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`ftl fmlnare e :oordinc~ ted jinamento :-3. lov. 1977. e 1973. tlmvAHHMi-Helltim aiamrtlcl Fr*u *KB*rr* * M. yj. T.w*. Srrlk ,nd J.H. Konu* ~ti jc^n/i-i/oo) t<m 107 TOXIC PORPHYRINURIA AND CHRONIC HEPATIC PORPHYRIA AFTER VINYL CHLORIDE EXPOSURE IN HUMANS M. 00SSa, C.E. LANGEb and G. VELTMANb M'7 department of Clinical Biochemistry, Faculty of Medicine of the Philipp University, Marburg an der Lahn, FRG. ^Department of Dermatology, Faculty of Medicine of the Rheinischen Friedrich- Wilhelm University of Bonn, FRG. SUMMARY Urinary porphyrin and porphyrin precursors excretion were studied in workers from a PVC (po)yvlnyl chloride) producing and processing plant. Secondary coproporphyrinuria and partial transition to chronic hepatic porphyria were found consistently in workers with vinyl chloride induced toxic liver damage. The pathobiochemical mechanism for the development of coproporphyrinuria and chronic hepatic porphyria Type A is probably based on a toxic disturbance of hepatic coproporphyrinogen oxidase and uroporphyrinogen decarboxylase by vinyl chloride. In medical supervision of VC (vinyl chloride) exposed workers the determination of urinary porphyrins is a diagnostic and preventive parameter, which Indicates toxic injury at an early stage. INTRODUCTION Due to the complexity and a 11-pcrvasive cultural, biological, and medical significance of the interactions between the environment and porphyrin meta bolism, it is not surprising that systematic experimental and ecological studies have been done in widely scattered often isolated fields. Any glooal solution to the problems involved will require interdisciplinary cooperation in the fields of pharmacology and toxicology, agriculture, biology, pathology, pharmacy, industrial medicine and hygiene, clinical medicine, veterinary medicine, clini cal chemistry and biochemistry. Common problems and methods from these varied disciplines have given impetus to a new specialty, environmental health sciences; it is to be hoped that this field will provide a suitable context for continued systematic work on the topic of porphyria and the environment, with emphasis on lead and potyhatogenated aromatic compounds1. Finally, vinyl chloride disease^ should be mentioned: this industrial disease involves chronic liver damage, scleroderma-1 ike cutaneous changes, thrombocytopenia. R&S 023918 R&S 023919 loa eoproporphyrinuria and chronic hepatic porphyria3. (a workers of the noluvinvat phlnr'.Ma fowr\ ~:__,, j_________ SYMPTOMS AND SIGNS OF VINYL CHLORIDE DISEASE2,3 Scleroderma*!ike skin changes Raynaud's Syndrome Clubbing of terminal phalanges Acroosteolyses Liver damage 8iochemIcaI fIndings: Serum values of COT, CRT, AA activities normal or slightly increased 8SP-test pathological secondary coproporphyrinuria chronic hepatic porphyria Type A Histological findings; mild hepatocellular alterations intralobular, perisinusoida1, portal and capsular fibrosis Hemangioendotheliosarcoma of the liver Esophageal varices Splenomegaly Thrombocy topen i a Reticulocytosis material and methods In order to find biochemical parameters indicating toxic effects at an early stage, we have determined porphyrin precursors and porpnyrins in the urine cf bD patients from a PVC producing aid processing plant. Ei-h patient examined showed one or several of the following symptoms^: scleroderma-1 ike skin changes, Raynaud's syndrome, clubbing of terminal phalanges, acroosteolyses, pathological BSP test, esophageal varices, splenomegaly, thrombocytopenia, reticulocytosis. None of the patients from the PVC processing plant showed Raynaud's syndrome, sclerodcrma-Iike skin schanges, acroostcol/ses or esophageal  Ing Industry Inner organs Ic lesions creased at an in the patient na-1 ike `oosteoly>cytopenia, howed esophageal varices. Time of exposition in the group of PVC producing workers ranged from 1.75 to 20 years, in the group of PVC processing workers from 1 to 13 years. At the time of examination 12 of the patients from the PVC production plant had had no vinyl chloride contact for a time ranging from 3 to **3 months. Alcoholism could be excluded as cause for the porphyrinopathies. RESULTS The results of urinary porphyrin studies are given in tabic 2. Nineteen patients exhibited a mild secondary coproporphyrinuria, and in eight patients a moderate secondary coproporphyrinuria was found. Excretion of ,5-aminolevulinic acid was elevated in four cases with mild coproporphyrinuria. In ten patients with coproporpnyrinuria, excretion of pentacarboxyIicporpnyrin was found to be tii the upper range. In a few cases critical amounts of tricarboxylieporphyrin were found. The characteristic porphyrin pattern of chronic hepatic porphyria Type A was observed in three cases (table 2). DISCUSSION The most frequent symptom amongst the patients examined is the elevated coproporphyrin excretion, apart from thrombocytopenia, which can be related in this connection to toxic effects by vinyl chloride. There is no correlation between the amount of urinary porphyrin excretion and the activities of "liver enzymes" in the serum. A better correlation is seen between the BSP test and coproporphyrinuria. In patients who showed the symptoms thrombocytopenia, splenomegaly, pathological BSP test and on whom liver biopsis were performed so far, histological exami nation revealed no changes which indicated toxic influence by alcohol^. The investigations show clearly that the majority of the patients of the PVC producing and processing plants, whose biochemical and scintigraphic findings indicated liver damage, developed secondary coproporphyrinuria sometimes with slight 6-aminolevulinic aciduria. This disturbance of porphyrin metabolism led in some cases, which present an elevated excretion of uroporphyrin and hepcacarboxylieporphyrin, to chronic hepatic porphyria Type A (table 2). It can be suggested that by some toxic processes vinyl chloride diminishes the activity of hepatic coproporphyrinogen oxidase and in some (susceptible?) persons also the activity of hepatic uroporphyrinogen decarboxylase it can not be excluded that the uroporphyrinogen decarboxylase defect is purely toxic in these workers, depending upon dose and time factors of exposure. The results allow the con clusion that the determination of urinary porphyrins mignt become an Important I TABLE 2 URINARY PORPHYRIN AND PORPHYRIN PRECURSORS EXCRETION IN 40 PATIENTS WITH VINYL CHLORIOE OISEASE IN A PVC PRODUCING AND PROCESSING PLANT; Croups: I no disturbance in porphyrin metabolism, II mild secondary coproporphyrinuria, III moderate secondary coproporphyrinuria, IV chronic hepatic porphyria type A. For groups I, II and HI mean values are given. Group 1 (n10> II (n-19) III (n S) VC exposure (years) ALA P6C pmol/24 h (x+s> Total Porphyrins nmol/24 h (x+s) 1-21 2- )8 3-18 25 + 9 35 1 17 26 + 9 3.6 2.1 5.4+ 2.7 5.9 + 2.5 108 26 186 + 26 263 + 53 Uro Kepta >lexa Pen la Copro Tri Proto it) 13 3 1 \k 3 i 12 2 i 3 79 1 +. 4 77 1 4 8C 2 - IV : Patients CHP A 1. G.K.(6l) 13 2. U.S.<46) 7 3. K.H.(26) 3 Upper normal limit 28 19 12 >9 3-5 603 4.4 340 2.6 382 7.5 S30 18 10 17 92 21 9 t 2 1 3 67 1 <1 5 63 1 <| 4 64 1 <1 126820 StffcJ parameter in medical monitoring and protection of vinyl chloride exposed workers. ACKNOWLEDGEMENT The pathobiochemical studies were supported by the Deutsche Forsehungsge- meinschaft (Grant Do 13*0. REFERENCES 1. Doss, H, (1977) Porphyria and environment, in: Clinical Biochemistry and Regulation of Porphyrin Metabolism. Proc. German-Brati1ian Seminar on Medicine and Biomedicine (Rio de Janeiro 1975), DAAD, Bonn-Bad Godesberg, 21. 2. Veltman, G., Lange, C.E., Juhe, S., Stein, G. and Bachner, U. (1975) Ann, H.Y. Acad. Sci.. 2k6. 6. 3. Lange. C.E., Bloch, H., Veltman, G. and Doss, M. (1976) Urinary porphyrins among PVE workers, in: Porphyrins in Human Diseases (cd. M, Doss), Karger, Basel, 352.