Document zb5M66G0Y38r74KXMpymM4e0R

British Journal of Industrial Medicine 1988;45:93-97 Increasing evidence of the rise of cancer in workers exposed to vinylchloride V B SMULEVICH,1 I V FEDOTOVA,2 V S FILATOVA2 From the Atl~Union Cancer Research Centre,1 AMS USSR. Moscow, and Institute ofOccupational Medicine,1 Gorky, USSR abstract The results of a cancer mortality study among workers employed in the production of vinylchloride and polyvinylchloride between 1939 and 1977 suggest a significant increase in deaths from malignancies of the lymphatic and haemopoietic tissues. Mortality for tumours of the digestive organs, respiratory system, bone and connective tissues, brain, and skin are also greater than in the general population. There were no registered cases of liver angiosarcoma in the study cohort during the follow up period. The risk of cancer was highest among the workers exposed to concentrations of VC of 300 mg/m3 and more who had worked at the plant for 15 to 19 years. The relatively high number of leukaemias and lymphomas in the study group and the absence of liver angiosarcomas probably reflects specific carcinogenic action of different doses of vinylchloride. The carcinogenicity of vinylchloride (VC) has been studied only recently although this compound was synthesised almost 150 years ago1 and its industrial production in many countries started in the late 1930s. The first clinical and hygiene study of the oc cupational setting and health of workers in plants producing VC and polyvinylchloride (PVC) was un dertaken in the USSR in the early 1950s. This study showed heavy air pollution with VC in the shops of the plant, reaching levels of 100-800 mg/m3.2 This ex posure resulted in a high frequency of occupational toxic angioneuroses in the workers3 and led to the legislative limitation in the USSR (1957) of the VC level in the working zone to a maximum permissible concentration (MPC) of 30 mg/m3. VC and PVC induced diseases in the workers pro ducing these agents were described later by several foreign authors.4-4 Officially established MPCs of VC in the working zone in several countries before 1974 were as follows: United States--770 mg/m3; Italy, France. Finland, and Yugoslavia--1300; East Germany--500; West Germany--260; and Rumania--100.7 In 1970 Viola published the results of his animal experiments that were aimed at reproducing the aeroosteolysis observed in PVC workers. The animals de veloped tumours of the lung and skin and led the author to conclude that VC was carcinogenic.8 Many Accepted 20 October 19X6 other workers have confirmed that VC is carcinogenic to animals.9-14 In 1974 the first reports on cases of liver angiosarcoma among workers occupationally exposed to VC appeared. The frequency of this dis ease in the exposed groups was 300 to 600 times higher than in the general population.1316 The study presented here was aimed at evaluating the prevalence of malignant disease among workers employed between 1939 and 1977 in several Soviet enterprises producing VC and PVC. Materials and methods The base of the study was one of the oldest Soviet chemical plants where VC and PVC have been pro duced for various periods and under different tech nological patterns. The data on the specified workers were obtained from the registers of the administrative department and from attendance journals and lists of particular shops. For every member of the study cohort the fol lowing data were collected: specified occupation, du ration of employment in a VC exposed job, data and cause of death, and results of any postmortem study. The documents analysed were the death certificate, medical histories of disease, and necropsy protocols of those who had died from cancer. The cohort included all employees who had worked in a VC exposed job for at least one month as well as those who had changed their place of employment, were retired, left through ill health, or were dead. 93 94 Thus the study cohort consisted of 3232 workers (2195 men, 1037 women). The death rates in the cohort were determined by considering both the number of observed subjects and the period of observation,17 The numbers of personyears of observation for the entire cohort was 43 216 (27 059 for men, 16 157 for women). The expected numbers of cases of cancer for the cohort were based on the mean death rates in the city where the plant is located for the years 1959, 1969, and J 975 in the age group 15-74. The extent of risk was evaluated by means of standardised mortality ra tios (SMRs). The significance of the difference be tween the rates on the p level sS 0-05 was determined by the confidence limits of the variation of cancer fre quency.1 The results of the hygiene study of the occupational environment in VC production for the period 1953-66 were treated by methods of variational sta tistics with identification of average VC concen trations for particular workplaces.19 The extent of VC influence on the workers resulting from the average VC doses that they had been ex posed to while working was estimated within the fol lowing gradation: high level--mean concentrations of VC > 300 mg/m moderate level--VC concentrations 30-300 mg/mJ; low level--concentrations <30 mg/m2. For the quantitative estimation of the "share" of VC and PVC in the total process of cancer devel opment in the workers of this industry the technique of factorial dispersion analysis20 was used. Results Smulevich, Fedotova, Filatova Between 1939 and 1977 288 deaths were registered in the cohort, including 63 from cancer. Histological confirmation of the diagnosis of cancer was available for 60% of the cases. As shown by the SMRs, the workers in VC-PVC plants have an increased cancer mortality by com parison with the general population of the city (table 1). This was particularly noticeable for lung tumours, pancreas, bones and connective tissue, skin, and brain. The observed mortality from leukaemias and lymphomas is significantly higher than expected. No cases of angiosarcoma or other liver tumour were noted. For the male workers exposed to VC, the total can cer mortality was somewhat lower than in the male population of the city. The numbers of cases of pan creatic cancer, lung cancer, tumours of the bones and genitalia, and leukaemias, however, were higher than expected but not significantly so. The cancer mortality for the female workers was greater than expected due to malignancies of the stomach, rectum, skin, brain, and lymphatic and hae matopoietic tissues. The excess for leukaemias and lymphomas was statistically significant. As was clear from the analysis of working conditions at the plant there were three categories of workers based on the intensity of exposure to VC-PVC. The first group (highest exposure) consists of the workers of the major occupations (apparatus operators, fitters) employed in producing VC by dehydrochlorination of dichlorethane in the Table 1 Observed number ofdeathsfrom cancer (Obs) and SMRs ofcancer in the cohort of VC and PVC workers Men Sites [CDS, 196} Obs All malignancies Oral cavity and pharynx Digestive organs: Oesophagus Stomach Rectum Pancreas Liver Respiratory organs: Larynx Trachea, bronchus, lung Bones and connective tissue Skin Breast Reproductive organs Urinary organs Brain and nervous system Leukaemia, aleukacmia Other malignancies of lymphatic and haematopoietic tissue `Significant at p < 0 05. 140-209 141-149 130-159 150 151 154 157 160-163 161 162 170-171 172-173 174 180-1*7 18*-1*9 191-192 204-207 44 0 17 0 14 0 3 0 18 1 17 1 0 0 1 I 2 3 200-203. 20*. 1 209 SMR 98-2 74-8 -- 83-3 -- _172-2 1417 100 0 145 3 166*7 -- -- 125 0 3*5 90-9 428 6 100 0 Women Ohs 19 0 8 0 7 1 0 0 0 0 0 0 1 0 2 0 2 1 4 SMR 133-8 ___ 121-2 -- 142-9 125-0 ___ ___ -- -- -- -- 1000 0 ___ 71-4 -- 5000 666*7 2000-0* Both sexes Obs SMR 63 106-6 0-- 25 85-0 0 ___ 21 84*7 1 50-0 3 142-9 0 ___ 18 134-3 1 83-3 17 139 3 1 1429 1 200-0 0 ___ 3 83-3 1 345 4 153-8 5 500-0* 5 416-7* O too to o Increasing evidence of the rise of cancer in workers exposed to vinylchloride Tabic 2 Observed deathsfrom cancer (Obs) and SMRs in subgroups ofworkers with various exposures to VC Level ofexposure to VC Sites High All sites: Stomach Lung Lymphomas, leukaemias Moderate All sites: Stomach Lung Lymphomas, leukaemias Low All sites: Stomach Lung Lymphomas, leukaemias *Sigmficaru at p < 0 05. Men - Obs 28 8 13 8 15 5 4 1 i i 0 0 SMR 101-4 79-2 1711 3000 107-1 1220 129-0 166-7 31-3 83-3 -- -- Women Obs SMR 12 444,4* 5 3846* 0-- 4 4000 0* 5 113-6 2 133-3 0-- 1 1429 2 28-2 0-- 0 1 333-3 Both sexes Obs SMR 40 132-0 13 114-0 13 1688 7 636-4* 20 108-7 7 128-8 4 125-0 2 153-8 3 29-1* 1 270 0-- 1 200-0 95 medium of methyl alcohol and in producing PVC in the suspension who worked in these shops from the beginning of their employment up to 1959 (when certain improvements in working conditions were realised). second group (moderate exposure) is repreSKd by the workers in the new shops producing PVC with modem technology and those who were employed before 1971 in drying departments and ap paratus operators in the polymerisation departments where PVC was produced with imported technology. The third group (low exposure) is composed of em ployees of the new shops, the drying workers em ployed between 1971 and 1977 and laboratory assistants and other workers having minor contact with VC. The first and second occupational groups had a increased SMR for all cancers (table 2). More men in these groups died than in the general male population from cancer of the stomach and lung and from leukaemias. It is of interest that only in the high arid moderate exposure groups of male workers were cases of lung cancer noted. This supposes some effect of smoking, an essential factor in the development of lung cancer21-11 that might enhance the carcinogenic influence of VC. Among the female workers exposed to the highest doses of VC, the SMRs are high and significant for malignancies of the stomach, and for leukaemias and lymphomas. The workers in the lowest exposure group also had the lowest SMRs. Table 3 Observed deathsfrom cancer (Obs) and SMRs in various subgroups ofworkers by duration ofemployment and exposure to VC VC level Duration ofemployment (years) High 0-4 5-9 10-14 15-19 >20 Moderate 0-4 5-9 10-14 15-19 >20 Low 0-4 5-9 10-14 15-19 >20 *3j^ffcuni at p < 0 05. Men Obs 18 5 2 2 1 II 3 0 1 0 l 0 0 0 0 SMR 113-2 104 2 90-9 181-8 66-7 mi 130-4 -- 166-7 47-6 -- -- Women Ohs SMR 1 68-5 5 714 3* 1 333-3* 4 1333-3* 1 500-0 1 47-6 1 76-9 2 105-3 0 ___ l 142-9 0_ 0 ___ 0 ___ 2 285-7 0-- Both sexes Obs SMR 19 108-1 10 181-8 3 120-0 6 428-6* 2 117-6 12 1000 4 III 1 2 58-8 1 71-4 1 90-9 1 25-6 0 --* 0-- 2 250-0 0 fr Z' 96 Smulevich, Fedotova, Filatova Thus there is a clear relation between cancer mor tality and the level of VC exposure in the study co hort: the workers subjected to doses higher than 30 mg/m3 have a higher risk of cancer than those with minimal contact with this compound. Table 3 presents the distribution of deaths from cancer in the groups with different periods of employment. The highest SMR is in the group having worked at the plant for 15-19 years. The treatment of the results by factorial dispersion technique for estimating the share of influence of VC (in dependence of level and duration of its action) on the risk of cancer have confirmed its significant role (5-8%, p < 0-001) in the development of tumours among the exposed workers. Discussion Our study has shown an increased cancer mortality in the workers employed in the production of VC and PVC, compared with the general population. An in creased frequency in malignancies of the digestive or gans, respiratory tract, brain, and lymphatic and haematopoietic tissues observed in this study is in ac cord with the results of similar studies of workers in VC-PVC plants in the United Kingdom, W Germany, France, United Stales, and other countries.2*"29 In our study no angiosarcomas were noted; these tumours are considered by some authors to be a specific occupational disease of VC workers.23 30 The reason for this lack of angiosarcomas may be due to the measures for limiting airborne levels at work which were introduced earlier than in other countries and to effective protection (by relevant individual de vices) of workers in high exposure jobs. On the other hand, it may reflect a certain specificity of action on the organism of various VC concentrations; higher doses lead to the development of liver angiosarcomas whereas moderate ones may affect other organs. This idea is to some extent confirmed by animal experiments'* with different doses of VC (3690, 266, 25, and 14 mg/m3) where the lowering of adminis tered VC doses was accompanied by a change in the ratio of liver malignancies, lymphomas and leu kaemias towards the production of the latter. The finding of significant increases in SMRs for lymphomas and leukaemias, especially among female workers who usually have lower occupational ex posures to VC than male workers is noteworthy. This probably reflects a higher susceptibility of the women to the carcinogenic action of VC but this hypothesis needs further study. The relation between the carcinogenic action of VC and the level of exposure agrees with experimental evidence on this subject.12 This gives hope that cur rent measures for limiting VC exposure at work (low ering of the MAC in the USSR to 0-1 mg/m3, promotion of the hermitic sealing of the equipment used, and development of the non-stop technologies of VC production) will effectively serve to prevent the carcinogenic effects of VC on workers. References 1 Regnault V. Composition of a chlorinated hydrocarbon (oil from oil-forming gases). Justus Liebig's Annates Chemistry 1835;14:22-38. 2 Filalova VS, Gronsberg ES, Sanitary and hygienic labour condi tions in production of polychlorvinyl tar and measures of their improvement. Gigijena i sanitarija l957;NI:38-42.* 3 Smirnova NA. Clinical features of Ihe professional toxic angioneuroses. In: Matertaly po voprosam gtgieny truda i climky pro* fesstonatigeh bolesne; Gorky 1956:44-52.* 4 Sucui 1. Driman J. Valaskai M. Contnbutii la studiuc imbalnavtmor produse de chlorurc de vtml. Med intern 1963. 15:967-78, 5 Wilson RH. McCormick WE. Tatum CF, era/. Occupational acroostcolysis. JAMA I967;20t:577-8I, 6 Juhe H, Lange CE. Sclerodermiartige Hautferandeeungem Rejnaud-Syndrom und Acroosteolison bet PVC-Herstellenden Industre. Dtsch Med Wochrtschr 1973;97:1922-3. 7 Nikitin VS, Rjabets VA. MPC of the noxious substances in the workshops air in the USSR and abroad. In: Nauchnye Ruhoty Instttutu oitranv truda Vsesojutnngo Cemratnogo Soveia Projesstotuiligeh Sojusor Unrein,' 1973;84:22-9,* 8 Viola PL. Carcinogenic effect of vtnylchlonde. In. Tenth Inter national Cancer Congress, Houston. 1970. Vol 29. Houston: Medical Art Publishing Co. 1970. 9 Maltom C. Lefcmme G. Vinyl chloride carcinogenesis current results and perspective. Med Lav 1974:65:11-12. 10 Caputo A. Viola PL. Bigotti A. Oncogenic response of rat skin. lungs and bones to vinyl chloride. Cancer Res 1971;31:516-22. 11 Lee CC. Blandari GC. Winston JM. etal. Inhalation toxicity of vinyl chloride and vinylidene chloride. Environ Health Perspect 1977,21:25-35. 12 Maltom C. Lefemine G. Ciliberiy A. etal. Carcinogenicity bioassays of VCM: a model of risk assessment on an experimental basis Environ Health Perspect 1981;41:3-29. 13 Slovbur NN. Kurliandsky BA. Turusov VS. Towards the ratio nale of the permissible vinylchloridc contents in the working lone air. In: 7eri.tr dokIadov 6 Vsesojuzhal conferened. Lenin grad: 1979:288.* 14 Kurliandsky BA, Slovbur NN, Turusov VS. Towards the ques tion of hygienic regiamentation of vinyl chlondc. Gigiena t Santiariju 1981:3:74-86.* 15 Creech JL. Johnson ML. Angiosarcoma of the liver in the manu facture of PVC J Occup Med 1976;16:150-1. 16 International Agency for Research on Cancer, (Forking group on nnrl chloride. Lyon: IARC, 1974. (Int tech report N74/005.) 17 MacMahon B. Pugh T, Ipscn J. 77ir use ofepiileauoiogic methods in die studies ol noninteeuaus diseases, Moscow Mcdttzma, 1966. (Translated into Russian.) 18 Dvoinn VV. Analytical methods of the study in cancer epi demiology research. In: Chaklin AV. ed. Cancer epulemmlagy in CMEA countries. Moscow: Mcditzina, 1979. 19 Mcrkov AM. Poliakov LE. Siinnurv statistics. Leningrad: Meditzmu, 1974.* 20 Ptohinsky NA. Bionteire. Moscow: Moscow State University. 1970.* 21 Screbrov Al Tobacco smoking and lung cancer. 5V/t Med 1978:7 109-12.* 22 Chaklin AV. Gntzutc LA, Modern concepts about aetiology and pathogenesis of lung cancer. Vopr Qnknt 1982;2:3-9,* In Russian. R&S 000922 X Increasing evidence of the rise of cancer in workers exposed to vinylchloride 97 23 Doll R, Peto R. The causes of cancer. Oxford. New York: Oxford University Press, 1981. 24 Buffier PA, Wood S, Eifler C, etal. Mortality expenence of the workers in a VCM production plant. J Occup Med 1979:21:195-203. 25 Byrcn D. Enghoim G, England A. etui. Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environ Health Perspect 1976:17.167-70. 26 Fox AJ. Collier PF. Low mortality rates in industrial cohort stud ies due to selection for work and survival in the industry Br J Prev Sot Med 1976:30:225-30. 27 Monson RR, Peters JN, Johnson MN. Proportional mortality among VC workers. Lancet l974;ii:397-8. 28 Ott MG, Langner RR, Holder BB. Vinyl chloride exposure in a controlled industrial environment. A long-term mortality ex perience in 594 employees. Arch Environ Health 1975:30:333-9, 29 Waxwciller RJ, Stringer W, Jones J, etal Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Set 1976; 271:40-8. 30 International Agency for Research on Cancer, Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Vo! 19. Lyon: lARC 1979:377-438. Vancouver style Bill manuscripts submitted to the Br J Ind Med should conform to the uniform requirements for manuscripts submitted to biomedical journals (known as the Vancouver style) The Br J Ind Med, together with many other international biomedical journals, has agreed to accept articles prepared in accordance with the Vancouver style. The style (described in full in Br Med J, 24 February 1979, p 532) is intended to standardise requirements for authors. References should be numbered consecutively in the order in which they are first mentioned in the text by Arabic numerals above the line on each occasion the reference is cited (Manson1 confirmed other reports1'5...). In future refer ences to papers submitted to the Br J Ind Med should include: the names of all authors if there are six or less or, if there are more, the first three followed by et ai. the title of journal articles or book chapters; the titles of journals abbreviated according to the style of Index Medicus; and the first and final page numbers of the article or chapter. Examples of common forms of references are: 1 International Steering Committee of Medical Editors. Uni form requirements for manuscripts submitted to biomedical journals, Br Med J 1979;1:532-5. 2 Sotcr NA, Wasserman SI, Austen KF. Cold urticaria: release into the circulation of histamine and cosino-phil chemolactic factor of anaphylaxis during cold challenge. N Engl J Med 1976:294-687-90. 3 Weinstein Lm Swartz MN. Pathogenic properties of invading micro-organisms. In: Sodeman WA Jr, Sodeman WA. cds. Pathologic physiology mechanism^ of disease. Philadelphia. W B Saunders. 1974 457-72.