Document nkwa0N4e8ZKBR1R0qOXonV7ea

r. * Dangerous Properties of Industrial Materials Sixth Edition N. IRVING SAX Assisted by: Beniamin Fener/Joseph J. Fitzgerald/Thomas J. Haley/EBzabeth K. Weisburger VAN NOSTRAND REINHOLD COMPANY NEW YORK CINCINNATI TORONTO LONDON MELBOURNE RSV 0016816 2721 vmm CHLORIDC VINYL CHLORIDE CAS RN: 73014 mf: C>HC1; raw: 62.30 NIOSH KU 9623000 Colorless liquid or gas (when inhibited). faintly sweet odor. mp -160*; bp: -13.9*. lei - 4*. uel 22%; flesh p: 17.6*F (COC), fp: -139.7*. ddiqutd): 0.9193 ft I3V4*. vtp. press: 2600 mm <1 25*. vep d: 2.13. autotgn. temp.: 882*F. Slightly sol in water; sol in sic; very sol in ether. SYNS: atLoeocntsM* aaoucrHvLJMK CMLoeuei os vinyls (fssncm) CLMUSO IM VtNILS (ITALIAN) ETMYLXNX M0WOCHLOUDC uoNoaaoiotnuHt MONOCMLOeOCTHYUENS (DOT) VINYLCHLOCIO (OSSMAW) VINYL CHLOtlDC (DOT) VINYL CHLOMOI MONOMU VINYL C MONQMSS WINYLU CMLOUK (fOUSM) TOXICITY DATA: 3 mm> tirv 23000 ppm simiihU 2000 ppm/>4W.| WMii/ne 1 pph/24H-C iUmue TCLe; 30 mg/mJ (3Y msk) iU.ni TCLoJOO ppmStH (6-tSD PS> ihl*m TCLo:1300 ppm/24H (I-9D TO) ihiftt TCLe'.ICBO ppm/*H (12-ltD png)'ETA ihHif TCLe:300 ppm/4Y-l:CAJt orWn TDLo= 10 |m/kf/S2W.| :CAR iU-m TCLo'-SO ppa/32W.|: CAJt iki-fil TCLo-4000 ppm/4H/a2*ltO pn|>:CAJtC iprat TDU'-2) m*/k*/63W.l:ETA went TDLo:21 *g/kg/47W.l:ETA ihl4m TCLn:S0 ppm/30W-l:CAR ihMwm TCLe'SO ppm/4H/30W. 1-CA* iUm TC-2300 ppm/UW.l-NEO ihl-nt TC:230 ppaVSlW.t :GAR ihLmm TC: 90 ppm/4TW.| :CAh otMlt TP:M ^/kg/JY.|:CAJt lUms TC:2300 ppm/2*W*l: NCO iU*w TC-2300 ppm/3JW.CCAA ifci-fU TC!230 ppm/2Y-|:CAIt -1-1 *--- TC:300 ppm/4IW.[:NEO iU-ru TC;230 ppm/IOW.!:CAA ihUit TC-SO ppm/37W.|:CAJl ortn LD:300 m/k ikHPC LCLe:20 ppm/3QM CODEN: MUHEAV 9I.3SI.S1 ARTODN 47.7IJ1 MUREAV 9US1.S1 CTPZAB 24<5U*. TXAFA9 33.1J4J3 TXCYAC l |.43.n ANYAA9 271.431,74 JOCMA7 14.109.74 APOCOT 3J14.74 ANYAA9 271.431.74 ANYAA9 271.431,76 APOCDT 3JI6.74 APDCXJT 3.214,76 ANYAA9 271.431.74 APOCDT 3.214.74 ENVRAL 1&213.7I JTEHD4 4.13.71 nEHD4 4.15.71 EVHPAZ 21,1.77 ENVhAL 14JI3.7I ENV1UL 7.3*7.74 AAKUAW 34.1.74 MlgAAD 43.421.74 MELAAD 43.42t.74 MELAAD 43,421,74 QQW*p SSOVA7..1I40JS Aquatic Toiieity Rating: TL96:ovcr 1000 ppm WQCHM* 3,*,74. Carcinogenic Deteraunetaon: Human Pomtive IARC** 19.377,79. TLV: Air: 5 ppm DTLVS* 4.427.8a Toxicology Review: FAZMAE 18.363.74; JTEHD6 1(1X47,75; CMTVAS 10(3X49,73; CHWEAP 70,5,74; CANCAR 39.1792,77; MUREAV 32(2X93,76; ZHPMAT 166,113,78; BNYMAM 54.413.78; AfiMHAM 33.583.77; CBINA8 22,117.78. OSHA Standard: Air TWa 1 ppm; CL S ppm/ISM FEREAC 40,27073,73. DOT: Flammable Gas. Label: Flammable Gaa FEREAC 41.57018,76. Occupational Exposure to Vinyl Halides recm std: Air TWA 1 ppm; CL 3 ppm/lSM NTIS**. "NIOSH Man ual of Analytical Methods" VOL 1 178. NIOSH Cur rent Intelligence Bulletin 28, 1978. Reported in EPA TSCA Inventory, 1980. EPA TSCA 6E No. 03780104---Followup Reply Received as of ApriL 1979. THR: HIGH irr via inhal route and to skn, eyes and mu mem. In high cone, it acts as an anesthetic. Causes skn buns by rapid evaporation and consequent freez ing. Chronic exposure has shown liver injury m rata and rtots. Circulatory and bone changes in the fingertips reported in workers handling unpolymchxed A hmn brain CARC and an exper brain CARC. NEO, ETA via inhal route. May cause local irr. Fire Hazard: Dangerous, when exposed to beat, flame or oxidizers. large fires of this material are practically inextinguishable. Spontaneous Seating: No. Explosion Hazard: Severe, in the form of vapor, when exposed to heat or Same. Also, on standing, forms per oxides in air and can then explode DisasterHazard: Very dangerous; when heated to decomp it emits highly tox fusses of phosgene; can react vigor ously with oxidizing ----Before storing or han dling this material, instructions for its use should be obtained from the supplier. To Fight Fire: Stop Bow of gas. For further information see VoL 1, No. 3 of DPIM Report. RSV 0016817 nofield 0-163. tNVlBOl useakch 16. 285 -301 (1978) Putmonary Tumors Induced in Mice by Vinyi Chloride Monomer1 Yasunosuke Suzuki2 Environmentai Sciences Laboratory, Department of Community Medicine, and Deportment of Pathology. Mount Sinai School of Medicine of the Cin University of Sen York. Fifth Avenue and 100th Street. Sen- York. Sen York 10039 Received August 15. 1977 Neoplastic effects of vinyl chloride were siudied in lungs of 27 mice exposed to vinvl chlonde monomer at 2500 and 6000 ppm for 3 and 6 months. Pulmonary turnon were observed in 26 of 27 experimental animals. By light microscopy, the tumors were multiple and ar ranged in either tubulo--papillary or adenomatous formations. Although occasional mitotic divisions and invaginations into the bronctuolar lumen were observed, no mccastases were found. By electron microscopy. than microvilli, tight junctions between two adjacent cells, appearance of osmiophiiic lamellar bodies, large mitochondria of irregular shape, veildeveloped Golgi complexes, continuous or disconunoous basement membranes, occasional appearance of "sequestration" and of crystalloids, and lack of both eilia and mucous secret ory granules were observed as characteristic features of the neoplastic cells. Some of the cells were poorly differentiated and were equipped with poorly developed organoids, with out formation of osmiophiiic lamellar bodies. The pulmonary tumors corresponded to "alveologenic turnon or alveoiogcnic cancer," It is suggested that the neoplastic cells were transformed from type II alveolar epithelium via its hyperplastic form. It is concluded that mouse lung is an extremely sensitive indicator of the oncogenicity of vinyl chloride. INTRODUCTION Hepatic hemangiosarcoma has been accepted as a serious health hazard as sociated with vinyl chloride exposure among workers in vinyl chloride polymeri zation plants (1-7). A risk of lung cancer has also been reported among the workers on the basis of epidemiological studies (8. 9). Experimental studies in rats. mice, and hamsters have shown that, in addition to liver, various organs such as lung, brain, breast, and skin, including sebaceous glands, were involved in induction of primary neoplasia by vinyl chloride. Al though a number of studies have demonstrated that pulmonary tumors can be induced by vinyl chloride in mice, the significance of such occurrence and the nature of the turnon have not yet been appropriately explored (10-18). We have undertaken a preliminary study of pulmonary oncogenetic effects of vinyl chloride in mice to provide information on these questions. A num ber of significant observations have been made: frequent occurrence of pul monary tumors, unique ultrastmcture of the neoplastic cells, findings concerning the precursor of these cells, as well as data regarding the submicroscopic aspects 1 Supported by Center Grant ES 00928 from the National Institute of Environmental Health Sci ences, U-S- Department of Health. Education and Welfare. : To whom requests for repnms and correspondence should be sent: Environmental Science Laboratory. Mount Sinai School of Medicine. Fifth Avenue and 100th Street. New York. N. Y. 10029. 283 OOI3-J51/78'l6!J-o:a550:.ODO Copvnffii l*7* t" Scaatmic Pm. Ik Ml n|Mi at rcproaufiM* <n kvm frvrvrt II. 1 \ t} : ,,V-J- 286 VASUNOSUKZ SUZUKI ari :*V^i s?*' Fic. I. Two pulmonary tumors induced by vinyl chloride are seen in the peripheral pan of a mouse lung (2500 ppm in group IID, Hematoxylin and eosin: x.64. of the neoplastic transformation from the precursor cells. Details of these findings are reported here. MATERIALS AND METHODS Twenty-seven CD1 Charles River white strain male mice. 4 to 5 weeks old at first exposure, were used. These animals were divided into three groups. In group I. six animals were exposed to vinyl chloride at 2500 (three mice) and 6000 (three mice) ppm/hour. 5 hourvday. 5 days/week. for 5 months. They were then kept for 6 days without exposure before sacrifice. In group II. 13 mice were exposed at 2500 (seven mice) and 6000 (six mice) ppm for 6 months and were kept for an additional 2 days for recovery before sacrifice. In group III. eight animals (seven at 2500 ppm and one at 6000 ppm) were exposed to vinyl chloride monomer for 6 months followed by a 37-day recovery period. The inhalation exposures were accomplished at the Industrial Bio-Test Laboratory. Northbrook. 111. In addition to the experimental animals. 16 mice (four forgroup I. four for group II. three for group III. and five which were 12 months old) were simultaneously maintained as controls. The control mice were primarily of interest for providing data concerning the spontaneous occurrence of pulmonary tumors. Under anesthesia, the mice of both experimental and control groups were sac rificed by decapitation. Lungs were examined under a dissecting microscope after the organs were taken out of the bodies to determine whether tumors had occurred. Fic. 2. A p3 oeopliiuc cells For light m malin and t micrometer silver, periotin. and Va> pieces. smaJ neoplastic p at pH 7.2-7 in epoxy re? sections we: croscope wa major organ hemangiosai the hepatic < -4. Gross At Pulmonar 6000-ppm se tumors were lb RSV 0016819 rVLMONARV TL'MORS INOL'CCD BY VINYL CHLORIDE 6 Vti IT*0 :87 is* :*S* YA ;rai part of a mouse of these findings weeks old at iups. In group id 6000 (three ! then kept for re exposed at e kept for an jiimaJs (seven nonomerfor6 :posures were 111. four for group iimultaneousiy t for providing oups were sacicroscope after i had occurred. Fic. 2. A pan of the lower rumor sees in Fig. 1. A tubulo--papillary pattern is observed. The neopiasuc cells are basophilic. Hematoxylin and eostn; x 400. For light microscopy, the organs were fixed in 10% neutral buffered for malin and embedded in paraffin after dehydration in alcohol. Five- to sixmicrometer sections were made and stained with hematoxylin-eosin. Weigert's silver, periodic acid-ScbifFs (PAS) with and without digestion by diastase, elastin. and Van Gieson s picrofuchsin technique. For electron microscopy small pieces, smaller than 1 mm', were taken from both pulmonary tumors and nonneopiastic pulmonary tissues and were fixed in 1% phosphate buffered osmic acid at pH 7.2-7.4 for 2 hours. After alcohol dehydration, the blocks were embedded in epoxy resin. Ultrathin sections were obtained with an LKB microtome. The sections were stained with uranyi acetate and lead. A Siemens 101 electron mi croscope was used for ultrastructural observations. In addition to the lungs, other major organs, including the liver, were examined. To the present, three hepatic hemangiosarcomas were observed in the 2500-ppm series of group III. Details of the hepatic effects of vinyl chloride will be reported elsewhere (19). OBSERVATIONS A. Gross Anatomical Findings Pulmonary tumors were observed in all experimental mice except one from the 6000-ppm series of group II (26 of 27). None were found in 16 controls. These tumors were round, whitish in color, multiple in number, and variable in size from RSV 0016820 288 YAStNOSCKl SCZt'KJ I Fic. 3. A p*n of the upper minor sees in Fi|. t. An tJenomuoui pnaera is seen. Hematoxylin sad eosin: * S60. Fic. 4. Nt by diutuc. ' I to to 5 mm in diameter. No tnetastases to regional lymph nodes or other organs were observed. Neither parenchymal fibrosis nor fibrouc adhesions of the pleura were detected. chiolar air and reticul to neoplas' B. Light Microscopy changes ot As shown in Fig. 1. the tumors were usually seen in the peripheral pan of lung In Fig. 5. t parenchyma, although occasionally tumors were found in more proximal parts of lining cell? the lung. No direct connections of the tumors with bronchi or bronchioles were * be alveola, observed. The neoplastic cells were arranged in various ways, such as tubuio- cells. Hyp papillary (Fig. 2) and adenomatous forms (Fig. 3). Polymorphism and atypical shown in structures were not striking. However, sometimes abnormal mitoses were ob- lobe of the served, as shown in Fig. 4 (arrow labeled M). The nuclei were round in shape and not always small, and chromatin was generally finely distributed. Nucleoli were generally dent ident poor in development. Two different types, eosinophilic and basophilic, were dis not feasibi tinguished in the neoplastic cells (Figs. 2 and 3). Some of the cells stained with PAS (Fig. 4: arrow), and the substance so stained was digested by diastase, suggesting that it was glycogen. The neoplastic tissue was not encapsulated by connective tissue. Often, air spaces separated neoplastic tissue from normal tis sue. Although malignant invasion, such as destruction of preexisting tissue, was not observed in the animal lungs, invagination of the neoplastic tissue into bron- C. Elects Figure * 2). Ultras; round- or miophilic cent neop I PVLMONARY TL'MORS IVDCCED BY VINYL CHLORIDE :89 >des or other organs esions of the pleura chiolar air spaces was detected in instances of extremely large tumors. Collagen and reticular fibers showed little development in the neoplastic tissues. In addition 10 neoplastic changes, as shown in Figs. 5 and 6. focal and multiple hyperplastic changes of the alveolar lining cells were noted in lungs exposed to vinyl chloride. npheral part of lung In Fig. 5. the hyperplastic cells are seen just beneath the visceral pleura. Since the re proximal parts of lining ceils beneath the thin connective tissue of the visceral pleura are known to )r bronchioles were s. such as tubulo- be alveolar epithelium, the hyperplastic cells are assumed to be alveolar epithelial cells. Hyperplastic cells are also found in the deeper pan of lung parenchyma, as -phism and atypical shown in Fig. 6. Occasionally, neoplasia and hyperplasia coexisted in the same al mitoses were ob- lobe of the lung, and the distinction between neoplastic and hyperplastic cells was round in shape and not always dear, as some cellular similarities were found between the two. Confi teoli were generally dent identification of the cell types of both neoplastic and hyperplastic cells was >asophilic. were dis* not feasible at the level of light microscopy. le cells stained with gested by diastase. iot encapsulated by >ue from normal tis.-existing tissue, was 'tic tissue into bran* C. Electron Microscopy Figure 7 is derived from neoplastic tissue of the tubuio-papillary form (see Fig. 2). Ultrastnictural characteristics of the neoplastic cell included microvilli, large, round- or rod-shaped mitochondria, well-developed Golgi complexes, and osmiophilic lamellar bodies. Junctional structures (arrows in Fig. 7) between adja cent neoplastic cells and a basement membrane (B) were usually observed. Figure RSV 0016822 v'Hfc 292 YASCNOSl'KI SUZl'KI Fic. 8. A differentiated neoplasm seen in the animal lun| shown in F19. 3. Fonnauon of the tubular lumen and microvilli is poor, x 6500. spontaneously or by urethane. Intracytoplasmic vacuoles containing electrondense granules (diameter approximately 400 A) and amorphous material were frequently observed in the cell cytoplasm (Fig. 11). Since the limiting membrane was attached to ribosomes, the vacuole was identified as a cistema of endoplasmic reticulum. The intracistemal granules did not stain with uranyl acetate alone and therefore were assumed to be glycogen (Fig. 12). Occasionally, crystalloid struc tures were observed in the cytoplasm of the neoplastic cells (Fig. 13). though their significance has not been clarified. The above-described neoplastic ceils were quite similar in ultrastructure to type II alveolar epithelium. Capillaries in the neoplastic tissue consisted of single layers of nonfenestrated endothelium as seen in (he normal alveolar capillary. In addition to well-differentiated neoplastic cells, poorly differentiated ones were also recognized (Fig. 14). As seen in Fig. 14. the cells were cuboidal or cylindrical in shape and lacked formation of osmiophiiic lamellar bodies. Mitochondria were small in size, although the cells were rela tively rich in rough-surfaced endoplasmic reticulum. These cells seemed to cor respond to the basophilic ones observed by light microscopy. Except for the lack of a large amount of glycogen, these cells resembled immature alveolar epithelium, as observed in fetal lung in late gestation. Neither cilia nor mucinous Fic. 9. A mitochondria. secretory i it was stro epithelium illustrated were evide ences in u size and i; miophilic I chrondriak reticulum membrane served in t was derive type II cel form bet* pulmonary which ma> -if RSV 0016825 >J5~ X-* PULMONARY TUMORS INDUCED #V VtNYL CHLORIDE sm* Fomuuon of (he tubular containing electronphous material were e limiting membrane tema of endoplasmic ivl acetate alone and !ly. crystalloid struc* Fig. 13). though their neoplastic cells were m. Capillaries in the . endothelium as seen ated neoplastic cells, s seen in Fig. 14. the nation of osmiophilic t the ceils were rela* cells seemed to cor* . Except for the lack immature alveolar er cilia nor mucinous Fig, 9. A pan of the cell cytoplasm of neoplastic cell. The arrow indicates irrefular ensue mitochondnales (1300 ppm in group 1ID. * 29.400. secretory granules were observed in the neoplastic cells. Based on these findings, u was strongly suggested that the neoplastic cells were denved from the alveolar epithelium, particularly from type II cells. A hyperplastic pulmonary alveolus is illustrated in Fig. 15. Electron microscopically, aspects of the hyperplastic cells were evidently those of type II alveolar cells, although they showed some differ ences in ultrastructure from the normal type II cell. Mitochondria were large in size and irregular in shape (Fig. 16). and. occasionally, retention of huge osmiophilic lamellar bodies was noted in the cell cytoplasm (Fig. 16). Cristae mitochrondriales were arranged irregularly (Fig. 16). and weU*developed endoplasmic reticulum was frequently seen in the cytoplasm (Fig. 17). Early stages of the membrane formation responsible for "cytoplasmic compartments" were ob served in the hyperplastic cell (arrow in Fig. 17). It is suggested that the membrane was denved from the endoplasmic reticulum, in many respects, the hyperplastic type II cell is assumed to be the precursor of the neoplastic cell. An intermediate form between type I and II cells was frequently observed in the hyperplastic pulmonary alveoli. The arrow in Fig. 15 indicates a pan of the ceil cytoplasm which may represent a transitional form between type I and II cells. Though the ?** t 4\ illllMI ?! RSV 0016826 294 YASCNOSttt SL'Zl'KI Fic. 10. Intncytoplumic compartments formed by membrane structures (2500 ppm io group tin. * 20.000. attenuated cytoplasm corresponded to that of a type I cell, the presence of mi crovilli on the ceil surface was characteristic of a type II cell. DISCUSSION Experimental studies (10-18) on the oncogenicity of vinyl chloride have re vealed that the monomer can induce various neoplasms including hepatic hemangiosarcoma (rat. mice, hamsters), Zymbal gland carcinoma in the external audi tory meatus (rats), breast cancer (mice), nephroblastoma (rats), "lung adenoma" (mice), skin trichoepithelioma (hamsters), lymphoma (hamsters), and fore stomach papilloma (hamsters). Evidence of the pulmonary oncogenicity of vinyl chloride in animals has been obtained: (i) Viola et at. (10. 11) have reported that rats exposed to vinyl chloride exhibited lung cancer (32%). Histological features of the cancers were stated to be those of adenocarcinoma, with the exception of a single epidermoid tumor. Mai* torn and Lefemine (12, 13). however, reviewed the histological slides of Viola et al. and stated that the lung cancers reported by the latter were nor primary tumors of the lungs, but metastatic cancers from Zymbal glands, (ii). Maltoni and Lefemme (12. 13) also have reported on the pulmonary oncogenicity of vinyl Fit. Ii 60.000. chloride carcino induce Caden* Fic. I section i i ? RSV 0016827 PLLMONARY TCMORS INOL'CED BY VINYL CHLORIDE res < 1500 ppm in group W). * ;11. the presence of miceil. vinyl chloride have reduding hepatic heman~ia in the external audii rats), "lung adenoma" (hamsters), and fore* ;de in animals has been posed to vinyl chloride incers were stated to be .pidermoid tumor. Mai* jgical slides of Viola et ere not primary tumors nds. (ii). Maltoni and oncogenicity of vinyl Ftc. 11. Glycogen granules 10 a cisterns of the endoplasmic reticulum (2500 ppm m group II!) x 60.000. chloride on the basis of their own data. Though they could not find bronchogenic carcinoma in rats, rare pulmonary hemangiosarcomas and fibrosarcomas were induced in these animals. Unlike the case in rats, pulmonary tumors ("adenomas") were found in mice (89 of 471). Maltoni and Lefemine (12. 13) 296 YASL'NOSl'KE Sl/ZVKJ - Pic. 13. Crystalloid structure seen in the cytoplasm of a neoplastic cell <2500 ppm in group HI) x 30.000. noted that some of the adenomas underwent malignant transformation, (iii) Keplinger and associates (14) have found "alveologenic adenomas" in the lungs of mice exposed to vinyl chloride (44 of 49). (iv) Lee and associates (15) have stated that "bronchiolar adenoma" developed in mice 2 months after exposure to vinyl chloride at 50-1000 ppm. (v) Holmberg and associates (16) found "alveologenic adenoma" in 13 of 24 mice*exposed to vinyl chloride at 50 ppm for 24-52 weeks. Our present study has also confirmed that pulmonary tumors are frequently in duced by vinyl chloride (26 of 27). Fic. 13. P. epithelium. A: 4200. Fic. 16. A mitochondria. RSV 0016829 TXrmZEB vaslnqslki: suzuki v, *v be a seque cal conda; pnor to cu cally. both 34). It has immature 34). Some similar in riPxSf Fic. 17. Cytoplasm of a hyperplastic type II cell. Arrows indicate membrane formation. Endoplas these pers may be r alveolar e: mic reticulum is well developed (2500 ppm in croup III), x 26.600. Recentl due to lur The reports by Lee et at. (15) and Holmberg et at. (16) are noteworthy since the compared pulmonary tumors are induced by low doses and relatively long exposure and also cally and - because these reports demonstrated that the oncogenicity of vinyl chloride is dose adenocarc related. Based on all the data available, it can be concluded that, of all the tumors chogenic induced by vinyl chloride in all species, those in the lungs of mice appear earliest, cinogenes and that mouse lung is an extremely sensitive organ for demonstrating the on Neopta- cogenicity of vinyl chloride. it is kno\ Gross anatomical and histological aspects of the tumors in our investigation veoiogeniv corresponded to the "alveologenic tumor or cancer" of Stewan et at. {21. 22). tion occur though other designations such as pulmonary adenoma, bronchiolar adenoma, and tion of thi adenoma becoming malignant have also been used. The alveologenic tumor has fore dubb< been induced by various carcinogens (21-26) such as polycyclic hydrocarbons, Lafemine urethane, nitrogen mustard, methylcholanthrene. and nitrofur derivates and is undergo t known to occur spontaneously with aging (27-29). The cancer induced has ments. we m been distinguished from that occurring spontaneously by multiple primary foci, occasional formation of huge tumors, and occurrence without any relation to Alveole ble to ob* aging. It is also known that in certain strains, such as A and DD. spontaneous precursor tumors are quite common after 10 to 12 months of age. Spontaneous pulmonary Hepatic tumors could be excluded in our experimental animals; in addition to the above- vinyl ehlo mentioned points, oeoplastic changes in the lungs were absent in the controls. animals (r Electron microscopically, alveolar epithelium, particularly the type II cell, was are almost assumed to be the precursor of vinyl chloride-induced tumor in the mouse lung. cells of vi: This assumption was derived from ultrastructurai similarities between the normal these diffe type II cell and the neoplastic cell. Similar suggestions have been made by other chloride r investigators (20. 26. 30) after studying pulmonary tumors induced by agents other chemical, than vinyl chloride. lie aroma It was noteworthy that the processes of transformation of the normal alveolar known to epithelium into the neoplastic cell could be followed morphologically on the level be associa of ultrastruciure; the appearance of an intermediate form between type I and 11 carcinogen cells in the alveolar lining, the disappearance of type II cell in the lining due to vinyl chlo replacement by the hyperplastic type II cells, which were transformed from the intermediate form, and the neoplastic change of the type II cell were assumed to We witb t RSV 0016831 ms formation. Endoplas- noteworthy since the ng exposure and also vinyl chloride is dose hat. of all the tumors mice appear earliest, imonstrating the on- in our investigation ewart et al. (21. 22). chiolar adenoma, and veologenic tumor has cyclic hydrocarbons, fur derivates and is cancer induced has nuitiple primary foci, thout any relation to rnd DD. spontaneous mtaneous pulmonary addition to the aboveent in the controls, y the type II cell, was or in the mouse lung. -$ between the normal i been made by other duced by agents other jf che normal alveolar logically on the level etween type I and II .-11 in the lining due to transformed from the : ceil were assumed to PULMONARY TUMORS INDUCED BY V1N\L CHLORIDE -99 be a sequence of the process. The intermediate form appears in certain pathologi cal conditions, such as pulmonary asbestosis (31) and radiation pneumonitis (321 prior to cuboidat metaplasia of the attenuated alveolar epithelium. Embryologically. both type 1 and II cells are of the same origin, the entodennal epithelium i33. 34). It has been accepted that, at a late stage of gestation, rapid attenuation of the immature alveolar epithelium-, similar to the type II cell, occurs in mammals (33. 341. Some of the neoplastic cells, distinguished as poorly differentiated, were similar in ultrastructure to the immature alveolar epithelium of fetal lung. From these perspectives* the process of neoplastic alteration observed in the epithelium may be interpreted as a retrograde process of the normal differentiations of the alveolar epithelium. Recently. Waxweiler and associates reported an increased number of deaths due to lung cancer among vinyl chloride workers (8): They observed 12 cases compared to the 7.7 cases expected. Eight of the twelve were examined histoLogically and were classified as undifferentiated large-cell carcinoma (five cases) and adenocarcinoma (three cases). Since these human lung cancers are of bron chogenic origin, it may be that target pulmonary ceils in vinyl chloride car cinogenesis are different in human and mouse lung. Neoplastic invasion and metastases were not found in our material. However, it is known (21. 35--38) that sometimes both induced and spontaneous al- veologenic tumors of mice show such changes and that the malignant transforma tion occurs with some delay after initiation of the tumor. In addition, transplanta tion of this tumor has been accomplished (39). Stewart and associates (21) there fore dubbed it an "alveologenic tumor" or "alveologeoic cancer." Maltoni and Lafemine (13) have found that some vinyl chloride-induced pulmonary tumors undergo transformation. During the short period of observation in our experi ments. we did not observe this. Alveologenic tumors may be considered unique in some ways, since it is possi ble to observe the process of malignant transformation sequentially from the precursor to the malignant cell via hyperplastic and benign neoplastic states. Hepatic hemangiosarcoma is recognized as a specific malignant tumor related to vinyl chloride exposure. The tumor can be induced in a variety of experimental animals (mice. rats, and hamsters) (12. 13). and histological features of the tumor are almost identical in humans and animals, in contrast, the intrapulmonary target cells of vinyl chloride oncogenesis may be different in humans and mice. Beyond these differences, moreover, the induction of alveologenic tumors in mice by vinyl chloride may be predictive of a risk of human bronchogenic cancer from the chemical. Consistent with this is the fact that various carcinogens such as polycyc lic aromatic hydrocarbons, nitrogen mustard, and chromate compounds are known to induce alveologenic tumors in mice, on one hand. and. on the other, to be associated with excess bronchogenic carcinoma among workers exposed to the carcinogens (40). It is noteworthy that a similar relation has been suggested for vinyl chloride. ACKNOWLEDGMENTS We wish to (hank Mr. C. Din and Mr. R. Ashley for excellent technical assistance. 300 YASVNOSUKL Sl'ZL'KI REFERENCES 1. Cretch. J. L.. and Johnson. M.N i 19?4). Angiosarcoma in the manufacture of polyvinyl chloride. J. Orcup. Med. 16. I/O-- 151. 2. Falk. H-. Creech. J. L.. Heath. C. W.. Jr.. Johnson. M. N.. and Key. M M it9M). Hepauc disease among workers at a vinyl chloride polymerization plant. J. Amer VrJ. Ass. 230. 59-63. 3. Block. J. B. < 19741. Anposarcoma of the liver following vinyl chloride exposure. J. Amer. Med Ass. 229. 53 -54 4. Lange. C. E.. Juhe. S.. and Velunan. G. U974). Lber das Anftreten von Angiosarkomen der Leber von zwei Arbeitem der PVC-hentellender Industrie. Deut. Med w,rhtnsenr. Ji 1598-1599. 5. Lee. F. I.. and Harry D. S. < 1974). Angiosarcoma of the liver in a vmvl chlonde worker. Lancet I. 1316-1319. 6. Thomas. L. B.. Popper. H.. Berk. P D , Selikoff. I. J.. and Falk. H. U9"5). Vinyl chlondeinduced liver disease. A. Engl. J. Med. 292. 17-22. 7. Nicholson. W. J.. Hammond. E. C.. Seidman. H.. and Selikoff. 1. J-119751. Mortality experience of a cohort of vinyl chloride--polyvinyl chlonde workers. Ann. NY Acad. Sci. 246. 225 -- 236. 8. WaswetUer. R. J.. Stringer. W.. Jones. J.. Wagoner. J. N.. Falk. H.. and Carter. C <19761 Neoplastic risk among workers exposed to vinyl chloride. Amt. \. Y. Acad. Sci. 271. 39-48. 9. Tabenhaw. L. R.. and Gaffey. W. R. (1974). Mortality study of workers in the manufacture of vtnvl chlonde and its polymer. J. Oecup. Med. 16. 506-516. 10. Viola. P- L. 11970). 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