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* OSPEDALI Dl BOLOGNA Enta Oapadallaro Regional* (DAL POUCHNICO S. ORSOLA ITUTO Dl 0NC0L06IA * FELICE ADDARIIi Direttore: Prof. Centre Mallow Villa Ercolanl 4/2 - 40138 BOIOCNA Tal. 393824 .4 Bologna, ....1.57.4. Prot, N. Mrs. JEANNE FERRONE OSHA Room 240 1726 M Street, N. W. U. S. Department of Labor WASHINGTON, D.C., 20210 U.S.A. Dear Mrs. Ferrone, herewith enclosed you will find the text of my testimony ^^bo OSHA, of Februa,rryy 1155, 1974, with related tables and figures, as it was requested to me. I hope that everything is as you expected. When published on your records, I would like very much to have a few copies. My experiments are going on and progressing in the most interesting way. Thanking you for your collaboration, my best regards and wishes, Yours sincerely, CM/cn BOR 011142 OSPEDALI Dl BOLOGNA Enta Oapedallaro Regional* PEDALE POLICLINICO S. ORSOLA ITUTO Dl ONCOIOSM iFEUCE DDAII Direttore: Prof. Cesare Mallow vial* Eicolanl 4/2 - 40138 BOLOGNA Tel. 393824 Prot. N. Botosn.. .11/10/19.71 Istituto di Oncologia "F. Addarii" and Centro Tumori, Bologna, Italy. Cesare Maltoni, Giuseppe Lefemine and Luciano Gualano. PRELIMINARY REPORT ON THE CARCINOGENICITY BIO-ASSAYS OF VINYL CHLORIDE. (This research has been supported by the European Cooperative Group (ECG) which includes Montedison (Italy), ICI (U.K.), Solvay (Belgium), Rhone-R_e gil (France) ). The project of investigating the oncogenic potential of Vinyl Chloride (VC) followed the preliminary results of the pioneering work of Professor Viola, presented at the X International Cancer Congress (which took place in Houston in 1970) and was then extensively published in "Cancer Research" (1971) Professor Viola's results indicated that the exposure to 30,000 ppm of VC, four hours a day, five times weekly, for 10 months, produced tumours in rats. These tumours were interpreted by Professor Viola as arising in skin, lungs and bones. Immediately after the report in Houston we got in touch with Professor Viola, who kindly put at our disposal the manuscript of his extensive report still being printed, and several slides of the tumours. 0111^3 BOR OSPEDALI Dl BOLOGNA Em* Ospadallaro Regional* PEDALE POLICLINICO S. 0RS01A ITUTO Dl ONCOLOGIA FELICE ADDMIli Direttore: Prof. Centre Mallow Vial* Eivolanl 4/2 40138 BOLOGNA Ttl. 393824 Prot. N. Bologna. ... Ix/IQ/19.74 Page No. 2 On the basis of Professor Viola's results and material, we reached the following conclusions: 1) under Professor Viola's experimental conditions, VC definitely showed a carcinogenic effect on rats; 2) 30,000 ppm of VC v/as an extremely high level of exposure; 3) the tumours described as cutaneous were arising in the Zymbal glands, which in rats are responsive to a large spectre of carcinogens (2-ac_e tyl-amino-fluorene, benzidine, polycyclic hydrocarbons, aminostilbenes, ethyl-carbamate, etc.); 4) the tumours described as lung tumours were most likely metastases from Zymbal glands carcinomas. The pulmonary neoplastic deposits were in fact morphologically similar to the Zymbal'glands carcinomas, and all were observed in animals bearing Zymbal glands tumours. The need, therefore, emerged for an extensive investigation to further clarify the type and the degree of the carcinogenic effect of VC, with par ticular emphasis on experimental factors related to exposure, such as route, concentration, length, continuity or intermittance, etc., which could give more direct indications about the risk of occupational conditions. For these purposes, and since in our country the Institute of Oncology of Bologna is particularly orientated towards studies on cancer prevention and control, we were contacted by Prof. Bartolini, Head of the Health Service of Montedison, who guaranteed the backing of his 'Company for the experimental BOR OII144 1OSPEDALI 01 BOLOGNA EnM Oepedall.rQ Regional* OSPEDAIE POIICLINICO S. ORfOlA lino 01 OMCOLOGIA FELICE ADDARM i Diretlore: Prof. Cesare Mdtoni Vial* Ercolanl 4/2 - 40)38 BOLOGNA Tel. 393824 Prot. N. Bologna, 9.7.4. Page No * 3 project on the biological effects of VC. Montedison was soon joined by ICI, Solvay and Rhone-Pegil. To start the operative phase of the research we needed, first of all, to prepare proper conditions for atmospheric exposure. The studying and build ing of an apparatus for programmed and controlled exposure took us several months. Such an apparatus makes it possible to deliver concentrations vary ing from 30,000 ppm to 50 ppm, and to treat simultaneously nearly 1,200 experimental rodents. Basically it is built of inoxidable steel and glass (figures 1 and 2). VC has been supplied by Montedison. Each stock has been analyzed before the use in the chemical research laboratory of Montedison. The experiments are mainly performed on Sprague-Dawley rats; Wistar rats, Swiss mice and hamsters have also been used. All the animals, except for hamsters, have been bred in our Institute for years and, whatever their use, they are all examined at death by complete autopsy, which means that we know their current pathology quite well. 13 experiments have been started in sequence. Some of them were program med at the beginning, for some others the need, appeared on the basis of the first experimental results. The plan of the experiments and the up-to-date situation is shown in the following table 1, BOR 011145 JAfc OSPEDALI Dl BOLOGNA Enta OtfWd.ll.ro fteglon.lt OSPEDALE POLICUNICO S. ORSOLA TUTO Dl ONCOLOGIA tFEllCE ADDMIli Direttorc: Prof, Cetarc Mdtoni Vial* Ercoltni 4/2 - 40138 BOLOGNA T*l. 39 38 24 Prot. N. Bologna, ... H/l0y^l.9X4.... Page No. 4 Experiment 1 : studies the effect of the atmospheric exposure to 10,000, 6,000, 2,500, 500, 250, 50 ppm of VC, 4 hours daily, 5 days weekly, for 12 months. Two groups of animals were added as control; one untreat ed, as for all the following experiments, and one treated with Vinyl Acetate (VA) at 2,500 ppm, under the same conditions. This dose of VA appeared to he the maximum possible dose for a chronic exposure. Experiment 2 : was performed to investigate in a larger number of animals the effect jf doses among 250 and 50, that is 200, 150 and 100, under the same conditions as in experiment 1. It started after it was clear that 250 ppm was still showing oncogenic effects. Experiment 3 : was planned to study the effectsof a shorter period of exposure, keeping all the other conditions of experiment 1. Experiment 4 : studies the effect of the same type of exposure as in experi ment 1, in another species, that is mice. The treatment lasted 7 months in consideration of the higher mortality and shorter life span of the mi= ce of our line. Experiment 5 : was undertaken as a pilot investigation on the possible ef fects of the atmospheric exposure during pregnancy, on offsprings. Experiment 6 : we wanted to reproduce the same conditions of Professor Vio la's experiments. Experiment 7 : was planned to study the effects of the same type of exposure as in experiment 1, in another strain of rats, that is Wistar. BOR 011146 =>!U' OSPEOALI 01 BOLOGNA Ent Ospedailero Regional* OSPEDALE POLICLINICO S. ORSOLA ITUTO Dl ONCOLOGIA c FELICE ADDARIIi Direttore: Prof. Cetare Mdtoni Vial** Ercolanl 4/2 - 40138 BOLOGNA Tal. 393824 Prot. N. Bologna. .. itl.Q/fflA......... Page No. 5 Experiment 8 : studies the effects of the same exposure as in experiment 1 in a third species, that is hamsters, for the same period as in experiment 4. Experiment 9 : was planned to further assess whether or not inhalation of VC had any effect at a dose level of 50 ppm. * Experiment 10: studies whether a high, but short and/or intermittent atmos pheric exposure has any effect. Experiment 11: was performed to evaluate the possible effects of VC by ingestion. The doses have been chosen on the basis of early data on the release of VC by food containers of PVC, and following the indications of the EEC. Experiment 12: studies the third general route of exposure. Experiment 1 3: was started to assess whether the VC acts on tissues direct ly or through metabolites. All the animals were kept under observation until spontaneous death. A complete autopsy was made on each animal, and histological examination performed on Zymbal glands, interscapular brown fat, salivary glands, tongue, lungs, liver, kidneys, spleen, stomach, different segments of the intestine, bladder, brain, bones of the legs and feet and any other organ with pathologi al lesions. All the animals exposed to the highest doses (30,000 and 10,000 ppm) with or without tumours, were examined radiologically, during treatment BOR 011147 OSPEDALI Dl BOLOGNA ^ Ento Ojpedall.ro Aegionalo OSPEDALE POLICLINICO S. ORSOU (TOTO 01 0NC0106IA iFEHC: ADDASli. Dirtttore: Prof. Cetatt Maltont Vtil* Ereol.nl 4/2 40138 BOLOGNA Tl. 393824 Prot. N. Bologna. .Il/.l 0/19.74 Page No. 6 and/or at death. Moreover radiological examinations were made on animals bearing tumours, though exposed to the lower doses. The preliminary results and the other data on the up-to-date situation of the experiments 1, 3, 6 and 5 are given on the following tables 2-5. As far as the ether experiments are concerned we still have to wait for the results. The current macroscopic and microscopic pictures of the induced tumours are shown in figures 3-52. From the results presented in the tables, from the pathological observa tions and histological examinations, the following early conclusions may be drawn: 1) VC is oncogenic under our experimental conditions: it induces, in rats, carcinomas of Zymbal glands, nephroblastomas and angiosarcomas in the liver and in other sites. 2) A direct relationship exhists between the dose and the length of treatment, and the neoplastic response. 3) Zymbal glands carcinomas and nephroblastomas may be bilateral. 4) Liver angiosarcomas are often policentric. 5) Endothelial hyperplasia, associated or not with cellular atypias, is often observed in various organs and tissues in treated animals, with or without angiosarcomas. Therefore the effect of VC on endothelia should be considered systemic. BOR 011148 OSPEDAU Dl BOLOGNA Ent. 0>p*4iilsrt> Region*!* I,LE POUCIINICO S. ORSOIA I 0NC010GI* < FELICE *DMM> Direttore: Prof. Cesare Mdtont Vial* Ercolanl 4/2 - 40138 BOLOGNA Tal. 393824 N. Bologna, ..... I Page No. 7 6) The onset of two ossifying angiosarcomas suggests a new orientation in the pathogenetic interpretation of acrosteolysis in workers exposed to VC. 7) Up to the present moment no acrosteolytic lesions have beer., observed on our treated animals. Zymbal glands carcinomas, nephroblastomas and liver angiosarcjraas have lever been observed as occurring spontaneously in our breed of Sprague-Daw.ey rats. ^^bnly three cases of spontaneously occurring Zymbal glands carcinomas lave been recorded in rats (Sprague-Dawley) (Tannenbaum et al,, 1962). To jur knowledge, no spontaneous nephroblastomas and liver angiosarcomas of rats have been reported in literature. As far as we know kidney nephroblastomas have never been reported as ceing experimentally induced. As far as angiosarcomas are concerned, and in particular the hepatic ones, ley have never been experimentally induced in rats. In mice, extra-hepatic angiosarcomas have been induced by o-aminoazotoluene (Andervont et al., 1942; Andervont, 1950) and by p-dimethylaminobenzene-1-azo-2-naphtalene (Mulay and Saxen, 1953); some authors claim they have observed li= ver angiomas in this species, following treatment with urethan. In the rab bit, angiosarcomas have been produced by thorotrast (Zeitlhofer and Speiser, 1954). BR 01H49 OSPEDALI 01 BOLOGNA Ent* Ospedaitcro Regional OSPEDALE POLICLINICO S. ORSOLA TUTO Dl ONCOLOGIA < FELICE ADDARIIb Direttore: Prof. Cesare Maltoni Vtal* Ercolinl 4/3 40138 BOLOGNA Tl. 393834 Prot. N. > Bologna. ... I3/.1.Q/1..97-4............. Page No. 8 In man, angiosarcomas are quite rare. 117 accurately documentated cases were collected up to 1958 (Landells, 195*8), of which only 21 arising in liver. "* Two human examples of induction of angiosarcomas have been reported: one deals with a case of a liver angiosarcoma following the insertion of a radium needle (Ross, 1932), the other deals with cases of liver angiosarco mas following administration of thorotrast (MacMahon et al., 1947; Ludin, 1953). The results of our investigation have been periodically transmitted to the Members of the European Cooperative Group. When, more than one year ago, it became definitely clear that VC was able to induce angiosarcomas, nephroblastomas and other malignancies, our results were also communicated . to the major American Manufacturers of VC and PVC, to orient clinical observations and epidemiological investigations. BOR OlH50 OSPEDAU Dl BOLOGNA En* OspodsHaro Pe0ion*Jo EDALE POIICLINICO S. ORSOLA UTO Dl ONCOLOGIA FELICE ADBAIII. Direttore: Prof. Cesare Mdtorti V1l. Ercolanl 4/2 4013* BOLOGNA Til. 393824 Prot. N. Page No. 9 References ANDERVONT, H. B., GRADY, H, G., and EDWARDS, J. E.: J. nat. Cancer Inst i, 131, 1942. ANDERVONT, H. B.: J. nat. Cancer Inst.: _10, 927, 1950. LANDELLS; J. W.: In: RAVEN, R. W., Cancer: 2, 512, Butterworths, London/' 1958, LUDIN, M.: Schweiz. Z. allg. Path.: J6, 987, 1953. MacMAHON, M. E,, MURPHY, A. S., and BATES, M. I.: Amer. J. Path.: 2J, 585 1947. MULAY, A. S., and SAXEN, E, A.: J. nat. Cancer Inst.: JQ, 1259, 1953. ROSS, J. M.: J. Path. Back.: 899, 1932. TANNENBAUM, A., VESSELINOVITCH, S.D., MALTONI, C., and MITCHELL, D. S.: Cancer Res.: 22, 1362, 1962 VIOLA, P. L., BIGOTTI, A., and CAPUTO, A.: Cancer Res.: ^1, 516, 1971 ZEITLHOFER, J., and SPEISER, P.: Z. Krebsforsch.: 60, (2), 161, 1954. BOR 011151 FLAW OF THE EXFERIKENTS-UP '-.S FEBRUARY 10, lu-". ^ NO. OP THE KENTS BT1 BT2 BT3 BT4 BT5 BT6 BT7 BT8 BT9 r. HffENT ,'IMALS Route Doses of VC Length Age Spec la Strain (weeks) 10,000, 0,000, 2,500, Inha 500, 250, 50 ppm. lation Untreated controls Treated controls: VA 2.500 men. Inhalatioz 200, 150, Untreated 100 ppm. controls 4 hre. daily, 5 days Rat weekly, 52 weeks 4 hre. dally, 5 days Rat weekly, 52 weeks Inha lation 10,000, 6,000, 2,500, 500, 250, 50 ppm. Untreated controls 4 hrs, daily, 5 days weekly, 17 weeks Rat 10,000, 6,000, 2,500, 4 hrs. Inha 500, 250, 50 ppm. lation Untreated controls daily, 5 daye Houae weekly, 30 weeks Trans pla 10,000, 6,000 ppn. cental 4 hrs. daily, 7 dayk (from 12th to 18 th dw onaf npcvrflg Rat Inha lation 30,000 ppm. 4 hrs. daily, 5 days Rat weekly, 41 weeks 10,000, 6,000, 2,500, 4 hrs. Inha 500, 250, 50 ppm. lation Untreated controls daily, 5 days Rat weekly, 52 weeks Inha lation 10,000, 6,000, 2,500, 500, 250, 50 ppm. Untreated controle 4 hra. daily, 5 days weekly, 10 weeks Ham ster SpragueDawley 13 SpragueDawley 13 SpragueDawley 21 Swiss 11 SpragueDawley Breeden 12 days Embryos SpragueDawley 17 Wistar 11 Golden 11 8 268 280 262 250 no ' > 30 - Inha 50 ppm. lation Untreated controls Hill Rat SpragueDawley 11 200 No, Om Total 309 577 265 545 288 550 260 510 36 146 30 60 220 220 268 268 200 400 grouo LENGTH 0* MENTS <\T (weeks1 64-96 127 65-120 31 60-190 56 60-150 31 30-54 65 60 30-40 31 31 32-70 100 (o) 300 (t) 18 3 BT10 BT11 Inha 10,000. 6,000 ppm. lation Untreated controls Inge stion 16,6 mg.; 3,32 mg.; 50 mg/kg body weight, in olive oil Controls: olive oil 4 hrs. daily, 5 dayB weekly, 5 weeks; Rat 4 hra, daily, 1 das' weekly, 25 weeks; 1 hr.dai ly ,4 dtj^B weekly, 25 webRs 5 times weekly, 52 weeks Rat SpragueDawley SpragueDawley 11 13 420 420 840 120 160 160 320 80 3 3 BT12 BT13 Bndopi ritoneal injec tion 4,25 mg. in 1,0 cc. olive oil Controls: 1,0 co. olive oil Subcu 4,25 mg. in 1,0 cc taneous olive oil injec Controls: 1,0 cc tion olive oil 4, 3, 2 tlm ee by two months, and ore e Rat 1 injec Rat tion SpragueDawley SpragueDawiey 13 21 150 150 300 60 80 70 150 75 3 3 BOR 011152 GROUPS AMS IRRATMBIT I VA 2,500 ppn. II VC 10,000 pnm. in VC 6,000 opm. IV VC 2,500 ppm. V VC 500 ppm. VI VC 250 ppm. VII VC 50 ppm. VIII No treatment TOTAL EXPERIMENT BT1: RESULTS APTE8 YEEK5 J ANIMALS (SPRAGUE--DAWLEY RATS) Total Survivor* Zymbal glands care mom*# () Ho. ANIMALS WITH TUMOUKb Nephroblastomas (b) No. Angiosarcomas liver (c) No. Other sites No. Other type and/or site No. Tot No 06 - -- -- 60 13 3 fi - 1 (h) 2" 72 - 5 3 11 1 (d) 1 (l) 21 74 - 2 6 9 ' 3 (e) 1 (1) 21 67 67 1 64 3 68 1 577 5 3 _ 23 3 7 2 (f) 1 (m) 16 * 5 2 2 (g) 2 (n) 11 __ _ __ 20 35 8 10 96 a) Metastases to lung. b) Metastases to Liver and/or to lung and spleen. c) Metastasea to lung. d) Angiosarcomas in subcutaneous fibroeing angioma. e) 2 intrabdominal angiosarcomas (1 next to spleen and 1 next to ovary); 1 ossifying angiosarcoma of nec f) 1 pulmonary angiosarcoma; 1 angiosarcoma of uterus. g) 1 intrabdominal angiosarcana (next to spleen); 1 mtrathoracic ossifying angiosarcoma. h) 2 Zymbal glands adenomas; 1 neurilemmoma of the ear; 1 mammary carcinoma; 1 cystoadenocarcinoma of ovt i) Sebaceous gland carcinoma of shin. l) Zymbal glands adenoma. m) Minimal deviation hepatoma. n) 1 Zymbal glands adenoma; 1 salivary glendB carcinoma. BOR 011153 T3 EXPERIMENT BT3 RESULTS AFTER 56 WEEKS (l) Page No. 12 GROUPS AND TREATMENT ANIMALS (SPRAGUE-DAWLEY RATS) Total Survivors Zymbal glands carcinomas No. ANIMALS WITH TUMOURS Nephrobla stomas AngiosEire omas Liver Other sites No. No. No. Other type and/or site No. 1 Total No. I VC 10,000 ppm. II VC 6,000 ppm. 60 36 60 48 3 (11) 1 ( 3) - (1) - (1) - (1) -- - (3) - (1) - (4) - 3 ' '7) 1 ( 8) Ill VC 2,500 ppm. IV VC 500 ppm.. V VC 250 ppm. VI VC 50 ppm. VII No Treatment 60 54 60 56 60 44 60 50 190 183 - ( 2) - ( 1) -- - T - (1) -- - (1) - (1) - ----- - (1) - (1) -- -- - ( 5) - ( 3) -1 - TOTAL 550 471 4 (17) i ' (3) - (6) - (1) (1) Between brackets are recorded the tumours found in experiment BT1 after 56 weeks. - (6) 4 (33' i------------------------------- r BOR 0 1 1 1 5 4 TABLE 4' EXPERIMENT BT6: RESULTS AETER 31 WEEKS i GROUPS AND TREATMENT ANIMALS (SPRAGUE-DAWLEY RATS) . Zymbal glands carcinomas Total Survivors No. ANIMALS WITH TUMOURS Nephrobla stomas No. Angio sarc omas Liver Other sites , No. No. Other type and/or site ' ;al No. No. I VC 30,000 ppm. 60 60 2 - -- -- > ao to in ui TABLE 5 EXPERIMENT BT5: RESULTS AFTER 65 WEEKS1 Pape Nq^BI4 GROUPS AND TREATMENT I VC 10,000 ppm. Breeders II VC 6,000 ppm. Breeders III VC 10,000 ppm. Offsprings IV VC 6,000 ppm. Offsprings TOTAL ANIMALS (SPRAGUE-DAWLEY RATS) Total Survivors Zymbal glands carcinomas No. ANIMALS WITH TUMOURS Nephrobla stomas Angiosarc ora as Liver Other sites (1)._ No. No. No. Other type and/or r site No. Total v No. 30 28 - - -- - i 30 28 -- -- 34 30 - - -1 -1 32 30 - - -1 -1 126 116 -- - --2 --2 (1) In subcutaneous tissue 03 U1 pl Ml ' OSPEDALI Dl BOLOGNA Em* Oipedali.ro flegionil* OSPEDALE POLICLINICO S. ORSOLA UTO Dl 0NC010GM ifEllCi ADDARII, Direttore: Prof. Cesare Mallow Vial* Ercol.nl 4/2 40138 BOLOGNA Tal. 393824 Prot. N. Bologna,. Il/l.0/^1974 Page No. 15 Figure legends Pig. Fig. Fig. Fig. Fig. Fig. 1 2 3 4 5 6 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 Fig. 15 Fig. 16 Fig. 17 Fig. 18 Fig. 19 Fig. 20 The inhalation chamber. The laboratory unit for inhalation. Rat with Zymbal gland carcinoma. Rat vith Zymbal gland carcinoma. Rat with bilobated Zymbal gland carcinoma. Rat with hemorrhagic Zymbal gland carcinoma. Normal Zymbal gland, in rat. Hematoxilin and Eosin stain (H.-E.), x 46. Zymbal gland in an old rat. H.-E., x 46, Zymbal gland carcinoma with squamous pattern, in rat. H.-E., x 185. Zymbal gland carcinoma with solid pattern, in rat. H.-E., x 185Zymbal gland carcinoma with anaplastic pattern, in rat. H.-E.,x 185. Zymbal gland carcinoma with polimorphic pattern, in rat.H.-E., x 470, Zymbal gland carcinoma with glandular pattern, in rat. H.-E., x 185 Zymbal gland carcinoma with glandular pattern and abundant stroma, in rat. H.-E., x 185. Pulmonary metastasis from Zymbal gland carcinoma, in rat.H.-E.,x 46 Pulmonary metastasis from Zymbal gland carcinoma, in rat.H.-E., x 18 Pulmonary metastasis from Zymbal gland carcinoma with abundant stroma, in rat. H.-E., x 185. Rat with nephroblastoma. Rat with nephroblastoma. Rat with nephroblastoma metastasising to liver. oiii57 boR OSPEDALI Dl BOLOGNA EnM Osfwdallan) Regional* OSPEDALE POLICLINICO S. 0RS01A #>TO Dl ONCOLOGIA (FELICE ADDARII. Direttore: Prof. Centre Mdtoni Vll* Ercql.nl 4/2 40138 BOLOGNA T.l. 383824 Prot. N. Bologna, . I I/IQ/1.974. Page No, 16 Pig. 21 Pig. 22 Fig. 23 Pig. 24 Fig. 25 Pig. 26 Fig. 27 ^^ig. 28 Pig. 29 Pig. 30 Fig. 31 Pig. 32 Pig. 33 Pig. 34 Fig. 35 Pig, 36 Fig. 37 Pig. 38 Pig. 39 Fig. 40 Pig. 41 Nephroblastoma with characteristic pattern, in rat. H.-E., x 185. Nephroblastoma, in rat: nephrogenic blastema differentiating in glomerulus. H.-E., x 470. Liver metastasis from nephroblastoma, in rat. H.-E., x 185. Splenic metastasis from nephroblastoma, in rat. H.-E., x 470; Pulmonary metastasis from nephroblastoma, in rat. H.-E.,. x 185. Pulmonary metastasis from nephroblastoma, in rat, at s higher magnification. H.-E., x 470. Rat with liver angiosarcoma metastasising to lung. Rat with liver angiosarcoma. Rat with liver angiosarcoma. Liver angiosarcoma with characteristic pattern, in rat. H.-E.,x 185. Liver angiosarcoma with characteristic pattern, in rat. H,-E.,x 185. Liver angiosarcoma, in rat. H.-E., x 185. Pulmonary metastasis from liver angiosarcoma, in rat. H.-E., x 185. Pulmonary metastasis from liver angiosarcoma, in rat, H.-E., x 185* Rat with liver angiosarcoma and nephroblastoma. Intrabdominal angiosarcoma near to spleen, in rat. H.-E., x 185. Intrabdominal angiosarcoma near to sjleen, in rat. H.-E., x 185. Intrabdominal angiosarcoma near to spleen, in rat. H.-E., x 185. Rat with intrabdominal angiosarcoma near to ovary. Intrabdominal angiosarcoma near to ovary, in rat. H.-3., x 185. Rat with angiosarcoma of uterus. Angiosarcoma of uterus, in rat. H.-E., x 470. BOR Ollisa OSPEDALI PI BOLOGNA Ente Ospedailero Regional* OSPEDALE POLICLINICO S. ORSOLA TUTO Dl ONCOIOGIA < FELICE ADDARII* Direttorc: Pro/. Cesare Maltotti Vll Ereolanl 4/2 . 40138 BOLOGNA Tl. 393824 Prot. N. -> Bologna. I i/l 0/l 9 74 Pag. No. 17 Fig. 43 Fig. 44 Fig. 45 Fig. 46 Fig. 47 Fig. 48 Fig. 49 50 Fig. 51 Fig. 52 Angiosarcoma of lung, in rat. H.-E., x 470. Rat with laterocervical ossifying angiosarcoma. Non ossifying area of laterocervical ossifying angiosarcoma, in rat. H.-E., x 470. Laterocervical ossifying angiosarcoma, in rat. H.-E., x 185. Pulmonary metastasis from laterocervical ossifying sngiosarcoma, in rat. H.-E., x 46. Rat with subcutaneous angiosarcoma. Angiosarcoma of subcutaneous tissue, in rat ( offspring born from breeders exposed to VC). H.-E., x 185. Cutaneous sebaceous carcinoma, in rat. H.-E., x 185. Rat with salivary gland adenocarcinoma. Adenocarcinoma of salivary gland, in rat. H.-E., x 185. BOR 011159 Fig. 2 Fig. 4 BOR 011160 BOR 011162 -- ^ *s * * < '** ^ \ 'i\ \ :*. W V* f s. 13 ; W - /;: :.-m r. i*\.* *4y4'v*%i,#-.,'1 '. *V. ,*' * >tci. * f '. v-. ' ZHr?** &. <*.*. . 'V' s.' ^~\ j ' ' 4# *rU ,s 1>- .-; - ^ ' ' < ^ ' v ( **. *i *.'- * *'.** . . 'it 9 '*H"v . s . * .,,7'* *fc*- \" ' 4r,^. .,' * .,; ^ : t'** '. r v, < * ^, >. "' A- *'*"*-.^y * - .'/*. -J,' /\ V" ' v c '?-*' - < y[i Fig. 14 ^M * . * tf- ' ; V < *V * .>'a* _ * * . * m* v-'*.< v f \ * - ^ '* i-rf.irf --n *> \\ j ,.-,** *- *. rat*'* v- \ V mt / . 4T** ^ - - -- , !< ' A *? .V'- * *> 1 - -v. | ig. 1 5 _ -i^r,-4V. ' -- ' ^ k> . .. -Ij :< , , --** . * ^^ ^ I* k ^ L* V -/ ' i *J ' ' '* , ` ..v <* .. ' i V *V 1 - ' f* 4^. ^ ; - --*-w-- '4`--' -- BOR 011163 BOR 011164 1 0:' rr- t. t * -* i \' *: * w< Ser, ~-i, -1; 21 .1 ,i 4 ** *t r t ig. 23 * r, s; j. /* t > *>> i * .. *> * -1 * ** * -***: . * > ` * *: v.>, .U i . '4*^ V *4 Fig. -1 v- - - ^i .J * * t * ;.>j t.,< * s -> i v,-|; - v*: - \ . * ** '4 # <* *4* k * ^ k * ' * >T J v H Fig. *'* * : -'\ BOR 011165 > i i ig- 25 ; ? ... \ ig. 27 f r \ \ -4 > 28 BOR 011166 9- *> % V '* >* 1_1 tf-i'*\ ~ * .4 T*' * ry * ** f* " * ,* r~ * X 4. 1 *&j -- W * , ?.V V *'*r * ,* * k* ' " * M. P. I t ., >' -` v *av ,. .' * ; *' *. i * l;r"-.::-.V. * . ,t 1 * `k. - lr . 1 ' ;. 'v 'V ' Fi* 30 r _-.`'T.. >>v > ., v, > ' c.*' v v *: * .v-..- -3 ? Vr,t!` \ < *.' <.>. w'. '! . ><A < . - ` -*i ;1 --* r ff -* ^*-.--`-*--4l . ' _u *r> : V# l Ui!.j'-. '. ' .>Wt'-*. .Si','*.- --f > ,. , * n* .' -`'* ** * * -* .iVV;.*;; ' ' V^ i8* p' * f '. 1-0 s h w, * (i*?' : * _ __ i. /;. ,, J * - w- #f ^ v . ' y* *.i .v.> ,- 'Vs- * **. * ' . , .v . ,. -- . --U.% - i , ** . * ' S I v * ^ * <14 . *t * #> 7;- 1 - . .u. ' * v %1 * .i .*' '. i Fig. 32 ^ M* I < w/.-v V, '-*:. .... '- BOR 011167 I \ i > Lg. 33 f .^4 J Pig. 34 V 1U * \ *J A . Pig- 36 1 t 1 A **.* BOR 01X168 Fig- 37 I Fig. 39 r~ m I SO' I * # * 1 9 # C BOR 011169 1 1- i 'l t ig. 43 r* i j Fig. 42 Pig. 44 BOR 011X70 V BOR 011171 i r' 4 * J *V '"V-T' f *,* *- > %\ 4 '' v '' '' >A- / ' f4, r-- g. 49 *' < l*'-'*i* ^.V' " I, ^* * >' . ^ -',?\ * * *v v < 4 . `A* y ' i v _ -. \. , *^ > \ ' y . . * * * ' , Vf v . , .-v V . , *t .)** v *v % -* ' . . ` ' >' fca* 4, *..v * '' v. - / . ., . f * -* l . t\" t -i 4# > -t ' , ** w^' 4 * .. / V. ^ Vv -***' **1^J* -l * > * * 1 ' * t *, . T.* V , * . V ... jv- . it* . Fig. 50 -g. 51 jjhi n mrik. jjjfafci j 1 ,'** I. \ < *w . J' , ^s' Vt* ' 1 . t-J - V-" ff. v f , * ,^v:. Fig. 52 - *;/i . *' ` t ^~ * 'f %.4L- ' S * tl 1 I -f* * > *f; if* ki ll^ I r BOR 011172 J i 7?1 T " * 'S 1'7' ;! '4/-1/ r* ^ 'A ~~ I T ! t" I J ' : ' ' i/' ! /7 6 5 V " -- i- T !7 ^ ' |: T ? , _ it'-- - j n a -5 t .* i t ; t 'T TL l' A"- T'_, A'l'-r- BOR 011173