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INTEROFFICE (f) to DR. R. S. 3R00XMAN DATE FROM AUGUST 30, 1973 R. A. PARK Reference SUBJECT SYNOPSIS OF PAPERS PRESENTED AT :'JD - ,, ' SEPTEK3EE 12, 1975 CONFERENCE OF ROYAL SOCIETY COVERING VINYL CHLORIDE HEALTH HAZARDS G-D-Uc.j Reference: Letter to VCH/PVC Producers Group from John Lawrence (SPI), dated 6/2/76. Executive Summary Fourteen papers (36 pages) presented at the September 12, 1975 conference on vinyl chloride health hazards, are abstracted fron the Proceedings of the Royal Society of Tiedicine (London). "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. . ." 'A copy of the paper presented by Dr. Henry Falk and Mr. Richard J. V/axweiler is attached in its entirety. This paper gives "preliminary review of the results" of joint Firestone, University of North Carolina, NIOSH-CDC medical screening examination of 53C workers at Pottstown. Subject papers were published in the Proceedings of the Royal Society of Medicine, Vol. 69, p. 16 - 32. Originals arc on fil.e in library. (Copies available upon request.) Highlights foilow: Title: "Vinyl Chloride" by Dr. Susette Gauvain. Primary purpose of this paper is to summarize events leading up to current vinyl chloride interest 'with emphasis" upon events in Great Britain. "The purpose of the present symposium is to review 3ritish 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. . 22337001 -2- "The medical aspects of the code are contained in parts 12, lp and 14. Part 12 defines 'supervised workers'. Part 13 is concerned with their medical supervision. Supervised workers should undergo pre-employment medical examination. Those already employed should be examined, if this has not been previously done, within twelve months. The examinations should be repeated annually, and should include: (1) a full medical and occupa tional history;- (2) a clinical examination with 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 examination unless' issued previously. v "The physician engaged to provide medical supervision for the workers should see a supervised worker who reports symptoms which may 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 IS 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 Working Group on Vinyl Chloride Code of Practice for Health Precautions net on 8 October 1975 and adopted a new hygiene standard agreed by the Working Group as 'a ceiling \'alue 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 concentrations.1 The figures of 50 parts/10"' and 10 parts/,10 replace the original figures of 50 parts/10 and 25 parts/10o. - ." Title: "Vinyl Chloride and the Production of FVC" by Mr. A. W. Barnes. This paper discusses the polymerisation technique for FTC arid "interfaces between vinyl chloride and people," "... 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 general consensus of opinion throughout tire world, today, is that average atmosnheric exposure for polymerization workers between 1940 and 1970 night have been of the following orders: 1945-55* ,w'1030 partr./10'o; 1955-60, '-400-500; 1960-70, /^pOO-400; mid-19751 ^d-50; 1975 /~5 parts/10^. Across the world, 22397002 -3- there will have been variations around these figures because of differences in plant design or process operation. Even the way in which jobs were organized can have caused variations. In some countries or on some plants workmen were employed specifical.lv 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-tine cleaners, exposure levels as high as 2000 parts/10^ in the early days of the industry. . ." "Table 1 Vinyl chloride monomer levels in UK industry Polymerization January 1974 (parts/10) July 1975g (parts/10) VCI1 in plant atmosphere (weekly average) VCI1 emissions VCM in products r--150 0.75% of output 200-500 r-5 0.5% of output ^ 50 for most grades Fabrication and Use VCI1 in plant atmospheres VCM in PVC bottles VCM in beverages k-15 r-* 50 0.1 <2 /^2 0.001 "Table 2 Daily dosages at current and earlier exposure levels r Polymerization plant operator at 1000 parts./lO0 Polymerization plant operator at 500 parts/lO^ Polymerization plant operator now at /^5 parts/10^ g Fabrication plant operator at 1 pnrt/10 Average UK citizen throurrh ingestion in food Daily dose (g/kg body weight) 0.26 0.18 0.0018 0.0004 0.000000004 " "In later papers to this conference, a wide range of diseases or symptoms, which have been associated with or attributed to exposure to vinyl chloride will be discussed. It is> important to note that most, if not all, of these have been contracted by people who worked under conditions represented by the highest figures in the above table. Today no one is exposed to doses at this level. The exposure of workers in industry is'now at least two orders of magnitude lover, while the general public in the UK absorbs, through foodstuffs, a quantity which is some fifty million times lower. . ." 2397003 r -4- During the discussion of Iir. Barnes' paper, the following consents are recorded: "It van in the drying and bagging sections of the re producing process that exposure to solid FVC particles could arise but, despite extensive nodical investigation, no significant ^ abnormalities had been found among drier operators or packer3.' * It was perhaps v;ortn noting, too, that t.ne greater proportion of FVC powder was of a particle size similar to sand so it did not generally pose an airborne dust problem. For those powders which night cause true dust exposures it had been customary in industry, because of the nuisance and discomfort factors alone, to provide some form of respiratory protection. "Dr. C, S. Darke (Royal Infirmary, Sheffeld) said that he had investigated 14 cases of breathlessness in workers exposed to vinyl chloride monomer. . ." ". . .It night be of importance that some of the worst affected men were concerned in a polymerisation process that yielded 'plastisol', a very fine FVC powder with particle size around 0.5 -^m. These particles, containing vinyl chloride monomer, could be carried to the alveolar walls where they night be retained and thus set up a reaction of the type seen on light microscopy. "Professor I* J. Selikoff (Mount Sinai School of Medicine City University of New York) said that pulmonary abnormalities had been unexpectedly common findings among some 1200 vinyl chloride polymerizatio in his studie: Obstructive pulmonary function defects were noted in approximately 5'U^* Neither age nor cigarette smoking served to explain the findings. For those under age 40, obstructive findings were predominately among cigarette smokers, as expected. After that age, however, tm 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 nonsmokews. Radiographic changes were less common. Overall, 13.5(9 of 9S5 chest films showed linear, reticular or nodular changes characterized as 1/0 or 1/1 in the ILO U 'C Classification. Dyspnoea was uncommon and signs or symptoms of chronic bronchitis were not striking (Miller et al 1975, Miller 1975)- " Title: "Review of Animal Studies" by Dr. K. S. Williamson. Highlights of this paper include: "Purchase and his co-workers dosed Wistar rats daily by gavago at 500, 50 and 5 mg/kg for G months. Fourteen months from the -5- start of the experiment, a large proportion of the animals in the 300 mg/kg group and several of those in the 30 :ng/kg group have been found to have liver tumours. Preliminary histopathological work suggests that some of 'these tumours are hepatocellular carcinomata, though further work is necessary before this can be confirmed." f "It is of some interest to compare the doses received by animals in long-term studies with calculated theoretical doses for.men exposed to various shift-average concentrations of vinyl chloride at work (Table 3)* Again the calculated figures are no more than very rough indications of dose, but they do give a useful measure for assessing the animal data. Table 3 Ken at work Ventilation = 10 nr air per 8-hour shift Weight assumed to be 70 kg________ _________________________________ c. Parts/10 7. mg/rr Daily7dose Daily dose (mg/rn^ x 10) (mg/kg) Annual dose (bAb) (dailv dose x 250) 500 1250 12500 180 44.6 100 230 2500 40 8-9 50 125 1250 18 4.5 10 25 250 4 0.9 1 2.5 25 0.4 0.1 "Green : Hathway (1975) and Watanabe et al. (1975) have studied^the pharmacodynamics and metabolism of vinyl, chloride using ~ C-labelled material given by different dosing methods to rats. Both groups have shown that the proportion of the dose retained and metabolized is greater following small doses than large, though the absolute amount metabolized falls with diminish ing dose..." "Three principal eliminative routes have been identified by both groups: expiration of unchanged vinyl chloride by the lungs, expiration as COp by the lungs, and excretion of metabolites in the urine. The proportion of vinyl chloride eliminated by these different routes varies with dose. . "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. . ." "Discussion Dr. L Kagos (HRC Toxicology Unit, Carshalton) said that the dose plotted against the log of the number of malignancies gave a sott.6E r:?: r 6- - straight line, making it very difficult to draw any conclusion about the threshold or no-effect level, as the zero-effect level could theoretically never be reached. "Secondly, Dr. Williamson's data on the metabolism of vinyl .chloride depending on dose indicated that at low exposure levels a high proportion of vinyl'chloride was metabolized and less was exhaled unchanged. This might mean that increasing exposure above a certain level would exhaust the biochemical ability of the organism to convert vinyl chloride to a toxic metabolite responsible for the carcinogenic effect. "These considerations indicated that experimental data must be interpreted with the upnost care. . "Inferences and conclusions: (l) From the fact that haemangiomas occurred in the liver, and not in the lung (the primary site of entry), it could be inferred either that little or no vinyl chloride metabolism to free radical occurred in the lung, or that there was ample free SH to scavenge the vinyl radical. (2) Most important, the liver had a built-in antagonist 'to the vinyl free radical that provided the basis for a threshold for the carcinogenic response, in this case a threshold for an occupational carcinogen demonstrated by a specific biochemical constituent reaction. This finding explained the fact that among the tens of thousands of workers exposed only a small handfull of haemangiomas had been found. (3) Finding an oncogenic threshold of appreciable magnitude (between 50 and 10 parts/Kj ) removed concern about general exposure of the public to small amounts (see Barnes, p 280) of vinyl chloride in F/C plastic wrappings of foods; the United States FDA could forget it!(h) To bolster resistance to effects of vinyl chloride, vegetables of the Brassica family should be eaten. Factors reducing free SH were: certain industrial exposures that were detoxified.by cysteine, e.g. brombenze.ne; substances or conditions, e.g. certain _chronic diseases." Title: "Clinical Aspects of Vinyl Chloride Disease" by by Dr. B. J. Preston, et al. Arco-osteolvsis is defined as "dissolution of extremity of a bone and it is applied to the distal phalanges of the hands, feet. . ." Paper presents the radiological findings in four patients who had been involved in the production of P/C. "All patients had the following regions examined by plain film radiography: hands, feet, shoulders, elbows, knees, ankles, pelvis, chest, skull, mandible and spine. Case 1 (AD) also under went a barium swallow, meal and follow-through, angiography o-f the hands and serial films of the hands at 6 months and 2 years after presentation, and a film of the pelvis at 2 years. . ." 7- - "These 4 cases bhow the wide radiological spectrum that may be encountered in men complaining of symptoms which could be related to their work in the polymerization of vinyl chloride. In Cases 3 and 4, no specific changes were encountered; in Case 2 only moderate changes were recorded whilst in Case 1, extensive bony changes were documented. IndjSed, in Case 1, most regions of the body were involved and a review of the literature revealed that no previously reported case had such extensive bony changes. It has been suggested that personal idiosyncrasy nay be an im portant factor in the wide variation of the radiological findings (V/ilson et al. 1967)* " "Hoss (1970) stated that the bone changes regress after the sufferer is removed from the hazard but in our Case 1 the serial films of the hands, feet and pelvis indicated that the acro-osteolysis was extending. Fragmentation of the remaining tufts has been described as part of the healing stage by Wilson et al. (1967), but in our Case 1 it was only in the distal phalanx of the left big toe that there was any definite evidence on the 2-year film to indicate bony regeneration." Title: "Clinical Aspects of Vinyl Chloride Disease: Skin" by Dr. Anne E. Walker. "The study covers 37 men aged between 26 and 59 years (average 50 years 2 months). Length of employment at the plant ranged from 9 months to 5;- years (average 2 years 8 months). Thirty workers had at come time' been reactor operators, 4 were maintenance men, 2 'worked as 'baggers' and 1 was a warehouseman. . . "The commonest complaint was of excessive fatigue: men claimed to be excessively fatigued after minimal exertion and also reported somnolence. Coldness of the hands was also a frequent complaint." "Obviously these subjective symptoms were difficult to evaluate or measure. However, one feature was noteworthy: 56 of the 37 stated that on at least one occasion they had felt overcome by the vinyl chloride fumes, describing themselves variously an 'unsteady', 'slightly drunk'and 'rubbery-legged', and this suggested that the men had been intermittently exposed to very high levels of VCK, which in experimental studies produces anaesthesia. 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 VCH. "None of the 57 men had evidence of sclerodermatous skin change. One man previously employed at the plant had extensive sclerodermatous skin change affecting the hands, forearms, face, truck, thighs and dorsum of the feet; additionally he had extensive l\5 CL O o vi f 8- - lytic lesions of the bones, phalanges, feet, pelvis and jaw (K Lloyd-Jon'es, personal communication). In 5 nien there was clinical evidence of Raynaud's phenomenon; in d it was a marked feature, with rapidly occurring colour changes from blue black to blanched white to a flushed pink. Individual fingers on the same hand night show a different colour change at %o.ny one tine; on one occasion I observed a harlequin effect: the index finger was blanched white on the radial side and blue black on the ulnar side. Eight other men described symptoms of Raynaud's phenomenon but at exainination 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 narked 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 scleroedema rather than scleroderma. "Skin biopsd.es were obtained from the dorsum of the hand in 15 -men. The" epidermis and adnexal structures showed no abnormality. In the dermis there was. some destruction of elastic tissue, but it was probably a normal age change. In one man with severe Raynaud's phenomenon the dermal arteries showed some medical thickening." "Dr Marcus M. Key (University of Texas 'School of Public Health, Houston, Texas) asked if baggers and v:arehousemen had previously worked as reactor cleaners." "Dr Anne Walker replied that they had not. Usually men started as baggers end later became reactor'operatives and cleaners. The one warehouseman had never been in a reactor. One of the baggers had spent an initial training period as a reactor cleaner but had felt nauseated whilst in the reactor. After the first two weeks he had worked entirely in the dry building for four vears. The other bagger was an eoilertic and had never been in a reactor." Ti11e: "Evidence of an Immune Complex Disorder in Vinyl Chloride Workers" bv Dr A. Milford 'Ward. With respect to the occurrence of Raynaud's phenomenon and loss of bone density in associa tion with dermal thickening. . "Recent studies have indicated that the disease process is not confined to the skin and skeletal t issues, but is a multi-system one with involvement of many organs and tissues." . M M Cd CO o 9- - "The major features of the disorder include hyperinmunoglobulinaemia, cryoglobulinaenia and cryofibrinogenaemia, and in vivo complement activation via the classic pathway with C4 and C3 conversion. There is, in addition, evidence for a reduced T cell population, with lov; spontaneous cheep cell rocette counts, and an^,increased B-cell population, as evidenced by an absolute increase in lymphocytes showing membrane bound immunoglobulins. The total lymphocyte counts are usually normal or slightly increased. Some patients chow non'organ-specif ic antitissue anti-bodies of low titre but rheumatoid factor is universally negative.. ." . "The association of these experimental data with the observed immunological profile allows the construction of a theoretical model of the disease process. The initiating sequence is at present speculative and remains to-be proven by further study, but the later sequence of events can be adequately explained by the immunological abnormalities. . ." "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 theoretical, and at present speculative, initiating sequence of reactions in this disease process also raises the question whether other unsaturated halogenated hydrocarbons may also be involved in a similar chain of events." Title: "Chromosomal Effects in Peripheral Lymphocytes" by Dr. I. F. H. Purchase, et al. ". . . In common v;ith other carcinogenic chemicals, such as benzene, recent studies have demonstrated that workmen exposed to vinyl chloride have an increase in the percentage of lymphocytes with chromosomal abnormalities." "Studies of this type carried out on lymphocytes recovered from peripheral blood provide an easy clinically applicable method of assessing damage to living cells caused by carcinogenic chemicals. If there is a quantitative relationship between the percentage of chromosome abnormalities and the amount of exposure to the chemical, the estimation of chromosome abnormalities may provide a useful tool for determining levels of exposure which do not produce this mutagenic effect. "V/e have studied a population of 80 workers including exposed workers, nonexposed workers from the same industrial site, and nonexposed control subjects from another environment. . ." "The induction of chromosomal abnormalities is'indicative of a mutagenic effect of vinyl chloride. It is important to -know w'hether vinyl chloride is capable of inducing mutagenic effects in ether test systems and particularly whether such an effect is produced on germ cells. Accordingly vinyl chloride was examined for dominant lethal effects in nice. Groups of 15 male r 22397009 -10- rr nice were exposed to 3000,10000 or $0000 parts/10 of vinyl chloride for 6 hours per day for 5 consecutive days. Each male was mated with 2 virgin fenales per week for 8 weeks and the females were killed at 13 days and examined for dominant lethal effects. 'There was no significant increase in any of the parameters (early deaths per implantation, 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." Title: "Preliminary Results of Grey-Scale Ultrasonography in the Detection of Vinyl Chloride Related Liver and Spleen Disease" by Dr. K.J.V. Taylor, et al. ". . .a pilot project was carried out to ascertain whether ultrasound offered a possible noninvasive method for visualizing the liver and spleen in workers exposed to hepatotoxic agents. Initial results proved encouraging. . ." "The liver is scanned in a series of paramedian sections illustrated in the schema shown in Fig 1. The resulting ultra sound scan is shown in Fig. 2. Ultrasound is a fast means of acquiring data. Using this single pass technique through the liver as.shown in the diagram, good resolution is obtained without degradation by respiratory or cardiac excursions. This ultra sound technique involves no ionizing radiation nor other known hazards, no discomfort, and no need for contrast media. It does require considerable operator expertise and high quality instrumentation, which has only recently become commercially available. Machines which do not display the consistency of the liver are unsuited for examination of it.. "nineteen volunteers were selected from the factory work force, with varying exposures to vinyl chloride monomer. . ." "These preliminarv results suggest that ultrasound will result in a small incidence of false negatives (2 out of 19), so that the method is complementary rather than a replacement for current techniques. Both acquiring the ultrasound scans and interpreting them requires operator expertise, but automated scanners should become available within the next year, while experience car. be gained if the potential of the method is sufficiently.promising. Preparations are currently being made for a more extensive investigation of the appiication 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 VCN, as well as in workmen exposed, during the course of their employment. . .11 Title: "Collagen Studies in Acro-Osteolysis" by Dr. M. I. V. Jayson, et al. O tO Z G E Z Z -11- "Ihe skin changes of acro-osteolysis (aOL) are in many respects analogous of those of scleroderma. In both conditions there is severe rigidity and thickening of large areas of skin, suggesting qualitative or quantitative changes in the collagen. . tS X "By both crosslink analysis fend by measurement of 'n-proline incorporation into hydroxyproline, we have confirmed excess new collagen synthesis in the skin of a patient with ACL. These results are analogous to the findings in the skin in scleroderma and account for the thickening of the skin. It is possible that the effect is generalized, and excess collagen proliferation in the blood vessels could lead to chronic ischaemia with ulceration of the fingertips and further local collagen production. Ischaemic necrosis could similarly occur in AOL and so produce the typical bone lesions." "However, the AOI. bone lesions differ in appearance from those of systemic sclerosis." Title: "Epidemiological Studies of FVC Manufacturers and Fabricators, and" Primary Angiosarcoma of the Liver" by Dr. ?. J. Baxter ". . .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 manufacturing P/C in Great Britain. Present and future workers are also to be incorporated. Identification details of the workers, including duration of employment and details of past exposure, are entered by the factory personnel departments onto individual survey cards according to instructions provided by^ZHAS. Past exposure had^bcen graded into high C7 200 parts/10), medium (y 25 parts/10b), and low (</25 parts/10 *), with 'constant' and 'intermittent' categories. The cards are updated annually and sent to ZMAS headquarters. . "Tne main aim of this study is to identify and verify all diagnosed cases of primary angiosarcoma of the liver occurring from 19.74 onwards, and to evaluate their association with occupational exposure to vinyl chloride. . "Tne controls, matches for age, sex and death register (locality), will be chosen from the other liver cancer deaths and also from deaths from all causes. Pour liver cancer controls for each angiocarcome case will 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 case. . "In conclusion, prospective and retrospective studies are being carried out to provide a comprehensive assessment of the risk of occupational exposure to vinyl chloride and the development TT0Z6SZZ -12- of primary angiosarcoma of the liver. The prospective mortality and cancer registration studies will also permit the testing of hypotheses concerning the carcinogenicity of vinyl chloride in other sites, such as the lung and brain. And in the absence of a satisfactory objective test forjase in morbidity surveys, mortality data should enable the more serious complications of periportal fibrosis due to vinyl chloride to be assessed." Title: "Histopathologv of Liver Lesions Associated with Exposure to Vinyl Chloride Monomer" by Prof. K. V/einbren. "The tumour consists of cells which vary considerably in appearance but seem to have enough common features, particularly in their mode of growth, relationship to vascular spaces and stromal changes, to support the view that they are derived essentially from one cell type. "In general the -tumours show a gross appearance of dark haemorrhagic nodules in the liver; there is a variable distortion and apparent fibrosis in the intervening liver tissue. Sometimes foci are macroscopically less haemorrhagic. There is often frank necrosis." ". . .In sum, the tumour cell is distinguishable from hepatocytes, resembles cells normally associated with vessel val]s and appears to be closely related to vascular spaces with variable degrees of abnormality. "There are changes in other elements, both in tumour-bearing regions and in parts of the liver which appear to be free of tumour. These .changes seem to involve mostly the supporting stroma. . ." Title: "Epidemiological Studies of Vinyl Chloride Health Effects in the United States1' by Dr. Henry Falk and Mr. Richard <1 V/axweiler. Paper discusses history of vinyl chloride problem in USA; HAS surveillance; medical screening of vinyl chloride workers; cohort mortality study at four PVC polymerization plants. Since the discussion of this paper.includes reference to Pottstown, I am attaching the complete paper as "attachment A." Title: "Medical Surveillance of Vinyl Chloride Workers" by Dr. B. V/. Duck. Paper describes medical surveillance program of Great Britain. . .A programme of action was discussed end agreed with medical representatives of Government and Trade Union agencies 270 .GZZ I -15- and it was accepted that one of the main objectives was to gather clinical and epidemiological data to provide a reasonable foundation for future decisions concerning regular medical sur veillance. "The survey population was divided as follows: Vinyl chloride workers Grouo 1 - all autoclave floor workers, vinyl chloride monomer (VCfO production workers with five or more years' service; Group 2 - vinyl chloride nononer production workers with less than five years' service, all other VCIi/P/C production workers. Controls - workers from sane sites with no history of VC exposure. "A standard medical examination procedure was adopted: Initial examination comprising medical history (questionnaire), physical examination, biochemical tests (SGOT, SGFT, GGTP, alkaline phosphatase, bilirubin), platelet count, urinalysis. Follow up of abnormal findings, with repeat biochemical tests and platelet count, and persisting abnormalities referred to consultant for specialist investigation. "The programme was introduced simultaneously on the six production sites and the employees concerned were informed that it was not an individual screening test, but a joint investigation to provide data that would help to establish future medical policy. It v/as also explained that any individuals with suspicious findings, notably persistently abnormal test results, would be referred for appropriate specialist investigation by arrangement with their family doctors. . ." ". . .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. . "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 5 standard deviations) the normal range in order to be classified as abnormal. Repeat testing revealed persistent abnormalities in one third of the vinyl chloride workers in whom the initial findings were abnormal and these 5$ men were referred for further investigation. Comparable data for the controls are at present unavailable." Title: "Environmental Monitoring" by Mr. H. F. Henning. Paper describes instrumental monitoring techniques; presentation of results; influence of peaks; influence of sampling frequency; other problems (preservation nf _ ST iisLGeZZ RAP:blc cc: Mr. T. C. V/alker Dr. F. T. Dins Dr. L. H. Ballou - Akron Attachment A 45 Section ofOccupational Medicine 303 Dr Henry Falk (Cancer ant! Birth Defects Division, Bureau of Epidemiology, Centerfar Disease Control, United Stales Public Health Service, Department ofHealth. Education, and Welfare, Atlanta, Georgia 30333, USA) and Mr Riclurd J Wnxweilcr ( Division of Field Studies and Clinical Investigations, National Institutefor Occupational Safety and Health, Centerfor Disease Control, United States Public Health Service, Department ofHealth, Education, and Welfare, US Post Office Building, Cincinnati, Ohio 45302, USA) Fig 9 Bizarre and enlargedsinusoidal lining cells and hepatocyte mitotic abnormolily in same patient as . FigC.H&E. v.600 to be striking hepatocyte involvement, even with mitotic abnormalities (Figs 8-9). The question whether these lesions are signifi cant as prcmalignant changes is unanswered, as many of the alterations can be found in other conditions such as congestive cardiac failure, endothelial cell hyperplasia in cases of lymphoma, and of hepatocyte and other changes in many drug toxicity situations. Other pathogenetic questions also have to be posed, such as what is the primary lesion, which cell is involved in the formation of the tumour, what is responsible for the curious fibrosis and survival of the hepatocytes. Understanding these processes would probably enable us to make a better assessment of individual risk factors and perhaps to work out whether there is a tolerable exposure. REFERENCES Cakrr H Ur C, J'acrt C> EX Dano J (1936) /*'*.*/ofP.ukuinfyandItucirriohgy 72, 173--182 niocUJ D. (1974) /< f^r Amrrictu* Klrtlical A tsociuiion 229. 53--5^ l>rt J L. ?* K 1\ ilriwai S K, l`al N C. lla*u .VaJttcF K C. Ii*r? K 1.& A k (IV67) Am*uth of Internal Medicine 66, 41-67 LetFIX. I|jn DS (1974) Lasted i, 131A flrtflson U', Km V, Otpini J Si lleli^n*] J P (l#6K> Comerr (r/tihJ.tphiu) 21,314.-322 lUthF (1937) Zcitu hriftfur Krcbtfnrtchumc 61.4AH-50J 1 kiMtus L. I*. IVjv^r II. Il*rk K I). Srtihnll l J \ F.ilk H (1973) \Vv l nstUtrui Jouttuklof Alfda me 29!, 17-22 Vi<>lrlJl J &; I'vulitin II (1^72) Acta /\ttbal**4ifa ft Seanthmanca Stcttnn A DO, '*7-103 Epidemiological Studies or Vinyl Chloride Health Effects in the United Stales The vinyl chloride (VC) problem has had a con siderable impact in the United Slates during the past year and a half. Perhaps related to the age and conditions of the VC industry, or simply to the sheer size of it, the United States iias so far had the largest share of cases of VC-induced hepatic angiosarcoma (HAS); at the present time there have been 17 known cases in polymerization workers (Lloyd 1975). The finding of the initial cases was a dramatic event, and unlike what has occurred with many other proven or suspect carcinogens, the confirmatory experimental evi dence arrived almost simultaneously with the epidemiologic results (Multoni &. Lefomine 1974). The widespread industrial applications and uses by the consumer were instantly appreciated, and since the VC problem also arrived at a time of growing awareness and concern among workers and consumers about environmental and occupa tional hazards, it served to focus these concerns. Within the first few months after the initial cases were described a number of worrisome reports appeared. Investigators in Louisville, Kentucky, and also at Mount Sinai Hospital in New York demonstrated a high percentage of liver function abnormalities in polyrrierization workers, suggesting a broad problem (Mnkk c/al. 1974, Liiis ct al. 1975), and, in addition to this, the earliest mortality studies (Mnnson et al. 1974, Tabcrshaw A Gaffey 1974) suggested increased rates for nonhepatic' tumours, parallelling the multiplicity of tumour types seen in experimental studies (Multoni A Lcfemine 1974), Review of records at the Connecticut Tumor Registry, started in 1935. revealed 5 definite cases of HAS; 4 cases were clustered in one industrialized area and had occurred since 1967; 3 of these (and possibly a fourth case where the diagnosis was uncertain after review of slides) occurred in workers tit two polyvinyl chloride (I'VC) fabricat ing plants or in residents living nearby (Iaindrigan A Heath 1976). Further concern was generated by \ / / / / / / I 304 /Vr*c. rry. 5w. Med. Volume 69 April 1976 46 reports of the potential carcinogenicity of chemi Table 2 cals structurally related to VC. e.g. chloroprcne lirpalie mrieurronu ifc l`*tnJ State* # (Lloyd crul. 1973) and trichloroethylene (National hy ace at death aaJ ex. |VM-|V7J Cancer Institute 1975. unpublished data), and by the knowledge that VC workers irt many instances have been exposed to multiple related chemicals, including vinvlidene chloride and acrylonitrile (vinyl cyanide). J As part of the United Slates Public Health Service response to the VC problem, the National Institute of Occupational Safely and Health Atr ml Jrntk L> *'*) 0-9 1019 20-29 30-39 40-49 30-59 *4-69 70-79 Mule 2 ] 1 5 7 13 5 11 I / rmat* * 1 1 4 2 2 3 3 2 Toi*dl 4 * 2 9 9 13 10 14 3 (NJOSH) and the Bureau of Epidemiology, . 46 22 68 Center for Disease Control (CDC). have worked on a number of VC-related epidemiologic projects O Frrrm death certificate*. ICD Ccxfe 197.8 (8th Rcvuion). Data for New York City not included during the past year and a half; in this paper we will briefly review some of the early results of three of these studies. There was approximately I case of HAS for every 300 death certificates reviewed. HAS Surveillance A death certificate search for all cases of HAS recorded under ICD Code 197.8 (8th Revision), which encompasses various miscellaneous forms of liver tumour including most cases of HAS, was undertaken by CDC for the years 1966--73 in the United States. This search is almost completed, with only data for New York City not yet available at the time of this review. Table I shows the number of cases or HAS and non-angio hepatic sarcomas by year of death for 1966-73; there is no evidence for an increase in the incidence of these malignancies during this period. A review of the relative occurrence of hepatic sarcomas recorded under ICD Code 197.S showed angiosarcoma to be the largest group (35% of total hepatic sarcomas), followed by sarcoma of unspecified type (31 %). leiomyo sarcoma (13%), fibrosarcoma (7 %), and a grouping of miscellaneous sarcomas (15%). Table l Hepatic sarcoma in the United State*# by reported hittolnfi.v nJ >ear of death. 176**-1773 Yrot t>f 4emth 1966 1967 196* m9 1970 |M 1 1772 D 1973 All 31 40 23 14 31 9 23 196 Atvio*mecoi4i 9 13 9 7 I' * 1 9 4arcotmi 22 27 14 7 16 If 8 16 68 128 O From dcjtl* certificate*. !("!> Ctnle 197.S (Slh Kevinon). Data ir>m New Y*k C'My not m-'lmlcd tijlf year sample . Table 2 demonstrates a male to female ratio <Jf 2:1 for HAS. Sixty-two percent of cases occurred in the group aged 50 or more, with 26% in the 30-49 year age group. Non-angio hepatic sarcomas differed in having a male to female ratio of only 1:1, and an altered age grouping with 7K% of cases aged 50 or more and only 9% in the 30-49 year age group. These differences are con sistent with a hypothesis that occupational ex posure may be a more significant factor in the causation of HAS than of non-angio hepatic sarcoma. Only 2 of the patients with HAS in the death certificate review were recorded as having worked in PVC or plastics plants (I PV'C polymerisation worker a.id I accountant in a PVC fabrication plant): both were cases which had been identified prior to this study. No other occupation is recorded more than twice except for the occur rence of 5 printers. Although all were subsequently confirmed as printers, a preliminary review of pathology records and specimens suggests that 4 of the 5 cases may have been incorrectly diag nosed as HAS. CDC has supplemented the death certifr~.te survey with an intensive case-finding effiket, including a national mailing to all pathologists, state epidemiologists, and major cancer rcfbrral centres and tumour registries, seeking information on as many eases of H AS as possible diagnosed in the US during the \ears 1964-74. At the present time approximately 2-50 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 oT all cases to obtain more detailed histories regarding r- . 8 CJ co -J 0 h* 01 47 Section ofOccupational Medicine 305 past occupations, toxic exposures, and places of Table 3 residence is underway. Lm (anttf tiuftg X PVC p9>7mtruilM*Uai im rW Uni:*4 State* by h*ulo<*< (jroe ttitn* ! V'C mmwh m Medical Screening of VC Workers Together with the Occupational Health Studies Croup of the .University of North Carolina, NIOSH-CDC recently concluded a cross-scctional medical screening examination of 530 workers at a plant in Pennsylvania which contains both a large tyre-building facility as well as one of the oldest PVC polymerization plants *in the United States. Included in the study were approximately 130 current PVC polymerization workers and a Extent of rC xjpotutc ItAiotogic type Son* pdcrmod t Small cell uiHlilfcrtathu4 0 Adenocarcinoma 1 Lar^t celt uodilTcrctuiatcd 4 Utwlaushcd 1 Lets the* oe year 1 3 1 0 0 Ateee thorn or%4 ytoe 0 0 4 t 0 Totml 2 3 4 10 1 75 10 22 similar number of control workers from the tyre plan; who had never worked in the polymeriza tion facility. The 2 groups were comparable in if confirmed, this unusual cell type distribution age, alcoholic intake, and socioeconomic back may support the association between VC exposure ground; the controls were chosen from those and occurrence of lung cancer. areas of the tyre plant where exposure to solvents and dusts was least. There are, however, two additional features which should be considered in evaluating this Preliminary review of the results shows no potential relationship. When all or the workers significant differences between the 2 groups for at these 4 plants are considered, including those any of the 6 liver function tests performed (SCOT, who were net part of the defined VC-exposed bilirubin, alkaline phosphatase, LDH, GGTP, cohort, a total of 22 cases of lung cancer (out of and ornithine carbamyl transferase). Additional 4S) were available for pathologic review. The analyses based on levels of VC exposure, duration increased incidence of large cell undifferentiated 2nd type of job, and other subgroupings are and adenocarcinoma of the lung was seen in VC being done; these preliminary results however do workers with more than 1 year of exposure, while not suggest the occurrence of liver function a distribution more closely resembling the ex abnormalities on a broad scale secondary to VC pected small cell predominance was seen for VC exposure. One should of course be cautious about workers with less than 1 year of exposure. generalizing from the results at a single plant, and Interestingly, however, cases of lung cancer in it will be important to compare these findings to non-VC workers at these plants, although small studies at other PVC plants. It is also important in number, appeared to have a cell type distribu to realize that since liver function tests are rela tion which was also predominantly large cell tively insensitive to the early finding of VC- undifferentiated (Table 3). In addition, unlike the induced hepatic disease (i.e. fibrosis), the results situation for HAS in these plants where all but of this type of testing are not a reliable estimate one of the cases were long-term reactor cleaners for the prevalence of VC-induced disease. Liver and operators, the workers with large cell un scans were also performed on all workers with differentiated and adenocarcinoma of the lung more than 10 years duration of work in the PVC were distributed in a number of different job polymerization plant, and no cases of HAS were categories. As a result, cases of lung cancer seem detected. Some increase in frequency of palpable not to correlate as tightly with VC exposure as livers on physical examination was found, how cases of HAS and it is conceivable therefore that i ever, among VC workers. A full report of findings some additional chemical exposure at these from this comprehensive medical screening study plants may be working together with VC (or even is in preparation and will be available shortly. separately) to produce this effect. Further studies are currently underway in an effort to confirm Cohort Mortality Study at Four P VC Polymerization Plants One of the results of this NIOSH-CDC study was these preliminary pathologic findings. the demonstration of an increased SMR for respiratory system cancer among members of the cohort (Waxweiler et etl. 1976). On preliminary pathologic review, it was also noteJ that of the 12 lung cancer cases all 8 for which pathologic specimens were available were cither large coll undifferentiated or adenocarcinoma of the lung; REFERENCES LanUficjn P J A I loth C \V jr rm>aratin I.ilis It. AodtnM H. NkKoltM W J, Daum S, FncHWiaA S A SrUvIl I J (1973) Anmuh </ the ,\> York AeoJetny of Scir^cet NA, 22 UfdJ W (\97S) Journal of Occupational Marine 17,333 -'H* z;;V:.i.`.*' Hen \ 'i / / 306 Proc.roy.Soc.hltd. Volume69April 1976 48 L!o>d J \V. P & Morrt K M (1975) Jourm-tlr>fOeeupctiomul 17. 20 MiU 1^ ffmh J L jf, \\I*tKo J r. \t *V JoIwiwa M N (197-i) JoierrM**/Atftrrie*t*t A Ltor/td/rofi 2J0, 64 MaIiuu* C & Lt(iNM C 0774) Krtr+*<h 7, )*7 Mmvm R K. Prim J M Jfc JwIwisom M N (1974) lAKfrt ii, 397 TiWrOuw I K * Cjff#/ \V K (WH)Ju*rn~il*f(Jcrupctio*al.\trriifit** 16, 507 iVui)rf K J,S:r*g;rrW,JifwJ, \^3(MwrJ K. Falk I1& Ctrlrf C (IV7f) zIms/i /York. And*trt/ of Sdtmcrs(inprtu) DISCUSSION N10SH-CDC study, the TaK'rshaw study, and the Monson-l*rters study) had all looked at the Louisville, Kentucky plant where the initial angiosarcoma caws occurred as wvll as ar a varying number of additional plants. Compounding the problem v.a> the fact that the definitions for entrance into the cohorts studied differed from study to study, so that the result; even - at the same plant were not identical. Dr J A Donnell (Central Electricity Generating Board) asked whether, since vinyl chloride nionnmer was a carcinogenic agent, there was any evidence in experi mental ar.iir.als or in human clinical experience ;.iat' the skeletal or skin changes described might be premalig.omt conditions. Ur Mitchell It Zavon (Huron Rouge, Louisiana) asked whether the clinical examiner* at Pottstown knew whether or not the person being examined worked in vinyl chloride. Dr H Falk replied that none of the clinical examiners were aware of the occupational status of the workers at the time of the examination. I)r H Falk said that cases of angiosarcoma in the USA did not have a history of aero-osteolysis or skin problems, although they did not have the multiple tests for early changes of acro-ostcolysis. It would seem, therefore, that the skin changes were not premalignant conditions. Dr R I McCalluni (University of Newcastle upon Tyne) asked Dr Falk to give in mere detail the way in which histological diagnosis was made in the case of lung cancer shown in his slide. Was this done by one individual or by a panel of pathologists? How were the specimens of tissue obtained: by biopsy, surgical .resection or at autopsy? It was remarkable that in none of the cases was an oat ceil 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 (1967; was used. Four patho logists reviewed the slides and agreed on the inter pretation (Dr Louis 11 Thomas and Dr T Powell, National Institutes of Health: Dr M Kuschner, State University of New York; and Dr Las/.lo Makk, St Anthony Hospital. Louisville. Kentucky). All avail able pathological material for each case was reviewed. The expanded pathological review currently under way would include the selection of multiple control cases of lung cancer from the same hospitals (with simi lar age and date of diagnosis to the study cases) and a blind review by a panel of pathologists in a more detailed evaluation ofnvailarlr pathology material. To Dr Falk's knowledge large cell undifferentiated carcinoma of the lung had not been related to exposure to chemical carcinogens, which nude the findings itt the VCcohort even more intriguing. Dr A J Fox (Employment Alediettl Advisory Service, London) asked how many fucO'ihad been studied individually in the USA. What proportion of these had indicated vinyl-chloride-associated disease? Professor I .T SclikofT (A [mint Sinai School of Medicine, City University of New York) said that a review of known details of identified cases of vjnyl-chlorideassociated angiosarcoma of the liver by Dr Lloyd (1975) of the National institute for Occupational Sa: :ty and Health had demonstrated that the median duration from onset of exposure was approximately seventeen years. These cases were derived from the rather small number of polymerization workers em ployed during the establishment and initial growth of the vinyl chloride industry. Attempts were underway to identify and trace the initial groups of workers, employed during Ihe years I93S-55. since analysis of their experience would allow evaluation of the risks which might be suffered hy the very much iarger group of vinyl chloride workers expivsetl more recently, ' in a period during which I'VC production was in creasing at the rate of approximately 10?^ per annum. Limited data bearing on the problem had been obtained. In one polymerization process studied. 257 men had been employed for five years or more in the period between 194/). when the plant opened, and 1964. Each man had been traced to 1 July 1974, with 25 deaths from nil causes: 3 of the deaths were due to angiosarcoma of the liver (Nicholson cl al. 1975). each confirmed on review of autopsy material (Thomas Jc Popper 1975); in addition there was one death due to ruptured (esophageal varices. Another worker, examined during the clinical survey at this facility fLilts </ nl. 1975) had had a successful portacaval shunt operation for the same condition. These experi ences vuggestejFihat viiiyl-chloride-associated disease would be aa impori.uii ii.i/aid Tor vinyl ciiimidc workers in the future, unless control of exposure resulted in at least some reversal of the risk. Dr II Falk replied that cases of hepatic angiosarcoma had been seen at 5 of the S I'VC polymerization plants opened prior to 1950. There wav some confusion in this area in that a number of the VC worker mortality studies had been overlapping. Three separate studies, for example, (the l.n.s K. AniUrxon 1Nh'Wvm W J, f ).*< S, JL ^vl.kt.U ) J AS (1^7.^! w //?( Xcw Acniikmyi't 246. '2-41 U>d J inf 17. ,in-)l4 Nirtinlwfi W J, lljnimtwil II C. Vtdm.iH 11 A Nvlk4l I *1 (1^*51 ,\nn.,U of the .%>*' Ar**U'"tVof ,V c 246. 225-250 TIhmiwa L ft ,V }loiHM*r II (IV75) Arn.tlf ,>/ihr AYork ActtJrmy ofS\ #><** 246, 26.4-277 i' ATOZS2ZZ