3 11 1 Ftmnlt 2 1 1 4 2 2 3 3 2 Total 4 2 2 9 9 13 10 |4 3 ' 46 22 68 # From death certificates. ICD Code 197.8 (8th Revision). Data for New York City not included _ ^ There was approximately 1 case of HAS for every 300 death certificates reviewed. HAS Surveillance A death certificate search for all cases of HAS recorded under ICD Code 197.8 (8th Revision), which encompasses various miscellaneous forms of liver tumour including most cases of HAS. was undertaken by CDC for the years 1966-73 in the United States. This search is almost completed, with only data for New York City not yet available at the time of this review. Table t shows the number of cases of HAS and non-angio hepatic sarcomas by year of death for 1966-73; there is no evidence for an increase in the incidence of these malignancies during this period. A review of the relative occurrence of hepatic sarcomas recorded under ICD Code 197.8 showed angiosarcoma to be the largest group (35% of total hepatic sarcomas), followed by sarcoma of unspecified type (31%), leiomyo sarcoma (12%), fibrosarcoma (7%). and a grouping of miscellaneous sarcomas (15%). Table / Hepatic Brctxni in the United State*# by reported 6fctolo(y and yearoC death, 1966-1973 YtOrcf dtath 1966 1967 196! 1969 1970 1971 1972 1973 All jortwftf 31 40 23 14 31 23 ' 9 23 Anyiosatcotim 9 13 9 7 13 5 1 9 Sarcoma 72 27 14 7 16 IS ' 8 16 ' 196 68 128 # From death certificates. (CD Code 197.8 (8ih Revision). Data from New York City not included Half year sample Table 2 demonstrates a male to female ratio of 2:1 for HAS. Sixty-two percent of cases occurred in the group aged 50 or more, with 26% in the 30-49 year age group. Non-angio hepatic sarcomas differed in having a male to female ratio of only 1:1, and an altered age grouping with 78^ of cases aged 50 or more and only 9% in. the 30-49 year age group. These differences are con sistent with a hypothesis that occupational ex posure may be a. more significant factor in th^ causation of HAS than of non-angio nepat# sarcoma. TM Only 2 of the patients with HAS in the death certificate review were recorded as having worked in PVC or plastics plants (I PVC polymerization worker a.id I accountant in a PVC fabrication plant); both were cases which Had been identified prior to this study. No other occupation is recorded more than twice except for the occur rence of 5 printers. Although all were subsequently confirmed as printers, a preliminary review of pathology records and specimens suggests that 4 of the 5 cases may have been incorrectly diag nosed as HAS. CDC has supplemented the death certificate survey with an intensive case-finding effort, including a national mailing to all pathologists, State epidemiologists, and major cancer referral centres and tumour registries, seeking information on as many cases of HAS as possible diagnosed in the US during the years 1964-74. At the present time approximately 240 cases have been identified. Pathology specimens for about two-thirds of these are currently under review at the National Cancer Institute and the Armed Forces Institute of Pathology. An epidemiologic evaluation of all cases to obtain more detailed histories regarding . MS wupw j XL' f. jHUBJPMW* ia<WVrfih'ni 47 Section ofOccupational Medicine 305 past occupations, toxic exposures, and places of residence is underway. Table 3 I CMcrr amoftff worker* at PVC pofem*fiton planra in the Hotted States by histologic type and extern of VC exposure Medical Screening of VC Workers Extent of VC exposure Together with the Occupational Health Studies Group of the University of North Carolina, NIOSH-CDC recently concluded a cross-sectional medical screening examination of 530 workers at a plant in Pennsylvania which contains both a large tyre-building facility as well as one of the oldest PVC polymerization plants in the United States. Included in the 3tudy were approximately 130 current PVC polymerization workers and a Histohfie type Nom Epidermoid 1 Smail cell undifferentiated 0 Adenocarcinoma I Large cell undifferemiated A Unclassified I Lttsthpn Mt/MT t s. t 0 0 More thou one year 0 0 4 0 Total i 3 t 10 t 7J 10 22 similar number of control workers from the tyre plant who had never worked in the polymeriza tion facility. The 2 groups were comparable in if confirmed, this unusual cell type distribution ior age, alcoholic intake, and socioeconomic back may support the association between VC exposure ground; the controls were chosen from those and occurrence of lung cancer. areas of the tyre plant where exposure to solvents and dusts was least. i There are, however, two additional features which should be considered in evaluating this Preliminary review of the results shows no potential relationship. When all of the workers significant differences between the 2 groups for at these 4 plants are considered, including those any of the 6 liver function tests performed (SGOT, who were not part of the defined VC-exposed bilirubin, alkaline phosphatase, LDH, GGTP, cohort, a total of 22 cases of lung cancer (out of and ornithine carbamyl transferase). Additional 48) were available- for pathologic review. The analyses based on levels of VC exposure, duration increased incidence of large cell undifferentiated and type of job, and other subgroupings are and adenocarcinoma of the lung was seen in VC being done; these preliminary results however do workers with more than 1 year of exposure, while not suggest the occurrence of liver function a distribution more closely resembling the ex abnormalities ort a broad scale secondary' to VC pected small cell predominance was seen for VC exposure. One should of course be cautious about workers with less than 1 year of exposure. generalizing from the results at a single plant, and Interestingly, however, cases of lung cancer in it will be important to compare these findings to non-VC workers at these plants, although smail studies at other PVC plants. It is also important in number, appeared to have a cell type distribu to realize that since liver function tests are rela tion which was also predominantly large cell tively insensitive to the early finding of VC- undifferentiated (Table 3). In addition, unlike the induccd hepatic disease (i.e. fibrosis), the results situation for HAS in these plants where ail but of this type of testing are not a reliable estimate one of the cases were long-term reactor cleaners for the prevalence of VC-induced disease. Liver and operators, the workers with large cell un scans were also performed on all workers with differentiated and adenocarcinoma of the lung more than 10 years duration of work in the PVC were distributed in a number of different job polymerization plant, and no cases of HAS were categories. As a result, cases of lung cancer seem detected. Some increase in frequency of palpable not to correlate as tightly with VC exposure as livers on physical examination was found, how cases of HAS and it is conceivable therefore that ever, among VC workers. A full report of findings some additional chemical exposure ai these from this comprehensive medical screening study plants may be working together with VC for even is in preparation and will be available shortly. separately) to produce this effect. Further studies are currently underway in an effort to confirm Cohort Mortality Study at Four P VC these preliminary pathologic findings. Polymerization Plants One of the results of this NIOSH-CDC study was the demonstration of an increased SMR for respiratory system cancer among members of the cohort (Waxweiler et at. 1976). On preliminary pathologic review, ii was also noted that of the 12 lung cancer cases all 8 for which pathologic specimens were available were either iarge cell undifferentiated or adenocarcinoma of the lung; REFERENCES Undricin P J Sc Heath C W jr (I976Mm preparation) Litis R, Andcrton H. Nicholson W J, Daum S, Fitchbcia A S & Selikofl 1 J (1975) Annals ofin* New York Academe of Sciences 2 *6,22 LJojfd J W (1975) Journo ' Occupational Medicine 17,333 .* t ifrffctifrr--'fr-1 -'`fif-fr.in rw^J^:rrf iiariii ut ^ ^riijcg<ii>iifcif lit'1.1'liwi <1 306 Proc. roy. Sac. Med. Volume 69 April 1976 Ibrri J W. Dmuflc P St Moor* R M NIOSH-CDC study, the Tabcrshaw study, and the 13 (197S)Journal ofOccupational Medicine 17.263 Mokk L. Creech J L jr, Whelan J G jr St Johnson M N Monson-Peters study) had all looked at the Louisville, fia 0) : (1974) Journal ofthe American Medical A uoctaiion 130.64 Maltoni C St Ulcimnc G Kentucky plant where the initial angiosarcoma cases occurred as well as at a varying number of additional ij (1974) Environmental Research 7,387 Monson R R, Peters J M A Johnson M N plants. Compounding the problem was the fact that (1974) Lancet \u 397 the definitions for entrance into the cohorts studied oN> Tlbcnhiw 1 ft & GafTey W ft (1974) Journal ofOccupational Medicine 16.509 differed from study to study, so that the results even at the same plant were not identical. Wixteiler ft J. Strincer W. Jones J. Wtgooer J K, Falk H St o00 Cuter C (1976) Annals ofthe Sew York Academy of Seietteesiin press) Dr J A Bonne!! (Central Electricity Generating Board) asked whether, since vinyl chloride monomer was a \ ' carcinogenic agent, there was any evidence in experi mental animals or in human clinical experience that S: DISCUSSION the skeletal or skin changes described mighty be premaligaant conditions. . . 3; Dr Mitchell R Zavon (Baton Rouge, Louisiana) asked whether the clinical examiners at Pottstown knew Dr H Falk said that cases of angiosarcoma in the USA whether or not the person being examined worked in did not have a history of acro-osteolysis or skin vinyl chloride. problems, although they did not have the multiple tests for early changes of acro-osteolysis. U would Dr H Falk replied that none of the clinical examiners seem, therefore, that the skin changes were not pre- were aware of the occupational status of the workers malignant conditions. at the time of the examination. Professor IJ Selikoff (Mount Sinai School ofMedicine, Dr RI McCallum (University of Newcastle upon Tyne) City University of New York) said that a review of asked Dr Falk to give in more detail the way in which known details of identified cases of vinyl-chloridchistological diagnosis was made in the case of lung associated angiosarcoma of the liver by Dr Lloyd -it cancer shown in his slide. Was this done by one f!975) of the National Institute for Occupational `-J individual or by a panel of pathologists? How were Safety and Health had demonstrated that.the median the specimens of tissue obtained: by biopsy, surgical duration from onset of exposure was approximately resection or at autopsy? It was remarkable that in seventeen years. These cases were derived from the none of the cases was an oat cell carcinoma diagnosed, rather small number of polymerization workers e^^k as this was the type often considered a characteristic ployed during the establishment and initial growth^^ft result ofexposure to a chemical carcinogen. the vinyl chloride industry. Attempts were underw^^ to identify and trace the initial groups of workers, Dr H Falk replied that the WHO lung cancer classifica employed during the years 1933-55, since analysis of tion scheme of Kreyberg (1967) was used. Four patho their experience would ailow evaluation of the risks *! logists reviewed the slides and agreed on the inter which might be suffered by the very much larger * pretation (Dr Louis B Thomas and Dr T Powell, group ofvinyl chloride workers exposed more recently, -c National Institutes of Health; Dr M Kuschner. State in a period during which PVC production was in University of New York; and Dr Laszlo Makk, St creasing at the rate ofapproximately 10 ?; per annum. Anthony Hospital, Louisville. Kentucky). All avail Limited data bearing on the problem had been able pathological material for each case was reviewed. The expanded pathological review currently under way would include the selection of multiple control cases oflung cancer from the same hospitals (with simi obtained. In one polymerization process studied, 257 men had been employed for five years or more in the period between 1946, when the plant opened, and 1964. Each man had been traced to 1 July 1974, with lar age and date of diagnosis to the study cases) and a 25 deaths from all causes: 3 of the deaths were due to blind review by a panel of pathologists in a more angiosarcoma of the liver (Nicholson et al. 1975), each detailed evaluation ofavailable pathology material. confirmed on review of autopsy material (Thomas & To Dr Falk's knowledge large cell undifferentiated Popper 1975): in addition there was one death due to 1 carcinoma of the lung had not been related to exposure ruptured (Esophageal varices. Another worker, to chemical carcinogens, which made the findings in examined during the clinical survey at this facility the VC cohort even more intriguing. (Lilis et al, 1975) had had a successful portacaval J shunt operation for the same condition. These experi Dr A J Fox (Employment Medical Advisory Service, ences suggested that vinyl-chloride-associated disease London) asked how many factories had been studied would be an important hazard for vinyl chloride individually in the USA. What proportion of these workers in the future, unless control of exposure had indicated vinyl-chloride-associated disease? resulted in at least some reversal of the risk. ! Dr H Falk replied that cases of hepatic angiosarcoma had been seen at 5 of the 8 PVC polymerization plants Lillis R, Anderson H, Nicholson W J, Datura S, Fischbein A S St Sclikotr IJ (1975) Annuls ofthe Sew York Academy of Sciences 246. 22-4 I opened prior to 1950. Lloyd J W M975) JournaloiOccupntinnal \lcdiune 17. 333-334 i There was some confusion in this area in that a Nicholson W J. Hammond C C* Seidman H 4 Selikotf I J number of the VC worker mortality studies had been (1975) Annals ofthe Sew York Academy ofSciences 446,225-230 Thomas L 8 Si Popper H overlapping. Three separate studies, for example, (the (1975) Annals ofthe Sew York Academy ofSciences 246,2o8-277 ! J.mi muiff Jitja.tuurfili J .VWIjV.arT s 3>  |-n it I I,- -"fjjpM*-'--=-~ nd the lisville, i cases itional a that audied seven Board) was a ncperi that e pre- : USA f skin jltiple would t prc- Heine, ew of arideLJoyd ional edian lately n the vrh srwav rfcers, sts of risks larger ently, i$ inlum. been 1.257 in the . and with ue to each as &. to ter, iility caval tperj- sease oride osure it u 2so -177 49 Section ofOccupational Medicine 307 DrBW Duck such examinations would be beneficial to indi (Occupational Health Unit, viduals in terms of preventive medical action. In BP Research Centre, the latter context, effort had to be concentrated . Sunbury on Thames, TVS16 7LH) on urgent measures to reduce exposure to vinyl chloride, a task which was being energetically Medical Surveillance of Vinyl Chloride Workers tackled by our technical colleagues. Following the announcement in January 1974 of Nevertheless, there were many arguments in the first cases of angiosarcoma of liver among favour of inviting vinyl chloride workers to workers exposed to vinyl chloride in the USA, the attend site medical centres to participate in a Chemical industries Association in the United standard medical examination programme: (1) Kingdom set up a Vinyl Chloride Committee, Opportunity for personal discussion. (2) Establish with a number of specialist working groups, prevalence of disease. (3) Establish prevalence and including one on health aspects. significance of liver dysfunction, (4) Correlate The first task confronting this working group, positive findings. (5) Identify possibly susceptible which comprised medical representatives of the individuals. (6) Compare findings in VC workers four British companies engaged in the production and controls. (7) Assess feasibility and value of of vinyl chloride (VC) and polyvinyl chloride medical surveillance. (8) Establish data base for (PVC), was to review all the relevant medical and further studies. For these reasons it was decided toxicological information available and decide to carry out an initial clinical survey on aii sites what action should be taken to protect the health where VC and PVC were produced, based as far ofexposed employees. This is an interim report on as possible on the application of standard pro one aspect of the group's work. cedures to both vinyl chloride workers and At that time, little was known about angio controls. A programme of action was discussed sarcoma of the liver and its treatment. Due to its and agreed with medical representatives of rarity, there was considerable doubt about both Government and Trade Union agencies and it its natural history and appropriate methods of was accepted that one of the main objectives was early diagnosis. Reports indicated that non- to gather clinical and epidemiological data to ' malignant forms of liver pathology, such as provide a reasonable foundation for future - fibrotic changes, might be more prevalent among decisions concerning regular medical surveillance. vinyl chloride workers than had hitherto been The survey population was divided as follows: suspected, but the significance of such disturb- ' Vinyl chloride workers Group 1 - all autoclave ances of liver function and structure in relation floor workers, vinyl chloride monomer (VCM) to the development of angiosarcoma had yet to production workers with five or more years' be established. Similar considerations arose in service; Group 2-vinyl chloride monomer pro respect of the previously recognized condition of duction workers with less than five years' service., acro*osteolysis (AOL) and its various manifesta all other VCM/PVC production workers. Controls tions, since it was speculated that there might be - workers from same sites with no history of VC some common underlying vascular pathology. exposure. To complicate the situation still further, long A standard medical examination procedure term carcinogenicity tests on laboratory animals was adopted: Initial examination comprising had not only produced many angiosarcomas, but medical history (questionnaire), physical examina also a'considerable number of renal and other tion, biochemical tests (SGOT, SGPT, GGTP, tumours. alkaline phosphatase, bilirubin), platelet count, The situation was discussed with medical col urinalysis. Follow up of abnormal findings, with leagues in Government and Trade Union agencies, repeat biochemical tests and platelet count, and and speciaiists in liver disease, and much helpful persisting abnormalities referred to consultant advice was received from them and from various for specialist investigation. overseas sources, especially from doctors in the The programme was introduced simultaneously United States. It soon became apparent, however, on the six production sites and the employees that there was no established procedure for the concerned were informed that it was not an early detection of liver angiosarcoma that could individual screening test, but a joint investigation serve as a basis for a large-scale screening pro to provide data that would help to establish gramme in industry. As practical screening future medical policy. It was also explained that possibilities were very limited and the early any individuals with suspicious findings, notably diagnostic value of suitable techniques was un persistently abnormal test results, would be certain. vinyl chloride workers could not be referred for appropriate specialist investigation asked "to volunteer for medical examination on by arrangement with their family doctors. the grounds that this would detect early malignant Due to a variety of reasons, not least the prob disease of the liver; nor could they assume that lem of interpreting the significance of borderline wpir TrT.aawtwgi iji 1.1^111 um>i i,ui < s ! $; I r<i- & & r jv & Jf -sc * I ----*>--'- -Jt- -- --- --M'TiilM"1*^-Ji~:-~r'~*-' - -*'4jt*,;l"-'**-^ . I -4 t j 308 Proc. roy. Soc. Med. Volume 69 April 1976 # !i ij abnormalities and workload difficulties ex interest in view of the apparent rarity of AOtm^ perienced by both medical advisers on sites and the cases of liver angiosarcoma that have been .r1 consultants and laboratory staff in" National reported in the literature. The routine urinalyses Health Service hospitals, the programme has have revealed no relevant abnormalities. taken longer than expected and is still incomplete. Hence interim findings only can be presented at Tentative Conclusions this stage and no firm conclusions can be drawn Abnormal liver function test findings were until all the facts have been elicited and the mass relatively common in both vinyl chloride workers of data obtained has been appropriately analysed. (12.5%) and controls (16.5%) even though So far, 1337 vinyl chloride workers and 429 results had to fall well outside (2 or 3 standard controls have been examined. The examinations deviations) the normal range in order to be of vinyl chloride workers include S82 from classified as abnormal. Repeat testing revealed Group 1 (representing an average response rate of persistent abnormalities in one third of the vinyl 80%) and 475 from Group 2 (in which the pro chloride workers in whom the initial findings portion volunteering for examination is lower). were abnormal and these 56 men were referred Initial liver function test abnormalities have been for. further investigation. Comparable data for found in 12.5 % of the vinyl chloride workers and the controls are at present unavailable. 16.5% of the controls. Repeat tests on vinyl If less .stringent criteria of abnormality had chloride workers with abnormal findings have been adopted, the number of individuals for revealed persistent abnormalities in about one- retesting would have been considerably greater third of the individuals concerned (56 men, 4.1 % and the effect this might have had on specialist of the original group). No comparable data for investigation and disease detection is a matter the controls can be presented at this stage. for conjecture. The definition of abnormality is The 56 vinyl chloride workers with persistently critical in this context and merits further con abnormal liver function test results have been sideration and study if the correct balance is to be referred to consultants at local NHS hospitals achieved. for further investigation. These investigations In view of the findings to date, it is not sur have not revealed any eases of angiosarcoma and prising that opinions of working group members the consultants concerned have already attributed about the value of periodic liver function tests in many of the persistent abnormalities to patho vinyl chloride workers are divided. No obvi^^k logical conditions unrelated to vinyl chloride liver disease due to vinyl chloride exposure exposure. At present, the causes of liver dysfunc been identified so far, but evidence of no^ tion remain uncertain in about one third of these cirrhotic fibrosis has been found in some cases 56 cases, where precise diagnosis rests largely on and until the results of blind interpretation of the the final conclusions reached by expert patho liver biopsy specimens become available no firm logists who are studying relevant liver biopsy opinions can be expressed about the presence or *N1* specimens. To put these interim results in per absence of any specific pathology related to vinyl 1 spective, it should be noted that almost all the chloride in the survey population. The procedure men in the latter group remain in full employment, has enabled individuals with persistent liver although many of them have been transferred to dysfunction to be detected and removed from 73 work involving no further exposure to vinyl exposure to vinyl chloride, and some doctors CO chloride in case their liver dysfunction renders propose to continue regular liver function tests them unduly susceptible to potentially hepato- for this and other reasons, such as the need to toxic agents. assess sequential changes. On other sites, the No3 While this survey was in progress, previously yield of significant clinical findings has been so established procedures for the detection of AOL low in comparison with all the difficulties en 00 and related conditions among vinyl chloride countered that it is considered liver function NO workers remained in force and 2 new cases of tests should only be applied on a discretionary AOL have been diagnosed. The survey provided basis in future. In this connexion, it is argued that, an opportunity to assess the prevalence of in order to be effective, the tests used should: (a) Raynaud's phenomenon among controls on yield positive findings at an early stage of disease; 1 three sites and comparisons with findings in vinyl (b) produce few false positive and negative chloride workers suggest that the condition-may results, and (c) ideally, be able to differentiate be equally prevalent in the two groups. However, between pathological conditions due to vinyl 1 no standard diagnostic criteria were applied and chloride and those due to other causes, such as r the prevalence of the condition varied widely alcohol. ! between sites. No association has been observed It is also argued that continued application of a between Raynaud's phenomenon and liver battery of tests to vinyl chloride workers is likely function abnormalities in individuals, which is of to cause considerable alarm and disquiet if the 1 1. 1IL-Lf lit 11 J1 50a vsr- Sl Section ofOccupational Medicine 309 results serve only to raise further doubt and con fusion. At the present time, it appears that detec tion of structural rather than functional changes in the liver is likely to be more rewarding for screening purposes, and for this reason attention is now being focused on evaluation of grey-scale ultrasonography as an acceptable, noninvasive technique for the periodic examination of vinyl chloride workers. In conclusion, although the survey is in complete, it has already yielded information of value for planning purposes, as originally intended. From now on, it seems advisable to concentrate effort on smaller and more detailed studies that arc designed especially to evaluate vinyj monomer pollution had decreased rapidly over the past few years (as in the plant described by Mr A W Barnes) and data on those employed in-a factory where (as in Dr Anne Walker's cases) even in recent years acute narcotic episodes had occurred- This lack of distinction might completely distort Dr Duck's statistical evaluation of clinical data obtained during the survey. Dr B W Duck replied that Dr Magos* point was well taken. However, as explained in the text, the paper presented interim findings from which no firm con clusions could be drawn. When all the data were complete it was envisaged that the industrial doctors and their consultant colleagues would publish the results obtained from individual factories. Specific hypotheses, particularly in view of the fact that the stringent environmental standards now in force are expected to minimize, if not eliminate, any risks to health associated with exposure to vinyl chloride. Mr H F Henning (Health andSafety Executive, 40S-405Edgware Road, London NW2 6LN) DISCUSSION Dr A John Robertson (Liverpool) asked what was done for those whose tests, under the surveillance scheme, were abnormal. A man had been mentioned who was refused life insurance because of abnormal liver func tion tests. Taking a parallel with lead, a man could be suspended because of a raised blood lead level, and could then be refused industrial compensation because he did not have a scheduled disease, and yet the em ployer would not pay his wages. Environmental Monitoring . It is a common misconception that environmental monitoring is easy, just a matter of collecting a sample, analysing it and getting a figure. Environ mental monitoring is never easy and when an industry is faced with a sudden and substantial tightening of the standard to be applied there are equally suddenly many questions to be asked and Dr B W Duck replied that men with persistently abnormal liver function test results were referred to consultants for further investigation and their family doctors were kept informed throughout. In the light of the findings the consultants and other doctors con cerned decided whether removal from vinyl chloride work was indicated and the men in question were advised accordingly. It was then left to the men to decide whether to accept or reject this advice. To date, only one man had rejected such medical advice and the rest had been transferred to alternative work with no loss of pay. answered. In addition, when industry and Govern ment have to write a Code of Practice before the event, and therefore without the benefit of experi ence or hindsight, there are many more questions. Some of these arc discussed in this paper. Instrumental Techniques When the threshold limit value (TLV) for vinyl chloride monomer (VCM) was 200 parts/10*, that is before 1974, the instrumentation used for monitoring was relatively fairly crude and in sensitive. One common instrument had a lower Dr Robert Murray (Sudbury) said that this was a very real problem which it was proposed to deal with in the Employment Protection Eill currently under discussion in Parliament. This would give to a man laid off for preventive reasons, because he showed early signs of absorption, the right to full wages during the period of lay-off. The more sensitive the methods of early diagnosis or the more stringent the standards of exposure, the greater would be the need to have some system to cover the no man's land between absorption which was not compensatable and disease which was. In large organizations it was usually easy to transfer the individual, without loss of money, to alternative work not involving exposure, but in smaller industries this might be difficult or impossible. response at about 200 parts/10* so that a nil reading was taken to indicate a concentration beiow 200 parts/10*, a very convenient situation. Even the chemical indicator tubes were not designed to show concentrations below 100 parts/ 10*. With the introduction in early 1974 of the new standard of 25 parts/10* (time weighted average) and 50 pans/10* (ceiling value) other existing instrumental techniques had to be adopted for use in the VCM atmospheres. Unfortunately some of the equipment which had been designed for laboratory use was not flame proof and so could , not be installed directly in factory workplaces. Dr L Magos (MRC Toxicology Unit, Carshalton) said that in Dr Duck's paper no distinction was made between data on workers from a factory where poiy- However, many of the diffichlties were overcome and all the VCM and PVC manufacturing plants have now installed what we originally called * * 1 s iai. - '-.Va' mie.'' iiYSfint. 310 Proc. toy. Soc. Med. Volume 69 April 1976 continuous monitoring but which is more that any operator is necessarily exposed to such correctly termed automatic sequential fixed point peaks or to such a raised average, since many of sampling. This is supplemented where necessary the peaks may have occurred in specially selected by short-term sampling for investigations or for areas where no person works regularly or the checks on equipment and by long-term persona! operator may have known about the situation and sampling to show the work people's actual worn a respirator during that period. exposure over long periods, e.g. four or eight hours. Influence ofSampling Frequency The frequency of sampling can also have an in Presentation ofResults fluence on the picture. Let us assume that some The Code of Practice requires the results to be of the sampling points have been chosen to pick available to the workforce and for summaries to up leaks from the plant so that, say, 10"^ of the be posted in work rooms. Each fixed point readings are above the ceiling value of 50 parts/ monitoring system takes a sample once per 10*. In a multi-point monitoring system sampling minute and therefore provides nearly 500 readings every minute this means that 48 readings per per shift so that trying to decide beforehand how shift for that system alone will be above the the results should be summarized and presented ceiling value. Sampling at the minimum frequency was a major problem because there was little required by the Code of Practice, i.e. once per previous experience of monitoring, and recording shift, would give on average one high reading in the results of monitoring, on such a scale. each work area every tenth shift. Sampling at the One way of presenting the results would be to minimum frequency required by the US standard, take an overall average. This has recently been i.e. once per month, would give on average one done and figures provided by the industry show high reading in each work area every tenth month. that the average concentration in the UK factories We see therefore that frequent static sampling had been reduced in a matter of months from 24 at carefully chosen points can provide much useful to 6 parts/10*. Recent figures from some of the information but it does not necessarily tell us plants even show long-term averages of about cxacily what concentrations the work people are 2 parts/10*. This suggests enormous progress, as actually exposed to. This can be shown best by indeed it is, and compares favourably with aver ages published by other countries. However, an overall average such as this is influenced very personal monitoring which is normally done at less frequent intervals because it is time-consum-J ing for the testing staff and somewhat restrictive^ considerably by selection of the sampling sites and for the operator wearing the equipment. Never by the frequency of sampling, two aspects which theless this is an extremely useful supplement to are completely lost in this method of presentation the general workroom monitoring. and of course it offers little of use in the protection of the worker, which is the main objective of Other Problems monitoring. I have said nothing in this short paper about preservation of records, which provides many Influence ofPeaks < problems not previously encountered in industry, An average over any period of time is influenced nor about atmospheric monitoring in the PVC very considerably by peaks. For example, in a 20 user industry where general atmospheric con point system sampling every minute a single peak centrations are less than 5 parts/10* and usually of 600 parts/10* due to a transient leak from less than 2 parts/10*. with a few known and nearby plant would add 25 parts/10*'to the shift controllable problem areas. average. In the UK we feel that it is essential to In-short, we in the UK believe that atmospheric record these peaks, because they indicate escapes monitoring should be used to provide the maxi of VCM due perhaps to defective plant or perhaps mum amount of information. This means that to incorrect work practice, both matters which the monitoring schemes incorporating extensive ought to be remedied. If the monitoring points multi-point systems can provide (a) useful are selected to provide a balance between information on deficiencies in plant or in operat operator work stations and areas where leaks ing procedures, (b) information with which to may occur then we must expect to obtain some' demonstrate progressive improvements in our aim high readings. These occasions will generally be to reduce exposure to near zero, (c) information investigated and will therefore play an important on personal operator exposure which can be kept role in the long-term reduction of atmospheric for future reference. Unfortunately in the short concentration of VCM. but in the short term they term it also provides much ammunition for our make the picture look bad. both by their presence critics. This, however, is a small price to pay for as peaks and by their contribution to the overall the long-term benefits which we know will shift average. There is of course no suggestion accrue from our efforts. 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