Document 2q5OKJwGvEOZkMKRXVJLaV6Gg

k-nii- Q00') TH/iV-Wd o;: An excerpt from clinical research Authors:Frof. Dr. V/. Creutzfeldt Goett. Prof.. Londoj German Medical -Journal - 98 (1973) Paces 2311 - 231^ e-Georg Thiemc Publishers, Stuttgart, ) West Germany * to -* 03 C.hronic-toxic "liver damage in PVC production workers (0 Marstc? l<=>r, W.JC.Lelbach, R.Mueller, S.Juebe,_;C.E.Lsnge,H.G.Rohner and G. Veltmun -.... -r - -- --------* ------------- -- Medical Clinic (Director: Prof. Dr. K.J.Dengler) ^2?`Institute of Pathology (Director: Prof. Dr. P, Gediglc) and 3 Clinic for Skin Diseases (Director: Prof .Dr. A. Leinbrock) of the - Bonn University. Po}yv*nyl chloride (PVC) h?s boon a popular plastic for 30 yesre-. 3 ^ no;; because of its Civej.`o aijpxxvjia uiuu pouaibj.lx tj.es. x t is mere-- $ fore produced in large industrial volumes worldwide, (3) . That ur.- i ^.til 19o6 no observations were mode public in the western; world ccr.- Jj,/corning its chronic toxicity may be attributed to the widely ccccpt- _ ^r^eo belief that the production of PVC involves merely relatively in- Tert substances. I Cl i yThe re-publication of a Rumanian study, first disclosed in 19c3(lS), -v"SH^c'^our years lotcr(l9) deals with afflieetion caused by prolonged con- t \ tact with PVC. The study,citing such affllcctions as e.g. the Raynaud ^7 Syndrome, dermatitis, (scleroderma), thyroid insufficiencies ar.d hope- tomeg3ly pioneered other ucli studies originating froiiT'Prsnce (2,A,; % Britain (7), United States (3,5,6,13,1'!,22) and Germany (8,9,10,17). However these reports summarised the affliction on the basis of 55 1 patients examined as being "occupational acrncsteolysis". More in- depth symptomatology pointing to liver function bisi ur bonces was on ly verified in 8 out of these 55 patients (7,8,9,10). The diagnosis "occupational ocr-oosteolysis" overrules findings mode in 39"-9 in the USSR which re?:a cod verified liver damages to PVC manu facture and which wore diagnosed as more or less pronounced hope tit-- bcs. in 35 out of ^3 patients. Also ignored were the cited Rumanian find ing1; dealing with toxicity related hnpntomcyV les ( in * 50 cud of 163 patient.:-.) (18 anti 19) arid Rue:'inn reports citing, partially reb el ini col "chronic-cpithellal-hepatlbidce in l9x> of workers examined, Results The in several PVC plant workers substantiativc esophageal varices and splenomegaly together with uncharacteristic livcrparenchyma changes and the vague literary reference to "cub-clinical" liver damages motivated us to further pursue the morphological substrate of liver changes by means of laboratory analyses, radiology and scintigraphic examinations, laparotomy and target liver punctures. According to this procedure 20 out of ^5 autoclave workers in a PVC manufacturing plant between the ages of 30 to 56 and whose ex posure- to the chemical varies from 1-1/2 to 21 years, hove been examined to date in order to determine the presence of liver ir regularities. Tables 1 and 2 present corresponding findings. In addition the following parameters were rc-examlned, in most in stances more than once, and found to be near normal or normal: R&S 131150 Sedimentation tests, hemograms, sugar tolerance, tests, urine analys es, Lues reaction tests, cholinesterase tests, acid phospha tases, serum iron and copper, thymol, albumin tests and electro- phoretically divided sub-fractioning; cholesterol, S-lipoprotein,tri glyceride and plasmatic coagulation factor testing. To define sclero derma the following immunology parameters were analyzed: Rheumatic factors, anti-nuclear factors, LE cells,immunoglobulin fractions G A and M, complement fraction JH A and cold antibodies. These analyses were however later abandoned as it became increasing^^ !a 4" \"s ^ W (4 4 vs A 1 A aIp VS A 1 *SA *A A Atin4>vtAl 4 a f cttN A St ^ M a M P v/ere consistently negative. Only one patient examined showed signs of cholelithiasis (case 15) ; a changeable solitary concretion whose discharge was not obstructed. According to test results indicated in Tables 1 and 2, it may be deduced' that in most patients' coses neither the biochemical para meters followed to determine liver function nor laparoscopic and histological findings warrant special attention. The in, isolated cases found deviations from the normal were all very slight, incon sistent and ambiguous. Only a combined study of liver profiles and related histological evaluations acquired any significance when ap praised on the basis of job-related exposure to a given product(sj, otherwise such findings might be regarded as rather insignificant anamnesis. The outline of attention-worthy findings according to frequency of occurrence (Table 3)shows, that,in the grouping pre sented, the designated acroostoollysic was not the main symptom of occupational diseases within the PVC manufacturing field (2-0, 13,lA,22) but thrombocytopenia.and more or less pronounced chronlc- toxicliver damages (121 with splenomegaly and slgnb of portal hy- pertension in'some cases.------------ ---- - ... -3- Conclusions: Since it has been impossible to compile on?/ meaningful data relating to work-area concentrations to date and since our knowledge of olie PVC production process is only sparse, ques tions concerning etiological relationship and pathogenecity remain unanswered for the time being. The morphological picture Is however linked to acceptance of chronic-toxic liver impairment as might result from e.g. con tinuous or repeated contact with chlorinated hydrocarbons. Aside from other -as yet unclear subjects is the formal genesis of liver function changes and one question stands out from ot hers namely the question of why portal hypertension occurs in some cases. This point is of special theoretic and practical clinical interest. Classification of these cases in the cate gory of intra-hepatic, pre- or intrasinusoidal block formations and howr this relates to the histological picture on the basis of'septal fibrosis in the portal canal and system; fr. bro; 'with collagenisation of the sinusoidal murals (I,11,i6,l0) a; encoun tered in these cases has not been conclusively defined use of the fact that portal'vein pressures in these patleu .,ds not ' yet been measured. The relative frequency of slight to pronounced sol* omegaly en countered, points to asbu..option of liver fibrosis. Corresponding preventive clinical studies in other P'rC manufactur ing facilities and processing plants appear to warrant action. Periodic and subsequent checking of our patients er.d extensive animal experiments to gain more in-depth knowledge of cause and prevention are planned. l) From a total of - 120 PVC workers from a given plant, to date 45 have been examined in the Clinic of Dermatology of the Bonn University because of skin sensitivity manifestations and also on the basis of prophylaxis. Most of these workers showed signs of etiologicolly undetermined liver function dis turbances according to clinical and/or biochemical tests. By May 1973, 2C workers had been subjected to laparotomy as it was considered that their symptoms 'warranted .such action. Fre quency of liver function impairments cannot be made on this basis, ( R&S 131151 ,1c 1 Mi/wp.i"; i , clin3 enl :>rid bJ o r hr-mi cn 1 fi i i 711:; obtnli.cd . i-'.:-. As r -' * blUrusi:!, ts*anr:ii:.j iinrt' and a Ileal Inc j-husphi-taco, n v: cr oc"1 v.-d 6 analyses and 2 a no ] y:.os ittc mace' t.o determine liver lincl. J one c;i the bncia d^H uj.: bi'omophthaleln sodium or die,odium phenol tcti-abromophthsleln. JJ aO 0S CO <h o *-( 4-> 0 V) 40 81 C> 0. 0, 2 Q d O0 CO c O J-> .c 3O CO 8 4) fl^N H O p Cl CO mU 4) O O (0 O (0 W 0) 0. O O (0 < 8j K >1 Oa O w--- CO i a E <0 c 0 f--( 0 oC 0 0 r( CO S H*C *H O CO wA Q-P rrt-aot tofr-: o E0 WC c6) *0 r-t CJ O. <0 01 03 o +> ou n o. fc. o a) raI x w E xn.-HC Oo El!?!. r-< O lA 8. N JO (0 8f C J-> JO 4> 40 O SHrlJJ C 8t E O -H %-< fi C E *H Q O -H Tl o x; O lA fQ r-t P-4 rH-7 ** ** iH S3 E % H CM To CO CM 0J r-t r-t A A, H o o CO 8 &> to 4C->0 CO JZ wo o a> c rC-tOC-3O" SA C\O ol-l 0 m0 1 E,--- O >ro in N i; H 0d x\ EcA 0 0 ;<(A U r-( O E X K * E 8-<'--' CO & >> rl O O 4J ci O O P O < t\ 1 33 A 3'/i none 2 32 A+ 3V. ii .3 3J A J n 3 1.glass of wine 3 1 bottle beer 5.8 23 3 U.S 19 3 - 1.1 13.1 4 ' 4 41 A+ 3'/t 1 bottle beer U 1.1 g; 19 5 34 A 3 1 bottle beer <' <7 7 31 A+ 18 A+ 16V. 1972 Bill ArostchiteIsI Ca? none 3-*4 bottles veer U 33 ?. 21,4 j 1 *^rt>- I 41 II 17 15 i3 i 51 74 99'119/133 149/ICS/173 62/53/58/70/94 133 37/54/73/74/75 75.il/Sl 39-111/114/210 2jJ 11C'1!9/137 l*3.'i63 175 EO.'fO.?! /100 V.'/45/22 + + + 8 AS A 9 42 A si/ none i / j none 1 bottle beer 1'glass beer 10 31 A 4 none 11 47 A 12 since 1967 hyperlipicamy up to 2 12 56 A+ is (liver function pgif^uroence) bottles beer upper abdomen 2 bottles 8.8 13 u 13.3 23 23 (63) 3 1,7 7.1 (28) 1.5 5.2 15 15 6,1 17/25/30/37/38 2ly3':w23t5niA 92': 32/132 51/87/59/133 ",-'122/115/141 13 35 A 4>/< sensitive to' nonc-pressure beer 1 bottle 7.6 95/144/171 1-4 33 A ncSYse 13 35 A l'/l none 1C 30 A+ 21 1955 Icterus 1963 chronic l.f,d.(*) beer "u 1 glass beer3 1,3 8.5 32 30 (27) ]Ijlili 'll4/132 ' 6.3 17 17 56 115-134/211 8.7 15 15 12-'.';7J/J7fi 187/193 17 44 A 13V. none 1.9 1$ <1 + I'/i right upper up to.2 33 abdomen sensitive bottles (/> CO 19 30 A + 2Vi to pressure 20 30 A + 4 none none * /ijA-,P; beer up to 2 bottles 1.5 3 j,,O C1 CJ1 to 13 6.1 19 17 (47) 8.4 17 7.5 15 15 13S'149'152 151 143'160/189 l5'224 111/157/202 54'12i/IJ7 * A ^Autoclave maintenance worhei's plus other functions in the manufacturing procc ** Figures in parenthesis = values via substrnoptlnized method. * i/1 * i 1 1 Radiol o-', L col .'iivd 1 ;i]);!]'o:'con 1 c- hi:.' lul ogl cal fi icJ Ln,-.:- obtO.1 nod from 20 l'VC orhers (ri\.t t:t t*`t avc: ms 1: 11 e: i s. i c <- v;o rhors) y. - t ?; yr; esophagus (E)or fundus (f) varices Laparotomy Histology T" Signs of capsular centro-lobuiar col.i.agerui: fibrosis, splenomegaly of sinusoid murals,groups fatty degeneration 37 Bo --COt --I. cn CO 2 3 (E) 4 3 Obvious capsular flbro- centro-lobuiar collapse,slight -sis, initial reconstruc- increase collagenlc fibrils in tlon,considerable splerio portal system megaly Obvious capsular firbro- sis,initial reconstruc tion,*red spots and reti culation, splenomegaly Reticular capsular fibro Collagenization of sinusoid sis, hepatomegaly murals, slight fatty deg.of ^regeneration cells, slight starcell sidero sis Slight portal fibrosis,fatty deg', slight starcell activa tion, hydropic swelling 6+ (E&F) 7+ (E&F) 8 Initial to complete re construction, portal hy pertension, ascites,ob vious fcspiexiomegaly Septal and central fibrosis Reticular to surface co vering capsular fibrosis, initial regeneration,ini tial port3l hypertension, obvious splenomegaly Irregular to septal fibrosis, roundcell infiltration into portal system, white blood cell necrosis, starcell acti vation Spotti' capsular fibrosis Indication of portal system fibrosis, isolated fatty de generation 9 Slight capsular fibrosis, Indication of rcptal/portal slight splenomegaly fibrosis, ccnt7'olobulor colie genlzntion of sinusoid mure! fatty deg., slight starcell 10 Obvious capsular fibrosis activation initial reconstruction, splenomegaly Slight septal fibrosis,mas si', collogenizatJ c )i of sinusoid murals n Indicated capsular fibro sis, and possible initial Massive fibre: ! r of the porta reconstruction canals, sept:.!1 intralobular- fibrosis, stive activity not in civic'..-::':'.-, slight dis semination of .fatty deg. 1?f . 13 Ik 15 16 17 -' 18 iy 20 Irregular capsular fibro -* 1 *..: heps tumegsly Sep tel fibrosis in pcrtsO eo:. narrow intrslobihl er ee;-': , Slight choj or; hrwf-j r , 1.5 ghty l disseminated fatty dog. - Slight capsular fibrosis Slight fibrosis in port^^ca nal, slight cholcstcrosis, fatty deg. single cell necro nn n sis, glycogen deposits Isolated intralobular fibrosi massively disseminated fatty cleg. Obvious capsular fibrosis Indicated septal fibrosis in portal canals, massive fatty deg., starcell activation , (grouped) Slight capsular fibrosis Obvious capsular fibrosis -- -- ---^ . - Slight portal canal fibrosis, massively disseminated (small droplet) fatty deg.,slight starcell activation, massive glycogen deposits. Cirrho ti c/s-ep ta l('r c c ons tru c t i o .lumpy cell regenerates Fine to medium granular re construction Uncertain paunoiogical'finding Septal fibrosis, massive col.* genization of sinusoid murals widely disseminated fatty do slight starcell siderosls. m Indicated spetal fibrosnW^ slight (large droplet) fatty deg.,slight starcell activa tion - Hepatomegaly, questionable re construction, fatty' deg.in the liver Indicated septal fibrosis/ portal canals, massively dis seminated (large droplet) fr. ty deg.,single cell necrosis starcell activation R&S 131154 R&S 131155 Table 3.- Frequency of pc tholoy'.. cel f1 nd i i i in <:0 (' \a)!>:.era Symptoms Increased pbenoltetrabromophthalein retention Thrombocytopenia Liver-spleen changes determined via laparorrhaphic tests * ' Splenomegaly in selective spleen'iscintigrams (present in 2 patients1 liver-scinitgram as well) Clinical splenomegaly Clinical splenomegaly Acroosteolysis ' , -. , Esophageal varices (2 patients also showed signs of fundus varices) Count 19 16 14 7 7 6 U * All 19 cases showed signs of slight to massive hepatic changes, according to-histological findings. 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