Document 7Mq3YXxkK6L4gZL2jNkwndDnV

Environmental Health Perspective) VoUl.pp. US-151, 1981 Mortality and Cancer Rates among Workers in the Swedish PVC Processing Industry . by Gustavo Molina*, Bo Holmberg*, Stig Elofsson*, Lars Holmlund,* Rein Moosing,* and Peter Westerholm** Personnel lists from four PVC-processing industries were collected on production of employees with at least three months of employment at the beginning of 1945 and the last day of employment December 31,1974. Of 2073 persons, 103 could not be followed up, because they had moved abroad. The remaining persons comprise the cohort of 1970 individuals who were analyzed and compared w'ith the national population with respect to mortality from various diseases and cancer morbidity. The death risk from myocardial infarction is elevated in the cohort. This elevation is most clearly apparent in the subcohort which had at least two years of exposure time and where the analysis was directed at circumstances chronologically close to the time of exposure. The myocardial infarction risk related to vinyl chloride exposure is discussed in relation to earlier studies on the vascular effects of vinyl chloride. An indication of an elevated risk of morbidity and mortality from tumors in the digestive organs is also present. However, this is not statistically confirmed. A few future follow-ups of the present study are necessary in order to clarify any possible elevated risk of tumors in the PVC-processing industry. Vinyl chloride has been shown to cause sclerodermia, Raynaud's phenomenon, aCroosterolysis, liver damage and liver cancer (hemangiosarcoma) (1) in workers exposed to vinyl chloride monomer (VCM). This has been shown in studies (2, S) performed at companies which fabricate poly(vinyl chloride) (PVC). In animal experimental studies it has been reported that inhalation of VCM causes malignant tumors in different organs in rodents (4-6). In Sweden, in 1974, two cases of liver heman- *Occupational Toxicology Unit, Department for Occupational Medicine, Labor Medicine Division, Department of Occupational Safety, Box 100, 26 Stockholm, Sweden. ^Statistical Institution, Stockholm University, Box 6701, 113 5 Stockholm, Sweden, tGroup for Applied Statistics, Karlbergsvagen 82, 113 35 Stockholm, Sweden. "Bureau of Statistics, Department of Welfare, 10C 30 Stockho|m, Sweden. giosarcoma were diagnosed in employees at a company engaged in the processing of VCM and PVC (7).. Later another two cases occurred at the same factory. Studies on other forms of cancer (8, 9) suggest that VCM-exposed workers in the PVC fabricating industries may possibly run an elevated risk of contracting forms of cancer other than hemangio sarcoma in the liver. Earlier, an excess mortal ity from cardiovascular diseases was also observed (JO) in employees in the PVC manufacturing indus try. The present retrospective cohort study was per formed for the purpose of determining the pattern of morbidity and mortality in the PVC processing industry. The PVC processing industry, generally speaking, has had a lower level of exposure to VCM than the fabrication industry. In the Swedish PVC processing industry, at present, about 5000 persons are employed in production. Octohcr 1981 145 ucc 088243 Material and Methods Information for the study was rolled rd from four PVC processing companies. The four companies all used i'VC which, after additions of various chemi cals, is heat-treated for fabrication into floor cover ing, lace, pipes, and food packaging. Data Collection The following data were collected from the per sonnel lists at the companies: personal number, name, beginning and end of exposure (year and month) and class of exposure. In order for a person to be included in the original cohort, at least three months of employment was required in the period beginning in 1945 and the ending December 13, 1974. The exposure was classified as follows: class 3 (high), work in the mixing department; class 2 (medium), heat treat ment machines; and class 1 (low), other production departments. The collected data were transferred to punched cards and magnetic tape for statistical processing. The magnetic tape was coordinated with the na tional total population and the so-called death tapes for the 1961-1976 period and checked against the cancer registry by the Centra] Bureau of Statistics (SCB). The personnel numbers which could not be recovered at this time were checked by the national taxation office. The original cohort included a total of2,073 persons. Of these, 103 persons (5%) dropped out, 70 or whom had moved abroad, 5 were found in the missing persons register of the tax office, and 28 could not be traced. Study Cohorts For the statistical processing, the results of the cohort of 1970 persons were divided into a number of subcohorts (study cohorts): (1) all persons with at least three months of exposure (follow-up time from the beginning of exposure and through 1976); (2) all persons with at least six months of exposure ex cluding those who stopped before 1961 (follow-up time from beginning of exposure but no earlier than 1961 and through 1976); (3) all persons with at least six months of exposure and where the exposure began no earlier than 1961 (follow-up time from beginning of exposure and through 1976); (4) all persons with at least two years exposure (follow-up time from two years after beginning of exposure but no earlier than 1961 and through 1976 but no more than ten years after exposure stopped); (5) all persons with at least two years exposure (foliow-up time from ten years after exposure began but no 146 earlier than 1901 and through 1976), The two latter named study cohorts were chosen in order to study whether any differences existed in the death cause pattern with respect to when the deaths occurred after the beginning of exposure. The first of the study cohorts was intended to shed light on possible causes of death which occur rela tively early, e.g., accidents caused by the job. The second was intended to shed light on such death causes as occurred alter a longer time had passed. Tumors caused by occupational exposure, for ex ample, often have a long latency period, 5-10 yr or longer. Results The original cohort was relatively young at the beginning of exposure. The age distribution in the different exposure classes is given in Table 1. One finds various dissimilarities between the exposure classes. In class 1 (low), 41.7% were younger than 35 years at the beginning of exposure; in class 2 (average), 47.7%; and in class 3 (high), 50.6%. There Table I. Age distribution in original cohort at beginning of exposure % in each exposure class Age i 2 3 1-3 < 19 20-24 20-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 > 65 No. of persons 1.6 7.5 13.5 19.1 17.0 13.7 11.1 8.0 5.1 2.6 0.7 100% (1501) 2.0 14.6 15.7 15.4 13.2 12.6 12.6 7.8 3.9 2.0 0.3 100% (357) 8.9 14.3 21.4 17.0 10.7 9.8 8.9 5.4 1.8 1.8 oo \ 100% (112) 2.1 9.2 14.4 18.3 15.9 13.3 11.3 7.8 4.7 2.4 0.6 10%% (1970) Table 2. Distribution of exposure time in the original cohort. Months % in each exposure class 1 2 3 1-3 <6 6-23 24-59 60-119 > 120 13.1 38.4 25.0 15.3 8.2 0.3 8.4 17.4 45.7 28.3 0.0 8.9 10.7 15.2 65.2 10.1 31.3 22.8 20.8 15.1 100% 100% 100% 100% (M = 1510) (M - 357) (M * 112) <M 1970) Environmental Health Perspectives At ,,. `- :-'i *>' ' .- * i W:.o ^ -f *--.^^Lr.-r.in.-.- Cohort Exp. class 1 Exp. class 2 Exp. class 3 Exp. class 1-3 Table 3. Observed and anticipated number of deaths as of December 31, 1976, No. of Heaths Number Observed Expected Ratio O/E 1303 63 55.5 0.95 356 14 21.9 0.64 112 6 10.3 0.70 1171 73 87.8 0.84 Approx. 95% confidence interval 0.26 0.34 0.47 0.19 Table 4. Observed and anticipated number of deaths from certain causes during the 1969-1976 period in those with at least six months of exposure including those who stopped before 1961.* Ob Ex Ratio served pected O/E Malignant tumors 140-209 Digestive organ tumors 150-159 Cardiovascular diseases VII Myocardial infarction 410.90 Accidents, suicide, etc. XVII 17 14.0 1.21 8 4.9 1.63 22 24.3 0.91 15 20.0 1.49 13 9.2 1.42 "Risk calculated from the beginning of exposure but no earlier than 1961. Study cohort 2 (1771 persons). were also dissimilarities in the length of exposure with respect to exposure class (Table 2). However, it should be noted that the table includes cases which were still under exposure at the final date for entrance into the cohort (December 31, 1974), for which reason, a certain bias toward short exposure times is found. Regardless of this, exposure class 3 has longer exposure times on the average. The cohort as a whole reveals no noteworthy increase in the total risk compared with the na tional average, nor is there any indication of this in the subgroups making up the study cohort. Study cohort 1, which includes everyone with at least six months of exposure and with calculation of the risk from the beginning of exposure, is some what remarkable in that the anticipated number of deaths is significantly higher than that observed up Figure 1. Cumulative deaths (in percent): (V) observed; (?) anticipated. Expected value calculated from beginning of exposure. Study cohort 1 (1970 persons). The percentage for a given year was calculated as 100 (number of persons dying through year in question divided by the number of persons beginning exposure up to and including the year in question). to 1964 (Fig. 1). This is commented on further in the discussion. Study cohort 2 (Tables 3 and 4; Fig. 2) includes persons with at least six months of exposure, excluding those who stopped before 1961. The risk calculation is made from the beginning of the exposure, but no earlier than 1961 and up to the end of the follow-up time (1976). The observed number of deaths is somewhat lower than expect ed, much lower in exposure class 2. Classes 2 and 3 are relatively small and are sensitive to random deviations in this type of analysis. In order for random deviations not to influence the results, the classes, were combined. This is true of all study cohorts. This distribution with respect to the vari- Table 5. Observed and anticipated number of deaths as of December 31, 1976 in those with at least six months of exposure beginning no earlier than 1961." Cohort Number No. of deaths Observed Expected Ratio O/E Approx. 95% confidence interval Exp, class 1 Exp. class 2 Exp. class 3 Exp. class 1-3 1139 43 41.2 1.04 0.31 247 4 11.7 0.34 0.34 42 1 1.8 1428 48 54.7 0.88 0.35 "Risk calculation from beginning of exposure. Study cohort 3 (1428 persons). October 1981 147 UCC 088245 F/cure 2. Cumulative deaths (in percent). Expected value calculated through 1961. Study.cohort 2 (1771 persona). Percentage for a given year calculated as in Fig. 1. Figure 4. Observed death risk j>cr year at different points of time after beginning of exposure expressed in percent of corresponding anticipated risk in those who began exposure in 1961 or later. Study cohort 3 (1428 persons). Table 6. Observed and anticipated number of deaths from certain causes during the 1969-1976 among those with at least six months of exposure beginning in 1961 or later.* Ob Ex Ratio served pected O/E Figure 3. Cumulative deaths (in percent) of those who began exposure in 1960 or later. Study cohort 3 (1428 persona). Percentage for a given year calculated as in Fig. I. ous death causes is shown in Table 4. The observed and anticipated number ofdeaths during the 1961-1968 period is relatively small, only a few cases, and the death cause classification was modified as mentioned earlier in 1969, for which reason 1961-1968 period is not discussed separately. By and large, the picture is the same there as for the 1969-1976 period re ported on. From Table 4, one sees that the ob served number of deaths, especially those from tumors of the digestive tract, myocardial infarction and accidents, is somewhat higher than anticipated. However, the differences are not significant. Study Malignant tumors 140-209 Digestive organ tumors 150-159 Cardiovascular diseases VII Myocardial infarction 410.90 Accidents, suicide, etc. XVII 9 9.7 0.93 4 3.3 1.20 16 16.2 0.99 14 11.2 1.25 11 7.3 1.51 Risk calculated from the beginning of exposure. Study cohort 3 (1428 persons). cohort 3 (Tables 5 and 6; Figs. 3-5) which pertains to those who began working in 1961 or later but which otherwise satisfy the same criteria as study cohort 2, displays a similar picture. An analysis of study cohort 3 according to for mula B (Figs. 4 and 5) indicates that the annual risk during the first year of exposure is somewhat lower than the anticipated one, but that after about ten years, an increased risk occurs so that the observed risk becomes higher than the anticipated. Table 7. Observed and anticipated number of deaths from certain causes during the 1969-1976 among those with at least two years'of exposure.* Observed Expected Ratio O/E Malignant tumors 140-209 Digestive organ tumors 150-159 Cardiovascular diseases VII Myocardial infarction 410.90 Accidents, suicide, etc. XVII 5 (9) 2 (4) 15 (16) 11 (12) 4 (5) 7.4 (8.9) 2.6 (3.2) 12.7 (15.8) 5.4 (6.6) 4.6 (5.1) 0.86b (1.01) 0.78b (1.27) 1.18b (1.01) 2.03b <1.82)b 0.87b (0.97) "Risk calculated from two years after beginning of exposure and no more than five years (10 years) after end of exposure. Study cohort 4 (1155 persons). bp < 0.05. 148 Environmental Health Perspectives fZ - ,-V *T> UCC 088246 Table 8. Observed and anticipated number of deaths from certain causes during the 1969-1976 in those with at least two years of exposure.* Ob Ex Ratio served pected O/E Malignant tumors 140-209 Digestive organ tumors 150-159 Cardiovascular diseases VII Myocardial infarction 410.90 Accidents, suicide, etc. XVII 9 6.0 1.51 4 2.2 1.85 12 11.1 1.08 8 4.5 1.77 2 2.5- 0.79 *Risk calculated from 10 years after beginning of exposure. Study cohort 5 (680 persons). T..------------------------- --------------------- No. of risks Figure 6. Cumulative survival probability (in percent) of those who began exposure in 1961 or later and have at least six months of exposure. Study cohort 3 (1428 persons). Table 9. Observed and anticipated number of deaths from cancer during 1961-1976 in those with at least six months of exposure excluding those who stopped before 1961.* .1 Malignant tumors'(total) Digestive organ tumors (150-159) Ob- Ex- Ratio served pected O/E 51 44.6 1.14 11 8.5 1.29 Risk calculated from beginning of exposure but no earlier than 1961. Study cohort 2 (1771 persons). In study cohort 4 (Table 7) which concerns time during ongoing exposure or a relatively short time sifter the end of exposure, i.e., "short-term perspective," one sees an increased death risk from myocardial infarction. Other causes are somewhat lower here than expected. In study cohort 5 (Table 8), finally, one finds an indication of an increase in the death risk as regards tumors, but also for myocardial infarction. The differences between the observed and anticipated numbers are not, however, statistically confirmed at the 5% level. The result with respect to mortality can be sum marized as follows. In the study cohorts, overall, one finds no noticeable increase in mortality. On the other hand, there are indications of a shift in the death cause pattern compared with the national average. This shift is expressed primarily in the fact that the number of myocardial infarctions is noticeably higher during ongoing exposure or within a relatively short period of time after the end of exposure. There are also indications that the death from tumors can be elevated among persons with a long latency period (Tables 7 and 8). In the question of cancer morbidity, there is no certain increase in study cohort 2 (Table 9 and Fig. )* In the question of tumors of the digestive orI'ans, in the same study cohort, 11 cases were observed as opposed to an anticipated 8.5. The Figure 6. Cumulative rates of cases of all cancer (in percent). Study cohort 2 (1771 persons). The percentage for a given year was calculated as 100 (number of persons diagnosed through year in question divided by the number of persons beginning exposure through year in question). difference is not statistically verified. One of these eleven tumors was liver cancer (ICD 155.0). Discussion A noteworthy finding which arises in the analysis of the total cohort mortality (Fig. 1) is that the number of deaths at the beginning of the observa tion period (1947-1964) is significantly lower than one would expect in relation to the national aver age. This difference is so great that one cannot directly consider it to be randomly conditioned, nor can it be entirely ascribed to the so-called healthy worker effect. Theoretically, of course, the possibil ity exists that the selected cohort, in the question of mortality and the factors which influence said mor tality, deviates from the general population. A more credible possibility is, however, that the personnel register that was available at the company involved at the time of this study was incomplete in the matter of hirings during this early period. A per sonnel register which, in the mid-1960's, was purged October 1981 149 UCC 088247 of |arsons who began employment before 19(50, could lend to the difference mentioned above. The companies involved reported that such a purging did not occur, so far as they know. If such a purging (thinning out) nevertheless occurred, this would have resulted in the elimina tion of persons with a long observation time at the time of follow-up. In the present study, the risk calculations were limited to beginning no earlier than 19G1. This means a limitation of the analysis to pertain to the group of employees who were living at the beginning of 19G1 and where the risk of an elimination is positively eliminated. This limitation, however, signifies a weakening of the analysis, since parts of the cohort with long follow-up times are excluded. Basically, this weakening signifies a poorer possibility of discovering an elevated inci dence of cancer if one exists. The myocardial infarction mortality (ICD 410.90) is elevated in the cohort. This elevation occurs most clearly in the category of the total cohort which has at least two years of employment time and where the analysis was directed at the period of time following two years after the beginning of employ ment and extending to no more than five years after the beginning of employment. Therefore, this in volves that fraction of the mortality from myocar dial infarction which chronologically is relatively closely connected to the time of employment. It is impossible on the basis of such observations to draw conclusions that the elevation was caused by exposure to vinyl chloride. The observed increase in myocardial infarction mortality is, however, so striking that it, in combination with the known facts about the toxic properties of vinyl chloride, must be given consideration. There are no reasons to assume that varying diagnostics, standards or practices in filling out the death certificates alone could provide an explanation. A natural conclusion is, therefore, that if one disregards the possibility of a random local phenomenon, the increased fre quency is to be ascribed either to selection of indi viduals susceptible to the risk or an outbreak of risk factors in the close environment of employees. A combination ofthese two circumstances is, of course, also possible theoretically. In this connection, it should be noted that many risk factors for myocardial infarction are environ mentally conditioned in the fact that they constitute part of the lifestyle of the modern social environ ment in an industrialized country. Cigarette smok ing, physical inactivity, overweight and high blood lipids constitute environmental factors which are related to social behavior. It is a well known fact that the risk of coronary vascular disease in the heart varies, inter alia, with the total load of risk 150 factors. Among other risk factors, one can also name hereditary characteristics and high blood pres sure. In this connection, there is reason to recollect that the causal network of coronary disease is mui- tifactorial and that the disease has an environmen tal relationship in the broad sense. There is also reason to recall the aspect that the total risk in creases when several risk factors, known or un known, are allowed to collaborate (11, IX). It has not been possible to establish the distribu tion of such already known risk factors for coronary disease in the cohorts studied with respect to the national population in general. Therefore, no con tinued analysis of the matter of the causal relation ship between close environment and heart disease morbidity can be made within the limits of this study. Exposure classes 2 and 3 constitute subcohorts that are too small, in the present study, to allow a meaningful discussion of the myocardial infarction risks relative to the various exposure levels in the processing industry. In this connection, one should also consider the circumstance that the exposure classes in this study are based on interviews with the employees directed at the work environment at the time in question some 10 to 15 years ago. Therefore, this involves an environment which has subsequently undergone changes. Objective classi fication criteria in the matter of exposure, e.g., in the form of environmental measurements, do not exist. The distribution into exposure classes is, for this reason, fraught with uncertainty. In animal experiments, it has been found that the toxicity picture in rodents chronically exposed to VCM involves the blood vessels. Besides hemangiosarcoma in the liver and the other organs (4, 5) the inhalation of VCM is also believed to cause development of telangiectasis U) in the liver of mice which can lead to death from hemocoele. Changes in the sinus cells have been observed in liver biop sies in VCM-exposed workers (IS). Capillary changes in the skin of the fingers have also been observed (H-16), both m VCM-exposed workers with other vascular-involved diseases, such as acroosteolysis, Raynaud's phenomenon, and sclerodermia, and in VCM-exposed workers without such diseases. An over-representation of deaths from cardiovascular diseases has also been observed in a study on the PVC-fabricating industries (10). Animal experimen tal and previous medical studies of VCM-exposed populations therefore support the assumption that the increased risk of myocardial infarction observed in the present study could possibly be ascribed to VCM exposure. As regards the mortality and morbidity from tumors, the results are uncertain. There are certain Environmental Health Perspectives JL. of an elevation, but the differences are not statistically confirmed. One can think of two possibilities here: (1) in reality, there is no increase in the risk of tumors; (2) there is indeed an in creased risk of tumors. The results neither confirm nor refute this. Tumors do not occur until after a long latency period. The majority of the persons included in the study did not begin their exposure until the 60's and 70's and therefore could not be followed for a sufficiently long time. An accurate follow-up of the present cohort during the coming five-year period should bring greater clarity into this. In the present connection, it is of interest that in a recently published mortality study (17) on almost 4300 deaths in the American PVC-processing industi-y, an overrepresentation in cancer mortality appears to exist (all cancer), especially gastrointes tinal cancer in both sexes. 4 V REFERENCES 1. Holmberg, B., and Molina, G.: The industrial toxicology of vinyl chloride. A review. Work-Environ. Health 11:138-144 (1974). 2. Creech, J. L., and Johnsson, M. N. Angiosarcoma of the liver in the manufacture of polyvinyl chloride. J. Oceup. Med., 16:150-151 (1974). Lloyd, W. J. Angiosarcoma of the liver in vinyl chloride/ polyvinyl chloride workers. J. Occup. Med., 17: 333-334 (1975). 4. Holmberg, B., Kronevi, T., and Winell, M. The pathology of vinyl chloride exposed mice. Scand., 17: 328-342 (1976). 5. Maltoni, C. The value of predictive experimental bioassay in occupational and environmental carcinogenesis. An ex ample: vinyl chloride. Ambio, 4:18-23 (1975), 6. Viola, P. L., Bigotti, A., and Caputo, A. Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res., 31: 516-522 (1971). 7. Byren, D., and Holmberg, B. Two possible cases of angiosarcoma of the liver in "group of Swedish vinyl chloride-polyvinyl chloride workers. Ann. N.Y, Acad. Sci., 246: 249-250 (1975). 8. Monson, R. R., Peters, J. M., and Johnsson, M. N. Proportional mortality among vinyl chloride workers. Lan cet ii, 397-398 (1974). 9. Tabershaw, J. R., and Ga/fey, W, B. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occup. Med., 16; 509-518 (1974). 10. Byren, D., Engholm, G., Englund, A., and Westerholm, P. Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environ. Health Perspect. 17; 167-170 (1976). 11. RCP and BCS. Prevention of coronary heart disease. Report of joint working party of the Royal College of Physicians of London and the British Cardiac Society, J. Roy. Coll. Physicians, 10: 213-275 (1976). 12. Tibblin, G., Wilhelmsen, L., and Werke, L. Risk factors for myocardial infarction and death due to ischemic heart disease and other causes. Am. J. CardioL 35: 514-522 (1975). 13. Popper, H., and Thomas, L, B. Alteration of liver and spleen among workers exposed to vinyl chloride. Ann. N.Y. Acad. Sci., 246:172-193' (1975). 14. Marica, H., Johnsson, M. N., Whetstone, C. L., and Le Roy, E. C. Capillary abnormalities in polyvinyl chloride production workers. J. Am. Med. Assoc., 236: 1368-1371 (1976). 15. Marica, H., Johnsson, M. N., Whetstone, C. L., and Le Roy, E. D.In vivo capillary abnormalities in vinyl chloride workers. In: Microcirculation, Vo], 2, J. Grayson and W. Zingg, Eds., Plenum Press, New York, 1976. 16. Marica, H., Darke, C. S., Archibald, R. M., and Le Roy, E. C. In vivo observations of skin capillaries in workers exposed to vinyl chloride. An English-American compari son. Brit. J. Ind. Med., 35:1-7 (1978). 17. Chiazze, L., Nichols, W. E., and Wong, O. Mortality among employees of PVC fabricators. J. Occup. Med., 19: 623-628 (1977). IS. Chiang, C. L. Stochastic Processes in Biostatistics. An Introduction. Wiley, New York, 1971. /* October 1981 151