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kw^./ '>1 w ;:if '-.fXt. . \m medichem K-1711-(100) 1990 m " Vl OCCUPATIONAL HEALTH IN THE CHEMICAL INDUSTRY .^1 Papers presented at the XVII Medichem Congress Cracow, Poland 26-29 September 1989 |K \v IsUV Ifc'v 1 WORLD HEALTH ORGANIZATION REGIONAL OFFICE FOR EUROPE COPENHAGEN I \'- inii- BIOLOGICAL AND HEALTH MONITORING OF WORKERS EXPOSED TO VINYL CHLORIDE T. Popov, B. Galunska, and S. Tsankova Institute of Hygiene and Occupational Health, Medical Academy 5ofia, Bulgaria INTRODUCTION During long-term low-level occupational exposure, a gradual transition from health to illness may take place. The pro gression from health to disease goes through the following stages: absence of effect - compensated effect - early health disturbances - manifest disease. The experience of periodic check-up examinations shows that pathology related to toxic chemicals is easily diagnosed, especially--.when a target-oriented search is undertaken for characteristic clinical signs. These examinations arc thus aimed at finding disease at an early clinical stage. Much more effective, though far more difficult, is the de tection of health impairment. One major constraint on detecting early adverse health effects in an occupationally exposed popu lation is the difficulty of distinguishing a physiologically normal condition from a compensatory pathology. This is at tained by a systematic surveillance of the different biochemical parameters related to the mechanisms of the toxic effect. The choice of adequate tests for biological monitoring in occupational medicine will depend on the knowledge available and the mechanisms underlying the development of an adverse health effect. An adequate diagnostic test may be based on parameters manifesting the primary toxic effect, on the structural changes in the critical organ, or on the functional straining of adjust ment mechanisms induced by the primary toxic effect. Up to the late 1960s, vinyl chloride monomer (VCM) and polyvinyl chloride were thought to be entirely inert. During the 1970s, the situ ation was dramatically altered by reports of different hepatic abnormalities among vinyl chloride workers and the discovery of some cases of angiosarcoma of the liver. Later, the toxic ef fects of VCM were found to depend on its biotransformation to more toxic metabolites in the liver via the monooxygenase enzyme system, known also as mixed-function oxidases (MFO). A direct relation between activity of MFO and toxicity of VCM has been confirmed in experimental animals by a number of authors [1-3]. 189 -vi-' \ . is.. :...r- R&S 024970 V;' , HU ' I Nh -t---".v "" A literature search failed to find any data on the use of MFO activity changes for the purposes of biological monitoring. MATERIALS AND METHODS At the end of 1988, 137 workers exposed to VCM in a polyvinyl chloride production plant were investigated. Of these, 127 showed abnormal findings during the screening of more than 500 workers from the same plant in 1987. In addition, 10 newly employed operators and fitters exposed to higher VCM concentra tions were tested. MFO activity was determined by the method developed by Popov et al. [2]. This method consists of peroral loading with 6 mg/kg aminopyrine (AP) and colorimetric determination of its main metabolites 6-aminnantipyrine (6AAP) and N-acetyleaminoantipyrine (N-AcAAP) in 6-hour urine samples. In the first stage, AP undergoes 'N-demethylation with participation of MFO. The obtained 6AAP undergoes acetylation to form the conjugate N-AcAAP. A target-oriented search was undertaken by a gastroenterol ogist and neurologist for early clinical signs of chronic VCM intoxication. RESULTS Heptomegaly is most frequently combined with deviations in the activity of SGOT, SGPT, GGTP, induction or inhibition of MFO, increased G-6-PD activity, and increased lipid peroxide content (Table 1). The signs suggesting Raynaud-like phenomenon most frequently are combined with MFO inhibition and decrease of re duced glutathione. Table 2 shows the correlation of indices. There is 100% correlation between MFO inhibition and the decrease of the re duced glutathione. The most frequently found correlation is between MFO changes and deviations in the other indices. With regard to diagnostic significance, they are followed by the changes in GGTP, SGOT and lipid peroxides. The subjects varied in the intensity and duration of their exposure to VCM. For this purpose we used the formula proposed by Kassurov for determining the index of exposure: IE = C x T, where IE is the index of exposure, C, the average shift concen tration of the toxic agent on the workplace (in rog/m3), and 190 c ' i.' v - ' < : . ir, -a 'r-VN ~ P w '''VSi. r Table l. Correlation of biochemical parameters with clinical symptoms of chronic intoxication with VCM. Parameter No. of of sub jects nc Devi ation (X) Hepatomegaly n nc X Vasomotor^ disturbances n nc % SGOT 137 SGPT 137 AP GGTP 137 137 AAAP 93 N-ACAAP 92 A-AAP 93 N-AcAAP 92 G-6-PD 118 Vitamin 130 Reduced glutathione 130 Haemolytic resistance 12A Lipid peroxide 131 100 73 109 80 65 A7 2A 18 37 A0 38 A1 9 10 AA 35 30 67 52 69 5A 26 21 56 A3 100 39 109 A3 65 19 2A 11 37 v. 13 38 16 91 A2 35 13 67 25 39 100 38 39 109 A3 29 65 20 A6 2A 9 35 37 12 A2 38 12 11 9 7 50 A A 37 35 13 37 67 26 38 39 21 38 32 32 78 100 37 39 69 27 39 69 32 46 26 9 35 26 9 35 56 29 39 56 25 A5 SCOT = Serum glutamic opalacetic transaminase. SGPT = Serum glutamic pyruvic transaminase. AP = Aminopyrine. GGTP 1= Gammaglutamyl transpeptase. AAAP = A-Aminoantipyrine. N-AcAAP " N-Acetyleamionantipyrine. G-6-PD = Glucose-6-phosphate dehydro genase. nc Number of subjects with abnormal findings.* *Reynaud-like phenomenon. 191 Table 2. Correlation in the deviations from referent values of the biochemical parameters (in %),1 Parameter SCOT SCPT AP CGTP AAAP N-Ac- AAAP N-Ac- C-6- Vitamin Reduced Hacmotyt lc AAP APP PD E / glutathione resistance Lipid peroxide SCOT SGPT AP CGTP AAAP N-Ac-AAP AAAP N~Ac-AAP C-6-PD Vitamin E Reduced x 76 58 11 63 58 0 5 33 A6 X 56 12 26 A8 13 0 28 AO X 13 59 A1 12 0 26 39 X 60 0 0 0 50 1A X 59 X 0 38 53 X 0 X 23 43 20 0 20 X 00 X 53 X glutathione Haemolytic resistance Lipid peroxide 39 A5 38 86 2L 30 100 0 31 32 X 26 n n 16 29 15 0 0 27 17 13 X 6A 66 43 71 56 69 60 0 67 50 56 64 x SCOT = Serum glutamic opalacetic transaminase* SCPT = Serum glutamic pyruvic transaminase. AP Aminopyrine* CGTP s Cammaglutamyl transpeptase. AAAP = A-Arainoantipyrinc. N-AcMP = N-Acetyleamicnantipyrine. G-6-PD Glu ccse-6-phosphate dehydrogenase* 1 T is average time (in minutes) spent at the same workplace. In the cases where the worker had several workplaces with dif ferent VCM concentrations, a summed up index of exposure was calculated. Table 3 shows the exposure-response of workers, laboratory assistants have the lowest exposure followed by electricians, operators, and fitters. The frequency of clinical symptoms of chronic vinyl chloride intoxication increases with length of service. The deviations in the biochemical indices appear sig nificantly before clinical symptomatology. The earlier the de viations are found, the more significant the exposure. The correlation between intensity and duration of exposure on the one hand and the deviations on the other hand is best observed in the group of operators. With the length of service only, the number of the cases with biochemical deviations de creases, while the number of cases with clinical symptoms in creases. DISCUSSION The data offer a reasonable support to our hypothesis that the pathogenesis of vinyl chloride intoxication includes a "trigger ing mechanism" of the toxic effect as well as its development, leading to characteristic clinical manifestations. The high frequency of MFO induction combined with hepatomegaly would in dicate that the triggering mechanism of the intoxication is re lated to biotransformation of vinyl chloride into chiorethylene oxide, an exposidation that occurs with the participation of MFO. This explains the MFO induction as an adaptation to intake of high quantities of xenobiotic vinyl chloride. The MFO in duction in turn, presupposes the activation of G-6-PD as a generator of reduced nicotinamide adenine dinucleotide phosphate (NADPH), a donor of electrons for reduction of cytochrome P-*t50 and its inclusion in the cycle for metabolizing the vinyl chlor ide. Chlorethylene oxide is highly toxic at the site of its formation in the endoplasmatic reticulum of the hepatocyte. The structural damage of lipoproteinic biomembranes is related to abundant formation of lipid peroxides. This also explains the tendency towards exhaustion of tocopherol as a powerful anti oxidant, which renders harmless the generated lipid peroxides. Further, the generated chlorethylene oxide conjugates with the reduced glutathione, which explains the exhaustion of the glutathione. The reduced level of glutathione interferes with the function of the glutathione redox system, which is respon- 193 ;'*7' Vw<; Table 3 Expose re-response in workers exposed to VCH. Years of exposure _Labo catoryj s iis lan t s_ ___ Elitxiian_ '___Operators <1 1-3 3-5 5-10 >10 <1 1-3 3-5 5-10 >10 <1 1-3 3-5 5--10 >10 <1 1-3 3-5 5- 10 >10 With clinical N signs nc I 0 0 0 6 2 01 0 1 0 0 0 1 1 00 0 0 0 0 0 17 50 0 0 0 0 12 8 90 75 0 10 9 22 4 4 13 4 0 44 59 30 2 23 1 77 50 0 36 022 0 67 33 33 13 57 With biochemical deviations N nc 0 0 0 6 2 0 10 1 12 8 10 9 22 30 2 0 3 6 23 0 0 0 5 1 0 1 0 1 3 8 6 5 9 12 1 0 1 6 10 00 0 8 3 50 0 100 0 LOO 25 100 60 56 41 23 50 0 33 67 44 N Number of subjects tested. = Number of subjects with abnormal results. L SZ6fr30 SSH sible for rendering harmless the lipid peroxides. On the other hand, the increased amount of products of lipid peroxidation in blood interferes with the haemolytic resistance of the erythro cytes. The increase of transaminases and GGTP is explained by the toxic effect of epoxide upon biomembranes and on the cytomembranes of hepatocytes in particular. This determines the dis turbance of the permeability and transfer of these enzymes from hepatocyte to blood. CONCLUSIONS The adaptation of the organism to the effect of vinyl chloride is manifested by MFO induction. The functional capacity of a given organ may be increased through structural changes, ex pressed in hyperplasia and regeneration (i.e. increase in the size and number of hepatocytes). A tlinical manifestation of this process is hepatomegaly, a straining of the compensatory mechanisms. Of a special interest is the increase in the number of cases of MFO inhibition in workers with prolonged exposure to high concentrations of vinyl chloride. Without doubt, this ef fect is related to a breakdown of the mechanisms of adaptation. Clinically, it is combined with more frequent cases of neurovegetative syndrome and strengthening of its manifestations. Parallel with MFO inhibition, more cases are occurring with lower content of reduced glutathione (100 %) and higher level of lipid peroxides. These data prove that chronic intoxication with VCM pro ceeds in two stages: pre-clinical and clinical. The first re presents a pre-morbid state, when the absence of any clinical symptoms (including subjective complaints) is combined with changes in a number of biochemical indices. Continued exposure to high concentrations leads to clinical symptoms. The clinical manifestation also proceeds in two stages. In the first stage the clinical symptoms are combined with MFO induction. The second stage is characterized by the strengthening of the clini cal symptoms, when the MFO induction is related by a diametri cally opposed state: inhibition of the enzyme system and fur ther exhaustion of the glutathione due to disturbances in its synthesis. The results of the biological monitoring and targetoriented medical examination show that the frequency and severity of adverse health effects of workers are directly dependent on type of work and length of service.