Document Z48MvkEqa1ZORDxv6YeNg4x98

`dachttgung, dass die dor erhOhten Exposi- a, E. V a n C o, E. dad do loo trabajadoa al arstalco irtalidad on hombres, el contenldo elevado haltazgos an ol con* ueman ol carbfln con 3, D). En ol conjunto ilmlentos durante loo os malignos hacta ol roductiva; en el con- En los trabajadores ictlvos el 51 p. c. an /fr iz 'V ( 4 JOURNAL OF HYGIENE, EPIDEMIOLOGY AND MICROBIOLOGY AND IMMUNOLOGY 24, 1980. No. 285-294 ^ ' 73 \jt EXPERIMENTAL STUDIES ON THE CHRONIC TOXIC EFFECTS OF VINYL CHLORIDE IN RATS I. A. SOKAL. S. BARAftSKI, J. M A I K A, R. ROLECKI, I. 3TETKIEW1CZ, L. IVANOVA-CHEMISHANSKA, T. VERGIEVA, 0. ANTONOV, E, M I RKOVA. . KOLAKOWSKI, S. SZENDZtKOWSKI," K, WR0BLEWSKA Division 0f Industrial Toxicology and Department ot Pathomorphology, Institute of Occupational Medicine, E6dz, Poland Xue ol aumeoto do la INTRODUCTION irgo so demostd esta- esto mortan por loo / It Is now recognized that vinyl chloride (VC) causes neoplastic and non* atadlstico slgnlflcatt- neoplastic diseases In man as well as in animals. Animal studies have been ne muchos mlcroele- concentrated mainly on the carcinogenic and mutagenic action of VC (1, 5, 10, dco, contenldo en el 16, 19, 23, 27). Less Is known about chronic systemic effects of VC, their dose- ha probabilldad una ( response relationship and pathomechanism. Dherencla causal con The main objective of the present study was to document the time course of chronic toxic effects of VC in rats at different concentrations of VC ranging from 50 to 20 000 ppm. W. Philips, London MATERIAL AND METHODS , 6., Blinder, C-, G., on. Health Perspectl137. -- 12. Patras, J* irmat. Porech. 242, 13. Pinto, S,, Sn Ea se*, V., Varnar, ML, ! i Animals 340 two-month-old male Wlstar rats weighing 180--220 g were divided Into 4 equal groups: 3 experimental and one control. The rats were caged in groups with free access to food (Laboratory chow Murlgran) and tap water except during exposure In Inhalation chambers. erspectives 19, 1977, teacher, A., CM Car- tW-: J. occup. Med. I. -- 15. Srftm, *,, J,, Conditions of exposure Vinyl chloride of 99.7 % purity (kindly supplied by Chemical Plant, Tarndw, Poland) was used throughout the study. Rats were exposed to VC in dynamic Inhalation cham 3, 1974, pp. 308--315. .ratsnme, M.: Int ]. bers (X m1 volume] at concentartions ot 50 ppm, 500 ppm, and 20 000 ppm for 10 months (mo), 5 hours daily, 5 days a week. Control animals were maintained under the 0--317. -- 17. Tseng, same conditions but exposed to ambient air only. VC concentration in inhalation th Perspectives 19, climbers was checked daily by gas chromatography 19). 18. Yeh, 9.: Human Scope of investigations 9--485. Individual body weight, general appearance and behavior were recorded weekly. Before the onset and then after 1, 3, 8 and 10 mo of exposure the following determina [ygiene, Charles irob&rova 48, tions were performed: hematological indices (hemoglobin concentration, packed cell volume, counts of erythrocytes, reticulocytes and bllod platelets, total and differential leucocytes) and urine examination Including appearance, specific gra vity, pH, glucose, protein, occult blood, ketones, bilirubin, and microscopic constituents. 285 After l, 3, fl end o! exposure, total plasma protein, ptasma concentrations of urea. inorganic phosphates, citrates, and calcium, plasma activity of alanine amino transferase (ALATJ, aspartate aminotransferase (AspAT), lactate dehydrogenase (LDH) and serum activity of alkaline phosphatase {AP] were determined in blood samples from 7--10 rats of each group. Held mucopolysaccharides and hydroxyproline content in 24-hour urine samples from 14--20 rats of each group were determined before the onset and after 1, 3 and B mo of exposure [4, 6, 21). Five control rats and five rats exposed to VC at concentrations of 500 ppm and 2O0QQ ppm were subjected to X-ray analysis in order to control the state of the skeletal bones. The histopathological examinations of tissues were carried out in 114 rats exposed to- VC and 42 control, rats. The rats were sacrificed after 1.5, 3, 6 and 10 mo of VC ex posure. Bralp, cerebellum, medulla oblongata, spinal cord, lungs, heart, lymph nodes, bone marrow, spleen, liver, stomach, intestines, kidneys, urinary bladder, testes, epidi dymis, seminal vesicle^, hypophysis, adrenal glands, thyroid gland, pancreas, lacrimal glands, salivary glands, skin., muscles, bones, and blood vessels of the distal parts of the extremities were fixed in Baker's formol calcium. Additional blocks of liver, kidney, spleen and heart were fixed in Carnoy's fluid. Tissue specimens were embedded in paraffin, sectioned at 6 ^un, and stained with hematoxylin and eosin. Frozen sections of formalin-fixed liver and kidney were stained with Fat Rad 7B for neutral lipids. The ultrastructure examinations of the liver watte carried out in 36 rats exposed to VC for 3, 8 and 10 mo, and In 18 controls. Sections of the liver were fixed In 3.B % glutaraldehyde buffered with sodium, cacodylata. postfixed in 1 %. osmium tetroxlde, de hydrated in ethanol and embedded in Epon epoxy resin. Thin sections were double- stained with uranyl acetate and lead tartrate and then examined with the use of a JEOL JEM -- 100 C electron microscope. Statistical analysis Statistical significance of the dlfferece between the means was assessed by Stu dent's t-test or Cax-Cohran's C-test depending, upon the ratio of population variances (F-test). The frequency data were analysed by the chi-sguare test Fig. 1. Changes in mean body weight of rats exposed for 10 months to VC at concen trations: 1 -- 0 ppm, 2 -- 50 ppm, 3 -- 500 ppm, 4 -- 20 000 ppm. Each point repre sents the mean of 42--80 Individual body weights. 286 General condition of c During the total any evident changes l did not increase at th mo of treatment, the (p<0.05J at all levels en, liver, kidneys, hea of the exposed anlma and dose-related for tl jected to X-ray analys Histological and ultras No histological ch I to VC for 1.5 and .3 mo related tojhe treatmei gleal change* in the li cytes and proliferation I red in rats exposed to t level and In parallel c type (Fig. 2) were obse lion of hepatocytes de mv and disorders of s; the testicular epltheliu. only at this concentrat cells in the testicular 1 and testicular egltholiu Incidence rates of petocytes, proliferation is were significantly h. level than In the contr Two rats exposed u plasla of the liver. (Fig and in another at the 2i In the 10th mo of < tures of Interstitial pneu mals did not differ sign) The ultrastructural after 3 mo were progre dilatation of the cistern droplets of lipids were i ppm levels a number of A membrane were also oh 1 gtnatfons were still obse *) Details of histopatholog SL 097417 teln, plasma concentrations i activity of alanine amlnodate dehydrogenase (LDH) tennined in blood samples in 24-hour urine sample* onset and after 1, 3 and 8 entratlons ot 500 ppm and rol the state ot the skeletal led out In 114 rats exposed >, 3, 6 and 10 mo ot VC ex lungs, heart, lymph nodes, nary bladder, testes, epltff* 1 gland, pancreas, lacrimal isels of the distal parts of mal blocks of liver, kidney, cimens were embedded In and eosin. Frozen sections ed 7B for neutral lipids, ed out in 38 rats exposes! e liver were fixed In 3,8 1 % osmium tetroxide, dehin sections were double* ned with the use of a JEOL sans was assessed by Sts10 of population variances re test. months to VC at concen10 ppm. Each point repre weights. RESULTS General condttton of animals and gross observational During the total period of experiment the VC-exjjosed rats did not show any evident changes In general appearance or behaviour'but their body weight did not Increasfe at the same rate as In non-exposed animals (Fig. 1], After 10 mo of treatment, the difference from the contrors was statistically significant (p<0.05] at all levels of VC-exposure. At that time, the relative weights oft sple en, liver, kidneys, heart and testes were significantly elevated In some groups of the exposed animals, the difference being most pronounced for the splen and dose-related for the liver and kidneys (Table 1). The VC-exposed rats sub jected to X-ray analysis did not exhibit any alteration in the skeletal bones. Histological and uTtrastructural OfacFf No histological changes of internet organs were observed in rats exposed to VC for 1.S and ,3 mo. In the Tater period of exposure, the histologloal changrfTM" related to the treatment developed only in the liver and testes. Scanty histdfc^'"^ gical changes In the fTver, seen as Increased nucleus polymorphism* of bepWD- cytes and proliferation of retlculo-endothellal cells lining the sinusoid^ occur red In rats exposed to 500 and 20 000 ppm of VC for 6 mo but not at the 50 pja level and in parallel controls. After 10 mo of exposure, diffuse changes of that type (Fig. 2) were observed at all levels of exposure. In addition, fatty flhgenes* ( lion of hepatocytes developed, and necrotic foci of the spermatogenlc eplthe- \ Hus and disorders of spermatogenesis were noticed in the testes. The lesion of ( the testicular epithelium was most marked at the SOf^ppm exposure level and \ only at this concentration It was accompanied bv large multlnuclear svncvtlal f cells in the testicular tubules [Fig. 3). The histological alterations of the liver ) and testlcuTanpfthelium, were also detected in some of the 10 mo control rats.- '~ Incidence rates of such effects as increased nucleus polymorphism of he patocytes, proliferation of R-cells in the liver and disorders of spermatogenes is were significantly higher in animals exposed at the 20 000 and/or 500 ppm level than in the controls but they were not clearly dose-related (Table 2Ji Two rats exposed to VC for 10 mo developed adenomatous nodular hyper plasia of the liver. (Fig. 4). This tumor was found in one animal at 500 ppm and In another at the 20 000 ppm level, none was observed In control animals. In the 10th mo of experiment, some rats showed pathomorphologfcal fea tures of Interstitial pneumonia. The incidence of these findings in exposed ani mals did not differ significantly from the controls. The ultrastructural changes in the hepatocytes noticed for the first time t v after 3 mo were progressing with the duration of exposure. Proliferation and dilatation of the cisternae of smooth endoplasmic reticulum (Fig. 5) and small ii droplets ot lipids were seen at all concentrations of VC. At the 500 and 20iOQO ppm levels a number of swollen mitochondria and invaginations of the nuclear 1 membrane were also observed. After 6 mo of exposure, nuclear membrane inva ginations were still observed [Fig. 6a) and giant mitochondria with broken cris-s '1 Details ot histopathological and ultrastructural findings will be published elsewhere. ( 28? Table 2. Incidence of histopathologlcal lesions In the liver and the testes of male --------------------------------------------------_-t Concentration in ppm N Organ weights Heart Spleen 0 50 500 20 000 7 1413 156 998111 3251B 226 126 7 1466216 1094 257 35825b 26428b 7 1431315 1309 349 33858 30870b 7 137597 1127 143 3S831b 295 49* a -- male Wtstar rats. The data are expressed as the mean 4; SD b -- p < 0.05 slgnliicantly different from control tae (Fig. 6b) were seen for the first time at all exposure levels. The areas of focal cytoplasmic degradation developed at 20 000 ppm (Fig. 6c). After 10 mo, ultrastructural changes were more marked and observed in a higher number of hepatocytes at all exposure levels. No ultrastructural changes were noticed in the hepatocytes of control rats. Blood and urine analysis Plasma protein content and plasma or serum activities of alkaline phospha tase, alanine aminotransferase and lactate dehydrogenase were slightly elevat ed in VC-exposed rats, the difference from parallel controls being statistically significant only In some groups of animals (Fig. 7). The activity of lactate de hydrogenase was related, to some extent, to the duration of exposure and con centration of VC. The number of red blood cells was slightly increased after 10 mo at the SO and 500 ppm exposure levels and some fluctuations in coagulation time were ob served in the last period of exposure. Table 1. Absolute and relative organ weights of rats after rats expused to vinyl chloride for 10 months Vinyl chloride concentration (ppm) 0 50 500 20 000 Nuclear polymorphism of hepato cytes Proliferation of hepatic teticulosdotheHal oeUs Damage of epecmatogenic epithelium 2/28 3/28 3/28 5/21 18/34' 10/17 3.21 13/34* 8/17b 3/21 13/34* 5/17 a -- p <( 0.05 significantly different from control b -- p < 0,01 significantly different from control c -- p < 0.001 significantly different from control 288 10 months of tnhali absolute (g) relative (mg/100 g of' kidneys 1 1 M3327 71672 3062418 74961 3441 661 807 6Sb ) 3879 376 84940* c -- p < o.Ol slgnil d -- p < 0.001 sign \ Table 3. Excretion Vinyl chloride moccntration in ppm 0 so 500 20 000 * The 24-hour urlr kept together in a the results were at Table 4. Excretion t -------------------------Vinyl chloride 1 concentrations in ppm ( l -------------------------- 0 SO 500 i 20 000 A * The 24-hour url kept together In ; the results were a SL 097419 sight* Spleen 998 111 226 126 1094257 264 281* 1309349 308 106 1127143 295 49* svels. The areas of .6c). After 10 mo, l a higher number mges were noticed f alkaline phosphaere slightly elevat- being statistically ivity of lactate de exposure and cen ter 10 mo at the 50 atlon time were ob- weights of rats after ltlon'fpjna) 500 20 000 8/34 3/34* 3/34* A 10/17 8/17b 5/17 10 mottfhs o( inhalation exposure to vinyl chloride3 absolute (g) relative (mg/100 g of body weight) kidney* adrenal* teste* 3163 327 ' 71672 3062^418 749 61 3441 661 l 80765b 3279 376 l 849 40 65*16 15^3 60-12 15-4 59^9 14-1 70-15 184 300 505 677 99 2853573 692 89 3006 485 700111 3173549 821 1061* c -- p < 0.01 significantly different from control d -- p < 0.001 significantly different from control liver 9944-1234 2233 146 9776 1164 2393 202 10753-1600 2531-109* 12020-1216 3H6213<* l Table 3. Excretion of acid mucopolysaccharides In urine (in p/24 h) of control rats and rats exposed to vinyl chloride * Vinyl chloride concentration in ppm Before inhalation exposure Time from the onset of inhalation exposure 1 month 3 mouth* 6 months 0 so 500 20 000 99 26 9619 10123 9521 106 -- 47 107 37 104 25 101) 35 13043 13133 12738 110*36 15641 152 49 15334 152 47 a The 24-hour urine samples were collected twice with the 24 h interval from 2 rats kept together in a Simax metabolic cage. Two separate determinations were made and the results were averaged. The data are expressed as the mean SD of 7--10 averages. Table 4. Excretion of hydroxyproline in urine (in pg/24 h) of control rats and rats exposed to vinyl chloride * Vinyl chloride __ concentrations in ppm Before inhalation exposure Time from the onset of inhalation exposure 1 mouth 3 months 6 month* 0 50 500 20 000 300155 287 68 341 127 230 91 398 204 367 273 309-1-115 3074- 17 375121 354104 339140 332127 3684-131 328 92 3394- 80 331 137 * The 24-hour urine samples were collected twice with the 24-h interval from 2 rats kept together In a simax metabolic cage. Two separate determinations were made and the results were averaged. The data are expressed as the mean + SD of 7--10 averages. 289 The excretion of acid mucopolysaccharides and hydroxyproline in the urine of exposed animals did not differ significantly from the controls during the 6 mo observation time tlabrfs 3 and 4). There were no differences in the other hematological or biochemical indi ces studied and no alterations were observed in the microscopic constituents of the urine. | I ; j '( Chronic inhalation exp tive changes in the liver, perimental animals (2, 17, In our study on rats e treatment-related pathom tastes. The liver changes tions of VC than those In t Total Protein J- '- ^100- |---- rrr-Cl$ 75i ss ..Dim. -JTP--------- rm. #5-] . * O ,1m o 10Q- Atftol in -Phtss p hatas e ss nfl Hn fl 1751 1 *>#1 ', * $ B,! 4 1'wo- F---- 1- *> 73-1 Canine Aminotransferase s* nh .rLP-.db T35 MIdOO-, h 75- a bc IWdfafe Hehydrogenase - cjli. abc o be Itanths of exposure o be 2 mo 6 mo 10 mo Fig. 7. Serum activity ofafltallne phosphatase, plasma activity of alanine aminotransfe rase and lactate dehydrogenase, plasma total protein In rats exposed to VC at concen trations: a -- 50 ppm, b -- 500 ppm, c --OTOOO ppm. Results are shown as percentages of parallel control assumed as 100 %,, All results represent the means of 7--10 separa te determinations. 3 -- statistically significant difference from control. 1 j ] | 1 ! i '- [ ,i J, i I | | ' . I '| f1 ' Y I The increased organ/! accompanied by any hlsti kidney function disorders ces of the connective tls; we did not confirm the r< strain of rats and simitf histopathological alteratii was due to the 2 mo long) wared till now. It appear* al organ In the rat, this 24). The lesions in the te VC-exposuaifresiultlng in of our study did not peri dies suggested that VC p fttal mortality observed to VC (8). Short et al. posttmplantation loss in posed to VC for 11 weel exposed to 250 and 1000 The incidence of hi; posed rats did not corr considerably higher at a smalt difference (if 20000 ppm exposure le the general concept de fects resulting from blot not to the degree of ex compound. Since the to amount of VC metaboliz * expect that the biologic; with the concentration the rate mf VC metabol ''4',thlpgIycoltc acid (20 000 ppm) of VC I underlying the dose-re and testes, and the re to an active metabolite f- 290 SL 097421 ixypraline in the urlna e controls during thft 1 or biochemical indi* :roscopic constituents D. jn Jl a bc 10 mo of alanine aminotransfexposed to VC at concene shown as percentages means of 7--10 separace from control. DISCUSSION Chronic Inhalation exposure to VC has been reported to induce degenera tive changes In the liver, kidneys, spleen, brain, lungs, skin and bones of ex perimental animals (2, 17, 24, In our study on rats exposed to 50-- 20 000 ppm of VC for IP mo, appar'effl tKe"treatment-related pathomorphological changes developed txi liver and testes. The liver changps"'weTg"oE$erved mucTT earlier and at lower concentm- tions of VC than those in the testes. The Increased organ/body weight rations of spleen and kidneys were not accompanied by any histological changes in these organs and the indices of kidney function disorders were negative. No biochemical evidence of disturban ces of the connective tissue and mineral metabolism could be provided. TTnw we did not confirm the results of the study of Viola (26) who, using the same strain of rats and similar conditions of massive exposure to VC, descrfbStf histopathological alteration In the brain, kidneys, skin and bones. Whether It was due to the 2 mo longer exposure time m Viola's experiment, remains unaim wered till now. It appeared from our toxicity study that the liver was the crfim* al organ in the rat, this conclusion being In agreement with Torkelson's data J24J. The lesions in the testes observed in our study indicated the possibility of VC-exposure resulting in reduced reproductive ability of the males. The scope of our study did not permit a more specific Interpretation. Epidemiological stu dies suggested that VC produced germinal mutations as manifested by Increased fetal mortality observed in the wives of men who were occupationally exposed to VC [8). Short et al. [19] found no evidence of either preimplantation or postimplantation loss in .pregnant untreated females mated with male rats ex posed to VC for 11 weeks, however, reduced fertility was observed In male rats exposed to 250 and 1000 ppm of VC. X The Incidence of histopathological changes in the liver and testes of VC-ex posed rats did not correlate well with the exposure level. The Incidence wgm considerably higher at the 500 ppm level than at the 50 ppm level, and only a small difference (if any] was observed between the 500 ppm and the 20 000 ppm exposure levels. This phenomenon can be explained In the light of the general concept developed by Gehrlng et al. (7) stating that the toxic ef fects resulting from blotransformatian products of a chemical should be related not to the degree of 'exposure but rather to the amount of the biotransformed compound. Since the toxic action of VC Is attributed to Its metabolites and the | ^ 'amount of VC metabolized increases very slowly above 2500 ppm (7), one could expect that the biological effects of VC-exposure will be increasing only slightly with the concentration of VC at high exposure levels. In addition, depression of, the rate of VC metabolism could be inferred from the reduced rate of excretionof thioglycolic acid after long-term exposure tp high concentration* (20 000 ppm] of VC (25J. These toxlcokinetic features of VC were probably underlying the dose-response character of our pathological findings in the liver and testes, and the results further suggest that VC requires biotransformation to an active metabolite (sj for nonmalignant liver Injury, Two cases ot adenomatous nodular hyperplasia were considered to be in ^augmentation de polds derail duced by VC-expOsure since It is known irom literature (12, 18, 20) and from i'exposition. Au cours de Texp our own observations that this tumor is extremely rare in Wistar rats. So far, hfimatologiques dans le sang this type of tumor has not_^een reported to develop in animals and humans Quelques ellets toxiques y co exposed to VC. veaux les plus bos de ('expos Laboratory liver function tests have been reported to be frequently abnor rprsentent La concentration mal in VC workers (13, 14, 22) but their usefulness in the detection or diagnosis ( i'exposition pour i'industrie [ d savoir au taux de 5 ppm. of .VC-induced liver damage is controversial (3, 11, 15). The elevations we ob served in the activities of plasma enzymes in rats exposed to VC were very small. The estimations of AspAT, ALAT and AP seemed to be of doubtful diag nostic significance, also with respect to the lack of any relation to morpholo gical injury of the liver and the degree of exposure. The estimation of LDH may be of some diagnostic value since its activity is related better to the degree of exposure and the pathological changes in the liver. J. A. Sokal, B. Ba wicz, ]. Kolakowsi Eine experimental1* Stadia d> den Ratten From our toxicity study, the no-toxic-effect level of VC could not be estab lished. The lowest concentration of VC (50 ppm) still caused some toxic ef fects in rats: depression of the body weight increase, increased relative weights of some internal organs, slight hematological and biochemical changes and fluctuations and, what is more important, ultrastructural changes in hepatocytes and the tendency for an increased incidence of histological liver alterations. Considering our results from the health safety aspects, the 50 ppm could be re garded as the threshold concentration of VC in rat, and the safety factor of 10 would be resonable in view of the structural alterations present in the liver, the character of the dose-effect curve, and only one animals species studied. On the basis of these assumptions it could be suggested that the safe exposure li mit in industry in relation to systemic effects of vinyl chloride would be in i i i I Die Raxtenmaimchen wi 20 000 ppm fUrrf Stunden un Die morphologlscben Uslone und etnas ElektronmUcroskop zuwachses haben Rut der Lii das Experiments wurden as gen 4m BVut beobochtet ui Einiga toxtecRaf Wrkungen bar, entstandap^bfil dam nied settling , dMa 50 ppm die cherheitsgnnxa Wr die Int atner Hob* von 5 ppm bestii the region of 5 ppm. SUMMARY Male rats were exposed to vinyl chloride at the concentrations of 50, 500, and 20 000 ppm, 5 hours daily, 5 days a week for 10 months. Morphological lesions in the liver and the testes detected by light and electron microscope and depression in body "weignr increase intensified with the duration of exposure. Increased relative weights of some organs and slight hematological and biochemical changes Ln blood during the course ot the experiment were also observed. Some toxic effects including morphologic al liver injuries arose at the smallest exposure level, 1. e., 50 ppm. Assuming 50 ppm as the threshold concentration for rats, the 5 ppm level has been estimated as the safe exposure limit in Industry in relation to systemic effects of vinyl chloride. RESUME J. A. Sokal, &_Baraflskl, J. Majka, R. Rolecki, J, Stetkiewi^z, ). Kotakowski, S. Szendzlkowskl, K. WrOblewska: L6tade experimental* dee efteta toxiques chroniqnaa da chlorurs da vinyle inr lea rata Les mdles de rat fitalent exposes a du chlorure de vinyle dans les concentartlons de 50, 500 et 20 000 ppm pendant 5 heures par Jour et 5 jours par semaine au cours de la pdrlode de 10 mois. Des ltelons morphologiques sur le foie et sur les testlcules constatdes a i'aide du microscope lumlneux et fildctronique ainsl que la reduction de i I l 1 ! 1 J. A. Sokal, B. B wicz, I. Kotakow: El estudlo experimental da Los machos de las ratr 500 y 20000 ppm todas las meses. La lesidn morfolbglt plos lumlnos y electr&nlco mfls da lntensldadconladt obaervaban tamblta pequet gre y el aumento da peso r las leslones morfolOglcas d siclAn, o saa, a la de 50 ppc para las rates, el llmlte so; con los efectos de slstema t X. Anderson, D., Hodge, chase, f. F, H.: Mut Res. 370. -- 2. Basilaar, A. V., ' ehatkov, A. O.: Gig. Tr. were considered to be initure (12, 18, 20) and from rare in Wistar rats. So far, op in animals and humans ted to be frequently abnort the detection or diagnosis IS). The .'Sevatlons we ob- expoeed to VC were very ned to be of doubtful dlag- any relation to raorpholo re. The estimation of LDH related better to the degree r. 1 of VC could not be estabstill caused some toxic ef, increased relative weights I biochemical changes and itural changes in hepatocyIstological liver alterations. :ts, the 50 ppm could be ret, and the safety factor of rations present in the liver, animals species studied. On d that the safe exposure 11vinyl chloride would be In ^'augmentation de poids devenaient plus intensives au fur et 4 mesure de la dur4 de 1'exposition. Au cours de ['experiment on pouvait aussi observer de petits changements hdmatologiques dans !e sang et 1'augmentation du poids rfilatif de quelques organes. Quelques effets toxiques y compris des lesions de foie se produisaient pendant les atveaux les plus bas de ['exposition, 4 savoir a 50 ppm. Sous la condition que 50 ppm rfiprfisentent la concentration de semi pour les rats, on a fix# la limtte de sficuritfi de l'exposltion pour l'lndustne par rapport aux effets de systSme de chlorure de vlnyle, a savoir au taux de 5 ppm. ZUSAMMENFASSUNG J. A. S o k a 1, B. Baraftski, J. M a ] k a, R. R o 1 e c k i, J. S t e t k 1 e wlcz, J. Kolakowskl, S. Szendzikowski, K. Wrfiblewska: Eine experimentelle Stadia der chronischen, toxiichen Wirknngen dea Vlnylcblorldi ao den Ratten Die Rattenmflnjjchen wurden zu Vlnylchlorid bei Konzentratlonen 50> 500 und 20 000 ppm filnl Stunden und ftlnf Tags wdchentllch, Insgesamt 10 Monate exponlert Die morphologlschen LSstonen an der Leber und den Hoden die mlt Hllfe eines Llchtund eines Elektronmikroskop bestimmt wurden, sowie auch die Senkung des Gewichtgizuwachses baben mlt der L4nge der Exposition an der Intensltfit zugenommen. Wflht$od~ des Experiments wurden auch kleine hflmatologlsche und blochemlsche VerBndshtagen 1m Blut beobachtet und eine relative Gewichtszunahme elnlger Organs erulert, Einige toxische Wirkungen etnschltessllch der morphologlschen BeschSdlgung det Le ber, entstanden bei dem niedrigsten Expositionsniveau d. h. bei 50 ppm. Unter der Voraussetzung , dass 50 ppm die Schwellenkonzentration fflr die Ratten 1st, wurde eine Si* cherheitsgrenze far die Industrie in Bezug auf Systemwirkung des Vinylchlorlds in einer HOhe von 5 ppm bestimmt. RESUMEN concentrations of 50, 500, and . Morphological lesions in the scope and depression in body Increased relative weights of changes In blood during the effects including morphologlc, 50 ppm. Assuming 50 ppm as is been estimated as the safe of vinyl chloride. R ol ec k i, j, Stetkleiik I. K. Wrfiblewska: :h!orure de vinyls ter las rats rtnyle dans les concentartlons 5 Jours par semaine au cours ie la foie et sur les testlcules ]ue alnsl que Is reduction de , ( ( / I j J. A. Sokal, B. Bara A ski, J. Ma]ka, R. Eolecki, J. Stetkiewicz, J. Kolakowskl, S. Szendzikowski, K. Wrfiblewska: J El estndio experimental de loa efectos tfixicos crfinicas del vinilcloruro an rata* Los machos de las ratas se les exponlan al vinilcloruro en concentraciones de 50, 500 y 2QUQQ ppm todas las 5 boras al dla y los 5 dias por la semana, en total durante meses. La lestfin morfolfigica en el higado y los testlculos detectados por los mlcroscopios lumlnos y electrfinico asi que la disminuclfin del aumento de peso han obtenido mfis de intensidadconladuracifin de la exposlclfin. Durante el experiment se les observaban tambifin pequefias modlflcaclones hematolflgicas y bloquimicas en la sangre y el aumento de peso relatlvo de algunos firganos. Algunos efectos tflxicos, incluso las leslones morfolfiglcas del higado, origlnaban a los niveles m4s bajos , de la expo slclfin, o sea, a la de 50 ppm. 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Bl, 1970, pp. 174--180. -- 27. Viola, P. t,, Bigottl, A., Caputo, A.: Cancer Res. 31, 1971, pp. 516-522. - Received August 20, 1979 % "ft Sol II, Institute of Occupational Medicine 150 Eodt, P. 0-. box 133 Poland 294 IOUINAL or HYOie AND I STUDY ON THI L. IVANOVA-CHS Institute of Hygiene and 1 One of the most tm | long-term effects of chen * sible manifestations of e dotroplc and carcinogen j The chemical, tormulatlo I died obligatorily from 1 i both of directly exposed ] tions should be a comp 4 pesticide for the purpos There is dally clos' I pesticides in the condit ^ lag pesticide residues. ( Study of the changes i These studies are > - io-tftch group,- equal bAfte Wlstar rats or r Ik* required quaranttr awith the purpose of tr .* A* consequences Jm-the recundation aj fetus and also'to infei A* danger of' chemlc gatlon [functional, r bests Tot Tlsfc assess measures. Tt studle TJ prenters! rat kn subjected to the M--tlfflty, fertility ( sent of the- firaetk SL 097425