Document GmmRDb12KgjB2Q22apynqZEYN

Medicine del Lavoro March 1970 (VoX. 61. n.3.1970) ( pp 174-179 Zstituto di Patologia General dell * Universi t a di Perugia Direttore: Prof. A. Caputo PATHOLOGY OF VINYL CHLORIDE P. L. Viola During the last years a syndrome characterized by alterations of the skeleton, teguments, nervous system and hepatic function^* 2, 3, 4, 5, 6 has 1-een observed among the workmen associated with vinyl chloride polymerisation process. An experimental prograr-.e has beer, perforrrd in order to evaluate the toxic effect of vinyl chloride on the animal organism, and in order to try to .eprocuce in rats the acroosteolytic lesions observed in man. MATERIALS AKD KETKCDS i I s^ Twenty-five Wistar male albino rats, of average weight ISO gr., were exposed to vapours of vinjl chloride 4 hours a day for 5 days a week during 12 months. The animals were kept in ( a plastic air-tight container through which there was a constant flow of air containing 2% in weight, equal to 30,000 p.p.m. of vinyl chloride. At the end of treatment the surviving animals were killed at twenty-day intervals, and the paws, brain, liver, kidneys and thyroid were examined histologically after fixation, inclusion and colouration by the ematoxvlin-eosine. Van Gieson. PAS, Weighert, Bielschowsky-Gcmori methods. Twenty five rats of the same breed vjere set aside as a control. RESULTS During the period of exposure the animals were slightly soporific but the first few months of treatment were well tolerated and the rats showed no change in body growth or behaviour and no organic alteration visible macroscopically or by radiological means. After ten months some of the animals began to show a decrease in we.ight, in agressiveness, in their reaction to external stimuli, and often o disturbed equilibrium. Thirteen animals died from cardio-respiratory complications. Two animals died from hcroatoperitoneum. Host of the animals showed pathological involvement c CO *sj CD O o BFG08475 2- - Pathologv of Vinvl Chloride F. L. Viola of the brain, liver, kidneys, and thyroid. Six rats showed histopathological alterations of the skeleton. The small metatarsal bones showed an extensive periostal proliferation of cartilage-like material apparently originating by metaplasia directly from the bone. All around the newly formed cartilage the cellular components were compressed and arranged tangentially to the cartilage itself, forming a perichondral layer. The isogenous cartilagenous groups were irreg-V . ularly arranged and their nuclei were of varying size and often number per cell. The edges of the cartilage were irregular, showing digital extroflexions resulting from a varying growth potential. There was also evidence of chondroio metaplasia in areas of mature compact bone, in which the eartilagineous elements were grouped around a central nucleus of bone, as in typical osteochondromatosic processes. In the small bones the chondroid metaplasia was often very extensive and the bones seemed to be impregnated with a mucoid substance which altered the characteristic disposition of the bone tissue obliterating the. cemei:. lines. The skin of the paws showed areas of hyperkera tosis superficial thickening of the epidermis, vacuolization and degeneration of the basal layer, disappearance of the cutaneous adnexa and modest accentuation of the papillar layer of the derma. An almost constant state of edema was observed in the epidermic zone. The connective tissue showed dissociation of the collagen bundles and a diminution and fragmentation of the elastic retic ulum. The small arterial vessels showed signs of endothelial fibrosis with a thickening and dissociation of the elastic membrane, often accompanied by a partial hyaline degeneration and homogeniza tion of the walls and proliferation of the endothelium. Some of the vessels appeared completely blocked by a proliferation of the connective tissue in a formation not unlike that of onion skin. The small nerve bundles were often surrounded and invaded by fibrotic processes. A microscopic examination of the brain revealed diffuse degenerative lesions of the grey and white matter. The external granular layer was often reduced and in some areas this was true also the medium sized and giant cells. Numerous examples were found of hypercoloured, atrophic*neurons with disappearance of the. nucleoli and sometimes also of the nucleus itself. At the level of the white matter there were zones of intense, reactive gliosis consisting for the most part of cyto plasmic and fibrillar astrocytes, some of which were arranged in a concentric disposition around the blood vessels. There was evidence of neuronal phagokaryosis with satcllitosis and the deposition of neuroglial elements around the altered nerve cells. BFG08476 008^602 -3Pathologv of Vinv'i Chloride P. L. Viola There was modest proliferation of microglial elements, especially in areas of more intense gliosis and zcnes of intense spongiosis showing an accumulation of astrocyte-type elements with basophilic cytoplasm and abounding in gemistocytic and microglial elements similar in appearance to ."scavenger" cells. The cerebellum showed signs of atrophy of the granular layer which was often represented only by a few isolated nuclei. The layer of Purkinje cells was in some places profoundly modified, the cells appearing to be undergoing intense degeneration and all the various stages of this process were, observed, from the whole cell to the small homogeneous bodies with indistinct outlines which represent the most damaged form of the cell. Except for nnall and limited areas, the molecular layer seemed to be well preserved. the liver was often of increased volume, sometimes subicteric in colour, with a smooth surface and somewhat more brittle consistency than normal. A histological examination showed in the majority of cases signs of diffused interstitial hepatitis with numerous hepatic cells in the grip of regressive processes .varying from torhid degeneration of the cytoplasm'to necrosis with marked cytoplasmic and nuclear polymorphism. Some of the hepatocytes showed giant or double nuclei. In these areas of cellular necrosis a corpuscolar exudation was always present consisting of round cellular elements of the lymphocyte or plasmacellular type. There was evidence of an abnormal proliferation of the Kupffer's cells, which were often hypertrophic. The triangular spaces appeared to be increased by the infiltration of round and polynucleated cells and eosinophiles showing marked polymorphism. The portal capillaries, centrolobular veins and sinusoids were often blocked by numerous centrally-located areas of partial necrosis, often accompanied by a diffuse steatosis in the form of small drops with clearly-defined areas of acidophile necrosis and the formation of elements similar to the round acidophile bodies of viral hepatitis and the "Cauncilman" bodies of yellow fever. In certain cases evidence was found of an intense fibrosclerotic reaction alongside the degenerative processes. The kidneys did not appear to be excessively altered by the prolonged treabnent with vinyl chloride, although they showed signs of tubulonephrosis, sometimes accompanied by chronic interstitial nephritis. The thyroid often showed a colloid goitre and a marked increase in parafollicular cells. f1} 0378003 BFG08477 -4paf-holocrv of Vinvl Chloride F. 1*. Viola The control animals showed no histopathological alterations of the skeleton or of the various organs. *' CONCLUSIONS This research confirms that the animals are sensitive to the toxic action of vinyl chloride. The lesions of the bone and connective tissue are similar to those noticed in experimental osteo-latyrism and to those described in a man affected with acroosteolysis of the hands (Marin). It should be pointed out that the roentgen-- ological findings of skeleton in man rests on cartilaginous transformation of the bone tissue. Therefore according to reccomendation made at XVI International Congress on Occupational Health of Tokyo (1969) I should like some precautions to be taken in the manufacturing plants polymerizing vinyl chloride, such as reduction of the threshold limit value of monomer, and substitution of manual cleaning of autoclaves by automatic devices. i j j | ; The results of this investigation show that animals exposed to vapours of vinyl chloride may show degeneration of the skeleton and connective tissue with histopathological pictures similar to those observed in human acroosteolysis of the hands. The bones in fact undergo processes of intense periostium growth and diffuse, chondroidmetaplasis. The connective tissue is dissociated into collagen bundles with a reduced number of cells, the elastic reticulum is markedly reduced and fragmentary, the small vessels of the deep layers of the derma show hypertrophy of the walls with a diminution and sometimes obliteration of the lumen, the nerve endings are surrounded and infiltrated by fibrous tissue. Degenerative processes of the parenchyma were observed in the brain, in the liver and in the kidneys. NOTE: Figures on available copy were not suitable for reproduction. They are as follows: . *. 7. -- * :* \V V . Fig. 1 --- Periostal proliferation of metatarsal bone of a rat 16th months old, exposed to vinyl chloride vapours for 12 months ^ Fig. 2 -- Periostal proliferation of metatarsal bone of a rat, 16th months old, exposed to vinyl chloride vapours for for 12 months : fr00S460: BFG08478 T -oPathology of Vinyl Chloride P. L. Viola Pig. 3 -- Periostal proliferation of metatarsal bone of a rat# 16th months old, exposed to vinyl chloride vapours for 12 months. Fig. 4 -- Chondroid metaplasia in mature bone of metatarsus of a rat, 16th months old, exposed to vinyl chloride vapours for 12 months Fig- 5 -- Chondroid metaplasia in mature bone of metatarsus of a rat, 16th months old, exposed tc vinyl chloride vapours for 12 months Pig. 6 -- Chondroid metaplasia in mature bone of metatarsus of a rat, 16th months old, exposed to vinyl chloride vapours for 12 months I suus&60& BFG08479 / X CANCEROCSNIC EFfECT OF VTKYL CHLORIDE P. L. Viola * (Regina Siena Institute for Cancer Research) Rome, Italy Presented at the Tenth International Cancer Congress Houston, Texas Hay 22-29, 1970 The demonstration of oncogenic activity of some chemical organic compounds employed for the preparation of "plastics* has been widely investigated and tHe limits and the effective* ness of their oncogenic power have been well defined. The present investigation demonstrates that it is poss-.ble to obtain for sane experimental models a marked carcinogenic response to a monomeric precursor, i.e. vinyl chloride, of plastic polymers whica follows a peculiar pattern for different tissues and organs of the rat. Twenty-six Wistar (AR/.iRE) male albino rats, of the average weight of 150 gr. were exposed to vapours of vinyl chloride 4 hours a day for 5 days a week during 12 months. The animals were kept in a plastic, air-tight container through which there was a constant flow of air containing 3% in weight equal to 30,000 p.p.m., of vinyl chloride. At the end of treatment the surviving animals were killed at twenty-day intervals and the most important tissues and organs were histologically examined by conventional methods. Twenty-five rats of the same strain were kept aside as a control. During the period of exposure the animals were slightly soporific, but the first few months of treatment were well tolerated and the rats showed no change in body growth or behavior and no organic alterations visible micro scopically or by radiological means. 65% of the animals developed tumors of the skin and 26% of these showed tumors of the respirator tract exclusively localized in the lungs. Very few animals developed tumors in the bone and in this case the tumors were localised in the metaphysical region of the femurs, and it is worthy to mention that the femurs of both posterior limbs showed the carcinogenic transformation. Tumors of the skin The skin transformation which developed aiorc frequently in the para-aural region, has been the epidermoid carcinoma, $>ut wc have seen also papillomas and rarely mucocp.idermoid carcinomas. 20978006 f BFG08480 -2Cancerogpnic Effect of Vinyl Chloride ' P. L. Viola Tuwort of the rcniratorv tract Even if as far as the percentage is concerned these occur in a smaller number* their morphologic appearance is mainly of an adenocarcinoma; only in one rat it has been observed a :urnor of the epidermoid type. Sometimes the tumor showed*an early developmental stage and consisted predominantly of cubic or columnar cells arranged as regular or irregular tubular and papillary elements supported by_poorly developed fibrous stroma. Tumors of the bones In the metaphysical region of the four limbs a large proliferation of cartilaginous tissue arises outwardly to the periosteum and seems to derive directly out of the osseous cortical by the growth of its cells. The cartilagcnous growth is dishomogeneous as it is shown by the extension of finger-like prolongations into the boundary of neoformed tissue. Beside the chondroblastic, chondrocytic and angiomatous areas* manifestation of noticeable growth power, there are cartilaginous zones with regressive features* as fibrosis and hyalinosis. The results reported above indicated that vinyl chloride is..an effective carcinogenic agent for the rat. As for many carcinogenesis studies, where multiple tumors arise at different sites,-in different tissues and organs, the data obtained need to be evaluated considering a more prompt positive response according to the ideal concentration of the carcinogenic. 2t is noteworthy to emphasize that- the cutaneous system represents an impressive pattern of susceptibility to the vinyl chloride. Another point to be considered is that all the cutaneous tumors developed in the same site. i.e.. the region including the area. in_which.submaxillary and-parotid gland are located. No implications to himan pathology ean be extrapolated from ----tshe-expcrimental model reported in this paper. / * BFG08481