Document qd9av7Q74046LyezoGgZbjk3j

:sscn Mr. Anton Vittone President B.F. Goodrich Cherfiical Co 6100 Oak Tree Boulevard CLEVELAND OHIO 44131 LARGO DONEGAN1 1/2 20121 MILANO TELEFONO (025 S333 TELEGRAMM1 MONTEOlSON CASELLA POSTALS 3777 TELEX 31379 MQNTEOIS data 21 Giugno 1974 VS Pir. NS. RIF. DIPE/VDG/TEC/lra n 489 Dear Mr. Vittone, following up my letter dated May 21th, I beg your pardon for the misunderstanding and-X am sending you, herein enclosed, the report by prof. Maltoni. In these days ing. d'Arminio As out of Milan : on his', return ' I will discifss with him other subject reported in your letter. With the best regards. Enel. RENATO CALVI lQjuu^cr- 20249001 c;c rr iCf.AlP I * J MS AMD . r.Afi r M ? 1 - Tl'l AMI AMO < S . Vol 1 f> . ( " I ,M M lO*->9 BFG02646 i 4 td 3 Oo N> 0\ 4^ -4 S' # . cf S3 O 3 Pp-^*j C 0p 3 co < C2 H* hi O C3 3 -- n> OP 3 H- P 3 Pi P 0 z~ Pi 3* CD c P kO p HJ c+ C P o H* O cf 0 Pi 3 3 < O c+ 3* 0 Pi 3 < P v; HHi- 03 o on 3 H' cJ < s-e H> Pw 3 cf H* H _A < P H 3 po P- 0 PP H3 CO & O 3' . 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WvO cf pd3* Ocf Pi PO*o*->{ o OH (Hft* P f`> 3Pi Q 0 3cf 3o Hj o Vp3i tTi Q' HO 9 p H cf PH SV^i a w02 fe w jy H0 OH.V M P 3Pi MOCj CQ Mn3 hJ W 13 W Hh-J W o s r m u i oi rolcgv. a En'.ij 0pr.tfslle:o- Rioic*aio PEDALE PDUCUHICO S. ORSOLA .V in y l c h lo rid e (VC) has been produced in many c o u n trie s f o r a b o u t 40 t*> <Odd c: <ur 5C* o -i 2. a *. 1 -*X1o O O ' cv Wro wK O S V.) cpo| <oooJ> P Ln k.o OSPEDAU Di BOLOGNA Ent# Ospec'cllcfo OSPEDALE FOLICLWICO S. OHSCLA ISTIIUTO DI ONCCLCGIA zKUCZ ABDAPJS* Dircltorc: Prof. Cescrg Mallow Viol* Ereofanl 4/2 . Ol?3 CCIQGMA Tol. M3S24 Prot. N. Bologna. .May 5. j.... 15.7.4.. Page No, 2 they are produced and released on a large scale into "the human environment, should avoid later epidemiological evidence. , W 2) History In 1970 Professor Viola presented, at the X International Cancer Congres: (Houston), the results of a pilot experiment, which then were extensively published in 1971. Professor Viola reported to have observed on 26 rats exposed to vinyl chloride vapours for 4 hours daily, for 5 days weekly, for 10-12 months, surviving 10 months or more, 17 skin tumours, 7 pulmonary tumours, mainly carcinomas, and 5 osteochondromas. Immediately after the Houston Congress, Professor Viola kindly put some - slided of the tumours at our disposal. In our own interpretation, the ma(7 lignant tumours observed by Professor Viola in the skin were carcinomas arising from the Zymbal gland (a sebaceous gland of the exterior acustic duct) which is responsive to a large number of carcinogens. The malignan cies of the lung, in our opinion, were metastascs from Zymbal gland tumours We, therefore, started an extensive plan of investigations to further clarify the type and degree of the carcinogenic risk from VC. The project was encouraged and supported by Montedison (Italy), which later was joined by other major European Companies, that is, ICT (U.TC.) : Solvay (Belgium) and Ehone-Progil (France). C o o BpG02648 OSPEDALI Dl BOLOGNA Enl* Os^edoMero IlcolQnalo OSPEDALE POLICLIHiCO S. CP.S0LA ISTITUTO Dl ONCCIOGIA FELICE ADDARlb Direttcrc: Prcf. Cctare Meltoni V?f Erccbnf i/Z . 41fiS COCOCfiA Tol. 24 Prot. N. Bologna.... .4 Page No. 3 The Head of the Health Sez'vices of Montedison supplied us with all the technical data dealing with occupational exposure; this made possible the f reproduction in our experiments of the most important parameters of occu- V. _ pational conditions. 3) Planning, materials and methods This project included a series of experiments, which were started in sequence. They were designed to study the effects of VC, administered through different routes (inhalation, ingestion, peritoneal and subcuta neous injection), at different concentrations, for varying periods of time, by continuous or intermittent treatment, on animals of different species (rats, mice, hamsters), strains (Sprague-Pawley and Wistar rats), sex and ^age (adults, newborns, embryos). The planning of the programs and the preparation of suitable experiment al conditions, particularly the building of an apparatus for inhalatory exposure, took us until May, 1971* In July 1971 we started experimenting. 15 experiments have been started in sequence. Some of them were pro grammed at the beginning, for some others the heed appeared on the basis of the first experimental results. The plan of the experiments and the up-to-date situation is shovm in the following table 1. 20249004 BFG02649 OSPEDAU 01 BOLOGNA En'.o OipscJalljro Ceclcnala 08PEDALE POLICHiNiCO S. OivSOLA 1ST1TUT0 lit or.'CClCGZA <sF^LC5 ADDAS!! DfreUorc: Frof. Caere I-ij'.tor.i VUI* Eficisr.Tle<l,/23J.Gi3O2T1U GOIOCJ-U Prot. N. - Boioona....A;ay...5,... 1.97.4 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 untreated, 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 be the maximum possible dose for a chronic exposure. Experiment 2; was performed to investigate in a larger number of animals the effect of doses ranging from 250 to 50, that is 200, 150 and 100, under the same conditions as in experiment 1. Xt started after it was clear that 250 ppm was still showing oncogenic effects. Experiment 3: was planned to study the effects of a shorter period of exposure, keeping all the other conditions of experiment 1. OExperiment 4: studies the effects of the same type of exposure as in expe riment 1, in another species, that is mice. The treatment lasted 7 months in consideration of the higher mortality, and the shorter life span of the mice of our line, as compared with rats. 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 as in Professor Viola's experiments. o CocoOn BFG02650 T ' 'X ft Mo OSPEOAU 01 BOLOGNA Ent Osp^Jliera P.ccbn.ita OSPEDALE POLICUHiCO S. ORSQLA isimiro Dl OriCOLOCfA aF3L!Cc Dircftcrc: ?rcj. Cesurc Mi'to-ii Vlclo Ercola.H 4/2 <3129 B010CNA Tel. 295924 Prot. M. . w Bologna. Kav 1974 Page No. 5 Experiment 7: was planned to study the effects of the sane type of expo sure as in experiment 1, in another strain of rats, that is Wistar. C /'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 exp^o riment 4. Experiment 9: was planned, before tumours were observed at 50 ppm in exe.e riment BT/l, to further assess whether inhalation of VC has any effect at a dose level of 50 ppm. Experiment 10: studies whether a high, but limited and/or intermittent at mospheric exposure has any effect. - Experiment 11: was performed to evaluate the effects of VC by ingestion. PExperiment 12: studies .the third general route of exposure. Experiment 13: was started to assess .whether VC acts on tissues directly or through metabolites. _ Experiment 14: it has been included to study the responsiveness of newborni Experiment 15: it was started as soon as we found tumours in three animals of the first, experiment, exposed to 50 ppm *of VC for 1 year, and survi ving 135 weeks from the beginning of the treatment* The animals are controlled weekly, and weighted every two weeks during the period of treatment, and monthly after the treatment is over. All the BFG02651 22490Oq OSPEDALI 0! COIOGNA CnJo Gspid-iHero Rejian:! OSPEDALI: POLICUiilCO S. ORSOLA I5TITU70 DI C'JCOtCCIA ?SLiC ACBAiW* Dircttore: Prof. Caere Msltoni VUIo Ercotanl 4/2 0133 DOLOCN'A Tel. 303324 Prot. H. Bolcgna, ...A?ay...5.., 1.9.7. Page No. 6 detectable gross pathological changes are recorded during the control. All the animals are kept under observation until spontaneous death. The animals, when moribond, are isolated, in order to avoid cannibalism. A complete autopsy is made on each animal. Histological examinations are 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 pathological lesions. All the animals exposed to the highest doses (30,000 and 10,000 ppm) with or without tumours, are examined radiologically, during treatment and/or at death; moreover, radiological examinations are made on animals bearing tumours, though exposed to the lower doses. 4) Results . The current results of several experiments are shown in the following tables, For some others, we still have to wait. Tables 2-9 A few examples of macroscopic and microscopic pictures of the induced tumours arc shown in the next slides Figures K -O fiFG02652 CD Oo -4 OSPEDALl Dt BOLOGNA Eftlo 0*p';'.'.iNcro itajlonalB 03PEDALE POUCtiMICO S. 0330LA IST1TUT0 DJ O'iCOLOGIA sFELfCE AnDARHs Direlior:: F'raf. Ccsirc Md'.or.i Vial* Ercobnt tJZ . UOLOGNA Tl. 33?424 Prot. N. Boiogn3, ....May.,.3 >.....12.7.4 Page No. 7 . Zymbal gland carcinomas and nephroblastomas may be bilateral. Angiosarcomas are often polycentric. Tumours of different types may be present in the same animals. Blood vessel ectasias, endothelial hyperplasia, associated or not with cellular atypias and small fibroangiomas, are often observed in the liver and in other organs and tissues in treated animals, with or without angio sarcomas. Therefore, the effect of VC on blood vessels and endothelia should be considered systemic. Figures Hyperplasia of nephroblastema-like tissue is observed often in the kidney, with or without nephroblastoma. Fibro-angioblastic proliferation is frequently observed in the" spleen of the treated rats and mice. Figures .The onset of four ossifying angiosarcomas suggests a new orientation in the pathogenetic interpretation of acrosteolysis in'workers exposed to VC. Up to the present moment no acrosteolytic lesion has been observed on our treated animals. .. 5 ) Conclusions From the results presented in the tables and from the pathological observations and histological examinations, the following early conclusion: may be drawn: 1). VC is ongenic under our experimental conditions. BFG02653 3 OSPEDAU 01 BOLOGNA E.ilo Os.rci'atiftro neolocslo OSPEDALE POLICLIMiCO S. OiiSOLA isnruTo di cjicotoaiA rsucn iiDS.'.rriij Dircltorc: Prof. Cesnc Mdior.i Viaf Ercetsnl 4/2 - 43:53 GOlOC-'iA Tel. 533314 Prot. N. Bologna. ...May . 5.*.....19.7.4 Page No. 8 2) In rats it induces carcinomas of the Zysibal glands, nephroblastomas and angiosarcomas in the liver and in other sites. 3) In mice it produces pulmonary adenomas, mammary carcinomas and liver angiosarcomas. . 4) Attention should also be given to the few, cases of lymphomas observed in* hamsters. 5) Surprisingly no tumour has been observed up to now on Wistar rats. 6) A direct relationship exhists between the length of treatment, the con centration of VC and the neoplastic response. 7) By comparing the available results obtained in the experiments in which rats were treated respectively for 12 and 4 months, it clearly appears that reduction in time of exposure sharply reduces the neoplastic response. c 8) Tumours have been observed also after 1 year of exposure at 50 ppm of VC* The neoplastic response, however, greatly varies from 250 and 50 ppm, according to the incidence and latency time. In rats exposed for 1 year at 50 ppm the tumours arose in very old'animals. Were it pos sible to extrapolate from rat to man: regarding age and assuming that, on the basis of the average life span, two years and a half (130 weeks) in rats corresponds to 75 yearsin man, 1 year of treatment in rats would roughly correspond to 30 years of exposure in man, and 148 weeks of age in rats (the time at- which tumours arose in animals treated at 50'ppm of VC) would be equivalent to nearly 85 years of age in man. 0249009 BFG02654 OSPEDAU Dl COLCGNA Entc Osuciclisfo f.eola.vi!* OSPEDALE POLICUiilCO $. OSEOLA IST17UTO Dl OKCOLOGiA hFlLICE ADDA!] Dirdtorc: Prof. Ccstirc Mzltor.i Vial Ercelcnl 4/2 4QS23 BOlOCJtA Tel. 393324 Prof. N. Bologna. ...tl-y...5.>...197.4 Page No, 9 9) On the basis of the very late neoplastic response at 50 PP^ and of the delayed onset of tumours in animals exposed for 4.months, the experi ments on animals exposed to 25, 10 and 5 ppm. of VC, in our opinion, may be crucial, These conclusions however may hot be assumed as definitive. The major part of the experiments are still in progress, and a large part of the histological material is still to be systematically reviewed. Given the importance of the topic and the pressures of the events, we are doing .everything possible to have the data up-to-date. However, this is a difficult task and I am sure that those of you engaged in pathological screening of experimental material are aware of it. o 6) Final remarks . Our data have been and are periodically transmitted to the European Companies which have supported our research. Before the end of 1972, a short time after it v/as known that VC was inducing in rats not only Zymbal glands tumours, but also nephroblastomas and liver angiosarcomas, these results were made known also to MCA, I think now that it may be of some importance to show you on the last slide, the real story and the sequence of facts of VC carcinogenicity, since 1 feel that the scientific truth has been disappointingly twisted BpG02655 2 ) : PLAN OF THE EXPERIMENTS UP TO MAY 5 , 1974 HlI Wffcti c-< < 1-^*4 O0 Ofctl ft ft p ft c< C/2 e- 02 cfCC*oHOt1 fo1it1t fftt ft Hi i'T in'; ft PM Tio-- in P0i ^IOX Pi Hfcjj f-CPtVi OO ft h O* CO ft Oh wt?c\r3. a; /^S n fc> A0f =$ P -- cH3 PPi CO 0P1 o0rl Pi CO O CO oCr*M1 \O*o-- Vo> /ft 01 3fci) >P> <PPyii i--(JttfI CO ft -p w O VO irn- o/oft omr- Oirn' O r- oin CoO r1--ft *# TCM 0i PCh3o <--r0'SI uft d CO ft -P c5 ft . 01 pho >0 X3 ft PPii K5J CO ft p . ft CQ 0 1 P hD G0 w -ft 0g fi>t GO> +n fot >* ia 0> Ci rM\ CM > /ft C0Q o -&P a r-dP o oc -HHo >> PO- f.rti! o0t- CH OP *rl Pg P, " 4C-o . CO o -p !- vo ml CoM coo*v <o30 vr o CM mO C'HM Ci>J> ft - o1 . Pc0 >o> P i--t ft P CO -ft /rf--t 0i CPS3o f>ot3 P. c* CO ft / -P +> cj ft 1o%-H-i* CQ fCPtQi f->CHt->j fCJPtQ>i >f0>Oftt >00j4 4 02 >. CQ t >> w f00t Pi ft Hri c3 <rffl AO O 5t CM 20249011 BFG02656 i. ro :n Wft l < P, p; OW ft Pi CO pft* ft ^ 0 JH CO CO. 0 O r-< rn i . [O W W M p'i M ft 6-* L'-?. Ph rO *m- om ir\ ITS tx P.P o> o ^ ubo ft +C>5 o ft O* + O VO o VO o Oro o ot'~l ) o CM CM o CM CM Ot"I- CroM or oo oo V- r~i .CVOO CM OOTf CO VO oo CM CM oo CM o CM o <* CO o CM O CM ANIMALS co atio &a> . fHi 0I 4cU-d W O* cd I--I Uft 5 a to Pt C0O H O 0 tfot -fcpdt' U -tRd tHo 4* cd ft ft CD ft HeO? i f-i g0 td + Ww 0I ? oj r--I ^ St ft td to o -p td ft I 0 PHn >o> td r--I UPi td CO Q +cd ft G ft 4-> bO G 0 ft to K W }>J-cXt w >> >, ft o U ft f-Ht ftdt X0 td g> m to co P ft f>t5 H CO - >i P*> ft fctd Met O o cd 0 CM to - j*i to >> o CO fut ff;tt cd >> ft fctd ^00 0 5 O 0 * M f>-> X0 to t>> >>ft 0 fGt fftt fctd ^e> td 0 CM - l B - w- -A4 CO -cHd >c>j - - CO ^ - >., 0 ft ft ?- CO >3 ft 0 CO p>. >ift 0 n fpt -Hft ftpi 044 0> ^F- .fHt fctj >0: r? fPt - C ?s: o w 'X o BFG02657 BFG02658 PT06K>:o?r : PLAN OF THE EXPERIMENTS UP TO MAY 5, 1974 Length i 4; hrs. daily, 5 days . weekly, , 52 weeks 4 hrs, daily, .5 days weekly, 52 weeks 4 hrs. daily, 5 days weekly, 17 weeks 4 hrs. daily, 5 days weekly, 30 weeks 4.hrs. daily, 7 days (from 12th to loth day of preglV-'Vv.r) ANIMALS Species Strain Ago (weeks) ? No, Total Per group LENGTH OF THE EXPERI MENTS AT THE PRESENT BATE (weeks) Rat Sprague3? awl ey 13 268 309 577 64-96 135 (Ended ) Rat SpragueDawley -13 280 265 545 120-185 43 Rat SpragueDawley 2,1 262 288 550 60-190 68 Mouse Swiss 11 250 260 510 60-150 r( 19 Breed Rat Sprague- ers Dawley 12 110 36 146 30-54 days Embryos i 43 77 r ; PEAK OP THE EXPERIMENTS UP TO MAY 5 , 1974 6S9OOda tH O & CsJ o OSPEOAU 01 POIOCMA Cnta Oicxdallc'o fVgic'u!? 03PEDAI.E POLICLIrilCO S. ORSOLA /S7J7UTO DJ O.VCOICCW s^UCf: /1DDARJJ* Direllorc: Prof. Ctsare Mr.iloni Vial* Efcolanl 4(2 <OtM COlOCIUN Tftl. 33M24 Pro!. N. - ' DoJogna, Page No* 10 Table 10 In the early report of Doctor Creech and Doctor Johnson on the first' three cases of angiosarcomas of liver among the workers in the B.F. Goodri plan in Louisville manufacturing VC and FVC, reference is made only to the epidermoid tumours described by Viola, and furthermore it is stated "Since all three patients were treated by different physicians, no relationship to exposure to. polyvinyl chloride was surmised until the authors, recognis -the rarity of the tumour, and learning that all three had worked in the PY plant, brought the matter to the attention of the company". As I have shown in the last slide, the relationship between. VC and live-, angiosarcomas on an experimental basis had already been well knoY/n for mor than 1 year, and this was the information which oriented the clinical ebse: vations. In my opinion, it* is imperative that these facts be made known to stren: then the validity of predictive experimental testing. As a medical doctor, and as a man,- in fact, I can but auspicate that tlu VC carcinogenesis may serve as a convincing example for promoting experimei al bio-assays for all new industrial compound^, and for those compounds the are already widespread but whose effects we still ignore, to avoid occupa tional cancers. Italian industries are already oriented in this directicr and our Institute has been asked .to 'prepare a coordinated program. . N ^ BFG02660 or'