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l...'. j -, L /<f mn C '* Volume 69 Number 4 April 1976 ! w-S'o ^JUy-^f kbJ^^ VS*6+T Proceedings ofthe Royal Society of Medicine 1 r >WJWWW" HI Vinyl Chloride page 275 Published by The Royal Society of Medicine 1 Wimpole Street London w 1M 8ae ."JfeSW'T > ' 1 - ,.i-;i,i..-:vr' ' . vr 17 Volume 69 April 1976 275 Section of Occupational Medicine President Su/ette Gauvain mkc'1' if1 ' 43*0004/27* Meeting 12 September 1975 Vinyl Chloride L>r Suzctte Gauvain (Medical Advisory Service, Health and Safety Executive, Baynards House, l Chepstow Place, Westbourne Crave, London W24TF) Vinyl Chloride: Introduction to the Problem The story of vinyl chloride, when it comes to be written, will be seen as a watershed in the history of occupational medicine, forcing us to take a new attitude to occupational hazards and react quickly to first evidence of harm. The polymerization process of vinyl chloride to polyvinyl chloride was first discovered in Germany in the mid-1930.s. The lire and explosion risks and the narcotic effect were quickly appreci ated. Aero osteolysis, a condition mainly alfecung 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 at. 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 hepatitis like liver changes were reported by Tnbukh, from Russia, in 1949. However, until Viola reported (Viola et al. 1971) that he had failed in an attempt to produce aero-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 oT European chemical interests, including Imperial Chemical Industries, to undertake further studies, confirmed cancer in animals at exposures as low as 250 parts/IO' (Maltoni et at. 1973). As a result of Maltoni's work an epidemio logical study was undertaken in the USA on men who had preciously worked as cleaners of auto claves (reactors) in a polyvinyl chloride poly merization plant. Creech sV Johnson published this work in 1974, but their findings of a cluster oT 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 IS74 (United States Senate 1974) , to the Department of Employment IHM Chief Inspector of Factories) on 23 January, and to the Acting Chief Employment Medical Adviser on the following day. On 29 January 1974 Imperial Chemical Industries put out a press statement announcing that it was taking steps to inform government departments, the TUC, its own workers and its customers, of the facts available so far; and that a single suspected death in the United Kingdom was under urgent investigation. Subsequently this 70-year-old retired autoclave worker, who had died at the end of 1972 after twenty years of ex posure, was confirmed to have died of angio sarcoma of the liver. Since 1974 intensive investigations have taken place in this and many other countries. The United States government have published an account of the hearing before the Subcommittee on Environment of the Senate Committee on Commerce, on the dancers of vinyl chloride (United States Senate 1974), Senator Tunney, in 17 Volume 69 April 1976 275 Section of Occupational Medicine President Su/ettc Gauvain mkci* i i; !! : | Meeting 12 September 1975 Vinyl Chloride Dr Suzctte Cauvain (Medical Advisory Service, Health and Safety Executive, Buynards House, / Chepstow Place, Westbourne Grove, London W2 4TF) Vinyl Chloride: Introduction to the Problem The story of vinyl chloride, when it comes to be written, will be seen as a watershed in the history of occupational medicine, forcing us to take a new attitude to occupational hazards and react quickly to first evidence of harm. The polymerization process of vinyl chloride to polyvinyl chloride was first discovered in Germany in the mid-1950s. The fire and explosion risks and the narcotic effect were quickly appreci ated. Aero -osteolysis, a condition mainly all'ecting 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 (Cornier el at. 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 or 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 hepatitis like liver changes were reported by Tnbukh, from Russia, in 1949. However, uniii Viola reported (.Viola et at. 1971) that he had failed in an attempt to produce acro-osteolysis in rats exposed to 30 000 parts/IO` or 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 as 250 parts/IO" (Maltoni et al. 1973) . As a result of Malioni'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 w-ork 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 Stales Senate 1974) , to the Department of Employment (HM Chief Inspector of Factories) on 23 January, and to ihe Acting Chief Employment Medical Adviser on the following day. On 29 January 1974 Imperial Chemical Industries pul out a press statement announcing that a was taking steps to inform government departments, the fUC, us own workers and its Customers, of the facts available so far; and that a single suspected death in ihe United Kingdom was under urgent investigation. Subsequently this 70-year-old retired autoclave worker, who had died at Ihe 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 or the hearing before the Subcommittee on Envirnnmeni of the Senate Committee on Commerce, On the dangers of vinyl chloride (United States Senate 1974). Senator Tunney, in i.t J. I II ' [ ; R&s 026643 276 Proc. roy. Soc. Med. Volume 69 April 1976 18 his opening statement, said: 'This hearing will be focusing on ways to mitigate the problems in volved with vinyl chloride as well us wavs 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 (SclikofT & 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 1975. The International Chemical Workers Federation published for its members a handbook on vinyl chloride and its hazards (Levinson 1974). The Environmental Protection Agency in Washington, DC published in September 1974 a preliminary assessment of the environmental problems associated with vinyl chloride and poly vinyl chloride, in which it set forth recommenda tions to clarify and reduce the associated risks Meanwhile, the Department oT Employment staff in the United Kingdom had been taking active part in consultations in Europe and in the United States. As soon as the information was communicated in January 1974, 11M 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 vviih 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; these 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 Salety Executive, states that the code sets out to (a) define an interim hygiene standard that must not be exceeded; (hi require regular monitoring to measure the concentrations of vinyl chloride in the atmosphere; (c) outline methods of achieving (a)\ Id) 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 ... 1 he success of the Code depends primarily on the united efforts of management, supervisors and employees. This is very much a first edition of the Code in temporary formal; 1 hope that those who have suggestions for improving it will put them forward via the joint consultative machinery required by the Code.' Medieul 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 given by experts on diseases of the liver and relevant diagnostic procedures. Because of the difficulty of determining which medical tests indicate the effects of vinyl chloride on the liver preceding the development of angiosarcoma, they `concluded that insullicient 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 P\'C . . . '. As a result of experience gained from these tests and from other information, `formal recommendations may be issued as a supplement to the Code in due course'. The medical aspects of the code are contained in parts 12, 13 and 14. Part 12 defines 'supervised workers'. Part 13 is concerned with their medical supervision. Supervised workers should undergo pre-employment medical examinations. Those already employed should be examined, ir this has not been previously done, within twelve months. The examinations should be repeated annually, and should include: (11 a full medical and occupa tional history; (2) a clinical examination with particular reference to the abdomen, skin and extremities; (3) X-ray examination of the hands; (4) such further tests as may be indicated by the above procedures or may be recommended in supplements to the Code. The leaflet describing the early effects of vinyl chloride monomer should be given to the supervised workers at this exami nation unless issued previously. The physician engaged to provide medical supers ision for the workers should see a super vised worker who reports symptoms which may R&S 026644 R&S 026645 18 tons illy, 19 Section ofOccupational Medicine 211 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. Vindicated, 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 oT the present symposium is to review British experience of the environmental, clinical, epidemiological and pathological effects of exposure to vinyl chloride arising in the course of polymerization of vinyl chloride monomer to polyvinyl chloride, and to exchange information. International Agency lor Krvareh on Cancer (1974) Internal Technical Reptirt N*o, 74/tX)5. I ARC, Lyon (197$) Internal Technical Report No. 74/001.) ARC, Lyon l,e*ifiM>n C'(I974) Work Hazard Vmv] Chloride. International Chemical Worker* Federation Switzerland I,ilu K. Anderw/n 11, NiihnUon W J, Damn S, FiuhbnA A S Ift SrlikoH 1 J (197$) Annuli the .S>w York Academy of Science* 24ft, 22 4) Maltom C, C'mpi M A Burch P J K ed (1973) r.xccrput Medu u International Congress Senri No. 275 SelikoM I J d> Hainmond K f ` ed (197$) Annul) of the Ar* York 4cademy of St tenets vol 246 Trihukh S I.. Tikhomirnu N P, Levina S V A Kotlov L A (1949) Gigienu Sunn \ I), Ih (Jotted Statca Sctmtc Cninmitte* on (.'nmnirrir, .Subcommittee OO Environment (1974) Second Scsnon on Dangers of Vmyl Chloride. Senal No. 93-110 US Government Printing Olhce, Wiuhinuton, DC Viola P 1Rigotti A & Caputo A (1971) Cant er Research 31, 516 The implications of the association of angio sarcoma of the liver with exposure of workers to vinyl chloride monomer have had such a pro found effect on industry, workers and govern ments that these effects must be seen in the wider context of occupational carcinogenesis generally. I think it is necessary to consider what the future may hold in the way of carcinogenic risks. We can, I believe, regard the experience we have gained throughout the world with vinyl chloride as a pilot study on a newly discovered occupa tional carcinogen, Frank and open discussion between government departments and both sides of industry is indispensable to the achievement of success. Postscript The Working Group on Vinyl Chloride Code of Practice for Health Precautions met on 8 October 1975 and adopted a new hygiene standard agreed by the Working Group as `a ceiling value of 30 ppm and a time weighted average of 10 ppm, allowing that wherever practicable exposure should be btought as near as possible to zero con centrations.' The figures of 30 paris/10* and 10 parts/10* replace the original figures of 50 parts/10* and 25 parts/I0*. Other requirements of the Code, including medical supervision, are currently being re viewed. Ritt-ERENCLS Conjier J M, C. Ltfew* M J & A (19t;6) Cahier* 1/< MrJr* Jo Travail 4, 14-19 hJL|r & Johnson M N (i 974) J*Mtrna! of Oi caputtonal Medictnr 1ft, 509-5 18 EatirovamOk) ProUxtion Agency {1974) Preliminary As*e*imen: of the Environment! J*rnbkc-ii* Associated *ih Vinyl Chloride nd Polyvinyl Chloride. ^ .vhmaion, DC Health A Safety Knerume (197$) Vm>I Chloride Cfnie ol Prjctuc for Health Precaution* ( Temporary Format). London Mr A W Barnes (1CI Plastics Division, fVelwyn Garden City, Hertfordshire) Vinyl Chloride ar.d the Production of p VC Polymerization Characteristics of Cinyl Chloride Vinyl chloride has a boiling point of -I3.5rC: under normal pressures and temperatures it is a gas. In its liquefied form under pressure, it can be readily polymerized at temperatures in the range 40-70C to give polyvinyl chloride (PVC), a 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 itself is insoluble in the liquid monomer and so precipitates out as it is produced. The polymer is, however, capable of absorbing high proportions of monomer (41)"' 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 wilhin 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 tne speed of polymerization becomes uncconomically slow. These are the fundamental characteristics of vmyl chloride and its polymerization mechan ism which decide the principal features of indus trial processes for the production of PVC. in ijjh, HI Proc roy.Soc. Med. Volume 69 April 1976 The Production Processfor P VC conversion and solving some of the problems Because it. must be polymerized in liquefied form connected with vinyl chloride toxicity m this way. at temperatures above its boiling point, the At the termination point of the reaction, there industrial process must be carried out in pressure fore, the 5 -fj% residual monomer (still at a pres vessels fat 50'C the vapour pressure of vinyl sure of 4-5 atmospheres) is vented back to a chloride is --7 atmospheres). Ifecau.se ihc reaction gasholder and a slurry of PVC particles (100-150 J is exothermic, means must oe found for removal pm diameter), suspended by stirring in water, is or the heat produced so that the temperature of left in the reactor. reaction (and thus the pressure, and the properties of the end-product) may Ik kept under control. Now to a description of the process in engineer In the most widely used process, this control is ing rather than chemical terms: polymerization achieved by dispersing the liquid monomer into is carried out in cylindrical, stirred, jacketed tiny droplets (about 100 pin in diameter) in ap pressure vessels. To begin, water, surfaciivc proximately equal quantities of water, by means agents and free radical catalyst tire added to the of mechanical agitation together with the addition reactor: the air space above this liquid phase is of small quantities of surface-active agents which purged of oxygen (which inhibits polymerization) facilitate the breakdown of the monomer into and liquid Xinyl chloride is then injected into the droplets and stabilize :t in this form. This line reactor. (In the UK., reactor sizes range from subdivision of liquid monomer enables the heat 10m1 to 40m3 and the monomer charge per batch evolved from the polymerizing monomer to lie ranges up to about 15 tons. I The reactor contents rapidly transferred to the surrounding waiorand arc then heated to and maintained at reaction then removed by a cooling picket on the reactor, temperature. After a reaction tunc of the order of the process being aided by agnation. "I he sub eight hours, excess monomer is vented to a gas division oT the monomer into droplets has also holder (for recycling! and the reactor is evacuated, the vital property of ensuring that the polymer, at elevated temperature, to strip as much mono which is produced within each droplet, is pre mer as possible from the polymer on which it sented at the end of the reaction in finely divided, is absorbed The polymer slurry is t.ien trans powder form, and not as an intractable horny ferred to closed tanks prior to the nest stage in mass. 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 dioplcts which arc in turn dispersed in a continuous water phase. A great deal of research has been demoted in the past thirty years to the control and stahili/.mon of this rather delicate colioidal system but, even so, small quantities of polymer are stih thrown out from it and form a thin continuous film of PVC on the walls of tile reactor. If left, this will in crease in thickness and, since PVC is a poor thermal conductor, will reduce the heat transfer characteristics 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 ease of controlling fugtlivc monomer in a PVC plant. As polymerization nears 90-92% conversion, the rate of reaction slows down markedly and at about 95%, conversion has become so slow as to be quite uneconomic. There is no possibility therefore of continuing polymerization to 100% Meanwhile the empty autoclave, which still contains vinyl chloride gas at a low partial pre'ssttic 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 atlmity for I'VC and the last traces of it are difficult to remove from the polymer; the polymer in the slurry after stripping therefore still contains around 5(X) parts/IOf of vinyl chloride. This slurry is centri fuged to remove the vvater 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/IO' of monomer. Interfaces between Vim ! Chloride and People This description of tnc production process give-' some indication of the relative potentials of different parts of the process for creating signifi cant exposures of people tt- vinyl chloride. If we take a plant capable of making 100 000 tons per annum (tpa) of PVC then the polymertzalton building will, during the eoursc of a year, have handled over 100 Out) tons of vinyl chloride tn 20 problems bis way. there* |t a pres et to a [100-150 water, is ngineerrization [jacketed urfactive to the | phase is rization) |into the Be from er batch (contents J reaction (order of |o a gas- |ed, 1' it transI stage in pieh still [tial presening to re water [polymer i cycle is Unity for ) remove ry after Und 500 centrithe wet S; during noved in [tder curamcr. ess gives ntials of signifiBc, If we [tons per erization fea^uve Bt^^Bin 21 Section ofOccupational Medicine 279 liquefied form under pressure. Into the drying section will have passed SO tons of vinyl chloride in a form strongly absorbed on the polymer and at a concentration on polyinct' of about 0.05 Vo 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 ofT so that in the final fabri cated article only --5 parts/IO" of monomer remain or 0.5 tons out of the original annual total of 100 000 tons. In fabricated articles which are used for foodstuffs packaging (bottles, film and foil), and which represent about 10% of total UK. production, the monomer concentration is still lower, and the pro rata amount absorbed on foodstuff containers from a 100 000 tpa plant would be 50 lb. Of this quantity 3J lb might migrate into the foodstuff where its average con centration is unlikely to exceed 10 parts per thousand million. Since total UK production is about 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: w-iih this performance ground level concentrations at the factory boundary are welt 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 parts/10*. These figures should make clear that by far the biggest potential for exposure exists in the poly merization section of the plant, since here 100 000 tons per year of a liquefied gas under pressure are handled in a confined space, in contrast to other parts of the process and to the later down stream operations of the plastics industry. In these downstream operations the corresponding quantities, this time in the form of absorbed vapour at a low partial pressure and not confined to a single geographic situation, range from 5 tons down to 3 lb per year. That the polymerization section is in fact the area where hazard has existed in the past is confirmed by the fact that all the authenticated cases of vinyl chloride-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 arc com posed of a large number of batch reactors of small capacity per batch, relative to the total annual throughout. In each reactor, two complete cycles per day are carried out and each cycle requires vinyl chloride to be injected under pressure, heated, contained, stirred and polymerized almost completely: at the end of the cycle unpolymcrizcd 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 io be harmless and when a recommended exposure limit did not exist or, laic in the 1950s, was set by regulatory authorities, industrial hygienists, &c., al 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/1 O'; 1955-60, --400-500; 1960-70, --300-400; mid-1973, -- 150; 1975, --5 parts/10'. Across the world, there will have been variations around these figures because of differences in plant design or process operation riven 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 of jobs 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. VVuh 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 Tabic 1, which also shows improvements made at all the other interfaces described earlier in this paper. Al though, as we have seen, the exposure levels in these other places are many orders of magnitude lower than on the polymerization plants, industry has aimed to reduce fugitive vinyl chloride levels l*PWWm 'I- 280 Proc. roy. Soc. Med. Volume 60 April 1976 22 at every point in order to eliminate concern wherever it might exist. With work still in pro gress, 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 t Viayl chJoridr monomer leveia iq UK industry DISCUSSION' Polymerization VCM in plant atmosphere (weekly average) VCM emissions January 1974 {parts) UP) -150 July 1975 {parlsj 10*) -5 0.75"i of output 0.3*1 ofoutput Dr M D Kipling {Einployment Medical Advisory Service, Birmingham) said that it was known that workers bagging the PVC powder were sometimes covered with the dust and that this powder contained a percentage of vinyl chloride monomer. He asked VCM in product 200-500 < 50 for most grades whether any information was available on the particle size of the dust produced in differing processes through Fabrication and Use ( VCM in plant atmospheres 2-15 <2 VCM npVC bottles -50 ~2 out the world and the incidence of vinyl chloride disease. VCM in beverages 0.1 0.01 Mr A W Barnes replied that the particle sizes of PVC powder did vary very widely, depending on the Finally a few rough calculations of the daily dosages at the current exposure levels and at the application for which the PVC powder was made. However, most manufacturers produced all grades of polymer so that it was unlikely that any medical higher atmospheric levels which previously could conditions peculiar to a particular manufacturing site have existed on PVC plants may be helpful in could be explained in terms of the polymer and its putting current plant performance arid present downstream exposures into perspective, one with another, and in comparison with earlier figures (Table 2). particle size. Moreover, it should be remembered that all the significant medical circcts under discussion at this conference fangiosarcoma, aero-osteolysis &c.) had. throughout the world, been observed exclusively in workers on polymerization plants or, in two eases, Table 2 plants handling liquid vinyl chloride under pressure. Features common to all these workers were that they Daily dotagts *( current and earlier exposure levels were exposed to vinyl chloride vapour in the atmo Polymerization plant operator at 1000 parts/10* Polymerization plant operator at 500 parts/10* Daily dait (g/kgbody wight) 0.36 0,1 H sphere but were not exposed to PVC dust since the polymer was maintained in aqueous suspension throughout this stage of the process. It was in the drying and bagging sections of the PVC-producing process that exposure to solid PVC Polymerization plant operator now at -^5 pans/10* Fabrication plant operator at I part/10* Average UK citizen through ingestion in food 0 001R 0.0004 0.000000004 particles could arise but. despite extensive medical investigation, no significant abnormalities had been found among drier operators or packers. It wax perhaps worth noting, too. that the greater proportion of PVC powder was of a particle size similar to sand In later papers to this conference, a wide range so it did not generally pose an airborne dust problem. of diseases or symptoms which have been For those powders which might cause true dust ex 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 posures it had been customary in industry, because of the nuisance and discomfort factors alone, to provide some form of respiratory protection. 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 Dr C S Darke (Royal Infirmary, Sheffield) said that he had investigated 14 eases of breathlessness in workers exposed to vinyl chloride monomer. The findings were: no abnormal physical signs; chest radiographs two orders of magnitude lower, while the general normal: routine respiratory function tests difficult to public in the UK absorbs, through foodstufTs, a evaluate but some results slightly below predicted quantity which is some fifty million times lower. values, especially impaired CO diffusion in (> indi viduals: perfusion and vcntilalion scans showed 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 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. Histology revealed focal alveolar wall thickening with macrophages in the alveolar spaces and increased rcticulin and collagen ''yjwaiawij 22 |*er - levels iis, quite [generally, ft eighteen Advisory nown that | sometimes contained He asked he particle sthroughyl chloride i of PVC on the |was made. I grades of py medical during site ner and its nbered that cussion at ysis &c.) gclusivcly i two cases, fr pressure. :that they the atmosince the I suspension ons of the [solid PVC ve medical had been It was (proportion ar to sand kt problem, be dust cxI because of 1 to provide aid that he [in workers jings were: adiographs [difficult to predicted ; in 6 indi- showed be slide re| lobes. One ` the three aled focal n the collagen 23 Section ofOccupational Medicine 281 formation seen on electron microscopy. No obvious vascular abnormality except on fluorescent examina tion. It might be of importance that some of the worst affected men were concerned in a polymerization process that yielded 'plasiisol', a very fine I'VC powder with particle size around 0.5 m1"- These particles, containing vinyl chloride monomer, could be carried to the alveolar walls where they might be retained and thus set up a reaction of the type seen on light microscopy. Professor I J Sclikoff (Mount Sinai School ofMedicine, City University of Nevt York) said that pulmonary abnormalities had been unexpectedly common findings among some 1200 vinyl chloride polymerization workers in his studies. Obstructive pulmonary function defects were noted in approximately 50%. Neither age nor cigarette smoking served to explain the findings. For those under age 40, obstructive findings were predominantly among cigai cite smokers, as expected. After that age, however, the prevalence of changes was very much the same among smokers and nonsmokers. Of course, age correlated strongly with duration of employment. These two factors were analysed separately and it was found that the changes were generally among smokers with less than 20 years from onset of exposure, but that thereafter they were present in both smokers and nonsmokers. Radiographic changes were less common. Overall, 13.3% of 985 chest films showed linear, reticular or nodular changes characterized as 1/0 or 1/1 in the !LO U/C Classification. Dyspntta was uncommon and signs or symptoms of chronic bronchitis were not striking (Millereta/. 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 histopathological changes in the lungs of guinea-pigs exposed to PVC powder in a PVC plant. In the polymerization facilities investigated by Professor SelikolT, there had usually been opportunity for PVC dust exposure as well as vinyl chloride exposure, cither by a period of work with the polymer during the employment span and/or as the result of incomplete separation of the various parts of the production process. PVC dust was often to be found in several parts of the plants. It would seem of interest to study further the in fluence of vinyl chloride and PVC in the experimental animal, as well as the pulmonary status of workers producing vinyl chloride monomer but not exposed to PVC during or after the polymerization process. REFERENCE5 PrOAKt* N, Spmaxzola A & Uur*rcll A (1974) Medtcina del iMvoto 65, 521-342 Miller A (1975) Knnronmental Health Perspective 11, 247-250 Miller A, Tcintcin A S, Chuang M & Srliknff [ J (1975) Annals of the He* York Academy ofSciences 246,42-52 Dr K S Williamson (IC/ Ltd, Central Medical Group. Ftdshaw Hull, 1 Vitmslow, Cheshire, SK9 1QH) 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 al. (I9fi0), who found that the lethal concentra tion for mice, rats and guinea-pigs exposed for 30 minutes was between 200 and 300 000 parts/10*. In long-term studies few toxic effects were re ported, though Torkelson et al. (1961) found that inhalation oT vinyl chloride resulted in minimal microscopic changes in the liver and kidneys of several species of experimenlal animals exposed seven hours a day to 500-200 parts/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 al. reported that while attempting to produce acro-ostcolysis 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 scries of animal studies available to us arc those conducted by Maltoni and his co workers (Maltoni 1973, Maltoni & Lcfemine 1974). In these experiments groups of rats were exposed to vinyl chloride vapour concentrations ranging from 10 000 to 50 parts/I0` 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 have also been found in mice and hamsters by Maltoni and by Keplinger et al. (1975), who reported the findings of angio sarcomata and lung adenomata in mice exposed 282 Ptoc. my. Soc. Med. Volume 69 April 1976 24 by inhalation to 2500, 200 and 50 parts/10* of vinyl chloride. More recently both Maltoni c; til. (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 ei at. dosed Sprague Dawlcy rats daily by gavage at 50, 16.6 and 3.3 mg/kg for 12 months. They reported the occur rence of one angiosarcoma of the thymus in the 50 mg/kg group and one angiosarcoma of the liver in the 16.6 mg/kg group in an interim report approximately 1.3 months after the start of the experiment. Purchase and his co-workcrs dosed Wistar rats daily by gavage at 300, 30 and 3 mg/kg for 6 months. Fourteen months from the start of the experiment, a large proportion of the animals in the 300 mg/kg group and several of those in the 30 mg/kg group have been found to have liver tumours. Preliminary histopathological work suggests that some of these tumours are hepato cellular carcinomata, though further work is necessary before this can be confirmed. To facilitate comparison between the dosage of vinyl chloride received by the animals m these very different long-term experiments, I have made some simple calculations which are presented in Tables I 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 ! Rtt inhalation Kudin (data of Maltoni) Ventilation 100 ml air/min -6 litres/hour 24 litres per 4-houf exposure period ^ 0,024 m1 Weight of rats assumed to be 00 g Parts! !0* 500 250 50 niglm1 1250 625 125 Daily dose (nix) (0 024xmx!t*) 30 15 3 Daily dose (mgtk g) 60 30 6 Annuul dose (g'kit) (daily date ' 250} 15 7.5 1.5 Table 2 Ral oral dosing studies 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 hgurcs arc no more than very rough indications of dose, but they do give a useful measure for assessing the animal data. Table J Men at work Ventilation 10 m* aif [>*r 8-hnur shift Weight assumed to be 70 kg Parts! HP 300 UK) 50 10 ) mglrn1 1250 250 125 25 2.5 Daily dote (mglm* - 10) 12 500 2500 >250 250 25 Daily dose 1kg) IH0 40 18 4 0.4 Annual dose (jilkg) (daily dose , 250) 44.6 8.9 4.5 0.9 0.1 Green & Hathway (1975) and Watanabc et al. (1975) have studied the pharmacodynamics and mciabolism of vinyl chloride using uC-labelled material given by different dosing methods to rats. Both groups have shown that the proportion of the dose retained and metabolized is greater following small doses than large, though the absolute amount metabolized falls with diminish ing dose (Table 4). Table 4 Amount* of smvl chloride metabolized after dilltfrini; winglc doses Cutn orally in corn oil Kirccn & lijthvnjy IV75> Dose (mgikg) 450 300 30 3 I 0.25 Percentage n.etabolt;ed 8 12 46 69 86 96.3 Amount metahaltjrd P"*1**) 36 36 13.8 2.1 0.86 0.24 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 dOje (Table 5). Study Maltoni (250 doses) Doily dose (mgikg) 50 16.6 3.3 Total dose (x.'htt) 12.5 4.0 O.S Purchase (>25 doses) 300 30 3 37.5 3.7# 0.4 tumours found Table 5 Proportion of a tinclc oral do*c of >m>l chloride eliminated b) various routes (Green At Hathway 1975) Dose Proportion eliminated (*!) (mg/kg) Unchanged Co, Urine metabolites 0.25 4 450 92 12 75 16 R&S 026650 * I* 026651 24 i el at. and Ibetlcd to rats. Eon of Teater been Jof un* piration abolites Chloride with 25 Section of Occupational Medicine 2$ 3 Major metabolites identified in the urine arc: (I) thiodiglycolic acid; (2) S-(2-chlorethyl) cysteine and N-aectyl-S-(2-chlorcthyl) cysteine; (3) urea. Thiodiglycolic acid is derived from monochloraccnc acid (this can itself be detected in snail amounts in the urine) which in turn might reasonably be supposed to derive IVom cyclic chlore.'hylene 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 si/c of the glutathione pool may well be limited, vinyl chloride could cause significant depletion, so reducing the available protective mechanisms within the liver cells. Watanabe v: at. (1975) have reported progressive depletion of the hepatic non protein sulphydryl content (equivalent to gluta thione in this context) in rats exposed to 1000 and 250 parts/106 vinyl chloride by inhalation. No such depiction was found following exposure of rats to 10 parts/106 Tor 7 hours, Hathway (1975, personal communication) considers that the ethyl cysteines themselves may well be mutagens. Thus work on the metabolism of vinyl chloride has already begun to identify several interesting areas for further investigation. Though many important animal studies are still incomplete, there is already a substantial body of evidence to show that vinyl chloride is oncogenic, and there are some intriguing indica tions of the possible mechanisms of this action. The further studies which will be available in the near future may well help us to define working conditions which will not present health hazards to men exposed to vinyl chloride, and may perhaps allow us some insight into the fundamental mechanisms of the oncogenic effect. REFERENCES GreenT A Hathway D E (1975) Chrrnieo-btolof'H'ttl Ittlerfienons 11. 545-562 KepiirtRCr M l.. Good? J 'V Gordon DF.& Calandra J C (1975) Anna/so/the ,Se*> York Actktemvoj Sciences 2<6, 219-224 Maltoni C (1975) Exccrpto Medtrn International Canyrcss Series 275, 4 Maltoni C Cilib?rti A. Giannc L A (,`hivco P (1975) CU Ospedah delta Ytm 2, 65-tjti Maltoni C & Lclcmin? C (1974) Uncei-Rendn-tmtl della Clnsir di t Scienze Ftsiehc, .\fatnmitiche e Xtiiuruh 56, l -11 Mattromatm E, Fisher A M, Christie H & Dan/tRcr M (i960) American Indict rial ttyaene .Association Journal 2i, 394-398 Torkelton T R, 0> ?n f* A. Row? V K (1961) American Industrial Hygiene Association Journal 22, 354-361 Viola P L, Bicotti A A Cuputo A ' (1971) Cancer Research 31. 51 6-522 Watanabe P G, Mrfncr i( ir, McGowan G R A G?hnne P J (1975) Progress Report to ,\1 jmiljcumnu Chemists Association Task Group on Vm>) Chloride Research. Washington DlXCUSMOV Dr L Manns [MRC Toxicology Unit, Carsiniitan) said ih;il the dose plotted against the log of the number of malignancies past a straight line, making it very difficult to draw any conclusion about the threshold or no-ell'cct level, as the /cro-clfeci level could theoreti cally never bo readied, .Secondly. Dr Wj)Jja/mon\ data on the metabolism of vinyl chloride depending on dose indicated that at low exposure levels a high proportion of vinyl chloride was nietaboJi/cd and less was exhaled unchanged. This might mean that increasing exposure above a certain level would exhaust the biochemical ability of the organism to convert vmyl chloride to a toxic metabolite responsible lor the carcinogenic clfcct. These considerations indicated that experimental data must be interpreted with the utmost care. Dr H E Stokinger {Toxicology fhoncJi, National ins uniteJoe Occuptiltonal Safety and Healthy Cmenialtt. Ohio) said, m amplification of Dr Williamson's remarks on metabolism of vinyl chloride, that two metabolites had been identified m the liver of rats exposed to vinyl chloride: N-ucctyl*S-(2-h>droxyethyl) cystemc and thiodiglycolic acid The importance of knowing the nature of these endogenously supplied moieties was that they represented free, available sulphydryl (SID groups that acted as 'scavengers' of (he vmyl free radical, thus icmovmg us oncogenic poten* tial in a series of decreasing exposures of rats the find* ings were: at 1000 parts/lU\ rapid and complete satu ration of available free SM groups (liver); at 200 and 100 parts/10\ fairly rapid saturation of available free SH groups; at 50 parts, 10, a plateau of the saturation curve; at 10 parts IU\ no disturbance in the amounts of free SH. Infei dices and concludon*: (1) From the fact that h/cmangiomas occurred in the liver, and not In the lung (the primary site of entry), it could be inferred cither that little or no vinyl chloride metabolism to free radical occurred m the Jung, or that there was ample free SH to scavenge the vinyl radical. (2) Most important, the livci had a built-in antagonist to the vinyl free radical that prov ided the basis fora threshold for the carcinogenic response, in this case a threshold for an occupational carcinogen demonstrated by a specific biochemical constituent reaction. This finding explained the fact that among the tens of thousands of workers exposed only a small handful of htcmungionus had been found (3) Finding an oncogenic threshold of appreciable magnitude (between 50 and 10 pans/IQ*1) removed concern about general exposure of the public to small amounts (.uv Barnes, p 2S0) of vinyl chloride in PVC plastic wrappings of foods; the United Slates FDA could forget it! (4) I'o bolster resistance to effects of vinyl chlo-tdc, vegetables of the Hrassica family should be eaten. Tudors reducing fiee SH were: certain industrial exposures that were detoxified by cystemc, e.g, bromben/cne; substances or condi tions, c,g. certain chronic diseases. 284 Froc. roy, Soc. Med. Volume 69 April 1976 26 Clinical Aspects of Vinyl Chloride Disease Dr B ,J Preston, Dr K Lloyd .lones and Dr R C Grainger (Department.1 of Radiology amt Rheumatology. Harlow Wood Onhoptedic Hospital, near Mansfiekl, and Department of Radiology, Northern General Hospital, Sheffield) Acro-ostcolysis The word acro-ostcolysis means dissolution of the extremity or a bone and it is applied to the distal phalanges of the hands and feet. There are many causes, c.g. scleroderma, psoriasis, hyper parathyroidism, sarcoidosis, ergotism, diabetes, tabes, syringomyelia, familial and idiopathic acro-ostcolysis. 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 ul. (196ft), Wilson er al. (1967), Harris & Adams (1967), Dinman et at. (1971), and Lange et al. (1974), We would like to present the radiological findings in four patients svho had been involved in the production of polyvinyl chloride. Methods All patients had the following regions examined by plain film radiography: hands, feet, shoulders, elbows, knees, ankles, pelvis, chest, skull, man dible and spine. Case I (AD) also underwent a barium swallow, meal and follow-through, angio graphy or the hands and serial films of the hands at ft 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 75 years with symptoms of severe Raynaud's phenomenon, twin in many joints, trismus, and thickening and lightness of the skin. He had been engaged in the pnl.vmcii/ation processes of Vinyl chloride for 51 years. A radiograph of the hands (lug I) showed dissolution of Ihc central parts of all the terminal phalanges except for the little fingers, erosion of all the terminal tufts, thinning ot the central Paris of all the middle phalanges but particularly ihose oT ihe little lingers where there is extension into the have, thinning of the middle and distal parts of the proximal phalanges of the ring and hide lingers and elusions 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 over the wrist and the whole of the hand. A film of the feel showed aero-osteolysis of the terminal phalanges of hoth big toes, a large erosion in the head of the let 1 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 hmi^.iin|jij ifi pyi; iinmrimimi irmyo r it~fTTTTriitTffyff^ r ' f r i Tiiir 11 i" - V 'IL f > .f 3 EL. ~-rf'rWim: Fig 1 Case \ Hands (/.5.73), showing irunwcrsc deject* in distal phalanges, osteolysis, erosions andsoft tissue thickening !-I f'V'. ,, .4 ~v*dw- it-e- . ^-i*i'**v*v - 26 ng regions examined inds, feet, shoulders, chest, skull, man* )) also underwent a ^llow-through, angioal films of the hands presentation, and a ars with symptoms of pain in many joints, fchtness of the skin. He hcrization processes of kdiograph of the hands [the central parts of all for the little fingers, l thinning of the central anges but particularly [ there is extension into Land distal parts of the ; and little lingers and elcrotic margin at the pal and at the tips of In addition, soft tissue t wrist and the whole of pwed acro-ostcolysis of Oth big toes, a large first metatarsal bone ad of the right first ncdial and intermediate of the pelvis 27 Section of Occupational Medicine 285 " T-vVv ' t. 1 % ' - *;* `3 z.'i ,-'3 h 'i i y X*' TM x, y` * II >?, *> Vi- Fig 2 Case 1 Mandible, revealing marked erosion ascending rami revealed large erosions around both sacroiliac joinis. at the tips of the greater trochanters and along both ischial tuberosities. The radiographic survey of the peripheral joinis recorded erosions at the lateral end of the left clavicle, left upper humerus, medial and lateral epicondylcs of the right humerus, medial condyles of ihc 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 calcancum. Films of the mandible (Fig 2) revealed considerable erosion of both ascending rami, causing marked thinning of the bone; on the left side this extended up wards to involve the condyle. Films of the skull and spine and barium swallow, meal and follow-through examination showed no abnormalities. Monitoring films of the hands and feci were taken at six months and 2 years after presentation and these showed interesting changes. At 6 months, the films of the hands recorded the following changes: (a) central defects in the distal phalanges of the little finger: lb) further osteolysis, particularly of the bases of the distal phalanges; (r) periosteal reaction along the proximal phalanges of the left thumb and index finger, and right ring linger; (d) shortening of the distal part of the linger. 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 Ihc acroostcolysis of the big toes in the first fi-month period (Fig 3) but on the 2-year film there appeared to be some healing as ihcrc was new bone formation at the tip of the distal phalanx of the left big toe. However, the erosion at the head of the right first metatarsal bone had progressed in si/c over the 2-ycar period. The film of Ihe pelvis two years afler presentation showed a slight increase in the sice of the erosions of the ischial luberositics. 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 anaesthesia The large vessels were patent but in the left hand there were occlusions in ihc digual artery on the ulnar side of the thumb and radiahs indicts artery of the index finger, and nariowing of Ihe digital artery on the ulnar side of the, little linger. In the right hand, slight narrowing and lortuosity of [he radialis indicis ancry and medial digital artery of the little finger was shown. In both hands, hypervascularity of the terminal tufts was recorded. Case 2 F P, aged 38 years, had been engaged for two years in the manufacture of polyvinyl chloride Acro-ostcolysis was recorded in both index lingers and the right thumb. Erosions with a weil-eorticatcd margin were visualized at the base of the right first metacarpal hone, medial cpicondyle 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 ihe region over the radial and ulnar styloid processes. Case 3 D D. aged 28 years, had been involved for 2 years in the processes of polymerization of vinyl chloride, Th. skeletal -.urvey revealed no evidence of acro-ostcolysis or any other significant abnormality. R Fig 3 Cast 1 Feet, six months after presentation 11 |.,g)1 <--........ ..... * ****,*_<, 286 Proc. roy. Soc. Med. Volume 69 April 1976 28 Case 4 D W, aged 44 years, had been working ai the factory RHI-FRr.NCt S for five years. The skcleial survey did noi show acroosteolysis or any other significant abnormality. Chfnry W D (1965) American Juutniil of Rueni^emdmty 94, 595 -6i 7 Cordirr,J M, C. 1 vttstt M 4 A Sfrm A <1 (1966) Culuen itv Staler me tlu rra\mt 4, M -19 Dtnman (1 U, Cool* W A, W liiirliotiK W M, Mjfnuvm M J A I Discmu.ion DilchtU T(1971) Archnrt af !.nwrfmmemat Health 22. 61-73 * These 4 eases show the wide radiological spectrum {Jrtffibfrg H K A .Mem D M (1957) RadmUmy 69, 25V-262 Harm l) K A Adam* W OF that may be encountered in men complaining of ((967) nnir.'i Medical Journal in, 712-714 symptoms which could be related to their work in the polymerization of vinyl chloride. In Cases I.anL't? C 1', Jtihr S. Sirin Ci A Vtliman i) (197*1) fntrr/iniitutttlci Arilm tar Arheti imci/i;ifl 52, 1-32 W, H Saihh l< A A Smi J I 3 and 4, no specific changes were encountered. in Case 2 only moderate changes were recorded (J9l)7| litit(\li Jiwfntif uf Ritihnluitv 49, 740-747 Marshall 'I K, Nrusiadi l), C hiimiry W V A Kasdan M L (l'/M) K.iJifn'um X6. 299- KI3 -V whilst in Case I, extensive bony changes were documented. Indeed, in Case I, most regions of F^naosiliou (' Cargano F I' A W alln W I. (1990) American Juurnnl r>/ Raeni^erti/hU'v 83. 9X7-691 Ross J A (1970) In Symposium Wwium, Kd. A M Jcllille A the body were involved and a review of the litera R Stnckl.ind I ivm^sumc. f'.ihnburKh A I nmjnn. pp 321 -324 ture revealed that no previously reported case had such extensive bony changes. It has been suggested VViKon K 11, McCnntiK k W f`. Tamm FA {'rrli >1 L (} 967) Jfiurnul of ihe American Medical A \3ncmn0n 201, 577-581 that personal idiosyncrasy may be an important factor in the wide variation of the radiological findings (Wilson el al. 1967), DISCUSSION Dr L Magot said that Dr Preston's Case 1 might be The changes in the mandible in Case I have not been previously described in occupational acro-ostcolysis but it is interesting to note that atrophy of the mandible in idiopathic and familial idiopathic acro-ostcolysis aggravated by exposure to vinyl chloride. In the iwo->car tollow-up study Dr Preston had found improvement in the lingers, which were usually involved in occupational vinyl chloride acro-ostcolysis, at3d deterioration in the pclv is. acro-ostcolysis has been recorded by Greenberg & Street (1937), Papavasiliou el id. (I960), and Cheney (1965). Ross (1970) stated that the bone changes regress after the sufferer is removed from the Dr B J Preston replied that idiopathic ncro-osieolysis considered in rhe diiforcntial diagnosis of Case I but ihe distribution of the bony abnormalities other than those in the hands was dilTcrent from those recorded in idiopathic acro-ostcolysis. hazard but in our Case I the serial films of the Dr K Lloyd Jones added that Dr Preston's Case I also hands, feet and pelvis indicated that the acroostcolysis was extending. Fragmentation of the remaining tufts has been described as pari of the healing stage by Wilson et ul. (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-ycar film to indicate bony regeneration. 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) would be due to idiopathic .icro-osieolysis. It was not considered reasonable w> submit this patient to biopsy of the defects in the distal phalanges Biopsy of the lesion in the mar.Jiblc had been unrewarding He was The stenoses and occlusions of the digital employed as a production worker in a PVC plant and arteries and increased vascularity in the pulps of had never oecn exposed to vibration or the use of the fingers recorded on the arteriograms in the power tools first case have also been reported by Lange ei ul. (1974). Narrowing and occlusions of the digital arteries arc known to occur in Raynaud's phenomenon (Marshall et ul. 1966) Certainly, the disability due to the Raynaud's phenomenon in our case seemed out of proportion to abnor malities in the vascular tree. Lange el al. (1974) Dr Anne E Walker suggested that the dense vascular rete of the (Royal Hospital, terminal pulps of the lingers was due to stasis of Cheslerpeltl, Derbyshire) contrast in the vessels secondary to the shortening of the phalanges. This may be partly the case but Clinical Aspects of Vinyl Law's cl al. (1967) have observed hyper,i*mia of Chloride Disease: Skin * the pulps oT the fingers in a case of clubbing due Industrial acro-ostcolysis, a triad of Raynaud's to bronchial carcinoma and a similar mechanism phenomenon, sclerodermatous skin change and may apply in our case, as there is a strong clinical lytic bone lesions, has been well documented as resemblance to clubbing. occurring in workers engaged in the poly- 2J L377-581 [ might be osure to study Dr prs, which chloride steolysis tof Case 1 tics other those Be t also trodermai together Ivement. It in a vinyl Dr worker) | It was not t to biopsy psy of the g. He was t plant and hhe use of laynaud's hangc and [merited as the poly- 29 Seaton of Occupational Medicine 287 mcrizalion of vinyl chloride monomer (VCM) to polyvinyl chloride (PVC). Medical surveys of large numbers of employees have shown an incidence of approximately 3% (Wilson ri al. 1967, Dinman <7 al. 1971). Doth these studies also suggested that the disorder was largely confined toreador cleaners. In 1974 Lange cl al, described a more general ized disorder afTecting 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-ostcolysis. Clinical Study In February 1974 I saw one man with severe Raynaud's phenomenon, minimal bone changes in the fingers but no evidence of scleroderma. He was employed as a reactor operator at a local firm which manufactures PVC. Between February 1974 and February 1975, 36 of the men employed at this plant were referred with symptoms thought to be due to exposure to VCM. The study covers 37 men aged between 26 and 59 years (average 40 years 2 monlhs). Length of employment at the plant ranged from 9 months to 5J years (average 2 years & 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 occasion they had felt overcome by the vinyl chloride fumes, describing them selves variously as `unsteady', `slightly drunk' and Table 1 Presenting symptoms in 37 men Symptom Cold hands Parzithcsia Impaired grip power Cold titi Aches in bones Aches in muscles D>ipn<ra Excessive fatigue Lou of libido f No, ofeotts 20 16 15 J6 20 15 17 22 13 `robbery-legged', and this suggested that the men had been intermittently exposed to very high levels of VCM, which in experimental studies produces anatxthcsia. These symptoms were most frequently experienced when men were hosing down the reactors during emptying, but also by men when inside cleaning the empty reactor, and by maintenance men when unblocking pipes carrying VCM. None of the 37 men had evidence of sclero dermatous skin change. One man previously employed at the plant had extensive sclero dermatous skin change affecting the hands, fore arms, face, trunk, thighs and dorsum of the feet; additionally he had extensive lytic lesions of the bones, phalanges, feet, pelvis and jaw (K LloydJoncs, 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 1 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 sclcrccdeina 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 norma! age change. In one man with severe Raynaud's phenomenon the dermal arteries showed some medial thicken ing. Arteriography of the brachial arteries was carried out on 4 men. [n the one man with severe sclerodermatous skin change the digital sesscls in all the fingers were almost totally occluded. In the other 3 men there was patchy occlusion of the digital vessels, mainly in the ring and little fingers. --* i 288 Proc. roy. Soc. Med. Volume 69 April 1976 30 Blood flow measurements assessing total finger blood flow and capillary Mow were performed on a small number oT men. In 5 men capillary tlow fell abnormally on cooling and was slower in returning to normal on rewarming. In 3 men total finger blood flow was also abnormally reduced on cooling and slower to return to normal. Immunological studies have shown a high level of cryoprccipitate in the symptomatically affected men (A Milford Ward). Rf-FFRF.NCIJi f.'urriicr J M, I'imci C, L*f*rre M J A Srrnn A ft VMi) Cahirn iff bl+tfft inf da />aa/4, fi OiDmin It L),(.ook W A, VVhilt'lurusr W M 4 Mignuwn (I J (\*n\) An him uf l.nvitunntrntul ifcuffh 22, 61 -73 Harm I)K4 W fi F f IV67) Jlrtinh Medical Journal m, 712-714 IjnKr (' K, Jolt* S. Sirin fi A Vritmin C 11974) fn/rmattonulri Arrhtv far Arhtit\medi*tn 32, 1 MarUbwit; S -S, McDonald C J, I riltirrr W A Krrwrf M S (1972) Archi>p% of {}rtn,tiitihniy IUfi, 219 Stictu I, Diriman 1 & Vglaski M (1 Mfiitcirui fnlrtnu i Hat harm) 15, 967 Taltouchi Y A Mahuchi C (1973) Japanese Journal of Industrial Health 15, 385 Wilton R II, McCormick W K, Tatum C F A Crercli J I. (I967)fourgta/a//)tf Ameetevn Medical Association 201, 577 I Discussion In the survey of 37 men, of whom at least 36 appeared to have been exposed to high levels of vinyl chloride monomer on at least one occasion, sclerodermatous skin change was not observed. However, 5 had severe Raynaud's phenomenon and at least 5 others had abnormally cold hands which interfered with their normal dexterity. These circulatory changes arc only a part of a generalized disorder which may result in dyspnoea, cramp-like pains in the limbs, parxsthesia, exces sive fatigue and, in some cases, impaired liver function. The symptoms may be severe enough to niscussioN Or Ixxj Djerassi (Department of Occupational Medi cine. Haifu, 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 sclcrcidema fnot scleroderma) had already persisted for five years after exposure had ceased. tn one ease 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 limit normal activity and may occur without mononuclear elements. changes in the hands. In one case of Raynaud-like phenomenon which i started about eight months after initial exposure, the The relative sparsity of clinical change in the manifestations usually appeared two or ihrcc hours I skin or evidence of pathology on biopsy contrasts with the marked sclerodermatous and plaque-like 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 changes described by others (Cordicr er al. 1966, Djerasvi wondered w'hcthcr this was an immediate Harris & Adams 1967, Wilson er al. 1967). iransiem complaint due to the narcotic clfcct of vinyl Perhaps the early recognition and removal from chloride monomer, or a prolonged disturbance con exposure prevented more severe skin change in nected with the vinyl chloride disease as staled by the men under observation. Most of the above Dr Anne Walker. authors observed improvement in the sclero dermatous skin change on preventing further exposure. However, in one case described by Harris the skin change appeared to resolve spontaneously whilst the man continued working. Dr Anne Walker, in reply, said that the scleroidcmalike change observed in 4 of ihc men varied consider ably from day to day but in two men had persisted for at least eighteen months after the last exposure. In 15 biopsies from 13 patients an excess of inflam In my scries there has been little improvement, in the vascular signs during the period of ob servation, and this is in accord with the findings matory cells in c perivascular distribution were present in 4 of ihe specimens. The cells were largely lympho cytes. Loss of libido was the presenting complaint in one of others (Adams 1974, personal communication patienl and had persisted since the man left the firm and M N Johnson 1975, personal communica tion). However, Suciu describes the disappear ance of Raynaud's phenomenon within one year (Suciu cl al. 1963). In two instances cervical sympathectomy is recorded as producing clinical approximately three years ago. In 3 of the workers complaining of impotence, urinary excretion of androstcrone and d'hydroepiandrosteronc were very low. These measurements were made approximately twelve months after the last exposure to vinyl chloride. improvement (Takouchi & Mabuchi 1973, Markowitz er al. 1972). Dr Marcus M Key (University of Texas School of Public Health, Houston, Texas) asked if baggers and warehousemen had previously worked as reactor At the present time it is not known whether cleaners. the peripheral vascular disorder is directly i related to the presence of circulating immune complexes or to some other alteration in the sensitivity of the vessels to exposure to cold. Dr Anne Walker replied that they had not. Usually men slatted as baggers and later became reactor operatives and cleaners. The one warehouseman had i I R&S 026656 7f* MtmfM JO IHJ 1377 at Mtdi|his scries : was Jf sclera- I for five ademaonsideristed for inflampresent lymphoIt in one the firm workers of androry low. otimatcly chloride. ichooi of gers and reactor Usually reactor man had SI Section of Occupational Medicine 289 never been in a reactor. One of the baggers had spent an initial training period as a reactor cleaner hut had felt nauseated whilst in the reactor. After the lirsi two weeks he had worked entirely in the dry building lor four years. The other bagger was an epileptic and had never been in a reactor. Dr Prcmysl V Pelnar (Maulreal. Canada) asked what blood flow measurer'.ents were done? Dr Anne Walker said that blood flow measurements were made on 10 men. The subjects were kept m an ambient temperature of 27'C for one hour, then the room was cooled to I0C for the nest hour and finally the room temperature was raised to 27fC 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 io the middle finger by electrical impedance. Additionally, the skin temperature on the back of the hand was measured. Dr A Milford Ward (Department ofhnmunotofty, Hailamshire Hospital Medical School, Sheffield, S/0 2HX ) individuals from the factory who were completely asymptomatic. The major features of the disorder include hypcrimmunoglobuhnxmia, cryoglobulinemia and cryofibrinogentemia, and in viro complement activation via the classic pathway with C4 and Cj conversion. There is, in addition, evidence Tor a reduced T cell population, with low spontaneous sheep cell rosette counts, and an increased H-ccll population, as evidenced by an absolute increase in lymphocytes showing membrane bound immunoglobulins. The total lymphocyte counts arc usually normal or slightly increased. Some patients show non-organ-spccilic anlilissue anti bodies of low litre but rheumatoid factor is universally negative. lmmur.ofluorescent examination of biopsy material from skin (X patients), muscle U patient) and lung (I patient) has shown the presence of circulating immune complexes, with deposition on vascular endothelium and occlusion of small vessels. In those vessels which show subiniimul 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 in Vinyl Chloride Workers The occurrence of Raynaud's phenomenon and loss of bone density in association with dermal thickening which constitutes the syndrome oT acro-osteolysis (AOL) has been recognized in the vinyl chloride industry since the mid 1950s, but the overall frequency of the syndrome has been low and no series have been subjected to thorough immunological investigation. Recent studies have indicated that the disease process is not confined to the skin and skeletal tissues, but is a multi system one with involvement of many organs and tissues. Immunological and immunochemical investiga tion of 58 workers from a single factory has revealed evidence of a chronic soluble complex disorder in 21 individuals. The extent and seventy of the immunological abnormalities parallels the clinical features to a large extent, but sonic indivi duals show laboratory evidence of an active disease process at a stage when the clinical features are minimal or absent. Circulating immune complexes were demonstrated in 9 out of 10 individuals who were severely affected clinically; in 7 out of 15 individuals who were symptomatic to a degree that they were incapable of active employment; and in 5 out of 28 indivi duals who were symptomatic but able to work. Immune complexes were not detected tn 5 Experimental evidence on the metabolism of vinyl chloride suggests that at least part may be taken up by the liver and become incorporated into anunoacid synthesis.' The incorporation of the chloride radical into protein synthesis could result in a structurally abnormal protein which would react as antigcnteally 'foreign' material. The association of these experimental data with the observed immunological profile allows the construction of a theoretical model of the disease process. The initiating sequence is a: present speculative and remains to be proven by further study, but the later sequence of events can be adequately explained by the immunological abnormalities. Structurally abnormal or antigenically 'foreign" protein escapes tolerance and incites an immune response w-ith R-cell prolifera tion and hyperimmunoglobulinarmia. The immune Complex formed by interaction of the antigen and antibody is crvoprecipitablc and will activate the complement sequence. The cryopreeipitatc and the reactions secondary to complement activation will produce sascular occlusion and fibrinogen) fibrin conversion and polymerization. The frequency with which abnormalities have been detected in this series, especially in that group in whom there were no overt clinical signs, suggests that the disease process may be more common than generally supposed. The thcorcti- , ! 57 So tn fO 07 07 UI Nf Free, rtry Sue. .Mm.!. Volume 69 April 1976 32 i cal, and a! present speculative, initiating sequence Dr A Milford Ward replied that the classification used of reactions in this disease process also raises the in this study was a clinical one, based on history, question whether other unsaturated halogenated hydrocarbons may also be involved in a similar physical cxaminafion. and an assessment oT the patient's ability to continue his employment. H therefore included such aspects as splenomegal . chain of events. acro-osteolysis, and scleroderma. Further studies are in progress in an attempt to clarify the initiating reaction sequence and to Dr E Vigliani {Milan. Italy) asked whether the presence =J define the precise relationship between vinyl of It and T in the (issues could be detected by im chloride and the observed immunological anoma munofluorescence. lies. i Dr A Milford Ward replied that lymphorcticular tissue was not examined histologically or immuno- logically so the presence of T and II cells could not be assessed in tissues. T and U cell counts were per formed on peripheral blood. DISCUSSION i Dr Leo Djerassi said thai fatty liver might be the early Dr Ruth Lilis {Mount Sinai School of Medicine, New histological change in liver -aused by vmvl chloride. York) asked whether immune complexes were found In one of his eases which began with splenomegaly, in the kidney. There were in the literature a number of liver biopsy showed a fatly liver. The patient did not cases of Goodpasture's syndrome in person., exposed consume alcohol habitually. The finding was not to chlorinated hydrocarbons surprising, as chlorinated hydrocarbons were known to cause fatty liver. The Jinical development of this case brings us to the evidence of immunological phenomena in those exposed to vinyl chloride, and io 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 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 hiematuria. Antibodies to renal glomerular basement membrane were not detected. because of (esophageal bleeding The patient's condi tion improved sufficiently to enable him to work full time on a nonstrenuous job. Professor Margaret Turner-Warwick (Cardwthoracic Institute, Brampton Hospital, London SlYJ) asked svhat was the cause of the T cell depression mentioned, and whether the spontaneous sheep rosette T cell Dr I F H Purchase, Mr C Richardson and Dr D Anderson (1CI Central Tu.xteolo"y Laboratory, Aldcrley Park, near Macclesfield, Cheshire) counts were confirmed by other in vtiro tests such as PHA transformation. Chromosomal Effects i Was there evidence whether C3 conversion was in Peripheral Lymphocytes & triggered by the classical or by the alternative path way? Was evidence found of immune complex deposition Vinyl chloride produces liver tumours m animals exposed by inhalation (Maltoni & Lcfemine in capillaries of the skin and lung as well as in the 1974) or dosed by the oral route (Maltoni el at. larger vessels mentioned ? 1975, Purchase 1975, unpublished!. Epidemio logical studies demonstrated that workmen Dr A Milford Ward replied that the cause of the T cell exposed to vinyl chloride had an increased risk depression w'as not clear, but u was a feature often seen in circulating immune complex disorders and in autoimmune stales. 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 wnih conversion of C4 as well as C3, as would be expected with lgG class antibody directed against the antigenic groupings. 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 lympt.ocytes with chromosomal abnormalities (Funes-Cravioto et at. 1975, Ducatman ci at. I97S, Purchase et al. Immune complex deposition was found in capil 1975) . Studies of this type carried out on lympho laries and small vessels in skin, muscle and lung. cytes recovered from peripheral blood provide an i easy clinically applicable method of assessing Dr I. Magos said he would like to see the patients classified by grade, since it was always frustrating to read of `severely alTectcd' people without knowing wtvt `severely affected' meant. The grading could be damage to living cells caused by carcinogenic chemicals. If there is a quantitative relationship between the percentage of chromosome abnor based on degree of splenomegaly, acro-ostcolysis, malities and the amount of exposure to the chemi scleioderma &c. cal, the estimation of chromosome abnormalities emnr 1.1 ..n.uumuu.ww#.^i>.ii|ji WWgIULk.A >- 32 esence by im- r, New i found nber of xposed not clinical sidercd ence of renal ed. limals Scminc et al. dcmioSrkmen risk dlarly . 1974). nicals. stratcd ave an with doto et et al. nphovide an ssing nogcnic Sonship [ abnorIcheminalitics 33 Section ofOccupational Medicine 291 may provide a useful tool for determining levels of exposure which do not produce this mutagenic effect. We have studied a population of 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; Group 1 are autoclave operators ; Group 2 arc maintenance workers who have worked in the polymerization plant; Group 3 are those who work in polyvinyl chloride (PVC) production but not with auto claves; Group 4 are maintenance workers in the same area as Group 3. It is virtually impossible to define exposure of these groups of workers to VCM apart from saying that the autoclave workers have the highest exposure and Groups 3 and 4 the lowest. One worker, who was employed as an autoclave worker Tor 11 years and sub sequently as a maintenance worker for 14 years, has been included in Group I. Blood samples were taken and lymphocyte cultures were prepared using standard Difeo kits (Difco Laboratories, Detroit, Michigan, USA). Lymphocytes were cultured for 48 or 72 hours. All slides were coded before scoring, to ensure unbiased analysis. One hundred cells per indi vidual were analysed (except for one individual where 200 cells were analysed), using the classifi cation of Buckton & Pike (1964). Workers who had been exposed to X-rays or prolonged drug treatment were excluded from the study. The results of the chromosome analysis are given in Table 1. All individuals were found to have normal male karyotype, except for one who had a 46, XY karyotype with inversion of No. 3 chromosome. There was no significant difference between 43- 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 Funcs-Cravioto Table I Rnultt Irom analyirs ot chromtiftomc afinorinaliiK'i in worker! mployra in PVC mnnutortnro (It and C cells classified according lo Buckton X. Pike 1VMI Group l Group 2 Group 3 Group 4 Control* on *ilc Control* off site No. of Workers IS 2! 5 12 19 5 B Cells (%) 6.4 6,9 6.6 5.1 3.6 2.6 CU Cells CS Cells (%) (7.) 1.72 0.44 1.48 0.30 1.20 0.20 1.10 0.4 i 0.53 0.10 0.50 0.00 et al. (1975) and Dueatman et al. (1975) that workmen exposed to vinyl chloride have an in creased percentage of chromosomal abnormalities;. There is also some incomplete evidence that higher exposure results in larger increases in abnormalities. This relationship still requires to be studied in more detail. The induction of chromosomal abnormalities is indicative of a mutagenic effect of vinyl chloride. It is important to know whether vinyl chloride is capable of inducing mutagenic effects in other test systems and particularly whether such an clfcct is produced on germ cells. Accordingly vinyl chloride was examined for dominant lethal effects in mice. Groups of 15 male mice were exposed to 3000, 10 000 or 30 000 parts/108 of vinyl chloride for 6 hours per day for 5 consecu tive days. Hach male was mated with 2 virgin females per week for 8 weeks and the females were killed tit 13 days and examined for dominant lethal effects. There was no significant increase in any of the parameters (early deaths per implanta tion, early deaths per pregnancy). Vinyl chloride, therefore, did not produce dominant lethal effects in mice, indicating that it did not produce a mutagenic effect in germ cells even at these high levels. REFERENCES Ilurklon K K4 Rike ,N1 C (I 'it4) international Jt/ur/uil of Hitdmttvn Biotony t, 4 39 Crrcch J L &. Johnson M ,*S (1974) Journal of Qc< uponfinal Mrdn'tne 16, 150 Dueatman A. 11 lihofti K A Stlikod I J (197J) ,Mutation fft tcurcli Jl. 163 Fum-S'Cfjviolo 1'. LansbtTl 1), l.indstfn J. Fhrvnbtrt 1., N,iUrk!4rt A T A Oitorman-(<olk: *s /1 975) Lancet i, 459 Mstllftm C, C-'iltbsTti A, (/i.tnni 1,, A t'liu'vo R (IV75 r Otflrilfiii della 1 tta 2, 65-f(t Mrfllnm C A 1 efemm? (7 {! 974) tronmeoiul Feu'Oreh 1, 3fl7 Purchase 11' H. Kichardsoit C R A Anderroo D (1975) iMnecl ii. 410 DISCUSSION Dr S\hia D Lawler {Rovul Sfarulcn Hovpitu!, London 5I7J) asked were ihc chromosome breaks distri buted al 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 II Purchase replied that the chromosome breaks were distributed randomly. No banding tech nique was used. The people selected to take part m the study were randomly selected and had not been separated into those with and without symptoms. The only evidence that had been produced experimentally suggested that genetic effects did not occur in the gonads and no effect on fertility w'as seen. a nwimv 292 Proc. roy. Soc. Med. Volume 69 April 1976 34 Dr L dc Boer [The Hague, Netherlands) said (haL Mrs I Flcig had reported (Medichcm 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. Dr I F H Purchase said that his was the third study which had described such abnormalities, the other being those by Funcs-Cravioto el al. (1975, Lancet i, 459) and Ducalman et al. (.1975, Mutation Research 31, /63). Dr D G Smith {Zeroth Ltd, Islewnrth, 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 (I and 2) and those away from the autoclave (3 and 4), assuming that the autoclave area was the one of maximum exposure. Dr I F H Purchase replied that there was a statistically significant diffetence between the results from auto clave workers and controls, and between the results from all exposed workers and controls. DrKJW Taylor (Department of Diagnostic Radiology, Yale University School ofMedicine, New Haven, Connecticut, USA), Dr J J Barrett (Department ofNuclear Medicine, sis, portal hypertension, ccsophagcal varices and splenomegaly may he common results of VCM toxicity (Marstcller et at, 1973, Smith & Williams 1974, Makk et al. 1974, Thomas el al. 1975, Lange el al. 1974). In view of these adverse reports, a survey was undertaken oT4S7 workers with varying exposures to VCM by two of the authors (Williams et al. 1975). Full blood pictures were obtained and standard liver function tests were done. Two patients identified by a thrombocytopenia of 72 000 and 45 000/mm5, and slightly raised C-glutamyl transpeptidasc G-GT levels, were subsequently found to have periportal fibrosis, portal hypertension, splenomegaly and ccsophugcal varices on barium swallow, plain abdominal radiography, splenic venography and needle biopsy of liver. It was clearly unacceptable to carry out these invasive investigations on all exposed workers, but the less invasive techniques seemed relatively insensitive. Thus, a pilot project was earned out to ascertain whether ultrasound offered a possible noninvasive method for visualizing the fixer and spleen in workers exposed to hepatoio.xic agents. Initial results proved encouraging (Taylor cr al. 1975, Williams e/ al. 1976). Although ultrasound has been used as a diag nostic tool in obstetrics for many years, the instru- rclevant echoes to be displayed were of large Dr D M J Williams instrumentation, Kossoff (1974) developed greatly Dr P M Smith (Department of Medicine, Welsh National School of Medicine, Llandotigh Hospital, Penarth, South Glamorgan), and Dr B \V Duck {Occupational Health Unit, BP Research Centre, Snnhury on Thames) similar instrumentation, the technique was evalu ated for the investigation of liver and splenic pathology (Taylor et al. 1973, Taylor & Milan Preliminary Results of Grey-scale Ultrasonography an i in the Detection of Vin> 1 Chloride Related '<! Liver and Spleen Disease A number oT eases of angiosarcoma of the liver in (VCM) led to the recognition of the potential hazards of such exposure (Creech &. 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 tibro- tb&i.-.srj:. 34 l varices and suits of VCM |ith & Williams et al. 1975, a survey was ying exposures Williams ei al. obtained and re doric. Two ocytopenia of ilightly raised levels, were |portal fibrosis, and asopha|lain abdominal and needle Carry out these posed workers, emed relatively > carried out to bred a possible pg the liver and atotoxic agents. (Taylor a al. as a diagfears, the instrurude since the were of large sophisticated bvclopcd greatly pinically applied thyroid. Using pique .was evaluicr and splenic raylor & Milan rinfwclor |vn* evk pnsduccrto I in Fig 2, 35 Section of Occupational Medicine 293 e y-x. v. --c. " " - ,-4i, -.V r '* ^ -) w. ;>/*?;.;; -kb/-- , ' ! X.-1 'Cs.- 'X*.- " a-.- 'k " ' V. ` ' * *.#5s f - ,.h*wS Fig 2 Parasagittal scan ofliver 3 cm to right of midline shoving 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 parenchyma. The liver is scanned in a series of paramedian sections illustrated in the schema shown in big 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 Fig 3 Parasagittal section ofliverfrom patient tvilh vinyl cJiioridc-reiatedpat lal hypertension. The portal vein is diluted andhighly tortuous. Sate that there are very large echoesfrom the deep surface of the liver which is consistent with capsular fibrosis [art owed). (Reproducedfrom T'lylur cl al. 1975, by kindpermission) as shown in the diagram, good resolution is obtained without degradation by respiratory or cardiac excursions. This ultrasound technique invokes no ionizing radiation nor other known hazards, no discomfort, and no need for contrast media. Ii does require considerable operator expertise and high quality instrumentation, which lias only recently become commercially available. Machines which do not display the consistency of the liver arc unsuiteJ for examination ol it. Nineteen volunteers were selected from the lectors workforce, with varying exposures to vinyl chloride monomer which are summarized in Table I. Only 2 patients had no exposure al all, but 7 were normal on standard testing (Table 2). Table 1 Durttion inj levtlx of VCM txpoiures (from Willurm mil. I97XJ ConHQnl exposure Ifitfrtnillerii exposure Cast Low Medium fitltfi l 4! (No exposure) 2 40 (No exposure) 3 32 4 45 ly 3m 5 43 6 45 7 36 8y 6m 10m ly 3m i 47 9 30 10 45 M 56 5y 9m I5y 6m 2y 3m 2y 6m iy 8m 12 39 ly 13 41 3y 10m 14 42 6y 8m 15 50 lm 2y 8m 16 55 I2y 9m 17 32 6y 6m 18 43 7y 4m 19 46 7y Low A tedium (No exposu re) (No exposu re) 6y 4m ly 5m 1 5y 4m lOy 5m 3y 7m 3y 4m 1 y 10n> 8y 4m 7y 5m 6y 6m 2y 4rr 8m 5y 3m lm 3y 3m 3y 2m 17y 1 lm 3y 2m 3y Am 6y 5m 6y 3m 1I4y 3m ly 4m ly 7m Low exposure, 0-25 parts/10*: medium, 25-200 puns/10*, hitfh, > 200 pjrij/10* Time jiven in yean and months 1 ' :S WtflPijpwwj p "fli* rwj j SWUWW1 HiiHUHMtMflpF-J 1 294 Free. roy. Soc. Med. Volume 69 April 1976 36 The ultrasound examinations were carried out by the same operator (KJWT), who had no know ledge of the results of the screening tests carried out at that time nor of the exposure of any par ticular worker. Abnormal findings included in creased size and tortuosity of the portal vein associated with portal hypertension, probable capsular fibrosis (Fig 3) and splenomegaly (Fig 4). The results of routine screening and ultrasound are shown and compared in Table 2. Routine screening consisted of clinical examination, full blood picture, urinalysis and standard liver function tests. Repealed abnormality in any in vestigation led to further investigation including barium swallow, plain abdominal radiography, Table 2 Companion of abnormalities detected by standard method* and by ultrasonography (from William:, ft u/. 1976) Coif t 2 3 4 5 6\ 7 8 9 10 11 12 13 M 13 16 17 18 19 Standard mtthods Ull rdlunafiruphy Normal Norma) Normal Normal Normal Liver 6 cm enlarged Normal Slightly enlarged liver but normal consistency Normal Normal Normal Technically difficult (obesity). Enlarged portjl vein. 50% increase m spleen ute Normal Enlarged portal vein, splenomegaly (12 cm) Normal Enlarged liver with a degree of abnormal fibrosis Alkaline phosphatase 31 iu/l Portal vein not shown. Spleen twice normal sire, Liver consistency slightly abnormal Wedge liver biopsy, portal Enlarged liver with tract fibrosis m places possible tatty inhltration extending into parenchyma Bilirubin 31 p.mol/1 Portal vein slightly enlarged SCOT 60 iu/f Marked splenomegaly (IK cm) Liver technically difficult losee Needle liver biopsy: slight Normal fibrosis and fatty change SOOT 60 iu/l, GGT 95 iu/1. Portal vein and spleen Needle hver biopsy: normal. Liver riiflieuU moderate fatty degeneration to see (obesity) and mild portal fibrosis Platelets 106 000/mm1 Large portal vein and spleen {12 cm), Liver enlarged slight change in consistency SGPT 62 iu/l Needle Portal vein and spleen liver biopsy* fatty change normal, but possible cirrhotic changes in liver SCOT 60 iu/l Normal y-GT 39 iu/l Bilirubin 21 umul/l, GGT Marked enlargement of portal 66 iu/l, platelets 99 000/mm*. Vein and spleen Slight change Splenomegaly, crsophagcal in liver consistency vanes, periportal fibrosis GGT 82 iu/l, platelets Splenomegaly Marked 45 000/mm1, BSP 19% cirrhotic changes (45 min) Splenomegaly, and fatty inhltration ccsophageal varices Fatty degeneration with minimal periportal fibrosis Bihrubm 43 mol/1, Marked splenomegaly and SGOT 50 iu/l, platelets severe cirrhosis 80 000 mm1. BSP2l>; (45 mm). Splenomegaly. (Portacaval shunt 1968) -t*- ' `--' L1 , . ,I -V`` V 1 %rr s 'v; Jt.ll -L Fig 4 Ultrasonogram ofspleen scannedalone tenth left interspace. iVhcn the spleen is enlargeddue IP portal hypertension, loir-level echoes are returned and so appear dark. The grid squares are 2 cm apart, and the spleen is thus 17 em in length. This enlargement was not apparent an a plain abdominal radiograph cxsophagoscopy, splenic venography and liver biopsy. Comparison of the results of ultrasound and routine methods in Table 2 shows that known pathology in Cases 4. 9, 10, II, 14, 15 and 17-19 were confirmed on ultrasound examination. Cases 1, 2, 3 and 5 were confirmed to be normal. Cases 12 and 13 were known to have liver abnor mality on histological examination but this was not delected by ultrasound examination. How ever, additional information was obtained by ultrasound ;n Cases 6. 7. 9 and II. In all these workers, the ultrasound findings led to a review of the radiological results and these are sum marized in Tabic 3. The ultrasound results were confirmed in 3 patients and were not contradicted in Case G, in whom obesity prevented adequate assessment of spleen size on a plain abdominal radiograph. These volunteers were taken from a workforce of 4S7 of whom 20,9"' had abnormal biochemical or htcmatologic results on initial testing. Further, intensive investigation failed to reveal the early pathology which was demon strated by grey-scalc ultrasound and was con firmed retrospectively by radiological examina tion. The main advantage of ultrasound lies m its potential as a noninvasive technique for monitor ing populations at risk. The lack of ionizing radiation is a great advantage in this respect. These preliminary results suggest that ultra sound will result in a small incidence of false negatives (2 out of 19), so that the method is complementary rather than a replacement for current techniques. Roth acquiring the ultrasound scans and interpreting them requires operator expertise, but automated scanners should become available within the next year, while experience R&S 026662 36 liver and nown 7-19 ition. final, buk d by these eview sumwerc licted quate TLinal om a jrmal nitial cd to onconinain its tutor izing Ultrafalse lOd is t for lound rator come fence 37 Section of Occupational Medicine 295 Table 3 Farther (iltdintl lubirquenl lo ultfavOund cttimnalioB Initio/ Case assessment 6 Normal 7 Normal 9 Normal 1) Normal Ultrasonography Splenomegaly Splenomegaly Splenomegaly Splenomegaly further assessment lianum *wallow normal. Spleen not sun on X*ray abdomen. Barium swallow normal. Spleen wide transversely but did not eatend below level of I2th rib Barium swallow after Buscopan. Showed possible Grade i varices. Splenomegaly confirmed on review of straight X-ray of abdomen Possible Grade 1 varices can be gained if the potential of the method is sufficiently promising. Preparations arc 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. A cknowledgmcnt: We would like to acknowledge the cooperation of the Working Party on Vinyl Chloride Toxicity of the Chemical Industries Association, REFERENCES Block J B (1974) Journal ofthe American Medical Association 229, 53-54 Cfrtth J L & Johnson M N (1974) Journal of Occupational Medicine 16, 150-1 51 KomoA G (1974) Journal of Clinical Ultrasound 2, 61 -72 Langt C 1, Juht S. Stem G Si Veit man O (1974) Internationales Atchit fur Arbeitsmedizm 32, 1-32 Lee F I A Harry DS (1974) Ljincet 1. IJI6-U18 Makk L. Creech J L, Whelan J G a Johnson M N (1974) Journal of lbe American A fcdicol Aitocutfion 130, 64--68 Mantfllcr it J, Ltlbach W K. Muller R, Juhe S, I,anc< C E, ftohntr II G & Vrliman C (1973) Deutsche Medmmsche Wochenschrift 98, 2311-2)14 Smith p M A Williams D M J (1974) (hficsnott 10,321-322 Taylor K J W, Carpenter D A A McCrcady R (1973) Journal of Clinical Ultrasound 1,284--287 Taylor KJWA Milan J (1976) Proceedings of 1975 Conference on Tissue Signatures. National Bureau of Standards, Washington Ed. M Lmrcr <m press) Taylor K J \V, Williams 11 M J, Smith P M A Duck B W (1975) tjsncet l. 1222-1224 Thomas 1, B, Popper H, Berk P D, Seliknfl I A Falk H (1975) New EnglandJournal of Medic,ne 292, 17-22 Williams D M J, Smith I' M, Tay lor K J \V, Crcnslry 1 R A Duck B W (1976) llntish Journal of Industrial Medicme (in press) William* D M J, Taylor K J W, Crowley I R. Smith p M A Duck B VS (1975) Daemon 12, 362 DrMlV Jayson {Department ofMedicine, University of Bristol) Dr A J Bailey (ARC Meat Research Institute, lumpford, Bristol) Dr C Black (Deportment of Medicine, University ofBristol J Dr K Lloyd Jones (Harlow Wood Orthoptrdic Hospital, Mansfield) Collagen Studies in Aero-osteolysis Collagen is a fibrous protein present in most con nective tissues and it is the nature and arrangement of collagen fibres that arc principally responsible for the mechanical properties of these tissues. The collagen molecule consists oT three chains of amino acids formed into a triple helix, and these molecules tire aligned in the fibre in a parallel and quarter-stagger arrangement giving rise to the characteristic banded appearance of collagen seen on electron microscopy. This quarterstagger arrangement is maintained by specific lysine-derived intermolccular crosslinks and it is these crosslinks which are responsible for the strength of collagen. When collagen is newly formed, the intermolecular crosslinks are labile aldimine bonds, and can be detected by reduction with mtiated potassium borohydridc (Bailey et ai. 1970). How ever, as the collagen matures these crosslinks become stable and nonreducible and are therefore no longer readily delectable. Studies of the collagen crosslink patterns in normal human skin will therefore show the highest levels in infancy and during the rapid growth period, but will fall to virtually baseline levels by adulthood. If excess labile aldimine bonds are detectable in adult human skin, then proliferation of new collagen is occurring. Collagen Studies in Scleroderma The skin changes of aero-osteolysis (AOL) arc in many respects analogous of those oT 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 nonprogressivc scleroderma there was no excess of the labile bonds. Analysis of the centre and the growing edge of a plaque of morphav demon strated the maximum level of crosslinks at the R&S 026663 v i Collagen Studies in Aero-osteolysis Case I A D, aged 36 years, was a plasterer until six years before we saw him. He then started as a reactor cleaner and a `IV operator in a plant manufacturing polyvinyl chloride, scraping the inside of the reactor with n chisel, wearing gloves and overalls hut no mask. Following this initial three-week period he pM0H*P/ pMOH-P became an 'A* operator, working outside the reactor, and was involved in charging and recovery from the reactor and controlling the flow of chemicals including vinyl chloride through various valves. There was no direct contact with the chemicals, but he frequently noticed fumes escaping from the valves After three years he noticed the onset of Raynaud's phenomenon which progressed with gradual shorten I ing and instability of the lips of the lingers. `There was a gradual thickening anti coarsening of the skin Normal 10" Spreading up his arm*, on to the face and a little on the chest wall and axilla, Two years later he gave up work with marked weakness of his hands and arms, which caused great difficulty in gripping and lifting heavy Fig 1 Rote ofsynthesis ofhydroxyprohne refuted to the original hydroxyproline content oj normol ond AOL thins Ipmol) weights. Examination confirmed the features of avroostcolysis with gross thickening of the skin, but with the following ditTerences from scleroderma: (1) No ulceration of the fingertips, (2) Instability of the tips of the fingers. (3) Hair follicles and hair preserved (4) No puckering around the mouth (5) No iclangei- samples of skin from the patient with AOL anti also at surgery from patients with other conditions not thought to invoke any abnormality of collagen metabolism. They were cultured on a stainless steel raft at the interface between a cctasia. (6) General coarsening of the features. (7) No culture medium containing "I(-proline and an tightening of the skin across the nose. atmosphere of 20",', oxygen, 5"' carbon dioxide, Investigations showed slightly raised plasma viscosity or 1.80 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 cor.Jvlc of the temporo mandibular joint, and loss of definition of the right mandibular vertical ramus. 7y/,, nitrogen in a modified Macintosh Fildes jar at 37 C for 24 hours. Following culture the specimen was homogenized, dialysed to remove excess ;iH-proline, hydrolysed and separated in an amino acid analyser and the quantity of synthesized Hl-hydroxypmhne was determined. This was related to the hydroxyproline content of the original biopsy. The results are presented in Fig I and show that the fate of collagen synthesis Skin Crosslink Studies in Aero-osteolysis in the patient with AOL was considerably A skin biopsy was obtained from this patient. greater than that of the normal controls. Reduction with potassium borohydride revealed a high proportion of the hydroxylysinonorleucine Discussion crosslink typical of new collagen formation in By both crosslink analysis and by measurement scleroderma. There was also a second reduceable of aH-proline incorporation into hydroxyproline, component present in significant amounts but we have confirmed excess new collagen synthesis further studies will be required in order to in tile skin of a patient with AOL. These results identify its nature. are analogous to the findings in the skin in scleroderma (Laitinen el ol. I9fi9. Herbert ct til. Quantification of Collagen Synthesis 1974), and account for the thickening of the skin. Hydroxyproline is an amino acid (hat is unique It is possible that the effect is generalized, and to collagen and is formed from prolme. By grow excess collagen proliferation in the blood vessels ing tissue in a culture medium containing radio- could lead to chronic ischtemia with ulceration of active-labelled proline unci measuring the syn the fingertips and further local collagen produc thesis of hydroxyproline, an index of the rate of tion. lscha-mic necrosis could similarly occur in collagen formation can be obtained. We obtained AOL and so produce the typical bone lesions. JI,iijwgywJ ^ aJ1 tJ. wwwwyyBV1-weg ofAe L and itions r a d an \ide, cs jar c the move ed in ty or ined. ent of ted in the sis rably ment olinc, thesis esults in in et al. skin. , and csscls ion of oducur in sions. '^-csra.--- - njtrriiYfiiY- <"^i - t j--uj-.v-.J-ia > nrfhantiiU^i J9 Section ofOccupational Medicine 297 However, the AOL hone 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 arc of greater im portance in causing excess new collagen forma tion. In addition Johnson & Zilf (1974) reported that lymphokine from normal human donors can increase the rate of collagen synthesis. Several chemicals arc known to induce ab normal fibrosis. Practolol (Brown et al. 1974) can lead to peritoneal fibrosis. Methyscrgide can cause retroperitoneal fibrosis and ergotaminc can lead to peripheral ischtcmia 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 acro-osteolysis, and therefore as a further possible chemical cause of increased collagen synthesis. D-penicillainine is a useful agent in the treatment of scleroderma, but only when the disease is active and progressive, that is whilst the crosslinks arc labile and can be cleaved by the drug. When the collagen has matured, the crosslinks become stable and the drug is no longer effective (Herbert et al. 1974). It may be that D-penicillamine will be of value for treating AOL. but only for active disease. It is of fundamental interest to determine the manner by which vinyl chloride leads to excess collagen proliferation. This should lead to a better understanding of the processes of collagen synthesis and could well act as a useful model for the study of scleroderma. REFERENCES Bailey A J, Prach C M <& Fowler L J (1970) Biochemical Journal 117, 819 Brown P, Baddoiry H. Head A E, I)atic* J D A McGurry J 1477 Harm E D jr & Hohmson M S (1974) Journal oj Hiu-uttutrolony 1, Suppi 1. 149 Herbert C M, Lindbrrc K A, J jyson M I V & Bailey A J <I974)L/ui*f i, 187 Johnton RLd Zitt M 097-i) Journal ofRheumatology I, Suppi. 1,53 Laiunm O, Uitto J, JannukscU M & Musiakalho K K (1969) Annals ofClmlt ul Research 1,64 Leroy EC Journal of CUmt ol Investigation S4, 880 Dr Robin Walker ( Walton GeneralHospital. Liverpool, 9) spoke on the subject of Clinical Aspects of Vinyl Chloride Disease: Liver Epidemiological Studies Dr P .1 Baxter (Employment Medical Advisory Service, Health and Safety I. vocative, liaynards House, l Chepstow Place, London IV2 47"/') Epidemiological Studies of PVC Manufacturers and Eahricators, and Primary Angiosarcoma of the Liver The Joint Working Group on the Vinyi Chloride Code of Practice decided from the outset that epidemiological studies would be necessary to evaluale the extent of the risk to workers engaged in (he manufacture and fabrication of PVC. The Employment Medical Advisory Service (EMAS) proposed ihree studies: a prospecuve 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, MM 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 EC Manufacturers In the past, svorkers engaged in PVC" manufacture were exposed to vinyl chloride as a result of work ing inside autoclaves or from leaks occurring al various stages of the process. The main aim of this survey is to evaluate the effects of this exposure in terms of mortality and cancer registration rates according to certified causes by including all past workers at every factory manu facturing PVC in Great Britain. Present and future workers are also to be incorporated. Identification details oT ihe workers, including duration of employment and details of past exposure, arc entered by the factory personnel departments onto individual survey cards accord ing to instructions provided by EMAS. Past exposure bad been graded into high (f-200 parts/ 10'), medium (>2J parts'10'), and low (<25 parts/1 O'5), with `constant' and "intermittent' categories. The cards are updated annually and sent to fc'MAS headquarters. Under the new Code of Practice all present and future exposures will be 'low' Identification details of the workers are sent through EMAS to the National Health Service Central Registries in England and Wales, and Scotland. Death certificates for these persons Ww y yiutOjyjjgqtftyts*'Iw t1mct'spw J1 fftW"'"V C1**'**7" rmtTr iniufwa1 mfi A 298 Proc.roy. Soc. Med. Volume 69 April 1976 40 arc coded according to the International Classifi cation of Diseases (1967) by the Registrars General. Workers alive at the start of the survey arc flagged, a procedure which results in the coded death certificates being picked out and notified to EM AS at the lime of death. This procedure should result in an almost com plete follow up or workers. The total number of males and females identified as having worked in the manufacture of PVC is 7746 of whom only 84 (1 %) have not been traced, 72 (I %) have missing information, and 147 (2%) have emigrated. Workers entered into the present analysis number 7410, over half of whom arc current employees; 88% were exposed to `low' or `medium' con centrations, only 12% having worked in `high' concentrations; 46% had constant exposures. Statistical comparisons will be made between observed and expected deaths, calculated using the England and Wales sex-age-siandardized rules supplied by the Registrar General. PVC Fabricators Exposure to vinyl chloride during the manufac ture of the finished articles from raw PVC occurs as the vinyl chloride trapped in PVC synthesis is released during the further handling and process ing of the PVC. This survey aims to study the mortality and cancer registration rates for all causes in each sector of the industry and to deter mine whether these rates are related to vmvl chloride exposure. There arc at least seventeen different types of industry and twenty types of operation, and the size of the work staff varies from a handful to hundreds of men. Records of employment and exposures arc likely to be poor or nonexistent in some of the smaller factories and for this reason a sample will be taken of workers employed at, or near to, the present time, over a wide range of the industry, the names of the factories making up the sampling frame being provided by HM Factory Inspectorate and trade organizations. As many as 20 000 workers may be involved. The procedure for the follow up of workers and the analysis of the results will be similar to that described for the study of manu facturers. Retrospective Study ofAngiosarcoma The significance of cases of angiosarcoma of the liver occurring in vinyl chloride workers relalcs to the rarity or the tumour in the general popula tion. To assess its rarity and to look for any time trends, EMAS asked the Registrar General for England and Wales to collect all death certificates with a possible diagnosis of angiosarcoma of the liver between 1963 and 1973. The results of this study have been reported elsewhere (Baxter & Fox 1976) and showed that, on average, only 3 adull eases were certified a year in England and Wales. One case reported in 1972 had previously been employed as a PVC worker. (The only other angiosarcoma death in Great Britain known to have occurred in a PVC worker was in 1974. Both workers had been engaged on the manufac turing side.) The main aim of this study is to identify and verify all diagnosed eases of primary angiosarcoma of the liver occurring from 1974 onwards, and to evaluate their association with occupational exposure to vinyl chloride. From 1974 onwards, the Registrars' General Offices are sending all death certificates with an underlying cause of death stated as being iivcr cancer (including primary, secondary and unspecified categories) to EMAS headquarters, where diagnoses likely to be angiosarcoma are selected. Angiosarcomas arc also notified to F.MAS from cancer registries, hospital pathologists and hospnal discharges (Scotland only). A sample will be taken from amongst the other liver cancers, and for both these and the angiosarcoma eases the hospitals where they were treated will be contacted in order to request the loan of available histological material. Sections will be submitted for diagnosis to a panel of expert histopathologists w'nc will not know the history or identity of the eases. An estimate will (hen be made of how many angio sarcomas are misdiagnosed or miseemfied as other liver cancers. With the permission and assistance of the hospital consultants and genera) practitioners concerned, the next of kin of the deceased angiosarcoma cases will be traced and an interview requested with one of our Employ ment Nursing Advisers trained in interviewing techniques. The nurse will seek to obtain a full occupational history of the deceased. The controls, matched for age, sex and death register (locality), will be chosen from the other liver cancer deaths and also from dea'hs from all causes. Four liver cancer controls for each angiosarcoma case svill be randomly selected by EMAS. The controls of deaths from all causes will be selected by the Registrar General's Office from the same death register as an angiosarcoma ease. The next of kin of both sets of controls will be interviewed in an identical manner to the angiosarcoma eases. As far as possible the inter viewers will not know the cause of death of the deceased.. Finally, our Employment Medical Advisers svill investigate the places where the cases and controls worked and record details oT occupational exposure to vinyl chloride and other ^ nprt i"qimn )p.w jyjTHfgixixa.-T*. r IV1 '* 1 H1 " 11 tx V / */ Section ofOccupational Medicine 299 chemicals. They will also attempt to obtain photo copies of all hospital and genera) practitioner records for the verified cases of angiosarcoma. The verified eases of angiosarcoma will be entered into a register which will include occupa tional histories and the copies of the medical records, and an es'imalc of the true incidence of angiosarcoma will be obtained. Finally, the frequency of occupational exposure to vinyl chloride will be compared between the angio sarcoma cases and the controls. In conclusion, prospective and retrospective studies arc 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 lest 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 Weinhren (Department af Histapuihoiogy. Koval i'ostgruduute Mvdiral School, Du Cane Road, London 1172 OHS) lislopatliologv of Liver l esions Associated with l-.xposure to \'invl C hloride Monomer So far only 2 cases of angiosarcoma of the liver have been reported in British workers exposed to vinyl chloride monomer (Lee & Harry 1U74J hut more material has been studied in the United States by Bradford Block (197-1) and by Thomas el al. (1975). The lesions encountered in this last publication included 15 angiosarcomas and the structural changes are dearly presented by these authors. At the same lime, angiosarcomas have been described in Other circumstances, which included prolonged exposure to arsenical medica tion for psoriasis (Rcgelxon el til. 1968) arsenic toxicity in vineyard workers (Roth 1957) and after exposure to thorium dioxide lor arteriography (Visfeldt & 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 Bixttr P J & Foi A J (197$) Lancet li, 27-28 DISCUSSION Dr A J Fox {Employment Medical Advisory Service, London) 1 that in the prospective study of PVC manufacturers described by Dr Baxter great care had been taken to elucidate the role of (I) year or entry into the industry, (2) level of exposure as estimated by people who had worked in the individual plants. (3) length of exposure in the industry, and (4f 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, Carshalton) said that in the retrospective epidemiological study re viewed by Dr Baxter vinyl chloride workers were divided according to exposure time and level of ex posure. Flow could data be obtained on the level of exposure of a worker who had had twenty years' ex posure? In the German literature there were many cases of splenomegaly, fibrosis of the liver, and thrombo cytopenia. Dr Magos was surprised that no similar cases had been reported from the UK during the meeting. Fig I Angiosarcoma showing diluted sinusoidal spaces containing red blood cells and lined b v tumour ceils, H & E. x ISO j*. R&S 026667 fwft* w "*"fMWfiimfiMi*rr,wraiite 300 Proc. roy, Soc. Med. Volume 69 April 1976 42 \tr h v- v**'<; ' 'VT .- .3* 'I a f - 1 v^. * ^ & V. * a*v *j ^ yy H-v v a -r- ? *r ' . ^ 1 ' >> a W 'A**'-?"" Fig 2 Pupillaryformuhons ofHonour cells ore borne on a core ofconnective tissue and hepalocytes. II d E. x600 ' %* > .* *4t v'w tT-j*r*^Y7 /4 3^ Fig 4 Bizarre Riant tumour cell in papillary angio sarcoma H <C h\ 6dd efr' part agreed by these various workers and I pro pose to outline them, I shall also brielly discuss some of the oilier changes which have been noted in the livers of patients suffering from angio sarcoma and those of patients who had been #s it '/ *y* v exposed to vinyl chloride monomer but did not show evidence of the development of tumours. The tumour contists oT cells which vary con siderably in appearance but seem to have enough common features, particularly in their mode oT growth, relationship to vascular spaces and stromal changes, to support the view that they arc derived essentially from one cell type. In general the tumours show a gross appearance of dark haemorrhagic nodules in the liver; there is a variable distortion and apparent fibrosis in the intervening liver tissue. Sometimes foci are inacroscopically less hicmorrhagic. There is often frank necrosis. * 'V* Fig 3 Welbdtfferentiatedflattened tumour cells, resembling endothelial cells on connective tissue cores and lining vascular spaces, H & L. >. 400 The microscopical appearances at firs! glance arc variable, but analysis suggests a consistency. Thomas cl at. (1975) have delineated 3 main types depending really on the relationship of the tumour ' cells to- the vascular spaces: (1) The sinusoidal pattern, in which dilated hepatic sinusoids are lined by enlarged and proliferating tumour cells, R&S 026668 42 Rk J-i I prod iscuss i noted t angio- been fid not art. By con- inough iode oT and At they farancc Shore is 3 in the <ti are often f glance Atency. > types mour1 oidal as are cells, 43 Section of Occnpiintmul Methane 301 ( a V tSrt'G&$z'**Sp& * C i. "1 1 'h ?'$ a 'S'* i1. - -s --- p\ * " C >*, r i ^'7 /' P', T- `V' ?{? \ fc;rl V V O'. v. *<> , Vt- l\\ U w' -v.a vi .l^ -r-*- c-Vr j^j * -*1* ' * V t-.-r; .< #' ; j t hepatocyles, resentbles cells normally associated wuh vessel walls anil appears lo be closely related to vascular spaces wuh variable degrees of abnormality. There arc changes in other elements, both in tumour-bearing regions and in pans of the liver which appear to be free of tumour I hese changes seem to involve mostly the supporting siroma. In the regions of the tumour, the pensmusoidal rctieulm fibres are prominent, obviously in creased and appear to run between the tumourbearing sinusoid ant! the hepaloeyte plate, apparently causing rctieulm increase in the space of Disse. which esists bcuveen liver cell tint! normal sinusoidal wall. The alteration saries from a minor inconspicuous (as the authors abroad pul it) increase in retieulm fibres which may not be seen without the use of special slams (and in I'aet, both special stains and special optica! mana'uvres may he employed to highlight this change) to massive increase of collagen nitres which surround the hepaloeyte plates, clearly obstructing the lumen, sometimes apparently cm- V ** + . T A *...**>." *. rr-"iof jSTe-b* -lv Fig 5 Solidutett nf tumour rcu'tnhlni'C to/it/ spmtlle-ccll sarcoma, tl <t L, 400 with hepaloeyte plates clearly recognizable between the tumour cells. This appearance is found most often (l"ig I). (2) The second most common is termed the papillary type, in which papillary formations of tumour cells arc borne on a core oT connective tissue, which may include recognizable surviving hepatocyles, often with canaliculi containing inspissated bile pigment (Fig 2). (3) The cavernous type, in which the blood-filled spaces appear even larger and are surrounded by thief fibrous walls which seem to be lined by the tumour cells. In addition there arc several variables The tumour cells may be welldillerentiated in that they simulate endothelial cells oT 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 anti giant-cell forms (Fig 4). They may also present as solid bos-like polygonal cells, suggesting an appearance similar to carci noid or epithelial tumour cells. The helpful diagnostic feature may well be the eluse relation ship to hepaloeyte plates 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 spmtlle-eell sarcoma, without evidence in many foci of vascular spaces rl-ig 5), In sum, the tumour eel! is distinguishable from 6$ /? : -vV ' v** " * -r--vSc' V-f 1v : * V*s y by- . >. -V 'it fV-* > ' ;S rK:\;' \ ' -> _/ ^. * * < *- * i\ * 1 > - ^-r z C-* .-tg / I ' ^ f ft - .f*f c,* ^ ... * A - . if* . s ' m^ ^ > # ^ < * ^ * o * i' T ^ 4 , ' * , A fc`r ^ -v.= ^ J?r: ' Fit; ^ / throw J\mh njh'il u///f ohhii'ijtip/i of \tnusouis and dt Mtppcamm c tn an aph v of iicpaloi \ /*<> irt iinpiozurco/na Ii<i L. 150 302 Proc. roy. Soc. Med. Volume 69 April 1976 44 R&S 026670 trapping single hepatocytcs, and sometimes with no hepatocytes appearing to survive (t ig CO. It is, of course, not clear whether the fibrosis precedes hepatocytc loss or not, but appearances suggest that it does. Such hepatocytc survival occurs even in the middle of very poorly dilferentiated tumour, a phenomenon which is quite unusual in the case of other tumours. : .. ' 'fit. \ *<: \V V -A, 'j Remote from the tumour-bearing areas, such pcrisinusoidal rcticulin increase is recogiu/ed and again it varies from the minor inconspicuous form to quite striking librosis (Fig 7). There is also conspicuous fibrosis in portal tracts with a patchy, sometimes niarked, peri vascular and periductal fibrosis. The venous lumina which are thought sometimes to be com promised in other forms of fibrosis, such as the Indian 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 - 'A(, ? / tf \ .. 1 ` r .K " "* \ '^Vi 1 i n/w* ' ' 4 ^1 & .. - sc*7: **rv. ..o Fig 8 Hepatic cup\i`Lir fihrouiin pattern rA/wirif to vinyl chloride monomer and pre\enune *ith purml hipcrren.uon. II 15- - 150 > < repeatedly observed in the cases lrom the United States and tins seems sometimes to be continuous with the fibrosis in the portal tracts. suni* ~ \- 3 " \ 7J { t,,m ' r'jti'ir- ii1*^^' ^ Fig 7 Liver biopsy section* shoumg variations m intralobular sinusoidal rctiruhn. Upper, slight increase. Lower, much increase. Ciordon .S'wivr silver impregnation' Dark-ground illumination. < 360 The relevance of such nontumouruus changes to the subsequent development of angiosarcoma is of course one of the major practical issues til present. Such changes arc sometimes found in the livers of workers exposed 10 s ins I chloride monomer and sse hase had an opportunity to see sections refetred by several clinicians concerned with this problem, including Or I- l.ce. Dr Robin Walker, and Dr f F II 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 ami exposed patients base quite a content of fat and that several of the exposed personnel do show sinusoidal thickening, difficult to make out, but easier in dark-ground preparations One particu lar Case, which I hope Dr Frank Lee will report, presented with portal Inpertenston and had quite striking capsular thickening, diffuse sinusoidal rcticulin increase, hypertrophy and possibly hyperplasia of endothelial cells, and what seems 44 % -------...-..`z*: a .:--.-.f.,.^.r,.t., .asaw fry i-Hi-rtV1*iftt 45 Section ofOecuptthontil Afcdmnc 303 r <* ^ ^ `i aV'ir*' > J, i-.sG - >i / o- - -x a `S * - --* , -1 . > '! I)r llenry Falk [Cancer and Ihrih Defects Division. Hitreoti of Upidemaday l, ( enter for Disease C ontrol. United States Palilir Health Sena e. Department at Health, Indication. and W'elfare. Atlanta, Cietncta JO.IJJ, USA) and Mr Richard ,J Maxweiler (Division at t it-UtStudies and ( tmieal Invcstieotions. Xarinnal In ,male fur Occupational Safely amt Health. Center jar Disease Control, United States 1`nhhr Health Service. Department of Health, Inlncarion. and If el/are, US Post Office llnddniy. Cincinnati, Ohio 45202. USA) jLt,sr Gx3 i :- -...'* ' I p, '... ; : *** - rfa ;_r-> .* Fig 9 Beurre and enlarged tinuuiulal lining cclt\ tnnl hcpatocvlc mitotic abnormality in ionic flatten! a\ Fig 8. // c< . >:6K) i to be striking hcpatocytc involvement, even with mitotic abnormalities (Figs 8-9). The question whether these lesions are signifi cant as premalignant changes is unanswered, as many of the alterations can he found in oilier conditions such as congestive cardiac failure, endothelial cell hyperplasia in cases of lymphoma, and or hcpatocytc 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 invoked in the formation of the tumour, what is responsible for the curious fibrosis and survival of the hepatoeytes. Understanding these processes would probably enable us to make a better assessment of individual risk factors and perhaps to work out whether there is a tolerable exposure. REFERENCES Baktr M De C, P*;el G E & Davson J (1950) Journal of Puthv/ony and t ifnotcuy 72, 173-182 Block j n (1974) Journal of(he American Ma/mot A nacuuton 229, 53 -54 Boyrr J L., Sen Gupl* K P, Biswas i> K, Pal N C, llasu M allttk K C, IbtT FLA Basii A K (1967) innuts ofinicrmd Sledu me 6t>, 41-67 LteFIft Harry OS (1974) Lancet i. 1310 Kfgfluyn VV', Kirr, V, Oxpina J A 1 (olland J F (\96H) Canctr {Philadelphia) 21, 514-322 RothF (1957) 7.titschri/tfur Kreh\fonchut\K 61,468-503 Tbomii L R, H, llcrk I* I), ScItkoH I J A Falk H (1975) iVfH* F.mihind Journal of Medicine 292, 17*22 Vj*(eld( J A 1'oulson M (1972) Ado Pulholomt a ct Mlrrohiohyu'd Sctindminn'u Section A hU, 97-108 Fpidemiological Studies of Vinyl Chloride I lealth effects in the United Stales The vinyl chloride tVC) problem has had a con siderable impact in the United States during the past year and a half. I'erhaps 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 eases of VC-induced hepatic angiosarcoma 11 IAS); at the present lime there have been 17 known eases in polymerization workers (Hind 1975). The finding of the initial eases was a dramatic eseni. and unlike what has occurred with many other prosen or suspect carcinogens, the confirmatory experimental evi dence arrived almost simultaneously with the epidemiologic results iMaltom dk l.cfemine 1974). The widespread industrial applications and uses by the consumer were instantly appreciated, and since the VC problem a No arrived at a lime of growing awareness and concern among workers and consumers about environmental and occupa tional hazards, il 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 id. 1974, labs el al. 1975). and. in addition to iivis. the earliest mortality studies (Monson et al, 1974. Tabershaw dk Galley 1974) suggesied increased rates for nonhcpalic tumours, parallelling the multiplicity of tumour types seen in experimental studies (Maltoni dk l.efemmc 1974). Review of records at the Connecticut Tumor Registry, started in 1955. 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 case where the diagnosis was uncertain after review of slidesl occurred in workers at two polyvinyl chloride ll'VC) fabricat ing plants or in residents liv mg nearby (Landrigan & Heath 1976). Further concern was generated by BW*z,s*W|ir" 1t 304 Proc. roy. Sac. Med. Volume 6') April 1976 46 reports of the potential carcinogenicity oT chemi Table 2 cals structurally related id VC, c.g, chlomprcne {Lloyd ('/at. 1975) and trichloroethylene (National llvpjlir anc<o\arroutj m ihv CllUrd .Stairs hy icr at di*atk jind <vr\ , |966 *1973 Cancer Institute 1975, unpublished dutai. and hy As? of <irnth the knowledge that VC' workers in many instances iyeun) Mule female Tutu1 have been exposed 10 multiple related chemicals, including vinylidenc chloride and acrylonitrile (vinyl cyanide). As part of the United Stales Public Health Service response to the VC problem, the National Institute of Occupational Safety and Health 0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 HO - 22 4 I1 2 11 2 54 9 12 9 13 2 15 5 5 10 11 3 14 I2 3 (NIOSII) and the bureau of I'.pidemiology, 46 22 68 Center for Disease Control (CDO. base worked on a number oT VC-related epidemiologic projects during the past year and a half; m this paper we % hrom dcjrh temfiwJicA, ICD Code 197 8 (Rth Revision). L>4U for New/York ily no< included will briefly review some of the early results of three of these studies. There was approximately 1 case of HAS for 2 every 300 death certificates reviewed. 1 HAS Surveillance Table 2 demonstrates a male to female ratio of A death certificate search for all cases of HAS 2.1 for HAS, Sixty-two percent of cases occurred I recorded under ICD Code 197 X (Nth Revision), in the group aged 50 or moo-, with 26",, in the which encompasses various miscellaneous forms 30-49 year age group Non-angio hepatic of liver tumour including most cases of HAS. was sarcomas ditfcrctl m having a male to female ratio undertaken by CDC for the years l%fi-73 in the of only l;l, and an altered age grouping with United Slates. This search is almost completed, TV,, of cases aged 50 or mote and only 9 in the with only data Tor New York City not yet 30-49 year age group. These dilfercnces are con available at the time of this review. sistent with a hypothesis that occupational ex posure may be a more significant factor in the Tabic I shows the number of cases of HAS and causation of HAS than of non-angio hepatic non-angio hepatic sarcomas by year of death for sarcoma. 1966-73; there is no evidence lot an increase in the incidence of these malignancies during this Only 2 of the patients vvitb HAS m the ucath period. certificate review were recorded as having worked in PVC or plastics plants II PVC polymerization A review of the relative occurrence of hepatic worker a.ul I accountant in a I'VC fabrication sarcomas recorded under ICD Code 197. S plant); both were cases which had been identified showed angiosarcoma to be the largest group prior to this study. N'o other occupation is (35"' of total hepatic sarcomas), followed by recorded more than twice except for the occur sarcoma of unspcctltcd type (3I",,). leiomyo rence of 5 primers. Although all were subsequently sarcoma (12,,), fibrosarcoma |7",,). and a conltrmed as printers, a preliminary review of grouping of miscellaneous sarcomas 115",',), pathology records and specimens suggests that 4 of the 5 e.tses may have been incorrectly diag Table / nosed as HAS. /< Htputic v'lroHii.i ia (lid L'niU'd Sl.ilrs# !jv r<'p<irU'<! hi*tolJUV snd w.ir of diulh, 1966 -197 \ Year u) chath !%6 1967 1968 1969 1970 1971 |97:| 1973 ah {!* mu 31 41) 23 14 31 2\ 9 25 .-friviowromfl 9 13 9 7 IS 5 1 9 sun Ditin A2 :? 14 7 16 18 8 16 196 68 128 # front Je.nh ocnit'u-.iicv IC'D Code 197,8 (Hi h Re Dju from New > i>rk Cm> mu included Hjlf year sample CDC has supplemented the death certificate survey with an intensive case-finding efTort. including a national mailing to ail 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 19(>-4-7-t. At the present time approximately 240 cases have been identified. 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 Section of Occupational Medicine 305 past occupations, toxic exposures, and places of residence is underway. Table J Lung; cancer anutnc <*otktrs 4l FVC pnlvnu-rifftlion plant* m (hr United Suit* by IttMoloc'C Snd r*n*m til \ C` exposure Medical Screening of IT It'orders 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 ax well as one of the oldest PVC polymerization plants in the United States. Included in the study were approximately 130 current PVC polymerization workers and a similar number of control workers from the tyre plant who had never worked in the polymeriza tion facility. The 2 groups were comparahle 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 oT the results shows no significant differences between the 2 groups for any of the 6 liscr function tests performed (SOOT, bilirubin, alkaline phosphatase, LDH, GGTP, and ornithine carbamy! transferase). Additional analyses based on levels of VC exposure, duration and type of job, and other subgroupings are being done; these preliminary results however do not suggest the occurrence of liver function abnormalities on a broad scale 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 PVC plants. It is also important to rcaliz.e that since liver function tests are rela tively insensitive to the early finding of VCinduced hepatic disease (i.c. 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 eases 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 Stntlv at Four F VC Polymerisation Plants One of the results of this NIOSH-CDC study was the demonstration of an increased SMR for respiratory system cancer among members of the cohort (Waxweiler a ah 197b). On preliminary pathologic review, it was also noted that of the 12 lung cancer cases all 8 for which pathologic specimens were available were either large cell undifferentiated or adenocarcinoma of the lung; Latent of VC expmure //jwt>A;irr type Stone Lpidcrraoid 1 Small cell uml'llercntialfd 0 Adenocafkinomj 1 LJrne cell imdilicreniidted Uncl-iiMlied 4 1 Lest than tine year 1 3 1 U 0 Alure than one year 0 0 4 6 0 Tat 2 3 6 10 1 75 10 22 if confirmed, this unusual cell type distribution may support the association between 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 not part of the defined VC-cxpoxcd cohort, a total of 22 cases of lung cancer (out of 4S) were available for pathologic review. The increased incidence of large cell undifferentiated and adenocarcinoma of the lung was seen in VC workers with more than I year of exposure, while a distribution more closely resembling the ex pected small cell predominance was seen for VC workers with less than 1 year of exposure. Interestingly, however, cases of lung cancer in non-VC workers at these plants, although small in number, appeared to have a cell type distribu tion which vvas also predominantly large cell undilferentiaied (Table 3l. In addition, unlike the situation for HAS in these plants where all hut 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 dill'erent job categories As a result, eases of lung cancer seem not to correlate as lightly with VC exposure as cases of HAS and n is conceivable therefore that some additional chemical exposure at these plants may be working together with VC (or even separately) to produce this ctlccl. further studies arc currently underway in an effort to confirm these preliminary pathologic findings. Kr.FEKK.MCCS I1 J X, Hvjth C W jr (JV76I (in prtTMrat LJj* H, Anticr\t>n 'utbolstm \V J. Dyum S, frt*cbhein A S A Sclikolf I ./ (trS7f) .ht'itii\ of (he Ai'h* ) ark AuiJerny of Si 246. 22 J \V(!9?5) Journal of Occupoaona} Sfedtcme 17,333 R&S 026673 306 Proc. roy. Soc. Med, Volume 69 April 1976 48 Lloyd J YV, Ortoulle P A Moure K M (1975) Journal nf OfCupiitiaruil Afniit inr 17, J6.I Makk 1,, Cfi'fth ,) |, |f, Win I.in ,| (t \r Ji .lulmnn \] V (|9?4) Jtmrtutl nf{hr Ar'ifrn nn Mniu at A it<>< inimn 230, (4 Malioni C` A l.flrnuiK- (/ (1974) I tniroHwrntiil Hfifarfh 7, 3H7 Monwin K K, IVlfrt J M A .lulimon M .N (1974) ijtm ft u, V)1 Tahenhiw I It A (Utley W It (Journal of (it rufnUtonot ,VfJo < 16, 509 Waxttfilrr It .1, Scnnctf VV, -lonrt J, Wacnnrr J K, k?lk I ( A. Carter C(l97f>) Anruiii u/ {tic AV*` York AiaJemyn/ Sriencrj (in prcis) DISCUSSION Dr Mitchell K Zavon (Baton Houee, Lomuanu) asked whether the clinical examiners at Pottstown knew whether or not the person being examined worked in vinyl chloride. Dr li Falk replied that none of the clinical examiners were aware of the occupational status of the worker at the time of the examination. Dr R I McCallum (Utueeruty of S'eweaule itpon T\ne) 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. Wax this done b> one individual or by a panel of pathologistsHow were the specimens of tissue obtained: b> biopsy, surgical resection or ai autopsy? U was remarkable that in none of the eases was an oat cell carcinoma diagnosed, as this was the type often considered a characteristic result of exposure to a chemical carcinogen. Dr H Falk replied that the WHO lung cancer classifica tion scheme of Kreyberg (1907) was used, hour patho logists reviewed the slides and agiccd on the inter* pretation (Dr Louis li Thomas and Dr T Powell. National Institutes of Health; Dr M Kuschner, State University of New York; and Dr Las/lu Makk, St Anthony Hospital, Louisville, Kentucky). All avail able pathological material for cadi case was rev icwcd The expanded pathological review currently under way would include the selection of multiple control cases oT lung cancer from the same hospitals (w uh simi lar age and date of diagnosis to the study cases) and a blind review by a panel of pathologists i.; a more detailed evaluation of available pathology material. To Dr Falk's knowledge large cell undifferentiated carcinoma of the lung had not been related to exposure to chemical carcinogens, which made the findings m the VC cohort even more intriguing. Dr A J Fox (Employment .\fcdivul Advisory Set vice. London) asked how many factories had been studied individually in the US*\, What proportion of these had indicated vinyl-chlornJe-jssociated disease? NIOSH-CDC study, the Tahershaw study, ami the Monson-Peters studsI had all looked at the Louisville. Kentucky plant where the mural angiosarcoma cases occurred as well as at a varying number of additional plants. Compounding the prnhlcm 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 Donnell (Centra! lilectnnlv Gena atim* Board) asked whether, since vinyl chloride monomer was a carcinogenic agent, thc/e was any evidence in experi mental amrnaK or m human clinical experience that the skeletal or skm changes described might be premalig..nnt conditions, Dr 11 Falk said that cases of angiosarcoma in the USA did not have a history of ucro-oMeolysis or skm problems, although they did not h, \e the multiple tests for early changes of aero-osteolysis. It would seem, therefore, that the skm changes were not premahgnant conditions. Professor I .1 Sclikofl (Mount Sinai School of Medicine* Cite Uniu-tutv of XV iv Fo'A) said that a review of known details of identified cases of vm\I-chlorideassou.itcd angiosarcoma of the liver hv Dr Lloyd (I97sj of the National Institute lor (Aeupauon.il S.ifetv and Health had demonstrated that the median duration from onset of exposure was approximately seventeen years. `1 hese ca-ww were derived from the ralhei small number of pi*l> met i/nhon workers emploved during the establishment and initial growth of the vinyl chloride industry Attempts weio underway to identify and tiacc the initial gioups of workers, employed during the years I'HX 55. since analysis of their experience would allow evaluation of the risks which might be sintered by the very much larger gioup of v my! chloride wot kers exposed more recently, in a period during which PVC production was in creasing at the rate of approximately 10"l( per annum. Limned data bearing on the problem had been obtained In one polymenzatum process studied. 257 men had been employed for live veins or more in the period between I'>46, when the plum opened, and I9n4. T.ach man had been traced to I July 1974. with 25 deaths fiom all causes: 5 of the deaths were due to angiosarcoma ol the liver ( Nicholson et a! 1975). each Conti?med on review of autopsy material (Thomas & Popper 1975); m addition there was one death due to ruptured t esophageal varices, Another worker, examined during the cluneal survey at this facility (Lihs et ai 1975) had had a succc.sslul portacaval shunt operation for the same condition These experi ences suggested that v my I-chlonde-associated disease would be an important hazard lor vinyl chloride workers m the future, unless control of exposure resulted in at least some reversal of the risk Dr H Falk replied that cases of hepatic angiosarcoma had been seen at 5 of the 8 PVC polymerization plants opened prior to 1950. There was some confusion in this area in that a number of the VC worker morulas studies had been overlapping Three separate .studies, for example, (the Lillis H, vnili-r11, Nti W ,). Ojikii ,S, hist lilum \ S A St likfil! | ) llly?lil i<f m,* \,M. York -IcV`>r'ifi' nt ifm i*> 246. 22-41 lio'dJW I I 97 V ) Ji.i, riti.1 'if (J< i uf>iihnniit ./<* 1 7. til-334 Nit ln>lHi.ii \V ,I,| i.iniiiM'iiil k ( \ ,N IJ \ Sfia.1,11 I ) I ! 9 / 5 , fin ;/> lit inf V, i. ) ,11 ,y /,; i1 of n n\ (246, 22 X Z Ji) t Iii.mjM 1. 11 A l'up|>. r 1 { < 1 '*75l Annjh i>] ;hf Sf . ) ink ic,ij,'iiiy n/'Xt ifru >`j 246, 26X-277 R&S 026674 sr 0 . 0 49 Section of Occupational Methane 307 Dr inv Duck (Occupational Health Unit, UP Research Centre. Sunbury on Thames, 7 1(7(5 7l,N) Medical Surveillance of Vinyl Chloride Workers Following the announcement in January l`J74 of the first cases of angiosarcoma of liver among workers exposed to sinyl 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 engageJ in the production of vinyl chloride (VC) and polyvinyl chloride (PVC), was to review all the relevant medical and toxicological information available and decide what action should be utken to protect the health oTexposed employees. This is an interim report on one aspect of the group s work. At that time, little was known about angio sarcoma of the liver and its treatment. Due to its rarity, there was considerable doubt about both its natural history and appropriate methods of early diagnosis. Reports indicated that nonmalignam 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-ostcolvsis (AOL) and its various manifesta tions, since it was speculated that there might be some common underlying vascular pathology. To complicate the situation still further, long term carcinogenicity tests on laboratory animals had not only produced many angiosarcomas, but also a considerable number of renal and other tumours. The situation was discussed with medical col leagues in Government and Trade Union agencies, and specialists in liver disease, and much helpful advice was received from them and front various overseas sources, especially from doctors hi the United States. It soon became apparent, however, that there was no established procedure for the early detection of liver angiosarcoma that could serve as a basis for a large-scale screening pro gramme in industry. As practical screening possibilities were very limited and the 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 he beneficial lo indi viduals in terms of preventive medical action. In the laller contest, ellort had to he concentrated on urgent measures lo reduce exposure to vinyl chloride, a lask which was being energetically tackled by our technical colleagues. Nevertheless, there were many arguments m favour of inviting vinyl chloride workers to attend sue medical centres to participate in a standard medical examination programme: (1) Opportunity for personal discussion, (2) l.slahlish prevalence of disease (31 llsiablish prevalence and significance of liver dysfunction. (4) Correlate positive findings. (5) Identify possibly susceptible individuals. <(>) Compare findings in VC workers and c rntrols. Of 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 I'VC were produced, based as far as possible on the application of standard pro cedures to boih vmyl 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 mam objectives was to gather clinical arid epidemiological data to provide a reasonable foundation for future decisions concerning regular meuieal surveillance. The survey population was divided as lollows: Vinyl cnlonde workers Group I - all autoclave tloor workers, vinyl chloride monomer (VCM) production workers with live or more years service; Group 2 - vinyl chloride monomer pro duction workers with less than five years' service, all other VCM/I'VC production workers. Controls - workers from same sues with no history of VC, exposure. . A standard medical examination procedure was adopted' Initial examination comprising medical history (questionnaire), physical examina tion. biochemical tests (SCOT. SGl'T, GGTP, alkaline phosphatase, bilirubin), plaielei count, urinalysis Follow up of abnormal findings, with repeat biochemical tests, and platelet count, and persisting abnormalities referred to consultant lor 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. |i was also explained that any individuals with suspicious undines, notably persistently abnormal test results, would be referred for appropriate specialist investigation by arrangement with their family doctors Due to a variety of reasons, not least the prob lem of interpreting the significance of borderline 3 k R&S 026676 308 /'roc. roy. Soc. Meet. Volume 6 V April 1976 50 , abnormalities and workload difficulties ex perienced by both medical advisers on sites and consultants and laboratory stalT in' National Health Service hospitals, the programme has taken longer than expected and is still incomplete. Hence interim findings only can be presented at this stage and no firm conclusions can be drawn until all the facts have been elicited and the mass of data obtained has been appropriately analysed. So far, 1357 vinyl chloride workers and -129 controls have been examined. The examinations of vinyl chloride workers include 882 from Group 1 (representing an average response rate of 80%) and 475 from Group 2 (in which the pro portion volunteering for examination is lower). Initial liver function test abnormalities have been found in 12.5% of the vinyl chloride workers and 16.5% of the controls. Repeat tests on vinyl chloride workers with abnormal findings have revealed persistent abnormalities in about onethird of the individuals concerned (56 men, 4.1 % of the original group). No comparable data for the controls can be presented at this stage The 56 vinyl chloride workers with persistently abnormal liver function test results have been referred to consultants at local NHS hospitals for further investigation. These investigations have not revealed any cases of angiosarcoma and the consultants concerned have already attributed many of the persistent abnormalities to patho logical conditions unrelated to vinyl chloride exposure. At present, the causes of liver dysfunc tion remain uncertain in about one third of these 56 cases, where precise diagnosis rests largely on the final conclusions reached by expert patho logists who are studying relevant liver biopsy specimens. To put these interim results in per spective, it should be noted that almost all the men in the latter group remain in full employment, although many of them have been transferred to work involving no further exposure to vinyl chloride in case their liver dysfunction renders them unduly susceptible to potentially hepatotoxic agents. While this survey was in progress, previously established procedures for the detection or AOL and related conditions among vinyl chlorideworkers remained in force and 2 new cases of AOL have been diagnosed. The survey provided an opportunity to assess the prevalence of Raynaud's phenomenon among controls on three sites and comparisons with findings in vinyl chloride workers suggest that the condition may be equally prevalent in the two groups. However, no standard diagnostic criteria were applied and the prevalence of the vonduion varied widely between sites. No association has been observed between Raynaud's phenomenon and liver function abnormalities m individuals, which is of interest in view of the apparent rarity of AOL in the cases of liver angiosarcoma that have been reported in the literature. The routine urinalyses have revealed no relevant abnormalities. Tcntuti\e Conchi'.ion:; Abnormal liver function test findings were relatively common in both vinyl chloride workers (12.5%) and controls (16.5",',) even though results had to fall well outside (2 or 3 standard deviations) the normal range m order to be classified as abnormal. Repeat testing revealed persistent abnormalities in one third of the vinyl chljridc workers in whom the initial findings were abnormal and these 56 men were referred for further investigation. Comparable data for the controls are at present unavailable. If less stringent criteria of abnormality had been adopted, the number of individuals for retesting would have been considerably greater and the cllect this might have had on specialist investigation and disease detection is a matter for conjecture. The definition of abnormality is critical in this context and merits further con sideration and study if the correct balance is to be achieved. In view of the findings to date, it is not sur prising that opinions of working group members about the value of periodic liver function tests in vinyl chloride workers are divided. No obvious liver disease due to vinyl chloride exposure has been identified so far, but evidence of noneirrhouc fibrosis has been found in some cases and until the results of blind interpretation of the liver biopsy specimens become available no firm opinions can be expressed about the presence or absence of any specific pathology related to vinyl chloride in the survey population. The procedure has enabled individuals with persistent liver dysfunction to be detected and removed from exposure to vinyl chloride, and some doctors propose to continue regular liver function tests for this and other reasons, such as the need to assess sequential changes. On other sites, the yield of significant clinical findings has been so low in comparison with all the dilfieulties en countered that it is considered liver function tests should only be applied on a discretionary basis in future. In this connexion, it is argued that, in order to be effective,.the tests used should: (a) yield positive findings at an early stage or disease; (b) produce few false positive and negative results, and (r) ideally, be able to differentiate between pathological conditions due to vinyl chloride and those due to other causes, such as alcohol. It is also argued that continued application of a battery of tests to vinyl chloride workers is likely to cause considerable alarm and disquiet if the s y 51 Seaion ofOccupational Medhaie 309 results serve only to raise further doubt and eonfusion. At the present lime, it appears that detec tion of structural rather than functional changes in the liver is likely to be more rewarding for screening purposes, and for this reason attention is now being focused on evaluation of grey-scale ultrasonography as an acceptable, nomnvasivc technique for the periodic examination of vinyl vinyl monomer pollution had decreased rapidly over the past few years (as in the plant described by Mr A W Barnes) and data on those employed in a factory where (as in Dr Anne Walker's cases) even in recent years acute narcotic episodes had occurred This lack of distinction might completely distort Dr Duck's statistical evaluation of clinical data obtained during the survey. chloride workers. In conclusion, although the survey is in complete, it has already yielded information of value for planning purposes, as originally intended. From now on, it seems advisable to concentrate effort on smaller and more detailed studies that arc designed especially to evaluate Dr II W Duck replied that Dr Magos' point was well taken. However, as explained jn the text, the paper presented interim findings from which no firm con clusions could be drawn. When all the data were complete it was envisaged that the industrial doctors and their consultant colleagues would publish the results obtained from mdtsidu.il factories Specific hypotheses, particularly in view of the fact that the stringent environmental standards now in force arc expected to minimize, if not eliminate, any risks to health associated with exposure to vinyl chloride. Mr H F Henning (Health anil Safety executive, 403-405 Etlnwaie Road, London i\W36LH) DISCUSSION Dr A John Robertson (Liverpool) asked what wa, done for those whose tests, under the surveillance scheme, were abnormal. A man had been mentioned who was refused life insurance because of abnormal liver func tion tests. Taking a parallel with lead, a man could be suspended because of a raised blood lead level, and could then be refused industrial compensation Because he did not have a scheduled disease, and yet the em ployer would not pay his wages. Dr B VV 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 Environmental Monitoring It is a common misconception that environmental monitoring is easy, just a matter oT 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 substantia] lightening 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 write a Code of Practice before the event, and therclorc without the benefit ot experi ence or hindsight, there are many more questions. Some of these are discussed in this paper. cerned decided whether removal from vinyl chloride work was indicated and the men in question were Instrumental Tcchnh/nes advised accordingly. It was then left to the men to When the threshold limit value (TLA') for vinyl decide whether to accept or reject this advice. To date, only One man had rejected such medical advice and the rest had been transferred to alternative work with no loss of pay. chloride monomer (VCM) was 200 parts/10", that is before 1974, the instrumentation used for monitoring vvas relatively fairly crude and in sensitive. One common instrument had a lower Dr Robert Murray (Sudbury) said that this was a very response at about 200 pans'10" so that a ml real problem which it was proposed to deal with in the reading was taken to indicate a concentration Employment Protection Bill currently under discussion below 200 parts/10", a very convenient situation in Parliament. This would give to a man laid off for preventive reasons, because he showed early signs of absorption, the right to full wages during the period of lay-off. The more sensitive the methods of early diagnosis or the more stringent the standards of exposure, the greater would be the need to have somesystem to cover the no man's land between absorption which was not compcnsatablc and disease which was. In large organizations it was usually easy to transfer Even the chemical indicator tubes were not designed to show concentrations below 100 parts/ 10". With the introduction in early 1974 of the new standard of 25 parts/10* (time weighted average) and 50 pans/10"" (ceiling value) other existing instrumental techniques had to be adopted for use in the VCM atmospheres. Unfortunately some the individual, without loss of money, to alternative of the equipment which had been designed for work not involving exposure, but in smaller industries laboratory use was not flume proof and so could this might be difficult or impossible. not be installed directly in factory workplaces. k L Magos (MRC Toxtcolopy Urtil. Carshallon) said that in Dr Duck's paper no distinction was made between data on workers from a factory where poly However, many oT the difficulties were overcome and all the VCM and PVC manufacturing plants have now installed what we originally called XWj'isiw mu mas---r - - 310 Proe. roy. Soe. Med. I 'olumc t>9 April 1976 52 R &S 026678 i r i>taiagMaBfftirr"mwrtilliwif continuous monitoring but which is more that any operator is necessarily exposed to such correctly termed imtomtilic sequential lived point peaks or to such a raised average, since many of sampling. This is supplemented where necessary the peaks mas have occurred in specially Selected by short-term sampling for investigations or for areas where no person works regularly or the checks on equipment and by long-term personal oper.uot may have known about the situation and sampling to show the work people's actual worn a respirator during that period. exposure over long periods, c g. four or eight hours. Influence ofSampling [5 equatey The frequency of sampling can also have an in Pres entaHon of Results fluence on the picture. Uel us assume that some The Code of Practice requires the results to be of the sampling points have been chosen to pick available to the workforce and for summaries to up leaks from the plant so that, say, 10"' of the be posted in work rooms. Each lived point readings are above the ceiling value of 50 parts/ monitoring system takes u sample once per 10s. In a multi-point monitoring system sampling minute and therefore provides nearly 500 readings every minute this means that 4,5 readings per per shift so that trying to decide beforehand how shift for that system alone will be above the the results should be summarized and presented ceiling value. Sampling at the minimum frequency was a major problem because there was little required by the Code of Practice, i.e. once per previous experience of monitoring, and recording shift, would give on average one high reading in the results of monitoring, on such a scale. each work area every tenth shift. Sampling a; the One way of presenting the results would be to minimum frequency requiret! by the US slundard, take an overall average. This has recently been i.e. once per mouth, would give on average One done and figures provided hy the industry show high reading in each work area every tenth month. that the average concentration in the UK factories We see therefore lhat frequent static sampling had been reduced in a mailer of months from 24 at carefully chosen points can prov ide much useful to 6 pans/1011. Recent figures from some of the information but it does not necessarily tell us plants even show long-term averages of about exactly what concentrations the work people are 2 parts/1011. This suggests enormous progress, as actually exposed to. This can be shown best by indeed it is, and compares favourably with aver personal monitoring which is normally done at ages published by other countries. However, an less frequent intervals because it is nme-consum- overall average such as this is influenced very ing for the testing stall' and somewhat restrictive considerably by selection of the sampling sites and for the operator wearing the equipment. Never by the frequency of sampling, two aspects which theless this is an extremely useful supplement to are completely losi in this method of presentation the general workroom monitoring. and of course it oilers little of use in the protection of the worker, which is the main objective of Other Piuhlctns monitoring. I have said nothing in this short paper about preservation of records, which provides many Influence ofPeaks problems not previously encountered in industry, An average over any period of time is influenced nor about atmospheric monitoring ill the PVC very considerably by peaks, l or example, in a 20 user industry where general atmospheric con point system sampling every minute a single peak centrations are less than 5 parts/1 O' and usually of 600 parts/10* due to a transient leak from less than 2 parts,MO5, with a few known and nearby plant would add 2a parts/10" to the shift controllable problem areas. average. In the UK we feel that it is essential to In short, we in the UK believe that atmospheric record these peaks, because they indicate escapes monitoring should be used to provide the maxi of VCM due perhaps to defective plant or perhaps mum amount of information. This means that to incorrect work practice, both matters which the monitoring schemes incorporating extensive ought to be remedied. If the monitoring points multi-point systems can provide (/ useful arc selected to provide a balance between information on deficiencies in plant or in operat operator work stations and areas where leaks ing procedures. (/>) information with which to may occur then we must expect to obtain some ' demonstrate progressive improvements in our aim high readings. These occasions will generally be to reduce exposure to near zero, (r) information investigated and will therefore play an important on personal operator exposure which can be kept role in the long-term reduction of atmospheric for future reference. Unfortunately in the short concentration of VCM, but in the short term they teim it also provides much ammunition for our make the picture look bad, both by their presence critics. This, however, is a small price to pay for as peaks and by their contribution to the overall the long-term benefits which we know will shift average. There is of course no suggestion accrue Irom our elTorts. -