Document 6Rab0dXBMNB0DgQBJg5eeB6bo

As early as 1930 the first adverse health effects of vinyl chloride (VC) were reported.1 Since then, numerous observations and studies have indicated a wide range of toxicity attributable to the effects of VC on the central nervous system, the liver, the bones of the fingers, and the lungs.-'1" Lately, the spectrum of known toxic effects of VC broadened to include malignant neoplasms. Viola et al.,lt in 1971, reported the induction of tumors of the skin, lungs, and bones in rats exposed by inhalation to 30,000 ppm of & VC for twelve months. However, widespread acceptance of the carcinogenic activity of VC did not occur until early in 1974 after the announcement of * three cases of liver angiosarcoma among workers at a single VC polymerization r facility in the U.S.A.1- About the same time, Maltoni reported the same * cancerous hepatic effect in animals following exposure by inhalation to VC.11 Shortly thereafter. Maltoni and Lefemine 14 and Keplinger et oi.ls reported the induction of tumors of the brain, kidney, liver, lung, and lymphatic system in mice, rats, and hamsters exposed to VC by inhalation. Consequently, an epidemiological evaluation was undertaken by the Na tional Institute for Occupational Safety and Health (NIOSH) to assess the magnitude and spectrum of neoplastic effects in workers exposed to VC. This study included industrial hygiene surveys, retrospective cohort analyses of mortality patterns, and histopathologic evaluation of tumors. Retrospective Cohort Study Initially, two criteria were established for selection of facilities to be investi gated. Only those facilities that 1) had been engaged in the polymerization of VC for at least fifteen years and 2) had a sizable work force were considered. Following a telephone survey of all facilities in the U.S.A. known to be polymerizing vinyl chloride, four facilities were selected from among the many which met the study criteria. These four plants in 1974 were employing 230, 75, 250, and 250 VC polymerization workers and had been polymerizing VC OLI 6943 Waxweiler et ai: Workers Exposed to Vinyl Chloride 41 for 28, 20, 24, and 32 years, respectively. Vinyl chloride monomer had been made at two of the four plants, as had the compounding of polyvinyl chloride (PVC). All four plants produced various copolymers of VC at different times, vinyl acetate copolymer being common to all four and vinylidene chloride copolymer common to three. Since environmentally induced cancer often takes many years to become clinically manifest following exposure to a carcinogen, cohort study was restricted to those individuals having achieved five or more years of employment (exposure) and ten years since onset of initial employment (latency) in de partments and jobs directly related to vinyl chloride. In each plant the depart ments and jobs with VC exposure were determined following a walk-through survey by NIOSH personnel and review of company process, engineering control, and air-sampling data. Those specific departments and jobs classified as having VC exposure included VC monomer production, VC polymerization. PVC compounding.* and maintenance. Employment records were initially obtained of every individual who had ever worked at any of the four VC polymerization plants. All personnel records were subsequently checked to identify each individual who had ever worked in Table 1 Status as of December 31, 1973 of Workers with at Least 5 Years' Exposure and 10 Years since Initial Exposure to Vinyl Chloride Alive Deceased Lost to follow up Total Total person-years 1,151 136 7 1,294 12,720 (89.0%) (10.5%) (0.5%) (100%) departments or jobs classified as VC-exposed since the beginning of VC monomer production and/or VC polymerization. Follow-up of all study cohort members t was attempted from the time of termination of employment to December 31, 1973. Information from numer ous state and federal governmental agencies and other sources permitted the vital status determination of more than 99% of the 1294 cohort members (Table 1). Persons for whom vital status could not be determined were assumed to be alive so as not to overestimate the true risk associated with vinyl chloride. The death certificates obtained were coded by a nosologist according to the revision of the "International Lists of Diseases and Causes of Death" in effect at the time of death, and then converted into the 7th Revision numbers, using accepted rules of comparability for 135 of the 136 cohort persons who * The PVC compounding department of Plant 1 was not included because it was located in the same building as a tire-manufacturing operation; thus, mixed exposures were anticipated. t Workers who were not considered part of the cohort study were also followed up for inclusion in the histopatbology study. 42 Annals New York Academy of Sciences died before the study-ending date. A modified life-table technique was used to obtain the 12,720 person-years at risk of dying, according to five-year age group, five-year calendar period, years of work experience (exposure), and time since onset of exposure (latency) to VC. Comparison was made between the observed number of deaths among the study cohort members and that expected on the basis of the U.S. white male death rates specific for age, and calendar year and cause. Results Table 2 shows that a total of 136 deaths occurred among workers exposed to vinyl chloride as contrasted with 126.3 deaths expected. Only two causes of death were in excess among workers exposed to vinyl chloride: "Nonmalignant Respiratory Disease" (6 observed deaths vs. 3.4 expected) and "All Table 2 Mortality Experience among Cohort Workers Exposed to Vinyl Chloride Cause of Death All malignant neoplasms Heart Nonmalignant respiratory diseases Cirrhosis ' Violent deaths Residual Unknown Total ICD Code * (140-205) (400-443) (470-527) (581) (800-985) OB5. 35 57 6 2 13 22 1 136 EXP. 23.5 54.7 3.4 4.0 14.2 26.5 0 126.3 SMR 149 t 104 176 50 92 83 -- 108 * ICD = International Classification of Diseases, 7th Revision; OBS. =observed: EXP.=expected: SMR= (Standardized Mortality Ratio) = 9,biervej. x 100. Expected t Significant at p <0.05. Malignant Neoplasms" (35 deaths observed vs. 23.5 expected), the latter excess being statistically significant at p < 0.05. When malignant neoplasms were analyzed by site (Table 3), excesses were found for four organ systems: brain and central nervous system (CNS) (3 ob served vs. 0.9 expected), respiratory system (12 vs. 7.7 expected), hepatic system (7 observed vs. 0.6 expected), and lymphatic and hematopoietic systems (4 observed vs. 2.5 expected). The importance of latency when looking for occupationally induced malig nant neoplasia is demonstrated by Table 4. When the excess risk of death due to all malignant neoplasms and malignant neoplasms of each of the four organ systems is compared in the cohort of persons who achieved ten or more years since onset of exposure versus the subset of persons who achieved 15 or more years, the excess risk increases in every cause of death. The Standardized Mortality Ratio (SMR) for all malignant neoplasms increases from 149 to 184; for the brain and CNS, from 329 to 498; for the respiratory system, from C\-NC Br Bi OLI 6945 1 Waxweiler et al.: Workers Exposed to Vinyl Chloride 43 Table 3 Cancer Mortality Experience among Cohort Workers Exposed to vinyl Chloride Cancer Mortality AU malignant neoplasms grain & CNS cancer Respiratory system cancer Biliary & liver cancer Lymphatic and hematopoietic system cancer 1CD Code (140-205) (193) (160-164) (1J5-156A) (200-205) OBS. 35 3 12 7 4 EXP. 23.5 0.9 7.7 0.6 2.5 SMR 149 * 329 156 1155 t 159 * Significant at p <0.05. t Significant at p <0.01. 156 to 194; for the hepatic system, from 1,155 to 1,606; and for the lymphatic tand hematopoietic system, from 159 to 176. Thus, for both the respiratory system and brain and CNS system these excesses of cancer become statistically significant at p < 0.05; and for "All Malignant Neoplasms," at p < 0.01. Since Plant 4 contributed over two-thirds of the person-years to the cohort and since the plant included the three angiosarcomas of the liver announced prior to the initiation of this study, an additional analysis of malignant neo^ plasms was undertaken separating Plant 4 from the other three plants combined Table 4 Cancer Mortality by Latency among Workers Exposed to Vinyl Chloride Cancer Mortality All malignant neoplasms Brain and CNS cancer Respiratory system cancer Biliary and liver cancer Lymphatic and hematopoietic system cancer OBS. EXP. SMR OBS. EXP. SMR OBS. EXP. SMR OBS. EXP. SMR OBS. EXP. SMR ^10-Year Latency 35 23.5 149 * 3 0.9 329 12 7.7 156 7 0.6 1155 + 4 2.5 159 15-Year Latency 31 16.9 184 t 3 06 498 * 11 5.7 194* 7 0.4 1606 t 3 1.7 176 * Significant at p <0.05. i Significant at p <0.01. OLI 6946 44 Annals New York Academy of Sciences Table 5 Cancer Mortality among Workers Exposed to Vinyl Chloride with 15-Year Latency for Plant 4 vs. Other Plants Cancer Mortality All malignant neoplasms Brain & CNS cancer Respiratory system cancer Biliary & liver cancer Lymphatic and hematopoietic system cancer Plant 4 OBS. EXP. 26 13.7 2 0.5 9 4.6 6 0.4 3 1.4 Other Plants J OBS. 3 t 2 1 0 EXP.| ix4 o.i ii i.iij 0.0 j 0.31 (Table 5). Although the number of deaths in the three other plants is small,! there is no evidence to indicate that the observed cancer risk in these plants is any different from Plant 4 for those workers observed 15 or more years follow- .' ing initial exposure to VC. Histopathology Study Methods Irrespective of an individual's meeting the five-year exposure and ten-ye latency criteria, in all cases where a tumor or malignancy of any site or live disorder of any kind was indicated on the death certificate, attempts were made! to obtain hospital records, pathology reports, and tissue specimens for evaluaj tion by a panel of pathologists, t '*. Some cases had previously never worked in a department or job directly related to VC as defined for the retrospective cohort study. These cases were! occasionally exposed to low levels of vinyl chloride. Therefore, for these cases! latency was defined as the interval between initial employment at the plant and! death. Results As shown in Table 6, of the 14 histologically confirmed cases of biliary, and liver cancer among workers from the four plants, eleven cases of angio-J sarcoma of the liver were diagnosed. All of the eleven had worked at one time ' or another as reactor cleaners. Case 4 is noteworthy. This individual's only known exposure to vinyl, chloride occurred sometime during 1950-1954 at the VC polymerization opera* * tion. Seventeen years following his initial exposure to VC, this individual died at the age of 41 of hepatic angiosarcoma--an observation consistent with t Dr. Luis Thomas of the National Cancer Institute, Dr. Hans Popper of The Mount Sinai School of Medicine, City University of New York, and Dr. Marvio Kuschner of the State University of New York. Case Number 1 2 3 4 5 6 7 g 9 10 11 -* 12 * 13 * 14 * AH'. `4 diacc i basic ' crsihie. -sposur; As icmbe' a list; -bloric-. :obla` 1 his ce i sshi; rme cast sp id up Fro Makers -'sure husc e- ircinoinjitTer T\se i>nal p cd on OLI 6947 Waxweiler et alWorkers Exposed to Vinyl Chloride Table 6 Histologically Confirmed Liver and Biliary Cancer Cases AMONG WoRXERS EXROSED TO VINYL CHLORIDE 45 Case Number 1 2 3 4 5 6 7 8 9 10 11 * 12* 13 * 14* Histologic Diagnosis Angiosarcoma Angiosarcoma Angiosarcoma Angiosarcoma Angiosarcoma Angiosarcoma Angiosarcoma Adenocarcinoma of gall bladder or common bile duct Gall bladder cancer Adenocarcinoma of common bile duct Angiosarcoma Angiosarcoma Angiosarcoma Angiosarcoma Age at Total Death Exposure (years) (years) 38 15 58 27 49 22 41 3 43 14 52 15 51 19 Latency Period (years) 15 28 24 17 15 19 19 61 24 24 71 19 70 21 45 12 12 43 18 20 43 19 19 46 13 21 * Alive as of March 1, 1975; thus latency, exposure, and age are calculated at date of diagnosis. a basic tenet of carcinogenesis, that the cancer process once initiated is irre versible, even in the absence of further or prolonged carcinogenic stimulus/ exposure. As seen in Table 7, ten cancers of the brain (three among study cohort members) were diagnosed on death certificate, pathology report, aDd/or by tissue reevaluation, to have occurred among workers exposed to vinyl chloride. Of the ten brain cancer cases, nine were classified histologically as glioblastoma multiforme; no histologic diagnosis was available for the tenth. This cell type distribution appears unusual, vis-a-vis the Yale autopsy series in which 33% of the primary intracranial neoplasms were glioblastoma multiforme.1* Of the nine cases of glioblastoma multiforme, six had worked for at least some time in the VC polymerization areas, whereas the remaining three had worked in lower VC exposure areas. From the fourteen cases of primary lung cancer which occurred among workers having at least five years of exposure and ten years since initial ex posure to vinyl chloride, tumor specimens were available on eight. Among these eight bronchogenic carcinomas, no cases of squamous-cell or small-cell carcinoma were seen (Table 8), whereas five were classified as large-cell undifferentiated and three as adenocarcinoma. This distribution of cell type is i Twelve subjects with lung cancer were identified by death certificates. Two addi tional primary lung cancer deaths among cohort members, which had been misclassified on the death certificates, were confirmed by pathologic evaluation. OLI 6948 46 Annals New York Academy of Sciences i Table 7 Brain Cancer Cases Histologically Diagnosed among Workers Exposed to Vinyl Chloride Case Number 1 2 3 4 5 6 1 8 9 10 Histologic Diagnosis Glioblastoma multiforme Glioblastoma multiforme Glioblastoma multiforme Glioblastoma multiforme Glioblastoma multiforme Glioblastoma multiforme Glioblastoma multiforme Glioblastoma multiforme Glioblastoma multiforme -- Age at Death (years) 49 44 J3 54 56 43 42 58 65 33 Latency ;(years) 25* 17* ^ 30 151 2411C 20 20tl 21 tlK 19tSE 3 tt '* * Study cohort members: interval between initial exposure to vinyl chloride (VC) and death. t Non-cohort members: interval between initial employment and death, t Non-cohort cases who had worked in VC polymerization areas. 3 Non-cohort cases who never worked in VC polymerization areas. not consistent with the hypothesis postulated by Kreyberg tr and corroborated S by Archer et al.l* and Saccomanno et at.1* that small-cell undifferentiated and? epidermoid carcinomas of the lung are the principal types whose frequencyj is affected by inhaled carcinogens. Moreover, it differs from the findings of-s Whitwell et al.i0 that adenocarcinoma was the predominant cell type of lung! cancer among male workers with asbestosis who had been cigarette smokers.! Ofte groups t deaths t. rates. 1 "healthy a dispro of self-s employe To mini that per whereas workers a similar Inha demonst adeuoca ous othe In tl number lung, an demiolos agent in earcinoee strongly s of chemi. Table 8 Luno Cancer Cases Histologically Confirmed among Cohort Workers Exposed to Vinyl Chloride Case Number 1 2 3 4 5 6 7 8 Histologic Diagnosis Large cell undifferentiated Large cell undifferentiated Large cell undifferentiated Large cell undifferentiated Large cell undifferentiated Adenocarcinoma Adenocarcinoma Adenocarcinoma Age at Death (years) 39 40 52 61 61 45 57 72 Exposure (years) 14 13 22 16 8 19 12 15 Latency (years) 15 18 22 17 17 19 12 22 The of man; gratitudi of the S port, th. helped i onnel c -tutus de I- Psr to P> 2. LesP* A OLI 6949 Waxweiler et al.; Workers Exposed to Vinyl Chloride 47 Discussion Often in retrospective cohort studies of mortality among occupational groups there are overall deficits of observed deaths when contrasted with the deaths that would be expected to occur on the basis of U.S. general population rates. This observed deficit of mortality has recently been referred to as "healthy worker effect"21 and has been attributed to several factors, including a disproportionate number of newly hired employees still showing the results of self-selection due to good health, or preselection by industry through preemployment medical examinations and other health-screening mechanisms." To minimize this "healthy worker effect," the present study was restricted to that period following ten years since initial exposure to vinyl chloride. Thus, whereas previous investigators reported an overall deficit of deaths among workers exposed to VC,21 no such deficit was found either by this study or by a similar study conducted by Nicholson et al.** Conclusion Inhalation studies by Viola er al.." Maltoni,11 and Keplinger et a/.15 have demonstrated that vinyl chloride induces hepatic angiosarcoma, adenomas and adenocarcinomas of the lung, neuroblastoma of the brain, lymphoma, and vari ous other tumors in a variety of animal species. In the present study of workers exposed to vinyl chloride, an excessive number of deaths due to cancer of the same four sites was found, viz the liver, lung, and the lymphatic and central nervous system. The evidence, both epidemiologically and histopathologically, points to vinyl chloride as the causal agent in the etiology of such excessive cancer risk. The observation of the carcinogenicity of vinyl chloride, first in animals and subsequently in man, strongly supports the need for conducting animal bioassay prior to introduction of chemical and other agents into the industrial or community environs. Acknowledgments The epidemiological study reported here represents the combined efforts of many individuals and organizations. The authors wish to express their gratitude to the following who contributed to this study: Mr. Bruce Gehring of the Southwestern Ohio Regional Computer Center for data processing sup port, the numerous personnel from the companies and unions involved who helped in defining the cohort, and Mrs. Clorinda Battaglia, NIOSH, and per sonnel of the many Ohio and Kentucky State agencies that assisted in the vital status determination of the cohort members. References 1. Patty, F. A., W. P. Yant t C. P. Waite. 1930. Acute response of guinea pigs to vapors of some new commercial organic compounds. Public Health Re ports 45: 1963-1971. 2. Lester, D., L. A. Green>exa U W. R. Adams. 1963. Effects of single and re peated exposures of humans snd rats to vinyl chloride. Amer. Ind. Hyg. Assoc. J. 24: 265-275. 48 Annals New York Academy of Sciences 3. Kramer, C. G. & J. E. Mutchler. 1972. The correlation of clinical and en- ,*. vironmental measurements for workers exposed to vinyl chloride. Amer. Ind. Hyg. Assoc. J. 33s 19-30. -. 4. Veltman, G., C. E. Lance, S, Juhe, G. Stein 4 U. Bachner. 197J. Clinical " manifestations and course of vinyl chloride disease. Ann- N.Y. Acad. Set. 246: 6-17. ? J. Lance, C. E., S. Juhe, G. Stein 4 G. Veltman. 1973. Further results in poly-% vinyl chloride production workers. Ann. N.Y. Acad. Sci, 246: 18-21. 6. Lilis, R., H. Anderson, W. j. Nicholson, S. Daum. A. S. Fischbein 4 I. Selikoff. 1975. Prevalence of disease among vinyl chloride and polyvinyti chloride workers. Ann. N.Y. Acad. Sci. 246: 22-41. 7. Creech, J. L., Jr. & L. Mark. 1973. Liver disease among polyvinyl work^j ers. Ann. N.Y. Acad. Sci. 246: 88-94. 8. Gedigk, P., R. Muller & H. Bechtelsheimer. 1975. Morphology of livei damage among polyvinyl chloride workers. Ann. N.Y. Acad. Sci. 246: 27 285. 9. Marsteller, H. L, W. K. Lelbach, R. Muller 4 P. Gedigk. 1975. Uni splenomegalic liver disease as evidence by peritoneoscopy and guided Ihrccj biopsy among polyvinyl chloride production workers. Ann. N.Y. Acad. SeLf 246:95-134. 10. Miller, A., A. S. Tierstein, M. Chuang, I. J. Selikoff it R. Warshaw. 1975, ' Changes in pulmonary function in workers exposed to vinyl chloride and polyvinyl chloride. Ann. N.Y. Acad. Sci. 246: 42-52. 11. Viola, P. L, A. Bioootti 4 A. Caputo. 1971. Oncogenic response of rat skin. ' lungs, and bones to vinyl chloride. Cancer Res. 31: 316-519. a 12. Creech, J. L., Jr. 4 M. N. Johnson. 1974, Angiosarcoma of liver in the mano- facture of polyvinyl chloride. J. Occup. Med. 16: 150-151. 13. Maltoni, C. 1974. Preliminary report on the carcinogenicity bio-assays of, vinyl chloride. U.S. Dept, of Labor Informal Fact-Finding Hearing on Pc sible. Hazards of Vinyl Chloride Manufacture and Use. 14. Maltoni, C. 4 G. Lefemine. 1975. -Carcinogenicity bioassays of vinyl chloride? Current results. Ann. N.Y. Acad. Sci. 246: 195-218. 15. (Ceplinger, M. L., J. W. Goode, D. E. Gordon 4 J. C. Calandra. 1975. terim results of exposure of rats, hamsters, and mice to vinyl chloride. At N.Y. Acad. Sci. 246: 219-220. 16. Manuelidis, E, E. 4 G. B. Solitaire. 1971. Glioblastoma multiforme, fa Pathology of the Nervous System. J. Mincklev, Ed. Vol. 2: 2028. McGrav Hill, Inc. New York, N.Y. 17. Kreybero, L. 1962. Aetiology of Lung Cancer--a Morphological. Epidemiol gical and Experimental Analysis. Norwegian Universities Press. Oslo, Nor^ way. 18. Archer, V. E., G. Saccomanno 4 J. H. Jones. 1974. Frequency of different types of bronchogenic carcinomas as related to radiation exposure. Cancer 34tj 2056-2060. 19. Saccomanno. G., V. E. Archer, O. Auerbach et at. 1971 Histological of lung cancer among uranium miners. Cancer 27: 515-523. 20. Whitwell, F., M. L. Newhouse 4 D. R. Bennett. 1974. A study of the hi*-'! tological cell types of lung cancer in workers suffering from asbestosis in the United Kingdom. Br. J. Ind. Med. 31: 298-303. 21. Tabershaw, 1. R. 4 W, R. Gaffey. 1974. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J. Occup. Med. 16: 509-51**^ 22. Bayliss, D. L,, J. Dement, J. K. Wagoner, 4 H. P. Blejer. This annal. 23. McMichael. A. J.. S. G. Haynes 4 H. A. Tyroler. 1975. Observation on the evaluation of occupational mortality data. J. Occup. Med. 17: 128-131. 24. Nicholson, W. j., e. C. Hammono, H. Seidman 4 I. J. Selikoff. 1975. Mor tality experience of a cohort of vinyl chloride-polyvinyl chloride workers., Ann. N.Y. Acad. Sci. 246: 225-230. OLI 6951