Document 6x9Zq8vm8LYxrzvQa95BLE01

17 ]/c Volume 69 April 1976 ___ *x. /?7J Section of Occupational Medicine President Suzctte Gauvain mrcp 275 Meeting 12 September 1976 Vinyl Chloride Dr Suzett* Guvaio {Medical Advisory Service, Health andSafety Executive, Baynards House, l Chepstow Place, Westbourne Grove, London W24TF) Vinyl Chloride; Introduction to tbo Problem The story or 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 the mid-1930s. The fire and explosion risks and the narcotic effect were quickly appreci ated. Aero-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 (Cordier et al. 1966) and subsequently confirmed in a number of investiga tions of autoclave workers in Canada, England and the USA. Soil tissue changes, coldness and numbness of the hands and fingertips, resembling Raynaud's phenomenon, were also described. Lilts et at. (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 hepatitislike liver changes were reported by Tribukh, from Russia, in 1949. However, until Viola reported (Viola etat. 1971) that he had failed in an attempt to produce aenvosteoiysis in rats exposed to 30 000 poru/10* 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 ss low as 250 parts/10* (Maltoni et al. .1973). As a result of Maltoni's work an epidemioIqgical 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 (he 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 Inspeaor 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 whs 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 (her. 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 4 276 Proc. roy. Soe. Med. Volume 69 April 1976 18 his opening statement, said; `This hearing will be focusing on ways to mitigate the problems in* volved with vinyl chloride as well as ways to avoid crises of this type in the future.' Previously, on 10 and 11 May 1974, the New York Academy of Sciences, the American Cancer Society, the National Institute for Occupational Safety and Health and the Society of Occupational Environ mental Health held a workshop entitled Toxicity of Vinyl Chloride - Polyvinyl Chloride (Sdikoff & Hammond 1975). The International Agency for Research on Cancer (1974, 1973) published technical reports of a working group on vinyl chloride held in June 1974 and of a succeeding meeting in January 1973. The International Chemical Workers Federation published for its members a handbook on vinyl chloride and its hazards (Levinson 1974). The Environmental Protection Agency in Washington, DC published in September 1974 a preliminary assessment of the environmental problems associated with vinyl chloride and poly, vinyl chloride, in which it set forth recommenda tions to clarify and reduce the associated risks. Meanwhile, the Department of Employment staff1 in the United Kingdom had been taking active pan in consultations in Europe and in the United States. As soon as the information was communicated in January 1974, HM Inspectors of Factories and Employment Medical Advisers throughout the United Kingdom were notified, and industry on its own initiative set out to ensure that no person would be exposed to amounts of vinyl chloride vapour that were above a con centration of 30 parts/10*. * The TUC-and-the CBI accepted an invitation^ from HM Chief Inspector of Factories to form a* joint working group with representatives of government departments. The first meeting took place on' 14 June 1974. An interim hygiene standard was adopted and two subgroups were set up to draft the environmental and medical sections of a code of practice; theft were pub lished in February 197S in temporary format by the Health and Safety Executive (1975). In the Introduction Mr Bryan Harvey, Deputy Director of the Health and Safety Executive, sates that the code sen out to (a) define an interim hygiene standard that must not be exceeded; (b) require regular monitoring to measure the concentrations of vinyl chloride in the atmosphere; (c) outline methods of achieving (): (d) provide for medial supervision; (r) provide for joint consultation and education and training. He further states: '... the Code as now published is based on our existing knowledge and will be improved where additional information shows this to be necessary ... The success of the Code depends primarily on the united efforts of management, supervisors and employees. This is very much a first edition of the Code in temporary format; I hope that those who have suggestions for improving it will put them forward via the joint consultative machinery required by the Code.' Medical Subgroup The medical subgroup defined its terms of refer ence as being: *To examine the medical aspects f exposure to vinyl chloride; to decide in the light of existing clinical, pathological, toxicological and epidemiological information the examina tions which should be included in the Code of Practice; and to indicate those which require further research before inclusion in the Code*. The subgroup consulted and gratefully acknow ledged the help given by experts on diseases of the liver and relevant diagnostic procedures. Because of the difficulty of determining which medical tests indicate the effects of vinyl chloride on the liver preceding the development of angiosarcoma, they `concluded that insufficient experience with liver function tests or screening tests is as yet available to enable firm rccommendati ns to be made regarding them in this Code of Practice. Liver function tests for this purpose are however in use in factories making PVC... '. As a result of experience gained from these tests and from other information, 'formal recommendations may be issued as a supplement to the Code in due course'. the medical aspects of the code are contained in pans 12,13 and 14. Part 12 defines 'supervised workers'. Part 13 is concerned with their medical supervision. Supervised workers should undergo pre-employment medical examinations: Those already employed should bo examined, if this haa not been previously done, within twelve months. The examinations should be repeated annually, and should include: (I) a full medical and occupa tional history; (2) a clinical examination with particular reference to the abdomen, skin and extremities; (3) X-ray examination of the hands; (4) such further tests as may be indicated by the above procedures or may be recommended in supplements to the Code. The leaflet describing the early effects of vinyl chloride monomer should be given to the supervised workers at this exami nation unless issued previously. The physician engaged to provide medical supervision for the workers should see a super vised worker who reports symptoms which may ucc 006592 slows this to be necessary 3ie depends primarily on fSgement, superv isors and Such a tint edition of the |k; I hope that those who proving it will put them consultative machinery Sflned its terms of refer* 3* the medical aspects of 3; to decide in the light .oologies!, toxicological ^relation the examinen&iuded-in the Code of 3 those which require fusion in the Code*. ~r Snd gratefully aclcnow5Peru on diseases of the '3ie procedures. Because H?nining which medical vinyl chloride on the 3ment of angiosarcoma, "Tkient experience with 'eening tests is as yet .-.^commendations to be Shis Code of Practice. purpose am however |PVC... As a result ~ these tests and from ^*1 recommendations 3ent to the Code in due |he code are contained S12 defines `supervised nd with their mcdicai pricers should undergo ^seminations. Those 5 examined, if this has 3dthm twelve months. 3e repeated annually, 3 medical and occupa^*1 examination with * abdomen, skin and 2nation of the hands; S' be indicated by the |be recommended in |fhe leaflet describing 3-ide monomer should Workers at this examii'y- 'i to provide medical :: should see a luper- *mptoms which may 19 Section ofOccupational Medicine 277 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. The purpose of the present symposium is to review British experience of the environmental, clinical, epidemiological and pathological effects of exposure to vinyl chloride arising in the course of polymerization of vinyl chloride monomer to polyvinyl chloride, and to exchange information. liuwwiMoal Atrots tat tftwth*o Cattw (1974) laumol Taehniul Rrswt No, 74/003. IARC. Lroo (1*73) launulTaehaiaJ t.|W No. 73/Oul. (ARC. Lyno L**f*M* C (1974) Work Hu4: Vta)l CMorid*. latwnaiioaal Clwoia) Work-in FcOtniion.Switnftuie LiUt R, AUm H. Nkbotnui W J, Ohm S. FIkAWW a S *SaUaaOtJ(l7.4aiuh o/ittXeit Yartt AcaStTaf SrVrr 24*. 33-41 Maitoai C. Cinoi M A tank p J R *4 (1977) Sittrpta MrSL a larrraattammiCaagrru Stria No. 273 SaULoSI J A HhhmoS EC*4 11*73) Match afiht Saw Yatk MtaSrmx V Srlntn ol 24* TnWU S L. TKikMWan N P. Loriat S V A Ka>W L A (1949) CiM* Strut 1A 2t t-'aarrf Sam Sown Cioalwo -- Cooii SWiaoilln w CiAna<Himi Setad Saaaioa on Daaei of Via>t CAiorida. Serial No. 9J-ttA liS Cawaam Pifatta* OAca, Wuhiattoa, DC Vlala P U Sieaitl A A Capaaa A (1*71) Cawr Dototth St, 3tS The implications of the association of angio 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. 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 gained throughout the world with vinyl chloride as a pilot study on a newly discovered occupa tional carcinogen. Frank and open discussion between government departments and both sides of industry is indispensable to the achievement of success. . * Postscript The Working Group on Vinyl Chloride Code of Practice for Health Precautions met on 3 October 1973 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 should be brought as near as possible to zero con centrations.* The figures of 30 parts/10* and 10 parts/10* replace the original figures of50 parts/10* and 23 parts/10*. Other requirements of the Code, including -medical supervision, are currently being re viewed.- references CmteJ M. RwiC LWwi M J a .IwiiA (IMS) CtKttt St AUitttw A> TmU4,14-1* tC\VraUtc)hJJaLaZbje4fOerawuititNmtStHtch< ChIimimhI ttmtiiH An--) (Fi*liminAiy Auntmui ofiS* EswMuntuMl Yierhan Allocated m uh Vnyl ClilAftC* ant Fnl> - myt Oihei4. W attiinfioa, DC Htalilt Si Saltrj tiHumdO]) V inyi CUotUj Corf*oTl*ntit* tot Utahh PftuKtioa* <T*mrw*/y Format). LortOon Mr AW Barnes (1C!Plasties Division, Welwyn Garden City, Hertfordshire) Vinyl Chloride and the Production of PVC Polymerization Characteristics of Vinyl Chloride Vinyl chloride has a boiling point of -- 13.5'C: 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 40-70'C to give polyvinyl chloride (PVC), a white solid material. The addition polymeriation of about 500-1500 molecules of vinyl chloride produces one molecule of PVC and the polymeriation 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 proportions of monomer (40% by weight) so that as the polymerization reaction proceeds and more polymer is precipitated, so equally is more monomer absorbed by the polymer to the point at about 70% conversion where monomer ms a separate liquid phase d(appear* and the remain ing monomer must be polymerized in its dis solved state within the swollen polymer. As this phase of the polymerization proceeds, the con centration of monomer in the polymer decreases and the rate of reaction correspondingly dimin ishes until at about 92-93% total conversion the speed of polymerization becomes uneconomical!}* slow. These are the fundamental characteristics of vinyl chloride and its polymerization mechan ism which decide the principal features of indus trial processes for the production of PVC. ucc 006593 . i r- - 278 Proc.roy.Soe.AItd. Volume 69 April 1976 20 The Production ProcessforP 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 50*C 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 that 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 ofmechanical 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, fine subdivision 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 process 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 homy mass. 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 slurry 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, jteketed 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 10m* to 40m* 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 hours, 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 polymef on which it is absorbed. The polymer slurry is then trans ferred to dosed tanks prior to the next stage in theproeess. As polymerizition proceeds, the two phase system of monomer dispersed in water becomes a three phase system of solid polymer precipitated within liquid monomer droplets which are (n turn dispersed in a continuous water phase. A great deal of research has been devoted in the past thirty years to the control and stabilization of this rather delicate colloidal system but, even so, small quantities of polymer are Still thrown out from it and form a thin continuous film of PVC on the walls of the reactor. If left, this will in crease in thickness and, since PVC is a poor thermal conductor, wfll reduce the heat transfer characteristics ofthe vessel and make temperature control impossible. At the end of the reaction it is therefore essential that this film should be cleaned away. This is one of the basic reasons why a truly continuous process has never yet been developed for making PVC and why the polymer, the world over, is still made by a batch process in relatively small reactors. This, as we shall see, has a signifi cant influence on the ease of controlling fugitive monomer in a PVC plant. As polymerization nears 90-92% conversion, the rate of reaction slows down markedly and at about 95% conversion has become so slow as to be quite uneconomic. There is no possibility therefore of continuing polymerization to 100% Meanwhile the empty autoclave, which still contains vinyl chloride gas at a low partial pres sure is further evacuated before opening to atmosphere, and automatic high pressure water cleaning jets are activated to remove polymer scale from-the walls. At this stage, the cycle is complete. Vinyl chloride monomer has a strong affinity for PVC and the Iasi traces of it yre difficult to remove from the polymer; the polymer in the slurry after Stripping therefore still contains around 500 parts/10* of vinyl chloride. This slurry is centri fuged to remove the water phase and the wet powder is then dried in continuous driers; during this process further vinyl chloride is removed in the drier gases and the final dried powder cur rently contains about 50 parts/10* of monomer. Interfaces between Vinyl Chloride andPeople This description of the production process gives some indication of the relative potentials of different parts of the process for creating signifi cant exposures of people to vinyl chloride. If we take a plant capable of making ICO 000 tons per annum (tpa) of PVC then the polymerization building will, during the course of a year, have handled over 100 000 tons of vinyl chloride in 21 liquer sec-. ir a th1c pc*. strie p: furrr. son-'. m: - j rated rc 'a. u ai: arc U\ sti: fO-n. wc. mij cenr. thou abou inje. excee' ea.cu A point :_ and v of thi perfer facto: even dis:c arc- tior: par. I bigi mer: tons are v. other Streir the?.* qc:vat to a t dow ser tv' tf a: h. ucc 006594 ==of the problems ylwicity in this way. ^e reaction, there. =wr (still at a pres3er.ted back to a 3partidcs (100-150 fining in water, is :;.;jocess in engineer:5s: polymerization Jg stirred, jacketed ~ water, surfacrive -I are added to the Sus liquid phase is jits polymerization) ~n injected into the 3 sizes range from 3r charge per batch Hie reactor contents stained at reaction =3me of the order of =3s vented to a gasHeactor is evacuated, 3ip as much monolymer on which it .jny is then irans- the next stage in enclave, which still 5 a low partial presSefore opening to ijigh pressure water remove'poiyiner -IE stage, the cycle is a strongaffinityfor difficult to remove in the slurry after trains around 500 Shis slurry is centri3phasc and the wet 3uous driers; during Xoride is removed in 3 dried powder cur%10* ofmonomer. i s i Auction process gives Native potentials of i; for creating signifiVinyl chloride. If we ;ing 100000 tons per ij the polymerization jjrse of a year, have jof vinyl chloride in liquefied form under pressure. Into the drying liquid vinyl chloride under pressure was used in section will have passed 50 tons of vinyl chloride large quantities. in a form strongly absorbed on the polymer and at a concentration on polymer of about 0.05%. In The nature of the polymerization process, ss the finished product, 5 tons of vinyl chloride will described above, illustrates why exposures in the leave the factory, each year, still absorbed on the past could have been large. The plants are com polymer at a concentration of 0.005%. Although posed ofa large number of batch reactors ofsmall strictly outside the scope of this paper it is worth capacity per batch, relative to the tout annual proceeding further and pointing out that in throughout. In each reactor, two complete cycles further fabrication operations on the polymer, per day are carried out and each cycle requires , some of this small residual concentration of vinyl chloride to be injected under pressure, monomer is driven off so that in the final fabri heated, contained, stirred and polymerized cated article only --5 parts/10* of monomer almost completely: at the end of the cycle un remain or 0.5 tons out of the original annual polymerized monomer has to be removed and the total of 100 000 tons. In fabricated articles which reactor opened and cleaned. The possibilities of are used for foodstuffs packaging (bottles, film small leakages from pumps, valves, stirrer glands and foil), and which represent about 10% oftotal and from the opened reactor at the end of the UK production, the monomer concentration is cycle were obviously significant: and the manual still lower, and the pro rata amount absorbed on cleaning of reactors gave further opportunity for foodstuff containers from a 100 000 tpa plant high exposures. This was particularly true during would be 50 lb. Of this quantity ib might the long period in the 1940s to 1960s when vinyl migrate into the foodstuff where its average con chloride was thought to be harmless and when a centration is unlikely to exceed 10 parts per recommended exposure limit did not exist or, thousand million. Since total UK production is late in the 1950s, was set by regulatory authorities, about 400000 tpa this means that the annual industrial hygienists, Ac., at a level of 500 parts/ ingestion by the average UK citizen cannot 10*. exceed 0.0001 g, a figure which agrees well with calculations based on diet analysis. The general consensus of opinion throughout the world, today, is that average atmospheric A final potential interface arises because at exposure for polymerization workers between points in the production process, vinyl chloride is 1940 and 1970 might have been of the following exhausted to atmosphere. On a typical PVC plant orders: 1945-55. -1000 pam/10*; 1955-60, and with current levels of achievement, 0.3% --400-500; 1960-70, -300-400; mid-1973, of the monomer is lost to atmosphere: with this --150; 1975, --5 parts/10*.' Across the world, performance ground level concentrations at the there will have been variations around these factory boundary are well below 0.1 parts/10* and figures bearuse of differences in plant design or even these low amounts decay very rapidly with process operation. Even the way in which jobs distance.' In the band jH mile (Q.4-U6 km) were organized can have caused variations. In around one factory, for instance, the concentra some countries or on some plants workmen were tions determined are in the range 0.01-0.0001 employed specifically to dean out autoclaves paru/10*. (where, exposures, could have been very high) . while in others autoclave cleaning was part-only These figures should make dear that by far the ofa whole range ofjobs carried out by individual biggetf potential for exposure exists in the polyw- work people. Some;spokesmen have suggested,, merizstion section ofthe plant, since here 100 000 perhaps for full-timedeaners, exposure levels as ton* per year of a liquefied gas tinder pressure high as 3000 pans/10* in the early days f the are handled in a confined space, in contrast to industry^ other parts of the process and to the later down stream operations of the plastics industry. In With these very high figures as background, the these downstream operations the corresponding progress made by the PVC industry in the UK in quantities, this time in the form of absorbed reducing atmospheric concentrations since the vapour at a low partial pressure and not confined carcinogenic hazard of vinyl chloride became to a single geographic situation, range from 5 tons known in early 1974 is shown in Table 1, w hich down to 3 ib per year. That the polymerization also shows improvements made at all the other section ia in fact the area where hazard has interfaces described earlier in this paper. Al existed in the past is confirmed by the fact that all though, as we have seen, the exposure levels in the authenticated cases of vinyl chloride-related these other places are many orders of magnitude angiosarcoma of the liver throughout the world lower than on the polymerization plants, industry have been of workers engaged in plants where has aimed to reduce fugitive vinyl chloride levels ucc 006595 280 Proc. toy. Soe. Med. Volume 69 April 1976 22 at every point in order to eliminate concern wherever it might exist. With work still in pro* gross, all these figures will be reduced further though, in view of the effort already put in, it is likely that the polymerization plant atmospheres are approaching a limiting value of 2-5 parts/10*. some areas almost incomprehensibly lower - levels which prevail today. For it is on this, quite properly, that industry, and society generally, hare focused their attention in the past eighteen months. Table 1 DISCUSStOK Dr M D Kipttng (Employment Medical AdHsory rhwMm Jammer !9f* (rarulltn VCM la Nte imweiw -ISO (mUyamai) Jolt tttZ (jmrulttr) -1 Service, Binmntham) said that it was known that workers bagging the PVC powder were sometimes covered with the dust and that this powder contained I. i i VCM palHtonr vest in pmdaa 0.73% ofoutput Ol'/.o/ovlput 200-500 <50 formow ttoOm a percentage of vinyl chloride monomer. He asked whether any information was available on the particle size ofthe dust produced in differing processes through ir i UiMnieWIAi VCM tn pi*at luwxpfcra 2-15 <1 out the world and the incidence of vinyl chloride disease VCMJa FVC Souls -50 -1 VCMJa brnmeo Si 0.01 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 h 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 (he polymer and its putting cutrent plant performance and present downstream exposures into perspective, one with another, and in comparison with earlier figures (Table 2). particle size. Moreover, it should be remembered that all the significant medical effects under discussion st this conference (angiosarcoma, acro-osteolysis Ac.) had, throughout the world, been observed exclusively in workers on polymerization plants or. in two cues, plants handling rid vinyl chloride under pressure; t ri4 Table 2 BribtumutnimkiiiHinwnlwtb Features eomr.-.o :o all these workers were that they were exposed to vinyl chloride vapour in the aunosphere but were not exposed to PVC dust since the PadrSur itikttoer utlfkt) polymer wu maintained in aqueous suspension throughout this stage ofthe process. rollwnfrilli phm opmotat | IPOOpem/IO* 0J< It wu in the drying and bagging sections of the MmilatliipluiotnmiiMOpiiwio* 0.11 PVC-produdn; process that exposure to solid PVC nbw<OiiiM|ibnt|>mWM>ii --Spamne* FabMnplMt*iniKtpin/tt` Atme* UX cMMMhmirt iaewlioa to too4 .0.001* tow 0.000000004 particles could arise but. despite extensive medical investigation, no sicnifieant abnormalities had been found among drier operators or packers: It wu perhaps worth noting, too, that the greater proportion of PVC.powder wu of a panicle size similar to sand In later papers to this conference, a wide range so it did not generally pose an airborne dust problem. of diseases or. symptoms which have been For those powders which might came true dust ex i associated with or attributed to exposure to vinyl posures it had been customary in industry, because of t chloride will be discussed. It is important to note the nuisancs and discomfort factors alone, to provide I i that most, ifnot all, ofthese have been comraaed some formofrespiratory protection. by people who worked under conditions repre Dr C S Darke {Royal Infirmary, SMjfitU) said that he sented by the highest figures in the above table. had investigated 14 eases of brrtthlasiyn in workers Today no one is exposed to doses at this level. The exposed to vinyl chloridemonomer. The findmp were: exposure of workers fat' industry is now at least no abnormal physical signs: chest radiographs two orders of magnitude tower, while the general normal; routine respiratory function tests difficult to public in the UK absorb*, through foodstuffs, a evaluate but some results slightly below predicted quantity which is some fifty million times lower. values, especially impaired CO diffusion in 6 indi viduals; perfusion and ventilation scans showed While the conference win be concentrating striking ahwrmalities ts illustrated by one slide re vealing marked perfusion defects of upper lobes. One primarily on problems which have occurred in the patient underwent open biopsy of each of the three 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 alveolar wall thickening with macrophages in the i effects occurring at the markedly tower - and in alveolar space* *nd increased reticulin and collagen I t I 1 umihh" tiivenrew w. W.W4HWU..I' , _ ;V, -ijvr: ,j icQ A-. Vt.!* V- ,-'T - / 'V'' ; v ucc 006596 22 Hiensibly lower - levels is on this, quite ==d society generally. == in the past eighteen 2*nt Mtdleai Advisory 3t it was known that vi-wder were sometimes =this powder contained =3 monomer. He asked available on the particle raring processesthroughSnce of vinyl chloride Sr* particle sites of PVC ~y, depending on the SrC powder was made, ^produced all grades of ^ely that any medical --jilar manufacturing site S3f the polymer and its be remembered that ns under discussion at rial, acro-ofteolyiis Ac.) -=n observed exclusively flints or, in two cues, 31oride under pressure. 3otkers were that they 2t vapour in the atmoS3o PVC dust since the ~ aqueous suspension figging sections of the -exposure to solid PVC rrpitc extensive medical ^bnotmalitiea had been 3 or packers; It was " the greater proportion ^le site similar to sand 3*irborne dust problem. ht cause true dust cx_in industry, because of frSetora alone, to provide ration. 3. Sheffield) said that he ^thlesanese in workers r?ner. The tindinp were: 3: chest radiographs junction tests difficult to ;~ghtty below predicted -dp diffusion in 6 indi.filiation scans showed "rated by one slide rect of upper lobes. One :~y of each of the three -.jtoiog;' revealed foesI r macrophages in the reticuiin and collagen 23 Section ofOccupational A fedleme 281 formation seen on electron microscopy. No obvious vascular abnormality except on fluorescent examina tion. It might be of importance that some of the worst affected men were concerned in a polymerisation process that yielded `plastisol*, a very fine PVC powder with panicle sine around 0.8 tan. 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. Professor IJ Sdikoffi(Mount Sind SchoolofMedicine, City University of Hew 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 SO, obstructive findings were predominantly among cigarette smokers, is expected. After that age, however, the prevslcnec of changes was very much the seme 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 yean from onset of exposure, but that thereafter they were present in both smokers and nonamoken. Radio graphic changes were less common. Overall, 13.3% of 988 chest films showed linear, reticular or nodular changes characterized as 1/0 or 1/1 in the ILO U/C Classification. Dyspnaa was uncommon and signs or symptoms of chronic bronchitis were not striking (Miller ttai. 1978. Miller 1978). The pathogenesis of these abnormalities was not dear. 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 8 parts/lO* of retained vinyl chloride monomer, as welt as other agents added in the polymerization process. Inhalation ofsuch PVC particles might be associated with advene effect Froogia and his coHragwra <1974) had reported significant histopathological change* in the lungs of guinea-pigs exposed to PVC powder in a PVC plant In the polymerization (acuities invvstipiled by. Proftraor Sehkoff. there had usually been opportunity for PVC dud exposure as well as vinyl chloride exposure, either by a period of work with the polymer 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. refercncss Piwpi N, SMitwU A A Ittfurclli A (19%) A 32I-M2 Mill*? A11913) CitifMMfwil HtiHk Atrtffitttivt 11,247*230 Millr A, Tiimrii A 5. Clwfifit M A Wikid t J (I97.M A***lt of ,V# Kiwi Aendemy ufJtriwri 240,42*32 Dr KS Williamson (ICi Ltd, Central Medical Croup, Fulshaw Hall, Witmstow, Cheshire, SK9IQB) Review of Animal Studies Since vinyl chloride is a gas at normal temperature and pressure, inhalation is the important route of exposure in industry, and most animal studies have used this method of dosing. Many experi mental studies have demonstrated the very low acute toxicity of the compound. The acute in halation toxicity was studied by Mastromatreo */ at. (I960), who found that the lethal concentra tion for mice, ran and guinea-pigs exposed for 30 . minutes was between 200 and 300000 parts/10*. In long-term studies few toxic effects were re ported, though Torkelson ct al. (1961) found that inhalation of vinyl chloride resulted in minimal microscopic changes in the liver and kidneys of several species of experimental animals exposed seven hours a day to 800-200 pans/10* for sixmonth periods. No significant changes were found in any species exposed to 80 parts/10* for six months. In 1971, however. Viola ex al. reported that while attempting to produce acro-osteolysis in rats, they had found tumoun of the ceruminous glands, lungs and bones in animals exposed for 4 hours a day. 8 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 epidemiological and animal studies, many of which are still incomplete. The most complete series Of animal studies available to us are. those conducted by Maltoni and his co- workers (Maltoni 1973, Maftooi & Leferoine 1974). In thera experiments groups of rats were exposed to vinyl chloride vapour concentrations ranging from 10 000 to 80 paru/10* for 4 hours a day, 5 days a week, for 12 months. The snimals were then maintained for the rest of their lives unless they became QL Tumours of the cerumi nous glands, angiosarcomata of liver and other organs, nephroblastomata and a variety of other turnouts were found in animals exposed to vinyl chloride. In animals exposed to 80, 280 snd 800 parts/10* the logarithms of the numbers of animals having angiosarcomata and the foul tumour-bearing animals are linearly related to the dose of vinyl chloride, but in animals exposed to higher concentrations, this relationship is not found. Tumours have also been found in mice and hamsters by Maltoni and by Keplingcr el at. (1975), who reported the findings of angio sarcomata and lung adenomata in mice exposed UCC 006597 282 Proc. roy. Soe. Med. Volume 69 April 1976 24 by inhalation to 2500, 200 and 50 parts/I 0* of vinyl chloride. More recently both Maltoni tt ol. (1975) and Purchase (1975, personal communica tion) and his workers have found liver tumours in rats given high daily oral doses of vinyl chloride in oil. Neither investigation is completed yet. Maltoni et at. 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 Wtstar 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 animats 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 these very 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. Tablet an i-K.ImIm !< (<tt ofMstwO Vtnti'viian--100 ml ikjmi< tmVkw 14 sw pm i swnnw wtnsot4 in Wi|Mofnttmtmtmai m W 3001 rmuitm see zse se- pmyeiwtnt) nwiyetw <*/ <PM4xm&+) use j as is n. i- oo re itmaMiw (;*(** IS IS Table 2 Rat ^ara9 0aa4aa^4a4)aa It is of some interest to compare the doses 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 MwimHi VmilaiioA- 0a* s<r r*r B-fcaurthift Wi|hi Mtumi41* ht k* /#r**/W* SCO too se 10 t Orf/vOm mtire (**#* * ICfl 1230 12 J00 250 2500 125 1250 23 250 2J 3 OiilrSw <**:*ei ISO 40 It 4 44 W**)t<wtr *x2SP) 44.0 u 4,5 as 0.1 Green &. Hathway (197?) and Watanabe et aL (1975) have studied the pharmacodynamics and metabolism of vinyl chloride using "C-labelled material given by different dosing methods to rats. Both groups have shown that the proportion of the dose retained and metabolized is greater following small doses than large, though the absolute amount metabolized falls with diminish ing dose (Table 4). Table4 Ammo at -Wrt atmiit muWM *Tict Oiflatiac ii*ck Oam tn****** in rani att (Cram 4 Hathway 19759 OwNkf) # MO M 1V t 425 AmMfr mmMM 0 a 40 so OS NJ Amamt wmMiW 24 rs IJ.S 2.1 0JS Okie Three principal eliminative routes have been identified by both groups: expiration of un changed vinyl chloride by the lungs, expiration as COt by the Kings, and excretion of metabolites in the urine. The proportion of vinyl chi ride eliminated by these different routes varies with dose (Table 5). Wr Mtfceal <***> 90 ISA u IMSw ltei IW* 4.e u TaUeS 9riMHhtlt ritli wKw pi Hayt dhrUtftamtH hy wwh iwiMI (Cm* A Hathway 1979) PdkIum JOO (iZJeoHU 10 s OiwnoM rue 3-70 44' Dm* 0-25 450 U+ekmfi G* UHmtmftmMtn 4 11 tS 93 ! iMm*1 ucc 006598 t* ' ; " '* * * ' --h 5^* ./*? ' ,t ** v,, t 1 , * ' f* . r '. . - *' . v. ' - v * , '** % 7 * ,, *.-- - -* , ,. , - --; ^ * # _ t * T` * ,.--7``.* ^"v V`V '"' '* * I'm', iH -'' - ~-tsm.k--f^r'tV^v^'-*- 24 'i to compare the dotes :S: long-term studies with crses for men exposed to concentrations of vinyl ;;-3). Again the calculated St very rough indications pyt a useful measure for V^iyn QUfydut Omits) iso 40 tt 4 0.4 Ammsi** <r/*OMMr OntxlSO) 444 U 44 &i at Up5) and Watanabe tt al. ^pharmacodynamics and vsoridc using "C-labelled t dosing methods to rats. _?iji that the proportion of metabolized is greater han large, though the Cized falls with diminish* .`.McvmoB 13.1 "5.J* jvative routes have been vi>ps: expiration of un> pay the lungs, expiration = excretion of metabolites Crtion of vinyl chloride trent routes varies with V.1 0 mrtmhmlltft 25 Section ofOccupational Medicine 2S3 Major metabolites identified in the urine arc: <l) thiodiglycolic acid: (2) S-(2-chlorcihyl) cysteine and N-acetyl-S-(2*chlorcthyl) cysteine; (3) urea. Thiodiglycolic acid is derived from monochioracetic 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 er at. (1975) have reported progressive depiction of the hepatic nonprotein sulphydryl content (equivalent to gluta thione in this context) in rats exposed to 1000 and 250 parts/!0* vinyl chloride by inhalation. No such depletion was found following exposure of rats to 10 parts/10* for 7 hours. Hathway (1975, personal communication) considers that the ethyl cysteines themselves may vveil be mutagens. Thus work bn 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. URMXta G*-- T a HuWirDZ (Ittt) OWKSMefllWwnlM n. S45-5S1 KpfcewMt-G--SeJW.CfS--PtaCiheiraJC (lSMaHbV<WJV YmkAt^tmrrfSthunsl44,3lt-K4 MOWC (ITO) grarpts \tr4cw tm*nmtk*mtCmosrru Serin ITS, 4 Makai C CJBWnt A, Gima. L a CMm* p (is?*) ett OiftCaSSetts iw z. M-* MMC*lilllilC (1*74) Umri-tteeMenu!Srlti Close Jt , SeUmte fitkhe. .UWMMr r ,VnMl SS. 1-11 XtatmaMMW E. FWnrA M. CMni* H a Ouifctr H (ISM) Amtrtan ImduutlalHrtiese StmrlaiimJournal It. JW-WI ThMh- T R. Oj hi F * * V K (INI)ywWM IsAiariul Htrfieitr'AateluriaaJuueuulil. 3S4-JSV VMi P L. Ktmi A C CaMM A (ItlnCwn jw*JI.5IS-*21 H'ltuiWP r,. HttatrK Ulr.SttCrmuOK A CehtMufJ (I97M Pnfrrit Rtrott is N:snvjf*.`iurint OutnauAuotiaiica Tuk Croup on vinyl Chtnrid* Rnwch. Wnhinfian DISCUSSION* Dr L Mages (MAC Toxicology Unit, Carthoiton) 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 rero-efTect 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 E Stokinger (Toxicology Brandt, National Institutefor OccupationalSafetyand Health, Cincinottl, 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 chloride: N-acetyl*S-<2-hydroxycthyt) 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 scries ofdecreasing exposures of rats the find ings were: at 1000 pans/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/10Va plateau of the saturation curve; at 10 parts-iO*. no disturbance in the amounts offree SH. Inferences and conclusions: (1) From the fact that h*mangtomas occurred in the liver, and not in the lung (the primary site of entry), it could be inferred either that little or no vinyl cMoridc metabolism to free radical occurred in the- lung, or that there was ample free SH to scavenge the vinyl radical. (2) Mon important, the lives 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 fens of thousands of workersexposed only asmall handful ofhxmangiomas 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 2$0) of vinyl chloride in PVC plastic wrappings of foods; the United Slates 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 ehronic diseases. ucc 006599 -e-^-X'CJ- ~>v*-^V . -.-'''ffirffa-'-'.-^j I 1 284 /7oe. ray, Soe. Med. Volume 69 April 1976 26 1! -I- Clinical Aspects Methods of Vinyl Chloride Disease All patients had the following regions examined by plain film radiography: hands, feet, shoulders, I Dr B J Preston, elbows, knees, ankles, pelvis, chest, skull, man dible and spine. Case 1 (AD) also underwent a Dr K Lloyd Jones barium swallow, meal and follow-through, angio end Dr R G Grainger. graphy of the hands and serial films of the hands L (Departments ofRadiology and Rheumatology. at 6 months and 2 years after presentation, and a Harlow Wood Onkoperdie Hospital, . near Mansfield, film of the pelvis at 2 years. and Department ofRadiology, Northern GeneraI Hospital, Case Reports Case l Sheffield) A D presented at the age of 33 years with symptoms of severe Raynaud's phenomenon, pain in many joints, Acro-osteolysis trismus, and thickening and tightness of the skin. He The word acro-osteolysis means dissolution of the had been engaged in the polymerization processes of i extremity of a bone and it is applied to the distal phalanges of the hands and feet. There are vinyl chloride for 3{ years, A radiograph of the hands (Fig 1) showed dissolution of the central parts of all else terminal phalanges except for the little Angers, many causes, c.g. scleroderma, psoriasis, hyper erosion of all the terminal tufts, thinning of the central parathyroidism. sarcoidosis, ergotism, diabetes, parts of all the middle phalanges but particularly !, tabes, syringomyelia, familial and idiopathic those of the little fingers where there is extension into i i. ] acro-osteolysis. A similar appearance may occur 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 ] corded by Cordier et at. (1966). Wilson et at. both ulnar styloid processes. In addition, soft tissue \ (1967), Harris & Adams (1967), Dinman et at. thickening was present over the w-nst and the whole of the hand. A film of the feet ihnwed acro-osteolysis of 4!. i- : !' (1971), and Lange etaH 1974). We would like to present the radiological the terminal phalanges of both big toes, a large erosion in the head of the left first metatarsal bone 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 intermediate in the production of polyvinyl chloride. J> cuneiform bones. The radiograph of the pelvis : a: -i i I I Fig 1 Caw 1 Hands IJJ.7J), thawing transverse defects in distalphalanges, osteolysis, erosions endsoft tissue thickening i ucc 006600 M1,,: ; . '}M v.v.*a -VSJ rtf ikying regions examined hands, feet, shoulders, _||vis, chest, skull, man* =AD1 also underwent a ~fot1ow-through, angio~3ri*l films of the hands '^ter presentation, and a =? years with symptoms of Son, pain in many joints, -Rightness of the skin. He ==ymcrizaiion processes of ~ radiograph of the hands '=f the central parts of all =~pt for the little fingers, Sts, thinning of the central flanges but particularly j==re there is extension into EEIle and distal ports of the ~ng and little fingers and ~ sderotie marpn at the =3arpal and at the tips of -- In addition, soft tissue ^te wrist and the whole of howed acro-osieoiysit of __both big toes, a Urge ;2cft first metatarsal bone : Itead of the right first vH medial and intermediate 'heliograph of the pel\is ,::j * * . . .. *, ' -1 - ;'' y < ^-`L.. -V _ ''^ 'ilinirFf- ., .." .. - -' - .-., _ , ^ Section ofOccupation/!/ Medicine 2S5 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 bin in the left hand there were occlusions in the digital artery on the ulnar side of the thumb and radialis indicia 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 radialis indicia artery and medial digital artery of the little finger was shown. In both hands, hypervaseularity of the terminal tufts was recorded. Fig 2 Case t Mandible, revealing markederosion of ascending rand Case I F P. aged 31 years, had been engaged for two years in the manufacture of polyvinyl chloride. Aero-osteolysis was recorded in both index fingers and the right thumb. Erosions with a wetl-conicated margin were visualized at the base of the right first metacarpal bone, medial epkondyle of 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 ulnarstyloid processes. revealed large erosions around both sacroiliac joints, 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 cpicondyles of the right humerus, medial condyles of the left humerus, both olecranon pro 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 ifiarked thinning of the bone: on the left side this extended upwsrds.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 the hands recorded tbe following changes: fa) central' defects In the distal phalanges of the little finger; (6) further osteolysis, particularly of the bases of the distal phalanges: U) periosteal reaction along the proximal phalanges of the left thumb and index finger, and . right ring finger: id) shortening of the distal part of the finger. Radiographs of the hands taken 2 yean after presentation showed even further 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 aeroosteolysis of the big toes in the first 6-month period (Fig 3) but on the 2-year film there appeared to be Case} D D, aged 2S years, had been involved for 2 years in the processes of polymerization of vinyl chloride. Thi skeletal survey revealed no evidence of acroosteolysis or any other significant abnormality. Fig 3 On* t Feet, six months afterpresentation >"v*V. IW-WJV L, *..* 1 w, altlj ucc 006601 2S6 Proc. toy. Soc. Med. Volume 69 April 1976 :$ Ctx4 D W. aged 44 yean, had been working at the factory for five yean. 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, tn Cases 3 and 4, no specific changes were encountered; in Case 2 only moderate changes were recorded whilst in Case I, 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 REFERENCES Ch#*?VYD (IMS) American 94,595-91? C*f4*r J M, Ffet* C* UMU A 09*6) Cmkirts 4f Mid.-rim* *is DmM B Dt C*k W A, Whiiitow W M, HJ 4 Dtotofc T(I97|22, 61-7) Gifnkf B t A Sim D M (1957) Aerfftfecr *9,559-2*5 HimtOK AA4WGF (IM7) MrUisk \UJ**Um#**l iU. 713-7 14 LuctCEiJMtS, Sttfi G 6 G (HT4) Imtrmmtomtlrs AriArfir A 11. |-)3 U*i.l W, B Mat IIA Sc*|J T (19*7) MtuishJjuntmt of 4*, 740-T47 Mintol! T K Notm* D, OmWt W F & KiUm M L (!t**> AtoSMtaer #*. 299-m C G, Cut*** F f 4 WiBU W u (19*0) 4Mrr^M/MfiW4/4riVff>(4i^'lt)<6r-69t RmJ A (1970) In: Sjm^iMiir. Oiiium. B4- A M Jcllifft 4 1 Strickltiid. Usififuom. (4inbvr|fi 4 tv )]U)24 WOm* n H. McCmnmcU w . Tim C F 4 Ciwk J L (19*7) /wm/i/fif Amttitm* Meditmi Atmimti--t 101,577-511 that personal idiosyncrasy mav be an important factor in the wide variation of the radiological DISCUSSION findings (Wilson et ol. 1967). Dr L Magos said that Dr Preston's Case 1 might be Idiopathic acro-osteolysis aggravated by exposure to The changes in the mandible in Case I have vinyl chloride. In the two-year follow-up study Dr not been previously described in occupational Preston had found improvement in the fingers, which acro-osteolysis but it is interesting to note that were usually involved In occupational vinyl chloride atrophy of the mandible in idiopathic and familial acro-osteolysis. and deterioration in the pelvis. acro-osteolysis has been recorded by Greenberg Si Street (1937), Papavasiiiou et at. (I960), and Cheney (1965). Dr B 3 Preston replied that idiopathic acro-osteolysis was considered in the differential diagnosis of Case I but the distribution of the bony abnormalities other than those in thu hands was different from those Ross (1970) stated that the bone changes recorded in idiopathic acro-osteolysis. regress after (he sufferer is removed from the hazard but in our Case I the serial films of the. Dr K Lloyd Jones added that Dr Preston's Case I also hands, feet and pelvis indicated that the acro- had severe involvement of the skin by the scleroderma- osteolysis was extending. Fragmentation of the remaining tufts has been described as part of the healing stage by Wilson et at. (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. like condition seer, 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 The stenoses and occlusions of the digital employed as a production worker in a 7VC plant and arteries and increased vascularity in the pulps of had never been exposed to vibration or the use of the fingers recorded on the arteriograms in the power tools. first cue have also been reported by Lange et of. (1974). Narrowing and occlusions of the digital arteries are known to occur in Raynaud's phenomenon (Marshall ei 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 ol. (1974) Dr Ante E Walker suggested that the dense vascular rete of the (Royal Hospital. terminal pulps of the fingers was due to stasis of Chesterfield. Derbyshire) contrast in the vessels secondary to the shortening of the phalanges. This may be partly the case but Clinical Aspects ofVinyl Laws ei al. (1967) have observed hypenemia of Chloride Disease: Skin *.nc pulps cf (he fingers in a case of clubbing due Industrial acro-osteolysis. a triad of Raynaud's to bronchial carcinoma and a similar mechanism phenomenon, sclerodermatous skin change and may apply in our cue. as there is a strong clinical lytic bone lesions, has been well documented as resemblance to clubbing. occurring in workers engaged in the poly- ucc 006602 :s {wlntrl4.292-617 - te S+nto A ijnli, 14-1* W M, Miihm II1 & Hr*UkU,tl-11 3 KnOalBgrtt, 239-1*2 .11-11* ::-ti C --T .;X. 740-747 V,llk WL vMfatru.tn-**! :l4vfli.E.AMME'* .V*h * LoaOoo; pp J2I-I24 mCFXOwiWL ik*tAvrittUm 201, 277-<I nreston's Cue 1 might be >sravt*d by exposure to ijcir follow-up ^tudy Dr ment in the Angers, which zCupniioiul vinyl chloride Ration in the pelvis. iiidiopethic ecro-ostcolysis 3ntnl diagnosis of Case I ibony abnormalities other os different from those steolysis. : Or Preston's Case I also ;i shin by the sclerodermachloride workers together :;tsystem involvement. It if combination in a vinyl :: (autoclave floor worker) ^cro-mtcol>sis. It was not 5mit this pafifnt td biopsy phalanges. Biopsy of the 5een umewarding. He was sprker in a PVC plant and 3 vibration or the use of 3 a ! v a triad of Raynaud's 5tous skin change and ;an well documented as ngaged in the poly !9 Section ofOccupational Medicine 2S7 merization of vinyl chloride monomer (VCM) to polyvinyl chloride (PVC), Medical surveys of large numbers of employees have shown an incidence of approximately 371 (Wilson at td. 1967, Dinman et at. 1971). Both these studies also suggested that the disorder was largely confined to reactor cleaners. In 1974 Lange et al. described a more general ized disorder affecting men engaged in the manu facture of PVC They observed splenomegaly, thrombocytopenia, liver damage and impaired respiratory function, and these changes occurred both in the presence and absence of clinical and radiological evidence ofacTO-osteolysis. Clinical Study In February 1974 I saw one man with severe Raynaud's phenomenon, minimal bone changes in the fingers but no evidence of scleroderma. He was employed as a reactor operator at a local firm which manufactures PVC. Between February 1974 and February 1975,36 of the men employed at this plant were referred with symptoms thought to be due to exposure to VCM. The study covers 37 men aged between 26 and 39 years (average 40 years 2 months). Length of employment at the plant ranged from 9 months to 34 years (average 2 years 8 months). Thirty workers had at some time been reactor operators, 4 were maintenance men, 2 worked as `baggers' and 1 was a warehouseman. The presenting symptoms ate shown in Table 1. The commonest complaint was of excessive fatigue: men claimed to be excessively fatigued after minimal exertion and also reported somno lence, Coldness of the hands was also a frequent complaint. Obviously these subjective symptoms were difficult to evaluate or measure. However,- one feature was noteworthy: 36 of the 37 stated that on at least omroccasion they had felt overcome by the vinyl chloride fumes, describing them selves variously as `unsteady', 'slightly drunk* and Tabkl Symmm CntAtaMi rwealmia Impair,4 jilypo-tr coie Cm Attapiakeaa AtlM i 11,111Clip Diwmi Kjcwaiva fatlpva Lon ornate* M I* IS i* IS 17 22 ti `rubbery-legged', and this suggested that the men had been intermittently exposed to very high levels of VCM. which in experimental studies produces anesthesia. These symptoms were most frequently experienced when men were hosing down the reactors during emptying, but also by men when inside cleaning the empty reactor, and by maintenance men when unblocking pipes carrying VCM. None of the 37 men had evidence of sclero dermatous skin change. One man previously employed at the plant had extensive sclero dermatous skin change affecting the hands, fore arms, face, trunk, thighs and d num of the feet; additionally he had extensive lytic lesions of the bones, phalanges, feet, pelvis and jaw (K LloydJones, personal communication). In 3 men there was clinical evidence of Raynaud's phenomenon; in 2 it was a marked feature, with rapidly occur ring colour changes IVom blue black to blanched white to a flushed pink. Individual fingers on the same hand might show a different colour change at any one time; on one occasion I observed a harlequin effect; the index finger was blanched white on the radial side and blue black on the ulnar side. Eight other men described symptoms of Raynaud's phenomenon but at examination only had rather cold hands. Coldness of the feet was a common complaint, but difficult to evaluate clinically. During the last year 4 men have shown some thickening of the skin with limitation of extension of the fingers and mild `clawing' of the hands. These changes become more marked when the hands are cold. Of the 37,4 developed a curious swelling of the face, largely periorbital and tending t improve in wanner conditions; the swelling was firm, and suggestive ofscleradema rather than scleroderma. Skin biopsies were obtained from the dorsum of the hand in 13 men. The epidermis and adnexal structures showed no abnormality. In the dermis there was some destruction of elastic, tissue, but H was probably a normal aga change. In one man with severe Raynaud's phenomenon the dermal arteries showed some medial thicken ing. 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. ucc 006603 2S3 ' Proc. roy, Soc. Med. Volume 69 April 1976 JO 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 Anger blood flow was also abnormally reduced on cooling and slower to return to normal. Immunological studies have shown a high level of ayoprecipitate in the symptomatically affected men (A Milford Ward). 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, sclerodermatous skin change was not observed. However, 5 had severe Raynaud's phenomenon and at least 5 others had abnormally cold hands which interfered with their normal dexterity. These circulatory changes are only a part of a generalized disorder which may result in dyspmxa, cramp-like pains in the limbs, paresthesia, exces sive fatigue and, in some cases, impaired liver function. The symptoms may be severe enough to limit normal activity and may occur without changes in the hands. The relative sparsity of clinicd change in the skin or evidence of pathology on biopsy contrasts with the marked sclerodermatous and plaque-like changes described by others (Cordier ct at. 1966, Harris A Adams 1967, Wilson et al. 1967). Perhaps the early recognition and removal from exposure prevented more severe skin change in the men under observation. Most of the above 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. In my series them has been little improvement in the vascular signs during the period of ob servation, and this b in accord with the findings of otben (Adams 1974, personal communkation and M N Johnson 1975, personal communica tion)..However, Suchi describes the disappear ance of Raynaud's phenomenon within one yew (Suchi i d. 1963). In two instances cervical sympathectomy b recorded as producing clinical improvement (Takoucbi A Mabucht 1973. Markowitz e/ef. 1972). At the present time it is not known whether the peripheral vascular disorder b directly related to the presence of circulating immune complexes or to some other alteration in the sensitivity of the vessels to exposure to cold. REFERENCES CMdiwJ M, Flrvn C, Ltfeww M J t Srrra A (1944) Ctktmdt Mdtti*r At Tttvmtl*. 4 DiMMa B D. C--k W A* WfrttghpbM W M A --i~t H J tin* D K ft Aiv W C F <!947) Sntuk Afp4lemiJ*rul ft, 7!l*7U ltffCI.JttflSliw(; VgltmtC 09U) fmtwrmatbmU* Aixfi * Hit 32* I *UHi*vfesSS,McDMt(tf AKtqwMS (1973) Afd**et dffki wwi ou*gj 144,319 Ml,Df^H14VflliikiM (1943) Mrtklm /wm (IwM 15.947 TilMtMYIMMi C 15.355 4lMKH.M<Md(W^TitCF40M^JL AMfaM AuwMm 351.577 DISCUSSION Dr Lm DJcnssi (.Deportment of Occupational Medi cine, Hoi/P, Israel) said that in one patient in his scries the presenting syndrome of vinyl chloride disease was a pale tnoonlike face. This particular type of sclera, dema (not scleroderma) had already persisted for five yean after exposure had ceased. In one case of scleroderma-like syndrome a skin biopsy showed no change in elastic or fibrous tissue but several areas of perivascular mfiltrarion. small round nuclear cells, mostly lymphocytes and larger mononuclear elements. In one case of Raynaud-like phenomenon which started about eight months after initial exposure, the manifestations usually appeared two or three hours after work began, and the full-blown phenomenon could be observed on the shop floor. This tame patient left the factory because of lot* of libido, and Dr Djctassi wondered whether this was an immediate transient complaint due to the narcotic effect of vinyl chloride monomer, or a prolonged disturbance con nected with the vinyl chloride disease as stated by Dr Anne Walker. Dr Am Walker, in reply, said that the sclerademalike.changt observed in 4 of the men varied consider ably from day to day but in two men had persisted for timet eighteen months after the last exposure. In 15 biopsks from 13 patients an exeem of inflam matory crib in a perivasculardistribution were present in 4 of the specimen. The cells were largely lympho cytes. Loss of libido waa the presenting complaint in one patient and had persisted since the man left the firm approximately three years ago. in 3 of the workers complaining ofimpotence, urinary excretion ofandrostcrone and dfliydroepiandrosterone were very low. These measurements were nude approximately twelve months after the last exposure to vinyl chloride. Dr Maries M Key (L'nirersity of Texas School of Public Health, Houston, Texas) asked if baggers and warehousemen had previously worked aa reactor cleaners. Dr Amm Welker replied that they had not. Usually men started as baggers and later became reactor operatives and cleaners. The one warehouseman had JO HJ n,n-n t: ~-jW.Sl.l rEHWtlmMMS 3*7 '=^,115, j*j ^raowihJt, ~ itartmimtU.m f ZZ I %f Occupational Medi um paiieat in hit jerie* iart chloride disease was VSicukr type of scierocijeedy persisted for five ^Hke syndrome a sJdn --anic or fibrous tissue |6!*r infihratioo, small ijtnphocytcs and larger 3 phenomenon which r initial exposure, the 1 two or three hours 3-biown phenomenon :ibor. This same patient ;?* of Kbido, and Dr bs was an immediate Viarcotic effect of vinyl =gtd disturbance con-disease as stated by -jthat the sctcroedcmaTimen varied consider* jSncn had persisted for 3last exposure an excess of ttdlam* 3ribution ware present 3**rt larpdy lympho* Stag compMm in one nan id! the firm i of the workers gEretionofandro* were very low. approximately .0 vinyl chloride. a of Texas School of fftsked If bageers and = worked aa reactor had not Usually :-ter became reactor warehouseman had 31 Section ofOccupational Medicine 289 never been in a reactor. One of the baggers had spent an initial training period es e 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 Prtmysl V Pthmr {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 27*C for one- hour, then the room wss cooled to 10*C for the next hour and finally the room temperature was raised to 27*C for the final hour. During the three hours foul finger flow in the index finger was measured by means of a pkthysmograph and capillary flow in the middle finger by electrical impedance. Additionally, the sldn temperature on the back of the hand was measured. Dr A Milford Ward {Department ofImmunology, Hallatmhire Hospital Medical School, Sheffield, SIO 2RX ) individuals from the factory who were completely asymptomatic. The major features of the disorder indude hy* perimmunoglobulinxmia, cryoglobulinemia and cryofibrinogeiuemia. and in tiro 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 ceil 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 litre but rheumatoid factor is universally negative. Immur.ofluoresccnt examination of . biopsy material from skin (8 patients), muscle (1 patient) and lung (1 patient) has shown the presence of circulating immune complexes, with deposition on vascular endothelium and ooduston of small vessels. In those vessels which show subintimal proliferation, and luminal occlusion, immuno globulin, complement and fibrinogen are present in the subintimal legions of the vessel wall. Evidence oran Immune Complex Disorder Experimental evidence on the metabolism of in Vinyl Chloride Workers vinyl chloride suggests that at least part may be The occurrence of Raynaud's phenomenon and taken up by the liver and become incorporated loss of bone density in association with dermal into aminoacid synthesis. The incorporation of thickening which constitutes the syndrome of the chloride radical into protein synthesis could acro-osteolysis (AOL) has been recognized in the result in a structurally abnormal protein which vinyl chloride industry since the mid 1930s. but would react as antigeniciRy'foreign* material, the overall frequency of the syndrome has been low and no series have been subjected to thorough * The association of these experimental data immunological investigation. Recent studies have with the observed immunological profile allows indicated that the disease process is not corillned the construction of a theoretical model of the . to the skin and skeletal tissues, but is a multi- disease process. The initiating sequence is at system one with involvement of many organs and present speculative and remains to be proven by tissues. further study, but the later sequence of events can be adequately explained by the immunological i Immunological and immunochemical investlga- abnormalities. Structurally abnormal or attri tion of 53 workers from a single factory has genially 'foreign* protein escapes t lcrance and . revealed evidence of a chronic soluble complex incites an immune response with B-cell prolifera- disorder in 21 individuals. The extent and severity tion and hyperimmunoglobulirannia.The immune i ' of the immunological abnormalities parallels the complex formed by interaction of the antigen and * clinical features to a large extent, but some indivi- antibody is cryoprecipitable and will activate the duals show laboratory evidence of an active complement sequence. The cryoprccipttate and disease process st a stage when the clinical the reactions secondary to complement activation features are minimal or absent. Circulating will produce vascular occlusion and fibrinogen/ immune complexes were demonstrated in 9 out fibrin conversion and polymerization, of 10 individuals who were severely affected clinically; in 7 out of 15 individuals who were The frequency with which abnormalities have symptomatic to a degree that they were incapable been detected in this scries, especially in that of active employment; and in 5 out of 28 indivi- group in whom there were no even clinical signs, duals who were symptomatic but able to work, suggests that the disease process may be more 1 Immune complexes were not detected in 5 common than generally supposed. The theoreti- >re ucc 006605 290 Proe, roy. Soc. Med. Volume 69 April 1976 32 cal. and at present speculative, initiating sequence of reactions in this disease process also raises the question whether other unsaturaied halogenatcd hydrocarbons may also be involved in a similar chain or 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 Lao Djerassi said that fatty liver might be the early histological change in liver caused by vinyl chloride, la one of hit 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 shunt were indicated because of osophagcsl bleeding. The patient's condi tion improved sufficiently to enable him to work full time on a nonsutnuousjob. Dr A Milford Ward replied that the classification used in this study was a clinical cine, based on history, physical examination, and an assessment of the patient's ability t0 continue his employment, t; therefore included such aspects as splenomegai , acro-osteolysis, and scleroderma. Dr E Vigilant (Af/fen, Italy) asked whether the presence of B and T in the tissues could be detected by im munofluorescence. Dr A Milford Ward replied that lymphoretieular tissue was not examined histologically or immunologieally 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 Lflls (Afount Sinai School af Medicine, flew York) asked whether immune complexes were found in (be kidney. There were in the literature a number of oses 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 elinical evidence of renal disease, and it was not considered ethicallyjustified to biopsy the kidney in the abeence of proteinuria or hrematuria. Antibodies to renal glomerular basement membrane were not detected. Professor Margaret Turner-Warwiek {Cardioihoraeic Institute. Bromptan Hospital'. London SW3\ asked what was the cause ofthe T cell depression mentioned, and whether the spontaneous sheep rosette T cell counts were confirmed by other in ritro tens such as PHA transformation. Was there evidence whether C3 conversion was triggered by the classical or by the alternative path way? Was evidence found of immune complex deposition in capillaries of the skin and lung aa well as in the Isrger vessels mentioned ? Dr A Milford Ward replied that the cause of the T cell depression was not dear, but it was a feature often teen in circulating immune complex disorders and in autoimmune states. The low rosette counts were pertiatty confirmed by mild depression of the PHA tmafvity.ofthe peripheral blood lymphocytes. Comptement activation in vinyl chloride diacatt was by the dasrie pathway with conversion of C* at well es O. as would be expected with IgG dsis antibody directed tprfrnt the antigmic groupie*. Immune complex deposition was found in capobriss and small vessels In skin, minds and lung. Dr L Mages said he would like to see the patients classified by grade, since it was always frustrating to read of `severely afleeted' people without knowing what `severely affected* meant. The grading could be baaed on degree of splenomegaly, acro-oueobsit, scleroderma &c. Dr IF H Purchase, Mr C Richardson and Dr D Anderson (1C! Central Toxicology Laboratory, Alderley Park, near Macclesfield, Cheshire) Chromosomal Effects in Peripheral Lymphocytes Vinyl chlcri... produces liver tumours in animals exposed by inhalation (Maltoni & Lefemine 1974) or dosed by the oral route (Maltoni et al. 1975. Purchase 1975, unpublished). Epidemio logical studies demonstrated that workmen exposed to vinyl chloride had an increased risk of developing certain tumours, particularly hepatic angiosarcomas (Creech &. Johnson 1974). In common with other carcinogenic chemicals, such ss benxenc, recent studies hive demonstrated that workman exposed to vinyl chloride have an increase in the percentage of lymphocytes with chromosomal abnormalities (Funes-Cravioto et al. 1975, Dueatman et al. 1973, Purchase et al. 1973). Studies of this type carried out on lympho cytes recovered from peripheral blood provide aa easy clinically applicable method of assessing damage to living cells caused by carcinogenic chemicals. If there ts a quantitative relationship between the percentage of chromosome abnor malities and the amount ofexposure to the chemi cal, the estimation of chromosome abnormalities s * q g*f r c c r c e l e w r a t h lE h h c bh Or O- Cm Or Cc a. d sj 32 Hat the classification used .Bone, based on history, ;.`jan assessment of the iBs his employment. '! greets as splenomegal . __ ~ jed whether the presence 5: uld be detected by iro- 33 that lytnphoreticular .--lolofkally or immuno- and B cells could not. 3B cell counts were per* liirfoef of Medicine, Hew 3s completes were found i3e literature a number of Some In persons exposed B?t renal tissue *wjs not :=3tienis showed clinical it was not considered is kidney hi the absence of := Antibodies to renal :3ne were not detected.' Ezchardson .tt* ^oratory, fjzficld, Cheshire) :~er tumours in animals rSVfaUoni & Lefemine route (MaJtoni et at. tiblishcd). Epidemic tad . that ' workmen ^had an inaeased risk rjumouri,. particularly gbcch & Johnson 1974), |iraoog*nlc chemicals; 3ies base demonsrrated i|tdnyl chloride have an 3 of lymphocytes with iips (Funes-Cravioto et 3 197S, Purchase et aL Berried out on lympho* Bieral blood provide an ^ method of assessing Bused by carcinogenic Bantiutive relationship f7f chromosome abnorBexposure to the chcmi* Brtosome abnormalities I *5*; A-:'vjy* *47+2***%"*- Sin if if ~*) i iili*rf?**T1"*ieVitfi 33 Section ofOccupational Afcdicine 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, none*posed workers from the same industrial she, and nenexposed control subjects from another environment. The exposed population has been divided into groups based on the type of work carried out: Group I are autoclave operators; Group 2 are maintenance workers who have worked in the polymerization plant; Group 3 are those who work in polyvinyl chloride (PVC) 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 II 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. AO 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 drag treatment were excluded from the study. The results of the chromosome analysis are given in Table I. 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 oelb m various groupc is compared, it is seen that Groups 1 and 2 had higher percentages than Group 3 and thg control group. Thedifference between the com bined results from the exposed groupe and the control group it statistically significant. Thesis results confirm the findings of Funes-Cravioto Table I IWM te PVCsmIhH> (B MS Cute ilsuMlI twites to SmSw Atn* HM Cmsl Grate J Crawl Crate 4 Cwitrotsen site Cornell offsite Mi v PC*to Wmker* C/J It W4 31 a3 9 as It XI If 3-S 5 IS CVCtto CSCtto <%) i 1.72 0.4* 1.49 &J0 1.9 was 1*19 0.41 0.99 0.10 0J0 M0 et a/. (1975) and Duestman 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, 10000 or 30000 paroHO* 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 wes no significant increase in arty 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. XEFZXENCES awtateREAPSwMC (ISM) tanwMtmlHttodtwim Ktlotr S. MS OwtJUJiteiiMX (tffQte^VOmwiteiliMtev IC150 DmmA. HliwUWW K C SsHm* IJ (1*55) MUste JtaMK* SI, It) FateCniliw F. LraiMt >, Ltejtea J, DmaWri l Nstenira A T * OwnMbr5(1*55) tent i. 45* Makwl C, CKteiti A. Gtente L a OWt* F (1*55) OwteUrSMte 15m 2. SMS MikMC*UMteG (1*54) MwwmIJtrawe* 5. JS5 FmImm IFH.SMuWaaCRe AaSxuaD (l*55)ZteM*>S.4IO Dr SyMa D tide (ffeywf Mandat Hospital. Loudon StVJ) asked were the chromosome breaks distri buted at random? Was a banding technique toed? Were the people who actually had symptoms separated out? Genetic effects on human gonads were not absolutely excluded by negative results in s dominant lethal experiment fat mica. Was there any evidence of lower fertility? Dr I F H Purchase replied that the chromosome breaks were distributed randomly. No bending 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 sunested thet genetic effects did not occur in the gonads and no effect on fertility was seen. ti ` " ,*<f* *#*W * t* . 4 i ucc 006607 292 Proc. toy. Soc. Med, Volume 69 April 1976 id Or L dc Boer (The Hague, NetherlandsJ said that Mrs T Flcig had reported (MedichemConference on Chromo some Aberrations. Milan. October 1974, in press) on chromosome studies in which there were not more abnormalities in the exposed (roup compared with a control group. sis. portal hypertension, eesophagcal varices and splenomegaly may be common results of VCM toxicity (Marstellcr et al. 1973. Smith & Williams 1974, Makk et at. 1974, Thomas et al. 1975, Lange etal. 1974). Dr I F H Purchase said that his was the third study which had described such abnormalities, the other being those by Funes-Cravioto et al. (1973, Lancet i, 439) and Ducatman et al, (1973, Mutation Research 31,163). Dr D G Sadtb (Zerelit Ltd, hlewartk, 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 autoclave (3 and 4), assuming that the autoclave area was the one ofmaximum 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. DrK J WTajlor (Department ofDiagnostic Radiology. Yale University SchoolofMedicine New Haven, Connecticut, USA), Dr J J Barrett (Department ofNuclear Medicine, King's College Hospital, London SES). DrDMJ Williams (BP Chemicals International Ltd, Sully, Penarth, South Glamorgan), Dr PM Smith (Department ofMedicine, tVelsh National SchoolofMedicine, Uandottgh Hospital, Penarth, South Glamorgan), and Dr B W Duck (Occupational Health Unit, BP Research Centro, Sunbury an Thames) In view of these adverse reports, a survey was undertaken of487 workers with v arying exposures to VCM by two of the authors (Williams et al. 1973). Full blood pictures were obtained and standard liver function tests were done. Two. patients identified by a thrombocytopenia of 72 000 and 43 000/mm1. and slightly raised C-glutamyl transpeptidase G*GT levels, were subsequently found to have periportal fibrosis, portal hypertension, splenomegaly and tzsophagcal 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 noninvastve method for visualizing the liver and spleen in workers exposed to hepatotoxic agents. Initial results proved encouraging (Taylor et al. 1973, Williams ef el. 1976). Although ultrasound has been used as a diag nostic tool in obstetrics for many years, the tnstrumentation* was comparatively crude since the relevant echoes to be displayed were of large magnitude and did not require sophisticated instrumentation. Kossoff( 1974) developed greatly improvtd 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 air 1973, Taylor &. Milan Preliminary Resits of Grey-scale Ultrasonography In the Detection ofVinyl Chloride Related Liver and Spleen Disease A number ofcase 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, less dramatic changes including periportal fibro `N/truap.moe- ucc 006608 b r- ^ophageal varices and ;:fi:inon results of VCM ^>73. Smith & Williams S Thomas er /. 1975, reports, a survey was l^vith varying exposures ::!-:-thors. (Williams et at. j^s were obtained and sts were done. Two ^thrombocytopenia of = and slightly raised 3 G-OT levels, were 73e periportal fibrosis, 3jmegaly and o&opha^llow, plain abdominal y~ography and needle T^blc to carry out these all exposed workers, V^ques seemed relatively reject was carried out to ::|nd offered a possible dualizing the liver and to hepatotoxic agents, waging (Taylor et al. c:;J been used as a diag3nany years, the instruiS'ely crude since the f^piayed were of large ^require sophisticated .^*974) developed greatly 3 was clinically applied :o4=*t and thyroid. Using -3: technique was evalu=2 of liver and splenic ^973, Taylor & Milan "M oftransducer to ;;; shown in Fit 2. >r to the Is nv^a.:s:jTAS3 Section ofOccupational Sledicine 293 Fig 2 Parasagittalscan ofliver 2 cm to right of mhtUtte showing normalliter consistency,portal rein andInferior rentt care, {Reproducedfrom Taylor et al. 7975, hy kindpermission) 1976). This technical development was called grey-scale ultrasound, end the major difference between this end 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 parcnch) ma. The liver is scanned in a series of paramedian sections illustrated in the schema shown in Fig I. 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 Tig 3 Poresaginelsection ofliterfrompatient with rinylchloriJe~relatcdportalhypertension. Theportal rein is dilatedandhighly tortuous. .Vote that there ore verylarge echoesfrom the deepsurface ofthe liver . which is consistent with capsularfibrosis (arrowed). (Reproducrdfrom TayiortlsL 7975. bykindpermission) 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 kiu'wn hazards, no discomfort, and no need for contrast media. It docs require considerable operator expertise and high quality instrumentation, which has only recently become commercially available. 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 in Table I. Only 2 patients had no exposure at all. but 7 were normal on standard testing (Table 2). Tahiti IliiinliiwUlw^dVCMwemftBaWBto-- etoL 1ST*) CumifrjpMffr Cm 1 2 1 4 s. 0 7 ie 11 12 13 14 19 14 17 l IS doe Lm 41 (Sfi u men . m C*otm 22 49 4S 45 Sr < M 47 M tr tm 49 94 t3y 4m i* h 41 }f 10a 42 4y tm 90 lm 2y ta 12y fm 33 fry 4m 42 7y 4m 44 it *%4 * t* 2a ' 10m. 2s 2a It ta 2>r 4m If ta low JMa1 Mf$k (Sonow (Sompm *T 4a if 9m its 4a 10s tm 2s 7a . hr 4a lylte is 4a 10a 7y 2a 4r 4a is 4a ta Js 2a lm 2s ta 2s 2a 17211a 2s 2a 2s 4a *2 .< 4y 3m Us 2a lj 4m IS 7a LMMri ^39 ptro/10*: iMiun. 35 -3(10 pmu/10* ; rich, > 200 pare/lO* Tim pn ia ytait mumlit .. ucc 006609 .ro-su- 294 Proe.roy.Soe.Mtd. Volume 69 April 1976 36 The ultrasound examinations were carried out by the same operator (KJWT). who had no know ledge of the results or 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 ofclinical 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 C--p-rii-- f itmi||ii tmait Sr ntndtt* awSiii ntUiliniuumUlllwWltiiww.il. IS7SI Cur 1 >iwi--1 Normal 2 Nenaal Naiiml ] Norma! Normal 4 1 hat f tm mlmad SttfNty mUrgad Inr bot normal conalMaacy 5 Normal Normal 4 Normal Trcbrtkady'dtfBctiJl (obmityV Eniirud portal bria 7 Normal S0% ineraaiaiik srfat* ala Caiarsoi ponal miiie tplmomnilynirn) t Normal Enbrt4 lim with a dfR oftbaormal Abroug 9 AlkaMao phatpbaiatt Portal uoio not hom. JI1WI Iplma t*ict normal tlaa. Urn wmoiMKj ilifbtiy abnormal 10 WWt* liwr Merey: penal EaUffid Ihm wob nui Sknafc la placaa pmiibla frit; iiUlftilm mmShu lute pamithyma II lilimbia >1 iiiMifl Penal wiadcMyaalueae. SCOT40K1 MarttaepliaBanpily(ltw). LiWHtMalyetAklow is Naadlt Mm Many; Hki Normal OnkMt Oily thaw* u SOOTMM.OQTMM- penal win Me wlaM NweliBwrtbuy; etas, aiaeeaialkiireoaaawUM aaS renal Sfaaafc WwMeU<MtlwierllOit 14 PUNbU IMMW Lapp venal velaaaS wnMOloel. Uwiaknil. IS SQFTUM.NaeMa . MnileliaaielBa tie Map>l i Iknj ikaaji paaaikla 14 SOOT MM imoo t-GTJSM IT IMmMalt imbI/1.GOT Maikad elwwaie ef renal wta aaS laliM. SSkt rkiapa tlIIIinanity.mrka|il laRwraaUuaaty eitee. wb anal thrma It GCTEJM.rktrtou SplaMmfilyt Marbad 45 OuO/nus1. asr !y. rinheiia (45 mint. SpUftmufily. Mdtkityiaeinmiiae eauiiw lie auaiani BMafllJ ftkMBflR I* aiSmkfa 4} men. Marfca irk-anmaly uU SOOTSaip/LMuUm marednkeUi aoooo mm*. asr:t% (45 nil), SpkaeeMtaly. (Tmanl iSuM IMS) Fit 4 Ultrasonogram oftplttn scannedatone tenth ' left Interspace. When the spleen is enlargeddue to portalhypertension, lawderel echoes are returnedand so appear dark. The gridsguares are 2 em opart, andthe spleen is thus 17 em in length. Thisenlargement marnet apparent on aplain abdominalradiograph 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. II, 14,13 and 17-19 were confirmed on ultrasound examination. Cases 1,2, 3 and 3 were confirmed to be normal. Cases 12 and 13 were known to have liver abnor mality on histological examination but this was not detected by ultrasound examination. How ever, additional information was obtained by 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*4 had abnormal biochemical or hematologic results on initial, testing. Funher, intensive investigation failed to reveal the early pathology which was demon strated by grey-scale ultrasound end was con firmed retrospectively by radiological examina tion. The main advantage of ultrasound lies in its potential as a noninvaxrve 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 * T Ft C 4 ( 1 e ( < UCC 006610 - -j&vVwwa^- - ,CAi'.X -'"- >jaUi^jS^,. - i -py^-y'-, y V-fifr 36 --tretere 2 cm apart, andthe !-H< Thisenlargement teatnot ~^iiradiograph TM venography and liver tSjuUs of ultrasound and e 2 tbowi that known pO.ll, 14.15 and 17-19 resound examination. :onftrmed to be normal. _jwn to have liver abnorlamination but this was ;;-3nd examination. How. lotion was obtained by :~i 9 and IJ. In all these findings led to a review =as and these are sum* ^ultrasound results were 33 were noteoniradieted ^ity prevented adequate ^ on a plain abdominal Triers were taken from a 203% had abnormal psgic results on initial 5a investigation failed to .=Jy which was demonpuound and was con=3 radiological examinaof ultrasound lies in its ^technique for monitor* -- The lack of ionizing ^ge in this respect. pts suggest that ultra. 5-,aU incidence of false 30 that the method is 5an a repiaoement for pquiring the ultrasound 5em requires operator banner* should become 3year, while experience 37 Stcthn ofOccupational Medicine 295 Table 3 FnW Sadtaca itwu i ulmmit mailaarten MtU Ubr+* Cm# dlfflffiM fimtawoM 4 Nanml Spldnomfly Barium mllM normal Spletn not mm M X-ny abdomen. * Ndfsfii Sgknatmnhf Barium tuaRow aormaL Spurn <aid* manner bw did nor muid baton NormaJ tavdof IStbrib Buium t-mBww after Dr MIV Jayson (Department ofMedicine. University ofBristol) Dr A J Bailey (ABC Meat Research institute, Langford, Bristol} Dr C Black ( Department ofMedicine, University ofBristol) Dr K Lloyd Jones (Harlow IVood Orthopedic Hospital, Mansfield)' renewofaumieb* X-rayof abdooaa It Norma! Srhoontily reeaibta Grade 1vaitaae . 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 grey.scale ultrasonography to detect any liver pathology in a community in the United States which has been heavily exposed to air pollution with VCM, as well as in workmen exposed during the course of their employment This further study should allow a more derailed 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 Toxidty of the Chemical Industries Association. MFEMNCBS tack J V (IfWJAenrlafik* Amtrken Stroke!Ateerierim Uf. J3-M CmeJlSMaaMN - <l*T4)*wmfeOmmiMSOeOkkt IS. ISO-1S1 JtawtfO (im/wSefCBOee! V>iuWl41-T3 uwci,MiiSNi<cevenMfl (BUI awmOWr tertOv/tr ArOekneeMtla IS. I-Sl LmPIAHwwDS (l*M)rfl,IJI4-lll* MiaaUOmdiJUWSU--JCAlrWruMW tJ9tSSJmteolqfitAmttkmSSr0kalAteettenmS3a,eAi1> MamOhr HS.Letaark WK.Madtar a,Jibe S, Law C*. Batata H O A ValMM* C OfMI OraeMta SMbMMta **** SS.SII-SM4 ImSaPMA WWmmDM J (lM) ODeWlm IA Ml~m TajtarXJ W. Cwmw D A M McGrm* V * (imt/mmetefOOmf(Maataaad l. 3SU3ST < we rmwaa at xtn Ciaiiw Tj--Hpwvcw.Nii--luT--oftmdmii. WnMmm. tA. M Liiurr (I* rt*w) T.rWKitV.UVhmOMJ.SHtrMeiMilB (iVJl)Lmtitl, 1333-1124 timl b. rmtr 11. a*>v r n. s.u.e t a Mr h (1M) ,V OtlMi/wWigStrOkkr tn. u-n WiBtaiv n M J, SmM P M, Tartar K J W, Cnmiti IB h Dark a W II*7M MMAwWi/MMW A/nSrtar (la *nm) WIUmOM J. Tartar X J W.Ctautarl .SaWfcFM Dark H W (l7J) Olttukn 13. M3 Collagen Studies in Acro-osteolysis Collagen is a iibrous 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 quarter-' stagger arrangement is maintained by specific lysine-derived intemtolecuiar crosslinks and h is these crosslinks which are responsible for the strength ofcollagen. When collagen is newly formed, the intermolecular crosslinks are labile eldimine bonds, and cm be detected by reduction with tritiated potassium borohydride (Bailey et al. 1970). How ever, as the collagen matures these crosslinks become stable and nonreducible and are 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 eldimine bonds are detectable in adult human skin, then proliferati n of new collagen is occurring, ' Collagen Studies in Scleroderma The akin changes of acro-osteolysis (AOL) are fatmany respecu analogous of those of sderoderma. In both conditions there is severe rigidity and thickening of large areas of skin, suggesting qualitative or quantitative changes fat the collagen. In a study of skfat biopsies from adult patients with scleroderma (Herbert et al. 1974) we found an increased proportion of labile eldimine cross links in 9 of 11 patients with active progressing disease. In contrast, in patients with longstanding nonprogresshe scleroderma there was no excess of the labile bonds. Analysis of the centre and the growing edge of a plaque of morphcea demon strated the maximum level of crosslinks at the -** * *- <mrsnenjp>e.yr venoepr- a*w*r V*?V' ucc 006611 3S AOl ~3roxyproiine relatedto the -3M ofnormalandAOL =patient with AOL and U with other conditions - any abnormality of "3iy were cultured on' a -!e interface between a Jfng *H-proiine and an ISn, 5% carbon dioxide, 3d Macintosh Fildes jar following culture the :jpd, dialyseg to remove ifysed and separated in |l and the quantity of "dine was determined, v^roxyproline content of tts an presented m E f collagen synthesis, was considerably controls. and by measurement V3i into hydroxyproline, Blew collagen synthesis Sh AOL. These results .^dings in the skin in 3-jJ. 19*9, Herbert ct al. .^thickening of the skin. |ct is generalised, and jjjn in the blood vessels Irmia with ulceration of .Jocal collagen producL-uld similarly occur in li typical bone lesions. 39 Section ofOccupational Medicine 297 However, the AOL bone lesions diiTer in appear* anoe from those of systemic sclerosis. The cause of increased collagen synthesis in scleroderma has not been elucidated. Leroy (1974) studied the rate of collagen synthesis byindividual 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 ofcollagen synthesis. Several chemicals are known to induce ab normal fibrosis. Practolol (Brown et al. 1974) can lend to peritoneal fibrosis. Meihysergide ran cause retroperitoneal fibrosis aad ergotamine ran lead to peripheral ischxmia and has been used in the rat as an experimental model for scleroderma (Harris & Robinson 1974). Epidemiologies! in vestigations strongly implicate vinyl chloride in the pathogenesis of acro-oneolysis. and therefore as a further possible chemical cause of increased collagen synthesis, o-peniciliamine 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 o-peniciliamine 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 tlte processes of collagen synthesis and could well act as a useful model for the study ofscleroderma. P. I*4Mi7 K. IUa4A I, DnWJ D e .VUCanjrJ (IfMIlHOLKn IMimtIMhkAl OrUtJm^mtrfh%' i wharUS--M.Mt V MAJ (IIMliMHL 1ST MnHUtSM (IfHM--*<VJtlnnnnfct/l.Sral.l.Sl 1 O. fkw J. J--faiU M a MroUS, K X (ISSft MVCaunfAnwcS I. M LtnrKC (1#M)/manatafCthlrJ UmtifaUm S4. SM Dr Robin Walker (Walton GeneralHospital, Lirrrpool, 9) spoke on the subject of Clinical Aspects ofVinyl Chloride Disease: Liver Epidemiological Studies Dr P J Baxter (Employment Medical Advisory Service, Health andSafety Executive, Baynards House, 1 Chepstow Place, London IV24TF) Epidemiological Studies of PVC Manufacturers and Fabricators, and Primary Angiosarcoma ofthe 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 ftbrication of PVC. The Employment Medical Advisory Service. (EMAS) proposed three studies: s 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, and Scotland, the Royal College of Pathologists and experts from university departments and else where. Prospective Study of PVC 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 oncer registration rates according to certified causes by including ail 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 pans/ 10*), medium (>25 pans'10*), and low (<25 pans/10*), 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 iow`. Identification details of the workers are rent through EMAS to the National Health Service Central Registries in England and Wales, and Scotland. Death certificates for these persons v*V.- r.-sMMi ucc 006612 298 Proc. toy. Soc. Med. Volume 69 April 1976 40 are coded according to the International Classifi liver between 1963 and 1973. The results of this 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, only 3 are flagged, a procedure which results in the adult cases were certified a year in England and 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. plete follow up of workers. The total number of Both workers had been engaged on the manufac males and females identified as having worked in turing side.) the manufacture of PVC is 7746 of whom only 84 (1 %) have not been traced, 72 (1 %) have missing The mala aim of this study is to identify and information, and 147 (2%) have emigrated. verifyall diagnosed cases ofprimary angiosarcoma Workers entered into the present analysis number of the liver occurring from 1974 onwards, and to 7410, over half of whom are current employees; evaluate their association with occupational 88% 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 Genera). 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 tlie hospitals as the vinyl chloride trapped in PVC synthesis it 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 diagnosis mortality and cancer registration rates for all to a panel of expat histopathologists who will causes in each sector of the industry and to deter not know the history or identity of the cases. An mine whether these rates are 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 bandful to hundreds of men. Records of practitioners concerned, the next of kin of tbs 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 full time, over a widerange of the industry, the names occupational history ofthe 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 20000 workers register (locality), will be chosen from the other may be involved. The prooedure for the follow up .liver cancer deaths and also from deaths from of workers and the analysis of the results win be ' an causes. Four liver ctnoer controls for each similar to that described far 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 is an angiosarcoma ofAngiosareoma 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 viewas wfll 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 4'. chc:r CO.- rc en tin. ar fr cl st. h e- n of p sfv. wi;. CC Ol ' m th-. Ab ut t> DIS Dr U mcr. be.. ime P ler. fo `he: eflec. tion fltOiti' * Dr 1 thi: vkw divide pour CXpCfr- potu Ift! spier cytc case meem :: :z 40 ; Tlie results of this vjewhere (Baxter & Son avenge, only 3 3ar in England and I]972 bad previously La. (The only other 5 Britain known to 5rker was in 1974.. :rd on the manufac- if is to identify and 3nary angiosarcoma p4 onwards, and to ifwith occupational ^om 1974 onwards, tea are sending all ftderlying cause of S cancer (including Trifled categories) to diagnoses likely to Sd. Angiosarcomas jjm cancer registries, hospital discharges yill be taken from ?xn, and for both cases the hospitals # contacted in order nilable histological 'titled for diagnosis ihologists who wfl] ;ty f the cases. An t how many angioior miscertiiied as )e permission and ;iiltants and general isext of kin of the |will be traced and rie of our Employ ed in interviewing kk to obtain a full. age, sen and death sen from the other jfrom deexhs from t eontrols for each sdomly selected by hs from all causes 3r General's Office |s an angiosarcoma lets of controls will ial manner to the : possible the inter* jse of death of the bloyment Medical / places where the d record details of ; chloride end other 4r*wi* * J. 41 Section ofOccupational Medicine 299 chemicals. They will also attempt to obtain photo copies of ait hospital and general practitioner records for the verified cases of angiosarcoma. The verified cases of angiosarcoma will be entered into a register which will include occupa tional histories and the copies of the medical records, and an estimate of the true incidence of -angiosarcoma will be obtained. Finally, the frequency of occupational exposure to vinyl chloride will be compared between the angio sarcoma cases and the controls. In conclusion, prospective and retrospective studies are being carried out to provide a compre hensive assessment of the risk of occupational exposure to vinyl chloride and the development of primary angiosarcoma of the liver. The pro spective mortality and cancer registration studies will also permit the testing of hypotheses con cerning the carcinogenicity of vinyl chloride in other sites, such as the lung and brain. And in the absence of a satisfactory objective test for use in morbidity surveys, mortality data should enable the more serious complications of periportal fibrosis due to vinyl chloride to be assessed. Professor K Welnbrcn (Department ofHhtopathology. Royal Postgraduate Medical School. Du Cane Road. London W12 OHS) Histopathology of Liter Lesions Associated with Exposure to Vinyl Chluridc Monomer So far only 2 cases of angiosarcoma of the liver have been reported in British workers exposed to vinyl chloride monomer (Lee & Harry 1974) but more material has been studied in the United States by Bradford Block (1974) end by Thomas et at. (1975). The lesions encountered in this last publication included 15 angiosarcomas and the structural changes are dearly presented by these authors. At. the same time, angiosarcomas have been described in other circumstances, which included prolonged exposure to arsenical medica tion for psoriasis (Regebon et al. 1963) arsenic toxicity in vineyard workers (Roth 1957) and after exposure to thorium dioxide for arteriography (Visfeldt St Poulson 1972). The lesion has been encountered also in patients with no evidence of exposure to a particular toxin (Baker er at. 1956). The characteristics of the tumour are for the most agnasNCS Bntw P J a Fn a J unntmnt it. 2T-2S DISCUSSION Dr A J Fox {Employment Medico! Adxisory Sendee. London) said that in the prospective study of PVC manufacturers described by Dr Baxter great care had been taken to elucidate live role of (I) year of entry into the industry, (3) level ofexposure as estimated by people who had worked in the individual plants, (3) length of exposure h the industry; and f4) length of Mow up. These studies, coupled with theee of *haalthy population effect' and "survivor population effect* were of fundamental importance in the evalua tion of the multi of exposure to vinyl chloride monomer. Dr L Magee (MRC Toxicology Unit. CetMw) laid that in the retrospective epidemiological ttudy re viewed by Dr Beater vinyl chloride worker* mere divided according to exposure time and level of ex posure. How could data be obtained on the level of exposure of a worker who had had twenty years* ex posure? In the German literature there were many rases of splenomegaly, fibrosis of the liver, and thrombo cytopenia. Dr Mages was surprised that no similar cases had been reported from the UK during the meeting. Fig I Angiosarcoma themingSlatedsinusoidalspaces containing redbloodcellsandlinedby tumour cells. HAE.xlSO r-v -- rr* ucc 006614 J - ,.** ,,V . */ v* \-+ ' V .> ^ ^ ^ -1- " w'---.*. 'T ^1"*,. ` * , ` * *. ', ,, - 1 * " * 'fc !'' ` i' * i,* - -v1 ^ ^ ..............41 296 Froe. roy. Soc. Med Volume 69 April 1976 38 edge or 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 untfl six years before we aw him. He then started a a reactor cleaner and a 'S' 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 becune an `A' operator, working outside the reactor, and was involved in charging end recovery from the reactor and cunirollinc the flow ofchemicals including vinyl chloride through various valves. There was no direct contact with the chemicals, but he frequently noticed fames escaping from the valves. After three years he noticed the onset ofRaynaud's phenomenon which progressed with gradual shorten ing and instability or the tips of the fingers. There was a gradual thickening and coarsening of the skin spreading up his amts on to the face and a little on the chest wall and axilla. Two years later he gave up work with marked weakness of his hands and aims, which caused great difficulty in gripping and lifting heavy weights. Examination confirmed the features of croosteoiysis with gross thickening of the skin, but with the following differences from scleroderma: fl) 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. (3) No telangeiectasia. (6) General coarsening of the features. (7) No lightening of the skin across the nose. Investigations showed slightly raised plasma viscosity of I .SO cP, and positive antinuclear factor (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 pans of the terminal pliatangcs, the sacroiliac joints, certain costovertebral joints, the left condyle of the temporo mandibular joint, and loss of definition of the right mandibular vertical ramus. Skin Crosslink Studitsin Aero-osteolysis A skin biopsy was obtained from this patient. Reduction with potassium borohydride revealed a high proportion of the hydroxylyxinonorieucine crosslink typical of new collagen formation in scleroderma. There wus also a second reduceabie component present in significant tmounts but further studies will be required in order to identify its nature. Quantification ofCollagen Synthesis Hydroxyproline is an amino acid that is unique to collagen and is formed from proline. By grow ing tissue in a culture medium containing radio active-labelled prelinc and measuring the syn thesis of hydroxyproline, an index of the rate of collagen formation can be obtained. We obtained 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 on a stainless steel raft at the interface between a culture medium containing *H-proline and an atmosphere of 20% oxygen, 3% carbon dioxide, 75% nitrogen in a modified Macintosh Flldes jar at 37 "C for 24 hours. Following culture the specimen was homogenized, dialysed to remove excess *H-proIine, hydrolysed and separated in an amino arid analyser and the quantity of synthesized 'H-hydroxyproline was determined. This was related to the hydroxyproline content of the original biopsy. The-results arc presented in Fig I and show that the rate of collagen synthesis in the patient with AOL was considerably greater than that ofthe normal controls. Discussion By both crosslink analysis and by measurement of 'H-proline incorporation into hydroxyproline, we have confirmed excess new collagen synthesis in the skin of a patient with AOL. These results are analogous to the findings in the skin in scleroderma (Laitinen er ot. 1969, Herbert tt at, 1974), and account for the thickening of the skin. It is possible that the effect is generalized, and excess collagen proliferation in the blood vessels could lead to chronic ischsmia with ulceration of the fingertips and further local collagen produc tion. fschsemic necrosis could similarly occur in AOL and so produce the typical bone lesions. ucc 006615 3 V a r c t S' f v ( H 1( J u (I* L*' (I* r 1  . ->.*: - . '- * ** .-Ir-.'j-t}'!AS- ::::::;rX5 .:t= ". >;mjS :.=^V\ 'i*rVj( ilfepi 1#^ pv^ . - t1 p=|g|^g&; ipr*3S$ ^=3 J 300 Proc. toy, Sue. Afcrf. Volume 69 April 1976 'C^ /< y T<- e?v, . *w. U . >6'|0 %?.r V*-v ~ V-vr-<t F* <."-- > *. - " w. L ..**-. . fe ,^;ev-'' frV ' C h: \ , "* J v * 4s*' >- * ' 42 ,*% . -X-' * ** ****} '. \ If * .jgiV,,. ?%< to v- r / Fit 2 Papillaryformations oftumourcallsora borne on a core ofconnective tissue andhepotocytts. H & E. x600 qp**3*- -*Ng ' r*t /A~ /* * ^ /.-_*/ " .* / . V/ S m V/? 'V' ^ r,`^. .. ^r lV Fig 1 Well-differentiatedflattenedtumour cells, resembling endothelial calls on connectire tissue ernes andlining vascular spaces, //<. x 400 Fig 4 Bizarregiant tumour cellinpapillary anriotareoma. H&. . \ 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 hate been noted in the livers of patients suffering from angio sarcoma and those of patients who had been esppsed 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 hate enough common features, particujady in their mode of growth, relationship to vascular spaces and stromal changes, to support the view* that they are derived essentially from one cell type. In general the tumours show a gross appearance of darit hamonhagic nodules in the liver; there is a variable distortion and apparent Abrasis in the intervening liver tissue. Sometimes fod are tnacrascopically less homorrhagic There is often frank necrosis. The microscopical appearances at fust glance are variable, but analysis suggests a consistency. Thomas n al. (1973) have delineated 3 main types depending really on the relationship of the tumour ceils ttr the vascular spaces: (1) The sinusoidal pattern, in which dilated hepatic sinusoids are lined by enlarged and proliferating tumour cells. JJ 4 Si ' UCC 006616 '' rfniili ghujff &nt*c.i 42 _i*. :4&-.-*r >- w< ` * - j f f` *- :br ss JT"r"-Tj>*f * ) -wipapillary onflo ws workers and I pro* 11 also briefly discuss ?hkh have been noted buffering from angioj'ents who-had been i---------- T ^ ^ no( g ftumours. fch vary con* >have enough hah mode of dances at sfpirasctesglaancned ijggests aiecwontshiasttenthceyy, ilineatedty3pme.ain types qonship of the tumour is: (I) Thiseaspipneuasroaindcael iepatic sliinvuesro; itdhseraereis . stating ftiubmroosiusrincetilhse. Sometimes foci are vhagic. There is often 'fe^1 yrrl v^ ; Jul ., - s.-' 4$ j i-'*'; - - -- ^**' -V* - .J-V-M,'. ^ Section ofOccrtpanonai Atcdicinc 30! hcpatocytes. 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 pans of the liver w hich 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 end the hepatoevie plate, apparently causing reticulin increase m the space of Dtsse. which exists between liver cell and normal sinusoidal well. 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 f special stains (and in fact, both special stains and special optical manreuvra may be employed t highlight this change) to massive increase of collagen fibres which surround the hepatocyte plates, clearly obstructing the lumen, sometimes apparently en- Fig 5 Solidarm oftumourrriemb/tnf solidspimOt-etll sortomo. MtiE, >.400 with hepatoevie plates clearly recognizable between the tumour cells. This appearance is found most often (Fig t). (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 hcpatocytes, often with canalkuli containing inspissated bile pigment (Fig 2). (3) The cavernous type, in which the Wood-filled spaces appear even larger and ate surrounded by thick fibrous wafts which seem to be lined by the tumour cells. In addition there are - several variables. The tumour cells may be weft* differentiated in that they simulate endothelial cells of liver sinusoids (Fig 3) and it may be difficult to distinguish tumour cells from reactive cells, or they may be quite unusual, showing irregular Wane 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 weft be the close relation ship to heputocytc 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 spindlc-cell sarcoma, without evidence in many foci of vascular spaces (Fig 3). In sum, the tumour cell is distinguishable from Fig $ Fibrosisassociated with obliteration ofsinusoids and ditopprarasxr or atrophr ofhepatoesn* in anfiosoreoma. H A . X130 ucci . -.-vywajir^r 006617 302 Proc. toy. Soc. AM. Volume 69 April 1976 trapping single hepatocytes, and sometimes with no hepatocytes appearing to survive (Fig 6). It is. of course, not clear whether the fibrosis precedes hepatocyte loss or not, but appearances suggest that it docs. Such bepatocyte 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 reticuiin 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 lumina which are thought sometimes to be com promised in other forms of fibrosis, such as the Indian nonrirrhotie portal fibrosis, are not regularly affected in this way and would be unlikely to provoke the portal hypertension some times described. Subcapsular fibrosis has been 44 * V l Fit 7 Liter biopsy sections shonfint variations in intralobular sinusoidalreticuiin, Upper, slicks Increase. Loner, much increase. Cordon & Sweet sitter impregnation: Dark-groundillumination. <J60 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 nontutnourous changes toahe subsequent development of angiosarcoma is of course one of the major practical issues at present. Such changes are sometimes found in ihe livers of workers exposed to vinyl chloridemonomer and we have had an opportunity t see sections referred by several clinicians concerned with this problem, including Dr F Lee. Dr Robin Walker, and Dr IF H Purchase. The findings iB probably be incorporated in their own reports but, in summary, several liver biopsy sections have been looked at for the nontumour changes described. It happens that both controls and exposed patients have quite a content of fat and that several of the exposed personnel do show sinusoidal thickening, difficult to make out, but easier in dark-ground preparations. One particu lar case, which I hope Dr Frank Lee will report, presented with portal hypertension and had quite striking capsular thickening, diffuse sinusoidal reticuiin increase, hypertrophy and possibly hyperplasia of endothelial cells, and what seems T k` < ft l* C t r r c .F w fit 1* (i* m fee IW t ft* fl' ft . (` < I A ucc 006618 * patient exposedto withportal 5 ESset from the United fenes to be continuous tracts. fHitumourous changes VESnt of angiosarcoma practical issues at j^netime*fdund in the to vinyl chloride '5n opportunity to see i^dmicians concerned ;~Dr F Lee, Dr Robin =ase. The findings will f^t their own reports 3ver biopsy sections *j= nontumour changes ;iS both controls and content of fat and ;r= personnel do vliow vjjnh to make out, but -Orations. One partial* .EVrank Lee will report, pension and had quite -VS, diffuse sinusoidal . vi'phy and possibly . .'jilt, and what seems f-"" r > **'/ *- * '* a - * , *0 - *_ 4^ * i iV V ' T> tf Section ofOccupational Medicine 303 Dr Henry Falk (Cancer and Birth Defects Division, Bureau of Epidemiology, Centerfor Disease Control. United States Ptdtlie Health Service. Department ofHealth, Education, and Welfare, Atlanta. Georgia J033J, USA) and Mr Richard J Waxweilcr (Division of Field Studies and Clinical Investigations, National Institutefor Occupational Safety and Health, Centerfor Disease Control, United States Public Health Sendee. Department ofHealth, Education, and Welfare, US Past Office Building, Cincinnati, Ohio 4S202. USA) Fig 9 Bizarre andenlargedsinusoidal lining tells and hepataerte mitotic abnormality la samepatient as Fit 3. H & . <600 to be striking lwpaiocyte involvement, even with mitotic abnormalities (Figs 8-9). The question whether these lesions are signifi cant as prcmalignant changes is unanswered, as many of the alterations can be found in other conditions such as congestive cardiac failure, endothelial ceil hyperplasia in cases of lymphoma, and of hepatoevte and other changes in many drug toxicity situations. Other pathogenetic questions also have to beposed. such as what is the primary lesion, which ceil is involved' In the formation of the tumour, what is responsible for the curious fibrosis and survival of the hepato-cyies. Underfunding these processes would probably enable us to make"! better assessment of individual risk factors and perhaps to work out whether there is a tolerable exposure. . UKvtrHnDiN,Ccn.r>nteUDmJ <issU--i</Rjrtihgy CiBBUertt iTS-tu atHfcaa (1*74) Jemnotof|* AmrrinmStedketAartilam 22t. 51-54 Bww J L. Smi Cwt> K P. Bh>w S It. M N C Bw MtBUS K C IWr 0 L * Hw A K (l*<7) MYMMeJUtne tt. 4l-*7 I**FI*H*nrDS (IWW.MKVt {.111* a#nlMM W, Kin V. OwiM J a IMtaaS J W [IMI OmrtU'StitdrlrMe) 11. 51**M2 RatkF < IVjn ZciiitSti'; fir A'nWyStn(*HM<l.4*t-S05 IWu L B. P*T!Mf It. H*fk r D. Srfikaa IJ a Falk It 097SV AVw t*ii**JJournalefbtrOkim 191,17-21 V,M i tt Vy.luM H (19721 Arta PnitnAtttes rt Mil u*luljy(cj IiImImi in Xcfifcm A M. 97-101 Epidemiological Studies of Vinyl Chloride Health Effects in the United States The vinyl chloride (VC) problem has had a con siderable impact in ihc United States during the psst year and a half. Perhaps related to the age and conditions of the VC industry, or sin\piy to the sheer size of it. the United Sutes has so Tar had the largest share of cases of VC-induced hepatic angiosarcoma (HAS): at the present time there have been 17 known cases in polymerization 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 dence arrived almost simultaneously with the epidemiologic results (Maltoni St Lefemine 1974). The widespread industrial applications and uses by the consumer were instantly appreciated, and since the VC problem also arrived at a time of growing awareness and concern among*workers and consumers about environmental and occupa tional hazards, it served to focus these concerns. Within the first few months after the initial cases were described a number of worrisome . reports appeared. Investigators in Louisville, Kentucky, and also at Mount Sinai Hospital in New Vcrrk demonstrated a high percentage of liver function abnormalities in polymerization workers, suggesting a broad problem (Makk el al.; 1974, Lilis el al. 1975). and. in addition to this, the earliest mortality studies (Monson tt at. 1974. Tabershaw St Gaffcy 1974) suggested increased, rates for nonhepatic turnouts,- parallelling the multiplicity of tumour types seen in experimental studies (Maltoni & Lefemine 19741. Review of records at the Connecticut Tumor Regisrry, started in 1935, revealed 5 definite cases of HAS; 4 cases were clustered in one industrialized area and had occurred since IW: 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 197IS). Further concern was generated by ucc 006619 I 304 Prtic. roi . Soe. Mi'<i. Volume 60 April 1976 -'<5 reports of the potential carcinogenicity of chemi cals structurally related to VC. c.g. ehloroprene t Lloyd ctal. 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 vinylidene chloride and acrylonitrile (vinyl cyanide). As pan of the United States Public Health Service response to the VC problem, the National Institute 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 ofthese studies. Table! Mspgiie Mgtoilmwu ig rl* laai#4 Stain Q br Igt 314uk ud A. I944-I9?) Ant dtmk C.rfon) 4*9 io-if 24*3 JO-29 40-49 20-19 64-49 *4*79 14+ Mmk 2 1 S 1 11 9 It 1 Ftrnnlt x I 4 2 N 5 1 2 4 I 9 15 10 14 2 44 22 a O From Null ciniuuin. ICD Co** ISTAttUi tUvttaa). Dm* foe Now York City not ik-hM There was approximately I 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.S (Sth 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 1 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 197.3 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*.). Tahir I Hfirirn-- to ii IMuS faniS U h>k< tMwWmraeaL INS ISTJ Ymrtt 4rmk INS mi IMI mm ifm 1971 l*7JB \m AM Jl m* a* 1411 9 * 23 f IS ' s 7 IS s 1 Vw a si 14 7 IS It t 14 144 M 13 tt Fran itaath<nMcsM<. ICD CUCa 1*7.1(11* IuMmi. I >-u ftw* Now Var* Qty w IwtnCil K Hilf Table 2 demonstrates a mule 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 consistent with a hypothesis that occupational exposure may be a more significant factor in the causation of HAS than of non-angio hepatic sarcoma. Only 2 of the patients with HAS jn the death certificate review w ere recorded as haung worked in PVC or plastics plants (I PVC polymerization worker and 1 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 occurrence 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 diagnosed 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 esses of HAS as possible diagnosed in the US during the yean 1964-74. At the present lime approximately 240cases 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 47 past o; reside:.: Medicci Togetht Group nios:medic. a plar.t large oldest 3 State*. ' 130 c.r , plait; *tion age. ; groc - ares anc * r si; an.bf an an;..anc be> no: afcex; ger it stu to five ind of for sea me. poN~ -dete: live eve' from is ir- - Coke Polyr One c <h* c respir coho: pathc lung sp*-ir undr -T, * ** "/ *** .* '* ' ** w4 ` # 1 .. - * . .. ... ,. . ucc 006620 46 S3 S3 gXttkllvMa). of HAS for to female ratio of l of cues occurred , with 26*/t in the on-angio hepatic !iaie to female ratio ige grouping with ind only 9% in the ifferencra are conoccupational cx--cant factor in the SSnon-angio hepatic I^HAS in the death as havinjpvorked ==yC polymerization ^=j PVC fabrication ~?>ad been identified SHter occupation is IS)ept for the occur* 3 were subsequently ijnminary review of psens suggests that '^|jn incorrectly diag* Jie death certificate Siase-finding effort, BO all pathologists, 30r cancer referral Heeking information possible diagnosed Si-74. At the present ..ive been identified. v.\ two-thirds of these National Cancer .forces Institute of r. evaluation of all ^histories regarding 47 Section ofOccupational Medicine 305 past occupations, toxic exposures, and places of residence is underway. Medical Screening of VC Workers 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 study were approximately 130 current PVC polymerization workers and a similar number of control workers (torn the tyre plant who had never worked in the polymeriza tion facility. The 2 groups were comparable in age, alcoholic intake, and socioeconomic back ground; the controls were chosen from those areas of the tyre plant where exposure to solvents and dusts was least. Preliminary review of the results shows no significant differences between the 2 groups for any ofthe 6 liver function tests performed (SGOT, bilirubin, alkaline phosphatase, LDH, GGTP, and ornithine carbamyi transferase). Additional analyses based on levels of VC exposure, duration and type of job, and other subgroupings are being done; these preliminary results however do not suggest the occurrence of liver function abnormalities on a broad scale secondaty to VC exposure. One should ofcourse be cautious about generalizing from the results at a single plant, and it will be important to compare these findings to studies at other PVC plants. It is also important to realize that since liver function tests are rela tively insensitive to the early finding of VCinduced hepatic disease (i.e. fibrosis), the results of this type of testing are not a reliable estimate for the prevalence of VC-induced disease Liver scans were also performed on all workers with mare than 10 yean duration of work in the PVC polymerization plant, and no cases of HAS were detected. Scene increase in frequency of palpable livers on physical examination was found, how ever, among VC workers. A frill report of findings from this comprehensive medical screening study b in preparation and will be available shortly. Cohort Mortality Study at FourPl'C Polymerisation 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 al. 1976). On preliminary pathologic review, it was also noted that of the !2 lung cancer cases all S for which pathologic specimens were available were either large cell undifferentiated or adenocarcinoma of the lung; Table 3 Lme cuc*r wmu ndrni ,i pVC *tr*wri?a<iM H>n tk* 1'iM Siim kr kmliiii ex MlnimtfVC nn--, / VCtxpcmr* HititUik SaillnS 1 4 1AikflOdfCiAOM Lute cell uadiffltnmiuie 4 Uotiuiiflfid i StMiihm 1 J 1 Atrnln **>** 0 4 4 Ttttl 1 J 4 4 to 441 1 3 10 13 if confirmed, this unusual cell type distribution may support the association between VC exposure and occurrence oflung cancer. There are, however, two additional features which should be considered in evaluating this potential relationship. When ail of the workers at these 4 plants are considered, including those who were not pan of the defined VC-exposed cohort, a total of 22 cases of lung cancer (out of 46) were available for pathologic review. The increased incidence or large ceil undifferentiated and adenocarcinoma of the lung was seen in VC workers with more than 1 year of exposure, while a distribution more closely resembling the ex pected small cell predominance was seen for VC workers with less than 1 year of exposure. Interestingly, however, caseg of lung canter in non-VC workers at these plants, although small in number, appeared to have a cell type distribu tion which was also predominantly large cell undifferentiated (Table 3). In addition, unlike the situation for HAS in these plants where all but one of the cases were long-term reactor cleaners and operators, the workers with large cell un differentiated and adenocarcinoma of the lung, were distributed hr a number of different job categories. As a result, cases of lung cancer seem not to correlate as tightly with VC exposure as eases of HAS and it is conceivable therefore that some additional chemical exposure at these plants may be working together with VC (or even separately) to produce this effect.. Further studies are currently underway in an effort to confir these preliminary pathologic findings. asrexcNces LwWioa f J Hwk C W Jr (IffAti* ptipmiioii) Ltb K Ah*m Ha Nirfcdl*a W J, Dm S, ***** StttkaaiJ(lf?5)4<OTfa^r*r,Yc* >W* Stktott !4i Sm L*44 W (lff))/<hmi/</Q(ci>i>(wi/44i#ff ucc 006621 306 Proe. Toy. Soc. Med. Volume 69 April 1976 tt Usr4 J W. Okh<( r C M*m R .M (IfTSy/wniaf atOmtpuiUHtMl MaftciK* IT, 26J MikV L. Cntt* J I. jr. Wo J G jr C JahMaa M N {.W*)JbuhwIeft!* AmttknMtdcelAMtocwHan13H,U MmauiKwG <IS7<) Em-rimonnMXMK* T,}7 MmaiU,MMJMtJalaMMN n7*)Lrta, jT T*m** I It X G*f<r WII (MrUJn*natefOea)iwtltwnMi0leti*n.t n**U ft J, Snkwff W, Jn J. WicwrJ K. Falk H * C*rttfC<l7*Mwii /(**.*<> M^ataifV Mwnltn^RM discussion Dr Mitchell H Zaven (Scron Hotter, Louisiana) asked whether the clinical examiner* at Potistown knew whether or not the person being examined worked in vinyl chloride. Dr H Falk replied that none of the cimhal exammen were aware of the occupational tutus of the worker* at the time ofthe examination. Dr RI McGenam (Unirrmitr ofSeweessie upon Tyne) asked Dr Falk to give in more dcuil the way in which histological diagnosis was made in the case of lung cancer shown in his slide. Was this done by one individual or by a panel of pathologist*? Mow were the specimen* of tissue obtained: by biopsy, surgical resection or at autopsy? It was remarkable that in none ofthe cases was an oat ceil carcinoma diagnosed, as this was the type often considered a characteristic result ofexposure to a chemical carcinogen. Dr H Falk replied that the WHO lung cancer classifica tion scheme of Kieybcrg (1967) was used. Four patho logists reviewed the slides and agreed on the inter pretation (Dr Louis B Thomas and Dr T Powell, National Institutes of Health; Dr M Kuschncr, Sute University of New York; and Dr Laszlo Makk, St Anthony Hospital, Louisville, Kentucky). All avail able pathological material for each case was reviewed. The expanded pathological review- currently under way would include the selection of multiple control cases oflungcancer from the samt hospitals(with simi. iar sgs and data ofdiagnosis to the study cases) and a blind review by a panel of puthologisB in a more detailed evaluation ofavailable pathology malarial. To Dr Falk's knowledge large cell undifferentiated caianoma ofthe lung had not been related to exposure to chemical carctnogmi, which made the findings in the VCcohort even more intriguing. Dp A J Fee (Employment Medkni Advisory Service, London) askad hoar many factories had been studied individually in the USA. What proportion of them had indicated vbtyf-chloride-assocaitd disease? N10SH-CDC study, the Tabcrshaw ttudy, and the Monson-Petcrs study) had all looked at the Louisville, Kentucky plant where the initial angiosarcoma cases occurred as well as at a serving number of additional plants. Compounding the problem was the fact that the definitions for entrance into the cohorts studied differed from study to study, so that the results even at the same plant were not identical Dr J A Bcnneil (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 the skeletal or skin changes described might be premalignant conditions. Dr H Falk said that cases ofangiosarcoma in the USA did not have a history of acromstcoiysis or skin problems, although they did not have the multiple tests for early changes of acro-osteotysi*. it would seem, therefore, that the skin changes were not premalignant conditions. Professor IJ Setikolf(Meant Sinai Schooi ofMedicine, City University of Sew York) said that a review of known details of identified cases of vinyl-chlorideassociated angiosarcoma of the liver by Dr Lloyd (1973) of the National Institute for Occupational Safety and Health had demonstrated that the median duration from onset of exposure was approximately seventeen years. These cases were derived from the mther small number of polymerization workers em ployed during the establishment and initial growth of the vinyl chloride industry. Attempt* were underway to identify and trace the initial groups of workers, employed during the years 19J8-5!. since analysis of their experience would allow evaluation of the risks which might be suffered by the very much larger group ofvinylchloride workers exposed more recently, in a period during which PVC production was in creasing at the rate ofapproximately 10% per annum. Limited data tearing on tha problem had been obtained. In one polymerization process studied, 237 men Itad been employed for five years or more in tha period between 19-16. when the plaas opened, and 1964. Each man had been traced to t July I974..with 15 deaths from all causes:J of the death* were due to angionreema ofthe liver (Nkhokon /. 1973). each confirmed on review of autopsy material (Thomas tt Poppar 1973): in addition there was on* death due to ruptured osophageal varices. Another worker, examined during tha clinical survey at this facility fUIi* el of. 1975) had had a succenfui portacaval shunt operation for the same condition. These experi ences suggested that vinyl-chloride-aiaociatcd disease would be an important hazard for vinyl chloride workers in the future, unless control of exposure resulted in at least some reversal ofthe risk. Dr H Falk replied that cases of hepatic angiosarcoma had been seen at 1 of the $ PVC polymerization plants opened prior to 1930. There was soma confusion in this arts in that a number of the VC worker mortality studio had been overlapping. Three separate studies, for example, (the UfcS.cmimH.XW.IwSLIliwS.ratUiliAt *MMI1 (irn.4aaevi*f.vv r--* <r*wwTwJ;.m:r*. :^-i Liar* J (l*7*>>ar*WWOrr-r-'-Mt 'IT. JJ)-33-t ytrMa W J, KmhI E C Si Umm IIA MOW* IJ (IS7S)AmntsmttOr.Vc-' TV1 tralr-i.rr/frf--rrl,J T* "* titan LBO Pilut It Wily.SawlsrSiktXta rwttwliiiet>inMUtl:U'PT 1PW ucc 006622 : 32Si &USJ&*k :':Bjberthaw study, and the ,-;3 looted at the Louisville, angiosarcoma caret -i~Pt number of additional ^spblem was the fact that Sjnto the cohort* studied 53 so that the results even JxptieaL )0fidty GenmUnf Board) -331oride monomer u a -iS any evidence in cvperi^dtnical experience that ribed might be pre> 5=*xrcom* in the USA a^cro-osteolyvj or skin -Snot have the multiple gaxo-otteolysis. It would c^chanpa were not pre- 5S ffScnef Sdkeot ofMedicine, 5= aid that a review of ESjvset of vinyl-chloride* gjh Rver by Dr Lloyd glute for Occupational pirated that the median 1 ire vu approximately !__,.*r* derived from the fc^eriaation workers env* and initial growth of V^empa were underway Sjl groups of workers, 6p3-JJ, since analysts of ^valuation of the risks g3te wry much larger Exposed moctrecently, 32 production was inSStely 10% per annum. =23 problem had been =n process studied, 237 yean or more in the ~St pleru opened, and rrS) to I luly 1974, with i=9e deaths were due to 33son*ref. 1975). each 3j*tariel (Thomas & death due to her worker, Et this facility ul portacaval ;3dition. These experi;3e-svociated disease for vinyl chloride Control of exposure :.fthe risk. |?>S,FW*W*iAS IffrAwnree^n-ii .'.7;VSrfcrl?,Sl.t-JJ4 }}:- ASwiikaft t J Ut,"3~Zto **w> 144.IU-177 vs> Section ofOccupational Medicine 307 Dr B1V Duck (Occupational Health Unit, BP Research Centre. Simbury on Thames, TIVJ6 7LV) Medical Surveillance of Vinyl Chloride Workers Following the announcement in January 1974 of the first cases of angiosarcoma of liver among workers exposed to vinyl chloride in the USA. the Chemical Industries Association in the United Kingdom set up a Vinyl Chloride Committee, with a number of specialist working groups, including one on health aspects. The first tssk confronting this working group, which comprised medical representative* of the four British companies engaged in the production of vinyl chloride (VC) and polyvinyl chloride (PVQ, was to review all the relevant medical and toxicological information availible and decide what action should be taken to protect the health ofexposed employees. This is an interim report on one aspect of the group's work. At that time, little was known about angio sarcoma of the liver and its treatment. Due to its rarity, there was considerable doubt about both its natural history and appropriate methods of early diagnosis. Reports indicated that nonmalignant forms of liver pathology, such as fibrotic changes, might be more prevalent among vinyl chloride workers than had hitherto been suspected, but the significance of such disturb ances of liver function and structure in relation to the development of angiosarcoma had yet to be established. Similar considerations arose in respect of the previously recognized condition of aero-osteolysis (AOL) and its various manifesta tions, since it was speculated that there might be some common underlying vascular pathology. To complicate the situation still further, long term carcinogenicity tests on laboratory animals had not only produced many angiosarcomas, but also a considerable number of renal- and other tumours. The situation was discussed with medical col leagues in Government and Trade Union agencies, and specialists in liver disease, and much helpful advice was received from them and from various overseas sources, especially from doctors in the United States. It soon became apparent, however, that there was no established procedure for the early detection of Iher angiosarcoma that could serve as a basis for a large-scale screening pro gramme in industry. As practical screening possibilities were very limited and the eariy diagnostic value of suitable techniques was un certain, vinyl chloride workers could not be asked to volunteer for medical examination on the grounds that this would detect early malignant disease of the liver; nor could they assume that such examinations would be beneficial to indi viduals in terms of preventive medical action. In the latter context, effort had to be concentrated on urgent measures to reduce exposure to vinyl chloride, a task which was being energetically tackled by our technical colleagues. Nevertheless, there were many arguments in favour of inviting vinyl chloride workers to attend site medical centres to participate in a standard medical examination programme: (I) Opportunity for personal discussion. (2) Establish prevalence of disease. (3) Establish prevalence and significance of liver dysfunction. (4) Correlate positive findings. (5) Identify possibly susceptible individuals. (6) Compare findings in VC workers and controls. (7) Assess feasibility and value of medical surveillance. (S) Establish data bale for further studies. For these reasons it was decided to carry out sh initial clinical survey on all sites where VC and PVC were produced, based as far as possible on the application of standard pro cedures to both vinyl chloride works* and controls. A programme of action was discussed and agreed with medical representatives of Government and Trade Union agencies and it was accepted that one of the main objectives was to gather dinical and epidemiological data to provide a reasonable foundation far future decisions concerning regular medical surveillance. The survey population wes divided as follows: Vinyl chloride workers Group I - ait autoclave floor workers, vinyl chloride monomer (VCM) production workers with.five or more years* service; Group 2 - vinyl chloride monomer pro duction workers with less than five years' service, all other VCM/PVC production workers. Controls -workers from same sites with no history of VC exposure. A standard medical examination procedure was sdopted: Initial examination comprising, medical history (questionnaire), physical examina tion, biochemical tests (SGOT, SGPT, GGTP, alkaline phosphatase, bilirubin), platelet' count, urinalysis. Follow up of abnormal findings, with repeat biochemical tests and piatdet count, and persisting abnormalities referred t consultant for specialist investigation. The programme was introduced simultaneously on the six production that and the employees concerned were informed that it was not an individual screening test, but a joint investigation to provide data that would help t establish future medical policy. It was also explained that any individuals with suspicious findings, notably persistently abnormal test results, would be referred for appropriate specialist investigation by arrangement with their family doctors. Due to a variety of reasons, not least the prob lem of interpreting the significance of borderline "3 : r ucc 006623 308 Proe. ray. Sac. Med. Volume 69 April 1976 50 abnormalities and workload difficulties ex interest in view of the apparent rarity of AOL in perienced by both medical advisers on sites and the cases of liver angiosarcoma that have been 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 Temattre Conclusions tbts stage and no firm conclusions can be drawn Abnormal liver function test finding 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. (I2J%) and controls (16.5%) even th ugh So far, 1337 vinyl chloride workers and 439 results had to fall well outside (2 or 3 standard controls haw been examined. The examinations deviations) the normal range in order to be of vinyl chloride workers include 882 from classified as abnormal. Repeat testing revealed Oroup I (representing an average response rate of persistent abnormalities in one third of the vinyl 80%) and 473 from Croup 2 (in w-htch 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 w orkers and the controls are a: 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 it 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 cases of angiosarcoma and prising that opinions of working poup 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 obvious' logical conditions unrelated to vinyl chloride liver disease due to vinyl chloride exposure has exposure. At present, the causes of liver dysfunc been identified so far, but evidence of non tion remain uncertain in about one third of trese 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 specimens. To put these interim results in per absence of any specific pathology related to vinyl 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 work involving no further exposure to vinyl exposure to vinyl chloride, and some doctors 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 shea, the White 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 an the difficulties en and related conditions among vinyl chloride countered that it is considered liver function, workers remained in force and 2 new cases of tests should only be applied on a discretionary AOL have been diagnosed. The survey prov ided 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: () Raynaud's phenomenon among controls on yield positive findings at an early stage of disease; three sites and comparisons with findings in vinyl (A) 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 no standard diagnostic criteria were applied and chloride and those due to other causes, such as 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  ' * ' : <. SO ,nt rarity of AOL in ma that haw been je routine urinalyses prmalities. test finding were ?yl chloride workers 5 %) even though Je <2 or 3 standard ;e in order to be tat testing revealed c third of the vinyl the initial findings men were referred mparable data for vailabie. T abnormality had of individuals for onsiderably greater e had on specialist cction is a matter of abnormality is nerits further coll ect balance is to be date, it is not surng group members er fbnetion tests in vkied. No obvious oride exposure has evidence of nontnd in some cases iterprelation of the : available no firm ut the presence or >gy relatetHo vinyl on. The procedure h persistent liver nd removed from ind some doctors iver function testsch as the need to t other sites, the dings has been so he difficulties ened liver function >n a discretionary t. t is argued that, s used should: (a) y stage of disease; ve and negative > to differentiate ns due to vinyl r causes, such as 1 application of a workers is likely id disquiet if the SI 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 ar.d more detailed studies that are designed especially to evaluate 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. DISCUSSION Dr A Jobe 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 he 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. Dr B W Duck replied that man 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 men had rejected such medical advice and the teat had been ttamfcned to alternative work with no loos ofpay. Dr Rebar! Mailay (fti*irj) said that this was a very real problem which k was proposed to deal with in the EmploymentProrccdoo BUI currentlyunder discussion in Parliament. This would give to a man laid'off for preventive reasons, because he showed early sign* of absorption, the right to (toll stages during the period of layoff The more sensitive the methods of early diagnosis or the more stringent the standards of exposure, the greater would be the need to have tome system to cover the no man's land between absorption which was not compensatebit and disease which was. In large organisations h 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. Dr L Magas (AIRC Toxicology Unit, Carthallon) said that in Dr Duck's paper r.o distinction was mada between data on workers from a factory where poly vinyl 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 yean 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 \V 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 ware complete it was envisaged that the industrial doctors and their consultant colleagues would publish the results obtained from individual factories. Mr H F Henning (Health and Safety Exeetttire, 4O3M0S Edgware Road, London SH16LS) 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* faced with a sudden and substantial tightening of the standard to be applied there are equally suddenly many questions to be asked and answered. In addition, w hen 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 are discussed in this piper. Instrumental Techniques \Vhen the threshold limit value (TLV) for vinyl chloride monomer (VCM) was 200 parts/10*, that b before 1974, the instrumentation used for monitoring was relatively (airly crude and. in sensitive. One common instrument had a lower response at about-200 partstlO* so that a nil reading was taken to indicate a concentration below 200 pans/10*. e very convenient situation. Evan 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 pans/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. However, many of the difficulties were overcome and all the VCM and PVC manufacturing plants have now installed what we originally called ucc 006625 r ' * r r * 1^ A** ' * ~rm rjr'`-iflr'rl "ii ~'~ii iivuM'ii ;L_*2s 310 Proc. roy. Soc. Med. I 'ohur.t 69 April 1976 S2 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 tn specially selected by short-term sampling for investigations or for areas where no person woiks regularly or the checks on equipment and by long-term personal 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 Presentation ofResults The frequency of sampling can also have an in fluence on tbe picture. Let us assume that some The Code of Practice requires the results to be of the sampling points have neen chosen to pick available to the workforce and for summaries to up leaks from the plant so that, say, 10% of the be posted io 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 300 leadings 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 tbe results should be summarized and presented ceiling value. Sampling at the minimum frequency was a major problem because there was little required by (he Code of Practice, Le. 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 Le. 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 bad 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 tel) us plants even show long-term averages of about exactly 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 personal monitoring which is normally done at ages published by other countries. However, an less frequent intervals because it is rimeconsum overall average such as this is influenced very ing for the testing staff and somewhat restriaive 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 ofcourse h offers little of use in the protection of the worker, which is the main objective of OtherProblems 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 fiOO parts/10* dueto a transient leak from less than 2 parts/IO*,-with a few known and nearby plant would add 25 parts/10* to tht shift, controllable problem areas. average. In tbe UK we fed that it is essential to In sheet, we in the UK believe that atmospheric record these peaks, because they indicate escapes monitoring should be used to provide the maxi ofVCM 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 () useful are selected to provide e 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 expea 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. / ucc '"TV 006626 *