Document zop453wZexnBEmBmrQe6bkJ10

r. ;V; ^ h , k' Oi i r. i.. WA', A. i'Aohi, mu! A.l,to VTVTT * 1 ^*`'5 ' "* ' ^\l e> O ,'990 * v-;. - c " v ;m\l ', O"' ;. i V >.' <0-:;;;) c:.u:':T fm 1 J i.-omics to i`: - -I vine - f 'i.c '-'.in, mugs, : ;u,,> !T:h re pc.; red in hv. v !< ;n . \ _>' recor;'.!.':-! -y-j-Jr-rnI-J cr.-cimimus, j. r-'-.icc -J cm c;nf`>:i-s. Tj ;e ni.';;'1 c r i'' i ^ j. nf m; !.- {um-'u?, v.-hi-hi occurred h; . j uric jh` yc, (/ the H'-'iU jjicimnna ty; \v '"j V ol ; M;'/.'.. . >-:.!i`:;uf ;.t junior n-.v;;--.cp::ln.:,.?l cells. Jr. a honor nun cf r,u. ? hire prc-nfs r:-io:* of c. Lihginons tissus <h'.'i 1 e; ore, - m'k:;;Jiorr.a dec1.] >;-Cu in the m-rn. carpal and !!;' lous ! /eyu.r:.. of t!ic four limbs. URL 18900 IMTUGTM 7DN The rirtcog-'d: prc potties of r.rn . clic-mrcol organic cmupouinls use.! for (he prcpaia'io;'. of `'elastics'* have been widely i'/.o-'ir:.:.v',, and their hmi's and .effectiveness have been vreii est'iei::.l, Detailed infonruition on this subject nv.y be found in the literature id, f>. 8); however, all infu.inr'iicn o:nl icierences arc exclusively lelaLed to highly j/ol>compounds of roughly the same siae as 11510 in various in'.inslri'vj. Oticcginic polymers produce sarcomatous tumors, with the execution of poiyurcthans which, us reported by 11neper (6), also induce adenocarcinomas. Rebenliy, it has been dei'ior.stretcil that sarcomatous tumors (1--4, 7) arc transplantable, auJ it has been suggested that they may originate from the tissues of the capsule that gradually covers the plastic film. Thus, Brand et cl (2-4) have observed prent.jiif.nsnt areas made of poorly diffeicntiated fibroblasts which were firmly atiach:d to tfic plastic film up to the Tv.onvn! of iraliemrit transformation. Thus h'ves'igjiion demonstmtes that even the monomer MATERIALS AlhO METHODS vinyl chloride possesses oncogenic properties when used with an appropriate medal different from the models previously 'Ihe experiments were performed with \i:/l c?T reported by several authors (9--12). The carcinogenic response \CIU~CiIC3, the nionnal''sei*ate dcrivatne of e'liylcn:'} to vinyl chloride fTlows a singular pattern for the different coi'Uiier'via! grade (99% purity) assumed to 0: n! j;,: tissues and organs of ihe rat. in significant amounts of various noncaremr- gri.se contaminards. MATERIALS A?ri' METHODS Thrce-mcnliuold Wistar (Ar/'iRn-'ile albino nts {: J5Cg body weight) vsere exposed to vinyl eWorld: v::jv; ,'i i '( 4 hr a day, 5 da)s a v-eek, for 12 months. The animals < 1c in mete' or vinciic, air-tight ceges in which 2 cm' ~ . r ,, ........... . , jr> i . {TH*'i .. chloride, was iniro itrce l. T'.venr'-fb.e ret: 0. were ihe contio! group. At the vr.<! c the- 'rcaimcr.i surviving animals vwic killed ai 20-<J:.> mieriai:-, .-.ui l' c impo/tanl tissues mui organs were cx.ir.'.ir.cu hlstccb>-,10.:! standard r.ie 1 ht.i>. During the period of c\pci.'rc, the :m were sliglitly soporil'ic; however, iite first few v.j'itl treatment were wet'1 tolerated and uo changes in g-ow bcis.'ivior were m>:;ccd. After 10 months of H.\o.cvv.t. aunnait bogan ti' show a hard urns lr ;;ic nara.niiic;;1 :r r \vhi *ii became piogresshvsy larger *?n!i'it re::c'a ,I j.he^i/ waiiuit (Jr shghtiy laiger. In most cases, th: -jwe:! r- voihl era!: it wns bi!a!?/ a) in only r' few amni.ils. / r:>- r ( or 2 S*'. 1 11 [ ilie, the grow irv- woes bee.nr v L ci.-tcd ;l:i 1 11 = ii :i ris tic debris, v,life ;a eCTt.'in ;i iiiii'ii of ii,'. i! Vtv.m to form on ih.'ii surfaces, in J i i vc . !>,.! 1 ('-.it (X.- ;; i.'s'CS were rrt inf eqral p.irt .if if. c i'erc/TTi'i.f." !. 'iotr C..'Vj c J ;io: be Ji,;iy .. owed l'io ::1 If'.l v. o iK'Cf.'J :ie zones v.-;;c f w:nd. i'iw show..v difim? V'', tio:i c.f a ; i often is iUUcre i!!i', : cs 4 the h:n: s v. cm covCiod ifl ^ numh": o : V, .`,;'0 form:.lior.s as hwe s c min:, of nr C IT 1wen hri-wi .w i hinder !.. r. ti:e h;'.h;s .e'ves. in .1 Ciarcs, ij'ic iu"ii ;s s.C-; hvL'.f v. i;h n . thick il'.M. 1 in i; w ukum! ew i` iw.lhe l. ;:- wan sometimes i.i rented n size :md wry fi; y, i! *. The ns weic y.;b--:\ ted to X-ray u: ! V *'s e! dineWiW i mervJs from the bep.irirviiig of t reatment i; ! Old..r to control : ue state of thi: skvlctol uo::c>. Ail ill?1 animals that inhaled 'in yl cli loriuc showed a .-iiLs of pc. wnchyrna! lesions. Among tl-* v : C % most pro'.nin.e nr weie the rfj/'pearanre of jrnmj'Iar and !'u;: kifijc.: sells, degen-': alien of the cerebellum, see;:re chron,ic hepatitis, h>: Oismiat piVl'l nonia, snd mode,-:1itc sv.t'hi-f, -f r1 i-e kidney pan-:ithyma, often assuming the pattc rn of tr.hu! ouep lirosis. RESULTS The rates of suiviva! and ths main findings rr-e summarized in Table 1. Almost oil the animals developed iurnots of the skin and lungs. Very few animals developed bone tumors; in these cases, the tumors were localized in the metacarpal and metatarsal bones of all 4 extremities. Skin tumors were by far tl'.c most frequent, amounting to 65 or 70%. Skin Tumors. The tumor that developed most frequently in the naraeuricular region v/as the epidermoid carcinoma, but we also observed papillomas ,uid rarely mucoepidermoid carcinomas. In ail cases, the neoplasms veeie of epithelial nature. The 3 patterns noticed cannot be compared to venous histotypes but rather to a transition of one type into ths other or, and which is more likely, to different stages of the same proliferative type. . Warty subauriculai growths occurred iu some r3ts. The histological picture showed papiUar epithelial proliferation, with progressive increase in the thickness of the epidermis (Fig.l). The papillary warts of exophytic type had a fibrous vascular stroma and various degrees of inflammatory lymphocytic infiltration, marked hyperkeratosis, parakeratosis, acanthosis, and areas of individual dyskeratosis or pearl-likc horny formations. The epithelial cells of the penetrating columns (Fig. 2) were irregularly arranged ar.d were frequently accompanied by an inflammatory infiltration of the dermis. The typical features of the Malpighian layer and of the stratum corncvrn of the prickle cells and of germinal layers v.cre easily recognized (Fig. 3). The horny layer was composed largely of cell nesr; which appeared at certain points within the epithelial msTfses and assumed the weli-kncvn appearance of "homy pearls" (Fig. 3, crrows'); they were made of flatten: J ami crmpres.jil prickle celts without nue>ci and were located aromi.i a ecu wot coi; of keratin, Keratinization was irregular 2nd often parakeratosis was obsened in the areas of the tumor in which the cells were loosely aggregated and undergoing ar. individual rather than a collective type of keratinteation (Fig. 4). In dv:;kera,o:ic areas, a few epithelial cel's tended to form pearls. The tumor seldom showed an undifferentiated growth with cellular pleomotphism and seveid mitotic figures (Fig. 5). A few tumors showed little nests of isolated pale cells {hiys. 6 ar.d 7} cf 3 types: niucin-c.'cduc'uig cells (originating from the duct epithelium of sweat glun-Js or salivary glands); squamous cells; 3.id i;uetmc*lj:iie edit with minor tendencies towards differentiation. | j J^ URL 18902 sXaup.rj pin; j.iAti 3p jo ?'i';po.v\S B TL.'A 4JW|J `Sin* JO'M'.ito Sip JO AS3J X'.SA f UJ UqmciqC iX'JlA p3|TMjin ?c;;i s?rj m;; Xq pc-doi?A.->n vuoisr-f jcui/uyurjcd jo S3;IX? aqi 10 sjctur.i psdojaAap qnumt asaqj jo v.;rqq opijoiqa iXuia woqjT/A Jtc jo Moy jurtsuoo n 03 pcqoafqns &J9M auui ojcndoiddc m;: jv puc sir.i imujiuijcidxo atp si: suopipuoo ?u'cs ;p japun jd.vq a:3M stcj jom:o? aqx 'spuiniv fJMi3 tJjCipjbo jo S3|iv,o| futscpua puc gmjtuBdas Bid* iUJOJ 0] piCAVUl pjpUOJXS pUC 3Oq ]50nJC.' 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SJaiuqo umu> ui jo wo;? jaqjp `pox.incoo S}\?o oiiri ja.' t|`!ii.w ut uptii'.: jo aJs.'A 0icq t_ 'luton pUR s^jriqn; ?qj jo uaunq sirj o;;;i pc-jc'OM puc sjunouic 3'.iiX-12a 1:1 paonpoid utor.ui '.pourju yio'\ lapnu oijvuroupicdXq 11ji.`.\ u.'siijdjoui.'qod J!:|uj|aa jo poj `sco.u! cu:os iq .. ja:.t?td 3mai r.W'.u; jejuciAjc m;j oju! 3uip`:?J'?T SAOuy.'syj.T.ci Xrqi'...'?doii3pB `/'['.ucnbAJj '.(f 1 -3:.;) ct;:u Jou.-uj Xj;u:cj sca\ :;:i;j ;ujcjdoiXo r^'pUTiqc qj:,v. sji?; j'.'j,;--.;X[cAl 2:, `idu'uujoo `:v:;oa jo s.>.?,(p[ r;o'.u jo j Xq pc-quii; cu^.'a uc aj.hjoiujU -uiajjcd r!.;;xv.3Ju 3'.;; siv. cs::":u:,7 '((i( ';>j) 7;.r/c'j i.';o'`Apj ;qi ;<_ SA-U.if.i y_ io^'oiouu .c:j ',\iijcinuns s:u;i uiuXq.''ii.M!..; Xu-uouquii 1 [! oi:;; p;i3j>."> oj /juopua; c p3`AOt;J Sj;;n j ru: 1 l ? j.% C'puijou.'yqd ju y .;;:x^ijipun ;o r ppicMjs sc p-ju-^idt; puc pcut.Mij X;'.VjiC..'ujf 1/0j| > jt.a s\*jii,ijujupjcjJ lsr-.r uj p.'l-'jCAC'p X;;.vv! '(h'3: .[I c '.nciqy p.-u iodti:v; pi.;-(p'C! 0 s:u-:u,.-1^ Xuupdijit puc JV[l>CilJ .U.JiUU-'M JO S'! p.VUCJJ'C SiJA.1 J'lUUinjOD jo ;a.;io jo X; ii'.:'.u::op;.jd po;s:uuoa puc ]:i3iL-dup.*rp ,(;uj Jt.-u;; u: ua.-s 3:cia\ siou-u] ri;p 'sx'.njruinq Ui'ii -i-.u.i-HUUKup.ulr, oq: uioi| .U.-u-uiduo :mi;m , iouiijpsda in; a.u [oji ji-j ui X|;ir> s'.nn'uuoiiioiaaou ijuT Xpucui ajoa\ Xj,':'M '.biiJimAo `sioiunj jcrvij, Xiirjriidi.vj t'SS`ON As in iiunty cnrchu "cuexis studies in which nni^i i|A - minors . i-.c hi i'iiTcr ::i! *and or"' inv, \V <1.-r; rnuil '..s- v,;: i.-i'cil b\ t I. >) s ol' a IV-`TO [MCMTlU positive 1C ;,vrr,;cc tj UMC.I v. i? : t'v c/'iicci'i'tv'tioci of the c :re i.1 o~o;ch.* o< ii:.>.vjtiJ. I::; c'.:`:.!v.ivus e;. .viii is tin: n;or. i'.t ce;-tfbic to :!'C 0.1 iq.unic eh ut v:r,yi ch'. 'iidc. rn'1! a Co not wkv :h c cv {.nteoui ;'c the .'.me Site, <\y., tile region iuch.thrift in L-; whni/ih-'Y a:;--) parotid .".hinds arc k;.n J. I; if po.-hoi-.- tiu:t tnc s.hi'..--y !..nds juey by invoiced in :h .a o: n xc re l i c :i f'i "irM chloric1*: or son;c of ho ;.?o.: hccc.,:i;'-.oban puAiucts. 'lids hypothesis h strongly irr1 by inory!: .ilogiaal finding; shewing (he specific leu.! :ivV' of die desvioped tuv.or to appear as a jiu.o-ocp: .huooid r.'-rcincrna. which intlfcales the active of the mucus pLur.h:h:i' cells 10 (he tumorous y/ow.h, f.ucii kinds of histolypos are often related to some phiiu'ukir ;v'c,t""-,ic's, and, ihcivfore, :h.~ kh.iogcr.esis of human mucoeridenn-'ic! wucincrm i'j? bee;-, icstriclcd tn the cells of intruielstcd ducts. This hypothetic.'.] interpreiion must he coufirir.cd by fuu'LC experiments in v. 'b'jh the action of the vh.yI chloride shock; be restricted to the S2hv?iy system. At t!;e fOftLCittr.tiions tJ-,ed, sutur.nion snd wjUmv; of the fur rni-tbt welt be expected. Under (hose circumstances, the ir.riird cleansing habit of the mi mi^ht add a significant inpcstioji problem with subsequent concentration of vinyl chrfiide in tire salivary glands. Tire local extreme com cnlrafion couhl be the result of the difficulty of a complete cleansing by the rat. 'Che neoplastic response of the lower respiratory tract, although of lesser magnitude, is of relevant interest, since some of `he tumors '..ere nrcvphulosi.'aliy similar to those described for fito skin. The hypothesis tint mucus-producing cells may be capable of retaining vinyl chloride o: its decomposition products seems to be relevant once more. Obviously, a different interpretation is required for the pathogenesis of the bene tumors and for their simultaneous incidence at the level of oil 4 limbs. REFERENCES 1. Bzncrjec, M.. and Batts, R. Prevalence of Hctercpfoidy in Plastic Film-induced Primary Sarcomas. Brit. J. Cancer, 20: 555-563, 1966. 2. Brand, G., and Buoeu, L. Polymer Tumoiigencsis: Multiple Fi<?neopbstic Cones in Priority Order with Clonal Inhibition. Proc. Sec. Exptl. Biol. Med, !2S: 1153-1153, 195S. 3. Brand, G., Buoeu, L.. and Brand, I. Malignant Transformation and Maturation hi Mon-dividing Cells during Polymer Turnorigenesis. Proc. Soc. ExjnL Riot. Med., 124: 675-678, 1967. 4. Brand, (!*., Buoen, I.., and Brand. 1. Carcinogenesis from Polymer Implants: New Aspects from Chromosomal and Transplantation Studies during Premalignancy, i. Natl. Cancer Inst.,.??: 663-679, 1970. 5. Drjckrey, H. Kxperimentei's Celtraege wura Mcchar.ismtis der Carcinogencn Witkung, A/zneitnittcM-'ofsch., /: 383-395, 1951. 6. Huepcr, W. C. Cancer Induction by Polyutcthan aol Polysilicone flashes. J. Nall. Cancer Inst., 33: 1035-1027, 1964. \ . ' '- e. (... .trs 1 *nd Bran** G. Folyaie; lumorigcr.csis Clonal Octcminatiwii of ITbScpabi jtogkal Oiarac.eristics during Early Prciieoplasia; Kdatkinstiips to Karyolvpe, Meuse Strain, and Sex. J. Natl. Cancer Inst., 44: 785-793, 1970. 3. Kogan, A. Experimental lllastomegatcsii Cruised by Synthetic Polymer* (Plastics). Mcdririnc, Moscow, l: 215-237, 1955. 9. MttstromaUCQ, E., Fchtr, A. M., Owisti, II., and Panziger, D. Acute Ir.l nljtion Toxicity of Vinyl Chlorite to Laboratory Animals. Am. Irrt. Jlyg. Acc. I., 21: 394-397, I960. 10. Twkcrson.T. R., Oycn, F., and Rowe, V. K. Ttw Toxicity of Vinyl Chloride as IVtcsrair.ed by Reix*us*il Exposure of L:-l/orstory Animals. Jr.d. Hyj. I., 2S4--361, Oetot-er 1961. 11. Van Duran, it l... Sivik, A.. CoLlschirudl. B. M., K.ttz. C., atul MeHiionn-.*, S. C.TiS.iojf;ncit, of Ilalo-Lihcss. J. Nad. Cancer lnsC.43 431 I9b9. 7. Viola, P, J., F.ii.mloyy cf Vjnyl Cilnride. t6;'.i Irloinjiiourl ' .......... vein n! U- ,ii!i iftii.in N'c. \;s/" v.n .M,Y4isn Ac ivi. / 'l l'.1' .'I.;1.' :N . :" .; ..'.i ! 'i . \ 1 i * i;* .' . `' " " ' :' " - = ..," of......... -.; '' .' f:hd`\ '~i ; ' : i- l 1 I:. A- v.iv;: 5 J_i> s l* ul ic, !\>r a .k 1'. R..t l 2, 3 4 .5 6 7 3 M .S -.'i'. S\.-', :.iij ^ *in 2d- 303 310 \33 337 3`t? 357 354 >: -.) Tumor: Jojrg5 Mir? I:-;.-m:! Aacnoj:'an,Jio:ii.. F; i.: i 10 i/i-->'r. re;.' : i C;.i< M; . I,:", V '-i .i- No tumor Ad?r,- .'.ixcinonra r;1 lol'c- No tumor r.r-. .-r u.-.ri No tumor Li.: xfrizsd c.iu-i.ii.-.'* i ! inr : _ : 0 .=id t3K i c I.'pi.-r.';!, No tumor Nc tumor No tumor Horv.s O \ ochondrom.'i No lunior No tumor Osteochondroma Osteochondroma '* No'tumor G'kodiondroir.a No tumor I.', 17 2* 23 24 25 26 359 3S0 383 , 3S0 380 380 380 1'j iO- : i'.: J cj j :'-\i iip:-.; -: C-irCJ..-),:- Kpi-'.-. K<Tirf;i.'i5 I'p'lc-r.VV;' Er-i.lcrmo^ tsircirion;; Epldsnr.oIJ carcinoma Epidermoid carcinoma Adenocarcinoma No turnor No tumor No tumor Adenocarcinoma Oiteochondroma No tumor No rumor Muen-.-producirg adenocarcinoma (a.Neohr cell caicinoira?) No tumor No 'Minor No tumor Sqiirjnous cell carcinoma No tumor URL 18904 J Qaamsyy^il ^ i^Ai , CW^', _ fl+A* 'h*u+J%**> d***ff> ^7 . ^ f* 6-yt*+~~iy c L',- i-'eg J \o.._. rr*i.g , . f K i ~t ' n ( )' f- ry; i- .J h wk s -U! . in o <2 u j i*i a s' 3 ' \ r - a -;-, yy y-~yyyy-' c-- ....... ''- r " ' ' ' v'--!' ^v*V. -"V:-/. V- '. . _ |. ... ; .-, . .V, '- ' s . y y'' 'yy y-yyyyy 0- ' :. ,,`t ( ... .'v t.v.'' . ,. -1* y.*v.> .. -c..'-,' ; . ,y>,, v-.: y y : -- .--yyV''-y r L c' ' ;' `` ' / , ~y ,'.c:' 1 '* v:.^- v- '1 5 ' f-' ' .. <** w t \ .. . *: ' V>'V >-v' <' Wr Vv J*') ,/' - ? V. t;' -- ri Vf' ' . -'U ' tx-- - i' ,v h -' .w-Avi-/ f W*T , t ' > rr..-***---\ v-t j'~ ^:sr- ' , >* y/:;-^- ? y;, f . .-<>: . .7 ^ ' . - ; .ti;**'-; > 'v >> ' t. ... ^ 4 V; ' . #`^ ` l;v yy . :-y,y ^ 'y. } <. i-y . . /, , 'ly-y - - '/.:?y >v r.vJ f. ^.- ^v - * ... h. ^ COLi'f^fc/V t*' v r^.vv: V l r> k..?-v: . <-* .,.4^ . 9 t " > ^ v"' `v&vv';^' * ' \ V- *' ,< ^ L*'' f". 'V *` y.\ V) URL 13906 ~o #* P URL 18907 T.| C'-:-KSi CA'I-Y.i- : I s 5 Ta!:o 2/22-19 C Gilley F-^l ^ p. L. Viola, A. Biyotti, ivrl A. Caputo p. /,. Viola, A. Biyotti, and A. Copula p. L. Viola, A. Piyotli, end A. Capato p. L. Viola, A. Bigotti, and A. Caputo 000 000 000 MAY 197! MAY 1971 MAY 1971 MAY 1571 Or.coyoeic Activity of Vinyl O';/' /Activity of Vinyl CJ,l, . ' : Oncogenic Activity of Vinyl C/.':'1 Oncogenic Activity of Vinyl C:. CANCER RESEARCH VOL. SI CANCER RESEARCH VOL. 31 CANCER RESEARCH YOLO CANCER RESEARCH VOL. 31 f;CJ CO no C'Y> URL 18908 1A preliminary report of (he results reported hoe was given at the Tenth Internationa1. Cancer Congress, Houston, Texas, May 22-24, 1970. Received July 31, 1970; accepted January 12,1971. Figs. 1 to 18. All sections were stained with II & E. Fig. 1, Squamous cell papilloma of the skin. X 25. \ Fig. 2. Transitional stage from papilloma to infiltrative type of cancer. X 80. Fig. 3. Finger-like tiabeculau branch to form secondary processes showing homy pear! formation (j.tcwv). X 25. -? _ Fig. 4. Dyskcratotic area. Few epithelial ceils with a tendency tc form whorls. Little capacity to develop into horny pearls, x 250. Fig. 5. Atypical Cells parliy lacking priefcks and showing cor.sidct.ihk variation in size, shape and many 'miotic figures. X 250. Fig. 6. Mucoepidermoid shin tumor. Occunence of hydropic epidermoid cells, basal cells, columnar cells, ar.-l oxyph'iir c-elE. in vaE-.-uc proportions, x 100. Fig. 7. Mucoepidermoid skin tumor, showing differentiation of masses of squamous epithelium from columnar evils, lining and pr-slifere'inj into distended tubular spaces, x 100. Fig. 8. Micronodulnr adenocarcinoma of the Jim:? arising from a segmental bronchus. X 25. Fig. 9. Detail of Fig. 3 showing tubular aggregates made up by cells wit!; hypcrchroinatic nuclei Fig. 10. Nodular bronchiolar alveolar mucus-storeting adenocarcinoma. X 100. Fig. 11. Detail of Fig. 10, showing an alveoloeotitc pattern. X 250. Fig. 12. M*icuvprodud.;g cells with hyperehramitic and pleomoqjhic nuclei end occurrence of signet ring cells. X 250! Fig. 13. tsv.uarriMi', cell carcinoma of tnrr.n.*;. >; 100. Fig. M. Csteochoiulr.ma developing as a protuberance from the vmll bones of metacarpus and metatarsus. X 25. Fig. 15. Magnification of Fig. 14. The protuberance consists of bone trabeculae, capped by cartJage, and a fibrous Izy-it EmctioiV'^ perichondrium. X ICO. Fig. 16. Os'cochondronia. Cartilaginous growth characterized by ii.tyer-like proliferation. X 100. Fig. 17. Csteuchonilronn. Area of cndochottihbl ossification. X 100. Fig. 13. CcU-j'ui area of an osteochondroma showing the transition fror.t cartilage to osteoid, x 100. I 3.