Document EqNnXk6odBvJqrDYq41n3w8Jb

R&S 114468 BIO-HID I CAL. RESEARCH document description form Duplicate.In all cards; year as-1961- File number [Right justify fNumeric only] 77 78 1^ ' I Sub-Index Code Author (s), as Last Name. FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 1 20 2140 41_____________________________0 ' r~,k j'yOC J? J t 61 62 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation; do not abbreviate. 1 ------------- ~--:------------------------: ....- -0^ 21 22 23 24 Source (Journal, Vol., Number, Pages, Date ) 12 _______________________________________________________ /hu 7 'V t/Z- ' f 1 62 31 32 Brief Summary 12 10 SUMMARY: 61 62 61 62 63 64 1955 1960 1965 1970 1975 R&S 114469 JR HEALTH-& ENVIRONMENTAL SCIENCES, U.S.A. l';~C . ~V l--<, ~ ,n. -- -T-&Y~-v/L?' y^L i^- /^" FR0M T. R. TORKELSON 1803 Building 617/636-5197 T *1 . > -<? n w ,. Ki y vr yr c y ir w v rT'r-!'" i" w?"wryripj iii.^,M Lui ^ ..."ix /? ary ' on and the tfho >em xrry fersof ght ical na* -of lire 33 flo C0 .4. y. padth *nd ds; the in ing uld mi- ical pernay 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. If indicated, medical examination should be undertaken at any time. Section 16 provides for the keeping of confidential medical records of all supervised workers; these must not ` be destroyed without the agreement of the Chief Employment Medical Adviser. The purpose of the present symposium is to review British' experience of the environmental, clinical, epidemiological and pathological effects of exposure to vinyl chloride arising in the course of polymerization of vinyl chloride monomer to polyvinyl chloride, and to exchange information. International Ajctficy for Research on Cancer (1974) Internal Technical Report No. 74/005. IARC. Lyon (1975) Internal Technical Report No. 75/001. IARC, Lyon Levinson C(1974) Work Hazard: VinylChloride. International Chemical Workers Federation, SwiuerJand Litis R, Aodtrson H. Nicholson W J. Daom S, Ftsehbein A S it Seliknff IJ (1975) Annuli ofthe How York Academy of Sciences 244.22-11 Maltoni G Crcspi M it Burch P J ft ed (1975) Exctrpta Medico International Congress Series No. 275 Setikoft IJ Be Hammond Ced (1975) Annalsofthe Hew York Academy ofSciences vol 244 Trihukh S L, Tikhomirova N P, Levina SV& Kozlov L A (1949) Clgitna Sanlt 10,58 United States Senate Committee on Commerce, Subcommittee on Environment (1974) Second Session on Dangers ofVinyl Chloride Serial No. 93-110. US Government Printing Office, Washington, DC ' Yjo1aPL,Bifo?tiA&Cap(itoA (197I)CaficerR*s*4rcA3l,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 Croup 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 brought as near as possible to zero con centrations.* The figures of 30 parts/10* and 10 parts/10* replace the original figures of 50 parts/10* and 25 parts/10*. Other requirements of the Code, including medical supervision, are currently being re viewed. REFERENCES Cordicr J M* Ficvu C, Ltfetrt M J If Sent* A (1966) Cohiers de AfJdecine da Travail4, (4-19 Gvtch JLjr&Johnson M N (1974) Journal ofOccupational Afedicine 16, 509*3If Eannwontil protection Actncy (1974) Preliminary Assessment ofthe Environmental Problem Associated with Vinyl Chloride cad Polyvinyl Chloride. Washington, DC Health & Safety Executive (1975) Vinyl Chloride Code of Practice for Health Precautions (Temporary Format). London Mr AW Barnes {IdPlastics Division, Welwyn Garden City, Hertfordshire) ' - Vinyl Chloride and the Production of PVC Polymerization Characteristics of Vinyl Chloride Vinyl chloride has a boiling point of --13.5*0;. 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 4B-70C to give polyvinyl chloride (PVC), a white 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 (40% by weight) so that as the polymerization reaction proceeds and more polymer is precipitated, so equally is more monomer absorbed by the polymer to the point at about 70% conversion where monomer as a separate liquid phase disappears and the remain ing monomer must be polymerized in its dis solved state within the swollen polymer. As this phase of the polymerization proceeds, the con centration of monomer in the polymer decreases and the rate of reaction correspondingly dimin ishes until at about 92-95 % total conversion the speed of polymerization becomes uneconomically slow. These are the fundamental characteristics of vinyl chloride and its polymerization mechan ism which decide the principal features of indus trial processes for the production of PVC. CTwr/ m. i w T * * ^ - .c r-r.---.-3 -Sp :$ 278 /Vnc. roy. Soc. Med. Volume 69 April 1976 20 The Production Processfor PVC Because it must be polymerized in liquefied form at temperatures above its boiling point, the industrial process must be carried out in pressure vessels (at 5CTC the vapour pressure of vinyl chloride is ~7 atmospheres). Because the reaction is exothermic, means must be found for removal of the heat produced so that the temperature of reaction (and thus the pressure, and the properties of the end-product) may be kept under control. ___In. the most widely used process, this control is .achieved by dispersing the liquid monomer into tiny droplets (about 100 pm in diameter) in ap proximately equal quantities of water, by means of mechanical agitation together with the-addition of small quantities of surface-active agents which facilitate the breakdown of the monomer into droplets and stabilize it in this form. This finesubdivision of liquid monomer enables the heat evolved from the polymerizing monomer to be rapidly transferred to the surrounding water and then removed by a cooling jacket on the reactor, the process being aided.by agitation. The sub division of the monomer into droplets has also the vital property of ensuring that the polymer, which is produced within each droplet, is pre sented at the end of the reaction in finely divided, powder form, and not as an intractable horny mass. conversion and solving some of the problems connected with vinyl chloride toxicity in this way. At the termination point of the reaction, there fore, the 5-6% residual monomer (still at a pres sure of 4-5 atmospheres) is vented back to a gasholder and a slurry of PVC panicles (100-150 (jtm diameter), suspended by stirring in water, is left in the reactor. Now to a description of the process in engineer ing rather than chemical terms: polymerization is carried out in cylindrical, stirred, jacketed pressure vessels. To begin, water, surfactive agents and free radical catalyst are added to the reactor: the air space above this liquid phase is purged of oxygen (which inhibits polymerization) and liquid vinyl chloride is then injected into the reactor. (In the UK, reactor sizes range from 10m1 to 40m1 and the monomer charge per batch ranges up to about 15 tons.) The reactor contents are then heated to and maintained at reaction temperature. After a reaction time of the order of eight hours, excess monomer is vented to a gas holder (for recycling) and the reactor is evacuated, at elevated temperature, to strip as much mono mer as possible from the polymer on which it is absorbed. The polymer slurry is then trans ferred to dosed tanks prior to the next stage in the process. As polymerization proceeds, the two phase Meanwhile the empty autoclave, which still system of monomer dispersed in water becomes a contains vinyl chloride gas at a low partial pres three phase system of solid polymer precipitated - sure is further evacuated before opening to within liquid monomer droplets which are in turn atmosphere, and automatic high pressure water . > dispersed in a continuous water phase. A great cleaning jets are activated to remove polymer . deal of research has been devoted in the past scale from the walls. At this stage, the cycle is , thirty years to the control and stabilization of complete. this rather delicate colloidal system but, even so, smalt quantities of polymer are still thrown out Vinyl chloride monomer has a strong affinity for from it and form a thin continuous film of PVC PVC and the last traces of it are-difficult to remove on the walls of the reactor. If left, this will in from the polymer; the polymer in the slurry afterv crease in thickness and, since PVC is a poor stripping therefore still contains around 500 thermal conductor, will reduce the heat transfer parts/10* of vinyl chloride. This slurry is centri characteristics of the vessel and make temperature fuged to remove the water phase and the wet control impossible. At the end of the reaction it is powder is then dried in continuous driers; during therefore essential that this film should be cleaned this process further vinyl chloride is removed in away. This is one of the basic reasons why a truly the drier gases and the final dried powder cur continuous process has never vet been developed rently contains about 50 parts/10* of monomer. for making PVC and why the polymer, the world ' over, is still made by a batch process in relatively Interfaces between small reactors. This, as we shall see. has a signifi Vinyl Chloride andPeople cant influence on the ease of controlling fugitive This description of the production process gives monomer in a PVC plant. some indication of the relative potentials of different parts of the process for creating signifi As polymerization nears 90-92% conversion, cant exposures of people to vinyl chloride. If we the rate of reaction slows down markedly and at take a plant capable of making 100 000 tons per about 95% conversion has become so slow as to annum (tpa) of PVC then the polymerization be quite uneconomic. There is no possibility building will, during the course of a year, have therefore of continuing polymerization to 100% handled over 100 000 tons of vinyl chloride in R&S 114472 20 roblems his way. i, therct a presck to a 100-150 vatcr, is ngineer* rization Jacketed irfactive d to the phase is ization) into the je from er batch :ontentsreaction . order of gasjated, [tonoch it sss gives ltials of 1 signifile. If we tons per crization ar, have ioride in 21 Section ofOccupational Medicine 279 liquefied form under pressure. Into the drying liquid vinyl chloride under pressure was used in section will have passed 50 tons of vinyl chloride large quantities. in a form strongly absorbed on the polymer and at a concentration on polymeh of about 0.05%. In The nature of the polymerization process,'as the finished product, 5 tons of vinyl chloride will described above, illustrates why exposures .in the leave the factory, each year, still absorbed on the past could have been large. The plants are com polymer at a concentration of 0.005 %. Although posed of a large number of batch reactors of small strictly outside the scope of this paper it is worth capacity per batch, relative to the total annual proceeding further and pointing out that in throughout. In each reactor, two complete cycles further fabrication operations on the polymer, per day are carried out and each cycle requires some of this small residual concentration of vinyl chloride to be injected under pressure, monomer is driven off so that in the final fabri heated, contained, stirred and polymerized cated article only --5 parts/10* of monomer almost completely: at the end of the cycle un remain or 0.5 tons out of the original annual polymerized monomer has to be removed and the total of 100 000 tons. In fabricated articles which realtor opened and cleaned. The possibilities of are used for foodstuffs packaging (bottles, film small leakages from pumps, valves, stirrer glands and foil), and which represent about 10% of total and from the opened reactor at the end of the ` UK production, the monomer concentration is cycle were obviously significant: and the manuai still lower, and the pro rata amount absorbed on cleaning of reactors gave further opportunity for foodstuff containers from a 100000 tpa plant high exposures. This was particularly true during would.be 50.1b. Of this quantity 3i lb might, the long period in the 1940s to 1960s when-vinyl migrate into the foodstuff where its average con chloride was thought to be harmless and when a centration is unlikely to exceed 10 parts per recommended exposure limit did not exist or, thousand million. Since total UK production is late in the 1950s, was set by regulatory authorities, -. about 400 000 tpa this means that the annual industrial hygienists, &c,, at a level of 500 parts/ ingestion by the average UK citizen cannot 10*. exceed 0.0001 g, a figure which agrees well with calculations based on diet analysis. The general consensus of opinion throughout the world, today, is that average atmospheric A final potential interface arises because at exposure for polymerization workers between points in the production process, vinyl chloride is 1940 and 1970. might have been of the following exhausted to atmosphere. On a typical PVC plant orders: 1945-55, --1000 parts/10*; 1955-60, and with current levels of achievement, 0.3% --400-500; 1960-70, -300-400; mid-1973, . of the monomer is lost to atmosphere: with this .--150; 1975, --5 pdrts/10*. Across the world, performance ground level concentrations at the there will have been variations around these factory boundary are well below 0.1 parts/10* and ~~figur because of differences in plant design r even these low amounts decay very rapidly with process operation. Even the way in which jobs distance. In the band 1-1 mile (0.4-1.6 km) were organized can have caused variations. In around one factory, for instance, the concentra some countries or on some plants workmen were tions determined arc in the range 0.01-0.0001 employed specifically to clean out autoclaves parts/10*. (where exposures could have been very' high) while in others autoclave cleaning was part only - These figures should make clear that by far the of a whole range ofjobs Carried out by Individual biggest potential for exposure exists in the poly work people. Some spokesmen have suggested, merization section of the plant, since here 100 000 perhaps for full-time cleaners, exposure levels as tons per year of a liquefied gas under pressure high as 3000 parts/10* in the early days of the are handled in a confined space, in contrast to industry. ... * other parts of the process and to the later down stream operations of the plastics industry. In With these very high figures as background, the these downstream operations the corresponding progress made by the PVC industry1 in the UK in quantities, this time in the form of absorbed reducing atmospheric concentrations since the vapour at a low partial pressure and not confined carcinogenic hazard of vinyl chloride became to a single geographic situation, range from 5 tons known in early 1974 is shown in Table 1, which, down to 3 lb per year. That the polymerization also showt improvements made at all the other section is in fact the area where hazard has interfaces described earlier in this paper. Al existed in the past is confirmed by the fact that ail though. as we have seen, the exposure levels in the authenticated cases of vinyl chloride-related these other places are many orders of magnitude angiosarcoma of the liver throughout the world lower than on the polymerization plants* industry have been of workers engaged in plants where has aimed to reduce fugitive vinyl chloride levels iiliYy>Viri'>i'Mi';itVi'~'ti~j''J~' n 280 Proc.roy.Soc.Med. Volume 69 April 1976 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. R&S 114474 , Table 1 Vinyl cUoridc iMBoatf levels in UK uxhirtTy DISCUSSION Dr M D Kipling (Employment Medical Advisory ffolynttriaaiaa VCM m plant atmosphere (weekly average) VCM emission* January 1974 tparttim -150 July 1975 (paW/lO1) -5 - 0.75 Ji otoutput 0-3% ofoutput 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 300-500 <50 for most - grades whether any information was available on the paniclesize of the dust produced in differing processes through Fabrication and Use VCM io pUnt atmospheres 2-15 <3 out the world and the incidence of vinyl chloride disease. VCM in PVC bottles -50 ~2 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 application for which the PVC powder was made. Finally a few rough calculations of the daily However, most manufacturers produced ail grades of dosages at the current exposure levels and at the polymer so that it was unlikeiy 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 putting current plant performance and present downstream exposures into perspective, one with another, and in comparison with earlier figures CTable 2). could be explained in terms of the polymer and its particle size. Moreover, it should be remembered that all the significant medical effects under discussion at this conference (angiosarcoma, acro-osteolysis &c.) had, throughout the world, been observed exclusively in workers on polymerization plants or, in two cases, plants handling liquid vinyl chloride under pressure. Table2 . ' ' Features common to all these workers were that they Du>r <3ou* at curnot and Hrliw opomre lc*l were exposed to vinyl chloride vapour in the atmo Polymerization plnl operator t lOOOpartj/IO* Polymerization plant operator at 500 pam/10* Daily dart Ulktbcdy wtitho 0.36 0.1*. 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 ' --------- --Spatti/IO* 0.001*----- 7 Fabrication plant operator at I patt/10* 0.0004 Avcraae UK citizen through ingestion in food 0.000000004 particles could arise but, despite extensive medical investigation, no significant abnormalities had been found among drier operators or packers. It was perhaps worth noting, too, that the greater proportion of PVC powder was of a particle size similar to sand Ih 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 CS Darke (Royal Infirmary, Sheffield> said that he had investigated 14 cases of breathlessness in workers exposed to vinyl chloride monomer. The findings were: no abnormal ' physical signs; chest radiographs two orders of magnitude lower, while the general normal; routine respiratory function tests difficult to public in the UK absorbs, through foodstuffs, a evaluate but some results slightly below predicted quantity which is some fifty million times lower. values, especially impaired CO diffusion in 6 indi viduals; perfusion and ventilation scans showed While the conference will be concentrating striking abnormalities as illustrated by one slide re vealing marked perfusion defects of upper lobes. One primarily on problems which have occurred in the patient underwent open biopsy of each of the three 1 past, I hope it may find some time to consider lobes of the right lung. Histology revealed focal whether there remains any possibility of similar aiveoiar wall thickening with macrophages in the effects occurring at the markedly lower - and in alveolar spaces and increased reticulin and collagen 22 ver- levels his, quite generally, .t eighteen l Advisory nown that sometimes .* contained He asked :he particlee$ throughA chloride res ofPVC if on the was made. 1 grades of ly medical -turiog site ter and its ered that sioc at ?is &c.) iusively \cases, Ulir<> . --e of to provide aid that he in workers iin^were; adiographs difficult to predicted in 6 indi- a showed e slide re lobes. One r the three aled focal xs in the d collagen 23 Section ofOccupational Medicine 281 formation seen on electron microscopy. No obvious Dr KS Williamson vascular abnormality except on fluorescent examina (ICILtd, Central Medical Group, tion. It might be of importance that some of the worst. Fulshaw Hall, Wilmslow, affected men were concerned in a polymerization Cheshire, SK9JQB) process that yielded `plastisol', a very fine PVC powder with particle size around 0.5 pm. 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. 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 mosf animal studies have used this method of dosing. Many experi Professor IJ SeUkoff(Mount Sinai SchoolofMedicine, mental studies have demonstrated the very low City University of hfew York) said that pulmonary acute toxicity of the compound. The acute in 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%. halation toxicity was studied by Mastromatteo et al. (1960), who found that the lethal concentra tion for mice, rats and guinea-pigs exposed for 30 Neither age nor cigarette smoking served to explain minutes was between 200 and 300 000 parts/10*. the findings. For those under age 40, obstructive In long-term studies few toxic effects were re findings were predominantly among cigarette smokers, ported, though Torkclson et al. (1961) found that as expected. After that age, however, the prevalence inhalation of vinyl chloride resulted in minimal of changes was very much the same among smokers and nonsmokers. Of course, age correlated strongly with duration of employment. These two factors were analysed separately and it was found that the changes were generally among smokers with less than 20 years from onset of exposure, but that thereafter they were present in both smokers and nonsmokers. Radio microscopic changes in the liver and kidneys of several species of experimental animals exposed seven hours a day to 500r-200 pans/10* for sixmonth periods. No significant changes were found in any species exposed to 50 parts/10* for six months. graphic changes were less common. Overall, 13.3% of 985 chest films showed linear, reticular or nodular In 1971, however,' Viola et al, reported that changes characterized as 1/0 or 1/1 in the ILO U/C while attempting to produce acro-osteolysis in Classification. Dyspnoea was uncommon and signs or symptoms of chronic bronchitis were,not striking (Miller etal. 1975, Miller 1975). The pathogenesis of these abnormalities was not dear. It was not known, for example, whether they reflected another biological change associated with exposure to vinyl chloride monomer, or another factor. Mr A W Barnes had noted that manufactured 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 PVC might currently contain 5 parts/10* of retained led to further epidemiological and animal studies, vinyl chloride monomer, as well hs other agents added > many of which are still incomplete. The most In file 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 Seltkoff, there had usually been opportunity for PVC dust exposure as well as vinyl chloride complete series of animal studies available to us are those conducted by Maltoni and his co workers (Maltoni 1973, Maltoni & Lefemine 1974). In these experiments groups of rats were exposed to vinyl chloride vapour concentrations ranging from 10 000 to 50 parts/10* for 4 hours a day, 5 days a week, for 12 months. The animals exposure, either by a period of work with the polymer were then maintained for the rest of their lives during the employment span and/or as the result of incomplete separation or the various parts of the production process. PVC dust was often to be found in several parts of the plants. It would seem of interest to study further the in fluence of vinyl chloride and PVC in the experimental animal, as well as the pulmonary status of workers producing vinyl chloride monomer but not exposed to PVC during or after the polymerization process. unless they became ill. Tumours of the cerumi nous glands, angiosarcomata of liver and other organs, nephroblastomata and a variety of other tumours were found in animals exposed to vinyl chloride. In animals exposed to 50, 250 and 500 parts/10* the logarithms of the numbers of animals having angiosarcomata and the total tumour-bearing animals are linearly related to the dose of vinyl chloride, but in animals exposed to references PraafiM N, SpinixiftU A A BuetmUi A (1974) Mtdteina delLa*on> 45,321-142 Miller A {1975) Environmental Health Perspective 11, 247-250 MiiltfAfTcinui&AS, Outing M it SeliWoff IJ (1975) Await ofthe New York Academy ofSciences 244,42-52 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 1 S. i: m a/ L oV TREAT REP . 103 *ss. and need 107 Vmente/ 111 115 97 6 1e Triehe*: Treat* on 941 ngir "rue V*i941 , Berry R. Hem 4 of the ,eral Hospital Dvspne* in * 19* .......................... 944 '. SitCeik] als ?; ......................... 953 -ungt?............... 954 g Board ............................................ 954 dence 4c to ldoeun4ine - 954 Syiteiti 957 stations *.4. * # 957 ..................................... 957 ............................. 959 `M . 4 4444 4 4 4 44* 959 Hvart Failure with f\ pcr^lytetmt . * * * 962 Quality of Medical ............................................ 962 ublic Affairs V New Inquiry ., -. 963 ienItTTTOoNntents O 1976 by ISI Proceedings of 0000350 the Royal Society of Medicine VOL* 69 NO* 4 APRIL 197,6 Section ot Proctology //rt 1 Sectioo ofOccupational Medidne 237 Rectal Cancer: 275 Vinyl Chloride: The Spectrum of Selective Surgery 4 Introduction to the problem President's Address Sazette Gauvain by A York Mason 277 Vinyl Chloride and the Section of the History of Medicine Production of PVC 245 The Politics of Anatomy: A WBarnes Dr Robert Knox and Victorian Racism 280 M D Kipling, A WBarnes, C S Darke M D Biddiss 281 IJSetikoff United Services Section 281 Review of Animal Studies 25! Human Factor Problems in Helicopters - K S Williamson Research and Development 283 L Magos, H EStokinger JR Allan 252 Human Factor Aspects of Army Helicopter Operations 284 Clinical Aspects of Vinyl Chloride Disease 284 Aero-osteolysis K Edgington BJPreston, K UoydJones 255 Human Factor Problems of and R G Grainger Operating Helicopters at Sea A P Steele-Perkins Section of Surgery 286 L Magos, BJPreston, K UoydJones 286 Clinical Aspects of Vinyl Chloride-Disease: Skin 257 Trial and Error in Gastric Surgery President's Address Anne E Walker 288 Leo Djerassi, Anne Walker, Marcus M Key by Andrew M Desmond Clinical Section 2fi3 Sclerodermatomyositis with Megacolon, Small-bowel Involvement and Impaired 289 Premysl VPelnar, Anne Walker 289 Evidence ofan Immune Complex Disorder in Vinyl Chloride Workers A Milford Ward Lung Function 290 Leo Djerassi, Margaret Turner-Warwiek, VSrinivas (for V WJohnson) A Milford Ward, L Magos, E Vigtiani, 264 Calcinosis in Scleroderma RuthUlis JN Rosenberg 290 Chromosomal Effects in (for JC Lewis) ~~ "^Peripheral Lymphocytes 264 Mcnetrier's Disease and /FH Purchase, CRichardson, Carcinoma of Stomach and D Anderson J D Stamatakis 291 Sylria D Lawler, I FH Purchase (for AP Wyatt) 292 L de Boer, IFHPurchase, D G Smith 265 Severe Intra-abdominal Sepsis 292 Preliminary Results of Grey-scale C H Browne and E Gross (for Gillian C Hanson) 266 Ileocolitis Responding to Bowel Sterilization Stephen P Kane (for Graham Neale) Section of Ophthalmology 267 Cataracts in Early Childhood The Scope of the Problem Brian Hareourt 268 Etiology and Genetic Aspects BarrieJay 270 Cataracts in Early Life: Biochemistry Anthony F Winder 272 The Surgery ofCataracts in Children NSC Rice Ultrasonography in the Detection of Vinyl Chloride Related Liver and Spleen Disease KJ WTaylor.JJ Barrett. D MJ Williams,, P M Smith and B W Duck 295 Collagen Studies in Acro-osteolysis M l VJayson, A J Bailey, C Black and K UoydJones 297 Epidemiological Studies of PVC Manufacturers and Fabricators, and Primary Angiosarcoma of the Liver PJ Baxter 299 A J Fox, L Magos 299 Histopathology of Liver Lesions Associated with Exposure to Vinyl Chloride Monomer K Weinbren CONTENTS CONTINUED CURRENT CONTENTS 1976 by ISI C-13 r 30 (/> -4 O) f r s. -- v } ^ </i m 4*^ I * ESTABLISHMENT? PAST EXPOSURE CONCENTRATION IN VCM/PVC PLANTS June 25, 197' C *4/ * R&S 114477 Many, including Dr. David Rail of NIEHS, have noted that rodents appear more susceptible to vinyl chloride induced angiosarcoma than humans. If this were not true the exposures of workermen to vinyl chloride in previous years would have resulted in hundreds of angiosarcomas in the U.S. rather than"the 19-20 cases reported since 1961. This is extremely ' important to the vinyl industry since future animals studies will no doubt result in cancer at lower and lower levels of exposure. It would be most useful if we could at least semi-quantitatively ascribe *#*** numbers to previous exposures. These need not be precise^estimates, orders of magnitude will be adequate.. Therefore, it is requested that each company thoroughly investigate all the methods which it can to realistically evaluate previous exposures of their employees included in the Equitable Environmental Health (MCA) study. It must be remembered that prior to 1962"^Ehere was no accepted industrial >*- hygiene guide for vinyl chloride.\In 1962 Athe ACGIH suggested a time weighted average (TWA) of 500 ppm. Until 1963, there was no limit on peak exposures; thus a worker could have experienced less than 500 ppm as a TWA but have had peak exposures of several thousand parts per million for several minutes. The following are suggested as possible ways of documentating past vinyl * chloride exposures. Each has serious limitations but please remember we only need to establish whether exposures were nearer 10, 100, 1000, 10000 or even 100,000 ppm in order to show a difference between people and rodents. * ... SPEECH ON VINYL CHLORIDE GIVEN BY V. K. ROWE AT THE FOURTEENTH ANNUAL INDUSTRIAL HYGIENE^SS^P^RENCE, FONTAINEBLEAU HOTEL, MIAMI, FLORIDA, MAY 1^, 1974. J What I am going to try do do is to give you a chronological picture, at least as I know it, from away back up until today. Things are happening so fast, that I am not even sure about today. ._ R&S 114478 Years ago, and this goes back to the 40*s and perhaps even before that, no one was particularly concerned about vinyl chloride. The acute work that was done toxicologically, certainly indicated that it was nothing more than a darn poor anesthetic, as a matter of fact everybody knew it was a central nervous system depressant, but people tried it out as an anesthetic and it didn't work very well. In some applications along the way in the use and manufacture of it some people did find out that it was a fairly potent anesthetic. Back in 1949, there apparently was a Russian article dealing with vinyl chloride, which most of us have never seen. It has recently come to light and I have yet to see this article. I am told that it tells us that the Russian's had found the material to be a liver toxin. I don't think there is anything in there with respect to carcinogenesis, but I haven't seen the article. Perhaps someone who has can add to that informa tion later. j 2- - In 1958 and 9, I can become a bit more realistic/ because during the preceding years in our laboratory we had been studying a series of chlorinated hydrocarbons and at that particular time we decided that we were handling a lot of vinyl chloride so we thought we would introduce it into our inhalation program. Back in those days, the typical inhalation experiment involved several species of animals not too large a number, and exposures of 7 hours/day, for 5 days/week for a period of six months. Then the animals were sacrificed and examined to see what had happened to them. That was the typical thing we did back in those days. We studied concentrations of 500, 200, 100, and 50 ppm during the period of 1958 and 9. We found out that, in our rat colonly at least, these were Wistar rats in those days, that we had liver and kidney injury at 500, we had slight liver weight increases at 200, we had liver weight increases at 100 and nothing at 50. At the 200 ppm level, we also exposed guinea pigs, rabbits, and dogs and we found only liver injury at 200 with the rabbits, nothing in the other two species, either at that level, 100 or at 50 ppm. Nevertheless, we had the basic philosphy, I think that one kept the industrial hygiene limits and guidelines as low as he could practically and we set for ouselves the guideline of 50 ppm on a time-weighted average basis at that time with \' R&S 114479 -3- a maximum of 100 ppm. As I've said publicly before, we didn't always achieve that, but that was at least our goal. That paper was published in 1961 in the AIHA journal. In 1963 and 4, the problem of acroosteolysis came to be known in Europe. People hadn't recognized it, to my knowledge, in this country but very shortly after that, as a matter of fact in 1967 and 8 if I am not mistaken, U. S. industry, through the Manufacturing Chemists Association (MCA) under took an epidemiological study on PVC workers to see whether there was a significant amount of acroosteolysis in this country. Now that job was undertaken by some of our good -' i friends from the University of Michigan. The result was that they did find some acroosteolysis in some kettle cleaners in some of the PVC industries. We felt fortunate at that particular time because we didn't find any in our workers but we were also using different technology than some of the others and this was perhaps the explanation for it. Nevertheless, we were somewhat concerned about the picture with regard to vinyl chloride, so John Mutchler who is now with Clayton Associates, and Dr. Kramer who was in our Division Medical Department at that time undertook a study of all the clinical records that we had relative to people who had been employed in vinyl chloride, vinyl chloride polymers R&S 114480 33 C/3 4* 00 The Toxicity of Vinyl Chloride as Determined J by Repeated Exposure of Laboratory Animals - ' T. R. TORKELSON, M.S., F. OYEN, and V. K. ROWE, M.S. Biochemical Research Laboratory, The Dow Chemical Company, Midland, Michigan Groups of Laboratory animals were exposed repeatedly for up to six months to cither ' 500, 200, 100 or 50 ppm vinyl chloride in air. Detectable changes occurred at all but : the lowest concentration. The results are discussed and handling precautions suggested. Introduction The following report summarizes the result of repeated exposures of laboratory animals.! VINYL chloride (CHr=CHCl) is a chemical either 500, 200, 100 or 50 ppm of vinyl cblond of great industrial importance. It is used in The significance of the results is discussed the preparation of polyvinyl chloride resin, asrecommendations for a threshold limit valuer a copolymer in saran and other plastics, as a made. chemical intermediate and as a solvent. Be cause of the flammability of vinyl chloride, it has Experimental Procedures been generally assumed that the greatest hazard associated with vinyl chloride is that due to its flammability rather than its toxicity.1 The toxicity of vinyl chloride has been re viewed by von Oettingen* and more recently by Mastromatteo et all von Oettingen concluded that the gas was anesthetic in high concentra tions and that considerable interest had been shown in the use of vinyl chloride as a surgical anesthetic. However, its effect on the circulatory system has discouraged exploitation of this prop erty. No doubt the hazard front flammability lias also hindered tliis use. Only limited repeated exposures which were reported by Schaumann* were discussed by von Oettingen. These repeated exposures indicated little or no chronic effects even from anesthetic concentrations. Mastromatteo et all also discussed the pub lished data and reported the results of single exposures of mice, rats and guinea pigs which confirmed the low acute toxicity of vinyl chloride. Mastromatteo reported that only two human fatalities due to vinyl chloride had been reported. It can be concluded from the published toxi cological data that anesthesia is the only sig nificant effect of acute exposure. Sufficient re peated exposures have not been reported to draw conclusions about chronic toxicity. The Threshold Limit Value of 500 ppm suggested by Materials Tested c Vinyl chloride, CHs=CHCl, is a colorl___ It has a boiling point of --13.35C (+7JKPF}| and a freezing point of --154'C (--244.S2*._ The material polymerizes readily and henei sometimes inhibited with phenol or butylcatechol. Vinyl chloride is very tt: its flashpoint being --7S*C ( --103F). Tb# plosive limits are from 4% to 22"c by jtjms little odor although high concern ^nay'smeil faintly sweet. . .:,V, A single, uninhibited sample was used 81 studies. It was shown by mass spect - analysis to be essentially pure being the only impurity detected in grt|| samples. * Source and Feeding of Animals M The rats and rabbits used in this: obtained from the stock colony of thj*l tory, the guinea pigs were obtainTMT commercial grower and the doa ]" beagles obtained from a local . and dogs were fed Purina Labora or Fatno Laboratory Ration.' guinea pigs received tamo Ration. The guinea pig diet ** i with carrots. the American Conference of Governmental In dustrial Hygienists (ACGIH)5 is reported by Smyth* to be based on single animal exposures and human experience. Experimental Protocol The experiments Were cornu**TM: '"v phases. In the first pha.-o. znapt m * r 360 October, if Table IX Summary "of Average Hematological Values for Dogs Receiving Repeated 7^Hot. Exposures to Vinyl Chloride Dog * i 1Sex Concentration in ppm Months on Experi ment No. of Animals Hemo globin g/lOOg Hema WBX ! X Neutro- i tocrit 10* phils Lym pho cytes Mono cytes Dog *152.................... Dog *152.................... Dog *152............. . Dog #156.................. Dog #156.................... Dog * 156.................... Dog *162 .................. Dog *162.................... Dog *162.................... Dog #151............. . Dog *151.................... Dog #151............... . Dog #155.................... Dog #155............... Dog #155__ ......... Dog *161.................... Dog *161.................... Dog *161.................... M Unexposed control M . Unexposed control M Unexposed control M Air exposed control M Air exposed Control M Air exposed control 51 50 M 50 M 50 F Unexposed control F Unexposed control F Unexposed control F Air exposed control F Air exposed control F Air exposed control F 50 F 50 F 50 0 3 6 0 3 6 0 3 6 0 3 6 0 3 6 0 3 6 ii 43 12.9 41 1 i 15 52 19.4 42 50 4 15.5 54 15.4 52 40 I "is 1 ------ ---- -- 1 14.5 50 13.4 45 50 2 1 14 50 n.i 55 28 5 1 10.5 39 13-6 48 43 2 1 14.5 54 12.7 48 45 1 15.5 53 11.2 43 50 3 4 ,, fi 1H 46 13.3 59 30 3 9J 1 14.5 52 23.6 67 25 0 1 15.5 58 15.5 46 42 1 IS 46 14 61 37 3 0 *1 1 16 59 18.2 60 1 15-5 56 17.0 53 33 31 5 ``til 5 1 10.5 35 15.3 55 40 5 ' 0*4 1 15.5 53 13.4 56 42 2 1 15.5 56 12.3 43 43 3 in l,,,tn-tr:nl II T.v : >* * -era.,-,: B1 7W '*'7'/ n" Kin i-'- I H. F v A.M-I H. Tli ' ,,f F,- -- ttenli tiin-s H. F. 5l:tIJ`iJ"d5 lor /7,* 129 tl9$6i. flurry Hill Fa i( F'lrilllli.tr.- Milling adjacent to the leaks. The flammability of vinyl 500 ppm for 4.5 months. Repeated 7-hour erf chloride precludes such severe leaks if this haz posures at 200 ppm for six months resulted ard of vinyl chloride is to be controlled. micropathological changes in the livers of rab bits and statistically significant increases in Industrial Hygiene Standard average weight of the livers of male and fema The data presented indicate that little like lihood of injury would be expected if repeated daily 7- to 8-hour exposures are limited to 100 ppm or less. Although the level of 100 ppm may not ap pear to offer any margin of safety since rats ex posed repeatedly to this level were very slightly affected_ibe-yaat amount.of human pvp01''0"^ thtjtdslivailable while operating under an MAC rats but no detectable changes in dogs and*! guinea pigs. Repeated 7-hour exposures at 10 ppm resulted in slight increases in the aver weight of rat livers, the other species were nob affected. All species studied tolerated repeated^ daily 7-hour exposures to 50 ppm for six months^ with no detectable injury. Repeated daily 1-hour exposures at 200 and ppm * v'n-^ c^or^e were without effect 500 ppm indicates that inj-"Tr mt lilrrlr---^ger exposures caused a slight increase in liven* iiicewise the effects of even rather severe over exposure are not serious, hence this level seems jfiiswnrtilei ' ---- A time-weighted average for all exposure should probably not exceed 50 ppm. weight. The standard for evaluating regular daily 7^ to 8-hour exposures may be defined as the con centration below which`practically all analytic*1^* /results must fall. The value of 100 ppm is sug-4a gested as this standard for vinyl chloride, withiS* Summary a time-weighted average for all exposures not to*! exceed 50 ppm. . |||f Vinyl chloride (CHr=CHCl) is a monomeT used in very large quantities in the production of References plastics. Repeated exposures of laboratory ani 1. Manufacturing Chemists Assoc. Chemical Safety Dsin^jj1 mals to several concentrations of vinyl chloride in air were conducted to determine the chronic toxicity of this material towards animals in or der to assess the hazard to humans. Vinyl chlo Sheet SD-56 (1954). 2. vox Oettixge.v, W\ F.: The Halogenated Hydrocarbon^^ Toxicity and Potential Dangers, (l". S. Public Health `5, Service. Publication No. 414.) Government Printing Office. Washington, D. C. (1955). ride was found to have a .'light capacity to cause liver and kidney injury on repeated exposures. Male and female rats showed micropathological changes after repeated daily 7-hour exposures at 3. Mxstromatteo, E.f A. M. Fisher. H. Christie, D. Daszioer: Acute Inhalation Toxicity of Vinyl Chlo* ride to L&boratorv Animals. Am, Jnd. Hyg, Atsoc. J 3f*' 394 (1960). 4. Schaumann, O., cited by K. B. Lehman and F. Flcxt* wealth Amerii dustrif John C Jr., PI Colein. Kenne TUI co. Resea design have a istry" engine week, mediei the In ments, the cli polaro time ii It s should ginocr Regio T *> -13- Material V9/D0A (Dioctyl adipate V9) Vinyl chloride Vitamin C Voranol CP700 Z-6 " Z-ll methyl ester Z-200 Zinc bromide Zinc stearate Zinc sulfide diffuser 2693 IHG 500 ppm 10 ppm 10 mg 10 mg 1 mg - 1 ppm 0.5 ppm S mg 10 mg 10 mg Date 1975 1974 1976 1975 1977 1977 1977 1980 1975 1975 GLOSSARY 73 9f (/) Ceiling - This concentration should not be exceeded, even for brief periods. Excursion - An excursion guide establishes a maximum excursion concentration * -t* above the IHG. Although no duration or frequency limitations have CO CO been assigned to these excursion guides, the 8-hour time weighted average (TWA) exposures should be controlled within the IHG recom mendation. These excursion guidesLhaye been approved for a few chemicals which may have acute adverse effects and for which informa tion is available as a basis for a specific excursion recommendation. IHG - The Industrial Hygiene Guide (IHG) is the internal Dow guideline for 8-hour TWA exposures to airborne concentrations of materials. These guidelines were prepared by industrial hygienists in cooperation with toxicology, medical, production and product department representa tives and approved by the Dow Industrial Health Board. Skin - This material may be absorbed through the skin in amounts sufficient to cause toxic effects. Although the IHG is for inhalation expo sures, skin contact can contribute to the overall exposure to this and invalidate the TWA exposure evaluations. It is recommended that skin contact be avoided. Tentative This IHG has been approved only on a temporary basis and must be reviewed in one year. M. G. Swank Industrial Hygiene Laboratory 1803 Building - Midland 5976--------- RESTRICTED: for uaa within Tha Dow Chamteal Company only. 1 V t? s (S/c DOCUMENTATION OF THE THRESHOLD LIMIT VALUES for Substances in Workroom Air WITH SUPPLEMENTS FOR THOSE SUBSTANCES ADDED OR CHANGED ^ SINCE 1971 R&S 114484 AMERICAN CONFERENCE OF GOVERNMENTAL INDUSTRIAL HYGIENISTS Third Edition 1971 3RD PRINTING 1976 PREFACE TO THIRD EDITION The issuance in 1971 constitutes the third edition of the Documentation of the Threshold Limit alues for Substances in Workroom Air. The second edition (1966) comprised 367 substances; iis edition contains almost 500. The documentation for each substance has been updated and xpanded to include information through 1970, selected from the scientific literature for its releance to the TLVs. The general format of the 1966 edition has been retained, but chemical formulae !ave been added for precise identification of each substance, more than 100 substances have been ;ross referenced, and the size of the substances'captions has been greatly enlarged for more ready .eference. Specific statements on the toxicity and hazard, culled from the literature, or from the :ollective experience of the TLV Committee members, have been referenced for further examin ation and a clear, summarizing statement on precisely what basis the TLV has been selected is .ncluded in most documentations. This latter has been felt by the Committee to be a highly impor:ant adjunct for industrial hygienists administering the TLVs. This edition was placed in the capable hands of Dr. Hervey B. Elkins, Director, Massachusetts Division of Occupational Hygiene, and long-time member of the TLV Committee of the American Conference of Governmental Industrial Hygienists. Although the minutiae of the editorial work was entrusted to Andrew D. Hosey, much devoted care and attention to proper arrangement and content was given by TLV Committee recording secretary, William D. Wagner, and my secretary Eileen Fangmeyer. H. E. Stokinger, Ph.D. Chairman Threshold Limits Committee PREFACE -- SECOND PRINTING This second printing, three years after publication of the third edition, was occasioned by the relatively large number (72) new additions or updating of old documentations. The printing thus contains all the documentations of the third edition and as a supplement, the new and revised documentations since 1971, These additions or revisions are noted by a ^ and are arranged alphabetically as in the main text. V The edited, supplemental documentations represent the efforts of all members of the various TLV subcommittees. Accordingly, it would be appreciated" iLxeaders would call to the attention of the TLV Committee Chairman any errors or discrepancies in the supplement, as the docu mentations of the entire TLV listing are undergoing revision for the fourth edition. H. E. Stokinger, Ph.D. Chairman Threshold Limits Committee irk denotes 1974-1975 changes. A star * preceding the name of a substance in the main body of the text indicates that this documentation has 30 been revised and is to be found in the Supplement. 9f> (fl JP P GO cn iii r &S 114486 bQlism. The dominant response, however, was irritation of the eyes with evident lacrimation. ^^tsial experience has revealed severe irritation of the skin with blister formation(l). Acute toxicity is moderate; about 4,000 ppm represents a four-hour LCgQ for rats, 1,550 for mice, and about 2,500 ppm for rabbits. Although 240 ppm for four hours caused some *"" irritation (blinking and reddening of the sclera) in a beagle dog, 106 ppm caused no observjj^jkects(2). Rats exposed at this latter level exhibited normal growth and behavior after 15 ^^^Ix-hour exposures, but exposures at two and one-half times this level showed retarded ^th in females. Xo hematologic or pathologic abnormalities attributable to exposures as srhas 630 ppm were found(3). -Vinyl acetate is moderately hazardous by mouth. 2.5 g/kg was found to be the LDgg for rats s a single oral dose(4). Cage(5) found rats unaffected by repeated exposures at 100 ppm, and recommended 50 ppm ,j j working standard. - A;'report of 15 years industrial experience^) with 21 chemical operators in vinyl acetate ^eduction exposed at levels from 5 to 10 ppm indicated that vinyl acetate is not a significant jpper::respiratory tract irritant at 10 ppm, but around 22 ppm slight irritation was observed in $e'_form of cough and hoarseness. This level produced a significant subjective response in all arce -subjects tested. Medical records and multiphasic examinations revealed no evidence of jjroiiic effects from levels of 5 to 10 ppm. Vinyl acetate was not considered to be a serious skin srritant, or a producer of contact dermatitis, or a serious eye injurant provided prompt flushing theraffected part was carried out. At levels of less than 5 ppm, vinyl acetate is detectable by itorjtjy. most individuals, and by some at about one-tenth this value(3), Olefactory fatigue may ieenr;-.in a matter of a few minutes at levels around 20 ppm. Recovery is rapid, however(2). awS_I-"p- "' -Inflight of the above evidence that neither acute or chronic effects occur from repeated daily nposures after many years, and that irritation may be experienced,at around 20 ppm, but not at JSRmif.-a TLV of 10 ppm is recommended. fcicreinces: l Hytell Laboratory: Report of Toxicity of Vinyl Acetate (January, 1067). 1 C^Pfunication from Mellon Institute to TLV Committee (October 14, 1968). 1. Mistrial Hygiene Foundation of America: Repository of Anonymous Industrial Hygiene Data, Summary Report of Exposures to Vinyl Acetate (April, 1969). I. Union Carbide and Carbon Corp.: Dept, of Ind. Med. & Tox., Toxicology Range-finding Tests (December, 1956). J. Gage7 J.C.: Brit. J. Ind. Med. 27, 1 (1970). VINYL CHLORIDE CH2=CHC1 200 ppm (Approximately 770 mg/m^) 'Vinyl chloride is a flammable gas with anesthetic properties at high concentrations. At anesfctic"concentrations (8 to 12%) it has serious effects on cardiac muscle resulting in arrythmias ^sensitization in dogs(l,2). There is a wide margin between anesthetic and lethal concentrations ^4C%)(3). Torkelson, Oyen and Rowe(4) reported that repeated seven-hour exposures for six ^thsi-at 200 ppm resulted in histologic changes in the central lobular region of the livers of ^ts/'but not in rats, guinea pigs and dogs. At 100 ppm there was only slight liver enlarge^nt.i'A'' subsequent report by Lester, Greenberg and Adams(5) on the effects of repeated exJ^e-of rats to vinyl chloride assaying 99 + percent purity at 2 and 5% concentration stated ^"although liver changes were noted, they were not considered to be of pathological signif- In their opinion, a recommended TLV of 500 ppm was satisfactory for worker exposure. 277 APPENDIX A CARCINOGENS The Committee lists below those substances in industrial use that have proven carcinogenic in man, or have induced cancer in animals under appropriate ex perimental conditions. Present listing of those sub stances carcinogenic for man takes two forms: Those for which a TLV has been assigned (la) and those for which environmental conditions have not been suffi ciently defined to assign a TLV (1b). Ala. Human Carcinogens. Substances, or substances associated with industrial processes, recog nized to have carcinogenic or cocarcinogenic potential, with an assigned TLV: TLV t Acrylonitrile................ t+Asbestos Amosite.................. Chrysotile................ Crocidolite.............. Other forms............ bis (Chloromethyl) ether Chromite ore processing (chromate)............. Nickel sulfide roasting, fume & dust............ Coal tar pitch volatiles.. Vinyl chloride 2 ppm 0.5 fiber > 5pmlcc 2 fibers > 5^m/cc 0.2 fiber > 5/*m/cc 2 fibers > 5/cm/cc 0.001 ppm ' 0.05 mg/m3, as Cr 1.0 mg/m3, as Ni 0.2 mg/m3, as benzene solubles 5 ppm Alb. Human Carcinogens. Substances, or sub stances associated with industrial processes, recognized to have carcinogenic potential with out an assigned TLV: **. Acrylonitrile 4-Aminodiphenyl (p-Xenylamine) t Benzidine -- Skin ** Chloromethyl methyl ether ** Ethylene dibromide /3-Naphthylamine 4-Nitrodiphenyl +1980 Addition. ++1980 Adoption. "See Notice of Intended Changes. 40 30 </) 4* 4* 00 -4 For the substances in 1 b, no exposure or con tact by any route-- respiratory, skin or oral, as detected by the most sensitive methods -- shall be permitted. The worker should be properly equipped to insure virtually no contact with the carcinogen. A2. Industrial Substances Suspect of Carcinogenic Potential for MAN. Chemical substances or sub- ' stances associated with industrial processes, which are suspect of inducing cancer, based on i either (1) limited epidemiologic evidence, excluI sive of clinical reports of single cases, or (2) demonstration of carcinogenesis in one or more animal species by appropriate methods. 3-Amino 1, 2, 4-triazole tt Antimony trioxide production* tt Arsenic trioxide production Benzene Benzo(a)pyrene Beryllium ** Cadmium oxide production Carbon tetrachloride Chloroform t Chloromethyl methyl ether Chromates of lead and zinc, as Cr 3, 3'-Dichlorobenzidine Dimethylcarbamyl chloride 1,1-Dimethyl hydrazine Dimethyl sulfate -- Skin t Ethylene dibromide -- Skin t Hexachlorobutadiene Hexamethyl phosphoramide -- -- 10 ppm 2.0 jtcg/m3 -- 5 ppm 10 ppm -- 0.05 mg/m; -- 0.5 ppm 0.1 ppm -- 0.02 ppm Hydrazine 4,4'-Methylene bis (2-chloroaniline) -- Skin Methyl hydrazine Methyl iodide ttc 2-Nitropropane n-Nitrosodimethylamine n-Phenyl-beta-naphthylamine 0.1 ppm 0.02 ppm 0.2 ppm 2 ppm 25 ppm -- -- `Cigarette smoking can enhance the incidence of respiratory cancers from this or others ot these substances or processes. t1980 Addition. t+1980 Adoption. "See Notice of Intended Changes. 41 1 * 1, R&S 114488 * SUPPLEMENTS FOR THOSE SUBSTANCES ADDED OR CHANGED YEARS 1974 and 1975 ft I I l l * - * Information made available by the Eastman Kodak Company reveals that no injuries have occurred as * result of handling of the compound and that no special precautions are necessary other than those used for the routine handling of organic compounds(l). `' _ References: 1. Personal communication from Robert L. Roudabush, Director of Health and Safety Laboratory, East man Kodak Company. Letter dated April 12, 1973. R&S 114489 VINYL CHLORIDE CH2=CHC1 APPENDIX Ale Since vinyl chloride (chloroethene, CH2=CHC1) is a gas at room temperature and pressure, the com mon route of toxic exposure is by inhalation. As with many liquified gases, contact of the skin or eyes with escaping compressed vinyl chloride can produce freezing and frostbite(l). Vinyl chloride has long been considered to be very low in toxicity by acute inhalation. Lehmann and Flury(2) summarized the literature and reported work by Schauman who considered vinyl chloride to be a candidate surgical anesthetic. Schauman reported little pathological change even after repeated expo sure to anesthetic concentrations. Further work on the anesthetic potential of vinyl chloride indicated that vinyl chloride was unsafe for use as a surgical anesthetic in dogs and that because of its flamma bility, poor efficacy and its ability to cause cardiac irregularities at anesthetic concentrations vinyl chloride was not suitable for use as an anesthetic in humans- Despite the early reports ascribing low toxicity to vinyl chloride, injury during the production of polyvinyl chloride (PVC) resins was reported as early as 1949. Significantly this report came from Europe where production of PVC in Europe preceded U.S. production by several years and today the quantity produced in Europe still exceeds U.S. production by about two fold. In 1949, Tribuhk et al.(3) reported numerous effects in PVC workers in what by today's standards must be considered as primitive production facilities. These authors found a "considerable number of cases of hepatitis among workers" but were more concerned with other hepatotoxic chemicals such as chlorinated diphenyl and chlorinated naphthylene (Holowax (sic)) than they were with vinyl chloride. As a result of two deaths in Canada, the acute inhalation toxicity of vinyl chloride was studied by Mastromatteo et al.(4) who reported that exposure of mice, rats, and guinea pigs to 10, 20, and 30 volume percent vinyl chloride caused the following mortality: NUMBER OF DEATHS IN DIFFERENT GROUPS OF FIVE MICE, RATS AND GUINEA PIGS EXPOSED FOR THIRTY MINUTES TO VARYING CONCENTRATIONS OF VINYL CHLORIDE IN AIR Vinyl Chloride concentration (percent by volume in air) 10 20 30 40 Mice 0/5 1/5 5/5 -- Laboratory animal Rats Guinea pigs 0/5 0/5 0/5 0/5 5/5 1/5* -- 2/5* TOTAL 0/15 1/15 11/15 2/5 *A delayed death occurred within 24 hours following exposure. Some pulmonary hyperemia and engorgement was observed by these investigators, but liver and kid ney injury were remarkably low. Deaths were due to narcosis. The first report of studies to determine the effect of long-term repeated exposure (6 months) were summarized by Torkelson, Oyen and Rowe(l) as follows: 402 "Repeated exposures "of laboratory animals at several concentrations of vinyl chloride in air were conducted to determine the chronic toxicity of this material towards animals in order to assess the ` hazard to humans. Vinyl chloride was found to have a slight capacity to cause liver and kidney injury' on repeated exposures. Male and female rats showed micropathological changes after repeated daily 7-hour exposures at 500 ppm for 4.5 months- Repeated 7-hour exposures at 200 ppm for six months resulted in micropathological changes in the livers of rabbits and statistically significant increases in the average weight of the livers of male and female rats, but no detectable changes in dogs and guinea pigs. Repeated 7-hour exposures at 100 ppm resulted in slight increases in the average weight of rat livers, the other species were not affected. All species studied tolerated repeated daily 7-hour expo sures at 50 ppm for six months with no detectable injury. R&S 114490 "Repeated daily 1-hour exposures at 200 and 100 ppm of vinyl chloride were without effect, longer __ exposures caused a slight increase in liver weight. "The standard for evaluating regular daily 7-to 8-hour exposures'may be defined as the concentra tion below which practically all analytical results must fall. The value of 100 ppm is suggested as this standard for vinyl chloride, with a time-weighted average for all exposures not to exceed 50 ppm.". _-- --------- ------ -- - -- - ---------' Lester, Greenberg, and Adams(5) took exception to the conclusion of Torkelson et al. (1961) that 50 ppm should be a maximum time weighted average exposure for workers. On the basis of 3 months expo sure of rats to 2 volume percent and 19 days to 5 volume percent, they concluded that 500 ppm was acceptable as a TLV despite minor changes which they observed in rat livers and which they considered "were within the normal range and were not pathologic in nature." Since 1949 numerous articles describing conditions and problems in PVC production plants have appeared particularly in the Eastern European literature. Filatova and Gronsberg(6), Gabor et al.(7), Suciu et al.(8), Gabor et al.(9), Grigorescu and Toba(10), Antonyuzhenko(ll), and Kudryavtseva(12), have all described the effects of apparently gross chronic exposure. These papers and abstracts are difficult to interpret since there are generally inadequate descriptions of the exposure conditions and analysis of the workroom air, so no dose-response relationship can be determined. The injuries and effects described by the authors are not consistent with the levels of exposures claimed by the authors nor are the levels of exposure consistent with past or even present-day chemical technology. Furthermore, mix tures of chemicals are involved making it possible to ascribe the effect to any one of them. For example, Suciu et al.(8) (through translation) described nervous disorders including euphoria with whistling and laughing, incoordination and dizziness similar to alcohol intoxication. However, Suciu et al. ascribes these results to exposure of the order of 5.5 mg/m^ (2 ppm v/v) which is not consistent with other publications which indicate these effects will be apparent-only if concentrations greatly exceed 10,000 to 20,000 ppm v/v. Therefore, the following conclusions by the authors can be construed as being the result of massive and apparently repeated exposures: 1. Vinyl chloride and the vinyl monomers possess a narcotic action and produce, depending upon con centration, in addition to characteristic neuroIogic_manifestation, a state of euphoria (12%), fol lowed by a state of inebriation similar to that of alcohol intoxication. In certain cases narcosis can appear. After leaving the working environment, a state of somnolence (45%) persists, with hypersomnia. Vinyl chloride acts on the skin and produces a sensation of formication and of heat. 2. After repeated exposure, a neurologic asthenia sets in in which somnolence predominates. 3. After a variable period of time, dyspeptic disturbances are added to the neurologic manifestations; these are at first not characteristic; they are in the form of epigastric pains (16%), swelling, dis comfort, feeling of heaviness in the right hypochondrium (7%) or the left (5%) with anorexia, par ticularly for fats. In 30.2% of the cases, congestive hepatomegaly appears, which may mimic toxic hepatitis without jaundice; some cases may become chronic. In 6% of the cases, the hepatomegaly is accompanied by splenomegaly. The proteinogram and the aldolases are the most sensitive tests and show changes similar to those of acute hepatitis: increase in a-globulins and of the /3- and y-globulins; and thymol test, Greenstedt's reaction and the zinc sulfate test are positive only in few of the cases. R&S 114491 ^ 4. After 3 years-of exposure in 9% of the cases a syndrome typical of ulcer without radiologic changes < becomes manifest. *^ * 5. In 6% of the cases the Raynaud syndrome has appeared, particularly among the young men. Plethysmography shows in half of the cases an inhibition of the vasomotor centers. 6. In addition, allergic dermatitis in 4.4% of the cases, and scleroderma in 3.6%, has been observed. 7. The clinical and laboratory findings are of great importance in occupational pathology because in numerous cases diseases.appear in man that cannot be reproduced in the animal (Raynaud's syn drome and scleroderma). The sudden and frequent appearance of these manifestations in the PVC division of several plants, and in certain divisions in normal individuals who are still relatively young, and their disappear ance in the majority of the cases after the institution of protective measures and change of work, have shown us decisively that vinyl chloride and the vinyl monomers have played a part in the pro duction of these manifestations. (End of author's summary). In 1967, reports appeared in the literature describing a condition known as acroosteolysis in workmen engaged in polymerization of vinyl chloride to polyvinyl chloride. Harris and Adams(13) reported on two cases in Europe. Wilson et al.(14), reported on 37 cases in the B. F. Goodrich Company. Juhe et al.(15) described a syndrome consisting of (arranged in decreasing order of occurrence) thrombopenia, spleno megaly, liver damage, obstruction of ventilation, circulatory obstruction, and skin and bone alteration. As a result of this problem, the University of Michigan in 1967 was retained by the Manufacturing Chemists Association to investigate acroosteolysis in sponsoring American companies. The results of a large scale epidemiological study of workers then currently employed in vinyl chloride and polyvinyl chloride production were reported in three publications by this group Dinman et al.(16), Cook et al.(17), and Dodson et al.(18). Dinman et al.(16) summarized the study as follows: "An epidemiological study was performed covering 5,011 employees with 21,510 man-years experience in various phases of vinyl chloride (VC) and polyvinyl chloride (PVC) manufacturing in 32 plants throughout the United States and Canada. The total number of definitive cases of acroosteolysis (AOL) was 25; 16 other individuals were under suspicion. This condition is clearly associated with the hand cleaning of polymerizers- Workers engaged in other phases of VC or PVC manufacturing do not appear to be at risk of developing AOL. The importance of Raynaud's phenomenon as a concomi tant of AOL is emphasized. Several statistical approaches for rapid medical survey are suggested. Acroosteolysis appears to be a systemic rather than local disease. Presently, neither the etiological agent nor its portal of entry is known." Cook et al.(17) describes the polyvinyl chloride production process in considerable detail. They con cluded that although no etiological agent could be identified, "There appeared to be a correlation between the extent of degassing prior to entry Into the reactor" and the incidence of acroosteolysis. Mutchler and Kramer(19) presented a paper at the 1968 Gordon Research Conference which was sub sequently published (1972), which reported on "The Correlation of Clinical and Environmental Measure ments for Workers Exposed to Vinyl Chloride." The authors drew the following conclusion: "Our findings suggest that repeated exposure to vinyl chloride at TWA levels of 300 ppm or above for a working lifetime together with a very low level of vinylidene chloride may result in slight changes in certain physiologic and clinical laboratory parameters. The possibility of some impair ment in liver function tests must be considered, even though no overt clinical disease was evident in any of the individuals studied. We shall continue our study, but suggest that similar studies to help clarify the effects of this material be performed for other worker populations exposed to vinyl chlo ride alone." P. L. Viola, in an attempt to produce acroosteolysis in animals, exposed rats 4 hours per day, 5 days per week to 30,000 ppm (3%) vinyl chloride vapor. In his first report on the results of 12 months expo sure, he described metaplastic changes in the bones which he considered similar to the human disease acroosteolysis. He made no mention of having observed cancer in these animals until the Tenth Inter national Cancer Congress in May, 1970. In the abstracts of this meeting, and subsequently in May, 1971, Viola, Bigotti and Caputo(21) reported tumors of the skin, lungs and bones occurring first after 10 months of exposure- The authors summarized this work as follows: 404  "Rats (Ar/IRE* Wistar strain) exposed for 12 months to vapors of vinyl chloride developed tumors v of the skin, lungs, and bones. The cutaneous tumors, which always appeared in the area in which sub' maxillary and parotid glands are located, have been histologically recognized as epidermoid carci nomas, papillomas, and mucoepidermoid carcinomas. The morphological characteristics of lung tumors, which occurred in a lower percentage, were mainly of the adenocarcinoma type, with the exception of a single epidermoid tumor originating from the epithelial covering cells. In a minor number of rats, a large proliferation of cartilaginous tissue diagnosed as osteochondroma developed in the metacarpal and metatarsal regions of the four limbs." The report by Viola et al.(21) is apparently the earliest publication in which carcinogenic activity has been ascribed to vinyl chloride in man or animals. Although there were obvious deficiencies in Viola's study, such as his very impure sample, the presence of food and bedding in the exposure chamber, the excessive exposure concentration as well as in the statistical evaluation and interpretation of the lesions, the report was of serious concern and resulted in additional animal and epidemiological studies which are currently underway in Italy Maltoni(22). Maltoni and and Lefemine(23,24) and the U.S., Keplinger et al.(25). On January 22-23, 1974, the B. F. Goodrich Company notified its employees, NIOSH, the Kentucky State Department of Labor, and the public, that three workers had died of angiosarconias of the liver. The case reports of the first subject has been published by Creech and Johnson(26). The subject, a 36 year old male, was hospitalized January 5, 1970 and subsequently succumbed September 27, 1971. He had worked in PVC production from November 1955 until his illness. The history, clinical course and pathologic findings are consistent with the others who died of angiosarcoma. The work of Maltoni and Lefemine(23,24) has been reported publicly at the OSHA hearing, Washington, D.C., February 15, 1974, and included in the 1974 publication of the Second International Symposium on Cancer Detection and Prevention, Bologna, Italy, April 9-12, 1973. In these studies groups of rats as well as mice and hamsters have been exposed at concentrations of 10,000 to 50 ppm vinyl chloride vapor. Maltoni and Lefemine (1974) reported carcinomas of the Zymbal glands, nephroblastoma and angio sarcomas of the livers of rats at concentrations of 250 ppm to 10,000 ppm but not at 50 ppm. Subsequent unpublished information (August 31, 1974) reported "1 liver angiosarcoma, 1 extrahepatic angiosarcoma and 1 nephroblastoma, in three animals of the first experiment, exposed at 50 ppm of VC for 1 year, and surviving 135 weeks from the beginning of the treatment." The authors conclude that "a dose-response relationship clearly emerges, as far as angiosarcomas and nephroblastomas are concerned, in the lower dose ranges: from 500 ppm to 50 ppm for angiosarcomas, and from 250 ppm to 50 ppm for nephro blastomas. A comparison of the results available at the present moment in rats exposed for 12 months and 4 months (BT1 and BT3 experiments) shows that the neoplastic, response, as far as angiosarcomas and nephroblastomas are concerned, is affected by the length of exposure to VC." In their experiment BT3 Maltoni and Lefemine reported possible in utero production of angiosarcomas in offspring of pregnant rats exposed at 10,000 and 6,000 ppm. Keplinger et al.(25) in a study sponsored by American companies have confirmed the findings of Maltoni and Lefemine. In this study groups of 100 rats, mice and hamsters of each sex are being exposed seven hours per day, five days per week to either 2,500, 200 to 50 ppm vinyl chloride monomer. After seven months of exposure angiosarcoma and lung adenomas have been observed in mice at all exposure levels. Although the data are preliminary in nature and require confirmation, angiosarcomas were apparently also observed in rats at 2,500 and 200 ppm and in a single hamster gt 2,500 ppm. This study is still in progress and will not be completed until 1976 or 1977. Epidemiological studies on U.S. workers have been conducted by Tabershaw-Cooper Associates for the Manufacturing Chemists Association(27). The summary of this study is as follows: 1. This historical prospective mortality study of 8384 men who had at least one year of occupational exposure to vinyl chloride before December 31, 1972, demonstrated that cancers of the digestive system (primarily angiosarcoma), respiratory system, brain, and cancers of unknown site, as well as lymphomas, occurred more often than expected in those members of the study population with the greatest estimated exposure. The mortality from other cancers was lower than that of the gen eral male population, with the exception of cancers of the buccal cavity and pharynx. The explana tion for the latter finding is not apparent. The other major findings of the study are: (1) The overall mortality of the study population was approximately 75% of what would be expected in a comparable population of U.S. males; (2) No cause 405 R&S 114492 R&S 114493 * of death showed, a statistically significant excess over what would be expected in a comparable U.S. male population; and (3) No deaths identified as angiosarcoma of the liver were found other than those previously identified. This is the first epidemiological study which suggests that in humans vinyl chloride may also be associated with cancer of multiple sites. Vinyl chloride is tentatively assigned to Appendix Ale, "Substances awaiting reassignment of TLV because of recently discovered carcinogenicity." References: 1. Torkelson, T. R. et al.: AIHAJ 22, (5), 354 (1961). 2. Lehman, K. B. and Flury, F.: Toxicology & Hygiene of Industrial Solvents (1938). 3. Tribukh, et al.: Arg. Sanit 10, 38 (1949). 4. Mastromatteo, E., et al.: AIHAJ 21(5), 394 (1961). 5. Lester, D. et al.: AIHAJ 24 265 (1963). 6. Filatova, V. S. and Gronsberg, E. S.: Gigiena i Sanit. 22(1), 33, Abstract (1957). 7. Gabor, S. et al.: Prom. Toksikol. iKlinika Prof. Zabolevanii Khim. Etiol. Sb. 221, Abstract (1962). 8. Suciu, I. et al.: Medicina Interna (Bucharest), XV(8), 967 (1963). 9. Gabor, S. et al.: Ingiena Bucharest 1J(5), 409, Abstract (1964). ~ _ 10. Grigorescu, I. and Toba, G.: Rev. Chim. 17(8), 499, Abstract (1966). 11. Antonyuzhenko, V. A.: Gig Tr Prof Zabol 12(3), 50, Abstract (1968). 12. Kudryavtseva, O. F.: Gig Tr Prof Zabol 14(8), 54, Abstract (1970). 13. Harris, D. K. and Adams, W. G. F.: Brit. Med. J. 5567, 712, Abstract (1967). 14. Wilson, R. H. et al.: JAMA 201(8), 577 (1967). 15. Juhe, S. et al.: Dtsch. med. Wschr. 98, 2034 (1973). 16. Dinman, B. D. et al.: Arch. Environ. Hlth. 22, 61 (1971). 17. Cook, W. A. et al.: Arch. Environ. Hlth. 22, 74 (1971). 18. Dodson, V. N. et al.: Arch. Environ. Hlth 22, 83 (1971). 19. Kramer, C. G. and Mutchler, J. E.: AIHAJ 33(1), 19 (1971). 20. Viola, P. L.: Medicina del Lavoro 61(3), (March 1970). 21. Viola, P. L. et al.: Cancer Research 31, 516 (1971). 22. Maltoni, C.: Proc. 2nd Inti. Symp. on Cancer Detection & Prevention, Bologna, 1973, Excerpta Medica, Amsterdam (1974). 23. Maltoni, C. and Lefemine, G. Lincei-Rendiconte Della Classe di Science, Tesiche, Mathmatische Naturalo, 56, 1 (1974). 24. Maltoni, C. and Lefemine, G.: Carcinogenic Bioassays of Vinyl Chloride, Unpublished Data (1974). 25. Keplinger, J. L. et al.: Annals of NY Acad, of Sciences Working Group, May 10, 1974 (In prepara tion, 1974). 26. Creech, J. L. and Johnson, M. N.: JOM 16(3), 150 (1974). 27. Tabershaw, I. R. and Gaffey, W. R.; JOM 16(8), 508 (1974). 28. Patty, F. A. et al.: U.S. Public Health Reports 45, 1963, Abstract (1930). VINYLCYCLOHEXENE DIOXIDE - Skin 10 ppm (Approximately 60 mg/m3) A2 H2 H7-\2 I /c\ /,H c c. II | H-C-C-C V/N^X Il H Hr H ch2-cho-c6h9o This compound may also be referred to as vinylhexane dioxide. It has a molecular weight of 140, is a colorless liquid and has a specific gravity of 1.098 (20/20C). Its freezing point is - 108.9C and the boiling point is 228C. The flash point (open cup) is 230F and the viscosity is 7.77 centipoise (20). Thl 406 i TIM E-W EIG HTED-AVERAG E (TW A )-- PPM R&S 114494 f