Document 6RM4vDwkMwM9N3ENwwr4D5YRo

ORIGINAL ARTICLES and J Work Environ Health 1991; 17:159--69 licnd v collaborative study of cancer incidence and mortality mong vinyl chloride workers L Simonato, MD,1'2 *KA L'Abb6, PhD,13 A Andersen, MD,4 S Belli, DSc,s P Comba, DSc,5 Engholm,6 G Ferro,1 L Hagmar, MD,7 S Lang&rd, MD, PhD,81 Lundberg, MD,9 Pirastu, MSc,10 P Thomas, BSc,11 R Winkelmann, MA,1 R Saracci, MD,1 SIMONATO L, L'ABBls KA, ANDERSEN A. BELLI S, COMBA P. ENGHOLM G, FERRO G. HAGMAR L, LANGARD S, LUNDBERG I, PIRASTU R, THOMAS P. WINKELMANN R, SARACCI R. A collaborative study of cancer incidence and mortality among vinyl chloride workers. ScandJ Work Environ Health 1991;17:159--69. A large European multicentric cohort study has been coordinated by the International Agency for Research on Cancer with the objectives of investigating the dose-response relationship between liver cancer and exposure to vinyl chloride and assessing cancer risk for sites other than the liver. A nearly threefold increase in liver cancer was detected on the basis of 24 observed deaths and 8.4 expected (standardized mortality ratio 286, 95 % confidence interval 186--425). The excess from liver cancer was clearly related to time since first exposure, duration of employment, and estimated ranked and quantitative exposures. Other cancer sites investigated on the basis of a priori hypotheses were either not in excess (lung) or apparently unrelated to the exposure variables (brain and lymphoma). Key terms: brain cancer, cohort study, dose-response relationship, liver cancer, lung cancer, lymphoma. :nyl chloride (VC) is an established carcinogen for amans (1,2), and it is also one of the few substances r which the experimental evidence of carcinogenici- was available (3) before the carcinogenic effects on umans could be demonstrated. The concern about the hazards from exposure to this dbstance led to control measures which lowered the levels of exposure in excess of 500 ppm in the early 1950s to values generally below 1 ppm in industrial ized countries. In recent years, the development of laboratory tech niques in investigating possible effects at the molecu 1 International Agency for Research on Cancer, Lyon, France. : Present address: Registro Tumori del Vencto, University of Padova, Italy. 1 Present address: Department of Preventive Medicine and Biostatistics, University of Toronto, Toronto, Ontario, Canada. 4 The Cancer Registry of Norway, Oslo, Norway. ! National Institute of Health, Rome. Italy. ` The Construction Industry's Organization for Working En vironment, Safety and Health, Bygghalsan, Danderyd, Sweden. Department of Occupational Medicine, University Hospi tal, Lund, Sweden. ` Telemark Central Hospital, Department of Occupational Medicine, Porsgrunn, Norway. 1 Karolinska Hospital, Department of Occupational Medi cine, Stockholm, Sweden. 10 Department of Animal and Human Biology, University of Rome, La Sapienza, Rome, Italy. " Health and Safety Executive, Employment Medical Ad visory Service, Bootle, United Kingdom. Reprint requests to: Dr R Saracci, Unit of Analytical Epidemiology, International Agency for Research on Cancer. 150 Cours Albert-Thomas, F-69372 Lyon cedex 08. France. lar level (4) renewed the interest in this substance. In addition the epidemiologic data have recently been up dated (5--7) and reevaluated in a review (8). Although occupational exposures have decreased, important scientific and public health questions re main. In 1986 the occupational program of the Inter national Agency for Research on Cancer (IARC) in vited European epidemiologists involved in research on the effects of VC to combine their efforts in a multicentric cohort study. The collaborative cohort study reported in this presentation was undertaken with the following three objectives: (i) to determine whether VC is associated with increased cancer risk at sites other than the liver, (ii) to investigate the possible expo sure-response relationship between VC and liver can cer, particularly angiosarcoma of the liver, and (iii) to construct a data base which could be exploited in the future in relation to the assessment of potential risk at low levels of exposure. In this report, we present the methods and results of this collaborative study, further details of which can be found in an IARC report (9). Subjects and methods Collaborators from four countries (Italy, Norway, Sweden, and the United Kingdom) participated in the cohort study and contributed a total of 14 351 sub jects to the combined data base. Both existing studies and newly collected cohorts were enrolled from 19 fac tories. Where existing study populations were included (10--15) follow-up was extended, and/or more fac tories were added. In the majority of factories in the cohort there was mixed VC monomer/polyvinyl chlo- NoqcE; T5t'c mat^al vay ;; ffcizr::: 159 R&S 143158 ride (VCM/PVC) production (12 factories), two produced VCM only, four produced PVC only, and one was a PVC-processing plant. For the sake of homogeneity, we decided to include only subjects with at least one year of employment in the analysis, and therefore 1518 subjects (10.6 Vo of the combined cohort) had to be excluded. An addi tional 127 subjects (0.9 Vo of the combined cohort) were excluded for the following reasons: female gen der (N = 57), out of observation period (N =48), mem ber of more than one cohort (N = 21), and date of first exposure unknown (N = 1). After the total of 1645 ex clusions (11.5 Vo of the combined data base), 12 706 subjects remained for the analysis. The vital status of the subjects included in the mor tality analysis is shown in table 1, and the complete ness of follow-up at 97.7 Vo can be considered satis factory. For the 12 706 subjects included in the analy sis, the average length of follow-up was 17 (range 10--25) years, 36 Vo of the cohort having a follow-up period of 20 years or more. The total number of person-years at risk was 222 746, and the distribution of person-years according to duration and the num ber of years since first exposure is given in table 2. National incidence or mortality rates (men only) specific for age and five-year calendar periods were used for reference. The observation period differed by factory, the majority of subjects having been followed from 1955 (first year for which reference rates were available) or from the start of the second year of em ployment, whichever came first, to 1986. Two of the four countries, Norway and Sweden, were also able to provide follow-up for incidence through nationbased cancer registries, while mortality rates were com puted at IARC with the use of a data base belonging to the World Health Organization (WHO). As dif ferent revisions of the International Classification of Diseases (1CD) were used over the follow-up period. Table 1. Vital status of the cohort members.4 Vital status Alive Dead Unknown (lost or emigrated) Total N 10 981 1 438 287 12 706 * Person-years at risk: 222 746 % 86.4 11.3 2.3 100 Table 2. Person-years by duration of employment and follow up. Duration of employment (years) 1-9 10--19 a 20 Total Years since first exposure 1--9 10--19 20--29 2:30 9517_8 43 306 43 256 13 293 8 842 2 670 1 427 - - 11 810 2 965 95 178 86 562 33 945 7 062 Total 154 446 53 526 14 775 222 746 a conversion table for causes of death was used and can be found in the detailed IARC report (9). It should be noted that for this study liver cancer was defined as ICD 155--156 (seventh revision): liver, intrahepatic and extrahepatic bile ducts, and gallblad der specified as primary or secondary; ICD 155 (eighth revision): liver and intrahepatic bile ducts specified as primary; and ICD 155 (ninth revision): liver and in trahepatic bile ducts specified as primary and liver specified as secondary. Although ideally only primary liver cancer should be chosen as the definition, the seventh and ninth ICD revisions do not permit sepa ration of primary and secondary (as this distinction is often difficult in reality). In the eighth and ninth revisions, secondary liver cancer is classified by a four digit code, but specification of the national mortality rates to four digits in the WHO data base is not avail able from all countries. Therefore, it was necessary to choose the aforementioned definition for liver cancer. Angiosarcoma of the liver is distinguished from other types of liver cancer through histology. This type of information was sought from national investigators, and only cases histologically confirmed were included in the analyses. For the analysis, person-years at risk were calculated with the person-years program using a modified lifetable approach (16). In calculating the person-years, no censoring at old age took place, and the date of entry for the tabulation of person-years started at the beginning of the observation period according to the availability of reference rates in 1955 or on day 1 of the second year of employment, whichever occurred later. The standardized mortality ratio (SMR) or stan dardized incidence ratio (SIR) and the 95 Vo confidence interval (95 Vo Cl) for the SMR or SIR were calculated on the assumption of a Poisson distribution. Prior to the analysis, it was decided that four causes of death suspected a priori (ie, liver cancer, lung cancer, brain cancer, and lymphosarcoma) would be examined in de tail. The mortality analysis was performed according to several temporal variables, specifically years since first exposure, calendar period at hire, calendar period at exit, age at hire, and age at exit. In the analysis all of these variables were based on individual information available for each subject. Exposure variables were job title as autoclave worker'(ever/never), duration of em ployment, ranked level of exposure, and cumulative exposure in parts per million-years to VCM in the air. For the ranked level of exposure and cumulative ex posure indices, job histories were required, along with exposure estimates for specific jobs and calendar pe riods from job-exposure matrices. The job-exposure matrices specific for calendar period were provided by industrial hygienists for 13 of the 19 factories. These matrices were developed in various ways for the dif ferent factories. For most of them, job title was used as the basic unit with which exposure was assessed, and ! 160 R&S 143159 jo histories were available for all factories except two. Typical exposures" to VC in air were estimated as me-weighted averages by industrial hygienists using cveral sources of variable quality. In most factories, ccasional measurements of VC provided the basis for ast typical exposures, supplemented by knowledge of xposure conditions, processes, and technological hanges over time. Systematic measurements taken mce the mid-1970s provided the basis for more recent jxposure assessments, and an indication of the variibility of exposure levels between job titles. In terms of agents to which the workers were ex posed in VCM, PVC, and VCM/PVC production, VC was the main exposure, and virtually the only exposure In many of these factories. Use of butadiene was rare. In PVC processing (one factory in this study), how ever, additional exposures could have included PVC dust, asbestos, and other agents. All the job-exposure matrices referred only to VC exposure in air. Each job-exposure matrix was checked and validated by two independent industrial hygienists, who were able to provide, prior to the statistical analysis, an in dex for the ranked level of exposure (low: < 50 ppm; intermediate: 50--449 ppm; and high: a 500 ppm) in which the classification of the subjects was based on the highest level to which the workers were potential ly exposed, specific to their jobs and the years in which they worked, according to levels of VC recorded in the job-exposure matrices. The same information, that is, job histories and jobexposure matrices, was used to calculate cumulative exposure in parts per million-years (exposure level from the job-exposure matrices multiplied by duration of employment) for the subjects. In some of the analyses for cancer of the liver an estimated job-exposure ma trix was used for the four factories in the United King dom which were unable to provide their own matrices. The estimated job-exposure matrix was based on the matrices provided for the other factories in the United Kingdom. This matrix was checked with the industrial hygienist from the United Kingdom. In the following text, it is clearly noted if the analyses under discus sion include this estimated matrix. For liver cancer only, the Poisson regression analy sis was performed to assess the significance of several variables simultaneously. This analysis used observed deaths and the person-years distribution for crossclassified categories of temporal and exposure varia bles and performed an internal comparison with the base-line categories (ie, w ithin the cohort only) (17, 18). Mortality results Cause-specific mortality for the total cohort is pre sented in table 3. A statistically significant deficit for all-cause mortality was apparent (1438 deaths observed versus 1636.4 expected. SMR 88, 95 ?b Cl 83--93). The following four main causes of death contributed to this deficit: (i) diseases of the circulatory system, (ii) diseases of the respiratory system, (iii) accidents, poisonings and violence, and (iv) other known causes. Fbr all malignant neoplasms, the SMR was 104 (95 % Cl 95--114), with 445 deaths observed. How ever, there were two causes of death, both cancers, which showed statistically significant excesses. They were cancer of the liver with 24 observed deaths and 8.4 expected (SMR 286, 95 % Cl 183--425) and can cer of an unspecified site with 24 observed deaths and 12.9 expected (SMR 187, 95 % Cl 120--278). Increases which were not statistically significant were apparent for bladder cancer (21 deaths observed, SMR 146, 95 % Cl 91--224), malignant melanoma (7 deaths ob served, SMR 163, 95 % Cl 65--335), and lymphosar coma (7 deaths observed, SMR 170, 95 % Cl 69-- 351). In this report the results are not given by process. The statistically significant excess of liver cancer evi dent in the total cohort was mainly due to the excess in VCM/PVC production (19 deaths observed, SMR 311, 95 % Cl 187--486). Twenty-three sites were selected for analysis ac cording to the years since first exposure, and the results for 10 of these sites are presented in table 4. Apart from liver cancer, which will be discussed in detail, there were no noteworthy patterns in risk according to this variable. Four sites were investigated in detail for relation ships with temporal and exposure variables. Of the two sites with excess risk for the total cohort, cancer of an unspecified site was not analyzed further due to the diversity of cancers found in this category; they are however discussed in a descriptive fashion in the text. Liver cancer, lung cancer, brain cancer, and lym phosarcoma were chosen a priori for further analysis. Excesses of bladder cancer in PVC production (in the United Kingdom) and of melanoma (in Norway) were not investigated further for the total cohort since they were confined to one country. Liver cancer No liver cancer deaths occurred before 15 years since first exposure, after which the SMR was 483 (95 % Cl 208--951) for 15--19 years since first exposure, and it did not vary greatly from this level thereafter, the v value always being statistically significant. In table 4, the pattern by years since first exposure is seen in 10-year groups. When only those with 15 years since first exposure or more were included in the analysis (15-year latency), the overall SMR for liver cancer was 445 (95 % Cl 285--663). Table 5 shows the SMR values for liver cancer ac cording to the four exposure variables, without and with a 15-year latency analysis. According to job title, dichotomous as ever autoclave worker (suspected a priori as the highest risk job) versus never an autoclave worker, very high risk was experienced by those who 161 Table 3. Mortality by detailed cause. lO = observed number ot deaths, = expected number of deaths. SMR = standardized mor tality ratio, 95 % Cl = 95 % confidence interval! Cause of death* 0E AN causes (000--999) All malignant neoplasms (140--207) Buccal cavity and pharynx (140--149) Esophagus (150) Stomach (151) Intestine, except rectum (152--153) Rectum (154) Liver and intrahepatic bile ducts (155) Pancreas (157) Larynx (161) Trachea, bronchus and lung (162) Bone (170) Connective and other soft tissue (171) Melanoma of skin (172) Prostate (185) Testis (186) Bladder (188) Kidney (189) Brain (191) Thyroid (193) Unspecified site (199) Lymphosarcoma (200) Hodgkins disease (201) Leukemia (204--207) Other lymphatic neoplasms (202--203) Other malignant neoplasms Benign and unspecified neoplasms (210--239, 208) Circulatory system (390--458) Respiratory system (460--519) Digestive system (520--577) Chronic liver disease, cirrhosis (571) Accidents, poisonings and violence (E800--E999) Other known causes 1438 445 7 9 49 21 15 24 16 5 144 3 0 7 21 3 21 4 14 2 24 7 7 11 4 27 4 622 108 72 35 114 73 1636.4 427.8 9.8 12.1 45.1 25.9 17.6 8.4 19.3 7.3 148.3 2.5 1.4 4.3 20.2 2.5 14.3 10.0 13.1 1.1 12.9 4.1 5.3 13.4 9.9 19.3 6.6 712.8 140.9 77.2 39.7 144.0 127.0 * Code of the International Classification of Diseases (eighth revision) in parentheses. " Based on a Poisson distribution. SMR 88 104 72 75 109 81 85 286 83 68 97 120 0 163 104 118 146 40 107 181 187 170 133 82 40 140 61 87 77 93 88 79 57 95 % Cl 83--93 95--114 29--148 34--142 80--144 50--124 48--141 183--425 47--135 22--159 82--114 25--352 0-265 65--335 64--159 24--345 91--224 11--103 59--180 22--654 120--278 69--351 53-274 41--147 11--104 92--204 17--155 81--94 63-93 73--117 61--123 65-95 45--72 were autoclave workers at some time (SMR 896, 95 Vo Cl 447--1603). In the analysis with a 15-year latency period, a statistically significant increased risk was also apparent for those classified as "never an autoclave worker," a group which however included workers with job "unspecified" also. Duration of employment was associated with an in creasing mortality trend from liver cancer, which was statistically significant (xJ 19.5, P<0.001). With a 15-year latency period, the trend was not as strong (X1 5.70, P< 0.025). A very clear exposure-response relationship was seen for ranked level of exposure and liver cancer mor tality. Although the ranked level of exposure was un known for six deaths, increasing risk at progressively increasing levels of exposure was demonstrated (x! 7.99, P < 0.01). With the use of a 15-year latency period and the estimated job-exposure matrices from factories 10 through 13 from the United Kingdom, the SMR for the intermediate category (50--499 ppm) was also statistically significant (7 deaths observed, SMR 551, 95 % Cl 222--1136). The risk clearly increased with increasing total cumulative exposure to VC in parts per million-years (x` 20.4, P< 0.001). An analysis with a five-year lag in cumulative exposure made virtually no difference m any of the results, and therefore the data 162 are not presented. The results of the multivariate anal ysis for liver cancer in an internal comparison are presented in table 6. Only two variables, years since first exposure and cumulative exposure, had a statisti cally significant effect on the risk of liver cancer mor tality. Risk increased steadily with increasing exposure when years since first exposure was adjusted for. The tests for interactions were not statistically significant, and the addition of a quadratic term for cumulative exposure did not improve the fit of the model. The same procedure was followed when cumulative ex posure from the estimated job-exposure matrix for the factories from the United Kingdom was included, and the regression results we)e similar. The relative risk es timates varied slightly from the previous model, prob ably because of the effect of misclassification from the job-exposure matrices of the four factories whose ma trices were developed from those of other factories. Angiosarcoma of the liver Major characteristics of the 24 liver cancer deaths cer tified in the mortality data as ICD code 155 (eighth and ninth revision, as no death was coded according to the seventh revision) can be seen in table 7, When R&S 143161 Tabi# 4. Mortality by time since first exposure far selected sites, 3 = observed number of deaths. E = expected number of deaths. SMR = standardized mortality ratio, 95 % Cl = 95 % confidence interval) Years sines lirst exposure 1-9 10-19 20--29 a 30 0 E SMR 95 % Cl 0 E :SMR 95 */' Cl 0 E SMR 95 '/a Cl 0 E SMR 95% Cl O Total E SMR 95 % Cl All causes (000--099) All malignant neoplasms (140--207) Liver and intrahepatic pile ducts (155) Trachea, Dronchus and lung (162) Bladder (188) Brain (191) lympho sarcoma (200) Circulatory system (390--458) Respiratory system (480--519) Chronic Ihrer disease, cirrhosis (571) 207 313.9 66 57--76 529 562.5 91 63-99 471 502.6 94 85--103 231 237.4 97 85--111 1438 1636.4 88 83--93 56 73.5 76 58--99 173 155.6 111 95-129 151 138.6 109 92--128 65 60.2 108 83--138 445 427.8 104 96--114 1.5 0 0--245 8 3.2 253 109--499 11 2.8 388 194--694 5 0.9 561 182--1310 24 8.4 286 183--425 16 22.7 71 40--114 so 53.9 93 69--122 60 50.4 119 91 -- 153 18 21.3 64 50-133 144 148.3 97 B2--114 2 1 8 109 13--395 7 4.8 146 59--301 6 5.1 117 43--255 6 2.6 231 85-504 21 14.3 146 91--224 2 3.4 59 7--213 6 5.3 113 42--247 2 34 59 7-212 4 1.0 407 111--1041 14 13.1 107 59--1B0 3 1.3 225 46--657 4 1.6 258 70--662 1.0 0 0--381 0.3 0 0--1430 7 4.1 170 69-351 67 106.0 62 46--79 223 248.2 91 79--103 209 236.9 68 77--101 123 121.7 101 84--121 622 712.8 87 81--94 8 19.9 40 17--79 30 45.0 67 45--95 47 47.5 99 73-132 23 28.6 80 51 -- 121 108 140.9 77 63--93 2 8.4 24 3--87 17 17.0 100 58-160 14 12.2 ns 63--193 2 2.1 95 11-342 35 39,7 88 61--123 1 Code of the International Classification of diseases (eighth revision) in parentheses. Table 5. Mortality data for liver cancer according to the exposure variables.* (0 = observed number of deaths, SMR = standardized mortality ratio, 95 % Cl = confidence interval) Exposure variable 15 years of latency* O* SMR 95 % Cl SMR 95 % Cl Job title Ever autoclave worker Never autoclave worker*1 Duration of employment (years) 1--9 10--14 15--19 20--24 25 Ranked level of exposure (ppm) Low (< 50) Intermediate (50--499) High (>500) Unknown Cumulative exposure (ppm-years) 0--1999 2000-5999 6000--9999 10 000 Unknown Total 11 13 4 5 4 6 5 3 (4) 3 (7) 12 (12) 6 (1) 4 O) 4 (4) 4 (7) 3 (3) 9 (1) 24 896 181 94 327 310 714 1111 119 161 567 317 99 351 800 1429 357 286 447--1603 97--130 26--239 106--763 84--794 262-1555 361--2593 25-347 33-471 293--991 117--691 27-254 96--898 218--2048 295--4175 163--678 183--425 1358 284 678-2430 151--485 205 602 310 714 1111 56--525 196--1406 84--794 262--1555 361--2593 227 (244) 250 (551) 719 (719) 486 (125) 47--664 (67-625) 52--731 (222--1136) 371 -- 1255 (371 -- 1255) 182--1079 (3--697) 191 (348) 460 (400) 851 (1429) 1667 (1667) 536 (100) 52--490 (159--662) 125--1177 (109--1024) 232--2179 (574--2943) 344--4871 (344--4871) 245--1017 (2-557) 445 285--663 * The values in parentheses were determined in analyses including the estimated lob-exposure matrices. s In Norway, the longest-neld job was used. In Sweden |ob rotation was practiced, and no one was classified as an autoclave worker. 163 histology had been performed and this information was available, a liver cancer death could be classified definitely as an angiosarcoma or not. When histology had not been reformed or the information was not available, it was classified "unknown" as to whether or not it was an angiosarcoma. Deaths that occurred before 1974 when angiosarcoma of the liver was first reported in relation to VC (19) may not have been in vestigated as thoroughly as they would have been fol lowing the 1974 report. Of the 17 deaths for which histology (pathology) information was available, 16 were histologically confirmed angiosarcomas of the liver and one was a primary liver cancer. For the re maining seven, it is unknown whether or not they were angiosarcomas of the liver. A regression analysis was Table 6. Maximum likelihood estimates for final model with cumulative exposure and years since first employment for de aths from liver cancer (N = 24). (95 /o Cl = 95 % confidence in terval) Variable Relative risk 95 % Cl Cumulative exposure (ppm-years) <500 500--1999 2000--5999 6000--9999 210000 Years since first employment 0--19 20-24 2 25 1.0 1.2 0.1--11.4 4.6 1.0--21.0 12.2 2.5--59.6 17.1 3.1--93.6 1.0 5.6 1.4--22.4 6.8 1.7-27.4 performed to assess the risk of angiosarcoma of the liver. In total, 22 angiosarcomas were included, with 16 coming from the liver cancer deaths coded to ICD 155 (as seen in table 7) and six additional angiosar comas coming from other deaths, as seen in table 8. This table shows additional liver cancer deaths, not coded as 155 in the mortality data. In total, there were six angiosarcomas, one primary liver cancer, and five "unknown" liver cancers among the 12 additional deaths. The small numbers neces sitated combining the lowest two categories of cumula tive exposure (<2000 ppm-years) for stability of the base-line category. The results were similar to those obtained for the 24 liver cancer deaths in that the final model included years since first exposure and cumula tive exposure. The major difference is seen in table 9, where the relative risks for angiosarcoma arc higher at each level of cumulative exposure than those for liver cancer. The absolute risk of angiosarcoma is shown in ta ble 10, on the basis of the results of the regression analysis shown in table 9, when cumulative exposure and years since first exposure were both included in the model. At a 25 years since first exposure and .>10000 ppm-years, the absolute risk was 280 per 100000 In summary, the results from the regression analyses indicated that, while cumulative exposure and years since first exposure had had a detectable effect on the risk of liver cancer mortality and angiosarcoma of the Table 7. Characteristics of the 24 subiects who Pied ot liver cancer. (ICD = International Classification of Diseases) Subiec< Age htre (years) Year of hire Duration Length of expo of sure latency (years) (yearsl Year of death Cause'* ICO revision Angiosarcoma of the liver Histologi cal con firmation by pathol ogy of angiosar coma ot the liver Total cumulative exposure (ppm-years) 1 29 1955 16 17 1973 155.0 8 Unknown No 2 27 1957 13 15 1972 155.0 8 Yes Yes 3 21 1959 21 21 1981 155.0 9 Ye3 Yes 4 47 1953 14 32 1985 155.0 9 Unknown No 5 30 1953 28 31 1984 155,0 9 No Yes 6 41 1960 8 20 1980 155.0 9 Unknown No 7 32 1962 20 21 1983 155.0 9 Unknown NO 8 34 1950 21 21 1972 155.0 8 Yes Yes 9 36 1947 21 28 1976 155.0 8 Yes Yes 10 26 1941 33 36 1977 155.0 8 Yes Yes 11 43 1961 13 24 1985 155.0 a Yes Yes 12 45 1964 10 16 1980 155.0 8 Yes Yes 13 49 1958 4 18 1976 155.0 8 Unknown No 14 37 1951 18 21 1973 155.0 8 Unknown No 15 33 1954 18 25 1979 155.2 9 Yes Yes 16 20 1957 27 28 1985 155.2 9 Yes Yes 17 35 1954 24 29 1983 155.0 9 Unknown NO 18 19 1968 3 18 1986 155.2 9 Yes Yes 19 36 1951 21 28 1979 155.2 9 Yes Yes 20 26 1950 25 31 1981 155.2 9 Yes Yes 21 30 1962 10 17 1980 155.2 9 Yes Yes 22 24 1950 31 33 1983 155.2 9 Yes Yes 23 37 1965 16 19 1985 155.2 9 Yes Yes 24 18 1966 4 18 1984 155.0 9 Yes Yes * Code of (he ICD. 164 7 360 5 676 6 397 7 000 8 737 5 493 18 407 13 770 27 709 404 288 1 260 5 409 4 627 111 636 8 215 8 594 1 822 7 152 1 848 808 R&S 143163 Tabla 8. Cases of liver cancer on the basis of cancer Incidence and other information (not included as liver cancer deaths in the mortality analysts). (ICO = International Classification of Diseases) Subieci 1 2 Age at hire lyearsi 24 45 3 28 4 34 5 18 6 36 7 50 8 54 9 29 TO 32 11 43 12 42 Year Of hire Dura- Length tion of of exposure latency (yeara) (years) Year of death Cause* ICO revision Site of incidence or other information 1951 1961 1968 19 6 8 1965 1965 1957 1954 1369 1941 1953 1944 10 7 7 11 '9 31 20 22 1963 8 19 1970 8 1970 8 1974 197.8 197 8 197.8 a 8 8 12 1977 197.8 ? Emigrated - 7 1964 199.0 11 1965 199.0 10 I960 31 1972 22 1975 199.0 157.9 159.0 28 1972 227.0 8 - 8 9 B 8 a 17 I960 571 5 9 Cancer incidence: ICD 155.0 Death certificate: carcinoma of liver Osatn certifies!*: carcinoma of llvar, angiosarcoma, hepatic cinhosia Death certificate: hepatic fatltfre due to fiver cancer Cancer incidence: ICO 155.0 Best evidence (clinical): ICD 155.0 Best evidence (clinical): ICO 155.0 Cancer incidence: ICD 155.2 Cancar incidence: ICD 155.0 Beet evidence (pathology): ICO 155.0 Death certificate: hemangioendothelioma of liver, natural causes Oeath certificate: hepatic failure due to hepatic fibrosis 1 According to the ICO. Angio sarcoma of the Uver Histologi Total cal confir cumulative mation by exposure pathology (ppm-years) Yes Unknown Yes No 6 203 Yea Yes 1 749 Unknown No Unknown Unknown Unknown Yes Yes Yes NO Yes No No NO Yes Yes Yea 28 156 7 673 7114 Yes Yea 2 668 liver, age at first exposure and calendar period of ex posure did not. Very clear exposure-response relation ships were evident between the cumulative exposure to VC and the risk of liver cancer and angiosarcoma of the liver. Finally, an effect of misclassification was demonstrated when the estimated job-exposure matrix was included, although the effect was minimal for the angiosarcoma results. Lung cancer, brain cancer and lymphosarcoma The SMR for trachea, bronchus, and lung cancer was 97 (95 Cl 82--114) for the total cohort, on the basis of 144 observed deaths. The SMR values did not show any remarkable association with a particular process, and although no pattern was evident for years since first exposure, there was a statistically significant in crease at 25--29 years since first exposure on the ba sis of 33 observed deaths (SMR 147, 95 Vo Cl 101 -- 207), mainly from an excess in VCM production in this time period (5 deaths observed, SMR 486, 95 *7o Cl 158--1134). Calendar period at exit and at hire did not reveal any consistent pattern. Fourteen deaths from brain cancer occurred in the cohort, and, although the overall SMR was not in creased (SMR 107, 95 7o Cl 59--180). there was a statistically significant excess at >30 years since first exposure on the basis of four observed deaths (SMR 407,95 ro Cl 111--1041) (table 4). The excess was con fined to the calendar period of hire of 1945--1954 and was the most evident for VCM/PVC production. Ana lyses by calendar period of exit, age at hire, and age at exit did not reveal any patterns of risk for brain can cer mortality. Table 9. Maximum likelihood estimates (orthe final model with cumulative exposure and yeara since first employment for the deaths from angiosarcoma of the liver (N = 22). (95 */ Cl = 95 % confidence interval) Variable Relative risk 95 % Cl Cumulative exposure (ppm-years) <2000 2000--6999 6000--9999 10 000 . Years since first employment 0--19 20--24 25 1.0 6.8 24.7 45.4 1.0 l.l 6.2 1.1--41.7 4.1--150.1 7.3--281.1 1.0--22.8 1.4--29.0 Table 10. Absolute risk of angiosarcoma of the liver per 100 000. Years since first employment 0--19 20--24 2 25 Cumulative exposure (ppm-years) <2000 2000-- 5999 6000--9999 alOOOO 24.4 115.6 152.3 44 8 212.5 280.0 A detailed analysis of the seven deaths from lym phosarcoma showed no pattern in the SMR values ac cording to years since first exposure. Alt seven deaths occurred in VCM/PVC production, and for this process alone there was no excess apparent by calen dar period of hire or exit or age at hire or exit. 165 R&S 143164 In table 11, the SMR values for lung cancer, and in table 12 those tor brain cancer and lymphosarcoma, are shown according to the exposure variables. The analyses by job title, duration of employment, and cu mulative exposure showed no relationship with any of the three sites. Neither was lung cancer associated with the ranked levei of exposure, while brain cancer was slightly in excess in the high category of exposure. Lymphosarcoma showed a slight increasing pattern of mortality with increasing category of ranked level of exposure, but the entire analysis was based on four deaths only. Table 11. Mortality data for lung cancer according to the exposure variables.1 (0 = observed number of deaths, SMR = standardized mortality ratio, 95 % Cl = 95 % confidence interval) Exposure variable Job title Ever autoclave worker Never autoclave worker0 Duration of employment (years) 1--9 10--19 20 Ranked level of exposure (ppm) Low (<50) Intermediate (50--499) High (500) Unknown Cumulative exposure (ppm-years) <50 50--499 500--1999 2000--5999 6000--9999 10000 Unknown Total O* 25 119 73 51 20 37 33 35 39 20 (37) 32 (49) 14 (18) ii (16) 7 (10) 2 (2) 56 (12) 144 SMR* 97 97 95 107 83 94 116 98 87 98 (110) 101 (101) 101 (85) 83 (74) 141 (152) 106 (94) 93 (80) 97 95% Cl* 63--143 80--116 75--120 79--140 51--129 66--130 80--163 68--136 62--119 60--151 69--143 65-169 42--149 57--290 13-384 71--120 (77--151) (75--134) (51--135) (43--121) (73--280) (11--339) (41--139) 82--114 * The values in parentheses were determined in analyses including the estimated job-exposure matrices. 11 In Norway, the longest-held |ob was used. In Sweden |ob rotation was practiced, and no one was classified as an auto* ctave worker. Table 12. Mortality data for brain cancer and lymphosarcoma according to the exposure variables. (0 ^observed number of deaths, SMR = standardized mortality ratio, 95 % Cl = 95 % confidence interval) Exposure variable Brain cancer O SMR 95 % Cl Lymphosarcoma O SMR 95% Cl Job title Ever autoclave worker Never autoclave worker* Duration of employment (years) 1--9 10--19 20 Ranked level of exposure (ppm) Low (< 50) Intermediate (50--499) High (500) Unknown Cumulative exposure (ppm-years) <50 50--499 500 Unknown Total 2 85 10--307 12 112 58--196 8 106 46--208 3 78 16--228 3 183 38--535 3 91 19--265 1 42 1-235 4 128 35--328 6 141 52--306 _ 0 0--204 4 162 44--414 4 120 33--308 6 110 40--239 14 107 59--180 3 661 4 147 6 484 1 116 --0 1 127 1 76 2 134 3 310 1 233 1 156 1 142 4 288 7 221 136--1931 40--377 178--1053 3-648 0--1230 3--705 4--983 28--846 64--907 6--1296 4--868 4--794 78--736 89--455 * In Norway, the longest-held job was used. In Sweden 10b rotation was practiced, and no one was classified as an autoclave worker. 0 All six deaths in the periods 1--4 years. 166 R&S 143165 Cancer of unspecified site Twenty-four deaths in the cohort were classified as malignant neoplasms of unspecified sites (ICD 199), giving a statistically significant excess (24 deaths ob served, SMR 187, 95 Vo Cl 120--278). Additional in formation, such as cancer incidence data, was avail able for 20 of the 24 deaths. Three subjects had liver cancer and were therefore included in table 8. It was unknown, however, whether they had angiosarcoma of the liver since no histological information was avail able. No other clear excess of a particular cancer among those classified as cancer deaths of an unspeci fied site was apparent. Cancer incidence results For the 2643 subjects from the four factories in Nor way and Sweden included in the cancer incidence anal ysis, the total number of cancers observed was 127 (SIR 107, 95 Vo Cl 89--127), and their distribution by site is shown in table 13 (reported for one or more observed deaths). The only statistically significant excess was for liver cancer, on the basis of seven observed cases (SIR 303, 95 Vo Cl 122--623). Suggestive increases were found for stomach cancer (13 cases observed, SIR 150, 95 Vo Cl 80--256), lung cancer (22 cases observed, SIR 152, 95 Vo Cl 95--230), melanoma (8 cases ob served, SIR 184,95 Vo Cl 79--362), and brain cancer (8 cases observed, SIR 159, 95 Vo Cl, 68--312). Although the lung cancer increase was not statisti cally significant, it was investigated in more detail as other studies have suggested increased risk for lung cancer. There was no excess according to process type or category of years since first exposure. A slight ex cess was suggested for < 15 years of employment, while the SIR values were close to 100 for 15--19 and 20 years of employment. For the ranked level of exposure, the risks in the high and low categories were virtually identical. According to cumulative exposure, no ex posure-response was apparent (results not presented in tabular form). Without statistical significance and with little apparent relationship to VC exposure, some indication of increased lung cancer risk remained for one PVC-processing plant and one Norwegian VCM/ PVC production plant. The national investigator for the PVC-processing plant attributed the excess to ex posure to asbestos, which was utilized in the process (7), while the excess remained unexplained in Norway. Discussion This collaborative study was carried out with the main purpose of analyzing exposure-response relationships between exposure to VC and liver cancer and inves tigating whether exposure to VC could increase can cer risk for sites other than the liver. The results confirmed the association between ex posure to VC and liver cancer. The excess of liver can cer mortality was associated with duration of employ ment, and a clear association with ranked level of ex posure was found. The results were strengthened by the regression analyses, which indicated that the risk of liver cancer depended on cumulative exposure and years since first exposure. Twenty-two subjects had histologically confirmed angiosarcoma of the liver, and the regression analyses demonstrated that the risk was mostly influenced by cumulative exposure to VC. The relative risks were higher at each level of cumulative exposure than those for all liver cancer deaths, but it must be remembered that the same 16 angiosarcoma deaths were included in both analyses. The approximate incidence rate of angiosarcoma of the liver in Norway, for example, based on 1953--1988 data, was 1 in 10 million per year (personal communication from A Andersen, 1989). Others have estimated the annual incidence at 1 to 2 in 10 million (20, 21). Given 222 746 person-years at risk accumulated by this cohort, with an annual incidence of angiosarcoma of the liver of 2 per 10 million in the general popula tion, the overall expected figure for the cohort would be 0.045. The rarity of this tumor supports the use of internal comparisons to assess the significance of ex posure variables. Table 13. Cancer incidence, based on data for four factories in Norway and Sweden, by detailed cause. (O = observed num ber of cases, E = expected number of cases, SIR = standard ized incidence ratio, 95 % Cl = 95 % confidence interval) Cancer sue* O E SIR 95 % Cl Buccal cavity and pharynx (140--146) stomach (151) intestine, except rectum 052--153) Rectum (154) Liver end intrshepatic bile duel* (155) Pancreas (157) Larynx <16i) Trachea, bronchus and lung (182) Melanoma ot akin (190) Prostate (177) Testis (176) Bladder (161) Kidney (160) Brain (193) Thyroid (194) Lymphosarcoma end other lympnoma (200, 202) Multiple myeloma (203) Other malignant neoplasms 5 4.2 119 39--277 13 6.7 150 80-256 8 89 89 39-176 2 5.9 34 4--123 7 2.3 303 122--623 3 4.3 70 14--203 2 1.6 122 15--441 22 14.5 152 a 4.4 164 79-362 16 16.0 69 51 --144 i 2,2 45 1--252 7 79 66 36-182 4 54 74 20--186 S 5.1 159 66--312 3 0.9 327 67-965 1 3.6 28 1-154 1 1.9 53 1-297 16 11,9 135 77-219 All malignant neoplasms (140--205) 127 119.0 107 09--127 * Coda ot the International Classification ot Diseases in parentheses. Based on e Poisson distribution. 167 s iM & The exposure estimates used for the ranked level of exposure and cumulative exposure indices were based on the reconstruction of past exposures, and they ap peared to be an efficient tool for investigating expo sure-response relationships. Although the job-exposure matrices utilized for the analysis were often based on rough estimates and thus resulted in a certain degree of imprecision, the results demonstrate exposure-re sponse relationships for the carcinogenicity of VC. A recent study also estimated cumulative exposure to VCM, PVC, and butadiene and found that only cu mulative exposure to VCM had any effect on liver can cer risk (6). No increase was evident for lung cancer mortality, nor was there any association with the exposure vari ables, including ranked and cumulative exposure in dices. It should be noted that the power of the study would allow detection of a statistically significant (at the 5 Vo level, one-sided) SMR for lung cancer of 114 with 80 Vo probability. A slight increase in lung cancer was suggested by the incidence data, which corresponded to about 10 Vo of the mortality data. There was no apparent relation be tween lung cancer incidence and VC exposure. In one factory of the four included in the incidence analysis, a case of pleural mesothelioma was reported, and ex posure to asbestos has been documented for the PVCprocessing plant (7). Two other sites investigated for excess risk were brain cancer and lymphosarcoma according to the a priori hypotheses. The results from this collaborative study did not suggest an effect of exposure to VC on mortality from brain cancer, although the power of the study only permitted detection of an SMR of 182 or more, which could be labeled as statistically signifi cant with 80 Vo probability. The excess at >30 years since first employment was, however, an indication that an effect of exposure cannot be fully dismissed. For lymphosarcoma, although an excess was suggested, the small numbers and missing information on ex posure variables for some of the subjects prohibited interpretation in relation to exposure to VC. None of the other causes of death was in excess; in stead, some statistically significant deficits were ap parent. The deficit in total mortality was probably due to the healthy worker effect, both in the hiring of healthy workers compared with the general population and in a survival effect within the cohort due to the criteria for inclusion of employment for one year or more. These results are very similar to those reported re cently in the United States (6). In that study only liver cancer was in excess for the cohort of VCM workers (SMR 333, 95 Vo Cl 202--521), with no statistically significant excess of lung cancer (SMR 115, 95 % Cl 95--139), brain cancer (SMR 145, 95 Vo Cl 79--248) or hematopoietic cancers (SMR 78, 95 Vo Cl 48--121). In the nested case-referent analysis, liver cancer risk increased with increasing cumulative exposure (esti 168 mated as duration times categorized exposure level). Of the 19 liver cancers, 12 were angiosarcomas, and for this subgroup only, unlike our results, was the posi tive dose-response evident. Concluding remarks The results of this multicentric collaborative study on workers in the VC industry indicate that exposure to VC is associated with an increase in liver cancer. An exposure-response relationship was observed for both ranked and estimated cumulative exposure. The rela tionship was even more evident when only liver an giosarcoma was analyzed. No significant excess of mortality was found for the other sites suspected a priori to be affected by exposure to VC. Although the incidence of lung cancer was slightly increased, neither it nor lung cancer mortality appeared to be associated with any of the exposure variables. Brain cancer and lymphosarcoma mortality, although showing slight increases, did not appear to be consistently associated with exposure, although the small numbers prohibited firm conclusions. An increased risk of bladder cancer and melanoma of the skin was detected which did not appear to be related to exposure in that the association with employ ment in the VC industry was confined to one country only. No increased mortality was observed for the other main causes of death. Acknowledgments We are deeply indebted to Mr E Ljunggren from Nobel lr.dustrier Sverige, Sundsvall, Sweden, and to Mr B Mountfield from ICI Chemicals and Polymers Ltd, Macclesfield, the United Kingdom, for their contribu tion to the estimation of past exposure levels of VC. The following people from IARC are thanked for their contributions: Mr A Barbin, Ms B Chamay, Ms A Hanss-Cousseau, and Dr M Kogevinas. Ms E Zanellato, from the Registro Tumori del Veneto, edited and typed the final manuscript. The analysis for this study was undertaken during the tenure of a research train ing fellowship awarded to Dr KA L'Abbe by IARC. References 1. International Agency for Research on Cancer (IARC). Some monomers, plastics, and synthetic elastomers and acrolin. Lyon: IARC, 1979. (IARC monographs on the evaluation ol the carcinogenic risk ot chemicals to hu mans; sol 19.) 2. International Agency for Research on Cancer (IARC). Overall evaluations of carcinogenicity: an updating of IARC monographs volumes l to 42. Lyon: IARC. 1987. (IARC monographs on the evaluation of the carcino genic risk of chemicals to humans; suppi 7.) 2. Viola PL. Pathology of sinvl chloride. In: Proceedings ol the 16th International Congress on Occupational R&S 143167 Health, Tokyo: Japan Organizing Committee, 1969: 296--7. 4. Barbin A, Bartsch H. Mutagenic and promutagenic properties of DNA adducts formed by vinyl chloride metabolites. In: Singer B, Bartsch H, ed. The role of cyclic nucleic acid adducts in carcinogenesis and muta genesis. Lyon: International Agency for Research for Cancer, 1986:345--358. (IARC scientific publication; no 70.) 5. Jones RD, Smith DM, Thomas PG. A mortality study of vinyl chloride monomer workers employed in the United Kingdom in 1940--1974. Scand J Work Environ Health 1988:14:153--60, 6. Wu W, Steeniand K, Brown D, Wells V, Jones J, Schulte P. Halperin W. Cohort and case-control analyses of workers exposed to vinyl chloride: an update. J Occup Med 1989:31:518--23. 7., Hagmar L, Akesson B, Nielson J, et al. Mortality and cancer morbidity in workers exposed to low levels of vinyl chloride monomer at a polyvinyl chloride process ing plant. Am J Ind Med 1990;17:553-66. 8. Doll R. Effects of exposure to vinyl chloride: an assess ment of the evidence. Scand J Work Environ Health, 1988:14:61--78. 9. L'Abbe KA, Ferro G, Winkelmann R, Saracci R, Simonato L, Mortality and cancer incidence results of the European multi-centric cohort study of workers em ployed in the vinyl chloride industry. Lyon: International Agency for Research on Cancer, 1989. (IARC internal report; no 89/007.) 10. Byren D, Engholm G, Englund A. Westerholm P. Mor tality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environ Health Perspect 1976:17:167--70. 11. Molina G. Homberg B, Elofsson S, Holmlund L, Maasing R, Westerholm P. Mortality and cancer rates among workers in the Swedish PVC processing indus try. Environ Health Perspect 1981:41:145--51. 12. Storetvedt Heldaas S, Langard SL, Andersen A. Inci dence of cancer among vinyl chloride and polyvinyl chlo, ride workers. Br J Ind Med 1984:41:25--40. 13. Jones JH. Worker exposure to vinyl chloride and po lyvinylchloride). Environ Health Perspect 1981 ;41: 129--36. 14. Belli S. Benazzi PA, Comba P, et al. A cohort study on vinyl chloride manufacturers in Italy: study design and preliminary results. Cancer Lett 1987;35:253-61. 15. Pirastu R, Comba P, Reggiani A, Foa V, Masina A. Maltom C. Mortality from liver disease among Italian vinyl chloride monomer/polyvinyl chloride manufac turers; Am J Ind Med 1990:17:155--61, 16. Coleman MP. Hermon C, Douglas A. Person-years (PYRS): a Fortran program for cohort study analysis. Lyon: Intemationai Agency for Research on Cancer. 1989. (IARC internal report; no 89/006.) 17. Bresiow NE, Day NE, Statistical methods in cancer Re search: vol II (The design and analysis of cohort studies). Lyon: International Agency for Research on Cancer. 1987. (IARC scientific publications; no 82.) 18. Baker RJ. Glim 3.77: Reference manual. Oxford: Nu merical Algorithms Group, 1985. 19. Creech JL. Johnson MN. Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Occup Med 1974; 16:150--1. 20. Brady J, Liberatore F. Harper P. et al. Angiosarcoma of the liver: an epidemiologic survey. J Natl Cancer Inst 1977:59:1383--5. 21. Byren D. Holmberg B. Two possible cases of angiosar coma of the liver in a group of Swedish vinyl chloride workers. Ann NY Acad Sci 1975:246:249--50. Received for publication: 18 October 1990 169