Document 7R69qD3RoGw2X8YRkOkJVOBJV

kc:'vilisifttut^^fcwnhrschclnUch eln gentlgender Gnmd 2v V&rdfichttgung, dass tllo fpsigestelften^HKdchen In elnem kausalen Zusanvmenhang mlt der erhflhten Exposi tion z li At son Kind RESUMEN V D o n c k o, K. Symon, L. 5 t A l n J k, J. Btitora, E. V ii n C o( E. S v a ji [I o v A I.n porcifin do Ioj proccaos malignos on fa morialldod do lot irnbajodo* res do la* ccrtlralos Itfcmlca* on calocldn con la expa&icfAn eleTftda al artfinlco So establftcib ol andllsls relrospectlvo de la eslructura da m orto lid-ad on horn bras, trabnjadores de los centrales tfirmteas que queman el carbdn con el contenldo alevado de arsfinlco (conjunto A]. Los resirltados se los compard con los holl&zgos on el con* junto de los dlkmtos irabajadores do las centrales ISrmlcas quo queman el carbdn con los valorem Lisuntes del conianldo de esie elemenlo (conjenlos B, C, D). En el conjunto A los an caso.s. cn pI confunto lestigo los 159 cases de los ftflleclmlenios durante los 15 - Hi oslns parados fueson obtenldos, Lti poretdn de los proceeos malignos liacla ol jfl ..............cl con|Limto A do las personas dlfu-nta-s on Ee edad productive; on el conjuustj : tfs l j is u. pur e! con [rflito. esta porcldn adqulrla al 23 p. c. En los trabnjfldores nmunos tlespu&s do los 60 afios do edad liocEan los valores respectlvos el 51 p. c. en el conjunto A v el 43 p.-c, en el ennjumtu lestlgo. Al aitftllznr estedlsWcamfinte los procesos malignos se mostrd que el aumento de la poEcidn de &sios no fue de significance en ambos casos. Bln embargo se demostfi estodlsncftnifinie que los ttorrtbres mils fflvenos del conjunto A expuesto tnorfan por los protases mnbqnos despu^s de In expostcl&n del rpunto de vista estadlstlco slgniflcnt'lvamente nirts corta (ambos cada 0,05]. El carbdn quetnado contione imiohos microele ments Iji-oidgicamente actlvos, sin embargo la cumrila del ars6ntco, contenlilo en el carb6n [950 -- 1500 g en la lonetada de unateriassoa] da con mucho pvobabilldad una sospechfi' suTlciente para conslderar los resultados obienidos en ooherencla causal con )u expcstciOn numentada al ars&nico. REFERENCES 1 Heckman. G., Beckman* L,, Norden* son, I.: Environ Health Perspectives 19, 1977, pp 145 -- 340 -- 2. Hencko, V,f Sy* mon. K.: Envirun. Research 13, 1977, pp. 37p -- 3fl5 _ 3 Hencko, V.. Synion, K., Chlrtdek, V., Plhrt, ),: Envirun, Research 13, 1977, ]>p 386 -- 395 -- 4. Benck.ot V.: Envi ron. Health Perspectives 19, 1977, pp. 179 -- 102. -- 5 Hcrgogtlo, R.: M. Prensa Med, A i gr*nt 51. 1904. pp. 994 -- 998. -- 0. Biol, W., J.h Finumenl, J.: F. Lancet 1975 N 7920, pp 142 -- 144 -- 7 Buechley, R.: Acta Unlo hit [JnncMifn 19, 19G3, pp. 710--720, -- fl. Lee, a , M , Freumeni, J.: F* J. Nat. Cancer Inst 42, 1909, pp. 1945 -- 1052. -- 9. Oppenheim, |., E' 'hbolo, W.: N. Cancer Press 25, 1965, pp 960--905. -- 10. Paris, J,: A. Pharmacologlca III. W, Philips, London 1820. -- 11. Perahagon, G*. Eltndar, C., G.* Botander, A.: M. Environ. Health PerspeclH ves 19, 1977, pp. 133--137. -- 12. Polros, J., Bergor, A.; Arch, dermat. Forsch. 242, 1972, pp. 343--352. -- 13. Pinto, S., S., En* lorllne, P., E., Hendorson, V., Varner, M.* O.: Environ. Health Perspectives 19, 1977, pp. 127--130. -- 14. Rancher* A., C.; Car* tor, M,, W., Me Koe, D., W.: J. occup. Med. 19, 1977, ipp. 754--758. -- 15. Sr4m, R., J., Soncko, V.: Cs. Hyg. 19, 1974, pp. 308--315. -- 18. Tokttdomo, S., Kuratsumo, M.: Int. f. Cancer 17, 1970, pp. 310--317. -- 17. Tseng, W,, P.: Environ. Health Perspectives 19, 1977, pp. 109--119. -- 18. Yoh, S.: Human Pathol. 4, 1973, pp. 409--485. Received july 213, 1979 V. Boncko, Medical Faculty ot Hygiene, Charles University, 100 42 Prnha 10 Srobdrovo 48, Czechoslovakia 284 IOUINAI OF n V 11 I E N E. Kl' I H E M I O 10 BY A N-l) MtCROS O L O G AND IMMONOCOOY 2i, 1080. No. IS5-I9Y : .jpyrighted Material i.o Mot Reproduce Without iblisher's Perroisfoion EXPERIMENTAL STUDIES ON THE CHRONIC TOXIC EFFECTS OF VINYL CHLORIDE IN RATS J- A- SOKAL. n. n A It A ft 5 K I. J M A | K A, R. ROltCKI, J. STETKIEWICZ. !.. IVANOVA-CHEMISHANSKA. T. VEROIEVA. O. ANTONOV, E. MIR- KOVA, . (OUKOWSKI. S SZENOZtKOWSKI, K. WlOlLtWSK* Division of Industrial Toxicology and Department ol Pathomonphology, Institute ol Occupnllon.il Medicine, t6dt, Poland INTRODUCTION It Is now recognized that vinyl chloride (VC) causes neoplastic and noitneoplnstlc diseases In man as well us In animals. Animal studies have been concentrated mainly on the carcinogenic and mutagenic action of VC (1, 5, 10, 1G, 19, 23, 27). Less Is known about clironlc systemic effects of VC, their doseresponse relationship and pathomeclianism. The main objective of the present study was to document the time course of chronic toxic effects ot VC In rats at different concentrations of VC ranging from 50 to 20 000 ppm. MATERIAL AND METHODS Animals 310 two-moulh-old male Wlstar mis weighing 180--220 g were divided into 4 equal groups: 3 experimental and one control. The rats were caged In groups with free access lo food (Laboratory chow Murlgran) and tap water except during exposure In Inhalation chambers. CondHJons of exposure Vinyl chloride of 99.7 Vo purlly | kindly supplied by Chemical Planl, TarnOw, Poland | was used throughout the study. Rets were exposed to VC In dynamic Inhalation cham bers (1 m] volume) at concenlartlons ot 50 ppm, 500 ppm, and 20 000 ppm for 10 months (mo), 5 hours dally, 5 days a week. Control anlmels were maintained under the same condlUons but exposod to, am blent air only. VC concentration hi Inhalation climbers was checked dally by gas chromatography (9). Scope ol Inveslljotlons Individual body weight, general appearance and behavior were recorded weekly. Before the onset and then alier 1, 3, 0 and 10 mo of exposure the following determina tions were performed: hemaiolog.kca! Indices ; (hemoglobin concentration, packed coll volume, counts ot erythrocytes, ` reliculocyles and bllod pielelets, total and differential leucocytes) end urine examination Including appearance, specific graoily, pH, glucose, protein, occult blood, ketones, bilirubin, and microscopic constituents. ^ - After and 10 mo of exposure, total plasma protein, plasma concentrations of Lirea, pliosphflies, citrates, and calcium, 'plasma activity of alanlna amino transferase ^KaTJ, aspartate aminotransferase (AspATj, lactate dehydrogenase ]LDH) and serum activity of alkaline phosphatase (AP) were determined In blood samples from 7 --1U tats of each group. Acid mucopolysaccharides and Itydroxyprollne content In 24-hour urine samples from H --20 rats of each group were determined before the onset and after 1, 3 and 8 mu of exposure (4, 0, 21). Five control rats and five rats exposed to VC at concentrations of 500 ppm and 20 000 ppin were subjected to X-ray analysis In order to control the state of the skeletal bones 1 he htstopatliologtcal examinations ol tissues were carried out In 114 rats exposed to VC and 42 control rats. The rats were sacrificed after 1.5, 3, 8 and 10 mo of VC ex posure. Brain, cerebellum, medulla oblongata, spinal cord, lungs, heart, lymph nodes, bone marrow, spleen, liver, stomach, Intestines, kidneys, urinary bladder, testes, epidi dymis, seminal vesicles, 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 blooks of liver, kidney, sjilrm ami heart were fixed In Carnoy's fluid. Tissue specimens were embedded In p.it.tffin, sunluned at 0 pin, and stained with hematoxylin and eosln. frozen sections oI formulin-flxeri liver and kidney were stained with Fat Red 7B lor neutral lipids. I lie ultrastructure examinations of the liver were carded out in 30 rats exposed to VC for 3, 0 and 10 mo, and In 10 controls. Sections o! the liver were fixed In 3,0 % gitiifl i a Idtltydc buffered with sodium cacodylale, .postflxed In 1% osmium letroxlde, do- hydrnted In ethanol nmd embedded In Epon epoxy resin. Thin sections were double- stained with urnnyl acelate and lead tartrate and then examined with the use of a JEOL JEM -- 100 C electron microscope. Statistical analysis Statistical significance of the dlftarece between the means was assessed by Stu dent's t-test or Cox-Cohran's C-test depending upon the rallo of 'population variances (F-testJ. The Irequency data were analysed by the chi-square test. Fig l. Changes In mean body weight of rats exposed lor 10 months to VC at concenCations: 1 -- 0 ppm, 2 -- 50 ppm, 3 -- 500 ppm, 4 -- 20000 ppm. Each point repre sents ihe moan of 42--80 Individual body weights. 28G RESULTS General condition o) animals and gross observations. During the toto! period of experiment the VC-exposed rats did not show nny evident changes In general appearance or behaviour but tlielr body weight did not increase at the same rate as In non-exposed animals (Fig. 1). Attar 10 mo of treatment, the difference from the controls was statistically significant 1 p<0.05J at all levels of VC-exposure. At that time, the relative weights of sple en, liver, kidneys, heart and testes were significantly elevated In some groups of the exposed animals, the difference being most pronounced for the spleen 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 ultrastructural data' j No histological changes of Internal organs were observed in rats exposed to VC for 1.5 and 3 mo. In the Inter period of exposure, the histological changes relnled to the treatment developed only In the liver and testes. Scanty hlstologiciil changes in the liver, seen ns increased nucleus polymorphism of hepatocytes and proliferation of retlculu-endothelial cells lining the sinusoids, occur red In rats exposed to 500 and 20 000 ppm or VC for G mo but not at the 50 ppm level and In parallel controls. After 10 mo of exposure, diffuse changes of that type (Fig. 2) were observed at all levels or exposure. In addlllon, fatly degenera tion of hepatocytes developed, and necrotic foci of the spermatogenlc epithellus and disorders of spermatogenesis were noticed In the testes, The lesion of the testicular epithelium was most marked at the 500 ppm exposure level and only at this concentration It was accompanied by large multlnuclear syncytial cells In the testicular tubules (Fig. 3). The hlstologlca! alterations of the liver and testicular epithelium, were also delected In some of the 10 mo control rats. Incidence rates of such effects as increased nucleus polymorphism of hepalocytes, proliferation of RE-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 2). I wo rats exposed to VC for 10 mo developed adenomatous nodular hyper plasia or 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 pathomorphologlcal fea tures of Interstitial pneumonia. The Incidence ot these findings In exposed ani mals did not differ significantly Irom the controls. The ultrastructural changes In the hepatocytes noticed for the first time after 3 mo were progressing wlili the duration of exposure. Proliferation and. dilatation of the clsternae of smooth endoplasmic reticulum (Fig. 5J and small droplets of lipids were seen at all concentrations of VC. At the 500 and 20 000 ppm levels a number of swollen mitochondria and Invaginations of the nuclear membrane were also observed. Alier 6 mo of exposure, nuclear membrane Inva ginations were still observed (Fig. Ga) and giant mitochondria with broken erts- ) Details ot hista pathological and uliraslriiclural findings will be published elsewhere. 287 t 19HW) SSb Table 2, I ca of hlslopathologlcal lesions' In the liver and the testes ol male Concentration ia ppm N Organ weight* Heurt Spleen 0 50 500 20 000 7 1413 -156 min 325 18 226126 T 1466216 1094257 35825b 264 28b ' 7 1431315 1309349 338SB 30B70b 137597 1127143 3583lb 295 49* a -- male Wistar rats. The data are expressed as <the mean SD b -- p < 0.05 significantly different from control tae [Fig. Gb) werB seen tor the first time at all exposure levels. The'areas ot 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 hepatocyles at all exposure levels. No ultrastructural changes were noticed In the hepatocyles of control rats. Blood and urtne analysts Plasma protein content and plasma or serum activities of alkaline phospha tase, alanine aminotransferase and lactata dehydroganasB 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 soma extent, to the duration of exposure and con centration of VC. The number of red blood cells was slightly Increased attar 10 mo at the 50 titid 500 ppm exposure levels and some fluctuations In coagulation time were ob served in the last period of exposure. Table 1. Absolute end relative organ weights of rets after rats exposed to vinyl chloride for 10 months Vinyl chloride concentration (ppm) 0 SO 500 20 000 Nuclear polymorphism of hepato* cytcs ' Proliferation nf hepatic rcticulo* endothelial cells Damage of spcrmatogcnic epithelium 2/28 3/28 3/28 - 5/21 3.21 3/21 18/34* 13/34* 13/34* 10/17* B/17b 5/17 o -- p < u.05 slgrrttlcnmily different from control b -- p <0.01 significantly different from control c -- p < 0.001 significantly dlllerent [ram control 288 fci.0 months of Inhalation exposure to vinyl chloride9 absolute (g) relative {mg/100 g of body weight) kidneys adrenals testes 3I63327 71672 3062 416 74961 3441 661 80765b 3279376 849 40* 65 16 IS 3 60 12 15 4 59 9 14 1 70 15 18 4 300S0S 677 99 I8S3573 692 89 30Q64B5 700H1 3173549 821106b c -- p < 0.01 significantly different from control d -- p < 0.001 significantly different from control liver 9944 1234 2233 146 9776 1164 2393202 1G7S3 1600 2531109i 12020 1216* 3116213*i Table 3. Excretion ol acid mucopolysaccharides In urine (In f>!24 h) ot control rats and rats exposed to vinyl chloride * ' Vinyl chloride concentration in ppm Before inhalation exposure Time from the onset of inhalation exposure i month 3 months 6 months 0 50 500 20 000 9926 9619 101 23 95 21 106 47 107 37 104 25 1003S 130 43 131 33 127 38 110 36 156 41 152 49 153 34 152 47 * The 24-hour urine samples were collected twice with the 24 h Interval from 2 rats kept together In a Slmax metabolic cage. Two separate determinations were made and the results were averaged. The data ace expressed as the mean SD of 7--10 averages. Table 4. Excretion of hydroxyprollne Jn 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 month 3 months 6 months 0 50 500 20 000 300 155 287 6B 341 127 230 91 398 204 367 273 309 115 307 17 37S 121 354 104 339 140 332 127 368 131 328 92 339 80 331 137 * The 24-hour urine samples were collected twice with the 24-h Interval from 2 rats kept together In a Slmax metabolic cage. .Two separate determinations were made and the results were averaged. The data are expressed as the mean SD ot 7--10 averages. 289 39m0 SSd The excretion of acid mucopolysaccharides and hydroxyprollne In the urine of expossgfcnlmals did not differ significantly from the controls during the 6 mo obs^^Bon time (Tables 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. 175 Total Protein 100- -n-r-n. 75- ss m-. 1751 o 10075J 1751 Alkaline Phosphatase ss Dll__CtO__fin Alanine Aminotransferase ss 11 100- 1----- 1 ?5J -i --MB i 175-1 i1 .. u, n^. 75-1 o be loctate Dehydrogenase s < r ,,rh rT o bc o bc Months ot exposure 1 mo 2 mo 6mo ii) s jfl o ba 10 mo Fig. 7. Serum activity ot alkaline phosphatase, plasma activity of alanfna amlnotranslarase and lactate dehydrogenase, plasma total protein tn rats exposed to VC at concen trations: a -- 50 ppm. b -- 500 ppm, c --20 000 ppm. Results are shown as percentages ot parallel control assumed as 100 %. All results represent the means of 7--10 separa te determinations. S -- statistically significant difference from control. 290 b l SC US S I 0 N Chronic Inhalation exposure to VC has been reported to Induce c^^Hbratlvfi changes In the liver, kidneys, spleen, brain, lungs, skin and bone^mT ex perimental animals (2, 17, 24, 26], In our study on rats exposed to 50--20 000 ppm of VC for 10 mo, apparent treatment-related pathomorphologlcel changes developed In the liver and testes. The liver changes were observed much earlier and at lower concentra 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 or disturban i ces of the connective tissue and mineral metabolism could be provided. Thus V J we did not.confirm the results or the study of Viola (26) who, using the same l strain of rats and similar conditions of massive exposure to VC, described hlstopathologlcal alteration In the brain, kidneys, skin and bones. Whether It wan due to the 2 mo longer exposure time In Viola's experiment, remains unans wered till now. It appeared from our toxicity study that the liver was the critic al organ in the rat, this conclusion being In agreement with Torkelson's data (24). 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 o more specific Interpretation. Epidemiological stu dies suggested that VC produced germinal mutations as manifested by Increased fetal mortality observed In the wives ot men who were occupationally exposed to VC (B). Short et al. (19) found no evidence of either prelmplantatlon or postlmplantatlon loss In pregnant untreated females mated with male rais ex posed to VC for 11 weeks, however, reduced fertility was observed In male rats exposed to 250 and 1000 ppm of VC. The Incidence of hlstopathologlcal changes in the liver and testes of VC-ex posed rats did not correlate well with the exposure level. The Incidence was considerably higher at the 500 ppm level than at the 50 ppm level, and only a small difference (It any) was observed between the 500 ppm and the 20 000 ppm exposure levels. This phenomenon con be explained In the light of the general concept developed by Gehrlng et al. (7) stating that the toxic ef fects resulting from blotransformatlon products ot a chemical should be related not to the degree of exposure but rather to the amount of the btotronsformed compound. Since the toxic action of VC Is attributed to tts 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 ot the rate of VC metabolism could be Interred from the reduced rate of excretion of thloglycollc acid after long-term exposure to high concentrations (20 000 ppm) of VC (25). 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 blotransformatlon I to an active metabolite (s) for nonmallgnant liver Injury. ] wu ul adenomatous nodular hyperplasia were const doled lo bu i ti llu red by^^hexposure since It Is known from literature (12, 18, 20) and from our own ^^^vatlons that this tumor Is extremely rare in Wlstar rats. So far, this type of tumor has not been reported to develop In animals and humans exposed to VC. Laboratory liver function tesis have been reported to be frequently abnor mal In VC workers [13, 11, 22) but their usefulness In the detection or diagnosis 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 (he liver. from our toxicity study, the no-toxlc-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 hepalocytns and the tendency for an Increased Incidence of histological liver alterations. Considering our results from the health sarety 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, (he character of the dose-effect curve, and only one animals species studied. On the busts of these assumptions it could be suggested that the safe exposure li mn m industry in relation to systemic effects of vinyl chloride would be In the region of 5 ppm. SUMMARY Male rats were ex-posed to vinyl chlorldB at the concentrations of 50, 500, and 20 000 ppm, 5 hours dally, 5 days a week for 10 monlhs. Morphological leslon-s In the liver and the testes detected by light and electron microscope and depression in body weight iFicrease Intensified with the duration of exposure. Increased relative weights of some organs end slight hematological and biochemical changes In 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 ns the threshold concentration for rats, the 5 ppm level hits been estimated as the sate exposure limit in 'Industry In relation to systemic effects of vinyl -chloride. R S UM !- A. Sokal. B. Barartskt, J. Majka, R. Roleckl, J. Stetklewtez, ). Kolakowski, S. Szendilkows.hl, K. WrOblewska: L'dtude expftrlmentale des eflets toxlques chroniquas do cbtorura de vlnyle stir Ibj rats Les miles de rat fitaient exposfis a du chlorure de vlnyle dans les concentartlons do 50. 500 el 20 000 ppm pendant 5 heures par jour el 5 jours par semalne eu oours de la pftrlode de 10 metis. Des l&slons morphologiqu&s sur le tote et sur les teslfcules constatSes 4 faide du microscope lumlneux et fildctronlque alnsl que la reduction de 292 cV I'nug me illation^ do polds cl e vena Ion I |JUI1 inic.-nslvcs an fur cl A mosuru do la du 1'exposlllon. Au oours de l'expSrl-nient on pouval-t ausst observer de pettts cha^^B-tus hfimatologlques dens la sang et ['augmentation du polds rdlatlf de quelques ^ffutes. Quelques etfets toxlques y comprls tins l&slons de foie se produlsolemt pendent les nl- vonux les plus has de I'exposttlon, 4 sovotr ft 50 ppm. Sous lo condition que 50 ppm rftprftsoment lo concentrotlon de seui] pour les rats, on a flxd lo Kmlte da sdcuritd de I'exposHlon pour I'industrie por rapport aux effets de systdme de chlorure de vlnyle, ft sovolr nu toux de 5 ppm. ZUSAMMENFASSUNG J. A. Sokal, B. Borortskl, J. Majka, R. Roteckt, j. Statklewlcx, J. Kolakowski, S. Szundzikowskl, K. WrOhlewsko: Elrio experlmculollc Studio dcr ohroniscltcn, foxljchen Wlrkungen lias Vlnylchlorldi an den Ration Die Ra'tlenmflrynchen wurden zu Vlnylchlortd bel Konxentrallonen 50, 500 und 20 000-ppm ftlrrf Stunden und fflnf Tage wttchentllch, Insgesamt 10 Monato exponlert. Die morphologlschen 'Lttslonen on der Leber und den Hoden die mlt Hilfe elnes Ltchtund etnas Eloktronm'lkroskop besllmmt wurden, sovtrie ouch die Senkung des Gewichtszuwochses haben mlt der LBnge -der Expuslllon an der tatensltttt zugenommen. Wfthremd des Experiments wurden ouch .kdetne hflirartologlsche und btochemlsche Verftnderungen 4m Blut beohachtet und etne relative Gewlchtszunahme elntger Organa erulert. Elnlge toxlsche Wlrkungen elnschllessllch der morphologlschen Beschfldtgung tier Le ber, onlstanden bel tlem nledrlgsten Expos!tlnnsnlveau d. h. bel 50 ppm. Unler der Voroussetzung , dass 50 ppm dlo Schwellenkonzcntrallon (Or die Rotten 1st, wurde elne StcherlieUs3renze ftlr die Induslrle In Dezug auf Systemwlrkung des Vlnylchlorlds In elner Hfiho von 5 ppm besllmmt. It E S U M E N ). A. Sokal, B. Bara Ask), ). Majka, R. Ro'l-eckl, ). StelkJewlcz, ]. Kolakowski, S. Szendzikowsiki, K. WrOblewska: El ostudlo experimental de Ins otoctos l6iicos crhnlcos del vlnllcloruro cn rotas Los machos de las rates so les exponktn al vlnlktloruro en concentroctones de 50, 500 y 20 000 ppm lodas las 5 horas al dla y los 5 dies por la semarra, en total duranto meses. La lesl&n morfoldgtca en el hlgado y los tesllculos detectados per los mlcroscoplos lumtlnos y electrdnlco ast que la dlsirdnuclOn del aumento de peso han obtenldo mfts de InlensIdadconladuraclOn de la exposlcltm. Durante el experiment se les observaban tomblftn pequeflas modlflcaclones hematoldglcas y bloqutmicos en la sangro y el aumento de peso relatlvo do algunos Organos. Algunos efectos tdxtcas, incluso les leslones morloliglcas del hlgado, -oitglnaban a los otveles mfts bajos , de la exposlclfin, a sea, a la de 50 ppm. Suponlemlu que 50 ppm estfi una concentraclOn de umbra! para las t-alas, el If mile soguro do lu oxposlclOn se lljb al nlvul de 5 ppm en reloctGn con lus efeclos tie slstetna del vlnllclui ui-o. REFERENCES 1, Anderson, D., Hodge, M. C. E., chase, f. F. H.: Mut. Res. 40, 1970, pp. 370. -- 2. BasalaBr, A. V., Vaitn, A, N., chotkar, A. G.t Gig. Tr. Prof. Zabol. Pur- 1972, pp. 24--27. -- 3. Berk, P,: Ann. Int. 359 Med. 84, 1976, pp. 717--731. -- 4. 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Sch 248, 1975, pp. 22--41. -- 14. Mekk, L., Creeck, /. L., Whelan, /. C,, Johnson, H. N.: J. Amer. med. Ass. 230, 1974, pp G4 --68. -- 15. Mokk, L., Delmoro, F,, Dreeck, J. L., Ogdon, L. L., Fodell, E. H.. Songster, C L., Clanton, J., Johnson, M. N.. Chrtsloplierson , W. M,: Cancer 37, !`J7I>, pp. 149-159 -- 16. Mnllonl, C,, Le- Jojunio. G: Ann. N. Y. Acad. Scl. 246, kjuelvcd August 20. 1979 1975, pp. IMS --218. -- 17. Trodan, L., Suctn, L., Plslarti, V., Tien, E., Posen, l.: Ann. N. Y, Acad. Sol. 249, 1975, pp. 159--183. -- 18. Scheuer, A., Kunie, E. 1st: Pathology of tumours in laboratory animals (Turusov, V, S., Ed.), Vol. 1, Part 1, IRAC ScientificPublications No. 0, WHO, Lyon, 1978, pp. 41--72. -- 19. Short, R. D,, Minor, f. L,, Winston, J, M., Leo, C. C,: J. Toxicol, en viron. Health 3, 1977, -pp. 985--988. -- 20. Snell, K, C. In: The palhology of laborato ry amimells (Rlbelin, W. E., Me Coy, J. B., Eds.), Charles C. 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VEROIEVA. O. ANTONOV. EX. M I B K Q V A Instliule of Hygiene and Occnpanonnl llenllh, Medical Academy, Solle, Bulgaria One of the most Importnnt problems In up-Lo-date toxicology Is that of long-term effects of chemicals. It Is notable for Its complexity, embracing pos sible manifestations of embryotoxlc and teratogenic effects, mutagenic, gona dotropic and carcinogenic effects, changes in the cardlo-vascular system, etc. The chemical formulations for plant protection, the pesticides, have to be stu died obligatorily troin the aspects of their negative effect on the organism, both of directly exposed persons and their future generations. There investiga tions should be a compulsory pari of Hie toxicological characteristics of each pesticide for the purpose of hygienic standardization. There Is dally close contact in practice of a large number of people with pesticides in the condition of production, use and consumption of foods contain ing pesticide residues. Sfudy of the changes In gonads,, capacity for reproduction and generations under experimental conditions These studies are accomplished us model experiments on test animals -- 20 In each group, equal number of mates and females -- most frequently adult white Wtstar rats or mice kept under conditions of standard rood regimen and the required quarantine period. Using type and duration of exposure compatible with the purpose of Investigation. The consequences of the effect on the sexual glands could lead to Injuries in the fecundation and to Impairment of the Intrauterine developmeu of the fetus and also to inferiority ol the generation. Only a quantitative evaluation of the danger of chemical compounds, established by complex methods of investi gation (functional, morphological and biochemical), could be a reasonable basis for risk assessment and for recommendation of a system of profylactlc measures. The studies are accomplished as follows: 1) parenteral rat generation (Fo), directly exposed to the examined pesticide are subjected to the following tesist Integral -- Increase of weight, behaviour, mortality, fertility (obtaining first generation), etc., In male animals -- assess ment of the functional status of spermatoza (character and duration of move- 295 R&S 041466 "Experimental Studies on the Chronic Toxic Effects of Vinyl Chloride in Rats" Sokol, J. A. et al. (1980). J. Hyg. Epidem. Immun. 24: 285-294. Review of article by W. J. Breslin, 8/23/95 In this study, although the numbers of rats with "damage to spermatogenic epithelium" looks elevated at 500 and 20,000 ppm, there is no dose response. The 500 ppm group had a higher incidence than the 20,000 ppm group. I would think that this 'dose-response' was highly unlikely. The paper also references multiple figures (1-7), but only Figures 1 and 7 were presented. The photomicrographs of the pathology apparently were not included. Again, a very weak presentation of the results, making it difficult, if not impossible, to interpret the results. I would qualify this study as less than definitive.