Document NEb5R91Q9j3J3rmyvjQDvaZ0Q

5: i 1971 (1930). . Eas. Toxicity of vjr, . Y. Acad. Sci. 246:13 Environmental Health Perspectives Vol. il, pp. 95-99, 1981 Caputo, A. Oncogen bones to vinyl chloric erti, A., Cotti, G. ^ issays of vinyl chlvj, German Investigations on Morbidity and;sment on experimrfi II: 3-29 (1981). <2 agoner, J. K, Jones5 Mortality of Workers Exposed totic risk among work* Y. Acad. Sd. 271: ,,& Vinyl ChlorideA., and Westerholm,^ group of Swedish V(5i 'iron. Health Perspett 'r;- lortality experienced by H. Weber,* W. Reinl,* and E. Greiser* onomer in the manirfy Britain. Brit. J. hi ohnson, M. N. Prop*. ie workers. Lancet* Two studies on mortality and morbidity of workers exposed to vinyl chloride monomer (VCM) which have been carried out on behalf of the Ministry of Labour, Health and Social Affairs on Northrhine-Westphalia are reported. R. Mortality study d inyl chloride and iti 8 (1974). Suarez, L., and KiK.n srs in a vinyl chloride up. Med. 21: 195-HJ :r, P Vinyl cblande env lent. A v .irch. Environ idemiological study f Manufacturing Chon # ^9 Vin Chloride Mortality Study The aims of this study were to determine stan dardized mortality ratios (SMR) for male workers exposed to VCM, using the mortality rates of the West German male population as reference, to study the SMRs of a cohort of workers of the themical industry comparable concerning age dis tribution and observation period but not exposed to VCM and to determine the SMR of a cohort of worker in PVC-processing plants. The .dy was designed as a historic cohort study, covering the period from the beginning of the VCM- and PVC-production in all of the German plants till the end of 1974. Table 1 shows the main characteristics of the three cohorts investigated. Only Germans and Austrians were included in data analysis because of -^sufficient' mortality data on various foreign na tionals employed in German factories. To deter mine the mortality rates of Austrians, West Ger man ra* - -ere used. To calculate expectations of total nt . ....icy, the mortality rates of the adequate cars have been used. To calculate expectations of specific causes of death for all years before 1968, the rates of 1968 have been used; for the following years the rates of the corresponding years. Foliow- the procedure applied by Tabershaw (i), --taatlicher Gewerbearzt, Diisseldorf, W. Germany. ^Uiabct-s P.^earch Institute at the University of Diisseldorf, ~Q^r' ;?a! Statistics and Epidemiology, Diisseldorf, weighting of observed cases of specific causes of death according to unknown causes of death has been done with weighting factors calculated sepa rately for three observation periods (up to 1959, 1960-1969, 1970-1974) as well as for six age groups. In all of the cohorts, follow-up rates have been near or above 90%. The percentage of causes of death that could not be investigated due to loss or deletion of death certificates varied from 7.3% to 13.1%. To calculate age-standardized mortality ratios of specific causes of death, weighting has been done according to the procedure used by Tabershaw and Gaffey (1) to compensate for unknown or unidentified causes of death. Table 2 displays total mortality as well as some of the relevant specific causes of death. It can be observed that the otherwise observed "healthy worker effect" cannot be demonstrated in the German cohorts exposed to VCM or employed in PVC-processing plants. In the VCM cohort there are significant eleva tions of SMR of malignancies of the lymphatic and hematopoietic tissues (ICM 200-209), and of malig nancies of the GI tract (ICD 150-159). The latter is due to the paramount elevation of SMR of tumors of the liver (ICD 155). It must be noted that there is a modest elevation of SMR of tumors of the liver also in the cohort not exposed to VCM nor employed in PVC-processing plants. No obvious explanation for this observation can be offered. In addition elevated SMRs for ischemic heart disease (ICD 410-414) can be found in all of the three cohorts. Due to methodological 21137001 Octob,er 1981 95 shortcomings of the study no assessment of cardio vascular risk factors has been made. Therefore these results are of minor interest. When subdividing the VCM-exposed cohort ac cording to time of exposure there is a clear-cut increase of the SMR of liver tumors with time (Table 3). This seems to be highly suggestive of a time-response pattern. As it has been impossible^ determine concentrations of VCM retrospective) due to technological and methodological problenj no dose-response pattern can be established. Hoy ever time of exposure seems to be the best avaj able guess for dose. S Subclassification according to observation perio Table 1. Characteristics of study cohorts. Group I, VCM/PVC production Group II, reference group Population (Germans + Austrians) Man years Follow-up completed till 12/31/74, % deceased Observed Expected Unknown causes of death No. % Total mortality (SMR) Foreigners (excluding Austrians) Deceased 7.021 73.734 93.2 414 435 30 7.3 95 882 6 4.910 76.029 89.8 417 533 47 11.3 78 711 6 `i Group III, PVC j! processing '3 i- 4.007 ^ 52.896 92.1 360 > 380 v % 47 13.1 95 1.454 10 Table 2. Standardized mortality ratios. ICD 8 Cause of death VCM/PVC production Obs. SMR Total mortality 414 95 140-209 All malignant tumors 94 112 140-199 Malignant tumors of organs 79 103 200-209 Malignancies of lymphatic and hematopoetic tissues 15 214b 150-159 Malignant tumors of G1 tract and peritoneum 45 149s 155 ' Malignant tumors of the liver 12 1523b 191 Malignant tumors of the brain 2 162 410-414 Ischemic heart disease 91 127* 410 Acute myocardial 66 114 800-949 Accidents 61 137* aBevond 95% confidence interval (2). bBeyond 99% confidence interval (2). Reference group Obs. SMR 417 78 83 83 l i 83 6 77 27 71 4 401a 2 184 115 131* 83 120 44 99 PVC l processing -l Obs. SMR j 360 95 : 62 85 60 89 / 2 34 15 .. . _ 56 > 3 434 ; 5 535* ' 96 15Sb 69 143b 32 110 ' Table 3. Standardized mortality ratios by duration of exposure. ICD 8 Cause of death < 12 Obs. SMR Duration of exposure, months 13-16 61--120 Obs. SMR Obs. SMR > 121 Obs. SMR Total mortality 140-199 200-209 150-159 155 191 Malignant tumors of organs Malignancies of lymphatic and hematopoetic tissues Malignant tumors of GI tract and peritoneum Malignant tumors of the liver Malignant tumors of the brain 53 6 1 3 0 0 93 138 102 93 74 20 88 22 92 4 186 5 101 12 135 13 - 2 874* 3 - 0- 1 87 116 287 173 1525b 350 130 31 5 17 7 1 96 115 249 158 2528b, 278 96 Environmental Health Perspectives 21137002 r tinr 'sibleto etr ctively 'cal ^*oblems, Jlished. How- :he best aval IC. 8 Cause of death Table 4. Standardized mortality ratios by period of observation. To 1959 Obs. SMR Observation period 1960-69 1970-74 Obs. SMR Obs. SMR Total Obs. SMR rvation perio 4 140-199 200-209 150-159 l5o 191 Malignant tumors Malignancies of lymphatic and hematopoetic tissues Malignant tumors of GI tract and peritoneum Malignant tumors of the liver Malignant tumors of the brain 12 160 29 84 194 103 414 95 1 147 9 275s 5 168 15 214s 8 270* 13 94 24 177b 45 149* 1 1282 3 834' 8 2264s 12 1523s 1 557 0 - 1 223 2 162 Jup III, PVC * processing # Beyond 95% confidence interval. bBeyond 99% confidence interval. 4.007 52.896 92.1 360 380 ~ 4 * Table 5. Standardized mortality ratios by age. Age group 47 13.1 95 1.454 10 PVC T ssing 3 01 SMR ' 1CD 8 Cause of death 24 25-34 35-44 45-54 55-64 65 Total Obs. SMR Obs. SMR Obs. SMR Obs. SMR Obs. SMR Obs. SMR Obs. SMR Total mortality 10 68 45 111 65 104 90 101 105 80 90 103 414 95 140-199 Malignant tumors of organs 0 4 141 13 188* 19 141 22 76 21 100 79 103 200-209 Malignancies of lymphatic and hematopoetic tissues 0 2 194 4 303 4 264 3 162 2 197 15 214s 15 .59 Malignant tumors of GI CO % t-* tract and peritoneum 0 3 397 10 145 10 89 12 140 45 149s 155 Malignant tumors of the liver 0 0- 6 6865s 0 - 3 934s 3 1664s 12 1523s 191 Malignant tumors of the brain 0 0- 0 1 254 1 362 0 2 162 360 62 60 2 15 3 5 96 69 32 s 95 i 85 89 ; 34 56 V * 434 ' I 535* f 158s i 143s ; no - 'Beyond 95% confidence interval. sBevond 99% confidence interval. Table 6. Groups for subdivision of laboratory examinations. Gi. o Specification A-1 VCM/PVC production A-II PVC processing B-I VCM/PVC production and PVC processing, work capacity loss < 20% B-I I VCM/PVC production and PVC processing, work capacity loss s* 20% C-I Germans and Austrians C-II Foreigners (Excl. Austrians) D-l Plants with high morbidity D-1I Plants with low morbidity Table 8. Bromsulfalein retention.* Germans and Austrians Foreigners Retention noma] Retention abnormal Total 17 30 33 21 50 51 *Chi square! = 6.25 (p < 2.5%). Total 47 55 101 > 121 Obs. SMR 7 `s 7 130 96 6 31 115 4, 7 5 249 / 3 17 158 < 252S*V 278 Table 7.. Bromsulfalein retention.* VCM/PVC PVC Production Processing Retention normal Retention abnormal Total 26 21 44 10 70 31 aChi square! = 8.09 (p < 1%). Total 47 54 101 Table 9. Bromsulfalein retention.* Work capa- Work capacity loss city loss < 20%. > 20%: Retention normal Retention abnormal Total 41 6 32 22 73 28 Total 47 54 101 (Table 4) reveals a rather inconsistent pattern: malignancies of the lymphatic tissues (ICD 200-209) are significantly elevated in the sixties only, whereas SMRs for tumors of the liver increase till the end of the study period. This might be referred to differ ent latency periods for both kinds of malignancies, but other causes might likewise have contributed to these results. However, it has to be reported that the number of angiosarcomas confirmed histologi cally in the Federal Republic of Germany in pa tients previously exposed to VCM has actually come to 17 in contrast to mere 4 at the endpoint of the mortality study (12/31/1974). The distribution of SMRs by age (Table 5) demonstrates an obvious susceptibility of males aged 35-44 for malignancies in general as well as for malignancies of the liver. The data base for the German morbidity study consists of all of the reports of suspected cases of occupational disease due to VCM or PVC produc tion or PVC processing. The reference population for these reports has to be defined as the total MG/DL NORMAL 1.0 PATHOL. > 1.0 WORK CAPACITY LOSS < 20 * WORK CAPACITY LOSS 20 % Figure 2. Vinyl chloride morbidity study: oral glucose tole ance test, 120 min after loading (normal 120 mg/dl). VCM-/PVC PRODUCTION AND PVC PROCESSING WORK CAPACITY LOSS < 20 * VCM-/PVC PRODUCTION AND PVC PROCESSING WORK CAPACITY LOSS >20 % Figure 1. Vinyl chloride morbidity study: total bilirubin (normal 1.0). 98 AND PVC PROCESSING WORK CAPACITY LOSS < 20 % AND PVC PROCESSING WORK CAPACITY LOSS i20 % Figure 3. Vinyl chloride morbidity study: reticulocytes (n< mal 159E). Environmental Health Perspective 1 P<J * C PRODUCTION : processing OPACITY LOSS * al glucose toler-j 1 mf ' X-. working population in 1974 in the above mentioned branches, i.e., 6,500 workers in VCM or PVC production and 42,800 workers in PVC processing (a. given by the German Association of Plastic producing Industries). Till the end of 1974 , 269 reports of suspected cases of occupational disease had been received. As there has been no consistent set of examinations performed on each of the cases, numbers of observations for various variables ana lyzed vary according to examination method per formed. Insofar as the results of this study are of much lower validity than those of the mortality study, one should regard them as hints for further in -stigations. I mr attempts to subclassify observation on the 269 cases have been undertaken (Table 6). Only those results showing significant differences when applying (-tests or chi-square tests are so classified. Amazingly none of the more sensitive lab examina tions of liver functions showed a marked difference in all of the subclassifications besides bromsulfalein retention. In this instance there is a significant difference when subdividing by VCM/PVC produc ts' versus processing (Table 7), as well as by nationality (Table 8) and most pronounced when subdividing by extent of work capacity loss (Table 9). This latter result, however, must be expected when an effect of exposure on liver function is anticipated. An impairment of the excretory liver function is suggested by elevated total bilirubin values in the subgroup with work capacity loss greater than 20% (Fig. 1). There seems to be an impaired glucose tolerance in this group, although observed in a small subsample only (Fig. 2), as well as a lower number of reticulocytes (Fig. 3). The thromocyte count in both groups was the same. These results, however, lead to no sensible inter pretation, as all results attempts failed to standard ize the methods applied for thrombocyte counts by various laboratories. REFERENCES 1. Tabershaw, I. R., and Gaffey, W. R. Mortality study of workers in the manufacture of vinyl chloride and its poly mers. J. Occup. Med. 16: 509-518 (1974). 2. Bailar, J. C. Significance factors for the ratio of a Poisson variable to its expectation. Biometrics 20: 639-643 (1964). y-s- V; ~( p-<5 % >is, ftOfttMirtl All Environmental Health Perspectives Vol. 11, pp. 115-151. 1SH 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-processmg industries were collected on production ofemployees 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 with 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 bad at least two years of exposure time and where the analysis was diricted 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, 3) 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 U-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 85 Stockholm, Sweden. f Group for Applied Statistics, Karlbergsvagc-n 82, 113 35 Stockholm. Sweden. "Bureau of Statistics, Department of Welfare. 106 30 Stock holm, 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 hemangiosarcoma in the liver. Earlier, an excess mortal ity from cardiovascular diseases was also observed (10) 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 oOvv persons are employed in production. October 1981 21138001 1J5 Material and Methods earner man i^ui auu wu5 The two latter named study cohorts were chosen Information for the study was collected from four in order to study whether any differences existed in PYC processing companies. The four companies all ' --d PVC which, after additions of various chemis. is heat-treated for fabrication into floor cover- ...g. lace, pipes, and food packaging. 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 Cohort Exp. class Exp. class tively early, e.g., accidents caused by the job. The Exp. class Data Collection second was intended to shed light or* such death causes as occurred after a longer time had passed. Exp. class The following data were collected from the per Tumors caused by occupational exposure, for ex sonnel lists at the companies: personal number, ample, often have a long latency period, 5-10 yr or name, beginning and end of exposure (year and longer. Table 4. I certain cr month) and class of exposure. least six 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 Results The original cohort was relatively young at the fi' 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. 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 .i Malignant Digestive Cardiovasi Mvocardia Accidents. The collected data were transferred to punched cards and magnetic tape for statistical processing. The magnetic tape was coordinated with the na 35 years at the beginning of exposure; in class 2 (average), 47.7%; and in class 3 (high), 50.6%. There Risk ca than 1961. tional total population and the so-called death tapes for the 1961-1976 period and checked against the cancer registry by the Central Bureau of Statistics Table 1. Age distribution in original cohort at beginning of exposure were al? with re? (SCB). The personnel numbers which could not be % in each exposure class it shout recovered at this time were checked by the national Age 1 2 3 1-3 taxation office. The original cohort included a total of 2.073 persons. Of these, 103 persons (5%) dropped < 19 1.6 2.0 8.9 2.1 at, 70 or whom had moved abroad, 5 were found in 20-24 25-29 7.5 13.5 14.6 14.3 15.7 21.4 9.2 14.4 ,ie missing persons register of the tax office, and 30-34 19.1 15.4 17.0 18.3 2S could not be traced. 35-39 17.0 13.2 10.7 15.9 40-14 13.7 12.6 9.8 13.3 i 45-49 11.1 12.6 8.9 11.3 Study Cohorts 50-54 8.0 7.8 5.4 7.8 55-59 5.1 3.9 1.8 4.7 For the statistical processing, the results of the 60-01 2.6 2.0 1.8 2.4 which w entranci which rt times is has long The c increase tional a\ the sub) Study cohort of 1970 persons were divided into a number > 65 0.7 0.3 0.0 0.6 least six 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 No. of persons 100% (1501) 100%> (357) 100% (112) 10%% (1970) the risk what rei deaths i.- persons with at least six months of exposure ex cluding those who stopped before 1961 (follow-up Table 2. Distribution of exposure time in the original cohort. 1 time from beginning of exposure but no earlier than I J 1961 and through 1976); (3) all persons with at least % in each exposure class six months of exposure and where the exposure Months 1 2 3 1-3 Table 3. < 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 <5 6-23 24-59 13.1 ' -0.3 0.0 10.1 38.4 8.4 8.9 31.3 25.0 17.4 10.7 22.8 time from two years after beginning of exposure 60-119 15.3 45.7 15.2 20.8 Cohort Exp. cla.'-Exp. clav but no earlier than 1961 and through 1976 but no > 120 i i more than ten years after exposure stopped); (5) all persons with at least two years exposure (follow-up time from ten years after exposure began but no 8.2 28.3 65.2 15.1 100% 100% 100% 100% Oi = 1510) OI = 357) (Af = 112) (M = 1970) Exp. cb--Exp. cb-v Risk r. J 146 Environmental Health Perspectives Octobei J re chosen e: *>ted in v en the exposure, -d to shed e' r rela<; b. The ::ch death id uassed. tj for exo-xO yr or 1] l Tabic 3. Observed and anticipated number of deaths as of December 31, 1976. No. of deaths Cohort Number Observed Expected Ratio O/E Exp. class 1 1303 53 . Exp. class 2 356 14 1 Exp. class 3 112 6 j. Exp. class 1-3 -- 1171 73 % !li 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 t before 1961.* 55.5 21.9 10.3 87.8 A 0.95 0.64 0.70 0.84 Approx. 95% confidence interval s: 0.26 * 0.34 i: 0.47 = 0.19 >* ai ; at the s 1; Ob Ex Ratio served pected O/E .>,U in the -.Me 1. One epeposure * Malignant tumors 140-209 i. Digestive organ tumors 150-159 Cardiovascular diseases Vi I i Myocardial infarction 410.90 17 14.0 1.21 8 4.9 1.63 22 24.3 0.91 15 20.0 1.49 j^er than : sr -lass 2 JP; Accidents, suicide, etc. XVII 13 9.2 1.42 .(ft here *Risk calculated from the beginning of exposure but no earlier f than 1961. Study cohort 2 (1771 persons). 1i ;} ottrsnning of i were also dissimilarities in the length of exposure .-jf ;---------- with respect to exposure class (Table 2). However, i it should be noted that the table includes cases ' ' 1-3 which were still under exposure at the final date for ? 2.1 9.2 >- 14.4 18.3 r 15.9 u 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 13.3 11.3 7.8 4.7 ! ' 2.4 increase in the total risk compared with the na / v tional average, nor is there any indication of this in the subgroups making up the study cohort. j Study cohort 1, which includes everyone with at i 0.6 least six months of exposure and with calculation of the risk from the beginning of exposure, is some (1970) what remarkable in that the anticipated number of deaths is significantly higher than that observed up Figure 1. Cumulative deaths (in percent): (V) observed; (T) 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- vicir.al cohort. j 1-3 ; i ~ioT : I 31.3 ".8 i.8 15.1 jrectives 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.* V No. of deaths Approx. 95% Cohort Number Observed Expected Ratio O/E confidence interval Exp. class 1 Exp. class 2 Exp. class 3 Exp. class 1-3 1139 247 42 1428 43 4 1 43 41.2 1.04 11.7 0.34 1.8 54.7 0.88 = 0.31 = 0.34 = 0.35 * `Risk calculation from beginning of exjrosure. Study cohort 3 (1428 person?). I October 1981 i 21138003 147 deaths anticipated i>t mo i Figcp.e 2. Cumulative deaths (in percent). Expected value calculated through 1961. Study cohort 2 (1771 persons). Percentage for a given year calculated as in Fig. 1. V. death: -----------'anticipated --`-"'observed c i s i in in) i) years after beginning of exposure Figure 4. Observed death risk per year at different points of time after beginning of exposure expressed in percent-of corresponding anticipated risk in those who began exposure in 196) 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.* ^laligrur Digest:'.. Cardi.-.i Mynca.-;. Accidie .. Table ?. cunrrr iti c\p> Oli Ob Ex Ratio served pected O/E lh_\r. 1 .*- Figure 3. Cumulative deaths (in percent) of those who began exposure in 1950 or later. Study cohort 3 (1428 persons). Percentage for a given year calculated as in Fig. 1. ou? 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 340-209 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 i 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.* 1 hi *!: durv: - n:Vr :> **1 nr.. or Io*a i-r r In *: in*::.**'; r> diff:rvr nurr.i-*-: V:.r rrLir::/* *:; <j\ V:vT } death ji\rrr.p ri-.,h-* a-- u-'r- a Li Malignant tumors 140-209 ! ! Digestive organ tuihors 150-159 ' Cardiovascular diseases VII Mvocardial infarction 410.90 Accidents, suicide, etc. XVII Observed 5 (9) 2 (4) 15 (16) 11 (12) 4 (5) Expected 7.4 (8.9) 2.6 (3.2) 12.7 (15.8) 5.4 (6.6) 4.6 (5.1) - Ratio O 0.86b (1.01) 0.78b (1.27) 1.18b (1.01) 2.03b (1.82)b 0.87b (0.97) {rr<r. t: 1< :H C U Jr- *J t**r*^ i>. `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. r*hj*r* C)dc^ Table 8. Observed and anticipated number of deaths from 1. certain causes during the 1968-1976 in those with at least two I; years of exposure.* observed anticipated Ob Ex Ratio served pected O/E r rs after jtnning j ;<posure :*,it points of ir> percent of v i-Ti exposure it ff^alhs from i.,Jith at least Malignant tumors 140-209 Digestive organ tumors 150-159Cardiovascular 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. 9 Study cohort 5 (680 persons). _ 1 Table 9. Observed and anticipated number of deaths from I cancer during 1961-1976 in those with at least six months of l exposure excluding those who stopped before 1961.* *v Ob- Ex- Ratio / served pected O/E Malignant tumors (total) Digestive organ tumors (150-159) 51 44.6 11 ' 8.5 1.14 1.29 No. of risks Ficure 5. Cumulative survival probability (in percent) ofthose who began exposure in 1961 or later and have at least six months of exposure. Study cohort 3 (1428 persons). 7. cas es 7- expected observed Ej? y. "7 :..3 If 1 `..s Tatio O/E 0.93 1.20 0.99 1.25 1.51 t 'Itudv cohort i * A ) pertains tjlater but na as study <j ig to for- jinual risk e-.vhat lower .-r about ten I 'observed IV 1 t at least two I iw j |*7) '-'"sure. Study V *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 after the end of exposure, i.e., "short-term per spective," 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 o% 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. 6). In the question of tumors of the digestive or gans, in the same study cohort, 11 cases were observed as opposed to an anticipated 8.5. The 1900 ises 1*70 isrs Fjcure 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 Ort nhor 1 9S1 119 .of persons who began employment before I960, factors. Among otner hsk laciors, one can aUo could lead to the difference mentioned above. The name hereditary characteristics and high blood pro*. * companies involved reported that such a purging sure. In this connection, there is reason to recoiled / did not occur, so far as they knew. that the causal network of coronary disease is tnu'- If such a purging (thinning out) nevertheless tifactorial and that the disease has an environment occurred, this would have resulted in the elimina tal relationship in the broad sense. There is also { tion of persons with a long observation time at the reason to recall the aspect that the total risk in time of follow-up. In the present study, the risk creases when several risk factors, known or un calculations were limited to beginning no earlier known, are allowed to collaborate (11,12). than 1961. This means a limitation of the analysis to It has not been possible to establish the distribu pertain to the group of employees who were living tion of such already known risk factors for coronarv / at the beginning of 1961 and where the risk of an disease in the cohorts studied with respect to the * elimination is positively eliminated. This limitation, national population in general. Therefore, no con however, signifies a weakening of the analysis, tinued analysis of the matter of the causal relation since parts of the cohort with long follow-up times ship between close environment and heart disease are excluded. Basically, this weakening signifies a morbidity can be made within the limits of this t poorer possibility of discovering an elevated inci study. * dence of cancer if one exists. Exposure classes 2 and 3 constitute subcohorts * The myocardial infarction mortality (I CD 410.90) that are too small, in the present study, to allow a r. is elevated in the cohort. This elevation occurs most meaningful discussion of the myocardial infarction t clearly in the category of the total cohort which has risks relative to the various exposure levels in the j at least two years of employment time and where processing industry. In this connection, one should ' the analysis was directed at the period of time also consider the circumstance that the exposure ( following two years after the beginning of employ classes in this study are based on interviews with / ment and extendi ,g to no more than five years after the employees directed at the work environment at i the beginning of employment. Therefore, this in the time in question some 10 to 15 years ago. ( volves that fraction of the mortality from myocar Therefore, this involves an environment which has f dial infarction which chronologically is relatively subsequently undergone changes. Objective classi- I closely connected to the time of employment. It is - fication criteria in the matter of exposure, e.g., in j impossible on the basis of such observations to' the form of environmental measurements, do not draw conclusions that the. elevation was caused by exist. The distribution into exposure classes is, for * exposure to vinyl chloride. The observed increase this reason, fraught with uncertainty. in myocardial infarction mortality is, however, so In animal experiments, it has been found that the striking that it, in combination with the known ---toxicity picture in rodents chronically exposed to facts about the toxic properties of vinyl chloride, VCM involves the blood vessels. Besides heman- 1 must be given consideration. There are no reasons giosarcoma in the liver and the other organs (1,5) [ to assume that varying diagnostics, standards or the inhalation of VCM is also believed to cause practices in filling out the death certificates alone development of telangiectasis (4) in the liver ofmice , could provide an explanation. A natural conclusion which can lead to death from hemocoele. Changes is, therefore, that if one disregards the possibility in the sinus cells have been observed in liver biop of a random local phenomenon, the increased fre sies in VCM-exposed workers (15). Capillary changes quency is to be ascribed either to selection of indi in the skin of the finger's have also been observed viduals susceptible to the risk or an outbreak of risk (14-16), both in VCM-exposed workers with other factors in the close environment of employees. A vascular-involved diseases, such as acroosteolvsis. combination of these two circumstances is, of course, Raynaud's phenomenon, and sclerodermia, and in ( also possible theoretically. VCM-exposed workers without such diseases. An In this connection, it should be noted that many over-representation of deaths from cardiovascular : > risk factors for myocardial infarction are environ diseases has also been observed in a study on the mentally conditioned in the fact that they constitute PVC-fabricating industries (10). Animal experimen part of the lifestyle of the modern social environ tal and previous medical studies of VCM-exposed ment in an industrialized country. Cigarette smok- populations therefore support the assumption that ing, physical inactivity, overweight and high blood the increased risk of myocardial infarction observed lipids constitute environmental factors which are in the present study could possibly be ascribed to related to social behavior. It is a well known fact VCM exposure. that the risk of coronary vascular disease in the As regards the mortality and morbidity from heart varies, inter alia, with the total load of risk tumors, the results are uncertain. There are certain 150 Environmental Health Perspectives- l" -i.ililu :. ris .-- 1 ri .. bin! i :: thv ' a.-.I >\ -u |> v.-ar - I fill l v * .ha! ai :-!> t. .aiw v: *. I iilior I $ * f *conrvl-lion- : tt disease j5:< i f this A ., jn; RJtV'hortS 4j ito :;!low a &? infarction t jfvc!.' in the sf^jnc should exposure rrv;"\vs with :y, lent at '4 sago. tJ w hich has i-ciive classif n*. e.g., in rj its. do not classes is, for V.d that the exposed to -siilvs henian- -prans (4, 5) id to cause er ofmice . Changes if iiver biop-3 ;irv changes been observed -T* with other i i-osteolysis, l.mia, and in n diseases. An ( [diovascular ? ludy on the -a! experimenVOl-exposed option that bserved t> ribed to indications 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 Tong 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 (i 7) on almost 4300 deaths in the American PVC-processing in dustry', an overrepresentation in cancer mortality appears to exist (all cancer), especially gastrointes tinal cancer in both sexes. REFERENCES & 1. Holmberg, B., and Molina, G.: The industrial toxicology of vinyl chloride. A review. Work-Environ. Health 11:138-144 * (3974). 2. Creech, J. L., and Johnsson, M. N. Angiosarcoma of the liver in the manufacture of polwinvl chloride. J. Occup. Med., 16: 150-151 (1974). 3. 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. V ~ jbidity from are certain ' 'Vrspectivcs October 1981 Cancer Res., 31: 516-522 (1971). 7. Byren, D., and Holmberg, B. Two possible cases of angiosarcoma of the liver in a group of Swedish vinyl chloride-polyvinvl chloride workers. Ann. X. Y. Acad. Sci.. 246; 249-250 (1975). 8. Monson, R. R., Peters, J. M., and Johnsson, M. N\ Proportional mortality among vinvl chloride workers. Lan cet ii, 397-398 (1974). 9. Tabershaw, J. R., and Gaffey, W. R. Mortality study of workers in the manufacture of-vinyl chloride and its polymers. J. Occup. Med., 16: S09-51S (1974). 10. Byren, D., Enghobn. G., Englund, A.^znd Westerholm. P. Mortality and cancer morbidity in a group of Swedish YCM 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 vinvl chloride. Ann. N.Y. Acad. Sci.. 246:172-193 (1975). ' ' 14. Mariea, H., Johnsson, M. X., Whetstone, C. L., and Le Roy, E. C. Capillary abnormalities in polyvinyl chloride production workers. J. Am. Med. Assoc., 236: 1368-1371 (1976). 15. Mariea, H., Johnsson, M. X., Whetstone,\C. L,, and Le Roy, E. D. In vivo capillary abnormalities in vir.yl chloride workers. In: Microcirculation, Vol. 2. J. Grsvson and W. Zingg, Eds., Plenum Press, Xew York, 1976. 16. Mariea, 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 (1975). 17. Chiazze, L.. Xichols, \V. E., and Wong. O. Mortality among employees of PVC fabricate--. J. Occup. Med.. 19: 623-628 (1977). 18. Chiang, C. L. Stochastic Processes in Biostatistics. An Introduction. Wiley, Xew York, 1971. 151 excess of Jung cancel' (5 observed versus 1.98 expected.) Cancer of the Lymphatic and Hematopoietic System in Humans Table 4 summarizes data on cancer of the lym phatic and hematopoietic systems among workers exposed to VC. The relative risks for various studies ranged from 1.0 to 2.2, and none of the results demonstrated a significant excess. Although somewhat suggestive, the data need to be further analyzed by latency period and exposure levels combined. Analysis of data separately for lym phatic cancers and leukemia might also lead to meaningful observations. Summary In summary, epidemiologic evidence demonstrates that the carcinogenic effects of VC in humans extend beyond the liver. The brain and lung should also be considered target organs. Some studies indicate that the lymphatic and hematopoietic sys tems are also ir./olved. These observations in humans are supported by studies demonstrating the induction of cancer of these same sites in experimental animals. REFERENCES 1. Patty, F. A., Yant, W. P., and Waite, C. P. Acute response of guinea pigs to vapors of some new commercial organic compounds. Publ. Health Kepts. 45: 1963-1971 (1930). 2. Selikorf. 1. J, and Hammond. E. C., Eds. Toxicity of vinyl chloride-polyvinyl chloride. Ann. N'.Y. Acad. Sci. 246: 1337 (1975). 3. Viola. P. L.. Biopoui. A., and Caputo, A. Oncogenic responses of rat skin. lungs, and bones to vinyl chloride. Cancer Res. 31: 516-519 (1971). 4. Maltoni. C.. Lefemine. G., Ciliberti, A., Cotti, G. and Carrelti. D. Carcinogenicity bioassays of vinyl chloride monomer. A model of risk assessment on experimental bases. Environ. Health Perspect. 41:3-29(1981). 5. Waxweiler, R. J.. Stringer, W., Wagoner, J. K., Jones. J.,. Falk. H.. and Carter. C. Neoplastic risk among workers exposed to vinvl chloride. Ann N'.Y. Acad. Sci. 271: 40-48 (1976). 6. Bvren. 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). 7. Fox. A. J.. and Collier, P. F. Mortality experience of workers exposed to vinyl chloride monomer in the manufac ture of polvvinvl chloride in Great Britain. Brit. J. Ind. Med. 34: 1-10 (1977). 8. Monson. R. R., Peters. J. M., and Johnson, M. N. Propor tional mortality among vinvl-chloride workers. Lancet ii: 397-39S (1974).' 9. Tabershaw. I. R., and Gaffey, W. R. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occup. Med. 16: 509-518 (1974). 10. Buffler, P. A., Wood. S., Eifter, C., Suarez, L., and Kilian, D.' J. Mortality experience of workers in a vinyl chloride monomer production plant. J. Occup. Med. 21: 195-203 (1979). 11. Ott, M. G.. Langner. R. R. and Holder. B. B. Vinyl chloride exposure in a controlled industrial environment. A long term mortality experience in 594 employees. Arch. Environ. Health 30: 333-339 (1975). 12. Equitable Environmental Health. Epidemiological study of vinyl chloride workers. Prepared for Manufacturing Chem ists Association. 1978. Ge Vir by \ Vinyl The : darriize exposec West ( study t cnemici tributio VCM a worker.- The studv. i the VC! plants t Table three c Austria insufiici tionals mine th man rat total years h: specific t> e rat*years ir.g th*- Jhv-.>:rs ** W iVrr*** OctoSft 94 Environmental Health Perspectives^