Document K67XnQDZeaq045xkGgaNewQkX

..7\47:*-,7 K--1711-- (100} .^1 1990 f` 1 *r-W 1^ I &v\ * & Vy ;&>., I 4 -' '., 0; IIi&f-*v-r'-" \l*>f OCCUPATIONAL HEALTH Isjr- IN THEr." * ? CHEMICAL INDUSTRY I $44 \v. ;,,, 4^,., Papers presented at the * "iisSjf I s v/4- ; ,n. . ^ . V; :,*;4 /' . r' - JIWORLdIhEALTH ORGANIZATION! ^ wIrhgion ALi-OFFICE? FOR? EUROPEj [COPENHAGEN! v\J-f J, A ' , . -'">'>A*X-,' -v**' 7`^\ ^' . ' 7 Va,* V, ' . * Wvy;':v"'; ;.. /- * ; .'. i1 ' 4:,X ', ' X-X v';;-' X- I0il-0m>) 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 Sofia, 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^vis; easily...diagnosed, especial ly-^when a target-oriented search is, under taken f for'"'characteristic clinical signs. ' These 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 byi-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", in the critical ment mechanisms;_ . ..... . 'ay late 1960s,r yiriyl7chloride' monomer!{(VCM)!and' polyvinyl chloride' were .thoughtj.to be.entirely .inert.3. During the ,1970s, .tile situ-j ation was'' dramatically^alte'redj-jby^reports/ofrfdifferent .hepatic abnormalities araongJ'vinyl chlqride.-workers^and "the discovery of ; some' cases' of angiosarcoma' of the?Tiver! "VLater, -.the- toxic ef fects ofyVCM were found ,ito?,! depend.; on,1 its ,biotransformation to more toxic' metabolitesjin|the;.liver^vialithe" monooxygenase enzyme system, known also asymixed-function .oxidases. (MFO). A direct relation between'" activity . of MFO Vand ". toxicity , of VCM has been- confirmed in experimental animals.by a.number of, authors [1-3]. . 'M 'S& 'l, 189j>V -: 'ch , '}< . - *. \ ' ! - v mr A literature search failed to find any data on Che 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 Che screening of more than 500 workers from the same plant in 1987. In addition, 10 newly employed operators and fitters exposed to higher VCM concentrations were tested. ffe 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 A-aminnantipyrine (4AAF) and N-acetyleaminoantipyrine (N-AcAAP) in 6-hour urine samples. In the first stage, AP undergoes 'N-demethylation with participation of MFO. The obtained 4AAP undergoes acetylation to form the conjugate N-AcAAP. ,, A target-oriented search was undertaken by a gastroenterolvogist 'and neurologist for early clinical signs of 1 chronic ' VCM ; v.;. . intoxication. tog?.- RESULTS *! Heptomegaly is most frequently combined with deviations in the activity of SCOT, SGPT, CGTP, 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. C-'V llfc Table 2 shows the correlation of indices. There is 100X correlation between MFO inhibition and the decrease of the re. .duced glutathione'.... The most frequently found, correlation" is . ^^i:.^:>;dbetween 'MFO;-.changes .and deviations in the other indices.-';With ... mm UsSSE**'" ; tration i of'* the toxic 190' -r ij'L-.; .'1 ^ , ((-.&, '''..`Ct'.. ' - . sVTMw v 'J. mg** L;, 'fi,i - * ^ Table 1. Correlation o biochemical parameters vith clinical symptoms of chronic intoxication with VCH. Parameter No. of of sub jects nc Devi ation (1) Hepatomegaly n nc % Vasomotor_ disturbances n n* % SGOT 137 100 SGPT 137 109 AP 137 65 GGTP 137 24 AAAP 93 37 N-ACAAP 92 38 A-AAP , . -93, 9 N-AcAAP ''; . 92 , 4 G-6-PD 'V,: 118 - : 35 Vitamin E 130 67 Reduced glutathione 130 69 Haemolytic resistance 124 Lipid - i> peroxide 13! 26 56 73 100 39 39 100 38 38 80 109 43 39 109 43 39 47 65 19 29 65 20 21 18 24 11 46 24 9 38 40 37 35 37 12 ' 32 41 38 16 42 38 12 32 10 ; y9 .1 , H . 9 7 78 4 :/ U ' 2 50 . 4 4 100 ., 30 :'-35 13 37 35 13 37 52 67 25 37 67 26 > 1 39 54 69 27 39 69 32 46 21 . .26 9 35 26 9 35 43 , 56 29 39 56 25 .45 '$ ^t'.'i$i$P'l'..-^i 'XfV V'A^f-:"V.V' ''' ' ,*" ;\ .S&`^'> , ` ' >'t/:>. * i .' ' .,/f '. ': :.-?; ,, >s :; ;- . l,?-' ; */''. >y wy,i'i- . V-.v\ , ; *: vv v.J'Vr '. VV' 7.-, -i ~*ka ' iWS?"-.'-f.. f ty,^,- ' ' -'. ..... -' ~ - ^ 'J - * SGOTj^J, Serum ^glutamic opalaeetic.^ transaminase... SGPT * ; Serum ; glutamic j- pyruvic , transaminase - AP ,, *= - Aminopyrine. GGTP = . Gamma--p glutamyl ,. transpeptase. ;,4AAP.= ,y4-Aminoantipyrine. N-AcAAP " = N-Acetylearoionantipyrine. G-6-PD = Glucose-6-phosphate dehydro- , genase.^ns -i*,dumber; of .subjects'with abnormal findings. " lReynaud-lilce phenomenon.?; 3 ' - " y, - :-v ! v'i-. ` '-r-: k ... .- . -- ' v*-. 191V i^TiW&Sr *r > ' - ( . W.8.&V& -A-J'T' ;.U - - - ^ .1' sf; V- 'I-':/1 . ' ," r . ':* -: ' ` . . . ,p- L rJfceS , -C, ' . ' ' - K`3 . -K` t's'. '* . . >; ' !;i '-VvV - : v-.7vi-^ msmmma R&S 150878 Tab'le 2. Correlation in the deviations from referent values of the biochemical , '> parameters <in %).1 - P.-ir.imotor SCOT SGPT AP CGTP AAAP N-Ac- AAAP N-Ac- C-6- Vitamin Reduced Hacmolyt tc AAP AFP PD E/ glutathione resistance Lipid peroxide SCOT .x SGPT AP ; '. CGTP ' \T v AAAP ` N-Ac-AAP AAAP N-Ac-AAP C-6-PD Vitamin E Reduced glutathione Haemolytic resistance Lipid peroxide 76 X 58 n 63 56 u 26 X 13 59 X 60 X 58 0 5 68 13 0, 61 .12 . 0 33 28 26 0 O' 0 50 59 X X :o 0 . 38 X 23 X - 20 0 X0 X ` 66 60 39 16 53 63 20 0 53 X 39 65 38 86 21 30 100 0 31 32 X 26 21 22 IA 29 15 0 0 27 17 13 X AA A6 A3 71 56 69 60 0 67 50 5A 6A SCOT * Serum glutamic opal acetic transaminase. SCPT Serum glutamic pyruvic transaminase. AP * Amlnopyrlne. CGTP Gamma glutamyl transpeptase. AMP A-Aminoantipyrine. N-AcAAP N-Acetyleamionantlpyrine* G-6-PD Glu- cose-6-phosphate dehydrogenase. ,. 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 bv 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 chlorethylene 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-FD as a generator of reduced nicotinamide adenine dinucleotide phosphate (NADPH), a donor of electrons for reduction of cytochrome P-450 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 R & S 150880 161 l9809LS'S?d 'V'v .V1, s* vVv: f`*; - . 'Vrf1 a / , 't * - % '5^ ; I sible for rendering harmless che lipid peroxides. On Che ocher 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 CGTP 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 Clinical 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 X) 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. 195 \< - > -j,' f :' -t*JTi ft? R&S150882 ,W.-. " - `o? 'V'- V- f ' *.\, = ' '> t J ' " "J<;"