Document zQaky7LMwpBKMyGzEyyGyEw2n

7 / / MEDICAL P^iEOP- ^ OG> - c -O o co -o 'o a^r^i v'tf/ Tty TTGVCR o May 8, 1975 page 2 five times a v;eek for two weeks and (b) 50 ppm for 100 exposures, one hour each, five times a week for twenty weeks. We were invited to make formal application to visit with them in either an open or closed meeting to discuss details of their experiments. 4. * Standards in Other Countries * .attached is Dr. Brookman's' transmittal of infor mation onrthe'status of regulations throughout the world. 5,1 Articles* Received from the International Agency for Research on Cancer, 150 Cours Albert Thomas, 69008 Lyon, FRANCE (IARC) v_ Epidemiological Studies, Report No. 75/001 of January, 1975. ( by Oncogenicity of Vinyl Chloride at Low Con centrations rh Rats and Rabbits by A. Gaputo, et al. Item No. 250 citing research on vinyl chloride from IARC's most recent Information Bulletin (No. 4, November 1974) on the Survey of Chemicals Being Tested for Carcinogenicity. CdT) First pages which include summaries, of two articles on mxTCagenicity of vinyl chloride. 6. Attached also are title pages, indicating where copies may be obtained, for: a) "The Determination of Vinyl Chloride, A Plant Manual'* (92 pages) published by the Chemical Industries Association Limited and (b) "Guidelines for Carcin ogen Bioassay in Small Rodents" (65 pages) published by the National Cancer Institute. Sincerely, MF/etv Attachments Milton Freifeld Project Manager SCC 5-0173 APR 4 1975 Firestone Plastics Company eaiCRAI. OFFICES . o. mi ... FOrrronr. fcisnstcvama im4 division of the ftttesroNfc nut rubrir company HAB.VCY S. FlftSTON fOUNOEA POTTSTOWN. PENNSYLVANIA April 1, 1975 Mr- Milton Freifeld Project Manager Manufacturing Chemists Association 1825 Connecticut Avenue, N. W. Washington, D. C. 20009 Dear Milt: The reason I did not send you the summary of VCM regulations I promised is due to the fact that action in the various countries throughout the world continues to change on a regular basis. However, I have attached information that we were able to obtain in early November 1974* that we believe to be accurate of that date If you have any questions, please call. COr'^ 1 oil T7 RSB:djs Attachment cc: Mr. R. A. Park R. S. Brookman, Manager Research, Development and Technical Service see 5-0174 November 1974- JAPAN No angiosarcoma deaths reported to date. Three non-VCM deaths by angiosarcoma are recorded. It is estimated that ten deaths (nonVCM related) have occurred in Japan during the last- twenty years. The equivalent of the Japanese Dept, of Labor feels that chromo some abnormalities may be a problem, based on conversations with Dr. Selikoff of Mt. Sinai School of Kedicine. A VCM standard may be set at about 10 ppm (no TWA). Japan uses the term KAC (maximum" atmospheric concentration) since there are onlytwo closed (in) plants in Japan. A maximum of 1 ppm may be esta blished. New drafts (of standards) such as above must be approved by all other interested agencies in Japan, i.e., Marine Labor force, DOT, e'tc. It usually takes, about six months for this to occur. Currently MITI requested 300 ppm maximum VCM in low molecular weight resins; less than 100 ppm maximum VCM (high molecular weight resins). Work has been started to lower residual VCM in their resins. - STANDARDS CURRENTLY IN EFFECT: United Kingdom: 30 ppm maximum; 25 TWA (based on agreement among government, PVC associations, labor). West Germany: 1975 standard was ICO ppm maximum. 1974- standard was under chemical substances, Category B (cancer through animal test). Netherlands: 1973 standard was 200 ppm. 1974- standard was 50 ppm average; 100 ppm maximum. Row standard is 25 ppm average; 50 ppm maximum. Soon to be issued is 10 ppm average; 25 Ppm maximum for 15 minutes. "(Labor feels this is too mild.) France: No government regulation. Producers use .as standard 100 ppm maximum; 50 ppm normal 1975 standard is 50 ppm maximum; 25 ppm normal. France usuallydisagrees with USA. Belgium: No government regulation. 25 ppm TWA; 50 ppm "action level". Sweden: 1974- standard was 25 ppm TWA; 50 ppm maximum. 1975 will follow OSHA standard. Will scrap old plant and build new one. Norway: Finland: October 10, 1974 - Working on new standard. Plant currently shutdown until a decision is made. Same as Sweden. see 5-0175 Italy: Not regulated but active producers use 50/25 (TWA). Most Scandinavian countries will follow OSHA due to the strong labor union \I IAPC Internal Technical Report No. 75/001 REPORT OF A WORKING GROUP ON EPIDEMIOLOGICAL STUDIES ON VINYL CHLORIDE EXPOSED PEOPLE Lyon, 8-9 January 1975 see 5-01?6 X~ LIST OF PARTICIPANTS Dr P.J. Baxter Dr L. Bertazzi Dr C. Cavelier Dr N.E. Day (Rapporteur) Dr L. de Boer Dr B.W. Duck Dr D.P. Duffield Department of Eftployirvent Medical Services Division Baynard's House 1-13 Chepstow Place Vfestboume Grove London W2 UK Clinica del Iavoro "Luigi Devoto" dell'Universita di Milano Via S. Bamaha 8 20122 Milan Italy Institut National de Recherche et de Scurit Boxte Postale 27 54500 Vandoeuvre France Unit of Epidemiology 6 Biostatistics IARC Chief Medical Adviser Shell Internationale Petroleum Mij BV Carel van Bylandtlaan 30 The Hague The Netherlands Occupational Health Unit BP Research Centre The British Petroleum Company Ltd. Chertsey Road Sunbury;-on-Thames Middlesex TW16 7IN UK Division Medical Officer Imperial Chemical Industries Ltd. Mond Division Castner-Kellner Works P.O. Box No. 9 Runcorn Cheshire WA7 4JE UK SCC 5-0177 Dr A. Englund Dr V. Foa Dr S. Gauvain Dr L. Goerke Dr C* Heath Dr J. Higginson Dr B. Holmberg Dr R. MacLennan fRapporteur) Dr G. Marri - n- Tardsorganisationen Bamhusgatan 18 Stockholm Sweden Clinica del Lavoro "Luigi Devoto" dell ' Univers ita di Milano Via S. Bamaba 8 20122 Milan Italy Department of Employment Medical Services Division Baynard*s House 1-13 Chepstow Place Westboume Grove London W2 UK Bundeaninisterium des Innem Referat UB II 5 53 Bonn Federal Republic of Germany Chief Cancer & Birth Defects Division Bureau of Epideniology National Center for Disease Control Atlanta Georgia 30333 USA Director IARC Section of Occupational Tbxicology Department of Occupational Health National Board of Occupational Safety & Health Fack S--100 26 Stockholm Sweden Unit of Epidsniology & Biostatistics IARC Federazione Unitaria Lavatori Chimici via Bolzano Nc. 16 00198 Rcme Italy see 5-0173 1 Dr R- Montesano (Rapporteur) Dr M.S. Muir Dr H.G. Parkes ^ Dr E. Pedersen Dr R. Saracci Dr G. Snagghe Dr A.M. Oiiess Dr L. Tfccnatis (Secretary) Dr J.A.H. Waterhouse (Chairman) Dr H. Weber -m- Unit of Chemical Carcinogenesis IARC Chief Unit of Epidemiology & Biostatistics IARC Medical Director Health Research Unit British Rubber Manufacturers Association Ltd Scala House Holloway Circus Birmingham BIER UK Director Cancer Registry of Norway Ihe Norwegian Radium Hospital Montebello Oslo 3 Norway x Chief Biostatistics & Clinical Epidmiological Section, CNR Laboratory for Clinical Physiology University of Pisa via Savi 8 56100 Pisa Italy Service de M^decine et de Ibxicologie Prcduits Chimiques Ugine Kuhlmann 41 rue Pergolese Paris 16eme France Leitender Werksarzt BASF Aktiengesellschaft 6700 Ludwigshafen Federal Republic of Germany Chief Unit of Chemical Carcinogenesis IAFC Director Birmingham Cancer Registry Queen Elizabeth Medical Centre Birmingham B15 2TH UK Staatlicher Gewerbearzt Gurlittstr. 55 4 Dusseldorf Federal Republic of Germany SCC 5-0179 1- - REPORT 1* INTRODUCTION The meeting on vinyl chloride (VC), convened by the IARC in June 1974, recommended that the IARC coordinate the various epidemiological studies being conducted in different countries on the oncological hazards associated with VC exposure. The present meeting, following a small, working group held in September 1974, constitutes a first step in the development of such coordination. Die agenda for the meeting fell into three parts: (1) a consideration in general terms of the types of study that needed to be done and the principles underlying their design; (2) a review of the studies currently under way in the light of the principles so established; and (3) a discussion of hew the coordination of such studies could be implemented. It was recognized that there was a need to generalize fran the experience gained from VC towards the establish ment of more speedy and efficient information retrieval systems for the early detection of industrial and environmental hazards. 2. CASES CF ANGIOSARCOMA OF THE LIVER IN VC M3NCMER (VCM) EXPOSED WORKERS .The list of ^-related cases of angiosarcoma of the liver compiled in June 1974 (IARC Internal Technical Report No. 74/005*) was up-dated (see Table I). A total of 35 cases has been recorded so far, of which 29 were polymerization workers, two polyvinyl chloride (PVC) fabrication workers and two workers exposed to \Of. In addition, one case occurred in a worker employed in the insulation of electrical wires with PVC material and one was an accountant employed in a firm which made vinyl sheets and processed PVC resins. Since the meeting, eight additional cases have been reported to occur among the polymeriza tion workers of a factory in Canada (Lloyd, personal txmiiunication). Three cases occurred in workers exposed to VC for a period as. short as three to six years. The shortest latency period observed was six to eight years. The observation in the USA of two cases of angiosarcoma of the liver in persons with no occupational exposure to VC but who had lived for many years in *The statement on page 20, line 9 of this report is incorrect and should read the liver is in the order of 0.014" (and not 0.0014) "cases per 100,000" 08T0- 33S 2- - within a few miles of FVC-utilizing factories, raises the possibility that exposure of the general population to VC might occasionally be sufficient to cause angiosarcoma of the liver. 3,- PBQCJIREMEtnS EtJR EPIDEMIOLOGICAL STUDIES ON VINYL CHLORIDE A document suggesting a series of requirements for epidemiological studies of VC risk was presented to the meeting for consideration. Subsequent discussion demonstrated the difficulty of going beyond a general outline of minimal require ments. A surrcnary of this discussion is given below: 3.1 Establishing a cohort of those occupationally exposed to VC The feasibility of including in the study cohort all those ever employed in a factory producing VC was debated. It was pointed out that the VC plant itself was often part of a much larger factory, and that to include the entire factory would increase costs substantially. Furthermore, contract workers, for whan no records were usually available, were often used for the dirtier jobs. Nevertheless, in sate countries complete lists of workers could be obtained. The only criterion which seemed generally acceptable was that inclusion of a worker in a cohort should be independent of events subsequent to exposure to VC. It was stressed that cohorts need to be established now for long-term prospective follow-up. It was recognized that failure of risk to became apparent after ten years does not preclude the emergence of such a risk, perhaps at a different target organ, many years later. 3.2 Studies of residential exposure Although sane studies are planned, it was concluded that for evaluation of carcinogenicity, such studies were a cumbersane way of obtaining information alternatively obtainable by case-control or case-history studies. 3.3 Exposure The difficulty of establishing retrospectively an individual's history of exposure in a quantitative sense was recognized, a circuastance which emphasised the need to have careful monitoring of all manufacturing processes ab initio. Nevertheless, in any one plant, one would expect to be able to establish a see 5-0i3i -3- scale of exposure such as + , ++, +++. Even the same vrork station might imply quite different exposure levels in different plants; for example, an autoclave cleaner might be full-time in one plant, but only intermittently so occupied in another. Furthermore, for most work stations one would expect exposure to have fallen appreciably over the last 20 years, and exposure in more recent plants was likely to be less for any given work station than in older ones. 3.4 Confounding variables There was agreenent that retrospective information on a variety of con founding factors was often unreliable, and it was pointless to collect this for an entire cohort. Such information might be obtained on a case-control basis as cases arose, when esiphasis could be placed on accuracy. 3.5 Size of the cohort The minimum period between first exposure and tumour development is in the order of ten years. In the cohorts followed, there 'must thus be a sufficient number first exposed more than ten years ago for definite conclusions on risk to be made. Nothing is gained by swelling a cohort with those exposed for a short period except for the purpose of a prospective study (see Section 3.1). The prcblen of pooling data fran several studies is discussed in Section 4. 3.6 Follow-up of cohorts An attempt was made to put a level on the acceptable losses during the follow-up. The level of the losses depends mainly on the resources used for this purpose. Further, losses to follow-up are often greatest among those exposed earliest, i.e. the group of most interest. In the rubber industry study in the^UK, 97% success has been achieved, and it was pointed out that there was a higher proportion of deaths in the last few per cent traced. Similarly, an Italian study of a cohort of about 3,000 workers traced 92%, the earliest entry date to the cohort being as far back as 1935. This cohort was, however, frcra a snail area with little emigration. A figure of 90% was tentatively proposed as the minimum acceptable, provided that the proportion lost to follcw-up was the same in both exposure groups. The quality of information must also be satisfactory. see 5-0182 -4- 3.7 Case-control studies There was a suggestion that for both angiosarcomas of the liver and brain tunaurs (see Table II) case control studies were needed to define the level of risk over wider classes of exposure. .4 PRESENT STATUS CF EPIDEMIOICGICAL STUDIES A suninary of the epidemiological studies discussed at the meeting is given in Table II. In addition to these studies, mention was made of other studies in the USA, conducted at the Mount Sinai Hospital, the University of Louisville and the Boston School of Public Health. Uiere was a suggestion fran the Mount Sinai work that an increased risk of hepatocellular carcincna, in addition to. _ liver angiosarcoma, might also be associated with exposure to VC. Preliminary data fran the National Center for Disease Control, USA, show an excess of brain and lung tumours among workers employed in two PVC polymer ization plants (see Table III). It was stressed that these figures are subject to revision when follcw-up is ccnplete. 5. PERMISSIBLE EXPOSURE LIMIT IN SCME COUNTRIES In the USA a permissible level of 1 ppm (averaged over any 8 hour period) and a ceiling of 5 ppm (averaged over any period not exceeding 15 minutes) has been in effect fran 1 January 1975 and applied to the manufacture, reaction, packaging, repackaging, storage, handling and use of VC and PVC. Ihe same permissible level was established in Sweden/ and from January 1976 this level has to be achieved without respirators. This is considered feasible. A VC code of practice was established in the UK, which limits exposure to a timeweighted average of 25 ppm and a ceiling of 50 ppm for a maximum of 15 minutes. In the Federal Republic of Germany a permissible level of 100 pjxn in factories was effective up to 1974 and a new standard is expected by raid-1975* Similarly, new permissible levels of exposure to VC are expected in other countries. 6. DISCUSSION 6.1 Centralizing of results In the discussion attention was turned first to the value of unifying the see 5-013 -5- results of the marry different studies. Hie two main obstacles to unification of the results are the lack of comparability of exposure levels among tte different studies and the differences in quality of the data, both in terms of the losses to follcw-up and the quality of the available diagnoses. Differences in the base-line incidence of most tumours were also raised. It was pointed out that a ccntoined analysis could certainly take account of differences in exposure levels and base-line incidence figures, as one attempts to carbine the carparIsons rather than the absolute figures. Do statistical methodology, however, can combine a good and a bad study in a sensible way. Nevertheless, there was considerable support for sane attempt at centralizing the data. Tb this ervi, the IARC will shortly be circularizing proposals for the centralization of the data from the different studies, to invite ccmnents and to determine the extent of willingness to cooperate. 6.2 Register of angiosarcomas of the liver Both the USA and the UK have established review panels of pathologists and country-wide registers of angiosarcomas of the liver. Hie idea of IARC setting up a corresponding international register, aixl a further review panel, was discussed in view of a possible duplication of effort. However, there was sane support for establishing a pathology review panel, with the Wbrld Health Organization Cancer Unit, and a register of liver angiosarcomas operating in parallel with UK and USA bodies. 7. VINYL CHLORIDE AS A PROTOTYPE FOR FUTURE COLLABORATIVE STUDIES CN OCCUPATIONAL CANCER The carcinogenicity of VC was detected in experimental animals sane four years before it was found to be carcinogenic in humans. Hie meeting expressed a strong feeling that if priorities for investigation, based on known biological activity in the laboratory and on the extent of human exposure, could be assigned to suspect chenicals, and international collaborative studies initiated accordingly, then carcinogenic dangers might be identified and eliminated more quickly. As an example, the IARC Monographs on the Evaluation of the Carcinogenic Risk of Chenicals to Man have now considered 196 chemicals. Of these, 17 were found carcinogenic to man and 92 could be clearly seen as definitely see 5-0184 -6- carcinogenic in seme animal species. A number of these 92 are widely present in the human environment. It was stressed that the IARC Monographs are among the tools necessary to produce a list of chemicals on which to choose priorities for epidaniological studies. This priority list should be short enough to encourage seme action. International collaboration for such studies offers the advantage of reviewing world-wide patterns of use and production as well as experimental data to decide on the most suitable areas for investigating a particular caipouni. It was decided that the next meeting would not be limited to the consideration of VC studies t but treat the wider issue of selecting ccmpounds for immediate epi demiological investigation, and attempting to identify populations on which these studies could be performed, as well as suggesting better ways to carry out primary prevention by preventing exposures to chemicals for which a carcinogenic activity could be strongly suggested. The validity of tissue-mediated mutagenicity assays in determining the biological hazards of chemicals was discussed and data were presented on the mutagenicity of vinyledene chloride (2) and reports in the Soviet literature suggesting a carcinogenic risk of 2-chlorobutadiene for man were mentioned (3, 4). 8. RESPOEIBILIT5f CF INDUSTRY FOR FQLDCMING THE HEALTH QF ITS WORKERS The difficulty and expense of mounting ad hoc studies for each new suspected compound could be reduced if an appropriate system of records of exposure and medical status were developed for the workers in industry, and if this systott could be readily linked to national vital statistics, whether records of death or, preferably, cancer morbidity. Linking to the national records is essential for tracing past employees. Both Imperial Chonical Industries Ltd. and The British Petroleum Company . Ltd. in the UK, ard Ugine Kuhlmann in France, are developing systons of individual records, which are linkable to the national registers of deaths. It was recommended that the IARC lend its support to the establishment of such systems, and stress the desira bility that industry assume responsibility for the follow-up of the health of its workers, even when they have ceased employment. . It was also recommended see 5-01S5 -7 - that the IARC take steps to ensure that the record systems developed are occpatihle between industries, and that they can perform the tasks required of than. This approach should be canplemantary to the points stressed in Section 7, aiming at the identification of carcinogenic charticals before human exposure occurs. 9. NEXT MEETING It was agreed that a further meeting would be particularly useful if it included the content of Sections 7 and 8 above in its agenda. Dr L. Goerke, of the Bundesministerium des Innem, Bonn, offered support for the meeting to be held in the Federal Republic of Germany. REFERENCES " 1. Wagoner, T. Statement before the Subcommittee on the Envirorment of the US Senate Ccmmarce Ccnmittee, 21 August 1974. 2. Malaveille, C., Barbin, A., Brasil, H., Montesano, R. and Bartsch, H. The effect of drugs on iretabolism and in vitro mutagenicity of vinyl chloride (VC) and vinyledene chloride (VDC). Proc. Meeting European Soc. Ttaxicol., Montpellier, 1975 (in press). 3. Khachatryan, E.A. The role of chloroprene in the process of skin neoplasm formation. Gig. Tr. Prof. Zabol., 18, 54, 1972. 4. Khachatryan, E.A. The occurrence of lung cancer among people vrorking with chloroprene. Problems in Oncology, 18, 85, 1972. see --0186 TABLE X CASES OF ANGIOSARCOMA OF THE LIVER AMONG WORKERS EXPOSED TO VC OR FVC (January 1975) Case No. Country Da,te of diagnosis Age at diagnosis Years from first exposure to diagnosis total years of exposure Occupation 1 2 3 4 5 6 7 8 9 10 11 ` 12 13 14 15 16 USA USA USA USA USA USA USA USA USA USA USA USA USA USA USA USA 17 USA 18 19 c_n UK UK February 1974 May 1970 June 1952 August 1961 May 1968 May 1969 April 1964 March 1973 March 1970 1968 December 1973 March 1974 May 1974 March 1969 October 1974 June 1973 July 1972 December 1972 1974 45 36 43 41 55 50 52 49 61 45 58 43 53 41 43 ' 60 47 71 37 12 14 15 15 17 20 20 22 23 24 28 19 30 19 19 36 10 26 8 12 13 15 15 17 15 18 16 23 18 . 28 17 30 4 19 10' 20 ' 31 Polymerization worker it it it it nH Hm H it ii n n ii ii n ti H ii ii nn ii ii n ii n ii Insulation of electrical wire with PVC plastic Accountant in a plant making PVC fabric Polymerization worker ti n see -0187 Case . No. Country Date1 of diagnosis TABLE I (Cont*d) Age at diagnosis Years.from first exposure to diagnosis Total years of exposure 20 UK February 1970 55 24 11 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36-43 Norway Sweden Sweden FRG FRG FEG FRG FRG FRG , France Italy Italy Ffcmania Czech. Czech. Canada Decanter 1971 February 1970 May 1972 1971 September 1968 1974 July 1974 1975 March 1973 . February 1967 Decanter 1972 April 1971 1970a No it fl 56 43 61 40 38 44 49 43 43 43 43 36 27 data n II 22 19 27 14 12 17 17 13 21 19 15' 6 11 a vailable t> n 21 18 23 12 12 17 11 12 21 19 6 3 5i i A diagnosis of hepatocarcinorna associated with cholangiosarcana was made. Occupation Pouring PVC oil mixture onto fabric bases Polymerization worker H it Production of VCM Polymerization worker ii n n ii ii n ii n Filling pesticide cans with VC as propellant Polymerization worker n ii Production of PVC bags Polymerization worker it n n it hn see 5-0188 i r u o- L> U CO -H cn ci in i 9 i i**v ... <4n>ito|aa fo ind * M a* in "PI1` `*Kn*sad am* *4ll 0U| mveH TTV Evt w pu SAruadsQJd jn*TI "* nfJT*a0T RJ so awaao .owraaW. tt * .armsao. n M* Jam f UIX vp** *) itrjpwv -vo Kn %n* uraiq ta] jc hm# vn jo lonntfri v pm uar} vyiff jo tcw vy *jt; ct vwjAcd %oi vmjt 1 MtM '< m( et uo 4W mirtlni uni vni UM { JSJ pMcidi* uvcm so) Acmi n vi t n M> t Aif pniMul wan n|raw *m Cunaa r a* oiqorrw j uaa mno papcfe** poo'01 an jo jo --u a**n jo lervoinrp * 1u 'panMOJ aiaa JSA11 an JO an .naorfea 70 (a*TW t (--> tl Man >31 'ana* 01 JO nw pivimra tfT ttojoWJW 00 `JJ MR 1* paiooptij eoo'oc 'cm* u<n roninrtu 000 000 u 'M jo hliauiJ ap wj 'MT pl UOTWOUJ VT 'K n eii sourf aw ju ok as taaoda wq OAKI an txmJ JO aou Twa an lan pnarv >a t *M jo fcijaoao 4-sal an W| MO`OC- * na.uo|v>roaJ 3W VT OOO'tl 'CA jo WJTU| or VT MT>{ aaaenoj 'aaU* *1 anla[*o 70 i^v aiaaajd ao pus nuvid tvTJxuovMa aw js w w an ama OKT VT v^or wnaruj fa^TOVO fc*I0 Hal oillaCB mstmi Oqapn Of 'VKTMBd JT '** ^ an aapitf 71 3-(Mpoonapsq oi -Hn ' ft o aaooAa js aajtao -papafe! aaq M save t acy 0III OT U VT pinaw il 0an Jtro* ap jova " J RT *B 0 1 4JTJ t pOfi M < wfp jo w * <U aw !7 4vn* IT*- P 'VTF< * JUAB ||Jpt tfTVV>{LED Vf KTTV JO Aro uonandud uj uqwadaal #r - Jbuij or am Majlwqa on uj papaxaz taaqaaajaU w J r**oi - 'iTWTTTUV (anayaas T VM >o tLaongj pa/l^vac^a usaq a*aj aRaap '*< padwap as psrrw j"rt *"i t s" "UirpJ finnanTM TsAJlM rm n 00C 'iurta TTTW an `oawO JO ia\ 0 foon^a uaaq aaoy anapoa Wt 'mi vr Mr*oJodo <^0 **0*1 a 'anaynm l[iw *r ipca '^an* an VT ptsaaj ( hr jo \ MU l*4in> w wrwTToe va3 aU a aq jaw aca aiaaj 'Raid wnaipaatiol up M MO'l 0* tup* "q tpv> U DOT aq pan laantai mi <i'1 4pn jtRwvMu iiiiiivijiit VTwnafl loaais Wat aaaao miwitua aTI J paqva 3* n m V os anaafaa iri|iai|naJ|iJ an `irurainil yj `auajnai ao / >BTiar^<raf inrian jaainl * WRarruO an iaqd aw as a* VT waters maid wpanpuf a* MU aa^ifai vaqd uoywoad IGA . . - va^m^jQtj ay | wrwi UaoSa jo sdt| anuoo vi u7T0pvT J^ TC*w nato ^ WTVIM ' 000`M U-CMT JTad smt (Ufsv nnartav an uj laujavu aovao UJ -MTT t aOftov /puj ]onro mvj uuiaajiua M je Jpp> uspaMrfau aaouas T JsTTTlioa MTmdaonar unpan nou v bn^raqvj aw `aasvoa aw-a\ jo evruaao TOSTTW MM T VTWao ta TollBoajj Olartononaj JO ateTTQO T*y an pMao Juuitv 'tnow aan an[ail an jo aovnnaaa an ma 'nun^aii tnisaj wj ini* isruuoCuis I *oo|*JOS *100r*pv lantpaa Ua^O[<VW aniaiiaoihia jo asaar^ai apraaiDaJ M`I tapai jaata ^(TrrtnanpVT JO Jpna tjorq *7Ifivou JO wmtio JO) 40tayw paoote ten JtWWW t" UO O at CQ paaodaa ataaiaai h raa . poucdai away (Ct *"rTM jo am jo STCtfsay OOO'Ot OffT * Ajouoj aaou turarl uonapdaJ ftaa uu] >>aaojrTaa mTuafuM CuTpAiavT 'JaTOTWW UT Rtojo OnnaMpOT J <* **o vioi~>--acijvr itjaso mfen-TtvMdj t nv*na J0 JbVH 9FW 1 uo ^Vl**'C ^irngmiQ *prn^X 0 raavns jo t rraaiatevw RS Ajoiuorot l>o 1 ttstoiAw t*0|IL> JO /toaJcqnq *0 CW'f lire id wTf liluaf psooAas -trmMTpvr JO 4p>oo VOLfO JS wit |s*v%q 1 Q4 *3 wttw jv ^iuATvn 'ottfsn vttvtd ast^naavr [aJvRiTJd * avanovt *1 ou ou 34*1 /roir *rj irhivso ymnpm uhka hgiriTrn ivmnuwm 11 * see 0190 UT oi Jiiitmalm lunm am w V WP 1 'Pen f*i nv 'T--V*1 F"J B I it aopavotf au jb a m Jnno`fl'1 to *wPMOtB *eo SB ap jg tt b n*i -BM* * ksf Iratvif v1 w unm (urns n (w tnato v4 tiiiimi n (apBiinQ ukub jo mmam m fa uj|m w <wwi (HI 1 W****o "* BTwnnt 1 WH ln anm j 'nipil jo aniiuu pa um butt ibpacM pa imui feaao uo(*v'*B 1 'mv uijaK iiiiMi 'MM*) (fiirw oa <nmw q re MW M/K TT* 'WW IS noil (1 'paean u a ul fyy *a mm nn* FWt^J -- vaa '*nw wi t* nw piv . n"T--W a nwwr lne!JW M nr*r i VMuauy * 'mb'* ooo'c 0* W1 MU amjaq uaeq 'go*'! _t7Tno*V( pa 4|WQa isjo U paa.ilu ttiitnapii SKI *T puDi uauK ipnapcad aM-as /JOVBJ W uwa a*oo - | PM) Mi H 1f| 'IPI^W M taa* I^TU <r PM> na|nnjn Ml Kfl to *|**arj Kn--w> MmiiMt nwi*ini 9* ml i aaW mem au Uinta jo itfi \ao^f v}tT papHB %saalia ^ mow tit Vanns taataUipmapui MI'1 at tmaq as v utpoi paaate -fTTT*V<T to Jpai WQ MO'KKt mii pnmhn ^nH*w r fcn~uMn^^>rw**airMW w* r> nil <Pa rn Ul *3 ^0 PKH(SW! IQ T pen0 ^ prMfl OIU0T> >QJ, jac* y P^iia aj W 3Q wxona^ wm oo `l ttfpnksnpnmi am ijrrkVM 1 ma*rwWBT nrfpa/pM 1 rv*>n*n inn; 4 * r,*>) i s 1 * i TABLE III PRELlMXKARy ANALYSIS IN IMP VC POLYMERIZATION PLANTS CONCERNING WORKERS EMPLOYED 5 OR MORE YEARS AND WITH 80% PQLLCfrMJP (REP. 1) . EXPECTS) AND OBSERVED DEATHS FROM VARIOUS CANCER CAUSES (1950-1913) Years since onset of exposure in the selected departments Person years at risk 10 - 14.9 15 - 19.9 20 - 24.9 > 25 TOTAL Standard Mortality Ratio 9731 Significant at p < 0.05 All cancer Liver cancer Brain cancer Respiratory system cancer Lynphoma and Leukasnia Exp Ofas 4.91 6 6.30 11 5.81 11 2.72 3 Exp Obs .12 0 .17 3* .15 3* .07 0 5SE Obs .22 0 .25 1 .20 2* .06 1 SXP 1.50 2.08 1.99 .92 Obs 3 3 4 0 Exp Obs .61 1 .67 2 .55 1 .24 0 19.74 31* .51 6* .73 4* 6.49 10 2.07 4 157 1,176 548 154 193 Exp 2.46 3.-13 2.92 1.43 Obs 2 2 2 1 9.94 7 70 / i U1 o in h- n -o n :5 Vbl. 63, No- 2, 1975 APR 2 4 1975 n BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS cr vdkl chloride, oiiofceihyle3qxi;de, chlorqacetaloeiiyde AND CHrORCETHANOL C. Malaveille, H. Bartsch*, A. Bari)in, A.M. Camus, R. Montesano, International Agency for Research on Cancer, Unit of Chenical Carcino^nesis, 69000 Lyon, France; and A- Crodsy and P. Jacquignon, CNFS, 91190 Gif-sur-Yvette, France. Received January 28,1975 SUMMARY: Exposure of S. typh-umtrium strains TA 1530, TA 1535 and G-46 to vinyl chloride increased the number of hia rev./plate 16, 12 or 5 tiroes over the spontaneous nutation rate. The mutagenic response for TA 1530 strain was enhanced 7, 4 or 5-fold when fortified S-9 liver fractions frati humans, rats or mice were added. In TA 1530 strain, chloroacetic acid shewed only toxic effects, while chloroacetaldehyde, chloroethanol and cdrloroethylenecocide caused a mutagenic response. The latter compound was shewn to be a strong alkylating agent. VQi 1s extensively used for the production of polyvinyl chloride, other plastic material, and as a propellant for aerosols. The systemic 12 3 2 4--7 action of this carcinogen in rats ' ' , mice and humans , follo wing exposure to VQ4, as wel-l as its low chenical reactivity, suggest that the biological effects are dependent upon its metabolic activation. In these studies, we are reporting the mutagenicity of U34 aixl/or its presumed metabolites in S, typhimurium strains, mediated by liver frac tions of rat, souse and human origin. MATERIAL AND MEITCOS Chmicals: VCM (purity 99.9%) was generously provided ty Rh5ne-Progil, lyon, France. Chloroacetaldehyde (50% aqueous solution) , and chloro acetic acid (m.p. 61-63) (Merck-Schuchardt, Fed. Rep. of Germany), alcohol dehydrogenase (200 U/mg) (Boehringer Mannheim, Fed. Pep. of Germany) were obtained frem the sources indicated. All other ccrxtvercial products were of the purest grade available. The structure and purity * To whom reprint requests and correspondence should be addressed. Abbreviations: VCM, vinyl chloride monomer; PB, phenobarbitone; S-9 9,000 x g tissue supernatant; GDC, gas liquid chromatography. Copyright 1975 by Academic Press. Inc. AM rights of reproduction m any form reserved. SCC 5-0192 Int. J. Cancer: 15, 429-4_>/ (1975) Reprinted from (he International Journal of Canter @ Imeroauonai Union Against Cancer Pn in Switzerland APR \0i0 HUMAN, RAT AND MOUSE LIVER-MEDTATED MUTAGENICITY OF VINYL CHLORIDE IN 5. TYPHIMURIUM STRAINS by H. Bartsch, C. Malaveille and R. Montesano International Agency for Research on Cancer, Unit of Chemical Carcinogenesis, ISO Cours Albert Thomas, 69008 Lyons, France Exposure of S. typhimurium strains TA 1530, TA 153S and G-46 to vinyl chloride increased the number of His* revertantslplate 16, 12 or 5 times over the spontaneous mutation rate. After 6 h of exposure to vinyl chloride, the mutagenic response for TA 1530 strain was enhanced 7-, 4- or 5-fold when fortified postmitochondrial liver fractions from humans, rats or mice were added. The enzyme-mediated vinyl chloride mutagenicity was dependent on an NADPH generating system and the enzyme activity was localized in a liver microsomal fraction; 9,000 X g liver supernatant was three times more active than microsomes, while liver cytosol or alcohol dehydrogenase did not affect the mutagenicity. Phenobarbitone pretreatment ofrats and mice increased the mutagenic response by up to 15-40 % as compared to untreated controls. The relative mutagenic activities of VCM, taking the value from mouse liver as 100, for TA 1530 strain mediated by 9,000 x g tissue fractions were: rat liver, 80; mouse and rat kidney, 20 and 16; mouse and rat lung, less than 7; human liver (from four biopsy specimens), 170, 64, 70 and 46. Chloroacetaldehyde and chloroacetic acid, a urinary metabolite of VCM, showed toxic effects, while chloroethanol was weakly mutagenic for TA 1530 strain*. Vinyl chloride monomer (VCM) is extensively used for the production of polyvinyl chloride and other plastic material, and also as a propellant for aerosols. Carcinogenicity in rats, when exposed to 30,000 ppm VCM in air, was first reported by Viola et at. (1971). Subsequently, Maltoni and Lefemine (1974) showed that angio sarcomas of the liver, as well as other tumours, were induced in rats and mice exposed to various doses of VCM by inhalation. Recently, cases of angiosarcoma of the liver have been found in workers exposed to VCM during the polymeriza tion process and a causa! relationship between VCM exposure and this type of tumour in man ha^been established (Creech and Johnson, 1974; Heath et /., 1974; Lee and Harry, 1974; IARC, 1974). The systemic action of this carcinogen and its low chemical reactivity suggest that the biological effects of VCM are dependent upon its metabolic activation. In these studies, we report the mutagenicity of VCM and its presumed metabolites in S. typhimurium strains, mediated by liver and other tissue fractions of rat, mouse and human origin. MATERIAL AND METHODS Chemicals VCM (purity 99.9%) was generously provided by Rhdne-Progil, Lyons, France, contaminated with ethanol (30 ppm), water (20 ppm), methylchloride (<20 ppm) and non-volatile substances Received: October 16, 1974. 429 mo 5- IRCS (Research on: Cancer; PharmacoL-, ^Respiratory System; Social ar.d Occupation 'edicine* 2. I5$2 19741 ONCOGENICITY OF VINYL CHLORIDE AT LOW CONCENTRATIONS IN RATS AND RABBITS A. Capuio, P.L Viola and A. Bicoui. Regina Elena Institute for Cancer Research, Rome, Italy. Paper received: lOtk May, 1974; amended 22nd July, 1974. In the past four years we have demonstrated (1,2) that rats exposed to a flow of air containing 30 000 (part per million) of vinyl chloride develop cutaneous tumors in 70^ of cases, lung carcinomas in 20'' of cases ana. less TMr l. (mt- nnyt < hU tride M W* SS furtetpit </ thedt'U'. The tumtn _______________ tyipmrrd ftrtwfw A and 13 momtlind' treatment. frequently, osteochondromas. VC cofK,fr:;i:i>n (p.pJT-` xi co c<-: coo*: cow 20 ow HiUo types . S<w tqux--ous cell carcinoma Lung adenocarcinoma Lher inghiurcoma Liver dioiangioma Snail intestine adenocarcinoma Turnon animats under treatment 150 ZJ 150 IS 150 IJ'ISO 7/150 <5 45 14 12 <0.0005 9 5 In order to ascertain the degree of oncogenicity of vinyl chloride, experiments have been performed in which rats inhaled lower doses of this chemical. 1100 animals (3 month old Wistar Ar IRE male or female albino rats) were exposed for 4"hours a day, 5 days a week for 12 months to a flow' of air con 10 ato 10 wo io 10 tXO 10000 Stun squamous cell carciroma Lung idcrvitcuWTTU L-n* alver'ar carcinoma MeJiastinic reticuiourcoma Liver angiosarcoma - 34-COO 14 XO ; coo a/coo 16/200 17 7 l <0.0005 4 8 taining 20 000, 10 000, 5000,2000,500 or 50 - _ p.p.m. of vinyl chloride. With exception of the animals in the group exposed to the lowest dose (50 p.p.m.) all other experimental animals devel oped a high percentage of tumors. As reported in sow 5000 wv 50O? Skin squamous cell carcinoma Line adenocarcinoma U'er inprurcomi Peritoneal angiosarcoma CO-'COO 4/COO 12'ZCO 2/200 10 <0.0005 6 1 axo coo? coco coco Skin Kanthnma Liver mjKisarcuma Small intestine adenocarcinoma Lun j adenocarcinoma 6-COO I O'COO 6.200 8'C00 3 5 3 <0.005 4 SCO Skin squamous carcinoma 3*150 50C Liver anj^'iatcoma 4.150 43 <0.01 t^ C-r-r:'.* _ - 0 230 0 200 _ - * V1 re;.* * The ('jntfi n -t exposed to 1C. *xrekpt under the tone condition for 13 mrhs. Ts^te 2 f'-.i -ten*'effect'-firinyt .-rJt'nJe :r The tu'norj appeared nrer - c-iJ rK- nir- >:- vr.*. VC io io pcs S-..n acantioiiia L-~c jde-.'ccrcircna Jet ci? P* : C -0 o-O 30 15 <0.0005 V r i* .... ..... . .... f TV t err ted t I C. -ere iept 0 :n i' :U-- ic--e condition*. IPmths. table 1, the neoplasms originated in different tissues and organs, with prevalence of the liver. It is worth emphasizing that even using lower concentrations, it was possible to confirm the oncogenicity of vinyl chloride which, under the experimental conditions employed, is to be con sidered a very hazardous compound and one of the most powerful carcinogens. In a limited number of experiments utilizing other types of animals the appearance of tumors similar to those described in the rats was observed. These data, collected in table 2. indicate in particular that the rabbit, which is r.o* very susceptible to chemical carcinogens, displays high sensitivity to vinyl chloride. Even in this case, at the cotvceruration of 10 000 p.p.m.. the histotvpes reflect those obtained in the rats. We car. conclude that the carcinogenic effect of vinyl chloride has been clearly confirmed by the present results, which also indicate that almost ail tissues and organs are sensitive to tins carcinogen. 1. Viola. P.L <! Proc.-lOth International Cancer Congress. Houston, abstract 2q 2. Viola. P.L. Biconi. A. and Caputo. X. 119~|) Career Research. 31. 516 i j i see 5-0194 n iii<` iJn-.iifiriiTnr-- i. iKlgX Nome of Substance Synonym s) INFORMATION ON C A RCI NOGE NI Cl T Y TESiS UNDERTAKEN Species ( Strain Exposure Stage of Experiment Principal In v e s tigators "lie. Vinyl chloride (CAS Reg. No.: 75-01-4; Chlorethene; Chlorethylene; Choroethene; Chloroethylene; Ethylene monochloride; VC; VCM) HI. Vitamin A palmitate "(CAS Reg. No. : 7488^89-3) Flat (Wistar) Mouse (CBA & [AxIF]Fi p.o. in drinking water planned s,ee under Institute s.c. pat! logical examination to be carried out Flaks, A. Covntry Town Institute i See Index ; UK Carshalton (a) UK Leeds (a) / see -0195 'j i* THE DETERMINATION OF VINYL CHLORIDE, A PLANT MANUAL ANALYTICAL METHODS REQUIRED FOR THE CONTROL OF VINYL CHLORIDE CONCENTRATIONS IN AND AROUND MANUFACTURING AND PROCESS PLANTS Compiled by specialists convened by the Vinyl Chloride Committee of the Chemical Industries Association Ltd. and edited by W. Thain, M.A., B.Sc., M.Inst.P. Published by Chemical Industries Association Ltd., Alembic House, 93 Albert Embankment, London, SE1 7TU. December 1974 First Edition see 5-0196