Document pBYMkqX9x1ndd4xvDzvpBvNx7

l*Mi*-L* . 'MW l 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 ; l Editors JORMA JARVISALO PIRKKO PFAFFLI HARRI VAINIO Institute of Occupational Health Helsinki, Finland AP00019197 Under the condtocna staled fteto# the owner of copyright torthla book hereby gram* permission to users to make photocopy reproduction* of any perioral of its content* for personal or internal organizational use, or for personal or internal use of specific cttenu. This consent is given on the condition that the copier pay the stated par-copy fee through me Copyright Clearance Center, incorporated. 2f Congress Street. Salem, MA 01970, as listed in the most current issue of "Permissions to Photocopy" (Publish* efs Fee Ust, distributed by CCC, Inc.), tor copying beyond that permitted by section* t07 or 108 of the US Copyright U. This consent does not extend to other kinds of copying, such a* copying for general distribution, tor advertising or promotional pur poses, for cresting new collective works, or for resale. Library of Congress Cataloging in Publication Oata International Symposium on Occupational Hazards Related to Plastics and Synthetic Elastomers (1982 spoo, Finland) Industrial hazards of plastics and synthetic elasto mers. (Progress In clinical and biological research; v. 141) Includes bibBograghleal raierences and index. 1. Plastics--Toxicology Congresses. 2. Elastomers-- Toxicology--Congresses. 3. Industrial toxicology-- Congresses. I. Jftrvisaio, Jorma. it. Ffiffli. Pirkko, m. Vainio, H. (Harri). 1947. . IV. Title. V. Series. RA1242.P$6I58 1982 SIS.S'SI 03-24848 ISBN 04451-0141-2 Content*. Contributor! Preface Jorma Jdrvisat CHAPTER L S C Synthetic Poly Jukka M. Martir Polymer Proee: Vini Erl . . . Additive* In Sy> Lawrence Fishb* Carcinogenesis Evaluation at th. J.E. Huff and J-A Trends in Cance Industry William J. Nichols Reproductive Hs K. Hommlnki. M.-l CHAPTER II. PO Production and Pr Artel Hoff............ Th* Toxicology of Bo Hotmberg , . . Toxicity of the Cor Additives Lawrence Pishbein Phttialste Ester* C. J.E. Huff and W.M. f Occupational Haasi William J. Nicholson Preventive Measure Production Industry 8, Tarkowski .... AP00019198 I \ OCCUPATIONAL HAZARDS IN THE VC-PVC INDUSTRY William J. Nicholson, Paul JC. Henneberger and Herbert.Seidnan. - Environmental Sciences Laboratory, Mount Sinai School, of Medicine of CUNY, New York,* New York v 10029- (VJN, PH) and American Cancer Society, 4 W. 35th Street, New York, New York 10001 CHS). . 4m .rr- W-. INTRODUCTION^'*^-^ -- '^lrr matron January 24, 1974,-The Wall Street Journal publish* ed .jux article , describing -the occurrence of three deaths gy.jgk* *. _ I from hemangiosarcoma of the liver among polyvinyl chloride -.'(P7C)^productidh~'workers'^et the B.F. Goodrich Tire and ......R..u. bber Company plant in Louisville, Kentucky. This anaoun eiementl.' shattered./, the relatively. complacent view^tovrd_ *-*' ' h'Mith^;reffects f'associated^'with. 'plastic production . in general and FVC 'production' in--particular. At* the time, U.S.'^ind Western European production of* vinyl chloride _^(VC)Jexceeded..6<-x 10 metric tons.Numerous mortality and '^clinical studies'were undertaken in the major jproducing countries in'^aa ^attenpt.- to establish the extent of the ` "carcinogeaic Trisk 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 symposia*"'oa human health effects from VC exposure have been published recently. A" superb one is . by Lelbach'and Mar* stellar (1981). The exposures were high that led to the disease observed7in 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* * -4j: AP00019199 2 ceeded 5-10,000 ppm (where worker# lost consciousness) and, on occasion, 40,000 ppm (where plants exploded). During 1974, exposures were reduced to about 10-20 ppm in the TJ.S.` industry (Jones, 1981) and even further, follow ing the promulgation of a 1 ppm standard by the Occupa tional Safety and Htalth 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 chlorideTbxposed workers. The studies were independent with the exception that the portions of the population reported .. 'the 'Equitable Environmental Health Study (1978) were . included in some other U.S. studies. The proportionate .. p mortality study of Monson et al (1974) is not included as - *" '* the.lyc-exposed-individuals studied therein were included - . yia^theJcohort:6rtility*'tiidy of Wakweiler at al. (1976). The-size ' of-the cohorts varied greatly, from 255 in the studyjbf Nicholson et ai <1975) to 9,677 in the Equitable . "' :-S Environmental `Health study."- A notable * feature "of ell of - " J V:.%v the ^studies is .-that the^ population'followed were* 7 tiyely joung 'or recently "employedeven though many plantain.:; tudicsj started - production - in the 1940s*'- won rer^Tljired Europe_a_n - ^production after.Tl950,_jtheh^U.S. increased "s_ix_fold _in_ and WWeestern ' ten - years r:> (Nicholson'Viid^eneberiM"'l983)ius, few' "deaths ^gsy* occairked*^among j most of the' groups . observed and data oh \,?^^hi2SS^fe-effe3SI"-25 or^ more years? from onset of exposure are li- . altad-^Tbe "total mortality exceeded 10% of the observa- . -i.'4-TH ~tion'cbhort in"only three studies. Further, the inclusion '""'.jl.*;! r; of .^recently 'employed individuals or those with short * "Vr~- *;" W" employment diluted the effects from VC exposure. Only . " five?*tudies/limited consideration to individuals with v;r ' -'V3'-;--. mo re'than one "year of exposure. In all eases, however, ' 'r- some individuals vith"*more than 20 years from onset of employment were available for observation. The follow-up terminated in the mid-1970s for all studies. *3 ^ Table 2. compares the results for cancer of all sites and chronic liver disease in all 12 studies. Cancer is elevated in moat 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 AP00019200 i'. . .'I; 1 r . ' {- , `.'1 :,r ! 1 *. iS f'!v -.;r : ii " ; : : . -" -'i; t':, n., /V..*/ ';' :i-`! .; . 'Mi,*1 ' .r\ ' i- :'' .* i : : -]ix. Population and dollow-uprfchsi,ait6frl*clca of twelve J ''Itfifr' r; . studies of vUitI chloride exposed workers I Study loiljrili Percest . Dunbar < Parcant' HIbImm ' Hlnlwuo cohort additional- of deaths f, of exposure latency. Country alts uatraced analyzed ri-V- total (years) (years) Bereazzi st al. 1979 iuffler ct al. 1979 Byreo at al. 1976 Duck et al. 1975 Equitable Env. Health. 1978 Fox and Collier . 1.1 .= 393 : V 5.1 XI 1976. 1977 Hasuds JAP 304 0.3 26 8.6 1 1979 Nicholson et al. 1975 Otc et al. USA USA 253 522 O.B_.'' 'i'' : M ; ", t f * * ! ; ? o.o - ']} ^ `*9.4, i!lS.l.,; *i !; 3 >0 . 1975 Relol at al. cu 6544 7.3 414 6,3 >0 1979 Theriault and CAM 451 2.B . 59 13.1 5` Allard. 1981 Uaxweller et al. USA 1976 1287 1s 4 :.t Irr: 136. < 10.6 , ;! '5. -M 'IN- 4 1* Longer latencies coaeidered for som causes of *atb "j i l 10* >0 X) 5* 10* Earliest possible exposure 1949 1947 1942 NA 1943 1940 Kaxiaun `Last follow-up year of (years) follow-up 1977 1975 1971 1975 1972 1974* 20 1975 25 1974 31 1973 NA 1974 30 1977 22 1973 ; 1; . .-r:,i"'-'K;r AP00019201 , > r;!. * - I Table 2 ObtatvtA and axptcttd Atathi ibom -vIctI Caaear of all aleas Daaeha Chronic llT* aaaecr Daatba StudT Iiruici ec al Obaar. . Zxoae. 30 30.9 sxa 97 Obaar. Caroae. 5- SKK - Sufflas *t al 5 yr. latancy Sjcib at al Duck at al Zqulsabia t - 55 139 5.19 4.34 - 36.44 .141.39 154 136 - 96 104* 0-- 0---- 14 26.45 56++ Tex A Colllar U5 126.77 91 1 Haauda 8 s.s US 5 Hlebelaoa 9 3.9 230 1 Oct at al 13 15. yc. lataney ' 9 16.0 9.2 81 98 3 lain! at al .94 * 90.6 112* 14 Tbadaulc A Allard 20 16.37 122 -' Vamailar at al 15 yr.^ laeaaey 35 * 31 . 23.5 16.9 149+ 184++ .2 * Atfjeaead for uaknove\auaaa of dudi O Sadaaead am m pareanemja .+ H.S: rat** t f < 0.05 .. tt.9* 0.01 ~ ' T SOT-of control population aqually hf&. j" . : . 2.68 1.00 (0.6) 2.7 18.4 - 4.0 .. . 37 500*. 167 ui .-- $2 r-- -................. ....... : 50 ' expected (jT *<'~0^05)V * The absence of significant findings'" in other studies may be attributed to tbeir low power. The study of Bertezzi et al (1979)-may be biased because of low follow-up in the group. Fourteen percent of the population were uatraced 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 untraeed 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 el (1975) also was limitad by the number of deaths and further by virtue of e 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) vae significantly AP00019202 diluted by the inclusioa 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 observe* 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 , of `the liver and biliary passages and for cancer of. the lung, traehea and bronchus. In the case .of liver cancer, the overall data are' consistent and dramatic. Henan* giosarcomas of the liver were found in eight of the twelve ,stuoies. In each, of the eight, a very large and highly significant SHR 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 29 separste liver hemangiosareomss were identified in all twelve studies. "As the overall excess number of deaths from liver and biliary cancer in all studies was a/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 Table. 2 Obierved and expected deaths from selected eui aaong vinyl chlorlde-expod workers .... ,, Cancer of the liver and biliary passages Cancer of the lung, trachea and bronchus Oba .* s*p. BenangioSMX Obs. Exe. - SHE Bertsxxi - 1 a.ojb Sufflsr 5 yr. lataney 0 CO.17) Syren 10 yr* latency Duck 19 yr. latency 6 4 _ 0.97 0.66 Equitable 15 yr.- latency 10 (4*5) `.. ..... Fox and Ccllier 15 yr. latency -y.. . Hasudn 4 ` 0.71* r j-;"o.6* Nicholson oet ' Xlai?^g> 3 .. <0.12) 0 "(0.5) eSs - 12 : 0.9, (800)m __ 613t 589tt __ (224)+ *363tt 167 ` (2500)+++ 1523+H- 3 0 2 2 0 s 2 '0 3. 4, 7 (7.7)c (91) 5 1.73 289+ 4 1.49- 26S 3 1.79 168 16 14 45 41 46 20 .1 *0 4(57) 22 13.53 10.69 103 131 44.29 37.0 107 111 51.23 26.0 (0.9) (1.1) 5.2 90 109 ; (125) -- 77(967) 24.6 ' .95 Theriault' 15 yr.^lataney Waxueller. `15 yr**^Utsney 9 (0.5) * 7 .'*'0.6 7 --. 071 . (1600) t+'+ 1155t++ 1606t+t 9 r._. ` 6' " 6 2 2 12 11 5.79 6.25 7.7 \ 5.7 - 35 47 156 194+ local of noodupllcaced haesngloaarcoasa 29 - t < 0.03 ++ < o.oi V-l. ~*. ,, +++ < 0.001 "... a 111 verified liver cancer deaths. including choae established by review of all available infosaacien* b ( ) Expected daaeha estimated on the baais of 1950-1969 0.5. il~ adjusted rates, ICS L55/ICS 140-205. c C ) Expected deacha eaclaaced on the baais of national age adjusted rates. ICS 162-163/ICS 160-205. d One benaagiossreoaa occurred in a PVC fabricator, a Includes cancer of the pancreas. 7 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), Reiul, et al (1979), and Nicholson et al (1975), cohorts that would be expected to manifest a high risk on the basis of the many hemangioaarcoaas 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 St1* close to 100. Where available, data on subcohorts with longer latency (> IS 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 agenta. The analysis used a serially additive expected dose model (Smith et al, 11980) in. which a dose measure 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. ' Thn results. showed that the greatest correlation of luag .-^.., ^cancer was^with`exposure to FVC dust. " Secondarily, expo- v' sure to vi&ylidene chloride appeared to be important, but J "only for large`'cell and adenocarcinoma. The serially * additive doae fog VC monomer differed little in those with lung * cancer compared to others in the plant, except, possibly, for largiT cell cancers.. . __ ;;Thus, evidence to date does not establish that VC monomer is an important lung carcinogen in exposed worker ' populations, although it is racognized 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 . `;.v. "L. -v' yT-vefc.* AP00019205 8 possibility is unlikely, considering the many different" populations 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, -l981). The human data are also mitigated by the recent, finding of brain and central nervous system tumors in \a* '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 la 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 say case, the number of excess malignancies of the brsin 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 again, the analysis is limitad 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 i AP000I9206 Table 4 Obimd and A3cpct*d death* frea iiUefd caui* aoag vinyl chlarld* *xpod worker* Cancer of the brain 4 Caneer of the lyaohetic central aervoui itki And henatoooietic vcan Strcuti Obacr. Exneet. sot 1 ' C0.S)a 123 Obs*r. ZXDCt. SKI . 4 (3.0)* (133) Bufflar Syren 0 C0.1) 2 0.33 612* 0 (0.3) 0- - Duck ' -- -- - o Equitable 13 5.90 20 17.01 124' Fox & Collier Maauda 2 0 3.66 (0.13) 53 - 9 9.01 100 0 (0.3) . - Nicholson oec 1 .1 (0.1) UOOO) 0.4 C250) 2 (0.4) (500) 1 (1.6) (63) Falsi Tharlauie 2 1.3 . 162 ,1 ' 0.6 ' 13 7.7 214+1 1 1.67 60 Uuvtlltr 3 15 yr. latsocy 3 0.9 329. 0.6 49aT 4 2.3 159 ."t < 0.03 ... . "tt <0.01 ' ~'i" > * t ) Sxpoeted eetlaeeed fros eh* rcle of *g* atandardixed U.S. mu ICO 193/ICS 140-203. * . ( ) Expected estimated from eh* ratio of 1930-1969 O.S. racea ICD 200-203/ICD 140-230. confounding exposures precludes definitive statements. The overell exeess of such malignancies (about 10) is also much less than those from primary heoangiosarcomaa 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 henangiosarcomas have been noted among retirees. Ve 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- .I 10 ixation plant ia 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, Vest 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 Tibia 5 Observed ui expected deaths iaoo| Tlajrl chloride polynarlzatiea worker* Hlatara Falla. Nt. ( * 296) (January 1,' 1956 - Oeeambar 31, 1981) Causa of death Ob*agrad 56-44.T- 74-81 Total cauaas 3ras. ' all eancor - * .s lamg . * 0 Coloe/reetu* : i Brals 1 -' Liver \jr -- 3 lorwpbOM 1 -- Faneraaa 1 '^^dfTcixrhaflia of livar ' 2 * Cardleva*cclar dlsessa 13 dij.9 44 a 16 22 23 01 .3 V 6 1 3 Is 1 2 21 Expected 40.87 9.01 3.23 1.39 0.33 0.19 0.33 0,30 1.41 19.88 SMB 105 177* 62 216 303 3158b 545* 200 142 106 ~ ` .`....I'"'. (Caccabar 1, 1966 - December 31, 1980) ...J - Cattaa at death Observed 66-73 74--80 Total Exoeeted JCMU eaoaaa 12 ' eanear 2 Leaf. 1 .. Celoa/raetua 0 Brain Livar 0 0 Lrapbesa 0 Faneraaa Cirrhosis of livar 0# 0 Cardiovascular dlsaaaa S - 24 19 10 1 0' 0 4 0 0/.. l* 12 !* 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 . /9 0.05 P < 0 001 9 * O.OOOf I /t* sat 80 113 49 -- -- 1739' -- -- 55 73 AP00019208 11 . 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 hemangiosarcooas. Three of the hemangiosarcomas occurred in the period prior to 1974 and 2 subsequently. Similar findings occurred among the smaller group la Vest Virginia. Here, of 36 deaths, 4 were from hemangiosarcooa, 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. -^lt is not certain whether the results of these two plants.will be reflected in the results of other plants in ^futuke^'yeacs* .:r'.The. South Charleston plant was the first facility to commercially produce VC. The New York plant opened ' immediately following the cessation of World War II. ^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 .Fork plant were sufficiently high to cause loss of consciousness to some individuals (4.5% of those examined in the clinical survey of 1974) (liiis 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), aagioneurosis (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- 1 (fi 4ft oj APOOO19209 Tabla 6 Obatrved and txooctad dcathi aaon virrrl ehlorlda *xpoad workars ia two polTetriaatloa faeilltlaa bveia> from oesat of axoosurs Tears since onset of exposure Causa of death 10 - 19 20 - 29 30* Total Obs. Exr. Obs. bv. All causes 24 19.13 All eaaeas' 7 3.72 ' Lung 1 1.26 Liver 2* 0.03 grata 1 LjvphofiA 2. 0.27 Cirrhosis of liver 0 0.76 Cardiovascular 14 S.74 disease 30 34.83 9 7.98 1 2.96 3* 0.18 0 1 0.46 3 1.24 13 17.58 Obs. _ffii 26 31.64 12 8.03 2 3.08 5* 0.17 0 0 0.41 0. 0.87 12 16.40 Person roars 2924 2734 1404 Obs. **P- 80 85.61 28 19.66 4 7.31 10 0.42 1 0.76 3 1.14 3 2.85 41 42.73 SHE 93 142 55 2381 132 263 103 96 ' hesaaglosaxceas' b. 4 haaaaglosercomas sad 1 hepacene . ously considered in the Vest until the published descrip' tioa of Raynaud's syndrome, acroosteolysis, and pseudo- scleroderma in two Belgium VC reactor-cleaners (Cordier et ai,~ 1966). Additional cases were soon noted (Wilson ec*"/ al, *1967) and a comprehensive epidemiological study o 5,011 U.S. workers employed in production' and polymerize 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 perlsinusoidal and focal or diffuse capsular fibrosis were common ly seen. The portal hypertension could lead to bleeding esophageal varices, with possible fatal consequences. In i APOOOt9210 heavily exposed individuals, the portal hypertension and ' hepatic fibrosis often progressed after cessation of exposure (Martin et al, 1974), The histology of malignant and nonraalignant liver disease has been well described by Popper and Thomas (1975; Thomas et al, 1975), who suggest ed the possibility of an interrelationship between hemangiosarcoma and the proliferation of sinusoidal lining cells and hepatocytes seen in VC fibrosis. Lelb'ach and Marsteller (1951) have also noted that the vast majority of hemaugiosarcoma cases have appeared on a background of some degree of hepatic fibrosis. The implications of these - suggestions for a hemangiossrcomi dose-response relation are uncertain. Curing 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 Vest Virginia. The results from the New York plant (Lllis et al, 1975) indicated the presence of acroosteolysia in heavily exposed individuals. Hepato- and splenomegaly or hepatic tenderness was_commonly observed ""end 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, 4l% 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 GGFT 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. 2b SENS III! SPEC aa s&s > U' Figure 1: Sensitivity,and specificity of various biochemical screening tests'and their sensitivity end specificity sum values (S & S) based on 78 ?r with biopsy documentation of their hepatic status ,,`7vThxee of the..seven individuals who died after 1974 with heaangiosarcoma in the previously described mortality followup were examined in 1974.* . One, who died 22 months after * examination, had no noteworthy abnormalities on examination (alkalis* 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. _ - -p Pulmonary abnormalities also have been associated with VC/PVC exposure. SmalL opacities, predominantly irregular, of profusion I/O or greater were found in 20 of 1,216 workers employed at PVC production in an Italian plant (Mastrangeio et al, 1981). ..All had been exposed to high levels of PVC dust (>10 mg/m'3). Lilis et al (1976) AP00019212 reported that approximately 20% of VC/PVC worker* with -high exposures to PVC dust had abnormal X-rays, which correlated with duration of exposure and, also, with cigarette smoking. In contrast, only 4.7% 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 PEV./JVC and MKF/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. . Zhicataan et el (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 w^stresaa-. pled 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 decreased - in those who left the industry. In January 1978, no increased frequency was found in any worker. The authors attributed the decresse to the reduc tion in VC exposure. HEALTH HAZARDS IN THE PVC PROCESSING INDUSTRY Prior to identification of hemangiosareoma 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 hemangiosaccomas have been documented in th PVC processing industry, . one in an accountant in a PVC fabric and one in an Italian plant making PVC sacks. A third case may have occurred in an electri cal wire insulator, but tbe pathological diagnosis is uncertain (Lloyd, 1975). This is in contrast to 85 cases known to have occurred among polymerization workers (KIOSK, 1982). This is somewhat comforting and indicates a`signi ficantly lower total VC-related neoplaatie 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 4,34V deaths of former employees of 17 PVC fabricators Shlazze Jr., et al, 1977). Tbe 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 organa. 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 era 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.FMR'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 Pox (1976). SUMMARY Overall, the results of tbe 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 tbe etiology of nonhepatic malignancies. Bronchogenic carcinoma does not appear to be increased from exposures to VC monomer, although a relationship to FVC dust was suggested in one study. These conclusions must bs considered in light of limited data on workers followed more than 25 years from AP66di9214 onset of exposure* Considering Che numbers of observed and expected deaths in all studies, it would appear that the excess of malignancies at nonihepatic sites is less than the excess of liver tumors. Data presented elsewhere in this volume (Nicholson and Hennebecger 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, sclerodermalike 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, Leffiagwell SS, Lloyd JW, Waxweiler RJ, Miller RL (1980). Brain cancer in petrochemical workers: A case series report. An J Ind Med 1:115-123. Arnaud A, Pommier do Saati F, Garbe L, Fayan K, Charpin J (1978). Polyvinyl chloride pneumoconiosis. Thorax 33:19-25. Barnes AW (1976). Vinyl chloride and the production of PVC. Proc R Soc Med 69:277-281. Baxter PJ, Fox AJ (1976). Angiosarcoma of the liver in P.V.C. fabricators. Lancet 1:245. Beaumont JJ Bceslow NE (1981). Power considerations in epidemiologic studies of vinyl chloride workers. As J Epidem 114:725-734. Bertazzi PA, Villa A, Foa V, Saia B., Fabbri L, Happ C, Marces C, Manno M, tfarchi M, Mariani F, Bottasso F (1979). Aa epidemiological study of vinyl chloride exposed workers in Italy. Arh hig rad* tokslkol 30:379-397 (Suppl). Buffler PA, Wood S., Eifler C, Suarez L, Kilian DJ (1979). Mortality experience of workers in a vinyl chloride monomer production plant. J Occ Med 21:195-202. Byren D, Engholm G, Eaglund A, Westerholm P (1976). Mortality and cancer morbidity in a group of Swedish VCM and PCV production workers. Environ Health Persp 17:167-170. Chiazze Jr L, Nichols WE, Wong 0 (1977). Mortality among employees of PVC fabricators. J OccMed 19:623-628. Chiazze Jr L, .Wong 0, Nichols WE, Fereace ID (1980). Breast cancer mortality among PVC fabricators.' J Oce Med 22:677-679. . Cordier JM, Fievez 0, Lefevre MJ, Sevrin A (1966). Aero- osteolysis combined with skin lesions in two workers exposed in cleaning autoclaves. Cahiers Med Travail 4:14, 3-39. _ Dinman BD, Cook VA, Whitehouse WM, Magnuson HJ, DitcheckT (1971). Occupational Acroosteolysis. I. An epide miological study. Arch Environ Health 22:61-73. Ducatman A, Hirschhorn K, Selikoff IJ (1975). Vinyl chlo- -fide exposure and human chromosome aberretions. ' Mutation Res 31:163-168. Duck Btf, Carter JT, Coombes EJ (1975). Mortality study of .workers ' in a polyvinyl-chloride production plant. Lancet 11:1197-1199. Equitable Environmental Health, Inc, (1978). Epidemio logical' study of vinyl chloride workers. Equitable Enviroomentel Health, .Inc., 6000 Executive Blvd, Rockville MS 20852. Filatova VS, Gronsberg ES 8457). Hygienic working condi tions in the production of polyvinyl chloride resins and measures for improvement. Gig Sanit 1:38-42 (Russian text). Fox AJ, Collier PF (1976). Low mortality rates in Indus trial cohort studies due to selection for work and survival in the industry. Brit J Prev Soc Med 30:225-230. Fox AJ,' Collier PF (1977). Mortality experience of work er* exposed to vinyl chloride monomer ia the manufacture of polyvinyl chloride ia Great Britain. Brit J Ind Med 34:1-10. Greenwald ?, Friedlander BR, Lawrence CE, Hearae T, Earle X (1981). Diagnostic sensitivity - aa epidemio logic explanation for an apparent brain tumor excess. J Occ Med 23:690-694. Jones JH (1981). Worker exposure to vinyl chloride and polyvinyl chloride. Environ Health Persp 41:129-136. Lelbach. WK, Marsteller KJ (1981). Vinyl chloride-asso ciated disease. In: Ergebnisse dec Inneren Medizin uad Kinderheilkunde, Bd 47, Advances in Internal Medicine and Pediatrics. P. Frick et al Eds. Springer-Verlag, Berlin. Lilis R, Anderson H, Nicholson V, Baum S, Fisehbein AS, Selikoff IJ (1975). Prevalence of disease among vinyl chloride and polyvinyl chloride workers. Ann NY Acad Sci 246:22-41. lilis R, Anderson. H, Miller A, Selikoff IJ (1976). Pul monary' changes among vinyl, chlroide polymerization workers. Chest 69:299S-303S (suppl). 'Lloyd JW (1975). ~ Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers. J Occ Med 17:333-334. Maltoni C, Lodi P (1981) . Results of sputum cytology. among workers exposed to vinyl chloride monomer and poly(viayl chloride). Environ Health Persp 41:85-88. 'Maltoni C, lefemine G, Ciliberti A,. Cotti G, Carretti D (1981). Carcinogenicity' bioassays of vinyl chloride monomer: A model of risk assessment on an experimental basis. Environ Health Persp 41:3-29. Marsteller HJ, Lelbach WK, Muller R, Juhe S, Lange CE, Rohner HG, Veltmaa G (1973). Chronic toxic liver damage in workers of PVC.producing plants. Deut Med Wochschr 98:2311-2314. '' ' Marsteller HJ, Lelbach WK, Muller R, Gedigk P (1975). Unusual splenomegalic liver disease as evidenced by peritoneoscopy 'and guided liver biopsy among polyvinyl chloride production workers. Ann NY Acad Sci 246:95-134. Kastrangelo G, Saiu B, Marcer G, Piazza G (1981). Epi demiological study of pneumoconiosis in the Italian poly(vinyl chloride) industry. Environ Health Persp 41:153-157. Masuda Y (1979). Long-term mortality study of vinyl chloride and polyvinyl chloride workers in a Japanese plant. Arh hig rada toksikol 30:603-409 (suppl). Miller A, Teirstein AS, Chuang M, Selikoff IJ, Varshav R . (1975). Changes in pulmonary function in workers expos ed to vinyl chloride and polyvinyl chloride. Ann NY Acad Sci 246:42-52. Honson RR, Peters JM, Johnson MK (1974). Proportional mortality among vinyl chloride workers. Lancet 11:397-398. National Institute for Occupational Safety and Health CU.S.)(0ctober, 1982). Reported cases of angiosarcoma of the liver among vinyl chloride polymerization workers. (Unpublished). Nicholson WJ, Hammond EC, Seidman H, Selikoff IJ (1975). Mortality experience of a cohort of vinyl chloride- polyvinyl chloride workers. Ann NT Acad Sci 246:225-230. Nicholson WJ, Henneberger FK(19$3). Trends in cancer mor tality among workers in the synthetic polymers industry. This volume. Ott MO, Langner RR, Holder B8 (1975). Vinyl chloride exposure in controlled industrial environment. Arch Environ Health. 30:333-339.. Popper H, Thomas LB (1975). Alterations of liver and- spleen among workers exposed, to vinyl chloride. Ann NT Acad Sci 246:172-194. Purchase IFH, Richardson CR, Anderson 0, Paddle-GM, Adams WOP (1978). Chromosomal analysis la vinvyl chloride exposed workers. Mutation Res 57:325-334. Reial W, Weber H, Grelser E (1979). The mortality of German vinyl chloride. (VC) and polyvinyl chloride (PVC) workers. Arh hig rade toksikol 30:399-402 (suppl). Rowe VS (1975). Experience in industrial exposure con trol. Ana NT Acad Sci 246:306-310. Selikoff IJ, Hammond' EC, Eds. (1982). Brain tumors in the chemical industry. Ann NT Acad Sci 381:1-364: Smirasova HA (1961). On the question of bone lesions due to ehronic intoxication by olefins and vinyl chloride. Vestn Reaigeaol Radiol 36:63-66 (Russian text). Smith AH, Waxweiler RJ, Tryler HA (1980). Epideaiologie investigation of occupational carcinogenesis using a serially additive expected dose model. Am J Epidem 112:787-797. Sucui .1, Drejman I, Valaskai M. (1963). Contribution to the study of vinyl chloride disease. Med Interna 15:967978. Tamburro CH, Greenberg R (1981). Effectiveness of Fede rally' required medical laboratory screening in the de tection of chemical liver injury. Environ Health Fersp 41:117-122. Theriault G, Allard F (1981). Cancer mortality of a group of Canadian workers exposed to vinyl chloride monomer. J Occ Med 23:671-676. Thomas LB, Popper H, Berk PD, Selikoff IJ, Falk H (1975). Vinyl-chloride-induced liver disease. From idiopathic portal hypertension (Banti's syndrome) to angiosarcomas. N Engl J Med 292:17-22. Tribukh. SR, Tikhomirova NP, Levina SV, Koslov LA (1949). Working conditions and measures for their sanitation in the production and utilization of vinyl chloride plas tics. Gigiena Sanit 10:38-44. Vaxveiler RJ, Stringer W, Wagoner JX, Jones J. (1976). Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Sci 271:40-48. Vaxveiler FJ, Smith AH, Falk H, Tryoler HA (1981). Excess lung'cancer risk in a synthetic chemieals plant. Environ Health Persp 41:159-165. Wilson RH, MeCormiefc. WE, Tatum CF, Creech JL (1967).... Occupational acroosteolysis. J Am Med Assoc 201:577-581. compounds, Hum dioxide. hightir plants i are present and Scntrcio c capable of it important villus Jtarus. .tributed and lulls, among a beans and at1atoxins ' on .....v as -producing J in regions ccarcinomn; ition of food wsc observu!> iimt some rcinogens in !5 parts per .is produces *cd if it cause .mmali in stributed in especially in carcinoma is environment, from amines cs are potent c enough to i animals:*** n use as an nchymal cell laboratory is metabolic derivative is cell tumours c tnith'ojfenie c I249> It ;li> arc to'be vl by thorium . j but a lew 1 l.ikc the >|) following hi dioxide in rotru&t): the HEPATOBLASTOMA; ANGIOSARCOMA t:yt latent period is about 20 years, which is some five years longer than the average latent period before the thorium-induced angiosarcoma becomes mani fest. When administered into the blood stream, the particles of Thorotrast are taken up by reticulo endothelial cells and this accounts for the concen tration of the substance in organs such as the liver. Thorium is mainly an alpha-particle emitter, and this is the source of its oncogenicity. Its long halflife makes it exceptionally dangerous among the radioactive substances that have been adopted us aids to clinical diagnosis; it is seldom used nowa days, and it should not be used at all. In a recently recognized case, a rapidly growing parenchymal cell carcinoma became clinically manifest at the site of a former amoebic `abscess' in the liver: the extent of the cavity had been investigated radiologically, 44 years earlier, with the help of Thorotrast, injected into it as a contrast medium;*^ thorium was still recognizable in macrophages and scar tissue, both in conventional histological sections and by autoradiography. In sum, of the chemical substances noted, only two groups--the mycotoxins and the nitrosamines --merit consideration as environmental factors likely to be of particular importance in the causation of parenchymal cell carcinoma of the liver in man. Parasitic Infestation.--Gonorchiasisfsee page 1236) and opisthorchiasis (see page 1236) unquestionably predispose to carcinoma of bile duct origin, which is a comparatively common disease in those parts of the world where these fluke infestations are highly prevalent. The tumour may arise in any part of the biliary passages but most frequently in the exirtthepaiic ducts. Hepatoblastoma*" The hepatoblastoma is a very rare, highly malignant tumour of embryonic type, comparable to the nephroblastoma, neuroblastoma and similar growths. Like the latter, it is seen usually in the first few years of life. fn exceptional instances it becomes manifest in the second or t hird decade: such tumours are less anaplastic and the prognosis is sometimes good after resection. The childhood hepatoblastomas are poorly differentiated but retain some semblance of trabecular arrangement of the celts, the picture in places often being reminiscent of that of the embryonic liver; early and widespread metastasis is usual. Immature cartilage and bone are found in some of these tumours.*** Angiosarcoma Angiosarcoma (malignant haemangioendotheiioma) of the liver is a rare tumour. It occurs in two age groups, infants and adults. In infancy, the disease often takes the form of multiple, fleshy, pink and white and, in part, very vascular masses that com press the surrounding parenchyma. Microscopical examination shows the tumour to consist of com municating channels lined by one or more layers of large, often bizarre endothelial cells. In most cases the child is under eight months old and the disease presents with enlargement of the abdomen. Metastatic deposits are sometimes found in the lungs and elsewhere.**4 Heart failure may result from the extent of the arteriovenous shunt through the channels of the tumour when the growth is large. In adults, some hepatic angiosarcomas are attributable to exposure to oncogenic substances. Until recently, the only indisputable cause ol-these growths was thorium dioxide, in the form of Thorotrast: the hepatic angiosarcoma is the com monest neoplastic complication of the adminis tration of thorium (see above und page 1253). It has now been recognized that identical tumours of the liver may arise as an occupational disease following exposure to vinyl chloride monomer in the manufacture of plastics.*** This monomer induces similar tumours in rats.*66 The angiosarcoma of the liver in adults may be solitary or multicenlrie, ,and 1 may cause great enlargement of the organ. In about a third of those comparatively rare cases in which there is no recognized history of exposure to oncogenic sub stances the liver is cirrhotic. Cirrhosis is not a feature of the cases in which an occupational or iatrogenic cause has been identified. Micro scopically, the tumour consists of dilated sinusoidal spaces that are lined by large, bizarre cells that appear to be situated on the sinusoidal aspect of the liver plates. Disse's space is lilted with reticulin and collagen fibres and the adjoining hepatocytes are commonly atrophic. Sometimes the growth has a papillary pattern and sometimes there are lurge, blood-filled spaces lined by tumour tissue. Solid foci of anaplastic growth are a feature of some of these tumours.567, S6` The angiosarcoma has been considered to arise from the littoral ceils of hepatic sinusoids,*" but this is by no means proven. Others have regarded it as a KuplTcr cell sarcoma,*** although its charac teristics are not those ordinarily associated with tumours of reticuloendothelial cells. 5 AP00019220 (292 21; THE LlVf.lt Other Sarcomas Various other types of primary sarcoma of (he liver have been described. All are rare, fibrosarcomas possibly least so. In exceptional Instances Hodgkin's disease or other lymphomas arise in the liver and apparently remain for some time confined within it. Metastatic Tumours In the absence of cirrhosis the liver is one of the commonest sites of metastatic tumours (Fig. 21.67). The primary growth is often in part of the ali mentary tract that has its venous drainage by way of the portal vein. Other particularly common sources of secondary deposits in the liver are bronchial and mammary carcinomas. Melanomas also metastasize to the liver with particular fre quency. The incidence of secondary deposits in cirrhotic livers is uncommonly tow.*71 It is possible that the alterations in the .vasculature of the liver that are characteristic of cirrhosis are not conducive to the establishment of metastatic growth. Fig. 21.67, Multiple secondary deposits of carcinoma. The dark eolour of the liver tissue round some of the tumours is due to the local circulatory disturbance that they caused. REFERENCES ANATOMICAL AND PHYSIOLOGICAL CONSIDERATIONS 1/ Rappaport. A. M.. Microvaxc. Res.. 1973, ft. Hi. 2. Kicrnan. F,, Writ. Trans. 3. 1833. 123. 7] I. 3. Mall. F. P.. Antes. J. Anal.. 1906. 5. 227. *. RappaporT. A. M., Borowy, Z. Lougheed, W. M., Lotto, W. N., Amu. Rec., 1954, 119. 11. J. Morgan. J. D., Hartroft, W. S.. Arch. Path. (Chic.), 1961. 71. 86. 6. Elias. H., Anter. J. Amu., 1949, B4. 311. 7. Uo. T., Shibasaki, S., Arch, histol. Jap., 1968, 29, 127. 8. niava, C. G,, Lab. invest., 1964, 13. 840. 9. Farquhar, M. G., Palade, G. E-, /. CeU Biol.. 1963. 17. 375, 10. Lowelutein. W. R., Kanno. Y . J. Ceil Biol., 1966, 33, 225. 11. Lampeft, 1. A., Trenehev,. P.. Holborow, E. J., Virchows Arch. Abt. B, 1974. 15, 331. 12. Lee. S. H.. Tarack. R. M.. /. Cell Biol.. 1961. 39. 723. 13. Wilis. E. J.. J. CeU Biol.. 1963.14. 311. 14. Svoboda. D. J.. Manning, R. T., Antee. J. Path.. 1964, 44, 643. 15. Rcmtner. H.. Atuer. J. Med.. 1970,49. fit7. 16. Trump, 0. F,, Arstilla. A. U.. in Principles of /Win- Molofv, edited by M. La Via and R. Hill, page 9. New York, 1971. ]7. Hruban, Z., Rechnagci, M-. ttu. Rtr. CytoL. 3969, suppl. I. 18. Arstilla, A. U.. Trump, B. F., Amer. J. Path., 1968.53, 687. 19. Beams, H. W., Kessel, R. G., ttu. Rev. Cytot., 1968,23, 209. 20. Wcsscls, N. K.. Sponner, B."S.. Ash, j. F.. Bradley. M. O., Lauduena, M. A., Taylor, E. L.. Wenn, J. T., Yamoda. K. M.. Science. 1971, t7l, 135. Zl. Biava. C.. Lab. Invest., 1964,13, 301. 22, Tru / 23. Sw. 24. We 25. K.i 1 J 26. Fei 1 27. Go 1 28. Da 29. Per I 30. Ok 11 31. n: 32. Lh / 33. Wr 34. La1 35. Ait i ALT 36. Bo 37. Ad 38. As: 39. Oil 40. La 41. st; I 42. Sh 43. Pr- 44. Fi uv 45. Wi 46. Wt Al 47. hi 48. Di 49. Gi 50. W 51. Bi 52. Bl 53. U- AP00019221