Document emZ7pJGnvKeON9j1Kea6n6neq

LIVER DISEASE AMONG POLYVINYL CHLORIDE PRODUCTION WORKERS BFG67488 John L. Creech, Jr., M.D. Laszlo Makk, M.D. BFG67489 ABSTRACT A protocol for systematic testing of all employees of a chemical plant is presented. This factory manufactures polyvinyl chloride compounds and resins, Abson compounds and resins, and synthetic rubber. The results have been reviewed, leading to the discovery of two additional cases of angiosarcoma and 11 cases of portal fibrosis. Two of the 11 cases were found to have developed in other than polyvinyl chloride production employees. BFG67490 1. The 3.F.Goodrich chemical plant in Louisville, Kentucky, manufactures polyvinyl chloride resins and compounds, ABS resins and compounds, and. specialty synthetic rubber. Although there are over 200 chemicals used in these manufacturing processes, the principal chemicals used in the production of the polyvinyl chloride are the monomers vinyl chloride, vinyl acetate, and vinylidene chloride, whereas those used for the ABS and rubber production are butadiene, styrene, and acrylonitrile. These processes are housed in different parts of the factory complex, thus making cross exposure very slight or nonexistent. However, work histories of all employees show that many of the rubber and ABS people have been involved in or worked in the polyvinyl chloride produc tion area at some time or other. Also, the areas of production, other than the polyvinyl chloride production area, may have some very slight exposure to vinyl chloride as in the general plant environment. In an attempt to relate liver abnormality to the degree of vinyl chloride exposure, five categories of work are 8 have been determined: The higher exposure is in the area of (1) polyvinyl chloride production. This is followed in order by (2) other areas of production, including the rubber plant, (3) maintenance personnel for the polyvinyl chloride production, (4) all other _ _ ` <maintenance employees, and (5) All other employocs _ including administration, plant protection, H#1 c o y\r -I r o o a fin . BFG67491 r 2. In 1973 a series of events resulted In a need to review the death certificates of all former B.F.Goodrich employees'; This resulted In the discovery of five deaths due to angiosarcoma of the liver. A review of past illnesses of current workers revealed that three employees had had splenectomy and/or a shunt procedure for hypersplenism or portal hypertension. This resulted in the initiation of a aeries of tests to determine the extent of liver disease in vinyl chloride workers. As Figure #1 will show, the testing was started with a standard SMA-12, which included the SGOT, LDH, alkaline phosphatase, total bilirubin, albumin, total protein, cholesterol, uric acid, BUN, glucose, phosphorus, and calcium. The blood was drawn from fasting employees, then transported immediately to a local laboratory, where the testing was performed. As can be seen, if the SMA-12 was reported as normal, the test was repeated in six months. If only one liver function test (SGOT, LDH, alkaline phosphatase, or total bilirubin) was elevated, the test was repeated in three weeks. Should this elevation persist, a battery of liver function tests was then requested. If two or more tests were elevated on the original examination, the battery was requested without delay. In those cases where the battery showed major abnormality, the special procedures and treatment as indicated were carried out. The battery_of tests is listed in Table #1* BFG67492 3. These included (in addition to the repeat SMA-12) the fractionation of LDH, alkaline phosphatase, and total bilirubin - SGPT, gamma GT, alpha feto protein, ICD, protein electrophoresis; and a CBC with platelet count. X-rays consisted of chest X-ray and liver-spleen scan using Technetium 99M sulfur colloid. I The special procedures consisted of selective hepatic and i splenic angiograms, as described by Viamonte etal in 1970, including free hepatic vein pressure studies and wedge hepatic vein pressure studies, and hepatic vein flow studies^. .A liver biopsy was performed when indicated. The first eight cases requiring biopsies were done at laporatomy. All remaining cases have been done through the internal Jugular vein at the time of the hepatic vein catherlzatlon, using a method first described by Hanafee in 19^7 and more recently by Rosch etal in 1973^*^. In referring back to Figure #1, testing now continues in those cases showing improvement. If the no. 1 battery is found to be normal, the SMA-12 tests are repeated in six months. If there is questionable or only mild abnormality, then the chemical portion of the battery is repeated in three weeks. BFG6749 ' 4. If the no. 2 battery is normal, then a routine SMA-12 is done in three months. But if the no. 2 battery is found to persist or Increase in degree of abnormality, then the special procedures and biopsy are scheduled. Figure #2 will indicate the percentage of abnormalities found on the original examination of 1183 employees by using the SMA-12 tests. 315 Individuals had one abnormal test - 26.6#, 41 individuals had two or more abnormal tests - 3.5#. 75 individuals out of the 315 tested for the second time were found to persist in the abnormality. This represented 6.3# of the plant population, or 24# of the second SMA-12 group. A total of 116 cases had batteries run, or approximately 10# of the total plant population. Fifty-seven of the 116 cases were found to have normal batteries; seven cases were found to have major abnormality, requiring special procedures. Fifty-two cases had minor or questionable abnormalities; ten of these 52 later showed persistent or increased degree of abnormality, leading to special procedures examination. BFG67494 Creech, Liver disease polyvinyl chloride workers 5. The scans which were reported on 116 employees were broken down into five groups: 1. Patchy uptake - indicating cirrhosis or fibrosis. i 2. Enlarged liver - which is of doubtful value. 3. Enlarged spleen - over 14-cm as described by Siegel-*. 4. Cold spot - indicating tumor. 5. Normal liver-spleen scan. The arterial and venous studies were reported as: 1. Corkscrewing of vessels - indicating cirrhosis or fibrosis. 2. Tumor blush indicating tumor. (In angiosarcoma the blush persists for 20 seconds.) 3. Reversed portal flow - indicating portal hypertension with collateral circulation. 4. Portal or splenic vein thrombosis. 5. Level of free hepatic vein pressure. 6. Level of wedge hepatic vein pressure. 7. Corrected Blnusoidal pressure (#6 minus #5). 8. Normal arterial and venous studies. To date we have had 17 cases require special procedures, 16 of whom were biopsied. The nonblopsied case had no abnormal liver tests but showed a defect on the scan which turned out to be a normal functioning displaced gall bladder. BFG67495 Creech, Liver disease polyvinyl chloride workers 6. Table #2 will indicate the location of workers having abnormal SMA-12 examinations. It is seen that there was a greater percentage of abnormalities seen in the areas of production other than PVC, This, however, was of borderline statistical significance. The maintenance and other workers area also showed about the same degree of abnormality. Table #3 shows the location of abnormal batteries. Here the statistical significance is valid, with 10# for PVC production as opposed to 4.1# abnormal for other areas of production. Table #4 shows the percentage of individual abnormal tests of the SMA-12 with regard to location. The alka line phosphatase was seen to be the most frequently elevated test. This could be due to the number of young workers scattered throughout the plant. Fractionation of the alkaline phosphatase elevations shows that only 54# had elevations of the heated fraction of 25# or over. This implies that liver caused the elevation in only 5^# of the elevated cases. Table #5 shows the percentage of abnormal individual battery tests with regard to location. There is no outstanding single test in this group. BFG67496 ureecn, .utver uxuoase poxyvmyx cruorxue womera 7. Table tf6 shows the results of the scan, the special procedures, and of the liver biopsy In 17 cases. Two of the 17 had angiosarcoma. Both are receiving chemo therapy. These two patients also demonstrated periportal fibrosis on the microscopic study of the liver biopsy. As can be seen, there were five liver biopsies reported as normal - out of a total of l6 biopsies. Three of these five were anticipated, as neither battery, scan, nor special procedures showed any abnormality. The fourth case had miner liver function abnormalities with a cirrhotic scan. The fifth had an elevated liver func tion test. Two of the remaining ten abnormal liver biopsies were found in patients who had worked only in other produc tion areas. Both of these patients showed periportal fibrosis, as did the polyvinyl chloride worker. Peri portal fibrosis was the most common diagnosis according to biopsy. Two of the eight remaining had splenic vein thrombosis by special procedures tests. Including portal venogram at time of surgery. Both had esophageal varices; both had large spleens. Biopsy of both livers showed mild fibrosis. The findings have resulted in the removal of 59 employees to areas of no exposure to hepatic toxins. BFG67497 8. There may be some significance to the results of the fractionation of LDH. Isolated factor no. 4 elevations were seen in 66# of B.F.Goodrich employees, whereas there was an isolated factor no. 4 elevation in the hos pitalized patients (other than B.F.Goodrich employees) of only .02#. The reason for this is unknown. Another finding was the very high incidence of elevation of CFK found in the black worker (75) of B.F.Goodrich as opposed to the white (12). I know of no reason for this. Of the seven cases of acroosteolysis tested, only one had an abnormal battery. When asked to stop drinking, his battery returned to normal in three weeks. In conclusion, a protocol for testing has been presented. The results of these tests have been reviewed. It seems that no one Isolated test - be it SMA-12, battery, or special procedures - is adequate for a thorough work-up. It is certain that the SMA-12 or batteries without scan will not predict a cold spot in the liver. It is also true that a scan will not always predict fibrosis. The special procedures seem quite accurate in detecting abnormal pressure studies in the liver, indicating fibrosis or cirrhosis, and may be useful in diagnosing angiosarcoma of the liver (due to the persistent tumor blush). BFG67498 Creech, Liver disease polyvinyl chloride workers 9. It further seems that the battery of more sophisticated tests will need be run on some of the normal SMA-12 group to see if the SMA-12 is a reliable tool in dis covering liver abnormalities or in screening out normal cases. These studies will be continued through the working years of the employee and probably even after his retirement. Undoubtedly the protocol will change as more information is gathered and as research shows a better method for detecting disease, whether it be angiosarcoma, fibrosis, or portal vessel thrombosis with splenomegalla. I'm sure that everyone in this room hopes that manufac turing procedures have been or will be developed to such an degree that these abnormalities will not occur and thus will require no detection. BFG67499 I REFERENCES 1. Creech JL, Johnson MN: Angiosarcoma of the liver in the manufacture of polyvinyl chloride. Jour Occ Med 16:150-151, 1974. 2. Viamonte MJ, Warren WD, Formon JJ: Liver panan giography in the assessment of portal hypertension in liver cirrhosis. Radiol Clin North Am 8:147-167, 1970. 3. Hanafee WN, Weiner M: Transjugular percutaneous cholangiography. Radiology 88:35-39, 1967. 4. Rosch J, Lakin PC, Antonovic R, Dotter C: TransJugular approach to liver biopsy and transhepatic cholangiography. New Engl J Med 289:227-231, 1973. 5. Siegel RM, Becker DV, and Jurley JR: Evaluation of spleen size during routine liver imaging with 99 mTc and scintillation camera. JNuc Med 11:689-692, 1970. BFG67500 *r*s 1 Os t ^PPjSis'sSSS 'X o xi 'V 5-C x {/) <o N . - cs Q- C'v kiy>J5:l,xAi> bt> ^?> 5> JwS$2 'M vx,\- V. -. *vO X, XI y> ^ <o s. V? >1 vb V? ^ <0 x> ^ V> xx Nki X ^$ ^x & X IX X <o 1SJ S( o <x X ^ i ^, X31 *oss-ij XJ &kr< * '* F Sss x ^ $ ^!i&3 v>b5 XS: X v v- X $^ **s5i; {x x \\ s <o I X X x 0- V S; -- J X ; \ Is Cj SSr VI sr Co <o* \ ffe Vl xS x!> srP V* SJ Qi; ^ v5 <^c > X XI N VJ P S XX Vj XC x <j <\! I xx xx 1X^ 'vs.: $ ^PiCbVbvbktCi^yjJ. en < n tn th ( i>vf j 3 O 3 uO\ to if) Q->-. s tr eatm en t ^5 f^3 ^3 C5 ^ ^ Rj \J C<3 TABLE 2 ^0 S3 X IX r BFG67504 & 05 s; v ^ X R) S Q O ^3* 'v - ^5 ^ > J? < $ fe e<3 ^ r^ C^3 C\] ^ TABLE 3 5? . - - K, L% BFG67505 ^ C\$ ^ V) sSs ^ ,v> ^*y> Ni .Vj ^s. ^^ ^ ^ ^ 5^ $ S$ V. b <V) ^s $ t>J N vK *PKi TABLE 4 BFG67506 >5^3 S|^| ^ CO > ^ \0 55 ^ v? * Q $ ^ ^ S N ^5 C>! * co 5> ^ co >3 ^5 N* Csj ll&S v<* Vjr^ S> 5fl> 5? x*' r*5 \># y JJ) V ^3 ^ ^3 l) 8 X^ 3^ C5 C^j ^ ^5 Xt} etj fS^35 ?45 ^^ %S>* Cxi-j Cs ^ s& X ^5 0 ** 5S> 55> ^ .55 55 ^5 ^^^^ ^ ^^^N Sb k ^ ^ ^ g^^ *IKI^ 3el* ^ ^ ^iN K <t ^ [5 if rv Os <^i r^ ff SW ^ tv I =1j1 3: \ <s s d 0 BFG675M7 TABLE 5 55 v BFG67508 j r BFG67509