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I n Volume 69 April 1976 275 Section of Occupational Medicine President Suzette Gauvain mrcp Meeting 12 September 1975 Vinyl Chloride Dr Suzette Gauvain {Medical Advisory Service. Health and Safety Executive, Baynards House, 1 Chepstow Place, IVestbourne Grove, London W2 4TF) Vinyl Chloride: Introduction to the 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 w;as first discovered in Germany in the mid-!930s. The fire and explosion risks and the narcotic effect were quickly appreci ated. Acro-osteolysis, a condition mainly affecting the terminal phalanges of the fingers, sometimes the toes, and to a lesser extent the other bones of the body, was first recognized in autoclave cleaners in Belgium (Cordier et al. 1966) and subsequently confirmed in a number of investiga tions of autoclave workers in Canada, England and the USA. Soft tissue changes, coldness and numbness of the hands and fingertips, resembling Raynaud's phenomenon, were also described. Lilis et al. (1975), summarizing the findings in the world literature in relation to the prevalence of disease among vinyl chloride and polyvinyl chloride workers, make the point that hepatitislike liver changes were reported by Tribukh, from Russia, in 1949. However, until Viola reported (Viola et al. 1971) that he had failed in an attempt to produce acro-osteolysis in rats exposed to 30 000 parts/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 clear and further testing was necessary. Maltoni, commissioned- by a consor tium of European chemical interests, including Imperial Chemical Industries,' to . undertake further studies, confirmed cancer in .animals at exposures as low a 250 parts/104 (Maltoni et al. .1973). As a result of Maltoni's work an epidemio logical study was undertaken in the USA on men who had previously worked as cleaners of auto claves (reactors) in a polyvinyl chloride poly merization plant. Creech & Johnson published this work in 1974, but their findings of a cluster of cases of angiosarcoma of the liver in one factory were transmitted to the National Institute of Occupational Safety and Health (United States) on 22 January 1974 (United States Senate 1974), to the Department of Employment (HM Chief Inspector of Factories) on 23 January, and to the Acting Chief Employment Medical Adviser on the following day. On 29 January 1974 Imperial Chemical Industries put out a press statement announcing that it was taking steps to inform government departments, the TUC, its own workers and its customers, of the facts available so far; and that a single suspected death in the United Kingdom was under urgent investigation. Subsequently this 70-year-old retired autoclave worker, who hud died at the end of 1972 after twenty years of ex posure, was confirmed to have died of angio sarcoma of the liver. Since 1974 intensive investigations have taken place in this and many other countries. The United States government have published an account of the hearing before the Subcommittee on Environment of the Senate Committee on Commerce, on the dangers of vinyl chloride (United States Senate 1974). Senator Tunney, in i i:i> - r P ft**. r-i '1 V..'*" -v s ^ ucc 065493 4 ** --m,'iJ ilf. :SttiCyWvr; wins u4. a*ni / 276 Proc. roy. Sot. 3/r<f. Volume 69 April 1976 18 his opening statement, said: 'This hearing will be focusing on ways to mitigate the problems in* volvcd 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 (Selikoff &. Hammond 1975;. The International Agency for Research on Cancer (1974, 1975) published technical reports of a working group on vinyl chloride held in June 1974 and of a succeeding meeting in January 1P7J. 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 vv ith 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 staff in the United Kingdom had been taking active parr 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 50 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; thcSe were pub lished in February 1975 in temporary format by the Health and Safety Executive (1975). In the introduction Mr Bryan Harvey, Deputy Director of the Health and Safety Executive, states that the code sets out to (a) define an interim hygiene standard that must not be exceeded; (6) require regular monitoring to measure the concentrations of vinyl chloride in the atmosphere; (c) outline methods of achieving (aY, (d) provide for medical supervision; (e) 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 untied efforts of management, superv isors and employees. This is vicry 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.' Medicol Subgroup The medical subgroup defined its terms of refer ence as being: 'To examine the medical aspects of 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 giv en 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 recommendations 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'. "fhe 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^mployment medical examinations. Those already employed should be examined, if this has not been previously done, within twelve months. The examinations should be repeated annually, and should include: (1) a full medical and occupa tional history; (2) a clinical examination with panicular 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 v inyl 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 0f)5484_ IS 's this to be necessary depends primarily on ment, supervisors and h a first edition of the [ hope that those who vine >t will put them nsultative machinery ted its terms of refer tile medical aspects of to decide in the light tlogicRl, toxicological miion the examinauded-in the Code of those which require non in the Code*. id gratefully acknow:rts on diseases of the procedures. Because ning which medical inyl chloride on the rnt of angiosarcoma, iem experience with ging tests is as yet nmendalions to be w% Code of Practice. Purpose arc however v'C,..As a result hese lests and from 1 recommendations it to the Code in due code are contained 2 defines `supervised d with their medical ers should undergo laminations. Those examined, if this has thin twelve months, repeated annually, medical and occupa! examination with abdomen, skin and ation of the hands; be indicated by the e recommended in ic leaflet describing de monomer should rkers at this exami- o provide medical should see a super* npuims which may 19 Section ofOccupations! 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 Tevicw 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. IwimiMM) tar Hmarcb Career (1974) Internal Technical Ref*oft So. 74/WD5, IaRC, Lyon (lfTSjlmcmalTachntcai fect'onKo. 75/flol. IaRC. L)*ft Ltriawi C(1974) Work Mj-'ird; Vinyl Chloride. JMcrnatientl Ormiaal Worker Fcorw:on. S* iijeriand LB* R, Aaderw-P W J, $, FWbWii A S ii ScUkvA I J (197?) Ammeb the Sew York Actukmy SeWmtti 246.11-41 Maltwi C, Ctnri M A Burrfc F J X d (197?) rrrfyr MtMUt Uuermuitmmt C*mgrrti Stnet No. 275 Sflieifl IJi Hamaeni CC6 (I97J) ofthe .Wr Ymrk Attdemy *f Seiemta ol 24i TtiUkb $ L. TlkJwemirota N P, U'iM $ V 4 Knlo* L A (1949, Cifiema 10, U Uoiiad Staiac Scoai* C--nitlw * Cmtfttt, 5braamiu#e aa CmftWMirt ()S*4l cc4 on Dan(en cf Vn>l Cbkn.ie. Serial No. 92-110. L*S Cawwm Printing Office, " 4ilwr.cioc. DC Viola P L, Btgoni A ii Cmmo A 0971) Cmter JtriwrhM, 510 The implications of the association of angio sarcoma of the li\er 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. . 1 Postscript ` The Working Group on Vinyl Chloride Code of Practice for Health Precautions met on S October 1972 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 pwts/10* and 10 parts/10* replace the original figures of SO parts/10* and 2S pam/I 0*. Other requirements of the Code, including medical supervision, arc currently being re viewed. REFERENCES Corlitr J M, fitter C, Lcf*Tt M J Xenia K (1966) CA>r/<fr Ju TrcroU4t 14-19 Cff*ch J L j/ & Jelm'uti M N rfOavrui-.ivntlMeditlmt )6, 50P-5H LiMfOttftpnttl Ptoipcitoti -Vets?) (19^4) Prtiimtniry Aiwiiment of the Envsor.c*eiital Auoeiuic^ *-:h Vinyl Chloride and pnjv vinyl Ch*''ntfe. \V4*\xnijtpr, DC Hthh Fj<*ttiin(i75)\ myj Co<*t of Practice for Health PrGCJiif.'n* iTcm-vrafv Formjf' L*ndOA Mr A \V Barnes (Id Plastics Division. Welwyn Carden 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 while solid material. The addition polymerization of about 500-1500 molecules of vinyl chloride produces one molecule of PVC and the poly merization reaction is strongly exothermic. The polymer irsclf 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 as a separate liquid phase disappears 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 92-95% total conversion the speed of polymerization becomes uneeor.omically slow. These arc the fundamental characteristics of vinyl ehioride and its polymerization mechan ism which decide the principal features of indus trial processes for the product ion of PVC. wrjr-e --r.i UCC w-- 065485 c.;s 278 Proc. roy. Soc. Med. Volume 69 April 1976 20 The Production Processfor P VC Because it must be polymerized in liquefied form at temperatures above its boiling point, the industrial process must be carried out in pressure vessels (at 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 presure, 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 or the reaction in finely divided, powder form, and not as an intractable homy mass. conversion and solving some oT_the problems connected with v inyl 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 panicles (100-150 pm diameter), suspended by slining in water, is left in the reactor. Now to a description of the process in engineer ing rather than chemical terms: polymerization is carried out in cylindrical, stirred, jacketed pressure vessels. To begin, water, surfactive agents and free radical catalyst are added to the reactor: the air space above this liquid phase is purged of oxygen (w hich inhibits polymerization) and liquid vinyl chloride is men 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 polymei' on which it is absorbed. The polymer slurry is then trans ferred to closed tanks prior to the next stage in the process. As polymerization 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 in 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, will reduce the heat transfer characteristis of the 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 case 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'j 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 last traces of it ar.e difficult to remov e from the polymer; the polymer in the sluny 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 and People 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 tjkc a plant capable of making 100 000 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 ucc 065486 2t liqi sec i in a ac the lea' pol str pr<fur so* nv OZ-rcto at; ar u: sti fo Wt ce tl a* ir. e: cs pi er a: o, P* fa ed. ar tk pe bii me tor are otr stn the qu. va; to. dosec exi the ar. he 20 ' the problem* :ity in this way. reaction, there* (still at a pres* ted back t a Hides (100-150 ins >n water, is ^cess in engineer: polymerization stirred, jacketed vaicr, surfactive are added to the s liquid phase is polymerization) Injected into the zes range from tharge per batch reactor contents ined at reaction e of the order of vented to a gastor is evacuated, as much mono- r on which it is then trans* he next stage in lave, which still low partial pres* ore opening to h pressure water remove'*polyrner age, the cycle is strong affinity for lifficult to remove in the slurry after ins around 500 s slurry is centri* izse and the wet ous driers; during ide is removed in ned powder cur* T of mbnomer. tion process gives he potentials of :t creating signifi'> 1 chloride. If w* t ItVJOTiO tons per 'c polymerization of a year, have inyl chloride in 21 Section of Occupational Medicine 279 liquefied form under pressure. Into the drying section will have passed 50 tons of vinyl chloride in a form strongly absorbed on the polymer and at s concentration on polymer of about 0.05%. In the finished product, 5 tons of vinyl chloride will leave the factory, each year, still absorbed on the polymer at a concentration of 0.005 % Although Strictly outside the scope of this paper it is worth proceeding further and pointing out that in further fabrication operations on the polymer, some of this small residual concentration of monomer is driven off so that in the final fabri* rated article only --5 pans/10* of monomer remain or 0.5 tons out of the original annual total of 100 000 tons. In fabricated articles which arc used for foodstuffs packaging (bottles, film and foil), and which represent about 10% of total UK production, the monomer concentration is still lower, and the pro rata amount absorbed on foodstuff containers from a 100 000 tpa plant would be 50 lb. Of this quantity 34 lb might migrate into the foodstuff where its average con centration is unlikely to exceed 10 pans per thousand million. Since total UK production is about 400 000 tpa this means that the annual ingestion by the average UK citizen cannot exceed 0.0001 g, a figure which agrees well with calculations based on diet analysis. A final potential interface arises because at points in the production process, vinyl chloride is exhausted to atmosphere. On a typical PVC plant and with current levels of achievement. 0.3% of the monomer is lost to atmosphere; with this performance ground level concentrations at the factory boundary are well below 0.1 parts/10' and even these low amounts decay very rapidly with distance.' In the band J-l mile (0.4-1.6 km) around one factory, for instance, the concentra tions determined are in the range 0.01-0.0001 pans/10'. These figures should make dear that by far the biggest potential for exposure exists m the poly merization section ofthe plant, since here 100 000 tons per year of a liquefied gas under pressure are handled in a confined space, in contrast to other pans of the process and to the later down stream operations of the plastics industry. In these downstream operations the corresponding quantities, this time in the form of absorbed vapour at a low panial pressure and not confined to a single geographic situation, range from 5 tons down to 3 lb per year. That the polymerization section is in fact the area where hazard has existed in the past is confirmed by the fact that all the authenticated cases of vinyl chloride-related angiosarcoma of the liver throughout the world have been of workers engaged in plants where liquid vinyl chloride under pressure was used in large quantities. The nature of the polymerization process, as described above, illustrates why exposures in the past could have been large. The plants are com posed of a large number of batch reactors of small rapacity per batch, relative to the total annual throughout. In each reactor, two complete cycles per day are carried out and each cycle requires vinyl chloride to be injected under pressure, heated, contained, stirred and polymerized almost completely: at the end of the cycle un polymerized monomer has to be removed and the reactor opened and cleaned. The possibilities of small leakages from pumps, valves, stirrer glands and from the opened reactor at the end of the cycle were obviously significant: and the manual cleaning of reactors gave further opportunity for high exposures. This was particularly true during the long period in the 1940s to 1960s when vinyl chloride was thought to be harmless and when a recommended exposure limit did not exist or, late in the 1950s, was set by regulatory authorities, industrial hygienists, &c., at a level of 500 parts/ 10*. The general consensus of opinion throughout the world, today, is that average atmospheric exposure for polymerization workers between 1940 and 1970 might have been of the following orders: 1945-55. -1000 parts/10*; 1955-60, --400-500; 1960-70, -300-400; mid-1973, --150; 1975, --5 pans/10*. Across the world, there will have been variations around these figures because of differences in plant design or process operation. Even the way in which jobs were organized can have caused variations. In some countries or on some plants workmen were employed specifically to clean out autoclaves (where. exposures could have been very high) while in others autoclave cleaning was part only of a whole range ofjobs carried out by individual Work people. Some spokesmen have suggested, perhaps for full-time'cleaners, exposure levels as high as 3000 parts/10* in the early days of the industry.' With these very high figures as background, the progress made by the PVC industry in the UK in reducing atmospheric concentrations since the carcinogenic hazard of vinyl chloride became known in early 1974 is shown in Table 1, which also shews improvements made at all the other interfaces described earlier in this paper. Al though, as we have seen, the exposure levels in these other places are many orders of magnitude lower than on rhe polymerization plants, industry has aimed to reduce fugitive vinyl chloride levels ucc --aiuHsz r\'- 4- - ..' >*.* '1 ,-^aSSiSaSf -a `i. c^V'-SS# ! rr->j-V5-'- r--; If mV m.#m. >i;i ;l 'V'-* '1 . .;. .* * i - ii; t I1: *. .%"** -* J 250 Proe. roy. Sot. Med. Volume 69 April 1976 22 at every point in order to eliminate concern wherever it might exist. With work still in propress, 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, have focused their attention in the past eighteen months. Table l vrtcMUf> *t t* UK taAifity VCM to pbtt ftiftnoftpHcrc (feneckJjr tvtretc) VCMnuwo4l '* vest in proOna J974 (ramIIO') -1 0.7j^efou1M zoo-soo July ms `J 0.3" ofoutput 0forotoc( gndftft rahrlenti^nntUm VCM to pfeht fttioftphra J-IS VCM in yvC botda* VCM in bcwita -30 0.1 <z -a 0.01 Finally a few rough calculations of the daily dosages at the current exposure levels and at the higher atmospheric levels which previously could have existed on PVC plants may be helpful in putting current plant performance and present downstream exposures into perspective, one with another, and in comparison with earlier figures (Table 2). Tahiti Pai)y 4mii ftt cutmi iiid wtiT vrpoiwTt lt*di Oail) 4ott (xlktbtdy Polymeriattoft ptent operator ftt }00Q pans/10* PoJymcrufttion pUftt opcnior it WO ptru/l 0* PoJ)TTwritftien pitot pcrv.or bow at <^s p*runo* Ffttmc4uo*pbt>t operator t 1 pan/JO* Avtr*t< UK diiua th/oust iofaiion to food 0.H 0.U O.OQlt 0.0004 0.000000004 In later papers to this conference, a w ide range of diseases or. symptoms which have been associated with or attributed to exposure to vinyl chloride will be discussed. It is important to note that most, if not all, of these have been contracted by people who worked under conditions repre sented by the highest figures in the above table. Today no one is exposed to doses at this level. The exposure of workers in' industry is now at least two orders of magnitude lower, while the general public in the UK absorbs, through foodstuffs, a quantity which is some fifty million times lower. . While the conference will be concentrating primarily on problems which have occurred in the past. I hope it may find some time to consider whether there remains any possibility of similar effects occurring at the markedly lower - and in DISCUSSION Dr M D Kipling (Employment Medical Adrisary Service, Birmingham) said that it was known that workers bagging the PVC powder were sometimes covered with the dust and that this pow-der contained a percentage of vinyl chloride monomer. Ke asked whether any information was available on the panicle size ofthe dust produced in differing processes through out the world and the incidence of vinyl chloride disease. Mr A W Bamct replied that the particle sizes of PVC powder did vary very widely, depending on the application for which the PVC powder was made. However, most manufacturers produced all grades of polymer to that it was unlikely that any medical conditions peculiar to a particular manufacturing site could be explained in terms of the polymer and its particle s;cc. Moreover, it should be remembered that all the siptificant medical effects under discussion at this conference (angiosarcoma, acr&osteolysis &c.) had. throughout the world, been observed exclusively in workers on polymerization plants or, in two cases, plants handling liquid rinyl chloride under pressure. Features common to all these workers wore that they were exposed to vinyl chloride vapour in the atmo sphere but were not exposed to PVC dust since the polymer was maintained in aqueous suspension throughout this stage of (he process. It was in the drying and bagging sections of the PVC-producing process that exposure to solid PVC panicles could arise but. despite extensive medical investigation, no significant abnormalities had been found among drier operators or packers; It was perhaps worth noting, too. that the greater proportion of PVC .powder was of a panicle size similar to sand so it did not generally pose an airborne dust problem. For those powders which might cause true dust ex posures it had been customary in industry, because of the nuisance and discomfort factors alone, to proride some form ofrespiratory protection. Dr C S Darke Utoya! Infirmary, Sheffield) said that he had investigated 14 cases of breathlessness in workers exposed to vinyl chloride monomer. The findings were: no abnormal physical signs; chest radiographs normal; routine respiratory function tests difficult to evaluate but some results slightly below predicted values, especially impaired CO diffusion in 6 indi viduals; perfusion and ventilation scans showed striking abnormalities as illustrated by one slide re vealing marked perfusion defects of upper lobes. One patient underwent open biopsy of each of the three lobes of the right lung. Htstolofi' revealed focal alveolar wall thickening with macrophages in the alveolar spaces and increased reticulin and collagen t.--wrw gi' ijwwywcv** L -/.'i ly-.V' -i'k \ a ,, * - ucc " - 065488 22 ibly lower-levels s on this, quite society generally, the pert eighteen Medical Advisory it was known that jer were sometimes is powder contained nonomer. He asked :!sb!e on the panicle i processes throughe of vinyl chloride article sizes of PVC depending on the powder was made, educed all grades of ' that any medical ' manufacturing site he polymer and its be remembered that under discussion at Vo-osteolysi* &c.) Observed exclusively ms or, in two cases, >de under pressure, rkers were that they apour in the atmoPVC dust since the .queous suspension ;J, *# t iin; sections of the osurc to solid PVC c extensive medical ormalitics had been or packers: It was :e greater proportion size similar to sand borne dust problem, cause true dust exindustry, because of ora alone, to provide on. Sheffield) said that he ihlessnws m workers :r. The findings were: chest radiographs :xn tests difficult to :]y Iclow predicted elusion in 6 indi,ion scans showed ;cd by one slide se rf upper lobes. One cf each of the three revealed focal .aCTppnagcs in the icoiin and collagen 23 Section ofOccupational Medicine 2SI 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 polymerization process that yielded, `plastisor, a very fine PVC powder with particle size around OJ urn. These particles, containing vinyl chloride monomer, could be carried to the alveolar walls where t.-.ev might be retained and thus set up a reaction of the type seen on light microscopy. Professor l J SctikofT (Mount Sind School ofMedicine, City University of Sew 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 sge 40, obstructive findings were predominantly among cigarette smokers, as expected. After that age, however, the prevalence of changes was very much the same among smokers and nonsmokera. Of course, age correlated strongly with duration cf employment. These two factors were analysed separately and it was found that the changes were generally among smokers with less than 20 years from onset of exposure, but that thereafter they were present in both smokers and nonsmokers. Radiographic changes were less common. Overall, 13.3% of 985 chest films snowed linear, reticular or nodular changes characterized as 1/0 or 1/1 in the ILO U/C Classification. Dyspntxa wax uncommon and signs or symptoms of chronic bronchitis were not striking (Miller ero/. 1975, Miller 1975). The pathogenesis of these abnormalities was not clear. It was not known, for example, whether they reflected another biological change associated with exposure to vinyl chloride monomer, or another factor. Mr A W Barnes had noted that manufactured PVC might currently contain 5 parts/10* of retained vinyl chloride monomer, as well as other agents added in the polymerization process. Inhalation of such PVC particles might be associated with adverse effect. Frongia and his colleagues (1974) had reported significant histopaihological changes in the lungs of guinea-pigs exposed to PVC powder in a PVC plant In the polymerization facilities investigated by Professor Selikolf. there had usually been opportunity for PVC dust exposure as well is 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 pans of the production process. PVC dust was often to be found in several pans 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. REH-Rliscns Fionas N, ibpmtsjoU A & DttcauMi A (19%) AUom tns <tf, MiHfr A Health Prrtpeclivf 11, 247*250 Millar A, A 5. Clivai,c M A *likoH 1J (19*5) Anneif A(u4?r*.y t,fUditwrt 24$, 42*52 Dr K s Williamson (1C! Ltd, Central Medical Croup, futshaw Hall. U'Himlov, Cheshire, SK9 IQB) 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 Mastromatteo et ol. (1960), who found that the lethal concentra tion for mice, rots and guinea-pigs exposed for 30 minutes was between 200 and 300 000 pans/10*. In long-tenn studies few toxic effects w-ere reponed, though Torkelson ct oi. (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 500-200 pans/10* for sixmonth periods. No significant changes were found in any species exposed to 50 parts/10* for six months. In 1971, however, Viola et oi. reported that while attempting to produce aero-osteolysis in rats, they had found tumours of the ceruminous glands, lungs and bones in animals exposed for 4 hours a day. 5 days a week, for 12 months to 30 000 parts/10* of vinyl chloride. Viola's findings, which are the earliest to be published describing the oncogenic effect of vinyl chloride, caused considerable concern throughout the world and led to further 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, Maltoni & Lefemine 1974). In these experiments groups of rots were exposed to vinyl chloride vapour concentrations ranging from 10 000 to 50 parts/10* for 4 hours a day, 5 days a week, for 12 months. The animals were then maintained for the rest of their lives unless they became ill. Tumours of the cerumi nous glands, angiosarcomata of liver and other organs, nephroblastomata and a variety of other tumours^were found in animals exposed to vinyl chloride. In animals exposed to 50, 250 and 500 parts/10* the logarithms of the numbers of animals having angiosarcomata and the total tumour-bearing animals arc linearly related to the dose of vinyl chloride, but in animals exposed to higher concentrations, this relationship is not found. Tumours ha\e also been found in mice and hamsters bv Maltoni and by Keplingcr et al. (1975), who reported the findings of angio sarcomata and lung adenomata in mice exposed ucc 065489 2S2 Proc. ray. Soe. Mrd. Volume 69 April 1976 24 by inhalation to 2500, 200 and 50 pirts/10* of vinyl chloride, hiore recently both Maltoni et ol. (1975) and Purchase (1975, personal communica tion} and his co-workers have found liver tumours in rats given high daily oral doses of , vinyl chloride in oil. Neither investigation is completed yet. Maltoni et at. dosed Sprague Dawley rats daily by savage at 50, 16.6 and 3.3 mg/kg for 12 months. They reported the occur rence of one angiosarcoma of the thymus in the 50 mg/kg group and one angiosarcoma of the liver in the 16.6 mg/kg group in an interim report approximately 13 months after the start of the experiment. Purchase and his co-workers dosed Wistar rats daily by gmvage at 300, 30 and 3 mg/kg for 6 months. Fourteen months from the start of the experiment, a large proportion of the animals in the 300 mg/kg group and several of those in the 30 mg/kg group have been found to have liver tumours. Preliminary histooathological 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. Table J Rat inhiUiian ttvdtrt (tfau af Msliooi) \cn;iiaiipn -- JOCml tr/,iftina61iir4/tovr 24 litres per 4-hourcipovure period -0.024 m* Wight orrmti assumed tote 5001 Jrnmumidoit Dsify 4w (mg) Doily 4o* (t.'kg) (daily fcmpO* wtf/w** i0S>34 Kmg/tn*) imgfkg) 4o*txJ30) 900 1290 SO 290 025 19 90 129 I 90 13 30 7-5 9 1.5 Table 2 Rat ml stadias 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, bur they do give a useful measure for assessing the animal data. Tables M*at*vrk VcntiUiioft ** 10 m* air per 9-hour tfcift Weight attained 10 te 70 L( Mi.'/F 500 too 50 10 1 Doitydoo* mgfmA (mg.m* x JO) IZS0 250 (25 25 -< 12 500 2500 IZJO ISO 25 (mt'kt) 190 40 It 4 0.4 Ammttol 4ott U/*f) (doily 49**230) 44.4 *. 4.5 QJ 0.1 Green & Hathway (1975) 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 meiabolized falls with diminish ing dose (.Table 4). Table 4 Amoitti t( vinyl eMofid* metabolised i(tf iiflrtm; tifttlt dates ptw orally in mm oil (Green 4 Haih*> 19?J) Dote (m#/**) *1J0M003 . . 01 J5 Pttrerttogr m+tobotiied 414f2t 1K449.J 4mMeimstnofliztd imglkt) 7iut4s 00z.J.9i46 Three principal eliminative routes have been identified by both groups: expiration of un changed vinyl chloride by the lungs, expiration as CO, by the lungs, and excretion of metabolites in the urine. The proportion of vinyl chloride eliminated by these different routes varies with dose (Table 5). SrwJy Mslleeu (290dc*cs) Doily 49ft 50 149 5.5 TtlmieAfr (flit) i ttg 4.0 OJ Tables Freportion t a sinsle oral doe* of fiH chloride eliminated by various rentes (Green 4 Hathway 1975) Purchase 300 <J2 doses) 30 3 ^ tumours found jwc t.:o 0.4 tojr 0-25 450 Proportion e/iminorrd( *'.) Umehm*gtd Coa .>*** 4 12 75 92 t 9 2d i compere doses ig-term studies with for men exposed to centration* of vinyl Again the calculated :ry rough indications a useful measure for .ji lej]? doit 60 <0 '* 4 0.4 Ammuljut 4m* x .259) 44,4 4i 0,9 0J ) and Watanabe tt at. armacodynamio and dc using "C-labelled losing methods to rats, hat the proportion of ^etabolteed is greater large, though the i falls with diminish- ! Illft >fTl oil SihstA ive routes have been s: expiration of un the lungs, aspiration xcretion of metabolites don of vinyl chloride :nt routes varies with t mrttboiitrt 25 Section ofOccupational Medicine ;$3 Major metabolites identified in the urine arc: (I) thiodigtycolic acid; (2) S-(2-ch!orethyl) cysteine end N-acetyi-S-(2-chlorcthyl) cysteine: (3) urea. Thiodigb colic acid is derived from monochloracetic acid (this can itself be detected in small amounts in the urine) which in turn might reasonably be supposed to derive from cyclic chloreihylene 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. $0 reducing the available protective mechanisms w-ithin the liver cells. Watanabc et at. (1975) have reported progressive depletion of the hepatic non protein sulphydry'l content (equivalent to gluta thione in this context) in rats exposed to 1000 and ISO parts.' 10* vinyl chloride by inhalation. No such depletion was found following exposure of rats to 10 parts/1 O' for 7 hours. Hathway (1975, personal communication) considers that the erhyl cysteines themselves may well 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. REFERENCES Cm.TiHith...DE (1973) Chenrif^buAofif0i 11, $4M63 Kfflingrr M L 'V, Gfin D EJfc Cilsndr* J C (1975) Ammoit t>fthe AW Ymek AemAemy ofS<le*et* 246, 219-224 KUkooaC (1973) Eseetpia AtfAieoImuiiw/wm*/Ci*t*t**SrtUt 275,4 Msliooi C* Citibtni A, Gtaubv t Ouk# P (1975) GU OtpedstlideVo l7/e 2 65-54 Mfthoni C k G (1974) LiHtTi-RtrAiconu etcltj Ckm* Ji Seinef FUiehe. MatenmtU'lte e SetvreH 54,1-11 * MttirMitiH E- Fislftt A M, Qtrifiit H k Dsmifn H (1940) Xfurrtfsn Imduutiol Hygiene TorktlMtn T R. 0, ffl F A )' K (1961) Amend* InduttrialHytiine`As$9*Uitiim}0*rH9tlU 35^361 Viola P L, A & CiptftvA <197l)C<Mr**r /7rswrli31#5l6-*22 U'tiknaM P C. Hlf* R L jf, McGmtin G R k PJ (19*M PrefTC'-^ Repon to N:anyf*cturin$Chemit: Allocation iuV on Vinyl Chloride Rneirch. Washington DISCUSSION* Dr L Magos (MRC 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 dravv any conclusion about the threshold or no-effect level, as the zero-effect level could theoreti cally never be reached. Secondly. Dr Williamson's data on the metabolism of vinyl chloride depending on dose indicated that at low exposure levels a high proportion of vinyl chloride was metabolized and less was exhaled un changed. This might mean that increasing exposure above a certain level would exhaust the biochemical ability of the orpnism 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 Brunch, National Institutefor Occupational Safetyand Health, Cincinatti, Ohio) said, in amplification of Dr Williamson's remarks on metabolism of vinyl chloride, that two metabolites had been identified in the liver of rats exposed to vinyl chloride: N-acctyl-S-( 2-hydroxy ethyl) cysteine and thiodiglycolic acid. The importance of knowing the nature of these endogenously supplied moieties was that they represented free, available sulphydrvf (SH) groups that acied as `scavengers* of the vinyl free radical, thus removing in oncogenic poten tial. in a series of decreasing exposures of rats the find ings were: at 1000 parts/]0*, rapid and complete satu ration of available free SH groups (liver); at 200 and 100 parts/IO*. fairly rapid saturation of available free SH groups: at 50 parts/10*, a plateau of the saturation curve; at 10 partviO*. no disturbance in the amounts of free SH. Inferences and conclusions: (1) From the fact that hemangiomas occurred in the liver, and not in the lung (the primary site of entry-), it could be inferred either that little or no vinvt chloride metabolism to free radical occurred in the lung, or that there was ample free SH to scavenge the vinyl radical. (2) Most important, the liver had a built-in antagonist to the vinyl free radical that provided the basis for a threshold for the carcinogenic response, in this case a threshold for an occupational carcinogen demonstrated by a specific biochemical constituent reaction. This finding explained the fact that among the tens of thousands of workers exposed only a small handful cfhxmangiomas had been found. (?) Finding an oncogenic threshold of appreciable magnitude (between 50 and 10 parts,'10*) removed concern about general exposure of the public to small amounts (see Barnes, p 2S0) of vinyl chloride in PVC plastic wrappings of foods; the United Slates FDA could forget it! (4) To bolster res,stance to effects of vinyl chloride, vegetables of the Brasv'ca family should be eaten. Factors reducing free SH were: certain industrial exposures that were detoxified by cysteine, e.g. brombenzene: substances or condi tions. e.g. certain chronic diseases. v-ii.-r'v'. i ?-" e*V- ' `! *'&**& ^^ 2 : L- -';' '. -fmMr. ' . I -.,,W1 -, *c .4 . h.s.i'C; ^-V.Fj 'J ! vjv-S^*-v* 4S^it'-* Ii ' ssp.v &&& .: fc^,:sS;-J .- -- . -'-iT t! :! <! fe&ji li -- ;! P ^*. :1\- - * j! &l\ *:/ :*:-'. iajjiaLtf-r.'-ift7?-- eiaiCagJfcS^lv^;-.,t lx "''^u 2S4 Proc.roy,Soc. Med. Volume 69 April 1976 26 Clinical Aspects of Vinyl Chloride Disease Dr B J Preston, Dr R Lloyd Jones end Dr R G Grainger. {Departments ofRadiology and Rheumatology, Harlow K ood Ortkoptrdic Hospital, near Mansfield, and Department ofRadiology, Horthern General Hospital, Sheffield) Aero-osteolysis The word acro-osteolysis means dissolution of the extremity of a hone and it is applied to the distal phalanges of the hands and feet. There are many causes, c.g. scleroderma, psoriasis, hyper parathyroidism. sarcoidosh. ergotism, diabetes, tabes, syringomyelia, familial and idiopathic acro-osteolysis. A similar appearance may occur as a result of trauma. Recently, acro-osteolysis of the hands of workmen associated with vinyl chloride polymerization processes has been re corded by Cordier et ol. 09*6). Wilson et al. (1967), Harris & Adams (1967), Dinman et al, (1971). and Lange era/. (1974). We would like to present the radiological findings in four patients who had been involved in the production of polyvinyl chloride. Methods All patients had the following regions examined by plain film radiography: hands, feet, shoulders, elbow-s, knees, ankles, pelvis, chest, skull, man dible and spine. Case I (AD) also underwent a barium swallow, meal and follow'-through, angio graphy of the hands and serial films of the hands at 6 months and 2 years after presentation, and a film of the pelvis at 2 years. Case Reports Case 1 A D presented at the age of 35 years w ith symptoms of severe Raynaud's phenomenon, pain in miny joints, trismus, ar.d thickening and tightness of the skin. He had been engaged in the polymerization processes of vinyl chloride for JJ years. A radiograph of the hands (Fig I) showed dissolution of the central parts of alt tlie terminal phalanges except for the little fingers, erosion of all the terminal tufts. Ihinning of the central parts of all the middle phalanges but particularly those of the little fingers where there is extension into the base, thinning of the middle and distal parts of the proximal phalanges of the ring and little fingers and etosions with a well-defined sclerotic margin at the base of the right first metacarpal and at the tips of both ulnar styloid processes. In addition, soft tissue thickening was present e'er the wrist and the whole of the hand. A film of the feet showed acro-osteolysis of 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 metatarsal bone and the right medial and intermediate cuneiform bones. The radiograph of the pelvis .*5*. VV'iX** ~' ._*" ,.4, i*'v. >m C-j " 'V- 3,4 Fig 1 Case 1 Hand! (J.5.73), sho* inf trOMrrrte defects in eiisiaiphiilanges, osteolysis, erosions andsoft tissue thickening UCC 065492 26 g regions examined nos, feet, shoulders, , chert, skull, man>) also underwent a low-through, angioil Alms of the hands presentation, and a years with symptoms of n, pain In many joints, ghtness of the skin. He irritation processes of -adiograph of the hands he central pans of alt for the little fingers, thinning of the central nges but particularly there is extension into and di<tal pans of the and little fingers and tierotic margin at the pal and at the tips of n addition, soft tissue u rist and the whole of fed acro-osieolyrit of fh big toes, a large first metatarsal bone tad of the right first icdial and intermediate graph of the pelvis * .1 ri n K* i* - >' -'i vV^ i--yX'-v' lv.:- --_~ " *-3 JrACS'AC'.tiiittjtt %t3&sk&z V Section ofOccupational Medicine 2SS 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 hecB of the right first metatarsal bone had progressed in size over the 2-year period. The film of the pcls two years after presentation showed a slight increase in (he 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 anxsthesia. The large vessels were patent but in the left hand there were occlusions in the digital artery on the ulnar side of the thumb and radialis indicis artery of the index finger, and narrowing of the digital artery on the ulnar side of the little finger. In the right hand, slight narrowing and tortuosity of the radialis indicis artery and medial digital artery of the little finger was shown. In both hands, hypcrvascularity of the terminal tufts was recorded. Fig 2 Case 1 Mandible, rerroling marked eroiion of ascending rami mealed large erosions around both sacroiliac joints, at the tips of the greater trochanters and along both ischial tutvrosiiies. The radiographic survey of the peripheral joints recorded erosions at the lateral end of ihe left clavicle, left upper humerus, medial and lateral epicondyles 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 fiiarked thinning of the bone: on the left side this extended up wards to involve the condyle. Films of the skull and spine and barium swallow, meal and follow-through examination showed no abnormalities. Monitoring films of the hands and feet were taken at six months and 2 stars after presentation and these showed interesting changes. At 6 months, the films of the hands recorded the following changes; fa) central defects in the distal phalanges of the little finger; (b) further osteolysis, particularly of the bases of the distal phalanges; (e) 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 years 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 acroosteolysis of the big toes in the first 6-month period (Fig 3) but on the 2-vcar film there appeared to be Case 2 F P. aged 38 years, had been engaged for two yean in the manufacture of polyvinyl chloride. Aero-osteolysis was recorded in both index fingers and the right thumb. Erosions with a well-corticated margin were visualized at the base of the right first metacarpal bone, medial epicondyle 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 ulnar styloid processes. Case 3 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 acro-osteotysis or any other significant abnormality. Fig 3 Case I Feet, sir months after presentation ucc 065493 ` '*-'* *'* ' ` T*1 2S6 Proc. ray. Sac. Med. I 'ohmif 69 April 1976 28 Case 4 D \V, aged 44 years, had been working at the factory for fi\e years. The skeletal survey did not show aero* osteolysis 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 l, extensive bony changes were documented. Indeed, in Case 1. most regions of the body were invoked and a review of the litera ture revealed that no previously reported case had such extensk e bony changes. It has been suggested that personal idiosyncrasy may be an important factor in the wide variation of the radiological findings (Wilson et al. 1967). The changes in the mandible in Case 1 have not been previously described in occupational aero-osteolysis but it is interesting to note that atrophy of the mandible in idiopathic and familial acro-osteoly sis has been recorded by Greenberg L Street (1957), Papavasiliou et al. (I960), and Cheney (1965). Ross (1970) stated that the bone changes regress after the sufferer is removed from the hazard but in our Case 1 the serial films of the hands, feet and pelvis indicated that the aeroosteolysis was extending. Fragmentation of the remaining tufts has been described part of the healing state hv Wilson el at. (1967), but in our Case I it was only in the distal phalanx of the left big toe that there was any definite evidence on the 2-year film to indicate bony regeneration. The stenoses and occlusions of the digital arteries and increased vascularity in the pulps of the fingers recorded on the arteriograms in the first case have also been reported by Lange et al (1974). Narrowing and occlusions of the digital . arteries are known to occur in Raynaud's phenomenon (Marshall 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. Lai-ge et al. (1974) suggested that the dense vascular rete of the terminal pulps of the fingers was due to stasis of contrast in the vessels secondary to the shortening of the phalanges. This may be partly the case but l.aws c' al. 0967) have observed hyperttmia of :-e pivps cfihe Sneers in a case of clubbing due to bronchial carcinoma and a similar mechanism may apply in our case, as there is a strong clinical 'esem,blar.ee to clubb;ng. REFERENCES CWurf VV D OSS!) AmetiitAjtuttmilof Aarurfrwanr.i *4.5SS-4I7 C4*r J M. Fitui C. Lrifvtr M J t $*<na A <l**6) Cahirtt it Medeene fa TmttUi, 14-1* Dimua S D, Cuuk W A, VVluirimuM VV M. Mictuftn H J A DrtrtfCTd*:!) 4frAjt-j ,,/*, iriwter.ie.' Hcchh 21.*1-7) Crfansnt BE* Sir--1D M (l!7) SadtaL'ty **. H.rrii D K A Aiamt VV CF (l**7) Btitii/t \l, MeatJournaliti. 71 '-714 Lt*Ct C E. Jvic .. Stria C A WlimaaC 0*74) tfafaWHfaftri 4h4trSr U, 1-73 U* J VV. El Salta* RA 4 Sou J T (l*#7) Smith Juurmulnf'Sndiulnfr40. 740.747 Mintult T R, NririuSt D. Ckwulrr VV F A Ku4 M L (1**4) KmdieJugy M. C**-J0J CC. C*rt*u> FH WaDh VV L 11**01 Amrricmm Jot.imtl ejFmrtnrie) *7. *S7-**I Rhi J A (1*70) In. Svnipotiwir. Ouhim. Ed. A M JctlilFt A B Strickland. Lhinmont. Edinburgh A London: pp 771-714 Wiltau R H. MrCamiclt VV E. Tatum C F A Crmh J L <1*471 Journal ofthe Atorrieao Medical Attotiatiao 101. S77-7SI DISCUSSION Dr L Magos said that Dr Preston's Case I might be idiopathic acro-osteoly sis aggravated by exposure to vinyl chloride. In the two-year follow-up study Dr Preston had found improvement in the fingers, which were usually involved in occupational vinyl chloride acro-osteoly sis. and deterioration in the pelvis. Dr 8 J Preston replied that idiopathic acro-ostcoiysis was considered in the differential diagnosis of Case 1 but the distribution of the bony abnormalities other than those in the hands was different from those recorded in idiopathic aero-osteolysis. Dr K Lloyd Jones added that Dr Preston's Case I also had severe involvement of the skin by the sclerodermalike condition seen in vinyl chloride workers together with evidence of other multisystem involvement. It was most unlikely that this combination in a vinyl chloride production worker (autoclave floor worker) -w-ould be due to idiopathic acro-oteoly*is. 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 bee " unrewarding. He was employed as a production wcr. rr in a PVC plant ar.d had never been exposed to v - Jiion or the use of pow er tools. Dr Anne E Walker (Royal Hospital. Chesterfield. DerbyshireI Clinical Aspects of Vinyl Chloride Disease: Skin Industrial acro-osteolysis, a triad of Raynaud's phenomenon, sclerodermatous skin change and lytic bone lesions, has been well documented as occurring in workers engaged in the poly- ucc 065494 m :s 595-417 >e"rin A lt IA-19 ' M, Meciuto* IIJ 22,61-73 */<* 49, m*:c 714 G ntHiiim 12. 1-22 740-74? FAK*i.fiMU UWU -nCv U. 617-491 .m. Ed.AM Jelliffe* A London; pp 221-224 CFA Creech J L ol AxMxnuitui 20), 777-311 ton's Case 1 might be svated by exposure to ir follow-up ^tudy Dr m in the fingers, which p.iiioml vinyl chloride on in the pelvis. lopathie aero-osteolysis ijl diagnosis of Case ) ny abnormalities other dilTcrcni from those lysis. )r Presion'S Case 1 also kin by the sclerodermaloride workers together system involvement. It .ombination in a vinyl tuloclave floor worker) -o-osteolysis. It was not ut this pafiim to biopsy talangcs. Biopsy of the :ii uincwarding. He was ker in a PVC plant and ibration or the use of a triad of Raynaud's ious skin change and n well documented as igigcd in the poly- 29 Section ufOccupational Medicine 2S7 mediation cf vinyl chloride monomer (VCM) to polyvinyl chloride (PVC). Medical surveys of large numbers of employees have shown an incidence of approximately 3 % (Wilson et al. 1967, Dinman et al. 197t). Both these studies also suggested that the disorder waslargely 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 of acro-osteolysis. Clinical Study In February 1974 I saw one man with severe Raynaud's phenomenon, minimal bone changes in the lingers 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 i9 years (average 40 years 2 months). Length of employment at the plant ranged from 9 months to Si years (average 2 years S 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 are 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 one*oceasion they had felt overcome by the vinyl chloride fumes, describing them selves variously as `unsteady', `slightly drunk' and Table 1 Pmeting m 27 Symptom Cold hand! p*nixthnt Impaired grip po er Cold tax Aches in bonet Ache in tnuttle* D}^?n<ra Hjc&mv* futistic Lott of libido Ao, oftom 30 16 15 IS 30 15 17 U 13 `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 canying 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 dorsum of the feet; additionally he had extensive lytic lesions of the bones, phalanges, feet, pelvis and jaw (K LloydJones. personal communication). In 5 men there was clinical evidence of Raynaud's phenomenon; in 2 it was a marked feature, with rapidly occur ring colour changes from 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 to improve in warmer conditions; the swelling was firm, and suggestive of sclercrdema rather than scleroderma. Skin biopsies were obtained from the dorsum of the hand in 15 men. The epidermis and adnexal structures showed no abnormality. In the dermis there was some destruction of elastic tissue, but it was probably a normal age change. In one man with severe Raynaud's phenomenon the dermal aneries showed some medial thicken ing. Arteriography of the brachial aneries 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 \essels. mainly in the ring and little fingers. UCC 065495 2S3 Proc, toy. Soc. Med. Volume 69 April 1976 so 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 eryoprecipitate 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, S 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 dyspnoea, cramp-like pains in the limbs, parenthesis, 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 clinical change in the skin or evidence of pathology on biopsy contrasts with the marked sclerodermatous and plaque-like changes described by others (Cordier ei al. 1966, Harris & Adams 1967, Wilson er 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 there has been little improvement in tbe vascular signs during the period of ob servation, and this is in accord with the findings of others (Adams 1974, personal communication and M N Johnson 1975, personal communica tion). .However, Suciu describes the disappear ance of Raynaud's phenomenon within one year (Suciu et al. 1963). In two instances cervical sympathectomy is recorded as producing clinical improvement (Takouchi & Mabuchi 1973. Markowitz ttal. 1972). At the present time it is not known whether the peripheral vascular disorder is directly related to the presence of circulating immune complexes or to seme other alteration in the sensitivity of the vessels to exposure to cold. REFERENCES CuSiff J M, Finn C, Ulnn M J X Snri, A (1966) c**.i di suetiine* rivw,6 - - Diomoo a D, Cook VV A, WVilltiMf VV N| A HJ (1971) AreJU-rj ofoiirovrroUt MrOiih ZZ, 61-7? HhiuDKAASimWCF 0967) lirfiil KtrdieatJoormoi iii. 717-7)4 Lu(< C E, JUt S- Sm G 4 C (1974) lo'.tfnaiioooUt Arthirfur Arbeiti/ocC^i* 31,1 Muknta $ 5, McDnuM C J. Ftihirrt VV 4 K-rnu M S (1972) Atchirtl ofISrrmOIObtS >M. 219 Socin I, Drrjaui 14 ValuXi M (1963) MriitimA hifimtlkfUrrit) 15,967 TiXaucJii V 4 Mifcwfci C (1973) Jcsoorxr Joorooloflodoxtrio! Hroltk 15,395 R H. McOnMk W E. T(nm C F 4 CmS J L (1967)UwnM( ofl* AmertemH MtOieal Auocimiioo 301,577 DISCUSSION Dr Leo Djcrassi (Department of Occupational Medi cine, Haifa, Israel) said that in one patient in his series the presenting syndrome of vinyl chloride disease was a pale moonlike face. This particular type of sclere dema (not scleroderma) had already persisted for five years after exposure had ceased. In one case of scleroderma-like syndrome a skin biopsy showed no change in elastic or fibrous tissue but several areas of perivascular infiltration, 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 same patient left the factory because of loss of libido, and Dr Djerassi 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 Anne Walker, in reply, said tbat the scierademalike.ehange observed in A of the men varied consider ably from day to day but in two men had persisted for atleast eighteen months after the last exposure. In 15 biopsies from 13 patients an excess of inflam matory cells in a perivascular distribution were present in 4 of the specimens. The cells were largely lympho cytes. Loss of libido was the presenting complaint in one patient and had persisted since the man left the firm approsdmately three year* ago. In 3 of the worker* complaining of impotence, urinary e&eietion of androsterone and dihydroepiandrcsierone were very low. These measurements were made approximately twelve months after the last exposure to vinyl chloride. Dr Marcus M Key (University of Texas School of Public Health, Houston, Texas') asked if baggers and warehousemen had previously worked as reactor cleaner*. Dr Anne Walker replied that they had not. Usually men started us baggers and later became reactor operatives and cleaners. The one warehousemen had JO fcA * MitWM H J eu,l ' & Ktm M S 1 U, its 4 OmkJL uxytiitt 2t>i, in Occupational Midi' puicnt in hit series hloridc disease wtas Uar type of sslertsiy persisted tor five t syndrome a skin ic or fibrous tissue infiltration, small hocytes and larger hcnomenon which tial exposure, the Ko or three hours jwn pbenomenon This same patient of libido, and Dr *as an immediate ootic effect of vinyl i disturbance coniease as stated by the seleradcmarn varied consider* r. had persisted for =t exposure. ' excess of in/laro'UU'on were present re largely lympho* : complaint in one man left the firm 3 of the workers excretion of andro'e were very low, le approximately : to vinyi chloride. ' Texas School of .cd if backers and oiked as reactor h*c not. Usually r ncctme reactor a-chouseman hr.d ft 31 Section ofOccupational Medicine 269 never been in a reactor. One of the baggers had spent an initial training period as a reactor cleaner but had felt nauseated whilst in the reactor. After the first two weeks he had worked entirely in the dry building for four tears. The other bagger was an epileptic and had never been in a reactor. Dr Premysl V Pelnar (Montreal. Canada) asked what blood flow measurements were done? Or 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 was 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 total finger flow in the index finger was measured by means of a plcthysmograph and capillary flow in the middle finger by electrical impedance. Additionally, the skin temperature on the back of the hand was measured. Dr A Milford Ward (Department ofImmunology, Hallomshire Hospital Medical School, Sheffield. S10 2R.X) individuals from the factory who were completely asymptomatic. The major features of the disorder include hy* perimnunoglobulinzmia, cryoglobulinemia and cryofibrinogentemia. and in vivo complement activation via the classic pathway with C4 and C3 conversion. There is. in addition, evidence for a reduced T cell population, w ith low- spontaneous sheep cell rosette counts, and an increased B-ccll 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-spccific antitissue anti bodies of low titre but rheumatoid factor is unit ersally negat ive. lmmut.ofluoresceni examination of biopsy material from skin (S patients), muscle (I patient) and lung (1 patient) has shown the presence of circulating immune complexes, with deposition on vascular endothelium and occlusion of small vessels. In those vessels which show- subintimal proliferation and luminal occlusion, immuno globulin, complement and fibrinogen are present in the subintimal regions of the vessel wall. Evidence of an Immune Complex Disorder Experimental evidence on the metabolism of in Vinyl Chloride Workers v inyl chloride suggests that at least pan 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-osteoly sis (AOL) has been recognized in the result in a structurally abnormal protein which vinyl chloride industry since the mid 1950s. but w ould react as antigenically '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 confined 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 w ith 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 Immunological and immunochemical investiga* abnormalities. Structurally abnormal or anti tion of 5S workers from a single factory has genically `foreign' protein escapes tolerance 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 hyperimmunoglobulinzmia. The immune 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 cryoprecipitate and disease process at 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 13 individuals who were The frequency with which abnormalities have symptomatic to a degree that they were incapable been detected in this series, especially in that of active employment; and in 3 out of 2S indivi group in whem there were no evert clinical signs, duals who were symptomatic but able to work. suggests that the disease process may be more Immune complexes were not detected in 3 common than generally supposed. The theoreti- ucc 065497 290 Proc. roy. Sac, Med. Volume 69 April 1976 3: cal. and at present speculative, initiating sequence of reactions in this disease process also raises the question whether other unsalurated halogenated hydrocarbons may also be involved in a similar chain of events. Further studies are in progress in an attempt to clarify the initiating reaction sequence and to define the precise relationship between vinyl chloride and the observed immunological anoma lies. DISCUSSION Dr Lto Djermtsi said that fatty liver might be the early histological change in liver caused by vinyl chloride. In one or his cases which began with splenomegaly, liver biopsy showed a fatty liver. The patient did not consume alcohol habitually. The finding was not surprising, as chlorinated hydrocarbons were known to cause fatty liver. The clinical development of this case brings us to the evidence of immunological phenomena in those exposed to vinyl chloride, and to the possibility of another target organ-the spleen. Splenomegaly was the first deviation in this case, and increased progressively. Hypersplenism followed. Splenectomy and splenorenal shunt were indicated because of osophageal Weeding. The patient's condi tion improved sufficiently to enable him to work full time on a nonstrenuous job. Dr A Milford Ward replied thrt the classification used in this study was a clinical one. br-.sed on history, physical examination, and an assessment of the patient's ability to continue his employment, l; therefore included such aspects av splenomcgal , aero-osteolysis, and scleroderma." Dr Yjgliani (Milan, Italy) asked w helher the presence of B and T in the tissues could be detected by im munofluorescence. Dr A Milford Ward replied that lymphoreticular tissue was not examined histological!) or immunologically to the presence of T and B cells could not be assessed in tissues. T and B celt counts were per formed on peripheral blood. Dr Ruth Lilis (Mount Sinai School of Medicine. Hew York) asked whether immune complexes were found in the kidney. There were in the literature a number of cases of Goodpasture's syndrome in persons exposed to chlorinated hydrocarbons. Dr A Milford Ward said that renal tissue was not examined. None of the patients showed clinical evidence of renal disease, and it was not considered ethically justified to biopsy the kidney in the absence of proteinuria or tuemaiuria. Antibodies to renal glomerular basement membrane were not detected. Professor Margaret Tumer-Warwick (Cardiolhorarie Institute, Brampton Hospital. London SIVJ) asked what was the cause of ihe T cell depression mentioned, and whether the spontaneous sheep rosette T cell counts were confirmed by other in vitro tests 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 as well as in the larger vessels mentioned ? Dr A Milford Ward replied that the cause of the T cell depression was not dear, but it was a feature often seen in circulating immune complex disorders and in autoimmune states. The low rosette counts were partially confirmed by a mild depression of the PHA reactivity of the peripheral blood lymphocytes. Complement activation in vinyl chloride disease was by the classic pathway with conversion of C4 as well as C3. as would be expected with IgC class antibody directed against the antigenic groupinp. Immune complex deposition was found in capil laries and small vessels in skin, muscle and lung. Dr L Migot said he would like to see the patients classified by grade, since it was always frustrating to read of 'severely affected' people without knowing whit 'severely affected* meant. The grading could be based cn degree of splenomegaly, aero-osteobxis, scleroderma Ac, Dr IF H Purchase, Mr C Richardson and Dr D Anderson (!C1 Central Toxicology Laboratory, Alderley Park, near Macclesfield, Cheshire) Chromosomal Effects in Peripheral Lymphocytes Vinyl chloride produces liver tumours-in animals exposed by inhalation (Maltoni & Lefemine 1974) or dosed by the oral route (Maltoni rt at. 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 as benzene, recent studies, have demonstrated that workmen exposed to vinyl chloride have an increase in the percentage of lymphocytes with chromosomal abnormalities (Funes-Cravioto et at. 1975, Ducatman et al. 1975, Purchase et al. 1975) . Studies of this type carried out on lympho cytes recovered from peripheral blood provide an easy clinically applicable method of assessing damage to living cells caused by carcinogenic chemicals. If there is a quantitative relationship between the percentage of chromosome abnor malities and the amount of exposure to the chemi cal, the estimation of chromosome abnormalities 32 he classification lived i, based on history. isusment of (be his employment. 1! \i as splenomegai . whether the presence i be detected by im- that lymphoretieubr logically or immunoand B cells could not 3 cell counts were per- hoet of Medicine, Hew complexes were found literature a number of is in persons exposed renal tissue "was not :r.ts showed clinical t was not considered dney in the absence of Antibodies to renal were no: detected. ardson -crory, :!d, Cheshire) tumours in animals cltoni & Lefemine oute (Maitoni et cl. biished). Epidemio* cd that workmen id an increased risk moLTs, panicularly rh & Johnson 1974). rinojenic chemicals; have demonstrated nyl chloride have an pf lymphocytes with (Funes-Cravioto et ,975 Purchase et cl. tried out on lympho:re! blood provide an nethed of assessing sec by carcinogenic -.-.native relationship chromosome abnori posters to the chcmicsome abnormalities # -- ,,-vr - ----*?-rrwwW '-it it----iV-at-w r vura- 33 Section of Occupational ,\ Icdicine 191 may provide a useful tool for determining levels of exposure which do not produce this mutagenic effect. We have studied a population of SO workers including exposed workers, nonexposed workers from the same industrial site, and nonexposed control subjects from another environment. The exposed population has been divided into groups based on the type of work carried out: Croup I are autoclave operators: Group 2 are maintenance workers who have worked in the polymerization plant ; Croup 3 are those who work in polyvinyl chloride (PVQ production but not with auto* claves; Croup 4 are maintenance workers in the same area as Croup 3. It is virtually impossible to define exposure of these groups of workers to VCM apart from saying that the autoclave workers have the highest exposure and Groups 3 and 4 the lowest. One worker, who was employed as an autoclave worker for 11 years and sub sequently as a maintenance worker for U years, has been included in Croup 1. Blood samples were taken and lymphocyte cultures were prepared using standard Difco kits (Difco Laboratories, Detroit. Michigan, USA). Lymphocytes were cultured for 48 or 72 hours. All slides were coded before scoring, to ensure unbiased analysis. One hundred cells per indi vidual were analysed (except for one individual where 200 cells were analysed), using the classifi cation of Buckton &. Pike (1964). Workers who had been exposed to X-rays or prolonged drug treatment were excluded from the study. The results of the chromosome analysis are given in Table I. All individuals were round to have normal male karyotype, except for one who had a 46, XY karyotype with inversion of No. 3 chromosome. There was no significant difference' between 48- and 72-hour cultures so these data have been pooled. When the percentage of B and C cells in various groups is compared, it is seen that Groups 1 and 2 had higher percentages than Group 3 and the control group. The difference between the com bined results from the exposed groups and the control group is statistically significant. These results confirm the findings of Funes-Cravioto Table 1 Rvlit from intlyi** ( cfatBiwetMt* aWwmliiiit i* wpfktn to^loyrd U PVC naaufafturf (B and C*cUi dattifeO according to Buckteti & Pik* 1964) Group l Group 2 Group 3 Group 4 Control on fii Cent roll Off kite Vo. o/ M'orkttt It 21 5 12 19 5 M CV*7x <>;> .4 6.9 6.6 5.1 3.6 2.6 CUCrllt CSCelti C/J 1.71 I.4S 1.2) 1.10 0.53 0.30 <TU 0.44 0.30 0.20 0.41 0.10 0.00 et til. (1975) and Ducaiman et at. (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 vir.yl chloride is capable of inducing mutagenic effects in ether test systems end particularly whether such an effect is produced on germ cells. Accordingly vinyl chloride was examined for dominant lethal effects in mice. Croups of IJ male mice were exposed to 3000, 10 000 or 30 000 parts'lO1 of vinyl chloride for 6 hours per day for 5 consecu tive days. Each male was mated with 2 virgin females per week for 8 weeks and the females were killed at 13 days and examined for dominant lethal effects. There was no significant increase in 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. references >khM K E 4 p,-kr MC (!94) lnitTnalinn.ltJamnat ofRadiation BioiofY f, 439 Ci-rrh J L -V JaImim M N (I9~t)Journalo/OteupalionolSfrjieihf tS, 150 DuMiMia A. Hindihsm K Sfiikafl IJ (1975) Maioiion Rrtrtrrh 31.1*3 F, L*mfcrf1 B. UMun J, DitoiSrri L_ NaunjlA A T 4 Otlcimii C*ltar $ 119T5) Lanttl l, 459 M.ltMi C. CiliWni A. Cisni L4 Curt P (19751 OtrrdaliBtlla 17m 3. &3-M Mlti C 4 Lrftffltfl* C (1974) Enrironottotol Rtteo'th 7, 317 Patch... IF H, SicUUm C R 4 Aattnn D (1975) Lontrl ii.410 DISCUSSION Dr Sylvia D Lawler (Raya! Monden Hospital. London SiVS) asked were the chromosome breaks distri buted at random? Was a banding technique used? Were the people who actually had symptoms separated out? Genetic effects on human gonads were not absolutely excluded by negative results in a dominant lethal experiment in mice. Was there any evidence of lower fertility? Dr 1 F H Purchase replied that the chromosome breaks were distributed randomly. No banding tech nique was used. The people selected to lake part in the study were randomly selected and had not beer, separated into those with and without symptoms. The only evidence that had been produced expertmcn'.illy suggested that genetic effects did not occur in the gonads and no effect on fertility was seen. ucc V- 065499 292 Proc, toy. Sec. Med. Volume 69 April 1976 34 Or L dc Boer (The Hogue. Netherlands) said that Mrs I Flcig had reported (Medichem Conference on Chromo some Aberrations. Milan. October 1974, in press) on chromosome studies in which there were not more abnormalities in the exposed group compared with a control group. sis. portal hypertension, zcsophageal varices and splenomegaly may be common results of VCM toxicity f.Marsiellur et at. 1973. Smith & Williams 1974, Makk et at. 1974, Thomas et at. 1975, Lange et at. 1974). Or I F H Purchase said that his was the third study which had described such abnormalities, -the other being those by Funes-CravioiO et ol. (J975. Lancet i, 459) and Ducatman et at. (1975, Mutation Research 51.163). Or D C Smith (Zerelit Ltd, Isleworth, 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 of maximum exposure. Dr IF H Purchase replied that there was a statistically significant difference between the results from auto clave workers and controls, and between the results from all exposed workers and controls. Dr K J \V Tat lor (Department of Diagnostic Radiology. Vale University School ofMedicine, Sew Haven, Connecticut, USA), Dr J J Barrett (Department ofSuclear Medicine, King's College Hospital, London SES). Dr D M J Williams (BP Chemicals international Ltd, Sully. Pennrth, South Glamorgan), Dr P M Smith (Department ofMedicine. Il'c/sh Motional School ofMedicine, Llondottgh Hospital, Penarth, South Glamorgan), and Dr B W Duck (Occupational Health Unit, BP Research Centre, Sunbucy on Thames) In view of these adverse reports, a survey was undertaken of4S7 workers with varying exposures to V'CM by two of the authors (Williams et at. 1975). Full blood pictures were obtained and standard liver function tests were done. Two patients identified by a thrombocytopenia of 72 000 and 45 000,'mm*, and slightly raised G-glutaniyl trtmspeptidase G-GT levels, were subsequently found to have periportal fibrosis, portal hypertension, splenomegaly and oesopha geal varices on barium swallow, plain abdominal radiography, spienic venography and needle biopsy of liver. It was clearly unacceptable to carry ouf these invasive investigations on all exposed workers, but the less invasive techniques seemed relatively insensitive. Thus, a pilot project was carried out to ascertain whether ultrasound offered a possible noninvasive method for visualizing the liver and spleen in workers exposed to hepatoioxic agents. Initial results proved encouraging (Taylor et at. 1975, Williams et a!. 1976). Although ultrasound has been used as a diag nostic tool in obstetrics for many years, the instru mentation* was comparatively crude since the relevant echoes to be displayed Were of large magnitude and did not require sophisticated instrumentation. Kossoff (19741 developed greatlyimproved equipment which was clinically applied to obstetrics, the eye, breast and thyroid. Using simitar instrumentation, the lechnique was evalu ated for the investigation of liver and splenic pathology (Taylor et ol. 1973, Taylor & Milan Preliminary Results of Grey-scale Ultrasonography in the Detection of Vinyl Chloride Related Liver and Spleen Disease A number of cases or angiosarcoma of the liver in workers exposed to vinyl chloride monomer (VCM) led to the recognition of the potential hazards of such exposure (Creech Sc Johnson 1974, Block 1974, Lee & Harry 1974). To dale, 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 Fig I Schema to show movement oftransducer to display the anatomicalfi atm es .hewn in fig 2. The portal \cin it shown am, iior to the inferior vena cam ucc 065500 34 phageal varices and .on results of V'CM 3. Smith &. Williams homas <t at. 1975, iports, a survey was th varying exposures tors (Williams et ah were obtained and ots were done. Two ! hrombocytopenia of and slightly raised G-GT levels, were e periportal fibrosis, 'megalv and caopha!ow, plain abdominal ;raphy and needle c to cany out these -!l exposed workers, jcs seemed relatively ;ct was canied out to d offered a possible 2lizing the liver and ' hepatotoxic agents, kging (Taylor et al. been used as a diagany years, the instru:!y crude since the eyed were of large tquirc sophisticated 74)de\tloped greatly tas clinically applied and thyroid. Using technique was evaluof liver and splenic 73, Taylor & Milan oftransducer to - r in Fig 2. !C tl.C S3 Section ofOccupational Medicine 293 Fig 2 Parasagittal scan ofliver 2 cm to right of midiir.t showing normal liver consistency, portal vein and inferior vena cava. (Reproducedfrom Taylor et al. 1975. by kindpermission) 1976). This technical development was called grey-scale ultrasound, and the major difference between this and older instrumentation is the ability to display the normal tissue parenchyma. Thus, whereas the liver was previously found to be a relatively echo-free area in which only con tour and size could be distinguished, the display of the normal parenchyma allowed diffuse patho logy to be recognized due to an abnormal pattern. Small space-occupying lesions appear now as small defects of the normal parenchy 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 Parasagittal section ofliverfrom patient with vinyl chloride-relatedportalhypertension. The porta! vein is dilatedandhighly tortuous. Sotr that there are very large eehoctfrom the deep surface ofthe liver which is consistent with repsidorfibrosis (arrowed). (Reproducedfrom TayJoret a 1.1973, by kindpermission) as shown in the diagram, good resolution is obtained without degradation by respiratory or cardiac excursions. This ultrasound technique involves no ionizing radiation nor other known hazards, no discomfort, and no need for contrast media. It docs require considerable operator expertise and high quality instrumentation, w hicn 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 arc summarized in Table 1. Only Z patients had no exposure at all. but 7 were normal on standard testing (Table 2). Table I Dumtien end taels *f VCM expwurrt (from WHJitro rf t*/ 1976) Cor 1 2 1 4. 5 7 9 to It t: 13 14 15 14 17 11 19 41 40 22 45 4$ 45 36 47 JO 4 <6 39 41 42 50 53 32 43 46 Cant-W txpmvrt Lmw Stedhtm Hit* (No exposure) (No exposure) - ly Jm 10m. ly 6m 2y 3m 5y 9m : "m 2v 6m l?y 4m ly lm 3y 10m fcy Cm lm :> ttm 12y rn (v> 6m "> 4m 7v Iruirmiiiew isrpuiw L*% .4(return Alt* (No ttpeiun) (No exposure) 6y 4m ly Sbi 155 m I0y 5m Jy 7m 3y 4m lylOm ty 4m 7y 5m 6y 6m 10m 2y 4m lm 5v Jm lm Jy Jm h 2m I7y llm ?y 2m 3y 6m e>y 5m Gy 3m Uv 3m ly 4*n ly "m 1-f*'explore. 0-2S pares. 10*. mejsur-.r, Z*-ZM partvJO*;r:h. > 200 pjn*. 10* Time ci*** *n }*srt month* ucc 065501 294 Proc. my. Sac. Med. Volume 69 April 1976 26 The ultrasound examinations were carried out by the seme operator (KJWT), who had no know ledge or the results of the screening tests carried out at that time nor of the exposure of any par ticular worker. Abnormal findings included in creased size and tortuosity of the penal vein associated with ponal 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 screenin'; consisted of clinical examination, full blood picture, urinalysis and standard liver function tests. Repeated abnormality in any in vestigation led to further investigation including barium swallow, plain abdominal radiography. Table 2 CMptriiM f *bo*ruIi<ict and by ultra**gr&bh>- (from by tikadarg nrtMi tllumi n uL ) %*6) Cm methods UhrOj0* rtphf 1 Sormit Normal 2 Normal Normal ) Normal 4 Uvv f cm enlarged Normal SlitfhtK enlarged fi*ef but normal eomiftency 5 Norm*) Norma! 4 Norm*! Technics Dy'difticult (ebony). Enlarged pent) vein. Norms) 50 */m iticruM in tpfeen tiu Enlarged penal vein, tplcnomegaly (12 cm) Normal Enlarged (<vcr * tth a dtgrr* ofabnormal fibrous AUitii* phosphautc Porta ' vein not ahewn. ;i iaj/i Spleen i ice normal ***. Uvrr eemittciKy slightly abnormal 1Q |i*cr biofuy: ponal Enlarged liver with tract ftbrroi* in pbict teuiblc fatty ifihlirattcm mending imo parenchyma U Bilirubin 21 lino),] Penal Win slightly enlarged. SCOT 60 iu/) Marked splenomegaly (11 cm). Liver la'.imully d>dcult to aee 12 Nitillc liver biopty: alight Normal fcbTOti* and fatty thing* 1J SGOT 60iuH.GGT >5 ki/L Ponal vein and ipbta N**l* liv*r biopay; normal. Liver jiffcuU modem* fattydtgcnvaiion to m* (obesity) anti mild pons) ftbrbM* 14 Plaitku 106000/fiun* Lorgt portal vein and *ptmn<)2cml. Lrver enlarged, 15 SOFT 42 iu/L Kotdfc* alight change in twainwy Ponal vain and apiece Imr btopvy: fatty ehtfifr normal, bin poaaibte cirrhotic dtanm lie U SGOT 60 */) Normal r-GT 59 iy/1 17 Bilirubin 21 umol/t.GGT Marked enlargement of ponal 66iu/l.pUtku99000/mmf. vein and iplon, Slight change Splenomegaly, sophagat in liver consistency varies, pceiponat fibrout II GGT 12 iu/J, platckti Splenomegaly. Marked 4* CHtO/ir.mMSF 19 Cirrhr;e ehangm (45 min). Splenomegaly, and fatty infiltration oaophagezl tvwa. Fatty 4cntratipn with minima) periponat hbiotit 19 Bilirvbm43 m)/1, Marked splenomegaly and SGOT JO iuH, pUitlcu mm cirrhotit 0OOOruti#.BSP2l% (45 m:r.). Sakfiomcraly- (Fi>rtca*a) ihunt V*6S) Fifi 4 Ultrasonogram ofspleen scannedalong tenth left interspace. When the spleen is enlargeddue to portol hypertension, low-level echoes are returnedand so oppeer dark. The gridsquares sire 2 cm apart, and the spleen is thus 17 cm in length. This enlargement was not apparent on a plain abdominal radiograph osophagoscopy, splenic venography and liver biopsy. Comparison of the results of ultrasound and routine methods in Table 2 shows that known pathology in Cases 4, 9, 10, 11, 14, 15 and 17-19 were confirmed on ultrasound examination. Cases 1, 2, 3 and S were confirmed to be normal. Cases 12 and 13 were known to have fiver abnor mality on historical 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 Ca*e 6, in whom obesity prevented adequate assessment of spleen size on a plain abdominal radiograph. These volunteers were taken from a workforce of 4$7 of whom 20.9% had abnormal biochemical or hematologic results on initial testing. Further, intensive investigation failed to reveal the early pathology which was demon strated by grey-scale ultrasound and was con firmed retrospectively by radiological examina tion. The main advantage of ultrasound lies in its potential as a r orinvasive 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 nc\! year, while experience *;<*** J5 5iv- J. <2> t x*i ;3L I scannedalong tenth tn ii enlargeddue to tchocs are returnedand res are 2 cm open, end the Ti.is enlargement was not ' radiograph enography and liver !.s cf ultrasound and 2 shows that known , II, 14, 15 and 17-19 asound examination, ^r.nrmed (o be normal. to have liver abnorF.ination but this was . examination. Howon was obtained by ) and 11, In all these dinp led to a review and these are sum* trasound results wctc were not contradicted y prevented adequate )r. a plain abdominal :s uere taken from a 20.9 % had abnormal ric results on initial investigation failed to which was demon sound and was eonzdiological examinaf ultrasound lies in its .chnique for monitor*he lack of ionizing e in th\f respect. s suggest that ultra-;i incidence of false that the method is r a replacement for u:ring the ultrasound - requires operator -.'ers should become sir, while experience .i. _ 37 Section ofCceupu lonel A fedicine 295 Table 3 Fnhf fiwLip ivWMiMt i* hn4Mi! nAinitiiita /hiiiai Uht0` C*i tdtciimtw MWlrvV Ffttktr *?3*um*nt 6 Normil Sptaaomefely ftarium t fiorvtftl. Sp)cA not fictn *n X-fiy Abdomen. 7 Norrul Spknomifslj' *4 bwi t*4 net ruend below kvtlof 1life rib V Norm*! Splenomegaly Itfte^pcn. Sbo*4 routed Grebe I vane*. $pkftomtc*!y confirmed oo rrvirv oftiroifht X^y of Women Norm*I Splenomegaly Fotubl* Grebe I tuiui can be gained if the potential of the method is sufficiently promising. Preparations are currently being made for a more extensive investigation of the application of grey-scale ultrasonography to detect any liver pathology in a community in the United States which has been heavily exposed to air pollution with VCM, as well as in workmen exposed during the course of their employment. This further study should allow' a more detailed assessment of the relative value of this new tech nique. Acknowledgment: We would like to acknowledge the cooperation of the W orking Party on Vinyl Chloride Toxicity of the Chemical Industries Association. REFERENCES atwk J* (1974)Javrns!(tftht .^(Wffcei Mrcuot Auonjlion lit. 3J-54 Crncb JLX Jshntt-. M N - 0974) tuwIVOn'WW/Mediclm It. 1*0-131 Knult C (1974) JmenatafClinicml VOhmvWI. M-72 UonCLJittS. SitinG X- Vtlin.nO (1974) liuermeiienolrt Arrturftt ArOtiitmtOisin 31,1-11 LmFI*HmtD$ (1974)A*.tl, ms-tsit MikkLCmliJUttMuJcaJttaHMN (IP4|;wMl^it< MeOlent Atactatia* 130, (Ml MamtUtr H1. L'lbarh W K. MWItr R. Jntn S, Lutt C L. XtWiHCi VttunuC(1913) DrytseheAteOhinitehe Wodunsthrif, . 2311-1*14 Smitk P M a- Witu.*. D M J (1974) Diteidtn 10. J2I-322 Ti>lrK J VV, Cinmn DAS MtCinl; VR (1973)JmncAlifClinical (JilrOHmiut 1.2*4-237 T.jlor K J W 4 MfU* J < 197k) PrpcRdinp of 197* Cenlcnns a. Ttviuc S:cnaiurn- N.tidfi.1 Buruti ofStinda/di, W'4fhineinn. EU. M Einrct (in j-rc,,) Ttjlor K J VV. Wiilumi 0 VI J.Snitb P MX Dock B VV 11975) Lanl i, )222-1224 Tkonu L B. Foiwtr It. Rtrk P n. SclIVeS 1 X- Ft)k H (1973) .v>- CntlJiSJnmnel cf Su-iicinc IK, 17-22 Willi,TM p ,vt J, Smiih PM, Taj lor K J VV, Cronlrr t R X Pork C VV i 197k) tlniuhJvtrncl cf Insniriat Mrd.!ctr.e (in proa) W.lli-n,. D Vt J, Taj iol K J W. CikMtcv 1 R. Smith P M X Duel. II VV (1973) O rrliit-. 12, 34; Dr M1V Jayson (Department ofMedicine. University of Bristol) Dr A J Bailey {ARCMeat Research Institute, Langford, Bristol) Dr C Black (Department ofMedicine, University ofBristol) Dr K Lloyd Jones (Harlow IVood Orthopaedic Hospital, Mansfield) Collagen Studies in Acro-osteolysis Collagen is a fibrous protein present in most con nective tissues and it is the nature and arrangement of collagen fibres that are principally responsible for the mechanical properties of these tissues. The collagen molecule consists of three chains of amino acids formed into a triple helix, and these molecules are aligned in the fibre in a parallel and quarter-stagger arrangement giving rise to the characteristic banded appearance of collagen seen on electron microscopy. This quarter-' stagger arrangement is maintained by specific lysine-derived intcrmolecular crosslinks and it is these crosslinks which are responsible for the strength orcollagen. When collagen is newly formed, the intermolecular crosslinks are labile alditnine bonds, and can be detected by reduction with tritiated potassium borohydride (Bailey et at. 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 alditnine bonds are detectable in adult human skin, then proliferation of new collagen is occurring.- ~ Collagen Studies in Scleroderma The skin changes of acro-osteolysis (AOL) are inmany respects analogous of those of scleroderma. In both conditions there is severe rigidity and thickening of large areas of skin, suggesting qualitative or quantitative changes in the collagen. In a study of skin biopsies from adult patients with scleroderma (Herbert et at. 1974) we found an increased proportion of labile aldimine cross links in 9 of 11 patients with active progressing disease. In contrast, in patients with longstanding nonprogressive scleroderma there was no excess of the labile bonds. Analysis of the centre and the growing edge of a plaque of rr.nrplwsa demon strated the maximum level of crosslinks at the ucc 065503 296 Prof. roy. See. Med. I'olume 69 April 1976 38 edge or the plaque ar.d much lover levels towards the centre where the collagen has matured. This provides a direct confirmation of increased col lagen synthesis in the skin in scleroderma. 10' Collagen Studies in Aero-osteolysis Case 1 A D, aged 36 years, was a plasterer until six yean before we saw him. He then started as a reactor cleaner and a 'B' operator in a plant manufacturing polyvinyl chloride, scraping the inside of the reactor with a chisel, wearing gloves and overalls but no mask. Following this initial three**eck period he became an *A* operator, working outside the reactor, and was involved in charging and recovery from the reactor and controlling the flow of chcmkunS including vinyl chloride through various valves. There was no direct contact with the chemicals, but he frequently noticed fumes escaping from the valves. After three years he noticed the onset of Raynaud's phenomenon which progressed with gradual shorten ing and instability of the tips of the fingers. There was a gradual thickening and coarsening of the skin spreading up his arms on to .he face and a little on the chest wall ar.d axilla. Two years later he gave up work with marked weakness of his hands and arms, which caused great difficulty in gripping and lifting heavy weights. Examination confirmed the features of acroosteolysis with gross thickening of the skin, but with the following differences from scleroderma: fl) No ulceration of the fingertips. (3) Instability of the tips of the fingers. (3) Hair follicles and hair preserved. (4) No puckering around the mouth. (S) No telangeiectasia. (6) General coarsening of the features. (7) No tightening of the skin across the nose. Investigations showed slightly raised plasma viscosity of l.$0 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 parts of the terminal phalanges, 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 Studies in Aero-osteolysis A skin biopsy was obtained from this patient. Reduction with potassium borohydride revealed a high proportion of the hydroxylysinonorlcucine crosslink typical of new collagen formation in scleroderma. There was also a second reduceable component present in significant amounts but further studies will be required in order to identify its nature. Quantification of Collagen 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 proiinc and measuring the syn thesis of hydroxyproline, an index of the rale of collagen formation can be obtained. We obtained pMBH-P/ ,, p KQH-P I Fig 1 Rate ofsynthesis ofhydrox----- iir.e relatedto the original hydroxyproline content oj normal and AOL skins (junoi) 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 30% oxvper. 5% carbon dioxide, 75% nitrogen in a modified Macintosh Fildcs jar at 37 C for 24 hours. Following culture the specimen was homogenized, dialysed to remove excess *H-pro!ine, hydrolysed and separated in an amino acid analyser and the quantity of synthesized '`H-hydroxyproline was determined. This was related to the hydroxyproline content of the original biopsy. The-results are- presented in Fig 1 and show that the rate of collagen synthesis in the patient with AOL was considerably greater than that of the normal controls. Discussion By both crosslink analysis and by measurement of 'H-prolinc 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 (Laitir.cn et el. 1969. Herbert et el. 1974), and account for the thickening of the skin. It is possible that the effect is generalized, and excess collagen proliferation in the Wood vessels could lead to chronic ischtemia with ulceration of the fingertips and further local collagen produc tion. Ischtemic necrosis could similarly occur in AOL and so produce the typical bone lesions. ucc 065504 xyproilne relatedto l)i* ifnormalana AOL atient with AOL and with other conditions Iiriy abnormality of were cultured on a interface between a 5 5H-proline and an , 5 % carbon dioxide, Macintosh Fildes jar ollowing culture the 1, dialysed, to remove sed and separated in and the quantity of line was determined, oxyproline content of suits are presented in : of collagen syntliesis L was considerably nal controls. and by measurement into hydroxyproline, csv collagen synthesis h AOL. These result* lings in the skin in . 19f>9, Herbert et at. hickcning of the skin, rt is generalized, and n in the blood vessels -nia with ulceration of ncal cnllagen produc ed similarly occur in typical bone lesions. -.cr.-oii .j X t:*brvx: 39 Section ofOccupational Medicine 297 However, the AOL bone lesions differ in appear ance 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 by individual fibroblasts from scleroderma and control patients. He found that, when first cultured, scleroderma fibroblasts synthesize new collagen much more rapidly than controls. This implies that cellular factors are of greater im portance in causing excess new collagen forma tion. In addition Johnson & Ziff (1974) reported that lymphokine from normal human donors can increase the rate of collagen synthesis. Several chemicals are known to induce ab normal fibrosis. Practolol (Brown et at. 1974) can lead to peritoneal fibrosis. Mcthysergide can cause retroperitoneal fibrosis and ergotamine can lead to peripheral ischimia and has been used in the rat as an experimental model for scleroderma (Harris & Robinson 1974). Epidemiological in vestigations strongly implicate vinyl chloride in the pathogenesis of aero-osteolysis, ar.d therefore as a further possible chemical cause of increased collagen synthesis. i>-pcr.icil!amine 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 cleared by the drug. When the collagen has matured, the crosslinks become stable and the drug is no longer effective (Herbert et at. 1974). It may be that D-penicillaminc 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 or the processes of collagen synthesis and could well act as a useful model for the study of scleroderma. REFERENCES Biitf? A J. Phc* C M * l*r L J (1970) HarUvirelJournal U7,119 lim P, liMtlr H, R4 A E. D*t! JDE McCirry J 1)9747 Lmtou. )477 Hwri* E D (r A RoMwa M S (IV74\Jor*clofShrmwatahsts 1. Suppt.1,149 Hnten CM. LMfcn* K A. J.jwi M1V A EjiWy A J (t974)Caarfli. 1S7 JahurtRLAZiftM (1974)JournalofUtromoiolotJ 1, Sup?]. I,SI t4kiM O. L'iwo J* Jimub,s M t MwiCuUit K S (1969) Ammati *4Central Jtriwdi), 64 LrrpyEC (1974) Joatnat ofCtinirA InTttlifatlfln 54. SSO Dr Robin Walker (IVaiion CenerefHospital, Liverpool, 9) spoke on the subject of Clinical Aspects of Vinyl Chloride Disease: Liver Epidemiological Studies Dr P J Baxter (Employment Medice! Advisory Service, Health and Safety Eremite, Barnards House, ! Chepstow Place, London It'ldTF) Epidemiological Studies of PVC Manufacturers and Fabricators, and Primary Angiosarcoma of the Liver The Joint Working Group on the Vinyl Chloride Code of Practice decided from the outset that epidemiological studies would be necessary to evaluate the extent of the risk to workers engaged in the manufacture and fabrication of PVC. The Employment Medical Advisory Service (EMAS) proposed three studies: a prospective study of PVC manufacturers, a prospective study of PVC .fabricators, and a retrospective study of primary angiosarcoma of the liver. As these studies were intended to be as comprehensive as possible they could only be accomplished by drawing on the cooperation and expertise of a number of bodies: the industry. HM Factory Inspectorate, the Registrars General for England and Wales, and Scotland, the Royal College of Pathologists and experts from university departments and else where. Prospective Study of P VC Manufacturers In the past, workers engaged in PVC manufacture were exposed to vinyl chloride as a result of work ing inside autoclaves or from leaks occurring at various stages of the process. The main aim of this survey is to evaluate the effects of this exposure in ..terms of mortality and cancer registration rates according to certified rauscs by including all past workers at every factory manu facturing PVC in Great Britain, Present and future workers arc also to be incorporated. Identification details of the workers, including duration of employment and details of past exposure, are entered by the factory personnel departments onto individual survey cards accord ing to instructions provided by EMAS. Past exposure had been graded into high (>200 parts/ 105), medium (>25 parts'I O'), 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 `tow*. Identification details of the workers are sen: through EM AS to the National Health Service Central Registries in England and Wales, and Scotland. Death certificates for these persons ,*t -7* tiOC- ucc 065505. . ^- < ;i tV< ' t ! - :,*. -; i rs-ZZZ'i 29S Proc. roy. Sot. Med. Volume 69 April 1976 40 are ceded 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 3c General. Workers alive at the start of the survey Fox 1975) and shoved that, on average, only 3 arc Sagged, 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 ofdeath. 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 i* 7746 of whom only 84 (1 %) have not been traced, 72 (1 %) have missing The main aim of this study is to identify and information, and 147 (2%) have emigrated. verify all 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 SS% 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 scx-age-standardized rates - be angiosarcoma are selected. Angiosarcomas supplied by the Registrar General. are also notified to EMAS from cancer registries, hospital pathologists and hospital discharges PVC Fabricators (Scotland only). A sample will be taken from Exposure to vinyl chloride during the manufac amongst ihe other liver cancers, and for both ture of the finished articles from raw PVC occurs these and the angiosarcoma cases the hospitals as the vinyl chloride trapped in PVC synthesis is where they were treated will be contacted in order released during the further handling and process to request the loan of available histological ing of the PVC. This survey aims to study the material. Sections will be submitted for diagnosis mortality and cancer registration rates for all to a panel of expert 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 arc related to vinyl estimate will then be made of how many angio chloride exposure. There are at least seventeen sarcomas are misdiagnosed or miscertified a$ different types of industry and twenty types of other liver cancers. With the permission and operation, and the size of the work staff varies assistance of the hospital consultants and general from a handful to hundreds of men. Records of practitioners concerned, the next of kin of the employment and exposures are likely to be poor deceased angiosarcoma cases will be traced and or nonexistent in some of the smaller factories an interview' requested with one of our Employ and for this reason a sample will be taken of ment Nursing Advisers trained in interviewing workers employed at, or near to, the present techniques. The nurse will seek to obtain a full lime, over a wide Tange of the industry, the names occupational history of the deceased. of the factories making up the sampling frame being provided by HM Factory Inspectorate and The controls, matched for age, sex and death: trade organizations. As many as 20 000 workers register (locality), will be chosen from the other may be involved. The procedure for the follow up liver cancer deaths and also from deaths from of workers and the analysis of the results will be all causes. Four liver cancer controls for each similar to that described for the study of manu angiosarcoma case will be randomly selected by facturers. EMAS. The controls of deaths from all causes will be selected by the Registrar General's Office ' Retrospective Study from the same death register as an angiosarcoma ofAngiosarcoma case. The next of kin of both sets of controls will The significance of cases of angiosarcoma of the be interviewed in an identical manner to the liver occurring in vinyl chloride workers relates angiosarcoma cases. As far as possible the inter to the rarity of the tumour in the general popula viewers will not know the cause of death of the tion. To assess its rarity and to look for any time deceased. Finally, our Employment Medical trends, EMAS asked the Registrar General for Advisers will investigate the places where the England and Wales to collect all death certificates cases and controls worked and record details of with a possible diagnosis cf angiosarcoma of the occupational exposure to vinyl chloride and other 41 el ec TC cn tic re an fre cb sa st he> of *r V CL c a< m th fir r: >> D' 0 u m hr, ir. T* ler fo: h er; ticm Dr : ihat view divb post expe post In ?p!c: eyu*. ease m' ITT' 065506 ^S'L'&'iKSia 40 = results of this here (Baxter & average, only 3 in England and : had previously (The only other ilein known to t was in 1974. 3n the manufac- s to identify and try angiosarcoma onwards, and to :h occupational n 1974 onwards, are sending all rlying cause of ncer (including cd categories) to gnoses likely to Angiosarcomas tancer registries, Pita] discharges be taken from and for both r the hospitals 'ntaeted in order blc histological ed for diagnosis iogisrs who will of the cases. An 3W many angio- miscertiSed as permission and ants and general .t of kin of the 11 be traced and of our Employin interviewing to obtain a full ied. r, sex and death ; from the other :m deaths from onrrols for each smly selected by from all causes General's Office tn angiosarcoma s of controls will manner to the txsible the inter: of death of the v>'mer.t Medical aces where the t'tcord details of Ipriiie and other 41 Section ofOccupational Medicine 299 chemicals. They will also attempt to obtain photo copies of all 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 tru'c 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 Weinbrcn ' ` {Department ofHiiiopalhohgv, RoyalPostgraduate Medical School. Du Cane Road, London W12 OHS) Histopathology of Lit er Lesions Associated with Exposure to Vinyl Chloride Monomer So far only 2 cases of angiosarcoma of the liver have been reported in British workers exposed to vinyl chloride monomer (Lee A Harry 1974) but more material has been studied in the United States by Bradford Block (1974) and by Thomas ct ol. (1975). The lesions encountered in this last publication included 15 angiosarcomas and the structural changes arc clearly 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 (Regelson el al. 1963) arsenic toxicity in vineyard workers (Roth 1957) and after exposure to thorium dioxide for arteriography (Visfeldt A Poulson 1972). The lesion has been encountered also in patients with no evidence of exposure to a particular toxin (Baker et al. 1956). The characteristics of the tumour are for the most REFERENCE Baitir r J ii F A J (1*75) Lameri ii. 21-29 DISCUSSION Dr A J Fox {Employment Medical Advisory Smite, London) said that in the prospective study of PVC manufacturers described by Dr Baxter great care had been taken to elucidate the role of (!) year of entry into the industry', (3) level of exposure as estimated by people who had worked in the individual plants, (3) length of exposure in the industry,- and (4) length of follow up. These studies, coupled with those of `healthy population effect* and 'survivor population effect* were of fundamental importance in the evalua tion of the results of exposure to vinyl chloride monomer. Dr L Magos {MRC Toxicology Unit, Carshciton) said that in the retrospective epidemiological study re viewed by Dr Baxter vjnyl chloride workers were 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 tire German literature there were many eases of splenomegaly, fibrosis of the liver, and thrombo cytopenia. Dr Magos was surprised that no similar eases had been reported from the UK during the meeting. Fig 1 Angiosarcoma shelving dilatedSinusoidal spaces containing red blood cells andlinedby tumnur ceils. // tl f. x ISO ucc 065507 700 Proc. roy. Soc. Sit'd. Volume 69 April 1976 42 Fig 2 Pupillaryformations ofrumour cells ore borne on o core ofconnective tissue ami hepotoeytts. H & E. x600 Fig 4 Bilarre giant tumour cellin papillary angio sarcoma. H . E. ' 600 pan agreed by these various workers and I pro* pose to outline them. I shall also briefly discuss some of the other changes v, hich have been noted in the livers of patients suffering from angio sarcoma and those of patients who had been exposed to vinyl chloride monomer but did not sfi?w evidence of the development of tumours. The tumour consists of cells which vary con siderably in appearance but seem to have enough common features, particularly in their mode of growth, relationship to vascular spaces and stromal changes, to support the view that they are derived essentially from one cell type. In general the tumours show a gross appearance of dark hxmorrhagie nodules in the liver: there is a variable distortion and apparent fibrosis in the imer.ening liver tissue. Sometimes foci are macroscopicalty less hxmorrhagic. There is often frank necrosis. The microscopical appearances at first glance are variable, but analysis suggests a consistency. Thomas el al, (1975) have delineated 3 main types depending really on the relationship of the tumour Fig: H 'dUtUfferenriated (IcUencd tumour cells, reset'zhiin; endothelial cells on connective tissue cores cells to1 the vascular spaces: (1) The sinusoidal pattern, in which dilated hepatic sinusoids are atul lining vascular spaces. H A E. x <00 lined by enlarged and proliferating tumour cells, t 42 t- icr::' "v V$.V *5 *T4 ** K c% *L ^ . . jo' r?V^* ^r2^' 'A 4 spillary anglo- workers and I proiKo briefly discuss ;h have been noted cring from angious who-had been nomer but did not ent of tumours. !s which vary conem to have enough in their mode of cular spaces and the view that they : ceil type. a gross appearance n the liver; there is rent fibrosis in the metimes foci are a gic. There is often ices at first ;!anct jests a consistency, icated 3 main types ''hip of the tumour H) The sinusoidal 'isinusoids ate t r.g tumour cells. 43 Section ofOccupational Medicine 301 hepatocytes. resembles cells normally associated with vessel walls and appears to be closely related to vascular spaces with variable degrees of abnormality. There are changes in other elements, boih in tumour-bearing regions and in pans of the liver which appear to be free of tumour. These changes seem to involve mostly the supporting stroma. In the regions of the tumour, the perisinuseida! rcticulin fibres are prominent, obviously in creased and appear to run between the tumour bearing sinusoid and the hepatocyte plate, apparently causing rcticulin increase in the space of Disse. which exists between liver cell and normal sinusoidal wall. The alteration varies from a minor inconspicuous (as the authors abroad put it) increase in rcticulin fibres which may not be seen without the use of special stains (and in fact, both special stains and special optical manoeuvres may be employed to highlight this change) to massive increase of collagen fibres which surround the hepatocyte plates, clearly obstructing the lumen, sometimes apparently cn- Fig 5 Solidarte oftumour resembling solidspindlc-cctl sarcoma. H . .'. >.400 with hepatocyte plates clearly recognizable between the tumour cells. This appearance is found most often (Fig 1). (2) The second most common is termed the papillary type, in which papillary formations of tumour cells ire borne on a core of connective tissue, which may include recognizable surviving hepatocytes, often with canaliculi containing inspissated bile pigment (Fig 21. (3) The cavernous type, in which the blood-filled spaces appear even larger and are surrounded by thick fibrous walls which seem to be lined by the tumour cells. In addition there are several variables. The tumour cells may be welldifferentiated in that they simulate endothelial cells of liver sinusoids (Fig 3) and it may be difficult to distinguish tumour cells from reactive cells, or they may be quite unusual, showing irregular bizarre and giant-ccll forms (Fig 4). They may also present as solid box-like polygonal cells, suggesting an appearance similar to carci noid or epithelial tumour cells. The helpful diagnostic feature may well be the close relation ship to hepatocyte pljtes or obvious blood-filled spaces. The poor differentiation may be seen also in the frequently found solid areas in which the cells look like solid spindlc-ccll sarcoma, without evidence in many foci of vascular spaces (Fig 5). In sum, the tumour cell is distinguishable from Fig 6 Fibrosis associated with obliteration ofsinusoids anddisappearance or atrophy ofht'pineet let in angiosarcoma. HAS. x ISO ucc 065509 ^^BEl *3tv '^ft'f**-*: > Sr-TfctcJ'Xj^ I isaaflwQrt ^T-^fsr * . Trj- ` - -1 ^ ..-X j '-'Jf.'.'..' s 302 TVoe. roy. Sac. Med. Volume 69 April 1976 irapping jingle 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 hepatocyte survival occurs even in the middle of very poorly differentiated tumour, a phenomenon which is quite unusual in the case of other tumours. Remote from the tumour-bearing areas, such perisinusoidal reticulin increase is recognized and again it varies from the minor inconspicuous form to quite striking fibrosis (Fig 7). There is also conspicuous fibrosis in portal tracts with a patchy, sometimes marked, peri vascular and periductal fibrosis. The venous lumina which are thought sometimes ro be com promised in other forms of fibrosis, such as the Indian noncirrhotic 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 Fig S Hepatic eapsu/arfihresis in patient exposed to nr. 11 chloride monomer and presenting with porta! hypertension. HAS. * 110 repeatedly observed in the cases from the United States and this seems sometimes to be continuous with the fibrosis in the portal tracts. Fij 7 Liver biopsy sretinns showing reriotiuns in intruiobulur sinusoidal retieultn. I'pper, slight increase. Lower. much increase. Gordon < Sweet siher impregnation: Dari-yrot.luiii.'uinii.atiai: < j60 The relevance of such nomumeurous changes to .the subsequent development of angiosarcoma is of course one of the major practical issues at present. Such changes are sometimes found in the livers of workers exposed to vinyl chloride monomer and w* have had an opportunity to see sections referred by several clinicians concerned with this problem, including Dr F Lee, Dr Robin Walker, and Dr 1F H Purchase. The findings will 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 ease, w hich I hope Dr Frank Lee will report, presented with portal hypertension and had quite "Striking capsular thickening, diffuse sinusoidal reticulin increase, hypertrophy and possibly hyperplasia cf endothelial cells, and what seems ucc 065510 t I r / / i r c r c c a c *3 t f. i c p c K E 0 B (l B n Ir tl R n p n T t: \ : > -- *. 41 ;/cr; tz-pcned to -f m/A panel s from the United s to be continuous .ns. tmeurous changes '. of angiosarcoma practical issues at times found in the c vinyl chloride opportunity to see -.ieians concerned r F Lee, Dr Robin Tr,e findings wiD their own reports :r biopsy sections or.tunlour changes >cth controls and cc'tcnt of fat and v'sor.ncl do show to make out, but ons. One particu'.n Lee "w ii] report, 5 on and had quite c.fiuse sinusoidal and possibly k a: d what seems 'r' * . -v :sAj-gJ^lr: 45 Section ofOccupational Mi.iieine )03 Dr Henry Falk (Cancer and Birth Defects Division, Bureau of Epidemiology, Centerfar Disease Control. United Stoics Public Health Service. Department ofHealth. Education, end Welfare. Atlanta. Georgia 30J33. USA 1 and Mr Richard J Waxwcilcr (Division of Field Studies anti Clinical Investigations. National Institutefor Occupational Safety and Health. Centerfor Disease Control, United States Puhiie Health Ser\U e. Department ofHealth, Education, and Welfare. US Post Office Building, Cincinnati. Ohio ISlUl. USA) Fig 9 Bitnrre andenlarged sinusoidal lining edit and hr/mittcvir mitotic ubnormuiit i- in same patient as FigS.liAE. <600 to be striking: hopatocyte involvement, even with miiotic abnormalities (Figs S-9). The question whether these lesions are signifi cant as prcinalignant changes is unanswered, as many of the alterations can lie found in other conditions such as congestive cardiac failure, endothelial cell hyperplasia in cases of lymphoma, and of licpatocyte and other changes in many drug toxicity situations. Other pathogenetic questions also have to be.posed, such as what is the primary lesion, which cell is involved in the formation of the tumour, what is responsible for the curious fibrosis and survival of the hepatocytes. Understanding these processes would probably enable us to make'a betrer assessment of individual risk factors and perhaps to work out whether there is a tolerable exposure. references Baker H 0*C. P$*1 C (1956) Jpurmmt t/Fjttmksj mu/ Muneriutctr 72, 175-1B2 Block.; 0 (I97J) Journalcfthe AmericanMedic*/Auoei*:km229* 5J-M Bp; tf J J_ *Mt Cv?U K P. B*i $ K* P*l N C* B*iu Millick K C. IW r FLA Hwtt A K (1967) Aon*L* /Internal SfcJicine 66,41-67 Ut FT A H*fr> D 5 (!<i4*}^o^/i. 1516 HcovIwa W, Kit V. 0*ta) J A Holland J F (1W) Cooeet (F/wAiA-JfMa) 2t, <14-522 Rots F (1557) ZcUtck'i'i f+r A>s-A*/*rsr6i.f 61.465-50? Thorn*' L 11. l. Herk P D. Sehknfl 1 J & Kalk !! (W*< A> Medicine 292. l*-22 J ft Kfc-f!M*n H 11972) Act* PtniuthKlf* rt iroScrin'n A 6U, 57-1 OS Epidemiological Studies of Vinyl Chloride Health Effects in the United States The vinyl chloride (VC) problem has had a con siderable impact in the United States during the past year and a half. Perhaps related to the age and conditions of the VC industry, or simply to the sheer size of it, the United States has so far 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 ea->es 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 (Mahoni t 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 York demonstrated a high percentage of liver function abnormalities in polymerization workers, suggesting a broad problem (Makk et e/.' 1974, Litis etal. 1975), and, in addition to this, the earliest mortality studies (Monson et al. 1974. Tabershaw & Gafiey 1974) suggested increased rates for nonhepatic tumours,- parallelling the multiplicity of tumour types seen in experimental studies (Maltoni & Lefemine 1974). Review of records at the Connecticut Tumor Registry, started in 1935, revealed 5 definite cases of HAS; 4 cases were clustered in one industrialized area and had occurred since 1967; 3 of these (and possibly a fourth ease where the diagnosis was uncertain after review of slides) occurred in workers at two polyvinyl chloride (P\`Cl fabricat ing plants or in residents living nearby (Lanjrigan & Heath 1976), Further concern was generated by ucc 065511 HU Pn:e. ic>1. Soc. Mivf. l'a/ume CO April 1076 46 reports of the potential carcinogenicity of chemi cals structurally related to VC. e.g. ehloroprenc lUoy d 11 ill. 1975) and trichloroethylene (National Cancer Institute 1975, unpublished dam), and by the know ledge that VC workers in many instances hate been exposed to multiple related chemicals, including tiny lidene chloride and acrylonitrile (vinyl cyanide). As part of tlte United Stales 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-rclated epidemiologic projects during the past year and a half; in this paper xve will briefly review some of the early results of three of these studies. Table! mstoutcvihi in il*o I'mitd StaM ( b> art** At* (vrcnl M 10-19 20-19 30-39 40-t9 50-39 tO-H 70-79 *0+ frmalt Tor*/ 22 ii It 54 72 15 2 55 Tt i 12 4 : 2 9 9 15 tO H 3 44 22 tt O From tvxi:i:*ic*. ICD Cotfc 197.* ISih Revision). Data for Nn York Cit> not There was approximately J case of HAS for tvery 300 death certificates ret tewed. HaS Surveillance A death certificate search for all cases of HAS recorded under ICD Code 197.$ ($th Revision), which encompasses various miscellaneous forms of liter 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 daia for New York City not yet available at the time of inis review. Table 1 shows the number of cases of HAS and non-angio hepatic sarcomas by t ear 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 I97.S showed angiosarcoma to he the largest group (35 of total hepatic sarcomas), followed by sarcoma of unspecified type (31 leiomyo sarcoma (12%), fibrosarcoma (7%), and a grouping of miscellaneous sarcomas (15*.). Table I K*(ic tivniM in lit* Ctiid Suir*91if nvodfri 1*4 |%7 I9tt 1*4 1970 1471 (972 is Alt lifniwt M 40 * u H 31 :) 9 23 JjItHUCffAMT i. > t 15 5 1 9 Sm iff* JumNwr V* 17 14 7 1* It ( 16 1*6 IC* Prs'fn b'tfJth ICD C%t*c I^.S (&<h RtvnioM, ))*u friwfl Sew "i itrk Cn> not includ'd TZ Half yr*r >smpk- Table 2 demonstrates a male to female ratio of 2:1 for HAS. Sixty-two percent of cases occurred in the group aged 50 or more, with 26"j in the 30-49 tear age group. Non-angio hepatic sarcomas differed in having a male to female ratio of only l;l. and an altered ,.ce grouping with 78% of eases aged 50 or more ar.J only 9% in the 30-19 year age group. These dilferer.ccs are con sistent with a hypothesis that occupational ex posure may be a more significant factor in the causation of HAS ihan of non-angio hepatic sarcoma. Only 2 of the patiems with HAS ^thc death certificate review were recorded as haung worked in PN C or plastics plants (I PVC polymerization worker a.td t accountant in a PV'C fabrication plant): both were cases which had been identified prior to this study. No other occupation is recorded more than mice except for the occur rence of 5 printers. Although all were subsequently confirmed ai printers, a preliminary review of pathology records and specimens suggests that 4 of the 5 cases may have been incorrectly diag nosed as HAS. CDC has supplemented the death certificate survey with an intensive case-finding effort, including a national mailing to all pathologists. state epidemiologists, and major cancer referral centres and tumour registries, seeking information on as many cases of HAS as possible diagnosed in the US during the years 1964-74. At the present time approximately 240 cases hat* beep, idem ified. Pathology specimens for about two-thirds of these arc 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 i reside Merit To: G: N ir.i a: lsr ok St a 1?. sir pi: tiag ' at: an. I sigi ant bi;i an: ana anc beinc abr ex: Ef i; srv to tit inr of fo: SC P' 0-- li etfr. is Cc Pc Or thi re: cor pa. hr Sp ur ucc 065512 46 <*ih Jtaiuon). c of HAS for :d. female ratio of f cases occurred iih 26 *; in the -angio hepatic ; to female ratio grouping with only 9?i in the trenecs are conccupaiional ex it factor in the vangio hepatic in the death ; havinpworked polymerization fabrication j betn identified occupation is t for the oecurcre subsequently inary review of is suggests that incorrectly diag- death certificate ;-finding effort, all pathologists, r cancer referral Jng information bsible diagnosed 4. At the present e been identified, o-ihirds or these National Cancer ces lnsiiiute of %aiuaticn of all o-ies regarding 47 Section ofOccupational Medicine 205 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 olden 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 from 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 of the 6 liver function tests performed (SGOT, bilirubin, alkaline phosphatase, LDH, GGTP, and ornithine carbamyl transferase). Additional analyse* based on levels of VC exposure, duration and type of job, and other subgroupings arc being done; these preliminary results however do not suggest the occurrence of liver function abnormalities on a broad scale secondary to VC exposure. One should of course be cautious about generalizing from the results at a single plant, and it will be important to compare these findings to studies at other PV'C 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 more than 10 years duration of work in the PVC polymerization plant, and no cases of HAS were detected. Some increase in frequency of palpable livers on physical examination was found, how. ever, among VC workers. A full report of findings from this comprehensive medical screening study is in preparation and will be available shortly. Cohort Mortality SttiJy at Four PVC Polymerization Plants One of the results of this NIOSH-CDC study was the demonstration of an increased SMR for respiratory system cancer among members of the cohort (Waxweiler a a). 1976). On preliminary pathologic review, it was also noted that of the 12 Ittng cancer cases all S for which pathologic specimens were available were either large cell undilferentiated or adenocarcinoma of the lung; Table 3 Uft| (tarn thou iirkm il P'X Cnittd Sim fcy w pUu id th pi\Q up04wr jtr*/ if KC *jpcjrr Hluihtk Mw Esrfdcrmeid Sail) cell t 0 AUciwaiviftoaw 1 Larvc cell uodiffcrcmtiiftf 4 UncluijAe4 i 1 &u thmn pw/tr I J 1 0 0 s M**( thin 0 e 4 4 0 to Tct*l 2 i 4 ie 1 22 if confirmed, this unusual cell type distribution may support the association feetw een VC exposure and occurrence of lung cancer. There are, however, two additional features which should be considered in evaluating this potential relationship. When all of the workers at these 4 plants are considered, including those who were net part of the defined VC-exposed cohort, a total of 22 cases of lung cancer (out of 4$) were available fer pathologic review. The increased incidence of large cell undifferentiated and adenocarcinoma of the lung was seen in VC workers w-ith more than l year of exposure, w hile 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, cases of lung cancer 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 eases were long-term reactor cleaners and operators, the workers with large cell un differentiated and adenocarcinoma of the lung were distributed in a number of different job categories. As a result, cases of lung cancer seem not to correlate as tightly with VC exposure as cases 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 confirm these preliminary pathologic findings. REFERENCES Ltfldrif4Q P J A- Heath C W jv < 2 97*) (in pf aoctit) Lilii AfitftriMJ. Davffl 5.A.S4 SviiknH I J (IVTI) Annxhcj rv .V* r >WAr ScirmrfZii. 22 Lto)d J \V (1975) /hwjm/l/Sicdittft 17* 313 ucc 065513 - .*'. v-r--v^** , ; --^'K&apv-? It aJl.. ..*^*0? <yf *. i ^a>Sir*-sl .* .- '*rf* *,*'.* r ' -. J--^yir.p/r- ;; *-:\.'i ^-v4* / ,r -Y^1 */: f v^4fc.-sr^.! ^ r'^V*'vV'*r . r .- .AHl ;A,..C4C miC*. m iiVw.'iiMs..: 306 Froc. roy. $oc. A/erf. Volume 69 April 1976 AS Uor* J W. DimSt J* Mhh R M (}377) Jo*r*clof Owtpelivnjl KitdtctKi |7, 2*3 MiU L. Crvrrli J1. ir. V\ Mu JCjrt JetiAwp M N (1J7JJ yuriw/^rw Xn.f.'ifd MrAteai ^luruitu 130,63 Milixii C LMtrnnt C (1S74) Emtmn^ntti StUCrek 7, 317 Mw* R R, Pn.r, J M i J1hum M N (irji) Unntu.m TU>nU> IJU- Ci<v M' R (1914) JovraaiofOer,railarM MfrW 76.309 IVuniln R J. Strikerr W. Janat J, Wiimi; J K, F*tk H Cum C H7*> Amah afiht Sir r*ek Atajtir af Seimeri (in ptau) DISCUSSION Dr Mitchell R Zavun {Betan Rouge, Louisiana) asked whether the clinical examiners at Pottstown knew whether or not the person being examined worked in vinyl chloride. Dr H Falk replied that none of the clinical examiners were aware of the occupational status of the workers at the lime of the examination. Dr R I McCallum {University of Seveestlt upon Tyne) asked Dr Falk to give in more detail 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 pathologists? How were the specimens of tissue obtained: by biopsy. Surgical resection or at autopsy? It was remarkable that in none of the eases was an oat cell carcinoma diagnosed, as this was the type often considered a characteristic resul t ofexposure to a chemical carcinogen. Dr H Falk replied that the WHO lung cancer classifica tion scheme of Kreyber; (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 Kuschner, State University of New York; and Dr Lasxlo Makk, St Anthony Hospital, Louisville, Kentucky). Alt avail able pathological material for each care was reviewed. The expanded pathological review currently under way would include the selection of multiple control cases of lung cancer from the same hospitals (with simi lar age and date of diagnosis to the study cases) and a hliDd review by a panel of pathologists in a more detailed evaluation ofavailable pathology material. To Dr Falk's knowledge large cell undifferentiated carcinoma ofthe lung had not been related to exposure to chemical carcinogens, which made the findings in the VC cohort even more intriguing. Dr A J Fox {Employment Medical Advisory Service, London) asked how many factories had been studied individually in the USA. What proportion of these had indicated vinyl-chloride-associated disease? NJOSH-CDC study, the Tobershaw- study, and the Monson-Peters study) had all lookeJ at the Louisville. Kentucky plant where the initial angiosarcoma cases occurred as well as at a varying 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 Bonnell (Centrel 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 premaligaant conditions. Dr H Falk said that cases of angiosarcoma in the USA did not have a history of acro-osteolysis or skin problems, although they did not hr.se the multiple tests for early changes of aero-osteolysis. It would seem, therefore, that the skin changes were not premalignant conditions. Professor IJ Selikoff (Mount Sinai School ofMedicine, City linnet shy of Xev York) said that a review of known details of identified cases of vinyl-chlorideassociated angiosarcoma of the liver by Dr Lloyd (197S) 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 rather small number of polymerization workers em ployed during the establishment and initial growth of the vinyl chloride industry. Attempts were underway to identify and trace the initial groups of workers, employed during the years 193S-35, since analysis of thei' experience would allow evaluation of the risks w+ .' might be suffered by the very much larger group of vinyl chloride workers exposed more recently, in a period during which PVC production was in creasing at the rate of approximately I0*i per annum. Limited data bearing on the problem had been obtained. In one polymerization process studied. 257 men had been employed for five scats or more in the period between 1946, when the plant opened, and 1964. Each man had been traced to 1 July 19?4..with 2S deaths from all causes:.J of the deaths were due to angiosarcoma of the It er (Nicholson et at. 1975), each confirmed on review of autopsy material (Thomas 6: Popper 1975); in addition there was one death due to ruptured asophageal varices. Another worker, examined during the clinical survey at this facility (Lilts er al. 1975) had had a successful portacaval shunt operation for the same condition. These experi ences suggested that vinyl-chloride-aSsociated disease w'ould be an important hazard for vinyl chloride workers in the future, unless control of exposure resulted in at least some rev ersal of the risk. Dr H Falk replied that cases of hepatic angiosarcoma had been seen at 3 of the FYC polymerization plants opened prior to 1950. There was some confusion in this area in that a number of the VC worker mortality studies had been overlapping. Thtee sepirr.e studies, for example, (the Lilti* R, AntrhM M, .Yirhulta* VV J, DtIt'll s F'VhN'in A 5 (IS7S7 A/utitlt oftiic WAeoetemyot Seittteet 2J*. 27-37 U*j63 VV (7S7St JournalofOttt-^mitumti SftJteim- 17. 33MN Nirholun VV J. tlammwri F.C.S, Jems* H A bdi'-ufl IJ (lTi> Amnll f //,. .V`r, )V,i TSflfnn L D A- Po,'ocr (( 24*. 2i!-;30 (l>*7i) Amoii afll:t W-- i urt t.uitemy a/ScMees 246. 2tS- 277 ucc vnr,r 065514 hii:. v.-.. 43 "shew study. ami the oksd at ihe Louisville, :) angiosarcoma cates number of additional 'em was the fact that o the cohorts studied > that the results even dty Generating Board) ride monomer wit a my evidence in expertlinical experience that -scribed might be pre- 'OSi'coma in the USA rtxsieolysil or skin os hive the multiple -osteolysis. It would vanges were not pre- ri School ofMedicine, aid that a review of ss cf viny|jcMoridt- liver by Dr Uoyd e for Occupational ited that the medico - is approximately re cerived from Ihe iiation workers cmr,d initial growth of tpu were underway g~o.ps of workers, fd. smee analysis of iuation of ihe risks very much larger xvseC morarecently, production was in ly lC"i rerannum. p.'oclem had been roceis studied, 257 ears or more in the plan: opened, and c 1 July 1974. with deaths were due to cn t; cl. 1975), each -Attriil (Thomas & ;s one death due to Another worker, cy et this facility xassful portacaval tion. These expert* associated disease for vinyl chloride n'roi of exposure he role S, Ffvew.Scin A S -i r,.;t ::c, ::-si . w . * J", . >r ,wcf* 5 J ' **n rmr; 7 V * K*- t-t`f`i-rn'V^- Ji.tv.f.::j 49 Section ofOccupational Medicine 307 Dr BW Duck (Occupational Health Unit, BP Research Centre, Swtbury on Thames, TiV16 7LN) 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 task confronting this working group, which comprised medical representatives of the four British companies engaged in the production of viny! chloride (VC) and polyvinyl chloride (PVQ, was to review all the relevant medical and toxicological information available and decide what action should be taken to protect the health of exposed 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. Repons 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 acro-ostcolysis (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 Hver 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 deteaion of liter angiosarcoma that could serve as a basis for a large-scale screening pro gramme in industry. As practical screening possibilities were vert' limited and the early 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: (1) 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 base for further studies. For these reasons it was decided to carry out an 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 workers 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 ob.iectives was to gather clinical and epidemiological data to provide a reasonable foundation for future decisions concerning regular medical surveillance. The survey population was divided as follows: Vinyl chloride workers Croup 1 - all autoclave floor workers, vinyl chloride monomeT (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 adopted: Initial examination comprisingmedical history (questionnaire), physical examina tion. biochemical tests (SGOT, SGPT, CGTP, alkaline phosphatase, bilirubin), platelet count, urinalysis. Follow up of abnormal findings, with repeat biochemical tests and platelet count, and persisting abnormalities referred to consultant for specialist investigation. The programme was introduced simultaneously on the six production sites and the employees concerned were informed that it was not an individual screening test, but a joint investigation to provide data that would help to establish future medical policy. It was also explained that any individuals w-ith suspicious findings, notably persistently abnormal test results, would be referred for appropriate specialist investigation by arrangement with theiT family doctors. Due to a variety of reasons, not least the prob lem of interpreting the significance of borderline ucc 065515 rh*S&..*. .*s 1 * ' ^ " ';\ * 4 30S frf. ro\. See. .Med. Volume 69 April J976 50 abnormalities and workload difficulties ex- interest in view of the apparent rarity of AOL in perier.ced by both medical advisers on sites and the cases or liver angiosarcoma that have been consultants and laboratory staff in National reported in the literature. The routine urinalyses Health Service hospitals, the programme has havercvealed no relevant abnormalities, taken longer than expected and is still incomplete. Hence interim findings only can be presented at Tentative Conclusions tbis stage and no firm conclusions can be drawn Abnormal liver function test findings were until all the facts have been elicited and the mass relatively common in both vinyl chloride workers of data obtained has been appropriately analysed. (12.5%) and controls (16.5%) even though So far, 1357 vinyl chloride workers and 429 results had to fall well outside (2 or 3 standard controls have been examined. The examinations deviations) the normal range in order to be of vinyl chloride workers include 8S2 from classified as abnormal. Repeat testing revealed Croup 1 (representing an average response rate of persistent abnormalities in one third of the vinyl 80%) and 475 from Group 2 (in which the pro- chloride workers in whom the initial findings portion volunteering for examination is lower). re 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 wjih persistently critical in This context and merits further con- abnormal liver function test results have been sideration and study if the corrtet balance is to be referred to consultants at local NH5 hospitals achieved. for furrher investigation. These investigations In view of the findings to date, it is not sur- havc not revealed any cases of angiosarcoma and prising that opinions of working group members the consultants concerned have already attributed about the value of periodic liver function tests in many of the persistent abnormalities to patbo- 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 these cirrhotic fibrosis has been found in some cases 56 cases, where precise diagnosis Tests largely on and until the results of blind interpretation of the the final conclusions reached by expert paiho- liver biopsy specimens become available no firm logists who are studying relevant liver biopsy opinions can be expressed about ihe 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 ;he 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 then liver dysfunction renders propose to continue regular liver function tests them unduly susceptible to potentially hepato- for this and other reasons, such as the need to toxic agents. assess sequential changes. On other sites, the :l While this survey was in progress, previously yield of significant clinical findings has been so ' - established procedures for the detection of AOL low in comparison with all the difficulties en- 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 provided basis in future. In this connexion, h is argued that, ` an opportunity to assess the prevalence of in order to be effective, the tests used should: (c) Raynaud's phenomenon among controls on yield positive findings at an early stage of disease; three sites and comparisons with findings in vinyl lb) produce few false positive and negative chloride workers suggest that the condition may results, and (cj 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 these due to other causes, such as the prevalence of the condition varied widely alcohol. between sites. No association has beer, observed' It is also argued that continued application of a between Raynaud's phenomenon and liver battery of tests to viny l chloride workers is likely function abnormalities in individuals, which is of to cause considerable alarm and disquiet if the ucc 065516 *0 rarity of AOL in i that have been outine urinalyses nalities. t findings were chloride workers D even though (2 or 3 standard in order to be ' testing revealed third of the vinyl e initial findings "ten wore referred 'parable data for ilable. abnormality had individuals for siderabiy treater had on specialist lion is a matter >f abnormality is tits further eon* t balance is to be tte, it is not surJ Croup members "function tests in led. No obvious ide exposure has idence of non* d in some cases rpretation of the i vailable no firm t the presence or } reiaied-to vinyl i. The procedure persistent liver i removed from d some' doctors er function tests t as the need to other sites, the ngs has been so s difficulties eni liver function i a discretionary it is argued that, used should: (a) stage of disease; e and negative to differentiate ir due to vinyl causes, such as application of a workers is likely *J disquiet if the jf' 5/ Suction ofOccupational '<lc<iicit;c J09 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 fiver 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 ts in complete, it has already yielded information of value for planning purposes, as originally intended. From now on. it seems advisable to concentrate effort on smaller and more detailed studies that 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. John Robertson (LherpooT) asked what was done for these whose tests, under the surveillance scheme, were abnormal. A man had been mentioned who was refused life insurance because of abnormal liver func tion tesu. 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 net have a scheduled disease, and yet the em ployer would not pay hit wages. Dr B \V Duck replied that men with persistently abnormal liver function test results were referred to consultants for further investigation and their family doctors were kept informed throughout. In the light of the findings the consultants and other doctors con cerned decided whether removal from vinyl chloride work was indicated and the men in question were advised accordingly. It was then left to the men to decide whether to accept or reject this advice. To date, only one man had rejected such medical advice and the rest had been transferred to alternative work with no lots of pay. - Dr Robert Murray (Sudbury) said that this was a very real problem which h was proposed to deal with in the Employment Protection Bill currentlyunder discussion in Parliament. Hits would give to a man laid'ofT for preventive reasons, because he showed early signs of absorption, the right to full wages during the period of lay-off. The more sensitive the methods of early diagnosis or the more stringent the standards of exposure, the greater would be the need to have some system to cover the no man's land between absorption which was not compensatable and disease which was. In large organizations it was usually easy to transfer the individual, without loss of money, to alternative work not involving exposure, but in smaller industries this might be difficult or impossible. Dr L Magos (A(RC Toxicology Uni:, Corshatlon) said that in Dr Duck's r-'*per r.o distinction was made between data on workers from a factory where poly vinyl monomer pollution lud decreased tepidly over the r-ust few years (as in the plant desc ribed by Mr A W Barnes) and data on those employed in a factory where (as in Dr Anne Walker's cases) ever, in recent years acute narcotic episodes had occurred. This lack of distinction might completely distort Dr Duck's statistical evaluation oi clinical data obtained during the survey. Dr B \V Duck replied that Dr Magos' point w-u well taken. However, as explained in the text, the paper presented interim findings from which no firm Con clusions could be drawn. When all the data were complete it was envisaged that the industrial doctors and their consultant colleagues would publish the results obtained front individual factories. Mr H F Henning (Health and Safety Executive, 403-105 Edyuare Road, London JVM 7 6LS) Em ironmentat Monitoring It is a common misconception that environmental monitoring is easy, just a matter of collecting a sample, analysing it and getting a figure. Environ mental monitoring is never easy and when an industry is faced with a sudden and substantial tightening of the standard to be applied there are equally suddenly many questions to be asked and answered. In addition, when industry and Govern ment have to w rite 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 paper. Instrumental Techniques When the threshold limit value (TLV) for vinyl chloride monomer tYCM) was 200 pans/IO*, that is before 1974, the instrumentation used for monitoring was relatively fairly crude and in sensitive. One common instrument had a lower response at about 200 pans/10* so that a nil reading was taken to indicate a concentration below 200 pans/10*. a very convenient situation. Even the chemical indicator tubes were not designed to show concentrations below 100 parts/ 10*. With the introduction in early 1974 of the new standard of 25 parts/10* (time weighted average) and 50 parts/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 065517 310 Free. rov. Soc. Med. Volume 69 April 1976 SI continuous monitoring but which is more correctly termed automatic sequential Axed point sampling* This is supplemented where necessary by short-term sampling for investigations or Tor checks on equipment and by long-term personal sampling to show the work people's actual exposure over long periods, e.g. four or eight hours. Presentation ofResults The Code of Practice requires the results to be available to the workforce and for summaries to be posted in work rooms. Each fixed point monitoring system takes a sample once per minute and therefore provides nearly 500 readings per shift so that trying to decide beforehand how the results should be summarized and presented was a major problem because there was little previous experience of monitoring, and recording the results of monitoring, on such a scale. One way of presenting the results would be to take an overall average. This has recently teen done and figures pro' ided by the industry show that the average concentration in the UK factories had been reduced in a matter of months from 24 to 6 parts/) 0*. Recent figures from some of the plants even show long-term averages of about 2 parts/10*. This suggests enormous progress, as indeed it is, and compares favourably with aver ages published by other countries. However, an overall average such as this is influenced very considerably by selection of the sampling sites and by the frequency of sampling, two aspects which are completely lost in this method of presentation and of course it offers little of use in the protection of the worker, which is the main objective of monitoring. Influence ofPeaks An average over any period of time is influenced very considerably by peaks. For example, in a 20 point system sampling every minute a single peak of 600 parts/10* due to a transient leak from nearby plant would add 25 parts/10* to the shift average. In the UK we feel that it is essential to record these peaks, because they indicate escapes of VCM due perhaps to defective plant or perhaps to incorrect work practice, both matters which ought to be remedied. If the monitoring points are selected to provide a balance between operator work stations and areas where leaks may occur then we must expect to obtain some high readings. These occasions will generally be investigated and will therefore play an important role in the long-term reduction of atmospheric concentration of VCM, but in the short term they make the picture look bad. both by their presence as peaks and by their contribution to the overall shift average. There is of course no suggestion that any operator is necessarily exposed to such peaks or to such a raised average, since many of the peaks may have occurred in specialty selected areas where no person wotks regularly or the operator may have known about the situation and worn a respirator during that period. Influence ofSampling frequency The frequency of sampling can also have an in fluence on the picture. Let us assume that some of the sampling points have been chosen to pick up leaks from the plant so that, say, 10% of the readings are above the ceiling value of 50 pans/ 10*. In a multi-point monitoring system sampling every minute this means that 4S readings per shift for that system alone will be above the ceiling value. Sampling at the minimum frequency* required by the Code of Practice, i.e. once per shift, would give on average one high reading in each work area every tenth shift. Sampling at the minimum frequency required by the US standard, i.e. or.re per month, would give on average one high reading in each work area every tenth month. We see therefore that frequent static sampling at carefully chosen points can provide much useful information but it does not necessarily tell us exactly what concentrations the work people are actually exposed to. This can be shown best by personal monitoring which is normally done at less frequent intervals because it is time-consum ing for the testing staff and somewhat restrictive for the operator wearing the equipment. Never theless this is an extremely useful supplement to the general workroom monitoring. Other Problems I have said nothing in this short paper about preservation of records, which provides many problems not previously encountered in industry, nor about atmospheric monitoring in the PVC 'user industry' where general atmospheric con centrations are less than 5 parts/10* and. usually less than 2 parts/10*,-with a few known and controllable problem areas. In short, we in the UK believe that atmospheric monitoring should be used to provide the maxi mum amount of information. This means that' the monitoring schemes incorporating extensive multi-point systems can provide la) useful information on deficiencies in plant or in operat ing procedures, (b) information with which to demonstrate progressive improvements in our aim io reduce exposure to near zero, (c) information on personal operator exposure which can be kept for future reference. Unfortunately in the short term n -Iso provides much ammunition for our critics. . his, however, is a small price to pay for the long-term benents which vve know will accrue from our efforts. ucc 065518