Document OERd6KE1J0BJKBn4498RY9K7w

/ J. Soc. Occup. Med. (1979) 29, 134-141 Printed in Great Britain a/ Vinyl Chloride: a Review THE ENCLOSED INFORMATION V'AS OBTAINED FROM A VARIETY OF SOURCES. THEIR INCLUSION DOES NGT IMPLY ENDORSEMENT BY NIOSH. C. H. B. BINNS Senior Medical Officer, BP Oil Limited Summary The polymerization process for the industrial production of polyvinyl chloride from vinyl chloride was discovered in Germany in the mid 1930s. Since then, both have been produced in increasing quantities. The first cases of occupa tional acro-osteolysis in workers engaged in the industry were reported some thirty years later in 1963, and the first cases of angiosarcoma of the liver in workers similarly engaged were reported some forty years later in 1974. Intense public and medical interest were aroused and resulted in extensive investigations into the medical prob lems now seen to be associated with the industry. The chronology of these events is outlined, and the epidemiological, chemical, histopathological and biochemical investigations which resulted are briefly reviewed. Finally, possible metabolic processes, which could result in the known clinical manifestations, are discussed. Physical Characteristics Vinyl chloride (VC), ch, -- chcl, is gaseous at normal ambient temperature and pressure having a boiling point of --13-5 C. It is approximately twice as heavy as air, having a vapour density of 215. It is only slightly soluble in water, but soluble in ethanol, ethyl ether and polyvinyl chloride (PVC). The gas is highly flammable and explosive, having a lower explosive limit of 4 per cent and an upper explosive limit of 22 per cent in air. It is easily liquified by pressure, and in this form has the property of being readily polymerized at temperatures in the range of 40-70 C by exother mic reaction to form PVC, each molecule of which contains between 500-1500 molecules of vinyl chloride, and which in the raw state has the appearance of a fine white powder. History Vinyl chloride was first synthesized in 1833. The polymerization process was discovered some 100 years later in Germany in the mid 1930s. There after, the industry developed rapidly, both in Accepted for publication: April 1978. Europe, which accounts for about 50 per cent of world production, and in the United States, which currently accounts for some 25 per cent of world production. The fire and explosion risks of vinyl chloride were fully appreciated from the beginning of the industry, as was the acute narcotic effect induced by exposure to high concentrations of the gas. Indeed, as early as 1933 Peoples and Leake had investigated the use of vinyl chloride as a possible general anaesthetic. It was abandoned principally because of the adverse cardiac effects it produced in dogs at anaesthetic concentrations. Apart from the acute narcotic effect, vinyl chloride was regarded as being relatively non-toxic, and the first maximum acceptable concentration published by the Manufacturing Chemists Associa tion (1954) in the United States recommended 500 ppm for worker exposure on the premise that `in concentrations well above 500 ppm vinyl chloride acts as a mild general anaesthetic'. No attention appears to have been paid to a report by Tribukh et al. (1949) of hepatitis-like liver changes in exposed Russian workers. Until 1960 when two fatalities were recorded in a Canadian polymerization plant (Danziger, 1960), there had been no reported industrial fatalities, and these only served to underline the need for further precautions to prevent narcosis and effect rescue and resuscitation if it should occur. In 1961, the Dow Chemical Company reported slight liver damage in animals exposed to levels of 100 ppm and recommended that worker exposure levels be reduced to a 50 ppm time-weighted average (TWA) level. Despite this report, in 1962 the American Conference of Governmental Indus trial Hygienists, on the basis of further work at Yale, adopted a recommendation that a TWA of 500 ppm provided an adequate margin of safety for human exposure. This standard was subsequently 134 001357 X X r cent of es, which of world chloride ig of the duced by . Indeed, 'estigated : general / because n dogs at ct, myl ton-toxic, entration Associau mended raise that >m vinyl tic'. No report by r changes >rded in a r, 1960), lities, and or further ct rescue reported levels of exposure weighted , in 1962 al Induswork at TWA of Sdc~*y for .ntly * jj. -** 3 ? 4 3 VINYL CHLORIDE 135 adopted by the US Occupational Safety and Health Administration in 1971 as a National Standard which remained unchanged until April 1974, although, by 1970, the American Conference of Governmental Industrial Hygienists had signified an intended change to 200 ppm. Suciu et al. (1963) reported a symptom complex occurring in Rumanian workers involved in the polymerization of PVC which consisted of Ray naud's phenomenon allied with skin changes resembling, but not identical to, scleroderma. In 1966 two cases which were similar but which also had osteolytic changes in the terminal phalanges, and to which was given the name acro-osteolysis (AOL), were reported by Cordier et al. (1966) from Belgium. Further reports soon followed (Harris and Adams, 1967; Wilson et al., 1967). Dinman et al. (1971), of the University of Michigan, published the results of a survey which had been commissioned in 1967 by the Manufac turing Chemists Association into the clinical, epidemiological and industrial hygiene aspects of acro-osteolysis. The authors, however, were unable to determine the precise aetiology and recommended that animal studies be carried out. These were quickly forthcoming. Viola et al. (1971) of the Regina Elena Cancer Institute in Rome had been working with rats exposed to atmospheric levels of 30 000 ppm VC for 4 h per day, 5 days per week for a year, in an attempt to develop an experimental model for acro-osteolysis. They failed to do so, but noted the occurrence of tumours of the skin, lungs and bones which Viola first reported at the 10th International Cancer Congress in Houston in May 1970 and subsequently published in 1971 (Viola et al., 1971). Their foldings were subject to criticism, however, for technical reasons and for the excessive concentrations employed. Nevertheless, the report was of serious concern, and in order to produce unambiguous results, a group of European chemical producers shortly thereafter commissioned Maltoni of the Oncological Institute, Bologna, to carry out further animal studies (Maltoni, 1974). In addition, epidemiological studies were com menced, both in the United States and Britain (Manufacturing Chemists Association, 1974). By mid 1973, although the epidemiological studies had as yet shown no increase in the incidence of cancer of any type, preliminary results of Maitoni's (1974) work became available which re vealed the development of angiosarcoma, a tumour rare in both rats and humans, and one which might well therefore have been thought to have shown up during nearly 40 years of PVC production. Not withstanding, updating of the epidemiological surveys continued, and on 22 January 1974 three deaths due to angiosarcoma of the liver in former employees were reported to the National Institute of Occupational Safety and Health from the B. F. Goodrich Plant in Louisville, Kentucky (Creech and Johnson, 1974), and on the following day the news was transmitted to the Department of Employment in the UK (Gauvain, 1976). On 29 January, ICI issued a press statement that a single suspect death in a 70-year-old retired autoclave worker who had died in 1972, was under investiga tion. This was subsequently confirmed to be due to angiosarcoma of the liver. Polymerization of Vinyl Chloride Polymerization is carried out in cylindrical pressure vessels, surrounded by water jackets to control the temperature of the exothermic reaction. These vessels are termed variously, `autoclaves', `polypots' or `polykettles'. In the UK, reactor sizes range from 10 m3 to 40 m3 with monomer charges ranging up to 15 tons. Paddles situated within the vessels enable the contents to be stirred as the reaction proceeds. Two types of process are in use, namely the `suspension' process in which polymerization takes place in a disperse phase of de-ionized water, and the `mass' process in which polymerization occurs in the dry state. Apart from the water, in both cases the vessels receive an initial charge of liquid vinyl chloride (termed vinyl chloride monomer in industry to distinguish it from the polymer), organic peroxide initiators, surfactants, buffers, chain transfer agents such as trichlorethylene and emulsifying agents. The reaction proceeds under pressure, in the absence of oxygen. As polymerization reaches 90-92 per cent conversion, the rate ofreaction slows down, and, by 95 per cent conversion, has become so slow as to render 100 per cent conversion uneconomic. The residual unchanged vinyl chloride monomer is vented back to a gasholder to be re-used, and the newly formed polymer is trans ferred from the autoclave, dried (in the case of suspension polymer), graded and bagged or sent to bulk storage. The autoclave is then further evacuated by lowering the pressure to remove as 001358 136 OCCUPATIONAL MEDICINE much gaseous vinyl chloride as possible, before opening to atmosphere in readiness for the poly cleaners to enter and remove the residue of PVC `cake' from the walls and stirring paddles in the vessel. This was formerly done mainly by hand chipping and scraping, and vessel entry for this purpose was required after every batch of polymer, normally twice daily, with an average reaction time of 8 hours. In retrospect, based on experience with the very accurate methods now available for measuring ambient vinyl chloride levels, it is certain that this was the operation which involved exposure to the highest concentrations of monomer for the longest periods and with the greatest frequency. In the earliest days of the industry, it has been suggested that polycleaners may have been exposed to levels as high as 3000 ppm, whilst in the decade 1945-55, 1000 ppm would have been the likely norm. In the period 1955-60 the exposure level would have been approximately 500 ppm, from 1960 to 1970 perhaps 300-400 ppm and by mid 1973, 150 ppm. At the present time, the average levels in this country are 5 ppm or less, and, due to modifications in. the process, vessel entry is much less frequent, in some instances only being required after every 50 or 60 batches. In addition, cleaning is now mainly accomplished by high pressure water jetting which is quicker and does not always require vessel entry. For additional safety, every vessel opening and entry is now continuously monitored using infra red spectrophotometry sensitive to 1 ppm vinyl chloride and any increase in vinyl chloride level above the present UK TLV of 10 ppm (TWA) necessitates immediate withdrawal or the donning of breathing apparatus of an approved type. Apart from the problem posed by vessel entry, the problem of `fugitive' vinyl chloride escaping from the numerous pumps, valves, stirrer glands and blinds, required the development of a new order of engineering design and technology to reduce polymerization building levels of vinyl chloride in air to between 2-5 ppm. This is probably the limit which can be achieved with the present generation of plant. Clinical Manifestations of Vinyl Chloride Exposure Acro-osteolysis This is a rare clinical syndrome of which only some 75 cases of the familial type have been reported (Dinman, 1969). All the occupationally-induced cases have, with one exception (who was subse quently found to have been regularly and repeatedly exposed to vinyl chloride) (Steward et al., 1975), occurred in workers engaged in the hand cleaning of polyvessels as described above. The fully-developed syndrome has three main components: 1. Raynaud's phenomenon affecting the fingers and sometimes also the toes. Full development of the condition may be preceded by the feeling of tingling and numbness in the digits. 2. Skin changes resembling scleroderma, situated usually on the back of the hands or distal third of the flexor aspect of the forearm, and very rarely in other sites. 3. Bony changes, which, as the name implies, affect the terminal phalanges, usually of the fingers, but which may also affect the toes, radial and ulnar styloid processes, sacroiliac joints and lower poles of the patellae. The radiological appearances in the phalanges are those of band-like translucencies due to bony absorption, and, if the condition is advanced, there may be complete destruction of the tuft of the phalanx with a foreshortened spatulate appearance of the affected digits. Arteriography in these cases frequently demonstrates partial or complete occlusion of the digital arteries. The extensive epidemiological survey carried out by Dinman et al. (1971) involved 5011 employees with 21 510 man years' experience in various phases of vinyl chloride and PVC manufacture in 32 plants throughout the United States and Canada. It revealed 25 definite and 16 suspect cases (one of whom subsequently developed the syndrome). The `attack rate' varied between one case in 40 and one case in 60 polycleaners, or in terms of exposure time, one case per 25 man years in this specific job. In the survey by Wilson et al. (1967) the attack rate was less than 3 per cent with no age specificity and the condition was found to be virtually non existent in workers with less than 12 months' polycieaning experience. The low attack rate is suggestive of individual biological susceptibility being a factor in the aetiology. From the published cases, it would appear that any of the above changes may be present either alone, or in combination. Raynaud's phenomenon would appear to be the most frequently occurring condition in Britain, although there is doubt about its genuine occupationally induced incidence, since VINYL CHLORIDE 137 in all but one PVC plant in this country workers Other Effects Associated with Vinyl Chloride were not previously screened for Raynaud's Exposure phenomenon before assignment as polycleaners Hepatic Fibrosis (UK Vinyl Chloride Industrial Medical Advisory There have now been numerous reports (Juhe et al., Sub-Committee, 1977). 1973; Marsteller et al., 1973; Lilis et al., 1975; In their original papers, Suciu et al. (1963) and Smith and Williams, 1975; Thomas et al., 1975) of Cordier et al. (1966) state that upon removal from hepatic fibrosis of a non-cirrhotic type, frequently exposure, Raynaud's symptoms diminish or disap associated with splenomegaly and portal hyperten pear. This does not accord with recent British sion, in workers exposed to vinyl chloride, these experience (UK Vinyl Chloride Industrial Medical changes being significantly more frequent in workers Advisory Sub-Committee, 1977). It is of interest with longer exposure (Lilis et al., 1975). In some that Suciu et al. (1963) make no mention of of these cases the changes observed were identical radiological appearances in their cases, whilst in the changes described by Banti (Thomas et al., Dinman's survey (1969) most of the cases were 1975) and the changes described in association with found by radiological examination of the hands, prolonged exposure to inorganic arsenicals, which, only a few having sought medical attention because like vinyl chloride, may also' induce the develop of symptomatic complaints. In contrast to the ment of angiosarcoma of the liver. persistence ofsymptoms, on removal from exposure, The fibrosis which can be demonstrated in livers improvement in the radiological appearances of affected both with, and without, angiosarcomas, is phalangeal lesions, with recalcification, has been of a peri-portal type, and frequently accompanied demonstrated to occur (Williams and McLachlan, by marked capsular thickening of a `rice grain' 1976). appearance. In some cases it appears to be progres sive, and although the relationship of the fibrotic lesions to the development of angiosarcoma e Angiosarcoma of the Liver requires further study, Thomas et al. (1975) have n This is a rare malignant tumour. A recent survey by found evidence which they consider to be suggestive r Baxter et al. (1977) revealed that between 1963 and of a transitional stage. 1973, on average, there were only four recorded A feature of the condition is that hepatocytes do It cases per year in Great Britain and, when available not appear severely damaged, nor is reactive :s histological material was subsequently re-examined intralobular inflammation seen, a finding which .*5 by a specially constituted panel ofhistopathologists, could account for the erratic, or even normal, ts in only one-third of the cases did the panel agree results at this stage of those liver function tests It with the original diagnosis, and in only one of these which depend upon the integrity of the hepatocytes. >f cases could there be a confident association with This might also account for the apparent conflict in le exposure to vinyl chloride. In a further one-third of the findings of blood and liver function surveys in le the cases, the panel rejected the original diagnosis this country where no significant differences between re of angiosarcoma of the liver. Baxter et al. (1977) the exposed population and normal controls were fa. could trace only nine published cases of angio observed (Lee et al., 1977) and other surveys by :k sarcoma of the liver occurring in Britain before Lange et al. (1974) and Lilis et al. (1975), who ty 1963. The survey revealed no evidence of the reported the finding of significant abnormalities. ti occurrence of environmental cases. ts' By August 1977, following a search throughout is Western Europe, North America, Japan and Tumours of Other Sites ity Yugoslavia, some 63 cases of vinyl-chloride- Maltoni and Lefemini (1975) and Keplinger et al. associated angiosarcoma of the liver had been (1975), in addition to observing angiosarcomas of lat reported to the US National Institute for Occupa the liver in rats, mice and hamsters exposed to ler tional Safety and Health for confirmation. Thirteen vinyl chloride, also reported the induction of other on of these cases were still outstanding. tumours including cerebral neuroblastomas and n;* The average duration of exposure in the 50 pulmonary adenomas. The epidemiological studies >t confirmed cases for which data is currently available carried out in the United States (Tabershaw and ice is 17-8 years, with a range of 4-32 years. Gaffrey, 1974) indicated an excess of cancer of the COfSGO 138 OCCUPATIONAL MEDICINE respiratory system and brain in humans, but not such as to be statistically significant. In a more recent survey in the United Kingdom (Fox and Collier, 1977) of the mortality data of over 7000 men who were at some time exposed to vinyl chloride between 1940 and 1974, no evidence was found to support the hypothesis that cancers of sites other than the liver are associated with exposure to vinyl chloride. The authors point out, however, that since over 50 per cent of the workers in this country have entered the industry only within the last decade, any conclusions on mortality experience must be viewed with reserve, since the full impact of exposure may not yet have had time to become manifest. Mutagenicity and Chromosomal Effects In common with many other chemical carcinogens, vinyl chloride has been demonstrated to produce mutagenic effects in bacterial test systems (Rannug et al., 1974; Malaveille et al., 1975; Bartsch et al., 1975). Reports on chromosomal studies of exposed workers are conflicting. Funes-Cravioto et al. (1975), Ducatman et al. (1975) and Purchase et al. (1975) reported increases in chromosome aberra tions, mainly breakages, in the groups they studied, as compared with controls. Fleig and Thiess (1974), however, could find no evidence of increased aberrations in a group of ten workers, nor could Picciano et al. (1977), who, in much the largest study so far carried out, examined a group of 209 workers who had been employed in vinyl chloride manufacture for up to 28 years. They postulate that the reported-differences may be accounted for by the small numbers involved in some of the earlier studies, or by differences in exposure levels to which the groups were subjected, or both. They conclude that the level of chromosome aberrations in exposed workers is probably related to the length and level of exposure, and that adverse cytogenetic effects are unlikely to occur in controlled minimal exposure environments. The possibility of genetic risks to man has been raised by the work of Infante et al. (1976), who carried out a study on fetal wastage among wives of workers exposed to vinyl chloride in polymeriza tion processes by means of interviews with the workers on the outcome of pregnancies in their wives. The group exposed to vinyl chloride was matched for age with a similar number of current rubber workers selected from areas known to be relatively free from toxic substances. The results were claimed to indicate a significant excess of fetal loss in the wives of husbands who had been exposed to vinyl chloride, whereas there were no significant differences between the groups before such exposure. Very little experimental work has so far been published on the possible effects on germ cells. However, Purchase et al. (1975) demonstrated that in male mice, exposure to vinyl chloride at levels up to 30 000 ppm did not produce any dominant lethal effects in the offspring of virgin female mice with whom they were subsequently mated. Thus in mice, vinyl chloride did not produce a mutagenic effect in germ cells even at the very high levels to which they were exposed. Embryotoxic and Teratogenic Effects Although Maltoni (1975) exposed animals in utero to determine the oncogenic potential of inhaled vinyl chloride, the investigations were not specifi cally intended to be a teratological study. John et al. (1977) have, however, recently reported the results of such an investigation designed to assess the effects of maternally inhaled vinyl chloride on embryonal and fetal development in groups of pregnant mice, rats and rabbits during the period of major organogenesis. Concentrations of vinyl chloride to which the animals were exposed ranged from 50 to 250 ppm. Although exposure levels were sufficiently high to produce maternal toxicity in some instances, vinyl chloride alone did not cause significant embryonal or fetal toxicity, and was not teratogenic in any of the species at the concentrations tested. Pulmonary Effects Darke (1976) investigated 14 cases of breathlessness in exposed workers. There were no abnormal physical signs, chest radiographs were normal as were routine respiratory function tests with the exception of carbon monoxide diffusion which was slightly below predicted values in 6 subjects. The most striking abnormalities were marked perfusion defects of the upper lobes. Histology of lung specimens taken from one patient who underwent open biopsy revealed focal alveolar wall thickening with increased reticulin and collagen formation seen on electron microscopy. Some of the most severely affected of the men had however been 00?3'6l to be results ess of i been ere no before r been t cells. :d that vels up ninant e mice "hus in tagenic vels to n utero nhaled specifi- J^Hn te*. ; i assess ride on ups of period f vinyl ranged high to s, vinyl iryonal any of lessness 'normal rmal as ith the ich was ts. The irfusion of lung ierwent ckening nnation i? st er -en 1 VINYL CHLORIDE 139 working with a `paste' polymer which in powder protective mechanism. Watanabe et al. (1975) have form has a particle size in the range 0-5-1 pm and in fact reported such progressive depletion in rats n\v is therefore well within the respirable range, in exposed to levels of 250 ppm, but no such depletion contrast to the more usual type of polymer, which was found at 10 ppm exposure levels. At higher consists of powder with a particle size mainly in the exposure levels up to 100 ppm, the primary 80-100 pm range. It is not, therefore, clear whether metabolic pathway appears to be via the alcohol these findings were due to vinyl chloride per se or to dehydrogenase route involving sequential oxidation inhaled particulate polymer, or possibly vinyl to 2-chloroethanoI, chloroacetaldehyde (a known chloride absorbed onto the polymer. There is so mutagen) and monochloracetic acid. At even far no very convincing evidence of the production higher exposure levels, this route also becomes of a pneumoconiosis in workers exposed to PVC saturated, and it is speculated that one alternative powder. pathway may be by direct epoxidation to chlorethy- Szende et al. (1970) reported the case of a 31- lene epoxide or peroxide, both short-lived, but year-old male worker who had been exposed to powerful alkylating agents, which break down PVC powder for one year and in whom lung biopsy sequentially to mono-chloracetic acid and thiodigly revealed some granuloma formation and fibrotic colic acid (Hefner et al., 1975). changes. Granular material, which was non Ward et al. (1976) have postulated that chlorethy- crystalline and non-birefractive in polarized light, lene oxides could bind with free sulphydryl or was stated to have been found in association with amino radicals and that the incorporation of these the histological changes. No previous medical or into protein synthesis would give a confirmationally occupational history was given and there do not altered molecule that would be antigenic. The appear to have been any follow-up reports. antigen could then stimulate the formation of Frongia et al. (1974) reported the occurrence of antibody and their interaction could produce a histological changes in the lungs of guinea-pigs and soluble cryoprecipitable complex capable of initia rats subjected to continuous exposure, both day and ting complement fixation. These reactions could night, to extremely heavy concentrations of PVC then in turn produce platelet aggregation, apparent powder in a bagging plant for periods ranging from thrombocytopenia, fibrinogen/fibrin conversion 2 to 7 months. and vascular occlusion, either temporary or A recent study of British workers, all with at permanent. Such occlusion would be enough to least 10 years' exposure in the bagging of dry explain the observed clinical, radiological and powder, independently carried out by the National histological findings in skin, skeletal and soft Coal Board Radiography Service revealed no tissues and lung. By producing ischaemia, vascular abnormalities of any kind (UK Vinyl Chloride occlusion would also stimulate new collagen Industrial Medical Advisory Sub-Committee, 1977). synthesis as observed by Jayson et al. (1976). In view of Darke's (1976) findings, however, and the prolonged exposure time which may be required Conclusion to produce pneumoconiosis, continued observation In summary, it now appears that all the varying would seem prudent. manifestations of vinyl chloride exposure, namely acro-osteolysis, angiosarcoma of the liver, hepatic Metabolism and Possible Mechanism of Action fibrosis, splenomegaly, portal hypertension, throm Major metabolites which have been identified in the bocytopenia-and lung changes, may be different urine are thiodiglycolic acid, S-{2 chlorethyl) manifestations of a single disease entity for which cysteine and N-acetyI-S-(2 chloroethyl) cysteine. the term `vinyl chloride disease' would seem The cysteine-containing metabolites may be pre appropriate, and for which it is possible to postu sumed to have arisen from the reaction of vinyl late a common underlying pathogenic mechanism. chloride with hepatic non-protein sulphydryl groups Despite the widespread search for cases, angio (Williamson, 1976), which therefore exert a sarcoma of the liver was, and still remains, one of protective action by detoxifying the vinyl chloride. the rarer tumours, although many thousands of If the available sulphydryl groups are limited in workers must, during the past 40 years, have been quantity or in speed of replacement, this action exposed to high levels of vinyl chloride. More could well cause their depletion thus reducing the vinyl-chloride-induced cases may be expected, but 140 OCCUPATIONAL MEDICINE with the passage of time it seems increasingly reasonable to speculate that there exists a level of exposure below which there may be no discernible carcinogenic effect. Finally, if manifestations such as acro-osteolysis are associated with individual susceptibility to vinyl chloride as the evidence would seem to suggest, it will be interesting to observe whether any further cases develop in association with the more recent low levels of exposure. REFERENCES Bartsh H., Malaveille C. and Montesano R. (1975) Human, rat and mouse liver-mediated mutagenicity of vinyl chloride in S. typhimurium strains. International Journal of Cancer IS, 429. Baxter P. J., Anthony P. P., MacSween R. N. M. et al. (1977) Angiosarcoma of the liver in Great Britain, 1963-1973. British Medical Journal 2, 919. Cordier J. M., Fievez C., Lefevre M. J. et al. (1966) Acroosteolysis and related cutaneous lesions in two workers engaged in cleaning autoclaves. Cahiers de Medecine du Travail 4, 14. Creech J. L. jun. and Johnson M. N. (1974) Angiosarcoma of liver in the manufacture of polyvinyl chloride. Journal of Occupational Medicine 16, 150. Danziger H. (1960) Accidental poisoning by vinyl chloride: report of two cases. Canadian Medical Association Journal 82, 828. Darke C. S. (1976) Discussion. Proceedings of the Royal Society ofMedicine 69, 280. Dinman B. D. (1969) Occupational acro-osteolysis--a new disease of polyvinyl chloride synthesis workers. Paper given at the 16th International Congress on Occupational Health, Tokyo. Dinman B. D., Cook W. A., Whitehouse W. M. et al. (1971) Occupational acro-osteolysis: 1. an epidemiological study. Archives of Environmental Health 22, 61. Ducatman A., Hirschhom K. and Selikoffl. J. (1975) Vinyl chloride exposure and human chromosome aberrations. Mutation Research 31, 163. Fleig I. and Thiess A. M. (1974) Chromosomen-Untersuchungen bei Vinylchlorid-Exposition. Arbeitsmedizin Sozialmedizin Praventmedizin 9, 280. Fox A. J. and Collier P. F. (1977) Mortality experience of workers exposed to vinyl chloride monomer in Great Britian. British Journal of Industrial Medicine 34, 1. Frongia N., Spinazzola A. and Bucarelli A. (1974) Pul monary lesions induced in laboratory animals by prolonged inhalation of PVC powder under industrial conditions. Medicina Del Lavoro 65, 321. Funes-Cravioto F., Lambert B., Lindsten J. et al. (1975) Chromosome aberrations in workers exposed to vinyl chloride. Lancet 1, 459. Gauvain S. (1976) Introduction to the problem. Proceedings pf the Royal Society of Medicine 69, 275. Harris D. K. and Adams W. G. F. (1967) Acro-osteolysis occurring in men engaged in the polymerization of vinyl chloride. British Medical Journal 3, 712. Hefner R. E. jun., Watanabe P. G. and Gehring P. J. (1975) Preliminary studies of the fate of inhaled vinyl chloride monomer in rats. Annals of the New York Academy of Sciences 246, 135. Infante P. F., Wagoner J. K., McMichael A. J. et al. (1976) Genetic risks of vinyl chloride. Lancet 1, 734. Jayson M. I. V., Bailey A. J., Black C. et al. (1976) Collagen studies in acro-osteolysis. Proceedings ofthe Royal Society ofMedicine 69, 295. John J. A., Smith F. A., Leon B. K. J. et al. (1977) The effects of maternally inhaled vinyl chloride on embryonal and foetal development in mice, rats and rabbits. Toxicology and Applied Pharmacology 39, 497. Juhe S., Lange C. E., Stein G. et al. (1973) Uber die Sogenannte Vinylchloride-Krankheit. Deutsche Medizinische Wochenschrift 98, 2034. Keplinger M. L., Goode J. W., Gordon D. E. et al. (1975) Interim results of exposure of rats,.hamsters and mice to vinyl chloride. Annals of the New York Academy of Sciences 246, 219. Lange C. E., Juhe S., Stein G. et al. (1974) Die Sogenannte Vinylchloride-Krankheit--Eine Berufsbedingte Systemsklerose? Internationales Archiv fur Arbeitsmedizin 32, 1. Lee F. I., Harry D. S., Adams W. G. F. et al. (1977) Screening for liver disease in vinyl chloride workers. British Journal of Industrial Medicine 34, 142. Lilis R., Anderson H., Nicholson W. J. et al. (1975) Preva lence of disease among vinyl chloride and polyvinyl chloride workers. Annals of the New York Academy of Sciences 246, 22. Malaveille C., Bartsch H., Barbin A. et al. (1975) Muta genicity of vinyl chloride, chloroethylene oxide, chloro- acetaldehyde and chloroethanol. Biochemical and Biophysical Research Communications 63, 363. Maltoni C. (1974) Proceedings of the 2nd International Symposium on Cancer Detection and Prevention, Bologna 1973. Amsterdam, Excerpta Medica. Maltoni C. (1975) The value of predictive experimental bio-assays in occupational and environmental carcino genesis. An example: vinyl chloride. Ambio 4, 18. Maltoni C. and Lefemini G. (1975) Carcinogenicity bio assays of vinyl chloride: current results. Annals of the New York Academy of Sciences 246, 195. Manufacturing Chemists Association (1954) Chemical safety data sheet SD-56 vinyl chloride. Washington DC. Manufacturing Chemists Association (1974) Vinyl chloride chronology: MCA-3846. Washington DC. Marsteller H. J., Lelback W. K., Muller R. et al. (1973) Chronixch-toxische Leberschaden bei Arbeitem in der PVC-Production. Deutsche Medizinische Wochenschrift 98, 2311. Peoples S. A. and Leake C. D. (1933) The anaesthetic action of vinyl chloride. Journal ofPharmacology and Experimen tal Therapeutics 48, 284. __ Picciano D. J., Flake R. E., Gay P. C. et al. (1977) Vinyl chloride cytogenetics. Journal of Occupational Medicine 19,527. Purchase I. F. H., Richardson C. R. and. Anderson D. (1975) Chromosomal and dominant lethal effects of vinyl chloride. Lancet 2, 410. . J. (1975) 1 chloride :ademy of al. (1976) i Collagen al Society The effects zonal and "oxicology lie Sogentdizinische al. (1975) d mice to ademy of jgenannte : Systemitsmedizin al. (1977) workers. 15) . _-vapoiyvinyl tademy of :5) Mucae. chloroical and emotional !, Bologna jerimental I careino18. licity bioals of the ical safety )C. 1 chloride al. (1973) m in der :henschrift etic action lxperimen- )77) Vinyl Medicine 11 >75) ot vinyl 1 I a ii) f:l 1 -i4 > 1 i t VINYL CHLORIDE 141 Purchase I. F. H., Richardson C. and Anderson D. (1976) Chromosomal effects in peripheral lymphocytes. Pro ceedings of the Royal Society of Medicine 69, 290. Rannug U., Johansson A., Ramel C. et al. (1974) The mutagenicity of vinyl chloride after metabolic activation. Ambio 3,194. Smith P. M. and Williams D. M. J. (1975) Vinyl chloride and cirrhosis. European Association for the Study of the Liver, paper no. 35. Steward J. D., Williams D. M. J. and McLachlan M. S. F. (1975) Acro-osteolysis in a polyvinyl chloride worker with an atypical industrial history. Journal of the Society of Occupational Medicine 25, 103. Suciu I., Drejman J. and Valaski M. (1963) Contributions to the study of affections caused by vinyl chloride. Medicina Interna 15, 967. Szende B., Lapis K., Nemes A. et al. (1970) Pneumoconiosis caused by the inhalation of polyvinyl chloride dust. Medicina Del Lavoro 61, 433. Tabershaw I. R. and Gaffrey W. R. (1974) Mortality study of workers in the manufacture of vinyl chloride and its polymers. Journal of Occupational Medicine 16, 509. Thomas L. B., Popper H., Berk P. D. et al. (1975) Vinyl chloride induced liver disease. New England Journal of Medicine 292, 17. Tribukh S. L., Tikhomirova N. P., Levina S. V. et al. (1949) Working conditions and measures for their improvement in the manufacture and use of vinyl chloride plastics. Cigeniena l Sanitariia 10, 38. UK Vinyl Chloride Industrial Medical Advisory Sub- Committee (1977) Personal communications. Viola P. L., Bigotti A. and Caputo A. (1971) Oncogenic response of rat skin, lungs and bones to vinyl chloride. Cancer Research 31, 516. Ward A. M., Udnoon S., Watkins J. et al. (1976) Immuno logical mechanisms in the pathogenesis of vinyl chloride disease. British Medical Journal 1, 936. Watanabe P. G., Hefner R. E. jun., McGowan G. R. et al. (1975) Progress report to the MCA Task Group on vinyl chloride research. Washington. Williams D. M. J. and McLachlan M. S. F. (1976) Healing of phalangeal defects in acro-osteolysis. Journal of the Society of Occupational Medicine 26, 81. Williamson K. (1976) Review of animal studies. Proceedings of the Royal Society of Medicine 69, 281. Wilson R. H., McCormick W. E., Tatum C. F. et al. (1967) Occupational acro-osteolysis: report of 31 cases. Journal of the American Medical Association 201, 577. Requests for reprints should be addressed to: Dr C. H. B. Binns, Senior Medical Officer, BP Oil Limited, Medical Centre, BP House, Victoria Street, London, SW1E 5NJ. CLINIC OF PSYCHOTHERAPY 3 Harmont House, 20 Harley Street, London WIN 1AL Telephone/Ansafone 01-580 1148 Long established non-profit making concern (reg'd charity No. 260427), offers prompt consultations, assessments and psychoanalytic psychotherapy, also seminar leaders to meet special needs. Members fifteen part-time well established Consultant PsychoAnalysts (two thirds are medically qualified and one third women). For details please contact Administrative Secretary by telephone or letter. For further information circle 23 on enquiry card 0