Document BRzB3EY8Jmb3gxy5knr08GRoJ

Figure 3A, B. in PstJent 2 an 26 February 2974 (A) ira) 16 October (3) show tumor in tin right lob* (arrows) and tortueatty of ttW IntrshepetJc vessels. C, 12. Antam- posterior and 1*1wa! fwpstk ?e*n in Patient 2 on 14 Match 1974. Th* large tvmW (a a^Vc. f nr. filling defect within tha right Job*. ated chemotherapy wy/wizli nadir leukocyte counts befweeu 2000 nun' and 3000 tms?. and nadir platelet counts ot approxi mately 80 000 mnrV-fccauce &/ tbc dose-iututing cardiac toxicity of adrtamycin, the $en* received a maximum total dose to 480 mg/m\ and tie is*t dote >vas given on 27 August 1974. He bad transient eiT/?-:ist2s of *&!& pfaetphaisse during April and May t? vs'<v-.<&.t6. with the resumption of heavy alcohol intake. \VisA 'a - liver function returned to nor mal, and the patiezu rc^KitiScJ scymptotcalfc. The patient war readfUiiTtei,!-itf -October 1974 for reevalostion. Repeat angiography and `fienotindicated persistent lesions with out definite chang? in Repeat liver function tests had normal findings excep? BSP retention of 9% at 45 minutes. Because cf the total ('sue bmitstioss of adrtamycin, the patient was started on ia'cimltis^rcyclopboapharaide chemotherapy. The patient dkd u> March 1975 of missive intra-abdominal hemorrhage resulting ftum'a ruptured angicsarcoraatous cyst in the liver. At autopsy, there'ww-extensive angiosarcoma in both lobes of the liver, wttij d'-ttet extension to the diaphragm. Metastases were found in regional lymph nodes, lung, skull, and scalp- searched for autopsy and biopsy tissue from past and pxw** cm employees. Several abnormalities were repeatedly set* .1 in these tie?u*s including angiosarcoma of the Uver, portal fibrosis, esopliageal varices, and splenomegaly. Thera tftA 'i obvious potential interrelations among these abnormality* ; Pertinent findings from the first eight positive cases t tested by this search are summarized is Table 1. All p* ' tienta had had a relatively high exposure to the chesucds-i used in plastic production, especially vinyl chloride Furthermore, there was a very long history of exposure to '* these eight workers: more than 10 years in seven cases aari 20 or more yean in five. .s Figure 4 shows the proposed screening method. Berea ; hundred eighty-three employees have had many of tor. appropriate tests in rids program. However, some of tot*'* proposed segments cf the program have not yet bea [; st&ned. We are now doing, a wide range of tests, but tof 'n results are constantly being evaluated and the props* modified to use those tests that prove most sensitive ani - specific. Some of the more elaborate studies done in pw - tients with known liver disease are specifically intended ' net only to be of diagnostic value, but also to provide b> * formation about the pathophysiology of liver injury in toil- - population. Appropriate consent is obtained for s0 pfW;s csdufes. Besides the studies shown in Figure 4, other tsefl \* are done when indicated, for example, HB,Ag and HBAg to rule out viral B hepatitis, reticulocyte counts lf.*S hemolysis to suspected, and so forth. f '` `Sjfl All employees of the piaot have now been tested, son J of them several times, with a standard SMA-12, aagmesto&-r| by an SOFT and gamma-glutamyl transpeptidase (GGTFV^I As noted in Figure 4, a liver/spleea scan is also roudo^ w To date, 650 scans have been done, 193 in workers fit*' areas with high vinyl chloride monomer (VCM) expw* 4 (high VCM) and 457 in employees with low vinyl chloride, monomer exposure (low VCM). Among the signifies^;'' abnormalities reported in these scans are decreased beprtto uptake, defect within the liver, and splenomegaly (TsSto- 2). The total percentage of abnormal liver/spleen seanstov the high-VCM workers (12.4%) was comparable to tori'in the low-VCM group (11.8%). The only signifiesat rifr. ferenee between these groups was in hepatic filling defeat* which were almost three times more common in the tosgto^ industrial Screening Dr. John Creech*: Data were obtained from examina tion of approximately 1200 employees of a plastic and rub ber manufacturing factory in Louisville. Kentucky. The chemicals most often used in the manufacturing processes at this factory were vinyl chloride, vinylidene chloride, and vinyl acetate for plastic production and butadiene, acrylo nitrile, and styrene for rubber production. When three em ployees were found to have angiosarcoma of the liver (8), an intensive study of the health of both present and former employees was begun. Two major routes of investigation were undertaken. Before the initiation of a surveillance program to screen for liver disease among present employees, investigators * CUaial Auodm Prefmor, Deponent of Surge*?, Univwitt? of Louwrille, LouisvtUc, ferae*?. > Tabte 1. Hepette IMm in Werinre in LeutwiBa, Kenbftfcy. Hth Exposure to Vinyl Chloride: Fnturee of the Flret Bftt W* Patient Duration of Exposure fit 1 21 2 30 3 18 4 29 5 14 6 28 7 24 86 Runary Disease Found Angio Penal sarcoma Fibrosis i 4* ' + + 4- + -- + + + + 444+ Associated Findhagi Esophageal Sffe* Varices e* + *4 --+ 1 -- +4 --' 4- -- 720 Jvn* 197S Armais of Intomil Motfiein* Voiuma M * Number t RSV 0012104 :7.n I 1,"ll jmT V :*>.; __! -sSe-i I <: --mm ' Li~fl . ! J_ 1 4W ?* - .s.%. I 4> A program tor the systematic eoaanlng <* lh*r dltoa-- `krinyt diforida workers (cm text for details), A* indicated by an tha frequency of routine screening ft determined by the ' ptw* c# exposure to vinyt chloride monomar within ttia plant. ,'CfCscamptata Mood taunt; Q1 = gestrelnteetinel; LFTssthrar 'ttartltn taaC SOOT = aarum glutamic oxaiecetic treneamlirese: -'IQPTsaanim glutamie pyruvic transaminase: GQTPss gamma* .-'pxttmyt tranapaptidaaa; LOH = lactic dehydrogenase; Aik. PToaa = r^dBiina phosphetaae. _ ^ VCM group (Table 2). Filling defects included not only `'l*gio*afeomas, of which there were two, but also lesions ; igpsrently produced by a prominent porta hepatis, vmscucllW abnormalities, or even congenital mal-location of the bladder. These diagnose* were ultimately confirmed by xj or oral cholecystography, or both. In our the moat common explanation for false-positive liver ,`gaas was benign vascular defect . Y-{Sdntigraphy showed enlarged Spleens (> 14 cm in fastest duaenrion) in 55 workert, or 8.4% of the total l^ypup examined. The abnormal spleens ranged from 15 cm 19 cm. Again, the incidence of splenomegaly was no gjptpfor:in workers using monomers other than vinyl chlo ride, principally for rubber production, ihe in those with ^bigb-VCM exposure from plastic production (Table 2). To date, liver biopsies have been done on 47 workers, Lin the high-VCM group and 29 in the iow-VCM group, v'fadfcatioa for liver biopsy has been persistent abnormal ^fading* in the biochemical tests or an abnormal finding "'ar Ibe liver/spleen scan. Fatty tnetamorpbosis of varying , nvuiity has been found in 44%' cf the biopsies from workr. m with higb-VCM exposure and In 34% of those from ';tte Iow-VCM areas. Interestingly, the iow-VCM group has : ibovn s higher prevalence of portal fibrosis (44%) than the high-VCM group (33%^ although these differences ' sis not statistically rigniflrggf, Two more cases of angio sarcoma have been dtagnomd by liver biopsy, both from rakers with high exposure to vinyl chloride monomer. An important part of the program is to determine which lots will beat predict abnormal hepatic histology. Of the patients with abnormal findings from biopsies, 87% bad an abnormal SGPT level, 80% ea abtmnnal SGOT level, , tod 80% an abnormal GGTP level Within oar relatively sail biopsy series, every patient in whom all three of these test* showed abnormal results or in whom plasma indocyanine green clearance was abnormal, had abnormal liver biopsy findings, whereas completely normal values for each of these variables was always associated with a nor- * liver biopsy. Splenomegaly was not a useful predictor of hepatic histology, as the prevalence of biopsy-proved portal fibrosis was essentially the same in patients with normal spleens (50%) as in those wtih splenic enlarge ment (43%). Prospective employees at this plant now undergo our routine biochemical tests during their pre-employment physicals. The origin*! testing of all 1183 employees showed 26% rate of abnormal findings in one or more "liver function tests.** The abnormality rate in the preemployment group, consisting of supposedly healthy men with no exposure to vinyl chloride or other monomers, was 24% (that is, 44 of 181). Alcohol consumption prob ably accounts for some of this high "background** rate of abnormal liver function tests. One other preliminary observation is worth noting. We have recorded elevated inferior vena cavel pressures (> 10 mm Hg) in 21 of 40 patients with splenomegaly or ab normalities in other preliminary screening tests. We have no definitive explanation for this. Based on our own data and those of others, we plan to continue an expanded screening program that will include indocyanine green and bile-acid clearance studies in the initial evaluation. Other tests we may do more routinely are 11} barium swallow for varices and upper gastroin testinal series in patients with splenomegaly; (2] more ex- ~ tensive hemodynamic evaluation, including umbilical vein ^ catheterization for portal pressure measurement and portal a venography to determine the role of portal hypertension in 4 the splenomegaly of vinyl chloride-associated portal fibro sis; and {3} extensive pulmonary evaluation, including pulmonary artery catheterization, pressure studies, and possible biopsy, to evaluate the high prevalence of elevated vena cava! pressures. Dr. Paul Berk: Dr. Creech has been in the forefront of developing a screening program for vinyl chloride workers. Some of the problems he faces ore clearly indicated in Table 3, which summarizes data obtained during admission to the Clinical Center of five workers from two vinyl chloride plants, including the two patients presented in detail here. Three, including the first patient discussed, had significant hepatic fibrosis seen on light microscopy, and, in the fourth, a characteristic pattern of fibrosis was seen with electron microscopy (17). Patient 5 had an extensive angiosarcoma and severe alcoholic liver disease with cirrhosis. Note that only this patient had biochemical abnormalities or defective BSP or indocyanine green metabolism. Table 2. Results of 650 Uwor/Spleen Seans In Worker* Exposed to Vinyl Chloride Monomar (VCM) at a Banks and Rubber Manufac turing Bant Finding High VCM (193 scam) Low VCM (457 scans) Decreased hepatic uptake Hepatic filling defeet Enlarged spleen Total Abnormalities % 1JJ 2J9 829 12.43 2.19 0.88 8.73 11J2 arir at el Vinyl Chloride and ilvar Disease 721 RSV 0012105 Tebfa 3. Laboratory Mi in Vinyl CfclorMo (VC) Unodatart Uw Piaoow. NIH ftortaa Patient Hepatomegaly Splenomegaly Routine Liter Function Tests* 1 -f- + Normal 2+ 3m + Normal Normal 4. 5 -- Normal Occasional increased alkaline phosphatase Normal mean so * Bikinibia. SGOT/SGPT. eikiiin* ptoipbeteee. t Cbantai iadlcativa ef vc iajiwy by leans micteicopy. 45-Minute BSP Retention % 3i 19 11 11 9J <5 Indocyanine Green Rate Contents (min*4) 05 SA mg/kg 017 0.21 020 0.25 0.20 024 023 OlO 022 018 0.03 002 Histologic Diagnosis VC-associated bepaw fibrosa (severe) VOassociaied hepatic fibrosis (severe) VC-a$$ociated hepatic fibrosis (mild) No pathologic diagnewt Angiosarcoma, bepatie fibrosis, curboso The normal values recorded for so many tests of liver function in Patients 1-4, despite tbe significant histologic lesion, pose serious problems for designing an adequate screening regimen to detect liver injury among vinyl chloride workers. Furthermore, as shown by the first case presented, follow-up studies of patients with proven vinyl chloride-associated liver injury, after their removal from exposure, cannot be based on any routine tests now avail able. Tbe suitability of bile-acid clearance studies for this purpose certainly merits further evaluation, as these seem to be tbe most sensitive indicators of hepatic disease that we have, short of liver biopsy. Tbe absence of abnormal ities in so many tests of hepatocellular function probably reflects the fact that the principal anatomic lesion is vinyl chloride-associated liver disease is fibrosis, with relative sparing of tbe bepatocytes. Unfortunately, we have no simple test for hepatic fibrosis without hepatocellular dys function. Epidemiologie Studies: A Cohort Approach Dr. living Selikoff*: With Dr. Creech's discovery last year of his clinical cases of angiosarcoma, we have come full-circle. Since Rehn first reported aniline-induced blad der cancer in 1895, there has bees a discrepancy that has bothered many scientists; that is, although many chemical carcioogens have been identified in laboratory studies, very little human cancer has been reported to be associated with industrial exposure in the vast and growing petro chemical industry. The paradox is, therefore, one of many laboratory carcinogens but relatively few human neo plasms. Aside from bladder cancer due to beta-naphthylamine and benzidine, and coal-tar skin cancers, we simply had not seen much malignancy among chemical workers that was related to occupation. Recently, with the recogni tion of bischloromethyl ether cancers of the lung and upper respiratory tract, our suspicions were heightened, but, until last year when Dr. Creech and associates (8, 9) reported their cases and Drs. Maltoni and LeFemine (12) presented their elegant laboratory studies, we could not explain tfcr discrepancy between our anticipated clinical findings sa4.1 what actually occurred. Recognition of this problem actually began a few J ago, in the mid-1960s, when simultaneous reports cud* from Europe (2, 3), the United States (1), and Graf Britain (4) describing acro-oeteolysis among worker* *' posed to vinyl chloride monomer. Tbe syndrome i> acterized by a Raynaud-like phenomenon, paeudo-clabtaaf of the fingers resulting from the collapse of the temuad phalanx, and local bone resorption. At tbe suggestion d-j the British plastics industry, a study of tbe pathology if.., acro-osteolysis was begun. Rats were exposed to gaseous vinyl chloride in centralions of up to 30 000 ppra. The investigator* (U)-.j reported an interesting set of data on the pathology of ds^J bone changes and also described the appearance of Jjwbd.'-'') cell tumors in the rats. Unfortunately, these findings Jf not receive much attention. w' Such zymbal cell tumor* had been seen with potyeyfe aromatic hydrocarbons, benzidine, and several other c* ctoogenic chemicals. It was perhaps thought that this * yet another laboratory curiosity. Nevertheless, the M*'. changes and some fragmentary information about changes did attract attention, especially because of excellent work of investigators at the University of They found that many of their patients with ecnxtftMfc. ^ ab also had liver disease (7, 18, 19). However, tbsy i*r` ported no cancer (20). That was the state of our knowledge at the end of 19ft j Matters changed in 1974, with the report of three *< of angiosarcoma of the liver among workers at tbe - and rubber plant in Louisvilli (8, 9) and the report* more animal studies (13) that appeared soon after. Vtajl chloride monomer was seen to be a carcinogen both h animal* *od Humana. Because the chemical and its ; met, polyvinyl chloride, were widely used in industry _ elsewhere, it was important to elucidate tbe true dnnefld** * Professor ot Medirinc and Cotaanitjr Medicine; Director, Eaviree- mental Health Sciences Rmiich Center, Mourn Sinai of Medicine, New York, New York. r of the problem. First, we examined and did biochemical tests oa 722 June J97S Annals of Interna! Medicine Velum* *4 Number 0 ' RSV 001^106 a j2d0 workers at three plants, representing three difl&tot sett of conditions and three different sets of ex* jtafCB. These were in addition to the 1200 workers turined by Dr. Creech in Louisville. Only one test, an > tinted alkaline phosphatase, proved valuable in screening l&pe workers for vinyl chloride-associated liver injury, tfcvcnl other laboratory studies that were done showed nsoy other abnormalities, but the overlap with 400 simu)naeous controls and the variability in split samples jcadered them inefficient as diagnostic aids. We found no 7 aide predictive of either liver injury or angiosarcoma . (J). Whether ultrasound (24 ) or liver scanning will ulti' nalely prove to be of greater help, we do not know, v; When angiosarcoma of the liver was described, we all appreciated that it was, in general, rare. There has been > one established case of angiosarcoma in 52 000 coo* - Mtutive autopsies at the Los Angeles County Hospital. A March of the files at the Bronx Veterans Administration '.-.'Hospital showed not a single case of angiosarcoma in )0 000 autopsies. We saw a significant number of cases < ttdy at Mount Sinai Medical Center in Dr. Popper's files, __ where one can find everything hepatic, culled from many -sources. * 7 Besides vinyl chloride, at least two other chemicals were known to cause hepatic angiosarcoma in man: thoroCast (22, 23) and arsenical*. Arsenical-induced hepatic < Mfjosarcoma had been seen among vineyard workers ex- arsenical-containing insecticides used to spray the &'ynperines (24), and in patients chronically ingesting in*; oUpnir medicines containing arsenical* (25). Thorotrast ^Mpmarcomas were particularly worrisome. Although the fTanaerial had been used in diagnostic radiology since 1926, '-'Hafisst bemangiosarcomas were not seen until 20 years Thb was consistent with the long period of clinical we knew to be characteristic of most environmental Md occupational cancers. It also correlated with what Dr. (Neck saw in Louisville. The plant had been opened in TfcMfc and the first angiosarcomas were seen in 1968. Dr. CtMBh showed us one case of angiosarcoma seen 12 yean enact of exposure, but most of the others became pMMtt after a considerably longer time. jfMtongfc the plastics industry is relatively new--many segments began operating during World War n-- ten known of vinyl chloride for a long time. The States began producing it on a very tentative fpprimental basis in 1928, and on a small commercial in 1938. However, production has markedly exvn>w only in the past decade. In 1950, the total worldride production of plastics was only about a million and ! tons; in 1970, it was roughly 15 times more. 'tithe question now is whether the current cases of hepatic Igjr--are derived from the small population of I960 workers, or from the full pool of vinyl chloride including those beginning work from 1960-1974. .frjgerience suggests that current cases are derived primarily the early group. Lloyd (26) analyzed the first 19 Rported in this country and abroad. The average of clinical latency, from first exposure to diagnosis, about 20Vi years, with a range of 11 to 30 yean, of the people in this group had begun work is the 1940s and 1950s. The cases of angiosarcoma now being seen are therefore derived from a very small population. Because most of the total work force was first exposed to vinyl chloride in the late 1950s end early 1960s, angiosar comas are not yet seen among them. These and other data have established that vinyl chloride-induced caocer, as well as most other environ mentally induced neoplasms, has a long period of clinical latency. We do no! know, however, if it will be a common problem or in infrequent one. Three groups are studying this, using a cohort approach. First, the plastics industry has mounted an extensive investigation (27). The cohort is composed of all men knows to have worked in the relevant facilities for a year or more before 31 December 1972. Data have been gathered on 8384 men, but, un fortunately, about 1200 men still have not been traced. Thus it is difficult to evaluate the information gathered. Nonetheless, the data now available point to increased risk of cancers of the lung, brain, buccal cavity, and pharynx (27). Although more information is needed for conclusive evidence, the same suggestions have been found in a second study, done at the National Institute for Occupational Safety and Health (28). Our laboratory has searched for information on a key question: How common frill angiosarcoma be among populations exposed to vinyl chloride monomer? At one plant we identified all workers employed there for 5 years or more from the time the plant opened in 1948 to 1964. There were 257 such workers, all of whom have been traced. There were 25 deaths, of all causes. Three died of hemaagiosarcoma of the liver, each confirmed by autopsy and reviewed by Dr. Popper and Dr. Thomas. Thus, approximately I of 8 death* among vinyl chloride workers, at least in this plant, was due to angiosarcoma of the liver. Another death, caused by ruptured esophageal varices, was also related to vinyl chloride exposure. If these data are confirmed by other studies, it would seem that the risk of death from angiosarcoma of the liver will in crease greatly 15 to 25 years after the initial exposure in those who began working with the chemical between 1955 and 1974. In dosing, it is worth noting that until recently, the chemical industry had been making plastics, not doing medical research. We in the medical profession had been doing research, but not paying great attention to the chemical industry. In both instances, changes are being made. Further Epidemiologic Studies Dr. Henry Falk*: The first four cases of vinyl chloride monomer-induced hepatic angiosarcoma identified in Louisville were all in polyvinyl chloride polymerization workers. This is as expected, since the job done by these workers, opening and cleaning the reactor vessels after polymerization, involves the highest exposure to vinyl chloride monomer. Other cases of the tumor have since been identified in workers, primarily among those involved in the polymerization process. We now know of 15 cases Medical Efridctniolofift, Cancer and Binh Defem DtvUlon. Bureao of Epidemlolofy, Center for TXirati Control, U.3. PubUc Health Service, Atlanta, Gcoriia. Bar* at it a Vinyl Chloride and llvar Dlaaasa 723 RSV 0012107 TaMa 4. Cim of Hspstfc AngtoMrcoma m Polyvinyl CWortda PelyrnsriTtolnti (FW) Warfare (U3.) (Canter tor Hum Control. Mtarf* Nouambar 1*74) Fattest* 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Age Race Sex Date of Initial PVC Work yn 52 W M 43 W M 41 w M 36 w M 49 w M 58 w M 45 w M 43 w M 43 w M 40 w M 54 w M 60 w M 45 w M 52 w M 50 w M 6/44 7/52 5/50 11/55 12/48 11/45 1/62 5/45 6/35 10/46 6/51 tO/46 8/44 8/44 9/49 Dau of Diagnosis 4/64 8/67 3/69 5/70 3/73 12/73 2/74 2/74 11/74 4/61 5/68 3/70 3/68 4/74 5/69 Date of Death 4/64 1/68 3/69 9/71 3/73 12/73 8/61 5/68 3/70 3/68 7/74 3/69 Duration from Initial PVC Work to Diagnon yrt 19 15 19 14 24 28 12 28 19 14 16 23 23 29 19 Fluent* I Uircuih V were expoled to PVC at a plant to Loujirille, Kentucky; Paucau 10 terouth 12, in Niagara Falla. New York; Paucau U 14, m 5oud> Ctaartenon, Wear Virginia; and Patient 13, in Poll*town. Pcsniylvuia. in the United States (Table 4), 9 is workers at the Louis ville plant and 6 at three other plants. Of particular con cern is that cases seem to be increasingly more common in recent years. Table 4 shows several important epidemiologic features. The latency period, as reviewed in detail by Or. Selikoff, is quite long. The duration of exposure for most of these workers is equally long. However, Patient 3 worked with polyvinyl chloride only 4 years and developed a tumor 15 years later. This suggests that relatively brief periods of exposure can be significant, and that, once started, the carcinogenic process may not always be reversible with removal from the monomer exposure. It has been widely assumed that the highest sustained levels of vinyl chloride monomer exposure occurred in the early years of the industry (1940s and early 1950s), and that most of the patients bad begun work during those yean. Patient 7, however, first began working in 1962, and, therefore, the carcinogenic risk factors were still present in the early 1960s. Most cases of spontaneous hepatic angiosarcoma (and other hepatic sarcomas) occur in older sge groups, whereas, despite the long latency period, the vinyl chloride monomer-induced cases occur at a relatively early age for this type of tumor. Is the epidemiologic study of these initial cases, two important questions arise: [1] Why is the disease more prevalent at the plant in Louisville; and [2] Why, in par ticular, did it develop in these 15 workers; that is, might factors such as chemical exposure, work patterns, or past medical history serve to promote or accelerate the develop ment of angiosarcoma in these particular persons? The Louisville plant, which opened in 1942, is the second oldest polyvinyl chloride polymerization plant in the United States. Only seven such plants started operating before 1950, and the four plants in which cases of angio sarcoma have occurred are in thia group. The age of the plant is, therefore, important, and this probably relates to both the long latency period for the'disease and the less stringent precautions for working with the monomer that pertained in the early years of the industry. Many of these cases of angiosarcoma were initially mis diagnosed. Most were called hepatoma or cirrhosis, and it is only with a full review of mortality data, including re-examination of autopsy or biopsy tissues, that soon cases have been uncovered. Moreover, the last three cue at the Louisville plant were identified during intenun screening programs, as described earlier by Dr. Creech. Therefore, this initial clustering in Louisville may be only artificial, and, with continued surveillance in the industry, a more uniform distribution of cases may become ip parent. On the other hand, there are specific conditions in the Louisville plant and in the 15 reported cases that may ba - significant in the early appearance of angiosarcoma M . these workers. There are four polymerization buildings * the plant The two that produce the straightforward pdf* : vinyl chloride resins show the least relation to the cases si angiosarcoma, whereas the two that produce more complex ``j products have a stronger relation (14). One of the latte? - two buildings produces polyvinyl chloride latex (at aqueous suspension of polyvinyl chloride), and the wort >; practices in this building differ slightly in that it takes longer and is more difficult to clean these reactor vessels Kn the ones that produce polyvinyl chloride resins. Other factors that might also lead to greater exposure wbil* * cleaning a reactor include age and size of the reactor . vessels, frequency of cleaning, and the lining material used in the reactor. Differing work practices related to product and equipment may, fberefore, be important i*;>; the distribution of angiosarcoma. `- '' I) The building most directly associated with the ugfe* J* sarcoma cases is the one where copolymen and terpolf*; ? mere are produced. In this process, vinyl chloride monomer and other monomers are polymerized together to produce ' polymers with different qualities. Several of the monomefl ;* that are reacted with vinyl chloride monomer, such to A* vinylidene chloride (vinyl dichloride) and acrykmitrito (vinyl cyanide), have similar structures and cbeinfrl - jj 724 Jun* Annals af Internal Matfielna Voium* S4 Number 6 RSV 0012108 j^ldtibtia. The sax workers in other plants were- also ^opened to these end other vinyl compounds. One man in 'In Niagara Falls plant worked in the polymerization of | jotyvinyi alcohol for 5 yean before switching to polyvinyl l&loctde. Since knowledge about the long-range effects of ietut of these chemicals is scanty, we must consider the ppoibility that they may interact with or enhance the , effect! of vinyl chloride monomer. Thus, these initial cases jasy be related to exposure to multiple chemicals, and in !:-psrticular, to the vinyl chloride monomer--vinylidene (blonde mixture, which is found mainly in the Louisville plant t Chemicals similar to vinyl chloride monomer are also oud outside the polyvinyl chloride industry, for example, vinyl fluoride and chlorobutadiene (vinyl vinyl chloride), sod it will probably be some time before we appreciate the foil scope of the hazards posed by this class of compounds. A recent study (26) has also suggested that cases of fflgiosarcoma may not be limited to the high-risk poly- jaerizstion workers but may also occur in workers who ms the plastic resins to produce a variety of plastic prod ucts and in people who reside near polyvinyl chloride- plants, Of the six patients with hepatic angiosarcoma in the - Connecticut Tumor Registry, two lived within the vicinity ef piolyvinyl chloride fabrication plants, one was an ac countant at a polyvinyl chloride fabrication plant, and one (whose tumor, on pathology review at NIH, is classified ; m an indeterminate type of sarcoma and only possibly an tagiosarcoma) worked at a plant where he applied both ^otyvmyl chloride and non-polyvinyl chloride insulation to Vtkctrical wires (29). t Malroni and LeFemine's (12,30) inhalation studies showed that vinyl chloride monomer can induce cancers of the lung, brain, and kidney as well as angiosarcoma. Several recent studies suggest that the incidence of hmg 'cancer, brain cancer, and lymphoreticular malignancies may also be higher in vinyl chloride monomer worker*. .The somber of deaths among the younger workers at these ; polyvinyl chloride plants is still small, however, and con- .teased surveillance will be necessary to confirm these aaso- dsdom (27, 28,31). The most ominous feature of the vinyl chloride studies j the unknown in the future. It is possible that, in time, tre will begin to see not only more patients with angio- nrcoma, but also significant numbers of patients with other, ss yet unrecognized, manifestations of vinyl chloride . monomer-induced disease. And we do not know whether, ,ia what has been called the "plastics age," related chem icals will pose similar hazards. ^ * Metabolism of Vinyl Chloride ^ Dr. P. G. Watanabe*: Angiosarcomas, zymbal gland carcinomas, and nephroblastomas developed in rats ex posed to from 50 ppm to 10 000 ppm of vinyl chloride monomer 4 h per day, 5 days per week, for 12 months (12). The rats were observed until death occurred. The . incidence of tumors at 50 ppm was less than that predicted Torieotovr temrefc Laboratory; Daw Cbnoted Co., MMUnd, kfiebifta. Dr. Watanabe* uaociatea la ttaae nwUm wen Drw . E. Hdarr. JrH G. JL McGowan. aa4 P. I. Oahrias. from a log dose-response curve generated from the tumor incidences at higher exposure levels of 250 ppm to 10 000 ppm. Because the tumor incidence at SO ppm was lower than expected, and since vinyl chloride monomer per se b not a potent alkylating agent, we thought that the car cinogenic potential of vinyl chloride monomer might be mediated through the formation of reactive metabolites. Therefore, studies were designed to elucidate what happens to vinyl chloride monomer after it is inhaled. A 4.7-litre Plexiglas inhalation chamber was designed and constructed to that four rats could be simultaneously exposed to various concentrations of vinyl chloride mon omer. To minimize contamination of fur and skin, only the nares of the rats protruded through a rubber mem brane into the chamber. The appropriate initial concentra tion of vinyl chloride monomer (Matheson Gas Products, East Rutherford, New Jersey, 99.9% pure) was generated in the chamber at the start of the experiment and contin uously analyzed by circulation through an infrared spec trophotometer. Carbon dioxide was continuously removed from the recirculating system by absorption on an Aacarite* (Arthur H. Thomas Co., Philadelphia, Pennsylva nia) column. Filtered air was metered into the system to re plenish the oxygen consumed. Since the amount of air consumed was within -- 10% of baseline for all experi ments, respiratory variables were not significantly changed during the approximately 1-h exposures. Rats used in these studies were Sprague-Dawley, Spartan substrain (Spartan Laboratories, Haslett, Michigan), ranging in weight from 165 g to 200 g. Disappearance of vinyl chloride monomer from the recir culating inhalation chamber, resulting from uptake and sub sequent metabolism, occurred according to apparent first order kinetics as described by the formula: dc ------- ---- kC dt In this equation, C is the concentration of vinyl chloride monomer (ppm) at time t (minutes), and k (minutes*1) is the rate constant for the decline in vinyl chloride monomer concentration. The rate of disappearance of the monomer and the corresponding half-life (t*) were calculated from the slopes of the log concentration-time curves. The rate of decline of vinyl chloride monomer in the empty chamber due to nonspecific leakage was also determined at each initial concentration, and the disap pearance rates in the animal studies were corrected for tins loss. The rate of disappearance of vinyl chloride monomer from the chamber was slower at concentrations of 1000 ppm than 50 ppm (Figure 5). Other experiments using initial concentrations ranging from 50 ppm to 105 ppm of vinyl chloride monomer showed a linear disappearance with a rate of (8.03 3.40) times 10** minutes*1 (mean so), corresponding to an average t* of 86 minutes. At initial concentrations of 220 ppm to 1167 ppm of vinyl chloride monomer, the rate of disappearance was much slower (2-65 * 1.35) X I(H minutes*1, corresponding to an average t* of 261 minutes. Assuming that the rate of disappearance from the inhalation chamber was primarily Sark it J. Vinyl CMorMi and llwr Otami 725 'M*i4rM in i RSV 0012109 olized predominantly by a single pathway that, we hah speculated, may involve alcohol dehydrogenase. Hove** it concentrations exceeding 220 ppm, this pathway be comes saturated and the significance of secondary pa4 ways, presumably including microsomal mixed fuadfel oxidases, increases (32). $ Dose-dependent processes for the elimination of a ctafft teal are of prime importance in toxicology. Many sew bolie. and excretory processes have finite capacities, as doses of a chemical are increased, these processes fcfr come saturated or overwhelmed. If the function of ta saturated process is detoxification, a disproportionate crease in toxicity may ensue above those doses that cul saturation. Therefore, toxicity occurring with large M of a chemical must be interpreted cautiously, and it dot not necessarily imply that comparable types of toxidQ will be observed at lower doses. j GQtette (33) recently summarized the role of cbemiw reactive metabolites of foreign compounds in tosidm Compounds such as bromobenzene (34) and acetiffliaw phen (35, 36) induce hepatic necrosis only after the ddj is high enough to overwhelm the detoxification psdtwql for the reactive metabolites of these compounds. Om jugation of the alkylating metabolites of these chemiedj with glutathione is a primary mechanism for detoxificitielt Necrosis is induced only after the glutathione teveh m. Figure 9. Overeat*, with tint*, of vinyl cfclerM* monomw (VCM) concentration* in tin inhalation apparatus. Rats war* exposed to initial VCM concentrations of appreximataty 50 and 1000 ppm. Also shewn are th* respective decline* In VCM concentration from tha unoccupied inhalation apparatus. Th# rata constants and half-lives of disappearance of VCM from the system during metabolic experi ments were corrected for nonspecific leakage from the chamber (sea text). a function of metabolism, the slower rate of disappearance of the monomer K concentrations of 220 ppm or greater suggested that the metabolism of vinyl chloride monomer may be a dose-dependent process whereby low concentra tions are metabolized through pathways that, with higher doses, become saturated. Viny)- chloride monomer metabolism was also studied using metabolic inhibitors. Pretreatment of rats with eth anol (5\mg/kg body weight, by intraperitoneal injection) 1*4 Ir"before exposure to the monomer caused almost complete inhibition in rats exposed to 50 ppm, but only a mild inhibition in rats exposed to 1000 ppm (Figure 6). SXF-525A (Smith Kline ft French Laboratories, Phil adelphia, Pennsylvania), a commonly used inhibitor of certain reactions mediated by the mixed function oxidase enzymes, did not inhibit metabolism of the monomer in rats exposed to concentrations up to 50 ppm, but did cause a slight, approximately 20%, inhibition at 1000 ppm. Con sidering these data, we hypothesized that the monomer is metabolized by several different pathways, dependent on the dose. At concentrations up to 100 ppm, it is metab 726 June 1976 Annals of Internal Medicine * Velum* #4 i Humbert RSV 0012110 *3 ft Fw iSkam Flfun 7. LafL Irregular fibrosis of portal tracts and fecal nodular flbrosia of tha hepatic capaula. (Hamatoxylln and eoain: original magnlfl* cation, x 45.) NIH accaaaion number S74-411. Right Portal tract from the aame liver shown in Figure 1. The fibrosis interrupts the limiting plate and extends into surrounding hepatic parenchyma. There is a slight infiltrate of lymphocytes and minimal prolifaration of bile ducts. (Hematoxylin and eoain; original magnification, x 160). NIH accession number 574-411. (Reproduced by permission. Ann NY Acad Set 246: 174-194, 1975.) react with other intracellular macromolecules (DNA, INA, protein, lipids). Although Gillette and others have pot yet attempted to correlate the covalent binding of reactive metabolites to DNA with carcinogenesis, such a reaction has been speculated as a potential mechanism for carcinogenesis. y Recent work in our laboratory and elsewhere, much of it itill unpublished, has included studies in rats on the file of ingested 1*C-vinyl chloride monomer, and the isola tion and identification of the major urinary metabolites of this chemical. The ingestion study showed that vinyl 'chloride monomer is metabolized to polar products that are readily excreted in the urine. These results also sup port the hypothesis of dose-dependent metabolism. The hepatic nonprotein sulfhydryl content of rats exposed to vinyl chloride monomer showed a progressive depression related to the concentration and duration of exposure. Consistent with the sulfhydryl depression, two of the three urinary metabolites isolated thus far have bees identified as thiodiglycolic add and N-acetyl-S (2-hydroxyethyl) cysteine. Thus it seems that vinyl chloride monomer or its reactive metabolites covalently bind with hepatic gluta thione and are subsequently hydrolyzed and excreted in (be urine as conjugates of cysteine. Other studies on vinyl chloride monomer continue to upport the hypothesis that its carcinogenicity is related to the metabolic formation of reactive metabolites. Studies (37-39) have shown an enhanced positive mutagenic re sponse in certain strains of Salmonella typhimurium ex posed to vinyl chloride monomer if microsomal enzymes a fortified liver homogenates are present. The metabolites f the monomer identified in the urine of rats exposed to the chemical indicate that the primary deactivating mech anism is by conjugation with the hepatic -nonprotein sulf hydryl compounds, glutathione and cysteine. Our current research is directed toward further elucidating the metab olism of vinyl chloride monomer to reactive products and their potential to bind with intracellular macromolecules. Resolution of the metabolism and pharmacokinetics of vinyl chloride monomer will undoubtedly be of great help in resolving its hazards and will ultimately provide a scientific basis for guidelines concerning tolerable levels of exposure. Histologic Features: Hepstie Fibrosis Dr. Hans Popper*: Only little more thari half a year ago, 1 became acutely aware of an effect of vinyl chloride exposure on the liver when, within 1 week, three persons called this connection to my attention. Doctor Lelbach from Bonn, Germany, sent a reprint about a peculiar intra lobular. fibrosis of the liver seen by peritoneoscopy and liver biopsy in workers exposed to gaseous vinyl chloride (7); Dr. Seltkoff called me and asked what I knew about hepatic angiosarcoma, a rare tumor newly observed in the same type of workers in this country; and Dr. Thomas, here in Betbesda, showed me histologic slides from several such workers. Subsequently, 1 have had the privilege of studying, with Dr. Thomas, a large amount of histologic material that been collected in the Laboratory of Pathology of the National Cancer Institute. The following report is based on this cooperation, and, I hope, shows the heuristic value of environmental pathology (40) in rapidly assembling information that might enlighten other areas of pathology and medicine. - Ciatavs L. Lory Ditto(uiihed Sarvica Prafoaor, Mew Sinai School o< Mediant. Ntw York, Ntw York Berk *t el. * Vinyl Chloride and Liver Disease 727 RSV 0012111 - .. " 'W , Figure 4. Irregular. focal dilatation of htpatlc atauaoltfa. Tha six* and number of the sinusoidal lining cells are increased. The hapatocytei also vary in size and fecalty appear to bo proliferating. (Hematoxylin and eoein; original magnification, x 400.) NiH eoceseion number S74-415. Id reviewing 'the serious hepatic lesions encountered in vinyl chloride polymerization workers, we saw that two distinctive lesions were prominent. One, angiosarcoma of the liver, has been the focus of most of the attention in this study, and its histologic features will be presented by Dr. Thomas. The second ia characterized by a peculiar form of hepatic fibrosis, which, in many instances, was initially diagnosed as cirrhosis. In some of these workers, the lesion was associated with portal hypertension and variceai hemorrhage, leading to the performance of a portacaval shunt, during which time a wedge biopsy of the liver was obtained. In other cases, the lesion was diag nosed on the basis of a needle aspiration biopsy. It is of considerable interest that, ia vinyl chloride workers in West Germany, severe portal fibrosis with significant portal hypertension, splenomegaly, and tbombocytopenia--pre sumably on a spienomegalic basis--is relatively common while angiosarcoma is rare, whereas the relative incidence of these two lesions in American workers seems to be reversed. The typical lesion of vinyl chloride-associated hepatic fibrosis consists of three features (Figure 7). The first is a typical but nondiagnostic portal fibrosis, varying in degree throughout the liver. In places, it seems aggressive, in that fibrous tissue extending into the lobular parenchyma distorts the limiting plate. It also extends into the walls of the portal vein branches, separating their muscular fibers. Sometimes accumulation of dense connective tissue is as sociated with proliferation of bile ductules and periductuiar inflammation. Inflammatory cells also aggregate around some bile ducts, and this pericholangitis might explain the focal canalicular cholestasis seen in some specimens. The second is capsular and subcapsular fibrosis, in a nodular form; it is the most characteristic lesion, partic ularly visible if the surface of the liver is inspected on peritoneoscopy, as reported from Bonn (7, 20). Distinc tion from cirrhosis by gross inspection is difficult. The third type of fibrosis is subtle and reflected in a focal intralobular accumulation of connective tissue fibers, rec ognized distinctly by light microscopy only in connective tissue stains. Electron microscopy (17), by contrast, de tects a'`dense but thin connective tissue coat surrounding the bepatocytes and associated with many fibroblasts ud fat-containing mesenchymal cells--Ito cells (41) or lipo cytes (42)--which have been postulated to be precursor! of fibroblasts (43). This fibrosis differs morphologically from that seen both in chronic active hepatitis and in alco holic liver disease and suggests a different mechanism of development Where the intralobular fibrosis is conspicu ous, it is associated with bulging sinusoidal lining ceils with a prominent diastase-resistant periodic-acid Scbiff reaction of the cytoplasm, which is sometimes granular, as is phagocytosing macrophages, but more typically dif fuse. The bepatocytes show no significant changes excep that is the areas of prominent sinusoidal lining cells, they show variation in size of both cytoplasm and nuclei in that large hepatocytes, sometimes even multinuclear, alternate with small cells (Figure 8). In some instances, particularly in autopsy specimens, regenerative nodules are seen with out cirrhosis. Besides this pattern of fibrosis seen in all specimens, some specimens--both from patients apparently free of angiosarcoma and in two in whom angiosarcoma was later found--a focal irregular sinusoidal dilatation was noted (Figure 8). It did not seem to be related to passive con gestion, since it was not predominantly in the centrolobular area. The same type of focal sinusoidal dilatation, pro gressing almost to peliosis, has been observed in patients after treatment with anabolic steroids (44) and contracep tive pills (45). However, in these latter instances, there have not been any reports of progression to angiosarcoma. In our vinyl chloride cases, the sinusoidal dilatation is associated with proliferation of the sinusoidal lining ctGfc which become enlarged and show bizarre nuclei and, as will be discussed below, progms to angiosarcoma. Thus, we can conclude that this sinusoidal dilatation is a pre cursor to the tumor in vinyl chloride exposure, but we have not yet clearly identified the nature of the cell under going malignant transformation. In cases where we were able to study the spleen, we found it distinctly enlarged, and, particularly on laparos copy, it showed a nodular but irregular type of capsular fibrosis (7). On the cut surface, the follicles were con spicuously enlarged, in contrast to cirrhotic fibrocongestivt splenomegaly. Histologically, fresh hemorrhage was sera in most spleens, although some showed calcification and iron incrustation in the form of Gamna-Gandi bodies. The cords of the pulp contained many erythrocytes, characteristic of hemolysis. The lining cells of the sinuses were activated but, for the most part, not fibrotic. Study of the pathogenesis of vinyl chloride-associated liver injury (46) showed that vinyl chloride or its metabo lites seem to induce a hyperplasia of two types of cells: tbs mesenchymal sinusoidal lining cells in liver and spleen, sod the bepatocytes. In the spleen, activation of the sinusoids! cells may result in splenomegaly, and, in the liver, in fibrosis contributing both to portal hypertension and the forsutioa- 728 Jun*l7t Annals of Intamai Modlcin* Volume *4 HwmbsrS RSV 0012H2 * Figure . Left Sinusoidal pattern of angiosarcoma. Sinusoidal spaces ara iarga and irraguiar. Angiosarcoma calls line those spaces and an* stwat*) hepatic cord celts and an increased number of non-naoptastle-a ppaaring catis in the space of Dlsaa. Bile plugs are present in bile i; canaiieult. (Hematoxylin end eosin: original magnification, x 392.) NIH accession number A74-31. (Reproduced by permission. Ann NY Aced ;: lei 246:268-277. 1975.) Right. Another ares of tha same angiosarcoma shown in Figure 4. Spurlike projectiona of hepatic tissue protect into Y< isigai, more cavernous cystic spaces. The hepatic cords are disrupted_by degeneration of hepatocytes. The tissue space of Oisae contains in- creased collagen and retieuiin fibers. (Hematoxylin and eosin; magnification, x 100.) NIH accession number A74-31. of septa. These septa may progress to cirrhosis. Although vc have not is yet Doted this progression, it haj been ob' served by others. Sinusoidal dilatation develops, and in this setting angiosarcoma ensues. The role of the activation of the hepatocytes, which seemingly form a scaffold, is problematic. However, it is worth noting that we have anecdotal evidence of primary hepatocellular carcinoma in persons exposed to vinyl chloride. While studying these cases, we became aware that pro longed exposure to trivalent inorganic arsenicals, such as Fowler's solution used to treat psoriasis, results in the same clinical and histologic picture (47-49). Histologic examination of two cases made available to us by Dr. Peter Scheuer showed the same histologic changes as in vinyl chloride-induced fibrosis. Moreover, exposure to such arsenicals has also been associated with hepatic angiosar coma (25). In vineyard workers, in addition, it has been associated with primary hepatic carcinoma and cirrhosis (24). The mechanism of toxicity of arsenic has been re ported to occur through its reaction with 6,8-dithiooctanoic arid (o-lipoic add), with the arsenic forming a stable bridge between the two sulfhydryl groups (32). Certain hypothetical metabolites of vinyl chloride formed by the mixed function oxidases would also be expected to react in a similar fashion with o-lipoic acid, possibly explaining the similar pattern of both fibrosis and neoplasia seep with these two superficially unrelated chemicals. Interestingly, thorium dioxide (thorotrast) also produces the same spec trum of lesions (22). The pathogenesis of the noncirrhotic portal hypertension in all these instances may be related to a discrepancy be tween increased splenic blood flow, induced by the hyper plastic splenomegaly, and to the impairment of the distensibility of the hepatic vascular bed produced by the various forms of fibrosis, which by themselves are not conspicuous (50). The fact that this type of portal, hyper tension has been produced by chemicals, at least some of them environmental, suggests that idiopathic portal hyper tension, found ooiy sporadically in the Western world but more often in some areas of Asia and Africa, might result also from toxic, possibty environmental, chemicals. Histologic Features; Angiosarcoma Dr. Louis B. Thomas*: We have reviewed the available pathologic material for a group of vinyl chloride workers who had a peculiar hepatic fibrosis and focal sinusoidal dilatation associated with proliferation of sinusoidal lining cells, la addition, we have studied the hepatic lesions of 15 vinyl chloride workers who developed angiosarcoma of the liver. The hepatic changes described by Dr. Popper were also seen in the nonangiosarcomatous areas of the liver in all cases in which suitable sections were available for review. From these observations, we concluded that a continuous spectrum of changes occurs,, starting with multifocal areas of stimulated sinusoidal cells, followed by increasing degrees of atypia and proliferation of these cells, and culminating in progressively growing, multi centric, infiltrative angiosarcomas (51). Of those patients with angiosarcoma who died and were autopsied, postmortem examination of the livers showed massive involvement by cystic, blood-filled tumors that replaced most of the tissue. The liver weights ranged from 1860 g to 7300 g. The average weight was 4236 g. In the larger specimens some of the cystic spaces were several centimeters in diameter and were associated with large areas of hemorrhage and necrosis. Rupture of these large cavernous cysts followed by intraperitoneal hemorrhage occurred both spontaneously and at the time of surgery, and it was the immediate anatomical cause of death in several patients. The liver tissue was also irregularly re placed by small cysts that varied in size from 1 nun to 1 cm in diameter. Most of them were filled with blood; only CWe/, Laboratory of Tattoology. National Cancer Inatlnitc. Bor* at L Vinyl Chloride and Uv*r Diaoaaa 729 RSV 0012113 a few contained thrombi. The hepatic surface was irregular due to bulging masses of the angiosarcoma, and portions of the liver not involved grossly by angiosarcomas had irregularly shaped areas of capsular and portal tract fibrosis. The formalin fixed livers were dark green because of bile stasis. Microscopic examination showed the angiosarcomas to be multicentric, with several structural patterns. The sinu soidal pattern, illustrated in Figure 9A, consisted of neo plastic-appearing sinusoidal cells that bad enveloped cords of hepatocytes and formed irregular sinusoidal spaces. In these areas, the hepatocytes were well preserved and bilesecreting, with no degeneration or necrosis. Macrophages, fibroblasts, and lipocytes proliferated in the space of Disse. With increased growth of the angiosarcoma cells, the hepatocytes atrophied and disappeared, and the space of Disse was filled with collagen fibers, so that larger, cystic spaces formed. The papillary growth pattern was an inter mediate stage characterized by papillary projections of blind-ending, disrupted hepatic cords extending into the irregular, multilocuiated cystic spaces of the angiosarcoma (Figure 9B). These spurlike projections were covered by angiosarcoma cells that ensbeathed the various other cells in the spaca of Disse and the residual fragments of hepatic cord cells. The cavernous pattern had larger blood-filled spaces surrounded by a thick wall of dense, relatively acellular fibrous connective tissue. These larger, cystic spaces were lined by variable, sometimes quite scanty, layers of angiosarcoma cells. We also observed more nodular, anaplastic focuses of angiosarcoma in some of the liven, but in every instance these specimens also had other focuses of angiosarcoma that showed the progression from sinusoidal to papillary to cavernous growth patterns. Thus, this series of changes seems to represent multi centric development of angiosarcoma, starting with the precursor lesions of sinusoidal cell proliferation and atypia. Some of these precursor lesions progress to the fully de veloped cavernous angiosarcomas, which become clinically evident. We do not have adequate morphologic criteria to . separate the earliest histologic changes of sinusoidal cell atypia and hyperplasia from the progressive, fully devel oped angiosarcomas. As noted earlier, proliferation of hepatocytes and of non-neopisstic-appearing fibrocytes, tipoblasts, and macrophages plays some role in the devel opment of the angiosarcomas. Proliferation of these cells was especially noted in the areas of sinusoidal and papil lary growth patterns within the angiosarcomas. Many of the histologic features observed in the evolu tion of the hepatic angiosarcomas in the vinyl chloride workers have also been described in the hepatic angio sarcomas caused by thorotrast and by inorganic arsenical*. Studies are now in progress to evaluate the similarities and dissimilarities between the lesions produced by these chemicals and the hepatic angiosarcomas of unknown cause that occur sporadically. Summary Dr. Berk: We began this conference with a list of ques tions that I thought might define the .scope of the problem of vinyl chloride-associated liver disease. Although at least some progress has been made toward answering all them, it is clear that there has not yet been enouj progress in fully answering any of them. It is worth recalling that we have been aware of tl problem for less than a year (as of November 1974). Tl efforts presented at this conference represent an outstam ing example of effective, if often informal, collaborate among university, industry, and government scientist which, if pursued at its current pace, is certain to prt vide us in the near future with answers to at least tom of the critical questions. ACKNOWLEDGMENTS: The authors thank Dr. Allan Hofmaa of the Mayo Clinic for helping ua with our bile acid diaappearanc tests: and Dr. Bernardo Kotelanski of the Veieraas Administrate. Hospital. Washington, D.C* for the hepatic vein estheterizatia studies on one of our patients. Received 16 February 1976; accepted 2 March 1976. Requests for reprints should be addressed to Paul D. Berk, M.D. Chief, Section oa Diseases of the Liver, Digestive Diseases Branch National Institute of Arthritis, Metabolism, and Digestive Diseases Bldge 10, Room 40-52, National Institutes of Health: Betbeada, Ml 20014. References 1. Wilson RH, McCoucxz WE, Tatum CF. at: Occupational acrooeteoiysis: report of 21 cases. JAMA 201:577.311, 1967 2. SUCTU 1, DlXJMAN 1, VALASKA! M: Cootributii la Mudtd ImbolnJvrrilor piuduaa de clorura de vriuL Med Interna {Bueur) 15:967-971, 1963 3. Coantxt JM, Fsvaz C, 14 Ftvaa MJ, et al: Acrooateolyw lesions cutanea asiodees cbez deux owners affrciee a ucttoysfB d'autoclava. Cah Med fw 4:14, 1966 4. Haaxa DK, AjmMs WGF: Acro-oateolysis occurring in men regaged in the polymerization of vinyl chloride. Sr Med / 3:712-714, 1967 5. Lius R. Anboson H, Nksouoh WJ, et al: Prevalence f disease among vinyl chloride and polyvinyl chloride works* Ann NT Acmd Set 246:22-41, 1975 6. Fuskxn GA: [Affection of the liver and bile ducts in worker* -rr* in the production ct some types of plastics) (Rua.) Sev Med 28(2): 132-135, 1965 7. Maxstellsx HJ. WK, MuiLxn R, et al: Chrotuach- toxisebe Lebcndudea bei Arbeitera in der PVC-produktica. 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Porrea H: The heuristic importance of environmental pathol ogy: lessons from the vinyl chloride problem. Arch Pethot 99:69-71. 1975 41. Ito T: Recent advances in the study of the fine structure of the hepatic sinusoidal wall. Gunme Rep Med Sci 6:119-163, 1973 42. Beonrnmaiee S, Schafvnei F, Poprs Hi Fat storing cells (lipocytes) in human liver. Arch Pathol 82:447X53, 1966 43. Schnacx H, Stocunou L, Wiwalxa F: Adventibout coo* nective tissue cells in the space of Disse sod their relation to fiber formation. Rev Intern Hepet 17:855-839, 1967 44. Bagkeu hA, Botes JL: Peliosis hepatitis associated with an drogenic-anabolic steroid therapy. A severe form of hepatis ithjury. Ann Intern Med 81:610X11, 1974 45. Poulsen H, WINKLE* K: Liver diteese with periportal sinusoi dal dilatation (abstract). Dlgrttion 8:441, 1973 46. Popre H, Thomas LB: Alteration of liver and spleen among workers exposed to vinyl chloride. Ann NY Aced Sci 246:172194, 1975 47. Viallet A, Guillaume E, Cote J, et al: Presinutoidal portal hypertension following chronic arsenic intoxication (abstract). Gastroenterology 62:177, 1972 48. Motius JS, Schmid M, Newman 5, et al: Arsenic and nonarrhotic portal hypertension. Gastroenterology 66:86-94, 1974 49. Knoll* J, FSsjte* , Roessne* A. et eI: Die nicht-arrbotiscbe porule Fibrose (Hep*toportale Skleraae) nacb chronischer Aneavergitung. Ditch Med Wochenschr 99:903-908, 1974 50. TkoMAj LB, Form H, Beik P, et al: Vinyl chloride-induced liver disease: from idiopathic portal hypertension (Banti's syn drome) to angiosarcoma. N Eng! J Med 292:17-22, 1975 51. Thomas LB, Porm H: Pathology of angiosarcoma of the lives among vinyl chloride-polyvinyl chloride workers. Ann NY Acad Sci 246:268-277, 1975 -,,y. ' j /, ' Berk et al. Vinyl Chloride end liver DJseeee 731 RS V 0012113