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''tv s 2. iv'i , INDUSTRIAL HAZARDS OF PLASTICS AND SYNTHETIC ELASTOMERS Proceedings of the International Symposium on Occupational Hazards Related to Plastics and Synthetic Elastomers, Espoo, Finland, November 22-27,1982 Editors vis.' JORMA JARVISALO w PIRKKO PFAFFLI HARR! VAINIO Institute of Occupational Health Helsinki, Finland r1: - .. c-:: ** - 3 l-ir. ; 2- ALAN R. LISS, INC. NEW YORK 1 . i . -t 5.: ;n GENC 00110 ? Address all Inquiries to the Publisher Alan R. Liss, Inc., 150 Fifth Avenue, New York, NY 10011 Copyright 1984 Alan R. Liss, Inc. Printed in the United States of America. Under the conditions stated below the owner of copyright for this book hereby grants permission to users to make photocopy reproductions of any part or afl of its contents for personal or internal organizational use. or for personal or internal use of specific Clients. This consent is given on the condition that the copter pay the stated per-copy fee through the Copyright Clearance Center, incorporated, 21 Congress Street. Salem, MA 01970, as listed in the most current issue of "Permissions to Photocopy" (Publish, er's Fee List, distributed by CCC, Inc.), for copying beyond that permitted by sections 107 or 108 of the US Copyright Law. This oonient does not extend to other kinds of copying, such as copying for general disinbution, for advertising or promotional pur poses. for creating new collective works, or for resale. Library of Congress Cataloging in Publicstion DsU International Symposium on Occupational Hazards Related to Plastics and Synthetic Elasiomers (1982 :E$poc, Finland) Industrial hazards of plastics and synthetic elasto mers. (Progress in clinical and biological research; v. 141) Includes bibliographical references and index. 1, Plastics--Toxicology--Congresses. 2. Elastomers-- Toxicology--Congresses. 3. Industrial toxicology-- Congresses.' I, Jarvisalo, Jorma II Plaftli. PirKko. III. Vamio. H. (Harri), 1947- . IV. Title V. Senes. RA1242.P66I58 1982 6l5.9'5i 83-24&4B ISBN 0-8451-0141-2 Content. Contributors Preface Jorma Jarvisa CHAPTER I. I l Synthetic PoK Jukka M. Man Polymer Proct Vaino Era . . Additives in S: Lawrence Fish: Carclnogenesi Evaluation at t J.E. Huff a' J Trends \ Industry l __ William J, niche Reproductive H K. Hemminki. M CHAPTER II. F Production and Ariel Hoff . . . The Toxicology i Bo Holmberg . . Toxicity of the C Additives Lawrence Fishpe Phthalate Esters J.E. Huff and w.m Occupational Ha: ' William J. Nichols; Preventive Mease Production Indus S. Tarkowski . . . G^C \04 OCCUPATIONAL HAZARDS IN THE VC-PVC INDUSTRY William J. Nicholson, Paul K. Henneberger and Herbert.Seidman. ^ Aw* ^ Environmental Sciences Laboratory, Mount Sinai School of Medicine of CUNY, New York, New York 10029 (WJN, PH) and American Cancer Society, 4 W. 35th Street, New York, New York 10001 (HS). INTRODUCTION ,, 1 -jitatSrvr *. - On January 24, 1974,-The Wall Street Journalpublish ed ".'in' article describing the occurrence of three deaths 1 from KemangiosTrcoma of the liver among polyvinyl chloride ` .-(PVC)^;producti6n ., workers ,T*t the B.F. Goodrich Tire and . Rubber Company plant in Louisville, Kentucky. This announ...,, cement,, shattered ^ the relatively complacent view toward j '' health"Veffects. associated1 with plastic production .in general and PVC production" in particular. At the time, U.Sv~and Western European production of' vinyl chloride ; (VC)'exceeded 6 x 10 metric tons. , Numerous mortality and - clinical studies were undertaken in the major producing countries in "an attempt to establish the extent of the carcinogenic risk and to identify clinical parameters useful for surveillance of exposed groups. Because of the immediate concern in 1974, most of these studies were com pleted between 1974 and 1977. Several reviews and sympo sia "on human health effects from VC exposure have been published recently. A'superb one is by Lelbach and Marsteller (1981). The exposures were high that led to the disease observed;in these various studies. Typical concentrations in the industry were estimated to be about 1,000 ppm prior to 1955, from 300-500 during 1955-1970, and from 100-200 during 1970-1974 (Barnes, 1976). However, variations from such exposures would have occurred in specific plants (Rowe, 1975). While historical average exposures were generally less than 1,000 ppm, peak exposures often ex- GEI 2 ceeded 5*10,000 ppm (where workers lost consciousness) and, on occasion, 40,000 ppm (where plants exploded). During 1974, exposures were reduced to about 10-20 ppm in the U.S. industry (Jones, 1981) and even further, follow ing the promulgation of a 1 ppm standard by the Occupa tional Safety and Health Administration in 1974. MORTALITY STUDIES OF VC-EXPOSED WORKERS -'Table 1 shows the populations observed and the follow up characteristics of twelve cohort studies of vinyl chlo- ride'^exposed workers. The studies were independent with the exception that the portions of the population reported ----- in "the .Equitable Environmental Health Study (1978) were included in some other U.S. studies. The proportionate mortality study of Monson et al (1974) is not included as the.37C-exposed -individuals studied therein were included - in'"theT"Cohort'mortality" study of Waxweiler et al.(1976). . The-`size ' of--thej cohorts -varied greatly, from 255 in the studjrjof Nicholson et al (1975) to 9,677 in the Equitable Environmental'Health study," A notable ' feature of all of the ^studies is that the populations 'followed were' rela- tiyely'^young or recently employed, even though many plants -in^the~. studies started_production in the 1940s. ' host ^ workers "were^'hiTed after '1950, when ' U.S. and Western European * -production increased sixfold in ten years - (Nicholson , and._ Henneberger, 1983). / ^ Thus, few deaths : occurred ; among; most of the groups . observed and data on effects 25 or . more years from onset of exposure are li- - -cvr ^-2- :, \ mited.'-iVThe total mortality exceeded 101 of the observa tion'-cohort in'only three studies. Further, the inclusion - ; '.i' of .^recently .'employed individuals or those with short - /: /; *. employment diluted the effects from VC exposure. Only five ` studies "limited consideration to individuals with more'than one year of exposure. In all cases, however, some -Individuals with^more than 20 years from onset of employment were available for observation. The follow-up terminated in the mid-1970s for all studies. ' Table 2 compares the results for cancer of all sites and chronic liver disease in all 12 studies. Cancer is elevated in most of the studies, although it does not achieve a 0.05 level of significance except in the studies by Waxweiler et al (1976) and Nicholson et al (1975). In the study by Ott et al (1975), a highly exposed subgroup with 15 years latency had 8 cancer deaths compared to 3.2 ^ - .-vT" f ' ' \ ' - h* ,1 S />! y / i t t , f . . j, , -t . : \ - ',1 ,i ' , 1 . ; ; |. ,, l i|-; ' ! v* i' 1;. ; ' 1' ' .* r > i. - *' t.-t .-i i , i . .v * Study ' if' ; 1 `table l'^.: 1 ' i - = + Population and follow-up fchiractAtisties of twelve 1 ` studies of vinyl chloride exposed workers t ;; f 1 iii 'i \ \ ' / ' : 1 i Analysis cohort Country size - Percent additional untraced Number ; Percent of desth s ; of analyzed : total Minimum ' exposure (years) Minimum latency. (years) *' * 1 ; r : ' 3' i Earliest possible exposure Bertazzl et al. 1979 Buffler et at. 1979 Byren et el.' 1976 Duck et al. 1975 Ef|iil table Env. Health. 1970 Fox and Col 1 ler 1976, 1977 Hasuda 1979 Nicholson et al* 1975 Ott et al. 1975 Relnl et al. 1979 Theriault and Allard, 1981 Waxweiler et al. 1976 * Longer latcncie a 1TAL USA SUED 6777 . ! 46^ ; i 750 13.8 i .... . 62 ,, b.i-L t.: v low 58 7.7 i UK 2113 0.3 136 . 6.6 USA UK 9677 . ' 7609 -'6.9 ! ; i 707 1 1 1.1 393 7 ,t> s.i JAP 306 0.3 26 8.6 USA 255 0.8 26 9.6 USA 522 ; 0.0 79 . V i5.i CER 6566 7.i 616 6,3 CAN 651 2.8 59 13.1 USA .1287 1. 7 0.5 , * 136 . 10.6 ;..i: r* 1 considered for some causes of desth. 0.5 , 0.5 , i;;:i ! : ..:V. . 0, 2*<; ' 'j 1 >0 >0* . >0 >0* : l. 1* >0 >0* l1 5 : >0 10* >0 >0 >0 5 5* 5. 10* 1952 . I. f:1968 1 1965 1968 (1935) 1960 1969 1967 1962 NA 1963 1960 * 7 ' 1, 1 i: : 1 i , * t*.. ( Maximum Last follow-up year of (years) follow-up 22 : ! 27 " 1977 i 1975 28 1976 20 1975 25+ 1972 35 1976' 20 1975 25 1976 31 1973 NA 1976 30 1977 22 1973 A1 * * l1 \| bENC 0 0 < ; 0 7 UJ IAble 2 Observed end expected deaths among -vinyl chloride exposed workers Id rvelve studies Cancer of all sites Death* Study Obeer. Expec. SMR Bertatzl et al 30 30.9 97 Buffler et al 5 yr. latency 8 6 5.19 4.34 154 138 Byren et al Duck et al - -- 35 36.44 96 Equitable 139 141.39 104* Tex l Collier 115 126.77 91 Haauda 8 5.8 138 Hlcholaon 9 3.9 230 Ott et al 15 yr. latency 13 9 16.0 9.2 81 98 Reini at al 94 90.6 112* Theriault 4 Allard 20 16.37 122 Uaxveiler et al 15 yr. latency 35 ' 23.5 31 16.9 149+ 164++ Chronic liver cancer Deaths Obser, Exnec. SMR 5 -- 0 0 - 4* --- 14 26.45 56++ 1 2.68 37 5 1.00 500* 1 (0.6) 167 3 2.7 111 14 18.4 -2 4.0 82 50 * Adjusted for unlaiovnVcause* of death ( ) - Ej time ted as a percentage of D.S. rate* + P < 0.05 +1" p < 0.01 a SMR' of control population equally high - c*pected (p < 0.05). The absence of significant findings in other studies may be attributed to their low power. The study of Bertazzi et al (1979) may be biased because of low follow-up in the group. Fourteen percent of the population were untraced and person-years at risk were calculated for these individuals as if they were alive. The low SMR of 44 for all causes of death suggests that proportionately more deaths occurred in untraced groups than in the traced. The studies by Buffler et al (1979), Byren et al (1976), Masuda (1979), and Theriault and Allard (1981) had very few deaths available for analysis. That of Ott et al (1975) also was limited by the number of deaths and further by virtue of a study group with rela tively lower exposure (through better industrial hygiene control). While having more deaths available for analysis (136), the study by Duck et al (1975) was significantly 30- 5 *' i -* m diluted by the inclusion of'many individuals with very short and recent periods of exposure. Turning to chronic liver disease, one remarkable finding is the absence of significantly elevated mortality from this cause in most of the populations under observa tion. The only study with a significant elevation is that of Masuda (1979) in which five deaths from chronic liver disease occurred where only one was expected. However, this must be considered in the light of an equally high mortality from liver disease (6 observed vs. 1.4 expected) in a comparison population followed for control purposes. Five of 62 deaths from chronic liver disease seen in the study by Bertazzi et al (1979) are unusual, but the limi tations of this study and lack of details make evaluation 'difficult. The generally benign results in other studies -contrast sharply with the severe liver disease from VC ' exposure documented in clinical studies (Marsteller et al, 1975). Hepatomegaly, hepatic fibrosis, portal hyper__ tension, and bleeding esophageal varices have commonly -- been found in individuals heavily exposed to VC, even . '"without concomitant exposure to alcohol. Table 3 lists the mortality data for primary cancer..' 1 of the liver and biliary passages and for cancer of the lung, trachea and bronchus. In the case .of liver cancer, the overall data are consistent and dramatic. Hemangiosarcomas of the liver were found in _eight__of the twelve _ studies. In each of the "eight, a~>ery large and highly significant SMR for liver cancer was seen. Methodological limitations can account for negative data in the other four studies. The large SMR's observed, however, are largely the result of low values for the expected number of cases rather than a high incidence of observed cases. Only 2$ separate liver hemangiosarcomas were identified in all twelve studies. As the overall excess number of deaths from liver and biliary cancer in all studies was V/Y some hemangiosarcomas may not have been identified. The low numbers must also be considered in light of the limited follow-up times in most studies. The evidence for lung cancer is less clear. There is an elevation in some studies, but at a level that does not achieve statistical significance, except in the 15 year latency population of Waxweiler et al (1976). This, in part, may be the result of the low power of many of the GENC 001109 - b Table,3 Observed and expected deaths frog selected eiuni among vlnvl chloride-exposed workers -'j:i Cancer of the liver and biliary passages Ohs .* Exp. BemangloSMR sarcomas Cancer of the lung, trachea and bronchus Obs. Exp. SMR Bertaxzl - huffier 5 yr. latency Byren , . 10 yr. latency Duck 19 yr. latency Equitable 15 yr.- latency Fox end Collier 15 yr. latency ' J ..... Masuda -r-^r - - - . Nicholson ' Ott kelnl^3f-: 8 <1.0)b 0 - (0.17) (800)+++ -- 4 0.97 413+ 4 0.68 589++ ---- --- 10 (*.5) r 4 0.71. 1 ^ 0.6 3 (0.12) 0 (0.5) 12 - 0-9 (224)+ 563++ 167 (2500)+++ ,_ *1523+++ 3 7 (7.7)c (91) 0 5 1.73 289+ 4 1.49- 268 2 3 1.78 168 2 0 16 15.53 103 14 10.69 131 5 45 44.29 107 41 37.0 : 111 2 46 51.23 90 28 26.0 -108 , ' ' ' 0 1 (0.8) . (125) . ... 3 0 (1.1) -- o . ; 4(5?) 5.2 . 77(96?) 4 22 24.6 ,95b *~-G Theriault 15 yr. latency 8 (0.5) (1600) ++'+ 8 2 5.78 2 4.25 35 47 Wexuetler ~ 7 0.6 ' 15 yr.'Jatency 7 ... 0.4 1155+++ 1606+++ 6 6 12 7.7 11 5.7 156 194+ ',: . - Totel of nonduplicated hemanglosarcomas 29 T t+ +tt a < 0.05 -- 1 < 0.01 < 0.001 All verified liver cancer deaths, including those established by review^ of all available Information. b ( ) Expected deaths estimated on the basis of 1950-1969 O.S. adjusted rates, 1CD L55/ICD 140-205. c ( ) * Expected deaths estimated on the basis of national age adjusted rates, ICD 162-163/ICD 140-205. d One beaangiosareoma occurred In a PVC fabricator. c Includes cancer of the pancreas. GENC 001110 studies. Only two have an 80% power to detect an overall risk of 1.5 (Beaumont and Breslow, 1981). Of signifi cance, however, are the very low SMR's in the groups studied by Theriault and Allard (1981), Reinl, et al (1979), and Nicholson et al (1975), cohorts that would be expected to manifest a high risk on the basis of the many hemangiosarcomas that were found. The four largest stu dies, although in some cases limited by inclusion of short-term and recently employed workers, also are note worthy for the SMR's close to 100. Where available, data on subcohorts with longer latency (> 15 yr) suggest some increased risk. Waxweiler et al (1981) undertook a detailed analysis of the exposure of those with lung cancer in their previ ously published study (Waxweiler et al, 1976) in an at tempt to identify particular etiological agents. The analysis used a serially additive expected dose model (Smith et al, 1980) in which a dose measurfe during each year of exposure was accumulated for each study individual for a variety of potentially carcinogenic agents. The cumulative doses for those with lung cancer were compared with those of other individuals in the plant under study. The results showed that the greatest correlation of lung cancer was with exposure to PVC dust. Secondarily, expo sure to vinylidene chloride appeared to be important, but only for large cell and adenocarcinoma. The serially additive dose for VC monomer differed little in those with lung cancer compared to others in the plant, except, possibly, for large cell cancers. - Thus, evidence to date does not establish that VC monomer is an important lung carcinogen in exposed worker populations, although it is recognized that limited long term observation has so far been available. In all stu dies considered here, a slight deficit of cases was seen compared to the number expected. In the subcohorts with more than 15 years from onset of exposure, an overall excess of 10% was observed. If, in addition, one consi ders a "healthy worker effect," any excess lung cancer would still be considerably less than the excess of liver cancer. A qualification to this conclusion is that no study specifically considered cigarette usage. If cigar ette smoking was much less common among VC workers than the general population, higher SMR's would have been seen if smoking specific data were available. However, this possibility is unlikely, considering the many differentpopulations studied- The uncertainty in human data is also.reflected in animal studies. Increased lung~cancers have been seen in mice but not in rats or hamsters (Maltoni et al, 1981). Table 4 shows the results for brain and central nervous system cancers and for cancers of the lymphatic and hematopoietic systems. Cancers of the brain and central nervous system were significantly elevated in a number of studies, although the results differed consider ably across studies. Again, negative data may be. simply the result of limited long-term follow-up or the low power of the study. In such cases the information is only sufficient to set an upper limit on relative risk of brain cancer. In contrast to lung cancer, however, the largest study group has a significantly elevated risk of brain and central nervous system malignancy. As with lung cancer, the data on brain and CNS cancer in animals are equivocal. Neuroblastomas and brain malignancies are observed in rats exposed to VC, but not among mice or hamsters (Maltoni et al, -*198l). The human data are also mitigated by the recent finding of brain and central nervous system tumors in variety of chemical plant exposure circumstances (Alexander et al, 1980; Selikoff et al, 1982). Excess ~ brain malignancies, but not the etiological agents, have been identified in several Texas and Louisiana chemical/ petrochemical plants. VC exposure was documented for some cases, but it could not explain the overall findings. As individuals in many of the VC studies considered here were exposed to other chemicals and petrochemicals, the pos sible role of these agents cannot be excluded. Further, it has been suggested that some . working groups, with employer-paid medical plans, may have better case ascer tainment than is generally available (Greenwald et al, 1981)_ and, thus, more brain malignancies identified. In any case, the number of excess malignancies of the brain and central nervous system (approximately 10) in all studies is considerably less than the number of hemangiosarcomas identified in the same populations. Similar results are obtained for malignancies of the "lymphatic and hematopoietic system. Here agaiQ, the analysis is limited by the few deaths and disparate re sults which occurred in different studies. Overall, there would appear to be an elevated risk, but the influence of Table 4 Observed and expected deaths from selected causes among vinyl chloride exposed workers Cancer of the brain h central nervous system Cancer of the lymphatic and hematopoietic system Bertazzi huffier Syren Obaer. 1 0 2 Expect. CO. 8)* (0.1) 0.33 SMR_______ Obser. 125 4 612+ 0 0 Expect. SMR . (3.0)b (133) (0.5) - -- Duek Equitable Fox 6 Collier Maauda Nicholson Ott SeinT Theriault Waxveiler 15 yr. latency 12 2 0 1 1 2 0 3 3 5.90 203+ 3.66 55 (0.15) - (0.1) (1000) 0.4 (250) 1.3 . 162 0.6 ' 6-9 329 0.6 498~ 20 17.01 9 9.01 0 (0.5) 2 (0.4) 1 (1.6) 15 7.7 1 ' 1.67 4 2.5 124 100 (500) (63) 214*1 60 159 t < 0.05 H < 0.01 * t ) Expected estimated from the ratio of age standardized D.S. rates ICD 193/ICD 140-205. b ( ) " Expected estimated from the ratio of 1950-1969 D.S. rates ICD 200-205/ICD 140-250. confounding exposures precludes definitive statements. The overall excess of such malignancies (about 10) is also much less than those from primary hemangiosarcomas of the liver. EFFECT OF REDUCTION OF EXPOSURE TO VC As mentioned previously, most mortality studies followed populations only to the 1972-1975 period. No data exist on the risk to previously exposed populations after cessa tion of exposure in 1974, although hemangiosarcomas have been noted among retirees. We have recently completed a follow-up through 1981 of the population reported in 1975 (Nicholson et al, 1975) to determine whether a high risk of liver cancer continues, following significant reduction in exposure. The original group employed at a VC polymer- * 2. 0* ization plant In Niagara Falls, New York, has been ex panded by 40 additional workers, all exposed for five years, who achieved ten years from onset of exposure subsequent to April 1974. Additionally, 195 individuals employed at a VC polymerization plant in South Charleston, West Virginia, with five years of exposure and ten years from onset in December, 1966, were identified and traced through 1980. Table 5 lists the observed and expected deaths by cause for both groups with the deaths occurring after 1974 separately identified. (These are preliminary data; full Table 5 Observed and expected deaths among vinyl chloride polyneriietioc workers * Niagara rails. KY . (N * 296) . V (January 1, 1956 - December 31, 1961) Observed . Cause of death 56-W' 74-81 Total Expected SMR - AH causes `j. All cancer "{ 6 Ol;.? 44 e 16 40.87 9.01 108 177* Lung Colon/rectua 0 2 2 3.25 62 1 2 3 1.39 216 . ' Brain 1 0 1 0.33 303 Liver - 3 ; 3^ 6 0-19 3158b . Lynphoae 2 i 3 P.55 545* -- Pancreas 1 0, 1 0.50 200 Cirrhosis of liver : 2 1.41 ' 142 -.^12- Cardiovascular disease 13 -8 21 19.88 106 -------- t% South Cherleston, -W (N * 195) _____ (December 1, 1966 - Decemberr 31, 1980) - vrv - Cause of death Observed 66-73 74-80 Total Expected SJffi all causes 12 V " All cancer 2 Lung. 1 Coleo/reetun Brain 0 0 tiver 0 Lynphooi 0 Pancreas 0, Cirrhosis of liver 0 Cardiovaecular disease 8 * 24 : > 10 1 00 4 0 U 1* 12 > "7 36 12 2 0 0 4 0 0 1 20 44.74. 10.65 4.07 1.89 0.43 0.23 0.59 0.67 1.81 27.24 80 113 49 -- -- 1739' -- -- 55 73 a p < 0.05 b p < 0.001 / c p * 0.0005 I IV I i / 6EW'- 00111^ pathological review of all available specimens has not been completed.) Among the 44 deaths that occurred in the Niagara Falls cohort, 6 were from primary cancer of the liver, including 5 hemangiosarcomas. Three of the hemangiosarcomas occurred in the period prior to 1974 and 2 subsequently. Similar findings occurred among the smaller group in West Virginia. Here, of 36 deaths, 4 were from hemangiosarcoma, all of which occurred subsequent to 1974. Thus, the risk of neoplastic VC disease continues undimi nished, even though exposures to the monomer have been significantly reduced. The combined data from both groups are shown in Table 6 and demonstrate an excess risk of cancer, which is totally accounted for by the enormously increased risk of liver malignancy observed in each time from onset of exposure category. The excess lymphomas which achieved significance at the p < 0.05 level in the Niagara Falls group lose significance when combined with the data from South Charleston. A deficit of lung cancer was observed in both study groups and brain malignancies were about equal to the number expected. *" -T^js*** `- -- --- - It is not certain whether the results of these two plants will be reflected in the results of other plants in future' years. . The South Charleston plant was the first facility to commercially produce VC. The New York plant opened immediately following the cessation of World War XI- Thus, we are observing effects in populations that include many individuals with long times from onset of exposure. There is no information -on whether the expo sures .in these two plants "were significantly different from those of the majority of other VC polymerization facilities. It is known that pre-1974 exposures in the New York plant were sufficiently high to cause loss of consciousness to some individuals (4.5% of those examined in the clinical survey of 1974) (Lilis et al, 1975). MORBIDITY AND CLINICAL FINDINGS AMONG VC-EXPOSED WORKERS Clinical abnormalities from VC exposure predated by 25 years the documentation of its carcinogenicity. Vari ous VC-related abnormalities were reported in Eastern European literature, including hepatomegaly (Tribukh et al, 1949), angioneurosis (Filatova and Gronsberg, 1957), osteolytic lesions of distal phalanges (Smirnova, 1961), Raynaud's phenomenon and sclerodermalike skin lesions (Suciu et al, 1963). However, VC disease was not seri- Table 6 Observed and expected deaths among tIutI chloride exposed vork.cn in p polymerisation facilities by Cine froa onset of expoeure Tears since onset of exposure Causa of death 10 - 19 20 - 29 30+ Total * Obs. Exp. All causes 24 19.13 All cancer 7 3.72 Lung 1 1.26 Liver 2* 0.08 Brain 1 Lyaphona 2- 0.27 Cirrhosis of liver 0 0.76 Cardlovaa cular 14 8.74 disease Person years 2924 Obs. Exp. 30 34.83 9 7.98 1 2.96 3* 0.18 0 1 0.46 3 1.24 15 17.58 Obs. Exp. 26 31.64 12 8.03 2 3.08 5b 0.17 0 0 0.41 0 0.87 12 16.40 2734 1404 Obs. - 80 83.61 28 19.66 4 7.31 10 0.42 1 0.76 3 1.14 3 2.85 41 42.73 SMK 93 142 55 2381 132 263 105 96 a. ' heaanglosarcona b. 4 hemantioeareomas and 1 hepatoma ously considered in the West until the published descrip tion of Raynaud's syndrome, acroosteolysis, and pseudoscleroderma in two Belgium VC reactor cleaners (Cordier et al, 1966). Additional cases were soon noted (Wilson et al, 1967) and a comprehensive epidemiological study of 5,011 13.S. workers employed in production and polymeriza tion was undertaken. It showed that 11.9% had possible X-ray signs of acroosteolysis, compared with 3.2% in a Michigan general population control group, with 2% defi nitely having Raynaud's phenomenon or X-ray evidence of acroosteolysis (Dinman et al, 1971). The conditions were clearly associated with the cleaning of reactors, in which a heavy exposure to VC occurred. Only one case of Ray naud's phenomenon occurred among 557 workers employed in PVC fabrication. During the early 1970's, VC liver disease was de scribed in detail by Marsteller et al (1973, 1975). Observations on selected workers showed hepato- and sple nomegaly to be common. Peritoneoscopy and guided liver biopsy identified severe portal hypertension in some, generally without cirrhotic fibrosis, although perisinusoidal and focal or diffuse capsular fibrosis were common ly seen. The portal hypertension could lead to bleeding esophageal varices, with possible fatal consequences. In heavily exposed individuals, the portal hypertension and hepatic fibrosis often progressed after cessation of exposure (Martin et al, 1974). The histology of malignant and nonmalignant liver disease has been well described by Popper and Thomas (1975; Thomas et al, 1975), who suggest ed the possibility of an interrelationship between heman giosarcoma and the proliferation of sinusoidal lining cells and hepatocytes seen in VC fibrosis. Lelbach and Marstellef (1981) have also noted that the vast majority of hemangiosarcoma cases have appeared on a background of some degree of hepatic fibrosis. The implications of these suggestions for a hemangiosarcoma dose-response relation are uncertain. During 1974, extensive studies were undertaken by the Environmental Sciences Laboratory of the total workforces of three polymerization plants in the states of New York, Michigan and West Virginia. The results from the New York plant (Lilis et al, 1975) indicated the presence of acroosteolysis in heavily exposed individuals. Hepato- and splenomegaly or hepatic tenderness was commonly observed and associated with duration of exposure and elevated alkaline phosphatase levels. Sixty-four of 354 had an enlarged or tender liver or spleen and of these, 41% had elevated alkaline phosphatase. Liver function tests were" not particularly revealing, except for a correlation of elevated alkaline phosphatase levels with duration of exposure. Additionally, carcinogenic embryonic antigen titers were slightly higher among vinyl chloride exposed groups than in a smoking matched control population (Anderson et al, 1978). Tamburro and Greenberg (1981) have evaluated the effectiveness of federally mandated screening tests for vinyl chloride exposed workers. Figure 1 shows the re sults on specificity and sensitivity for 78 individuals with hepatic status determined by biopsy. ICG clearance had the highest combined sensitivity and specificity, with SGPT the second most useful test. Elevated alkaline phosphatase had the greatest specificity of all tests, particularly for chemically-induced liver injury, but was lacking in sensitivity. SGOT and GGPT were of limited use because of their low specificity for chronic liver disease. They recommended the use of ICG clearance for screening, to be followed with alkaline phosphatase determinations for those with altered clearance. ' 14 SENS III SPEC BS S&S w g 10 -- i m iim iiiu i IIH IIIIIIIIII IIH IIIIIIIIII U lllllllll I8 | M > g M V5 0. 1*0 s AP SGOT SGPT GGTP ICG TESTS 0.5 , i I Figure 1: . Sensitivity and specificity of various biochemical screening tests and their sensitivity .and specificity sum values (S & S) based on 78. with biopsy documentation of their hepatic status. Three of the seven individuals who died after 1974 with hemangiosarcoma in the previously described mortality followup were examined in 1974. . One, who died 22 months after examination, had no noteworthy abnormalities on examination (alkaline phosphatase was 88, slightly high). A second, who died three years after examination, had a slightly enlarged, palpable liver (11 x 6 cm) with normal blood counts and chemistry. Only one of the above drank alcohol at all and he only drank 2-3 beers/month. The third, who died 22 months after examination, had a slight ly enlarged liver (11 x 8 cm) and spleen (13 x 8 cm), and slightly elevated alkaline phosphatase (93), SGOT (52) and CEA (4.7). Thrombocytopenia was also present (75,000). No data are available on later clinical parameters, but the above results are clearly not sufficiently specific for identification of a special risk. Pulmonary abnormalities also have been associated with VC/PVC exposure. Small opacities, predominantly irregular, of profusion 1/0 or greater were found in 20 of 1,216 workers employed at PVC production in an Italian plant (Mastrangelo et al, 1981). .All had been exposed to high levels of PVC dust (>10 mg/m ). Lilis et al (1976) genc oonts reported that approximately 20% of VC/PVC workers with high exposures to PVC dust had abnormal X-rays, which correlated with duration of exposure and, also, with cigarette smoking. In contrast, only A.7% of individuals in a PVC plant with low dust levels had abnormal X-rays. In addition to "typical pneumoconiosis," a granulatomous reaction to PVC dust has been reported (Arnaud et al, 1978). Miller et al (1975) have observed pulmonary func tion abnormalities (a reduction in the ratios FEV^/FVC and MMF/predicted MMF) in both smokers and non-smokers heavily exposed to PVC dust (and also to VC monomer). Maltoni and Lodi (1981), observed greater percentage of abnormal spu tum cytological results among VC exposed workers compared to several other groups of manufacturing workers or miners. Only workers in the chromium industry demonstrated a greater proportion of abnormal cells. Ducatman et al (1975) have observed an increased frequency of chromosome abnormalities in the lymphocyte cultures of VC workers.' Most of the abnormalities were "unstable" changes, such as fragments, dicentrics, and rings. This was confirmed by. Purchase et al (1978), among others. Some of the group studied by Purchase wfje.resampled 18 and 42 months later (Anderson et al, 1980). In those studied during January 1976, the frequency of abnor malities was increased in those who continued VC/PVC employment, but decreasedin those who left the industry. In January 1978, no increased frequency was found in any worker. The authors attributed the decrease to the reduc tion in VC exposure. HEALTH HAZARDS IN THE PVC PROCESSING INDUSTRY Prior to identification of hemangiosarcoma in VC polymerization workers, little effort was made to control either the concentration of residual monomer in PVC dust or exposures to dust and VC that occurred in the various forming operations of the PVC fabricating industry. VC concentrations in excess of 10 ppm occurred frequently. While these concentrations were significantly lower than those of the polymerization industry, the much greater employment in the processing industry (hundreds of thou sands vs. tens of thousands in the polymerization work) raised concern for population health effects, particularly for malignant disease for which no threshold was known. However, only two bemangiosarcomas have been documented in the PVC processing industry, , one in an accountant in a plant making PVC fabric and one. in an Italian plant making PVC sacks. A third case may have occurred in an electri cal wire insulator, but the pathological diagnosis is uncertain (Lloyd, 1975). This is in contrast to 85 cases known to have occurred among polymerization workers (NIOSH, 1982). This is somewhat comforting and indicates a'signi ficantly lower total VC-related neoplastic risk among fabrication workers. However, it should be noted that case finding is likely to be poorer in this group than in polymerization workers. proportionate mortality study has been conducted of deaths of former employees of 17 PVC fabricators dteniazze Jr., et al, 1977). The direct PMR's suggested an excess in total cancer mortality among both white men and white women with the major excesses concentrated in can cers of the digestive organs. An excess of breast cancer was also seen in women, but not confirmed in a case-con trol study (which was of very low power and could only detect a threefold increased risk) (Chiazze, Jr. et al, 1980).' The results of the proportionate mortality study must be considered cautiously. In such studies, elevated cancer risks and are typically seen because of a "healthy worker effect," which leads to a reduction in cardiovascu lar deaths relative to those of cancer. If PCMR's (pro portionate cancer mortality ratios) had been calculated, rather than PMR's, digestive cancer would still.be elevat ed but not at an 0.05 level of significance. Interest ingly, an excess of stomach cancer was seen in the propor tional mortality study of Baxter and Fox (1976). SUMMARY Overall, the results of the analysis of 12 studies of VC production and polymerization workers demonstrate an enormously'elevated risk of liver malignancies, the possi bility of a twofold increased risk of brain and central nervous system tumors and perhaps, also, of malignancies of the lymphatic and hematopoietic system. However, the role of other agents cannot be excluded in the etiology of nonhepatic malignancies. Bronchogenic carcinoma does not appear to be increased from exposures to VC monomer, although a relationship to PVC dust was suggested in one study. These conclusions must be considered in light of limited data on workers followed more than 25 years- from 17 onset of exposure. Considering the numbers of observed and expected deaths in all studies, it would appear that the excess of malignancies at nonhepatic sites is less than the excess of liver tumors. Data presented elsewhere in this volume (Nicholson and Henneberger, 1983) suggest that exposure reductions in 1974 may have virtually elimi nated the VC-associated risk of liver cancer if the current U.S. standard is met. To the extent that VC exposure is associated with other cancers, a similar risk reduction would be expected. Raynaud's phenomenon, acroosteolysis, sclerodexmalike skin lesions, hepato- and splenomegaly with noncirrhotic hepatic fibrosis, and severe portal hypertension have been associated with past heavy exposures to VC. Evidence exists that the liver disease and portal hypertension may progress following cessation of exposure. However, all of the above syndromes were found largely in heavily exposed individuals. Their occurrence would be much' less likely in workers exposed only to concentrations currently allow ed. Pulmonary deficits, X-ray abnormalities, and, per haps, lung cancer have been associated with VC/PVC expo sure. Because of the possible contribution of PVC dust to these findings, engineering controls during polymer dry ing, bagging and usage are warranted. REFERENCES Anderson HA, Snyder MS, Lewinson T, Woo C, Lilis R, Selikoff IJ (1978). Levels of CEA among vinyl chloride and polyvinyl chloride exposed workers. Cancer 42:1560-1567. Anderson D, Richardson CR, Weight TM, Purchase IFH, Adams WGF (1980). Chromosomal analyses in vinyl chloride exposed workers: Results from analysis 18 and 42 months after an initial sampling. Mutation Res 79:151-162. Alexander V, Leffingwell SS, Lloyd JW, Waxweiler RJ, Miller RL (1980). Brain cancer in petrochemical workers: A case series report. Am J Ind Med 1:115-123. Arnaud A, Pommier de Santi P, Garbe L, Payan H, Charpin J (1978). 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