Document 44MKa6XDRx0GbJg4aLggdaMQG

INTEROFFICE MEMORANDUM Pat 21 Auoust 1984 Sublet Surolcal Removal of Anolosarcoma To Prom L. B. Tcpper_______ ___ J. T. Barr Corporate Medical Department 0**nUtl*n, * DtM'inwM) Regulatory Response (LKlUM, 0'9A*UWM.*f DtHflMM) cc: S. Bays H. L. Watson The attached article Is. a report of an apparently successful surgical removal of an angiosarcoma from the liver of a PVC worker. It appeared at Br. J, Surg. 21 322 (1984). JTBrcsb * (320) AP00022241 ' Air Pmduett in* Ovcmteals, Inc. 5^ m A`r:aR. PA TtlOS tree**** 1218) <81*4911 W. V. Loscutoff Chief, Toxics Pollutant Branch CARS Box 2815 Sacramento, CA 95812 Re: Vinyl Chloride Dear Mr. Loscutoff: Ue are happy to provide some Information relative to vinyl chloride In response to the April request of P. D. Venturing This includes: 1. A paper by me given at the APCA, New Orleans meeting. 2. A paper presented at a CMA seminar In Washington, 9 December 1983. * 9 3. An unpublished review by me on the safety and health aspects of vinyl chloride, which contains several references not In the bibliography with the Venturlnl letter. 4. A report from 8r. J. Surg. 71 322 -(1964) of an apparently successful liver Resection on an ASL patient. 5. An article from EST 19 277 (1985) on biodegradation of TCE to VC. Note especially reference 10, Parsons, et. al., for corroborating evidence. You may want to get the Dade County report "An Investigation Into the Source of Vinyl Chloride Detected at the.Preston and Hlalfah Water Treatment Plants'1 by J. C.'Balter, 1983, for more details. # 6. A summary of a report on a 1984 bioassay by CIVO. 1 hope that these are useful to you In your evaluation of this substance. JT8:csb John^fjjSaHSrtianager Regdlatory Response ,v.** AP00022242 Chart netM and mm reports :-.tVuD Vinylchloride induced hepStlCUG Ji 1 1^34.ert norrmL Ultrasound showed a large dear tumour afthe right aAnn#g*iior<steaarrcr*onmmma be^lk lob* HiiharcasofMcroMl. The^e hepaticaaconfirmed . AW|dpmcneeefanilMefiMd<lliBtdeicetia the inferiorpan oTthe (^htlebemihtwosiiBklddiKUBthetevrloftbcUiiBk The liver eonputviaad lowogjophyrmafiniwri the imegrityofthe VA Louagie, P. Gianello. PJ. Kestens, F. Bonbled and J.G. Haot left lobe. A selective angiography of the eeliae sney moled a hypervascularized tumourofthe right hepatic lobe tFigur^.1% Department of Surgery of tha Alimaniary Tract. Lotrvafl'veo-VVfe/uW'* Medical School, and 5l Luc Hospital. 1200 Brussels. Belgium At a right thoneophrenoiaparacomy the tumour mv (bead to be confined to the right lobe An extended right lobectomy was then performed. The pooopemiv* recovery w*s uneventful and the patient was sort home with a monthlyadmhristruioa oTViwisiinc Correspondence to: Dr YJL Louapie, 20 Avenue d'Huart (bit 311150 Bruasals. Belgium (I mg IV) and Adriaiaycin (150 otp. itf IV) which diamosinued in June 1911. Repeated centres np to September I9SI by Ever sob end computerized tomography remained normal. The patient is Kill in The relationship between vinyiehloride exposure and good health It monifc trier thevBaeiiOK. human angiosarcoma ofthe liver (ASL) received attention in 1973 when a case of this rare tumour was dfegnoMri at Pathology autopsy. The resected specimen was 3030 g. On tnaercaeepial exaaination. the main tumour (13*3 * t crn> was ycllowish-and spongy and contained cystic and haemorrhagic zona. A second smaller Case report A 59-year eld man was first seen in July 1979 with pain in the right upper quadrant. The liver was palpated at the right costal margin. Oral cholecystography and barium swallow were normal and liver function tests were in normal limits. From 1965 to 1970 he had cleaned reactors used for the polymerization of the vinyiehlonde monomer in PVCand was thus exposed to high amounts. He was admitted 3 months later with persisting right upper quadrant pain, loss of appetite and fatigue. The liver edge was by then hard and 4 cm below the costal margin. The E5R was accele* rated (SO mm/h) and alkaline phosphatases and GGTP were elevated. Carrino^embryonte antigen (CEA) and s fetogJobulin haemorrhagic mas wax found at the inferior aspen ofthe right lobe surrounded bynumerous purple mastk Microscopically. the main tumour showed large arena ofacseszs and haemorrhagic pseudeeystse spacesfFifnnelL These space* wet* surrounded b> areas of dense vascular proliferation. The sinusoids were lined with variably sized irregular sarcomatous ceils with hypeichrematie nuclei. Elsewhere, blood-filled tpoem were surrounded by BrcomasDus eelIs. The sarcoma cells speempeued adjacent liver cells and bile ductules and infiltrated the pautnchyma. The patholojpal diagnosis of multiccsuric angiosarcoma was made. The rest of the liver was normal except for some moderately enlarged portal trass. Progressive fibrosis aepmsied hepatoeyins st the margins of the penal tram fiem adjaccas hepatic Fltur* 3 PIu&Hntm'vraphy */ iV aww utnumu ibitimr Mmd Hik'd t/tun terrmiiWiJ hr umtwufMit tell lluemtitoxytue e%t%m. APbbb2224j; Short notes and casareponr cord edit. An&oraryosa and aniiocytosit were frequent. K era* * `section hiopxy of the left lobe vhowed normal tissue with slight hepatocytie anbocaryeun The l>mph noda taken from the Iher hilum were hyperpiauie. The mam features ofihis tumour were iu multicentricityand the presence ofmild fibrosis. Diseuxsios The occurrence of liver angiosarcoma in vinylchloridepolymerizaiion workers was reported in 1974IJ. Prolonged exposure and long interval from initial exposure is required before liver disease becomes apparent The average interval ts 12 years (range 6-29H. Our patient eras exposed for 5 years and became symptomatic 14 years later. It is a rapidly progressing Glial disease, especially in adults. The clinical features include rapid liver enlargement with haemorThagie ascites. Gut deterioration and cachexia usually with death within 6 months. The treatment is disappointing and chemotherapy and radiation of palliative value only. If the diagnosis is made early, the disease is localized and there is no associated liver fibrosis or portal hypertension, reseciivc operation might ` prove to be curative. However, there are few reported eases . ofsueeessful operative removal ofhcpetic angiosarcoma and ' the longest survival has been Ift months*. 1 in our ease the tumour was confined to the right lobe and ' there was no sign of the extensive fibrosis. So (hr the patient ` is apparently free ofdisease after 38 months. This is; to our knowledge, the longest published survival. S References 1. Creech JL Jr. Johnson MN< Anpoartopn ofthe liver the mxnufeciurc of Polyvinyl Chloride J Ocrufi .Ifaf 1974; It: 1 150-1. 2. Block JB. Angiosarcoma of the Iher following vinyl chloride exposure..M.M.41974; 227:53-4. 3. Heath CW. Flak H. Creech JL Jr. Characteristics of eases of anpoarcoma ofthe liver amoni vinyl chloride workers in the United Suits. Aiut .V Y.hvdSci 1975:246:231-6. 4. Adam VO. Hwvet AG. Hxjdu 51. Malignant vascular tumours ofthe liver. AnnSurg 1972; 175:375-13. 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AU !* a p*won* P* I**?88 aada* ooTjaj, a qijw ptfw "Bpih aadxptaq aiBjatj* 01 anas aajj-armljo loan 4q xja 701-53 a a affwa um ia|A qst* jo ncaiBos tip `Mt^jam atp ioj tqwiq poqiaa tv ptndud um aqjds 13n'30J* asp anoqpjs 2*3** pa* *[* maqdoa '^-y qos lutcinuaa tpu VCpje njdwai qaaw-f *173 aoj (9) *ja&ws apnlio tjtp a 33,2, aqi jo xioptitotpa iai*oa ox per* Mqooym .nJhwoj,, rfm so fl*ni j* maqAoa atp, *q. 20Q a t r -.it" r .i|- SonirKioas Cfi^A (2) nmpaaad sqa anoq>nojqi pppropa^ *TO>noo 10J jpatp a ptn aawo\ vopaz^papA lantern os paiadaid im *ainS* `Du'33-L '*,P potfi qjoq ooij-ormho Xfso 107x001000 vpn^ (7) O0Oj m parsdMd ajaa'aa|dssi qoaiq'poipaa ptn (pnso^ *aqaM 11 pva *i *9 v* MtXfus soj p*AOtsu ut apru tp ;o tmqns *33X atpjo oopapulap ap^otoqd pjeUa 01 qnp qi 07 adaq wa M]dsm atp '[qrtaod a qsna *V *0* Z ta mtaqnav} tra m paov^d tnqi um qorqm '(jaanboig jo oojajAia^lgg) sfag>!qonaxrv `h/'OO pauapaaix um *71)4 pajaat aqj, *pmdid um t{dam qoaa jo aMaondna W"19 *qdd 0002) l5n*SM, 7*^01 papapqxnqimAmAqoag *jd {i %t ota oe mj Apin* Bt S{ paov^d pax^m a Mfdaas *3da oopaj, tpjMpataacuu*707*aqx (npogiaaSW/D0 cintre 10} pvqoaip pov 'uuiiqoi) ooqno a qfnoiqi panad *patn*!P ti moM aa^-omalzo} tpt* palmd oaaq prq tprqA) maw pan73*IP .aaJJ'OnrBSio. tptw 7*ny oaqi waw vfa]A aqi poa noopfpoos tqoiati amcua a |tiAtpaaap*ppafawiaamoaqiCojomjJaaQ npunod aoa apcal aQiaioA Iguaqpa dsa iaosu a q e 2J 0* 091 % pa[*q saaqpvqqorqw xtu jaqaa itt*? tq pa*ld n* xpdap qaaa noq pet jo aauf * npoqxajv Xpapjaanoa pasjaqo im jata oaaqXes qfy^paapqdd002tnasooa^ooaqiaa tpi* dTMVpdaxdd* painpp *sm, poa **001 `oaxadns mosj paMqarMSam4tpnptraa0TBalJoa{papA nrepvoTaaina *0a .MMlmaowisra rl (0) i*m*S<u*N*9 z'i to) *0* 'M<mowpn la> iaaMMaoww1!* M rnm<mbwfWP Fi Pu* waAMiraigia jo iraft amt >xnw--irt>M % mSu n*m. M Techno* 1IU, T9, 390-398 (j) Boum'.:RiBmaa,B.E4 McCarty. F.Xarereft.5d. TtcknoL ltd, 2$, 596-WS. (9) Bouvar, & J4 McCarty, P. 1. AppL Environ, iiknbioL In. 45,1284-139*. (10) Psaom. Fu Wood. P. &4 DcMareo, J. J.--Am. Wattr Woriu Jutoc, 1W4, 79,-. (11) Ctffflt, J, Iavredgatian* ef uncontrolled Heautfout Waste Sites",) 9(3, taiic report submitted to til* Environ- anul Protection Agency. Contract 68-01-4054. (12) Ead*y,D.M-K*opfistILD;C*mia. KVLJ.Auoc.Off, AmL Cktm. 19(1, U. (S3-6S& (IS) Loagbcnsm. i. 4 Iichtinberg. J. J. `Methods fox Or*aafe Analysts ofMusldpal tad Industrial Wasrewatre*; Ui. EodmsMtd Protaedoe Aftaqr: 1982; EPA 800/ 4-82-057, Method 624. (14) Pnfrn. P n la'?retied** taMiadWttre'sCuesd, W. o, Sd4 SSSA Pvb&bms Midfe*. WX, 1974; pp 133-202. 0$) Stanief. fL Y. /. SaettrieL 1I47,M339-'ML (18) Sprague. It Pool Buckriy, Scfeoh and Jecnigm. Denver, CO, privato mmauniffitioo, 1981 / FUttiuodformiosaAufujtSZ 1982 Rtniatdmanuscript rntwed May 7, 2994. Accepted Aufutt 9, 2984. Mention 0/product* end mimtfmeturm is ftr idantiflntionmfyand dots not imply tndoratmont by tht Environmental flwirtiM Agency. Ga*-Pha*t Hydrogtnolysis of Pofychlorobfphenyl* Jeffrey A, Mttan, Pelec Mulder, pad Robert Louw* Gorkova UborHWH. The University of Leiden, 2300 RA Lniden, The Netherlands Chloroarancs in an atmosphere of hydrogen art thersully dtehlorineted to ytWd HQ and benzene u major products between 700 and 925 *C, with residence times of ea. 10 *. Polyehlorobtphenyb (PCB*) art both dechlfr rimted and split into chiorisatoTbe&xeaes, with ephttmg about twice as ut aa dechlorination. Thermal hydrotenolysis, which occur* via radical mechsjifrms involving H stoma, may tharafnra be ooBsidtremps a useful method for workup of (toxic) chlorinated wa Following studies on thermolysis (1-0) on several free-radical ps-phiH aromatic substitution (4), cyanarion <$), nitration (8), and oxidation (Hr we are now engaged In thermei conversions of b*aaene\pd de rivatives with hydrofam Within this eatecory, . eraeldng" of chlori&ttsd snoes dmrvei special attest La general, ruction 1 is of potential interest ea a AHWCI-+ Ht -- Ar<R)H + HQ - <1J for deehlorinedon of (highly) chlorinated Industrial waste materials etc. Thermolysis of chlorinated benzenes is an excess of Ha (quartz flow reactor, atmospheric pressure, residence time 5-15 a) proceeds smoothly at 750 *C and shown very high depere ofconversion (HQ formation) at ca. 90Q *C (8). Sooting is unimportant'even at 900 *C provided that the Hjisrea* molar intake redo it above 10. Aliphatic end oleiinie chlorides, la general, react much fester than chlorobanaancs (6). Polychlorobiphtnyla (?CBa) hart found widespread application, especially is transformer oQ, Hs use and dis posal entailing considerable environmental problem*. We therefore thought it worth while to examine the behavior of FCB ia hydrocracking (eq 1), Our observations, in cluding those on appropriate model compounds reported below, confirm our expectation that PCB can be com pletely converted Into HQ end non-chlorinated organic products, mainly benss&a. Hydrocracking thus constitutes an environmentally claaa alternative to incineration. Representative example* with Aroelor 1248 <Q - 48% wt) are outlined la Table L That conversion of FCB la essentially complete and Is illustrated by Figure L De chlorination of ehlorobenzane (PhCl) is 197%; monoehlorobipbeoyis art wea in minor amounts only, biphenyl comprising ca. 0.7% on the FhQ feed. This biphenyl sterna from PhCl--or better, from benzene made Table L TfcemeJysie at PCB la Chlsrebeaten* with Hydrogen* T, *C T,S coa>riiwr at PCB*. % PhCUM FbQ* % PUV% PUfcPbd molar rede 1 T19 U a(re. 10) L2 aoio 0089 aose fimea. 29 4 7S0 808 7I u U 7J8 tt TO u U 04 uonu aawioe 00.S0 Oil 0.19 <aot US 0J8 39 `Spixalhad mre tabular Soar manor QiaO *re*h Inflow (BMl/bh HS3l*4;PbC!.lUtAfMUreU4S<CL6k&u*de ef no* 40-48 stint prodoes eaflefttd la a tnp eoeied with Squid Nf * By GLC with Ph2r aaiatemal tunderd.* total efmtfne ini frem dieblasefaipbaBri as (laussioe Una > 27 nla, Fifure 1), n- auBfac reepame to be i&dcpeadiat of cUoriae eeotesfc Thne ausbm peteM three for degrere ef ditbinftwtim ef PbCU PbO, ea Phfli oadre the aana readteae*. *5UU pereaSeePCB via x &S. tfMale parent oa biana sot *I*OMr dauibiitiuu upern, I); naL 4*1&, ms L T7S7JS; we g. bMas. fleoaer dbteibnlca (ertbaaBetamen. rta l, toko* rm L 3ZSLSk na 3.944848. *Ccnfimed by CC with elretma eepture detectiwb The dh^nd tdchlorobsBzencs deaxiy sum from splitting of PCB and account for c*. 8% of the Arocbke feed. Chlorobetuaqe is produced via the aims rocta but is oly cured by ita uu m diluent. Its amount em be cefmated from what is known about the composition of the PCB nurture. SpedfiaJly, the Identified portion of Arochlor 1948, cmhalfc is camRpsed of the foBowiagretioe of phenyl unite FluPhCLPha^PhClj - O.O&iaaAie. If changes due to the small degrehof dechlorination art neglected, PhCl from PCB would thus be li(U * 008) * 6 re 4%, so ee to give a total degree o( splitting of about 10%, PhD alone yields ca. 8% of! ;dar these conditions eo this mode of hydrogenolysis is twice as fast as dtch]> rinatira. As we have reported elsewl 1,9), methane is also formed, ranging from 04% (run Dx il%<nm4)oaPhCl feed; small amounts ef C3H4 and' t and knees of art also produced. Simulta&Mus splitting and dechlorination ofPCB wQ causa the yields ef PhCl) and FhOg to Mss through a maximum with increasing temoerarure. VW AP00022248 THE DOW CHEMICAL COMPANY October 5, 1984 THE DOW CENTO MBUkNO> WOfl&tti Mtt Document Control Officer Management Support Division Office of Toxic Substances (W8-557) U.S. Environmental Protection Agency 401 M Street* S*W. Washington* D.C. 20460 XIRBORME Dear Sir/Madams Attached for your information please find a copy of a summary of a report on a Lifespan Oral Carcinogenicity Study of Vinyl Chloride in Rats which we recently received and which Z discussed with David Williams on Tuesday* October 2* 1984. This study was conducted in Europe by Civo Institutes TND and was sponsored by verband Kunstofferreugende Industrie E.V. (VKX) It is our understanding from VKI that the ERA will soon be receiving a copy of the final report* we do not have a copy* sp Upon review of this summery* we have been unable to determine whether this study presents any substantial risk information under the ERA'S Statement of Interpretation and Enforcement Policy* 43 Fed* Reg. 11110 (March 16* 1978)* It appears from the minimal data presented in this summary that the study is corroborative o.f effects already documented in. the scientific literature* Sineerelv. Attachment bees 8* D. Hoerger* 2020 WHDC B. 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Ears Air Produets sad Chemicals, to*.1' ZKTKODUGTCOtf The well-known regulatory history of vinyl chloride and Its role as a bellwether of current regulatory philosophy makes it a useful paradigm for examining the relationship of existing laws and the v Toxic Substances Control Aet (TSCAl for control of chronic hazards. To this end, we will first review some of the highlights of its regulatory history, and then engage in some speculation as to the response these events might elicit today under TSCA. | INDUSTRIAL AND COMMERCIAL USB OP YIHTL CHLORIDE' I Vinyl chloride became of Industrial importance about fifty } years ago, approximately a hundred yean after its discovery, when j Sereons discovered that its polymer could be converted into useful I articles by plastization with phthalate esters. Commercial develop* ment began first In Europe end then in this country in the lata 1/ Air Products and Chemicals, Ino., 19(1. ttt AP00022254 130 / BISK MANAGEMENT OF EE3STTNG CHEMICALS thirties, largely using existing rubber processing equipment, for it was rubber which it initially replaced in the market. For the same reason, the use of polyvinyl chloride (PVC) was sequestered by the government during the war years, and it was not until the early fifties that widespread consuntar applications developed. PVC is now a mature product, and its growth rate falls in step with the Gross National Product. Presently, about six billion pounds are used annually in this country, and about four times that in the world. Soma of the broader toxicological attributes of vinyl chloride (VC) ware recognized in the thirties. It was known to be an anes thetic, but problems with cardiac arrythmia prevented lts use in that application^ As pathological techniques improved, industry scien tists recommended In the early sixties that exposure be limited to 50 ppm. because of temporary liver enlargement in animals at that level, but the American Conference of Governmental and Indus trial Hygienists considered this overly conservative and accepted instead the 500 ppm recommendation of Harvard scientists.4' lifts was the value adopted by the Occupational Safety and Health Administration (OSHA) in Its formative days. Also in tiie early sixties, the European industry recognized among its workers a disease termed acroetteolysis, AOL, which is a degenerative disease of the bone tufts, particularly in the fingers, that is accompanied by Raynaud's phenomenon.5' An extensive epi- 2/ W. F. von Oettigin, "The Halogenated Hydrocarbons, Their Toxicity and Potential Dangers," Public Health Service Publication No. 414 (Washington, D.C.; U.S, Department of Health, Education and Welfare, 1955). 3/ T. R. Torkelson, F. Oyert, and V. K. Rowe, "The Jojdcity of VC as Determined by Repeated Exposures of Laboratory Animals," American Industrial Hygiene Association Journal. XXH (1931), p. 4/ American Conference of Governmental and Industrial Hygien ists, "Documentation of the Threshold Limit Value, 1963" (Cinein. nati, OK, 1863). 5/ S. Sueiu, J. Drejman, and M. Valaskai, "Study of Diseases Caused by Vinyl Chloride." Medical Intern.. XV (1963), p. 967. i i * i AP00022255 fog equipment, for it narlcet. For the same as sequestered by the j not until the early s developed. PVC is rails in step with the million pounds are used hat in the world, utes of vinyl chloride known to be an anessvented its use in that roved, industry scierr* xposure be limited to nt in animals at that ernmenttl and Indus* vetiva and accepted .rd scientist*.*' This i Safety and Health industry recognized ysis, AOL, which is a ularly in the fingers, 5' An extensive tpi- Hydrocarbons, Their i Service Publication of Health, Education The Toxicity of VC aboratory Animals," nal. XXn (1961), p. id Industrial Hygienalue, 1963" (Cincin- "Study of Diseases 1063), p. 867. demiologietl survey here and in Europe found about a hundred possi ble cases which were associated closely with manual cltailing of reactor walls between polymerization batches, but neither the pre cise etiological agent nor the disease mechanism was identified.'' An attempt was made to reproduce this disease in rats by the medical department of one of the European producers. An exact duplication of the human disease was not seen, bet many of the rets developed turnon at numerous sites. The reporting of this finding by Viola7' In 1970 evoked little interest in the regulatory community, possibly because of the very high doses used, several thousand ppm, which were frankly toxic to the animals, and the fact that the tumors were largely metastatic from the Symbol gland, an organ not present in humans. Nevertheless, both the European and domestic producers formed consortia to perform bloassays at lower concentration and also began epidemiological surveys of their employees. * Preliminary results of the European bioassay became available first la early 1973, and showed tumor development at much lower concentrations In organs which do have human counterparts. This result was transmitted to regulatory officials that summer, and industry screening of employes records was intensified.*^ This re* suited in the recognition that winter by an Industry medical director of a duster of three rare liver tumors termed angiosarcoma, ASL, in the employees of me facility.9^ The reporting of this fact to 6/ W. A. Cook, et aL, "Industrial Hygiene Evaluation of Thermal Degradation Products from PVC Fetus in Meat-wrapping Opera tions," Arch, Environ. Health. XXH (1971), p. 74. Also, B. D. Diman, et all, "Occupational Aoroosteolysis I, An Epidemiological Study,* Ibid., p. 61. 1 7/ P.L. Viola. "Pathology of Vinyl Chloride.* Medicine del Lavoro, LXI (1970), p. 174. ------ 1------------ * 8/ A. W. Barnes, "Id Ends Its Silence on Vinyl Chloride," Chemical Engineering News. (July 8, 1974), p. 21. 9/ J. L. Creech end M. N. Johnson, "Angiosarcoma in Worker* Ex posed to Vinyl Chloride aa Predicted for Studies in Bats." Journal of Occupational Medicine. XVI (1974), p. 150. -- AP00022256 132 / RISK MANAGEMENT OF EXISTING CHEMICAIE government officials led to the current regulatory status of vinyl chloride. It also led to a virtual explosion of research on the chronic toxicity of VC. The body of scientific literature on the oncogenicity of vinyl chloride is as large as that for any other substance. It is recognized that VC is a classical procarcinogen. Metabolism by the mixed function in the liver converts it to the ultimate car cinogen, an epoxide.' Detoxification of this intcrmedlata by the sulfhvdryl group of glutathione or ether proteins removes the toxic potential.*"^ Both of those mechanisms are saturable.**/ An over- load of the metabolic step assures that the vinyl chloride will pass through the liver end some wiU be metabolized in other organs* An overload of the detoxification step allows escape of the toxicant Into the sinusoidal passages of the liver where interaction with the chromosomal protein causes A5L to develop. An overload of both mechanisms can lead to tumor development outside of the liver, as is seen In mice end rats et very high doses. Despite the laige data base* however* information on the precise mechanism of these vari ous steps still is lacking. We do not even understand why some per sons respond with AOL and some with ASL, but none with both diseases. REGULATORY STANDARDS OSRA proceeded promptly in early 1974 to set an emergency temporary limit of SO ppm tor worker exposure, and later that year reduced the limit to one ppm* the current figure. Industry was given a grace period during which respirators could be used to meet this requirement, but now that level must be met by engineering prac- 10/ W. K. Lelbtch and R. J. Marsteller, "Advance in Internal Medicine and Pediatrics " Springer-Verlag* XL.VU (New York, 1981). 11/ R. Hefner, P. Watanabe, and P. Gehring, "Percutaneous Ab sorption of Vinyl Chloride Gas in Rhesus Monkey," Toxicology and Applied Pharmacology. JCXXJV (1975), p. 529. 12/ OSKA Standard for Vinyl Chloride, 29 CFR 1910.1017. AP00022257 ary fUtus of vinyl *ch on th chronic m the oncogenicity tr substance. h it Metabolism by the > the ultimate car* termediate by the removes the toxic .'able.**' An over- chloride will pass i ether organs. An >e of the toxicant terection with the ft overload of both de of the liver, ec ?lte the large data ilsrn of these varitnd why some per il none with both set an emergency md leter that year Industry was given used to meet this engineering prac- vtnee in Internal Mew York, 19*1). Percutaneous AbV* Toxicology end 110.1017. The Environmental Protection Agency (EFAJ promulgated m combined engineering and works practice standard in 1976 which be* resulted In ambient concentration* in the fractional ppb range near producing or using facilities. ' In the meanwhile, the Food and Drug Adafnistrattan (FDA) and Consumer Product Safety Comminion (CPSC) established prohlbl-- tions on the use of VC In aerosol or other consumer applications. a practice which had been discontinued is 1S73. The Bureau of' Alcohol, Tobaeco and Firearms of the Treasury Department (BATF) had already banned the use of PVC liquor bottles in 1973 because of concern for taste effect* from migration of residual VC into the contents. In 1975 the FDA proposed rtweidm of the generally regarded as safe (GRAS) status of rigid FYC packaging under the Delaney -livy-, alao because of mlgmaXen coucerna, but that proposal never has been promulgated, and the FDA has stated that tt is eonsldering withdrawal of the'proposal and reeoameafingr to BATF the reauthorization of plastic liquor bottles In light of the current vary low residual monomer levels la fabricated PYCartidesi Other regulations h*v followed as new statutes and rules bavo com* into play. The Department of Treaspertatiaa (DOT) aad the Coast Guard rsgulate the transportation of VC, of course, and VC la listed as e priority pollutant and hazardous waste under various water end solid waste rules, and has a reportable quantity of one pound under Superfund. Did the existing laws operate satisfactorily at the time of discovery of the chronio hazards of VCT tt appease that they did. A leading medical authority who waa deeply irvelved in the worker health evaluation in 1974 has termed VC a. Vur-aeo story." Rmluation of the risk to employees under the c* s ppm standard by a conservative nonthreehold extrapolation mother. ' yields a lifetime estimate of less then 10"8, a risk level which is not thought to be of concern. The comparable risk estimate for the general populate* te 15/ EPA Standard for Vinyl Chloride, 40 CEE 61.60. 14/ P. J. Gehrirg, P. G. Watanabe, and C. K. Park, "Bisk of Angio sarcoma ift Workers Exposed to Vinyl Chloride as Predieted for Stud ies in Rats," Toxicology and Applied Pharatteologv.* XUX (1979), p. IS. I AP00022258 1*4 / KISS MANAGEMENT OF EXISTING CHEMICALS severel orders of magnitude lower. EPA has stated on several occasions that it believes that vinyl chloride is regulated adequately. BISS ASSESSMENT Risk assessment'has been a popular avocation among these interested in VC, and more than a dozen have been performed. ' These can be divided generally into two daises: those which rely solely on- animal data; and thesa which attempt to' incorporate the human experience. Those in the first dais yield similar results, and show the normal spread of estimates from the various mathematical models in common use. These range from 1,500 to 10"' ppb for a lifetime risk of 10"*, or eight orders of magnitude. It is necessary to eliminate the high-dose data points, that is, those over 2,500 ppm from the Maltoni data*^ in order to get reasonable fits to most .models, because these doses show broad systemic toxicity. The lower doses, 500 ppm and below, as a group fall into a general pattern on a logprobit plot, but individual two or three dose experiments show tre mendous differences in slope when plotted separately. The papular multihit model predicts a lifetime risk of 1CS at fractional ppb levels. The human factor was accounted for in two ways. The EPA used some preliminary employee epidemiological data to confirm its animal-based extrapolation.1'1' Unfortunately, the human data were 16/ J. T. Barr, "Risk Assessment for Vinyl Chloride In Perspec tive," (Paper 82-9.2 presented at the ?5th Annual Meeting of the Air Pollution Control Association, New Orleans, LA, 1982), Lines 2025. 16/ C. Maltoni, et aL, "Vinyl Chloride Carcinogenicity Bioassay* <BT Project)," (Paper presented at "Le Club de Cancerogeneee Chemique," Institute Curie, Paris, November 10,1079). 17/ A. M. Kusmaek and R. E. McGoughy, "Quantitative Risk Assessment for Community Exposure to Vinyl Chloride," (Washing ton, D.C.: U.S. Environmental Protection Agency, December 5, 1075). AP00022259 tated on several Hated adetjuately. lion emong those sen performed.V*' those which rely o incorporate the ts, end shew the .metical models in Tor e lifetime risk tsszy to eliminate *00 ppm from the to most models, The lower doses, pattern on a log* riments-show tretely. The popular at fractional ppb ) ways. The EPA tata to confirm its i human data ware lorlde in Perspecal Meeting of the i, 1982), Lina 20- jeniclty Biosssays 3e Cancerogeneae Quantitative Risk iloride," (Washing* -ncy, December 5, seleeted from those location known to have ASL eases, while other faculty data were emitted. They also were In error on the pest exposures by more than an order of magnitude. This resulted in an estimate of 20 cases per year from the estimated 1974 ambient concentrations for the population within five mlla of production and processing facilities. , The ?A seldom bother* to check its estimates against avail able data, so it sometimes coma up with results such es that made for arsenle a few years ago that would have predicted It million cues of skin cancer a year In this country If it had been applied to Agency data on Die average arsenic concentrations is Atakinf water. Similarly, a survey of aU known ASL cue In this country tor the ten years before 1974 showed no cuts associated with residency near such plants,**' rather than the 200 predicted cue. It is rea sonable to assume Diet If any eeaes had developed since that time, the publicity associated with it would have brought them to light. Thus we have 110 mfiUon^erson years of negative history for nearby residents. This placa an upper limit on risk of lea than 10"7 per ppm-yr. Two studies applied pharmacokinetics in an attempt to obtain relevant human data. Behring and coworkers estimated a lifetime risk of 10* at one ppm from the probit model, based on e blotrans- formatlon of rat data. The unconstrained linear model predicted no risk at less than 99 ppm.*9' Anderson, Hoel and Kaplan carried this procedure one step further, and applied it to bound metabolic products, rather then to the total amount metabolized. Their results gave a lifetime risk of 10*7 at less than one ppm, with the probit model, or at las then two ppm with the linearized multistep model.20' 18/ H. Popper, et aL, "Development of Hep&tie Angiosarcoma in Man Induced by Vinyl Chloride, Thorotrast, and Arsenic," American Journal of Pathology. 3CCS (1971), p. 349. 19/ P. J. Gehring, P. G. Watanebe, and C. N. Park. Toxicology and Applied Pharmacology. XLDC (1979), p. 15, 20/ M. W. Andersen, D. G. Hoel, and N. L. Kaplan, "A General Scheme for the Incorporation of Pharmacokinetics in Low-dose Risk Estimation for Chemical Carcinogens. Ibid.. LV (1990), p. 154. anih s r t f i i I AP00022260 186 l K2SK MANAGEMENT OF UOSTIKO CHEMICALS Thus we tee that risk Is In the eye of the estimator, but it is clear that estimates Incorporating human data reflect the human experience for VC far better than do the direct application of ani mal data. There was understandable uncertainty on the part of both the regulator* and industry in 1974. This was the first commodity chem ical to be regulated under flit relatively new statutory situation as the result of new Information... Nevertheless, both the regulatory agencies and industry acted promptly to reduce exposures and emis sions to an acceptable level. The current count of occupational ASL cases Is about 100 worldwide, with 80 of these in this country.21' All these cases had their first exposure in-1964 or earlier, and there appears to be room for optimism that the steps taken in the mid-sixties because of the AOL information will have prevented any significant nun|per of eses developing from exposures commencing after that data. Cer tainly it Is reasonable to aspect that there have been no new eases Initiated after the early seventies. Bad TSCA been in place in the mid-sixties, would ithsve made any difference in the course of events? It appear* unlikely that it would. Certainly the AOL discovery would have resulted in a series of 6(e) notices to TSCA. The probable outcome of that would have been either recommendation from the Interagency Testing Com mittee (TTC) for more tests, or a Section 4 testing requirement. It is possible that, because of its commercial importance, VC could have been placed on the ITC list before the AOL data became available. Additional data could have been called for under Sections 6(a) and (d). The result of all tills most likely would have been a negotiated testing rule, under which industry would have initiated a series of studies which would have eulminated In x bioasssy, and the car cinogenicity of VC would have been discovered in due time. Yet, this is precisely what did happen in the absence of TSCA, except that the preliminaries were omitted, and the bioassay was performed concurrently with the screening tests. Thus it is possible that the 21/ J. Stafford, personal communication, Liver Angiosarcoma Cases, April 15, 1963. AP00022261 SMICAI5 * estimator, but It It a rtfleet the human H application of ani- the part of both the Tt commodity chemtatutory situation as both the regulatory exposures and amis* eases is about ]00 All these eases had s appears to be room sties because of the nificant number of ter that date* Cer been no new eases would it have made urs unlikely that it resulted in a aeries of that would have eney Testing Coroy requirement* It la nee, VC could have i became available, tr Sections 8(a) and s been a negotiated titiated a series of easy, and the earin due time. Yet, t of TSCA, except :**y was performed s possible that the ver Angiosarcoma VBTTL CHLORIDE / 1ST final critical data were obtained earlier than would have occurred under present conditions. Bear In mind that most of today's powerful testing methods were not evaSeble twenty years ago. That fact would not have baea changed by legislative fiat, and any decision made at that time had to be made in light of the available knowledge. If the data of Viola suddenly became available today instead, would there be any significant difference in the outcome, or the timing of that outcome? Probably so, but only because of the vastly more powerful scientific tools which we have available to us now. Neither the speed of agency motion nor the rate at whioh industrial facilities can be built or modified has increased. If anything, the latter has slowed, given the multiplicity of permits end approvals now required. Overall, it is possible that if today we knew nothing more about VC than was knowp in 1970, wa would arrive at a regu lated state a few months earlier than was achieved la IW4, but scientific progress, and not legislative or regulatory advaneemmxt* Should get the credit. What if VC were to become a new product today? Would it ran the same course in which it would be 40 years before there was full recognition of its ehronie potential? Certainly not. Again, however, the reason is due more to scientific progress rather than statutory development. One change might be apparent. If VC were the m*Ject of Premanufaeture Notification <PMN) today, rather than being the model to which all other aliphatic olefins are compered for struc ture-activity analysis. It would be judged by the others In its family. This comparison would be less dogmatic than the reverse is now. Ethylene and vinylidana chloride are not animal eareinogenst the relevance to humans of the carcinogenicity of high dotes of trichloroethylene (TCE) is equivocal and controversial; and vinyl acetate has only a preliminary "non-negative" report. Titus, this class of substances would have lost Its leader for structure activity comparison, and a decision as to the need for further testing from that analysis would not be clear-cut, based on analogous compounds. Neither would a full minimum premanufacture data (MPD) act be of any great assistance. VC responds poorly to the classical invitro tests, and only reoently has it become possible to obtain repro ducible positive results in many of these. If the position were taken AP00022262 140 / BISK MANAGEMENT 0? EX3STTHG CHEMICALS "little lists" for the executioners apparently is too put to be re sisted,*6' u Lester Levs pointed out recently. We believe that EPA can best obey its statutory mandate by developing a more efficient system for establishing priorities, and by Implementing more effectively its Section 9 procedure*.' - BBUOGTLAPHT American Conference of Governmental and Industrial Hygienists. "Documentation of the Threshold Limit Value, 1963." Cincinnati, OH, 1963. Anderson, M. W.; Hoel, XJ. G.j and Kaplan, K. L. "A General Scheme for the Incorporation of Fharaaoekinetic* In Low-dose Bisk Estimation for Chemical Carcinogens." Toxicology and Applied Pharmacology." VoL LV (1980), 151 * Barnes, A. W. TCI Ends its Silence on Vinyl Chloride." Chemical Engineering News. (July 8, 1974), 21. Barr, J. T. "Risk Assessment for Vinyl Chloride in Perspective." Paper 82*9.2, 75th Annual Meeting of the Air Pollution Control Association, Hew Orleans, LA (1982). Barr, J.T. "Establishing Regulatory Priorities." Toxic Substance Journal. VoL IV (1983), 290. Cook, W. A. "Industrial Hygiene Evaluation of Thermal Degradation Products from PVC Feta in Meat-wrapping Operations." Arch. Environ. Health. VoL XXfl (1*71), 74. Creech, J. I*, and Johnson, M. H. "Angiosarcoma of Liver in Manu facture of PVC." Journal of Occupational Medicine 3CVI (1974), 150. 26/ Lester Lave, "The High Cost of Regulating Low Risks," Wall Street Journal. August 19. 1983. u^m' CALS e great to be reutory mandate by priorities, and by ures. tri*2 Hygienists. 963.* Cincinnati, V General Scheme Low-dose ZUsle logy and Applied wide." Chemical in Perspective." Pollution Control Toxic Substance rmal Degradation orations." Arch. of Liver in Mam>- .XVI (1974), ISO. Low Risks," Wall VINYL CHLORIDE / 141 Diman, B. Dn at aL "Occupational Acroosteolysis 1, An Epidemio logical Study." Arch. Environ. Health. VoL XXII (1971). 61. Environmental Protection Agency. "The Cost of Clean Air and j Clean Water." Annual Report to Congress, Senate Document 96-31, I December, 1979. | Gehring, ?. J., Wilanabe, P. G., and Park, C. N. "Bisk of Aflgfo- j sarcoma in Workers Exposed to Vinyl Chloride as Predicted for Studies in Bats." Toxicology and Applied Pharmacology. VoL XI1X (1979), 15. Hefner, R.t Watanabe, P.j and Gshring, P. "Percutaneous Absorption of Vinyl Chloride Gee in Rhesus Monkey." Toxicology and AopUod Pharmacology. VoL XXXIV (1975), 539. i Kusmsck, A. and McGoughy, B. E. "Quantitative Risk Aasas*- I ment for Community Exposure to Vlryi Chloride." UA Enriroo- | mental Protection Agency, Washington, D.C.; December 5, 1975. j Lave, L. "Hie High Cost of Regulating Low Risks." Wall Street ; JournaL August 19,1983. Laibach, W. K., and Marsteller, H. J. "Advance in Internal Medicine and Pediatrics." Hew Yorks Springer-Vtrlag, VoL XLVH (1981). Maltoni, C., et aL, "Vinyl Chloride Carcinogenicity Bioassays (BT Project)." Paper presented at "Le Club de Cancerogenese Chemlqua," Institute Curie, Paris, November 10, 1979. National Research Council. "Regulating Pesticides." Environmental Studies Board, Committee on National Resources, Washington, D.C., 1980. Popper, K., et aL "Development of Hepatic Angiosarcoma in Men Induced by Vinyl Chloride, Thorotrast, and Arsenie." American Journal of Pathology. VoL ECU (1978), 349. Stafford, J. Personal communication, Liver Angiosarcoma Cases, April 15, 1983. rrv~ v- '' ' ~ ~' : :?. - ^' '*<.. -.>"tr; ;* :-r. --;. :;- . i." - -- --. ;- .'# -; . AP00022265 Its* Assessment for Vintl Chloride 99ZZZOOOdV For Presentation a t the 75lh Annual Meeting of the xA ir Pollution Control Association New Orleans, Louisiana June 20-25,1982 AP00022267 2-9.2 trrtwHw e ciakliuilM *1 circumstances tAIck found Uh carcinogenic Murd vinyl ctilM'Idt (VC) Ming dticwtrid il iknt Uh cm* tloa m Uh lenca of rlifc aoalyil* mi uadergalag rapid dwilapmit, and tM at caomerclal MmU and 1m| history af ost af Uh sub*tenet Ml iMltcd In a body at lltcralur* and pharmareltglral dal* greater than e caa expect to Mv* far oil substances. Il la tharefer* Initrvc la review IM n*ay risk umihhIi dilcl) Mve Me* prepared far against the avallabla blelealcat InferotlMn la dtUrmloa If we cm iat* IM vlripalillM aetbodt used, and to dlscatf IM carranl gelation* far VC In light af toll feparlw. tardi nf Vlae) Chlarlde ti necessary to decide first which af the Mzards presented by VC wW he IM haafa far IM rlih esllnatlan. TM substance prcsenla e acuta hatardt af frostbite fraa txpatura to the Hpilf, af mr ila el cenceatratleas aver I.M* ppn and taffacallan at higher xeatrations (van Sattlager, IMS). It ala* faras explosive si stores air atov* J.7S value* percent, and t* th* effarti to caatral IM /ileal safety af aparellani generally praclwd* exposure to acutely ik canceatratlnns. ?* caatral effnrts ware reinfected In IM fd'lMd't where It vat vcevtrcd (hell, IK)) that warken wto had Man exposed la wary fh leveH af VC developed "vinyl chlarlde disease," tha prlMry ilfestatlao af which wat acraeataalyala (Ml), a degenerative 41 scat* tM Mm ivflt In IM hands, aad aara rarely f tM feel and laahar lien. Although crippling to tana degree, toll dllease fa net total, I Is at least partially rewertfbl* If aapaanra |i allalnaled (Crealger. iker and hard, )N0|. vs I ten years later It ms fnwad toat sane af tM warktrs having liar exposure alsa war* davtlaplng anplesarcaM af IM fiver (til), apldly fatal disease. Oddly enough, there Is only ane paislble *fe varker develaplng toth MX. sad UL (Stafford. IM)) eaang M-pliis cims af ml and N*plw casts af til aaw knawn worldwide, haaph Mlh are IIuhii af tha vascular system. Several large dealalapy stadias were conducted an workers axpased ta VC (laxter I Faa, 197*; Chlaiee, 19*0; luck, Carter cad Caanto. 1979} Equitable Irenecolal Malik, 19)0; fan aadCalller, 1977; frenltel-leyM, nlu, and Ihelis, 1971; IhcrlawH and Allard, 1961), aad ASt was aaly fata) dliaasa fawnd consistently to M la axcait la IMsa a persant. MImI studies have shown an excess af tween at ether sites. Ml tM lowest expasurei at which these eccwr are considerably blotter than that far ASl. Far txaMl*, Neltanl (1979) rcparled tM fallowing data: Site Cenceatralton Far Slswlflcant Elevation Ferestanach ptpfllanes: Newrablastanai: ZyMal pland carclnenas: Nephroblastomas: Liver angiosarcoma tale: resale: Haaniry edenacarclnana; 90.000 ppu 10.000 pp 10,000 ppn 2S0 ppn ZOO ppn, SO ng/kg SO ppn, li.7 ngftg 5 PP* TM law concentration for onset af Manary tuner* was af concern wMa a preliminary stwdy af fabrication eapleyaee reported an awass nf breast twaOrs (Chlazte, at l., 1979) Mt a fallow-up casa-cantralled stwdy (thistle, 1900) found no aisaclatlan Mtween the case* and VC ewpoiwra. IM largesl stwdy nf VC-FVC workers In IM Ihilted States reported slight excesses af breia and lung tuners (Equitable Envlrannental Health, 1970), hut this was nat seen In the other stwdtes referenced ahev*. IM excess af brain tuners was snail, and not dasear exposure-related. TM avaratl exetss af Twig tuners resulted fren an excess In one plant only, and raaxanlnatlan of those cases also showed n* asssclatlan with VC exposure (UaxMlIer, 1971). Vinyl chloride Ms Men Found to M active In several In vitro auto- genetic lasts with Mctorla and yeasts (Ifcpkln*. 1979) and It appears U cans* Chranasone obnaraalUltS In exposed workers, Mt these changes are reversible wMa exposure Is reduced (KansUene, 1971) and several `studies af aefghMrheods around FVC plants have failed to show a sappartobl* association with birth dafects (Ednonds, I97S, 197b). It |a aal a torelegea In redfats (Johns, 1977), Therefore It appears reasanablo to assent that If there la nay signif icant chronic risk other than ASi, It la considerably waller than ttot far ASl, and ttot an adequate risk asteswent can M based an only IM llvar tuners. HOTETO EDITORS Under the new fedarel copyright law, poblicallan rl|Mi to this paper an retained by Ida aulhaft*). AP00022268 kevltw ef 9lk *ntnimili I. klntl^iraM, HU One af ik first attenpls ti mllltt m<m1 dels is istfaate risks at vry 1m mpttwil mi that f Schnaldtnun, Haetel and Ira* (HU). Ihev mad prellafnary Haltonl results to conpare Uk astlMlcs retained fron three possible nelteaeitcal mMs. Thf&99X assurance level ef a "safa* Past at a llfetlaa risk af IV * ms esttmtad fraa several extrapolation mdels as fallows: lap Prabtl (slap# I) logit (slap* 3.45) laplt (step* 2.9, ana-hit) 71 ppb 119 ppb {.I ppb Ite authors discussed the recognized difficulties af Mtcidlip these rat data ta Inman* and af providing mImI optrlaMU that caald answer satisfactorily tha gweetlan af hunsn risk at very tar daits, 2. Kutnack and HcGeughgr, 1975 Iha EM ms tha first group U atteapt a h--aw risk assassaant far vinyl chlarldc (Kuznack and HcCiughy, 1975). Ihls pteueerlng effort elteapled la ** hath mImI and kam data, and U tkw cooperative rasalti fraa hath IM linear and log-pmblt ngdels. It concluded that there was an Individual risk af 71 * II per pa af llfatlae anjMSwra ta VC by the linear eatrapalallM aathad, and that the leg-ambit results ten ene-lcMIi to Mt*kwMlrtdU af that. Ihls effsrt Is subject ta several scrlaus crltldsns. The (i|niic( data Med far hamw ptrlM* was tint (rw a pf with less than averape exposure, while the Ml rate sms chescn fran anly (hast plants which did reperl cases, and tpnared the reminder af the population. Ihm, Ihelr Incidence rata af 7.5X compares ta aw actual Heart ef ahaut I, IX. they used as their prlmvy aethad a linear extrapolation ef rat data, tdslch aften has heew seen ta everasllaete the actual rates by at least te ardert af nagnltode. and they assuaed the tatal cancer rate ta ha twice that rawed far Ml. This sane astlaata ms ased hy the EM (1979) to esllmte tha cancentratlan af VC In drlnklwp water Mich weald product various levels af risk, these etllmtaf am, af ceurtt, subject ta tha earn criticism. Nlsbel (I97) challenged the estlmte af tviaact and Hctoughy (1975) when It ms used hy Wilson In lestluony befere the OSMA hearing aa Its generic cancer pel Icy. Illshet stated that his calculatlans shewed tha risk ta ha 19*30 tines greater, fey Uw same cetcelatlen netted. Wilts* (1979) suggested several (laws IM.I l 1 4 In the Nlsbel procedure, Including the fact that fee chase far his ralrapalallan one point at 25 PP" Iron Haltonl experiment IT*IS, nnd that this point Is ml In good agreement with the whale body af data. Further, he chest to use total cancer Incidence In the rats. Including these at syubal glands, which have no counterpart In humans. telh Wilson and Kutamck and McGaughy had used a factor of two lloes ASl ta account far passible cancer at alher sites. Wilson did acknowledge a mihenetlcal error which nade his msulls half IN proper nuaber. Albert (1979) applied this sane general procedure ta athar peten* Hally carcinogenic air pollutants In the United Slates and calculated the expected annual cancer deaths as fellows: Arsenic * terrene Ceduluu Coke ovens VC (after regulation) 15.V 77.V K.2 149.5 1.9 I. Vetoing, 1979 Vetoing* at al., (1979) applied an experimentally derived hie* transforMlion correction (Cehrlng, et al., 1979) to rat data and estivated Uw Incidence In burnt at two different exposure* hy aeons of four dlfiereat extrapolation node is. their estlmtes at $09 and 200 ppm TWA bracket the ebserved experience far feuaans when derived.frm the problt and the wncaastralned linear mdels. The linear-throwgh-zer* and ene-Mt awdels camtstently ever* estlmled the Incldenca. Although net considered fey the authors, the linear tad prebit mdels natch rather closely tha total V.S. experience of occupational AH at aa assmed 1,900 ppa exposure, the linear uedel predicts no Incidence below 99 ppg-ln haws, The prehit aedel predicts a huoan risk af 1.5 n 19 " at 1 ppa. thus, a oechanlsn for adjusting far the difference In mUbellsu between aalnalt and hmons appears to be usarol. A llultallen of the Vetoing precedure Is that It met partial HaUent data, and tests the msulls against lb* CHA epidemiology study. That study ms net the "end of the experiment": It stepped at the end ef 1973, and several death* have occurred sine* then. Neither did It cever the entire papulation, but only the euplayees af that* plants which mi certain criteria far data retention and length af operation. The Stafford (I9V1) data daei ctvtr the entire papulation and extends the history far save* years. The site af the papulation Is not known, but a reasonable astlmte, based a* narual worker turnover rates and the nuaber af plants not Included In the CIIA study. Is certainly not less than 25,009. This weeId give a grass Incidence af abaut i.1J. Of these, the lumber actually exposed to substantial exposures would be about 25*39 per plant at any ana Hue. Multiplication by 25 plants, and a factor of three far Urn turnover during this parted, would glue ahaut 2,000 highly exposed persons, far an affective lad* S AP00022269 drote of Just ever \t. Persaeal experience mold Indicate Ut, for the period prior to 19(4. when alt of the first exposures of tkf fatal K cases M kcwtW, the mnge exposvres of tills Mfitly group csrtiisty was fa mtss af 1,000'ppe far the narking eay. (Ultenl (1919) fame a IK incidence at ahawt 1-10 ppu la rats. Calculation af tkt dose. apWilMl Uitf IkNcki In rats gives 9 ga by thi linear aeth#4 end 7.5 ppa Iran the log-problt agwetloe far the cmbJued NaltMi IsklliliM experiuents. this credo and svbjectlve estluito would then say that sm Is about 10# tlaes as resistant as tha rat ta VC iehala- Uaa. a figure generally la agreeMat arltlk alher ostlMtes (ICM, . M Safety Cornell 1070, 19M Ihe feed Safety Cornell has recixatxdad (FSC, W7I) the we af tha |wn aaltl-htt atdtl btconsa af Its flaalhlllty la headling Oast response date af varytag cervltlnoarlty at lea daset. It has calculated <f$C, 1900) tha aialnaa likely and lower 97.5X Halt dosas far satsUaces at vafJewt risk levels and with dlfferaat aetfels. Far VC, at If * risk, these resalts art fellers (hosed aa early HalUni data): One-hit AratUoe-Ooll Netball Multi-hit 2.0a Ml* ppa 2.0 a 1*J ppa 2.1 a lo^igppa l.t a M ' ppa for this substance, Use geodwtss of fit or the tfelbal! aodel (0.S0) MS superior to Uut af the aultt-blt (O.Jt). Neither af Uw other toe aodels govt acceptable Ills. This ms fa part hecaase'of the coaeava shape af the carve, which lacladtd oil af the high deeas la the dose roipeoso dale. i. Nae, 1919 A Paw Heath lean perfaratd a relative risk eftlaatlee far Mvaral cinpsiiniis danger, et nt., 1979) which canstderad prahahle expo sure, Use ceategeeece af eyesore, the physical state af tha* idilMM daring pracasslng, and'the carreat ispstm standards, this retailed In a value ef tot far VC In a "elated systea hat * with eepleyees la (ha vicinity." the saaa pracadare assigned hemrd rating valves to seat ether sahstaacet as follows; bonyono, II; phesgsae, tit; hydregoa salflde, S; arsine, 9,700; and bla-chlerenethyl ether, (9,100. In a hatch oparatlea with occasional annual handling* the hscard rating far DC facrpMad la 9,790 by this aelhed. (. Nohlr, 1901 Hahie, at ol., (1900) candactad a serial af lasts far the Canswear Product Safety Ceanfssfoa, part af dick cooslstod af exposing rats and alee to o carles af chart, high capewroi, rather then 1-9.7 A 0* tha usual enlandcd taw desage. They included nn*hOr exposures to rats and nice at SO, SOQ, S,000, end S0,00Q ppa. If and 00 hour exposures at S00 ppa, and 49 and 100 one-tour exposures at SO ppa. Alter llletioo nhsarvitlan they Imm4 no effects on rats, or their olfsprlng, nor an nice exposed to lass than 500 ppa. Those exposed u aver S00 ppa developed pwlnaaary deniaae, hat they alst had lafftrad froa pncunonltit. they considered the pahlfshed data aa aniaal caposarts and conclvdad that there was a lifeline ease helew which no encagealc response lr seen. This was estlaated to ha S,000 ppd-brs far lea and greater than 50,000 ppa far rats, regardless af whether the date was aMInfsterad aver a short ar long period. Ihls caacept of cgMlity of offoctlvaaoas for all aodei of exposure dees not have general KctfUact and weald aat appear to he cerrect, hated oa ear present vadentandlag af carcinogenesis. Oast-rate affects era, af caarsa, mII hnawn. However, tha degree to which this caa*to extended ta all types af effects is aat known. * These anthers alia asad the Cruy fines* aadet (Crwap# fiwess and Deal, 1977) ta cvalMta their data aa aause pelaaiiry cancer, and astlMted that exposure to 5,000 ppp VC doable* tha probability af cancer, while 50,000 PP* increased tha risk nine-laid, la view of tha fact that pneweooiti* ms present la all tolaals eapesed abava 500 ppa. It Is gMStloeeble If this was a direct encagealc response, or the result af aa nanganatfc event hacaosa af severe Iwng damage. Naltanl (1979) also reports aa Increase la Ivng tors la alee, bat aat fa rats ar ha**tart. Thus, the' significance af this finding to risk ta hanaas Is guestleaablo. , 7. Anderson, 1900. Andersen, et at., (ISM) extended the work of Cehrfng, et af., (1910 and 1979} to Incorporate the mount af Mtaballc products Iron VC which actually was hevnd to tha OKA af axpasad rats, (Gebrlng aad flaw. 1977) rather than tha total a*ennt Metabolized. They assigned various values to the paroueters la MichaelIsHenten conation depleting Um kinetics of the pelabollc process, and coopered Ihe results frea extrapolation to low doses by lag-prohit and nullt-Mt uudaU. Ihay found that the too extrap olation pedals responded gwHo differently to these variations at very low doses, and that It was not possible to select am aadel * tha *are appropriate fron the hlgh-dese data. Use af the values of Cohriag for tho prluary paraeeUrf,gava ostlnatos of the dose egwlvoiant to llfetlne risks afloat less than I ppa far tho prebit nodal and less than 2 ppa lar tho owlListaya nodal, correspondence which the authors pointed out was bettor than tha precisian af latorsptclet cooperItent. 0 s 1 *. J AP00022270 . EM, I9N Ihe final version af tha water quality criteria doc(Mat for VC (EM, 1900) wrt a dlfftml approach far risk liMltan. Th# tlifx af ike <KldM il all Unti il the Iawait doses >r IMUonl experiment |f-| wet adJlU4 far the traction af exposure, the feeding level U give (ha ink kllld concentration f VC ii by likdillM (icc wither and Collins, 1171), and the ratio *1 the surface area af hnum.ti. rati, ta product an estimate that llfetlna rlah af II * mid ha ceeied by drinking 1 t/day at water contslHng |0 |/1. Than It tana confusion In the Milwutlci given In the report, and the niMfllwii an which the adjustments art aada are far frea having general acceptance, althewgh generally fallowing MS racaanendatlans. It appear* that thl procedure avaritatas Lha rlik by aeveril ardera af aagntlude. 9. ims, me the national teidwy if Science (1977) calculated the upper fsX canfldence Unit-far rlk frea drinking water canlalnlng vinyl chlarlde frea the prehahfllttlc awltlstage node! and ar]y Halten! rat data. They report (KAJ, 1909) a lifeline risk af 10 * a* Nlnf equivalent it 3.0010 3 ag/kg/day. far a 70 kg aersaa consuming 2 l/day, this wewld calculate te an acceptable level ef 1 g/l. The difference between the EM and MS mnfcera cents fraa the different cwrvr*f1tl1ng aetheds far the anlael data. <1. Saylor and Kadell (1900) applied linear "Interpolation" ta the tame early Haltanl data need hy the feed Safely Cornell (ISM) ta Wrrlva at a predicted mexfmum risk af M *. ihe appar 17.11 confidence llnft af the anlnal data was taken as ana paint an Ilia Intcrpalatlve line, and iere Incidence at <era exposure as the other. Jilt produced a lower 97.5* cenfJdence Unit desage or 7.1 a 10 * ppa far a lifeline risk af 10 * In rats. Their apoHcatlan af the AraltMt'Oel! aaltlstage aadel gave S.2 |JI ppa as the dosage at 10 * lifeline risk coapared ta 2 a If * hjr the . land Safety Council. the difference It dwe la alternative assaap* tlans an the value of tha exponential data tern, I., Craap and Cwett (ISM) reviewed sane af the earlier risk estimates far vinyl chlarlde In drinking water, and recalculated the risks, using the ane-hlt and awltlstage awkli. Ihey arrived at an apper Ml canfldence Halt ef IlfeUae risk far drinking water containing I g/l of VC of 4 a 10 *, based an early tUHenl Inhalation data. Using the atsaaptlon that a 0.7% Incidence af Ut In warkers had reswlled fraa a llfetlna ewoture af 70 g/kg, they obtained a aanlam llkellhead risk af 10 1 fraa O.tt g/l by hath the nwltlttage and linear models, with SSX iawar canfldeacc Halts af tha tana rlsh at 0.24 g/l. These twa aodelt redact ta a linear fera when wed at very law-dates aad with tha atiwapllen af no threshold value. 13-1.1 .a These anthers die EM data an the accwrrence Of VC In public water imliit which hy their methods yield a llfcttae risk of U * 10 , r 12 deaths par year Iron this csuie in the United Elate*. Mans af these has bean observed, desalt* the accwoelalion af 19 years* data aa All deaths (Popper, 1171). 11 It, Scett (1981) ascribed the decreased Incidence af twears In rats it the higher dates ta a call killing process, and adapted the Uelbwll model to account far this. Application af the model ta tme early Kaltenl date produced a curve which III the data free 90-10,000 ppa. He did aat elteapc to extrapolate ta doses beyond the experlaental range. 13, Carlberg, 1981, also applied lha Uelbutl aadel la )t bloasiay reports an a variety af mIh) carcinogens, lie concluded that the ane-hlt aadel was aat appropriate and that carcinogens ceatd he divided lute categories according ta the shape af the curve, e.g.. concave ar convex., fie found that the early Haltanl data an VC fell Into the lamer category. Application af Ms paraaettr estimate* ta those fjU, assualng ne spontaneous Incidence ef ASL, gives 2.9 a 10 * ppa far a lirallap risk of 18 * for rats, later calculations Including all of the published Halted data did not change the results significantly (personal comwnl- catfon). He found the Velbwll shape paraueter te be apprsafuataly 0.S, which Is sssuaed te he the amber af stages for lunar Initiation. This Is consistent with the finding hy Gobring (1977) of a satur able aetaballc path which predwees the praxinate carcinogen. U alsa suggests that the mater of "stages" Is the lumber af ftntletaU steps baler# the rale-tlaltlng step. There nay ho other stages fallawlag, hut they are net rate controlling. Actually, them appears te he ft least twa saturable mechanisms Involved la (he pharaaceklaellct af VC, tha aatahalfsa to the altlaata carcin ogen and Ua delaxlflcatlaa by sullhydryl groups. 14. One further evaluation af huaaa risk can be node fraa tha experi ence or persons residing Mir VC-PVC plants. The EM estimated (ftwrmack and HcCaughy, 1979) that five alllion persons lived ultbln five miles al these plants, and were exptsed la an annual average concentration of 17 ppb. The present distribution ef ploats was generally wall-tslabllshed by 1999, thus wo have 22 years af history, ar about 118 allllaa person-years. About flva or six af these planla, with 1-2 ulllloa neighbors, *e back another 28 years, but these data art aat firm enough for incloslon. The fact that no case of ASL has been confirmed as arising fraa these aahlent.expesures places the upper bound of risk at lass than 2.7 a 10 ' per pf**yr. It |o beIlewd ibal the exposure data were overestimated by (PA, and that this result nay ha tea law, but ft Is In the sane general rang* as that arrived at by Cehrlng (1979) and Anderson (1900) sftar making carractlona for phamocoMnttics. 1-9.2 Extending Ult trvdt u1cUtiM| these five all lion persons ere tm* i|ynff by IPA to be exposed te 0.2 ppb (probably a High ' figure). which would predict ee nor* then 0.0001 deaths per year, er one per 1.200 years la that whale population due te VC exposer*, let ft else wst be recognised that with approximately 20 cases per year ef ASt In the genera) pepelatlM, there can he expected fro* a purely statistical basis tlpt there should ha ene case . every tun years er se --eg this greup ef 5 attltoii pleat aefghhers. fhe results nf these estlnetes djscessed above are papered In Table I, Her ceovertloa to a uni fern 10 * llfetlo* risk. Estimates 5, (Oeu 1921) and 12 (Scott, 1901) were net In e fnrm tn permit this ceuparltem. See OHM. (1900), far references te a few ether estlnetes that were ant considered here. it can bt seen that the results f|)l Inte two nejer catogeries. those -hlch praject that the risk ef M occurs et exposures of greater than I ppn. and these whip find that risk In the ppb range. The rstleates which yield the higher ellewahle expeseres in based an ween data (has. 1, 1 end 14) nr use n leg-prehit extrapolation model (He. 2, second estimate), er predict threshold (He. C). The '--Inder generally art hated an the linear, eee-thrvtfmld model, and ake ne biological cerrectlen. Tbe result Is a difference nf 1 or 4 ardert ef nagnltude. Iha eatlnates whip yield the higher ellewahle exposures er* fa hotUr agreenent ttt hunaa experlenca than an these of the other group. , additional Pate all of the extrapolations reported hare have used far the original dalieal data fren Ms experlnent IM. Ha has now reported (Haltonl, 1929) tape ether ceaporPle Inhalation experfnents m Uw s-- strain if rets, and -- en another strain, in addition la two Ingestion iindies. The results ef these experlncnts are shown In Figure l.nt log-problt scale. It can ha seen that they all follow a sluller oattera. hut that then an large variations In slope hetween the veriest data groups. Table III contains the teg-prohlt equations calculated fron sene of the Individual experlneals. end various groups >f experlncnts. excellent fits an Plained far a single experlnent; s would he expected fren the --II nu--r of dele paints, hutladequate fits are obtained far the group as a whale. Inclusion ef the historic central data an ASL (O.09X spontaneous Incidence) did net affect the fit sPstantlally, except far Iha very lew date data. Incleslaa or 1 the M (origin) as a data psiat did give significantly poorer fits. Iha cwhined experiments Indicate that a llfetlne risk nf If * far rats It PUImtd Iran a dost In the 1-2 ppb rang*. llaller varieties la seen with the other naUwoelkel expressions, inch as linear or exponential eqostfens. ' eowletory Status The current reguTetory status nf vinyl chloride Is so--rlied In TPIa II. the first regulatory action eo VC was taken In 1913 when the urea* ef fax. Alcohol and Firearms prohibited the ese af rigid M as liquor containers. This was based on It being present as aa sdulleraal, end nut en any consideration of risk. The Consumer Product Safely emission (CfSC), the feed and Irug Adnlrlstratlaa, (F9A). and the IPA all acted te ban the use ef VC as an aerosol propellant thus establishing a zero risk position. the FBA preposed (FDA. 1975) to withdraw the prior sanction status el rigid hfC as a feed package cooponent because ef the concern for residual VC that night afgralt. The flM has taken aa further action oa tMi proposal, and now It considering a "constituent- policy which would permit a lifetime exposure at -- fccopteble risk level. This risk has been proposed recently to he 10 * lifetime for the gluttonous cons--r. As was discussed above, the CPA required a best available technology approach which reduces the average exposure te these wlthlo S miles af a plant to about 0.2 ppb, by CPA estimates. MM established a rule In I9T4 which set I ppn for 0 hours as the maximum permissible exposure, and also sot 0.5 ppm as on action level below which most features of the regdlelloo did not apply. These were chosen as feasible levels, and not necessarily "lofe* doses (0SHA, 1974; IPA, 1925). The IPA has established an exposer* to the general papulation only g.M nf that allowed la Uw workplace. Tbe CPSC has required tera exposure, and the TBA has considered that approach. Depending aa which method ef estimation the FM nay choose. Its allowable exposure could be either greater or loss than those currently set by CPA aad 0SHA. tt has been estimated that the maxima amount af VC Ingested by the average Enrnpean, who uses much mar* plastic packaging than ue, ll , legs Uwn L g/day, (CCFIC, 1925) uhlch would be In the order ef e 10 9 or 19^ lifetime risk by even the most conservative models. There have been various estimates made of the cost-effectlv--se ef the Federal regulation for vinyl chloride. Crahan end Vavpel (1991) esllnated that the 0SMA rule cast $7.5 nltllon per life saved, aad 1499 theosaai per lira-year saved --r the option ef leaving the expesurn Hull at 5# ppm. Lufcea and Hiller (1901) state that the fapuled vein* #F a life fron the DSHA standard Is 14 nlllfon. Harrell (1902) uses an en--I cast nf $2* nil I Inn and an annual benefit ef l.l life saved te derive a cest/h--fit af 1200 allllea per life for tho QStlA rule, fhe EM has reported (IPA. 1979) that the cost ef coeplleece with fta VC standard was 9295 all I Ian through July 7, 1901, and will be an additional 9470 million during Uw next five years, all In 1972 dollars. If the CPA estlneta af up to 20 deal tbs per year vera correct, this would be a cast of 94.7 ulllten per life. H--ver, as discussed here, there Is ms evidence that any lives havo been saved by this rale. Ibare are many difficulties la obtaining accurate estlMtes of this a type, and aerteus prnbleos In detirnlalng the proper value te be assigned U * life, nevertheless, the doubtful-galore ef tbe claims v O o lb Si loi K> ll AP00022272 ff*r ny significant benefit Iron these rules teyiKlt Un ai best, ihew regulations are ticmlntly easily to society. therefore, we msI elteapt to Inprove bolh our data bate ami our Methods for Inter* M-eltog end applying the data. Htcussloe diet an be learned froa this exercise other than the already *ecogalied fact that various extrapolation hKIs can yield very Hfferent results? In this cose, at least, there are several points dilcb ore worth considering. I; Vinyl chloride Is no encoptlon to the rale that huoan data always oust be Incorporated whenever possible. The epltfeelc ef eccupa* Usually Induced AS1 which was feared In 1974 hat not materialized, probably doe to the slept that were taken In the early 1960's to reduce exposure because uf the discovery of Ml. ho Instances of Ml frao exposure In VC In the general population have been substantiated, the overpredicllen of occupational cases was due le tbe underestimation of worker exposure and everrcllance on raw anlal data without proper pharmacokinetic ndjustaenl. Ve ore not now able to extrapolate reliably between similar species end certainly not Iron rodents to Iwans, wllhowt wueh additional data. 2. The regulations for vinyl chloride were not based prloartly an scientific data, bet on socioeconomic and political decisions. This It no surprise {Crandall and lave. 1991), bwt Is a fact which should be acknowledged openly, alone with the understanding that this position will continue le penance peed science. 3. hatheoatlcal extrapolation nndels ere not adequate In ihewtlvet far predictions of risks ouch heyond the experimental range, no alter how good the tit Is to tbe dote to the observed range, the variability ef relatively saall experimental groups adds to the error range, thus, bleassays Intended fur quantitative risk assessment applications should be at as low doses as possible, and as large as possible, end should be Interpreted very can* Ileus ly. 1. The current statu of the art Is such that quantitative risk assessments nay be userul for determining relative risks Iran similarly acting carcinogens, but art not twlliblo for across1* Ihe'board application to oil awcbaolsms of corclnogeneslo. This Is not to say that we should abandon efforts at developing more effective risk assessment methods. We mast, however, recognize the problems Inherent In blind application or aathematlcal eodefs without proper assessment of the available blochenicol data, or an understanding of bow applicable the experloental data are le hwaam. M, 12 We have available to us at least as ouch data regarding vinyl cfilerlda #* we have for any ether substance, and we still have difficulty lo deriving a suitable expression for risk fron a purely oathenallcal er stollrtlcal basis. Only when hunan relevance Is considered cm we arrive at a prediction that approx {nates actual experience. The regulators are faced with a trewendonily difficult last when they arc presented with a few pieces of animal data which suggest Use need for concern and potential regulation. We oust develop a sellable program ta obtain and use at much relevant data as possible to assure that rational regulations are possible. The vinyl chloride experience con help ut understand the klhd ef date which are needed. UAS-A1 zni/tz IWi i) AP00022273 Itftreiicn Albert, . f., teller u A. $. lUtftit. (PA, "Cenparlsan af 1ny1 cblH-id* carclnagenlc rliks rltk fra* ether pellaum*-, ihiklatlw, DC, ii JM lt/t. Mtma, It U. *1 *1., Jm. AmI. ftey* r 154 (1SB). htlir, P. J., an* A. J. f*, lMi. j* itt- Carlkarg, F. W., Catnet. 1a. jt S OM*). CMC CwmUuc far We Tonicity of Vtfcyl Cklarlde, "Vinyl ChlarlAt Texldty m4 im via al NC far P*cUgl*f ftatatalfa," Iraualt. Fet. im. Cfclaitt, L, Bccwa. N. U (It) CI7 (Ittt). Chime, t., Jr., V. E, mcfc.li, aa* . *m, J. 9txm. OOTI. 12 J Crandall. I. W., an* l. Lava, *Tha Scientific Mill fcf Hm]* "* Safety Ireektnga lMllt*lla* Vaaklaita*. Ml. Creep, I. S., an* M. A. Cwti, >litlii| talar an* Cfctir,l PMi-mit?, tacMfcar, im (mf, i. S..N.1 tan, **.(. Hit, llaOdf!. U W#ttl own. lick, . j. |. CirMr, an* C. J. Caa*a, iwcrt US M* lit?. [fcMK, L.. *airlb Defect* an* Vteyl Cfclarlta". tree Conference m vmm **4 the Mnrknlace. Wethlaaten. K. lift. aliTTarafiwn? ? rw>:----------------- EfcM, L. N. f|lk*a*J. (. ilMlfc, tsscal WS Ittt. EnlrmAtil MkUm Apeaqr, Slander* Far Vl*l ChlerMi, 41 {Jl Mfc own. Ca.lrMM.UI pmiactlen Agency "VM Cfclarlda, RaAltnl Utter qualUy CrlUfii*. M-nim, Vetfcfnite*. DC, 1t?. EnelramenUt Prelection Aoency 'MliM Malar QwlUy Criteria far Vinyl Chlerlde," CM 44B/5-lt*B?t, Deleter, Ittt. (wlnuMikil PreMclIea Agency "The Caal af Clean Air an* Claaa Malar*, towtl fcpart ta tfca Cangrm. tecaatar, 9?. Senate iNWMl Ha. M*M. U.S. tavaravaal Printing Office, MetfclngUn, C. II CqaHafclc twIraaaewUI Health. Inc., "CpIdeaUlegical SlwJy af Vinyl ChlarUc Markers, final Atperl". Prepare* far Hanwfadoring Cheatsli Asiec., VMMnglM, DC, January, It/I. Fee* an* Drug Adalnlstrallan, Nile* af propose* raleaaklna, 40 Fra. Mi.. 4t,U9 (it/5). ------ foe* Safely Council Final Mparl "Propose* Sim fir Feat Safely Atiessaent*, HatkltfiM, K, Jane, IMO. Fee* Safely Council, Sclaallflc CoMttlee "Propose* SyiU. far Fee* Safety Assessaeat." Fee* an* Cesacl. Tan. It Sanel. i teceder 1S7B. Fax, A. J., an* P. F. Calller, Itj, jn*. 8cd. M 1 (It??). frealiel-geyae, R., T. Sctafte. an* A. N. Thles*. Arfc. Seclalne*. Present.. U tit (ll>, -------3--------------- Caylar. B. if.. an* I. U Ra*elt. R. 1.. J. EnvirM. Patfcal. Tax. 4 30SO9N). ---------------------------------- Cefcrlno, P. J.. an* 6. C. 11m, JL Cnelraa. Pathol. Toxical. I 1SJ Cchrfnf, P. J., p. C. Hatanafca. an* C. N. Park. Tax. an* Mai. Hum. 41 IS (1979). ------------- a*----------- Miring, P. J., at al., Toil Aoai. PfcaraKal. 44 SRI (IJ7R). . CrahM, J. t., an* J. V. taupeI. IHk Amlnls I It (IM1). Cranlger, R. 6., A. f. Malker, an* A. ft War* "Vinyl Ch1art* , Memner Intnce* tlfaaie; Clinical, Ratlalaglcal an* lanunalaglcal Atpecls," Ckaater II la 'laden* lltaasa; trug, lrra*1tllan, Occupnilan", l. Prtfar, t*., Crant an* Strallan, ian*an, |9M. Mamleana, al al., feUli.2l?U (IWS). Mefcir, R. ft, et al., 'Tantcalafy, Cardneoaalclty and Rapradncllva IffecU af Slngla an* ffcrIUple Exp.iarai la Vinyl Cfclarlda la Rail an* diet*, Pra-pakllcaltan draft, Fat. I, IM, t.S. Canaiatr Pradwct Safely CeMlulaa, WaiMnglaa, DC. Mepklna, J,, f*^ C.wwl. T*xk1,. MR (lt?t). Takfc, J. A., ft al., fan, an* Aaal. Pfcar--eal. M 4a? (It??). Keiaack, A. K.. an* R. I. ftcCaughy. "tuMlIUUve Rfsk AiMSfcNnt far Caanenlty Cnaaiura la Vleyl Cfclarlda*, t.S. EPA, Waefclngtan, DC, laager, R. A., S. K. Nerwead, B. C. Sacfce, an* N. A. Heyta, M. In*. ttffe fiisa*. L. ot) mm own, ' -- it AP00022274 . .M., and S. C. Miller, J. Air Pal. Central Jmt, 31 1254 I. " |, C., G. Urmlnc. A. CfHbertf, *. Cettl, and 0. Cerrettl, - Chloride Carcinogenicity Bloastayf, (I I fnjKl) it on *oenlal Netfel for Risk Identification and Alttismtl In Mental and Occupational CarcliiMMnlt! Presented at "It CIA ctnttMit Chlalque", Instllvtc Carle, Paris, . Iff, 1939. at Acadtny a1 faience, "Drink!** Hater And Health". MHlonal y fret*. 1973. a) Acadvmt *f Science, "Drinking Haler and HeaTIh", Vnl. 2, p. lliNl Acadcay Press, 1900. ml Cancer Advtsery hoard, "The Relation or Olasssey Once la the amt ( (he Risk el Carcinogens far Hnaans tander Conditions of <pesnro", SAca--lUee on Cnvlranpenlat Csrclnagenasta, Draft of citing dale Iran Heselsan and Rassell, 1979. .. I.C.T., halt-hearing sUlenenl la HM docket ffffff. SepteAer >70. llanal Safety and Health Mainfstratlan, Standard far Expasara yt Chloride. 29 Ee* Re*. 25,190 (1974). , H. el at.. Ml X falhal. W 249 (I97D|. deman, & A. H. Mantel, and C. C. Drawn, Ang. Iff Acad, 5cl.. i7 | 1975). I. Pall. Mathenatlcal fflelnav. In press, 1991. rd, J., private ceenMilcatlen (19tt). J., J. Orejaen, and It. Valaskal, Med. Intern. IS 907 (1993). wit, G., and P. Allard, 7. 0cmp. Med.. (10) *71 <1W). ttlngen, . f.. Mile Health Service PAIIcatlaa Ha. (II, H.S. nenl of Health, Education and Htlfarc, Msshlngtan, DC, I9SS. ter, I., et a!., "An Cpldealetagtcel Investigation nf an Excess Nicer Risk In n Synthetic Chenlcals Plant", Presented at the nth International Congress ler kcspatlml MesUh, DvhmvnU, Sept., 197*. , R. "Response la canaents of J. C. Mlskel." Past-hearing record locket 090, 197D. , A. R., andD. I. Collins, J. Tax, tnvlr. Health. 2 311 (197S). 2-9 A FIGURE 1 GRAPHICAL REPRESENTATION OF TABLE 1U LOG-PROBIT PLOT uotwo MMALATI SM C M 4 III C arts c NGCSTIO Ml Ml -* TABLE 1 SUMMARYOF ss -3 Hi in i r* i 55 5555 55 5 5 I' mm u: Sw S u I' ^ p v 5 `x`i V: IoSi**x l\vm 1 5* V- Spt*2:u82 Ml Hi 1 0 3~ .z H 1 < m 30 5 > 8 m 8 3 ,m I IH5 a:1ll1*5aa s1 si sisia 3 HI s 33 3 TABLE 11 REGULATORY STATUS OF VINYL CHLORIDE AGENCY BATP CPSC FDA EPA OSHA CONTROLLED LEVEL BANNED AS LIQUOR BOTTLE BANNED IN CONSUMER PRODUCTS USE IN RIGID FOOD PACKAGING QUESTIONED APPROXIMATELY 0.2 ppb 1 ppm 8-HR TWO MAXIMUM 0.5 ppm ACTION LEVEL PHILOSOPHY ADULTERANT ZERO RISK CONSIDERING ACCEPTABLE RISK BEST AVAILABLE TECHNOLOGY LOWEST FEASIBLE LEVEL AP00022275 TABLEJII EQUATIONS FOR CURVES FITTED TO VARIOUS SINGLE AND COMBINED MALTONl EXPERIMENTS EXPERIMENT BT-1 PLUS CONTROLS 8T.2 PLUS CONTROLS BT*1S PLUSCONTROLS ALL INHALATION STUDIES (41 PLUS CONTROLS ALL INGESTION STUDIES (2) PLUSCONTROLS ALL STUDIES IS) PLUS CONTROLS ALL STUDIES; LOW DOSES ONLY PLUS CONTROLS LINEAR v"ai*b a br 0-26 0.27 3.05 1.52 62 128 026 027 1.75 1.74 029 .029 326 2.47 0.67 0.67 629 1.13 1.0 0.66 136 020 12 0-B5 327 2JO 0.19 020 0J1 0.91 0.65 0J5 3JO 0.73 341 . 0.72 123 0J7 0.76 loq probit P* IN DOSE * b a br 021 2.76 039 1.60 0.86 13 0.66 348 1.0 02? 238 0.82 0.30 122 0.6S 027 3.06 0.62 0.S1 0.17 2S3 271 0.78 0.46 CONCENTRATION AT 10-* RISK. (LOS-PROSIT1, open 0.03 23 024 0302 0302 0301 042 03092 I AP00022276 LIZZZOOOdV 3SN03S33 30 33U31 QWV SHQ Oi iS3n&3* $133333 H1TY3H A XZQN333V ABSTRACT 0). 3. $oi:Ve CSOT (hA:^ IW) cc: .hW>< L T^ Three groups of pregnant Sprague-Dawley rats were exposed by INHALATION TO 600 PPM VINYL CHLORIDE (VC) A HRS/DAY, FROM THE 9th TO 21ST DAY OF GESTATION. ONE OF THESE GROUPS RECEIVED 5J5 ETHANOL (EtOH) IN WATER (V/V) EIGHT WEEKS PRIOR TO BREEDING AND THROUGH WEANING (30 DAYS AFTER BIRTH), AND ONE GROUP WITH NEONATES WAS AD DITIONALLY EXPOSED TO VC THROUGH WEANING OF PUPS. OFFSPRING, IN CLUDING THOSE OF ETOH AND FILTERED AIR CONTROL GROUPS/ WERE OBSERVED FOR LIFE. THE DEVELOPMENT OF ANGIOSARCOMA (LIVER, LUNG, MUSCLE) IN VC- TREATED GROUPS INDICATES THE TRANSPLACENTAL POTENTIAL OF VC TO INITIATE CANCER JN UTERO. INGESTION OF 51 EtOH BY VC-TREATED DAMS DID NOT ENHANCE THE INCIDENCE OF TREATMENT-RELATED MALIGNANCIES AS HAS BEEN OBSERVED IN ADULT MALE RATS. POST-NATAL EXPOSURE OF PUPS TO 600 PPM VC DID INCREASE THE INCIDENCE OF LIVER TUMORS, 10 OF 72 RATS WITH ANGIOSARCOMA AND 48 OF 72 WITH CARCINOMA. IN COMPARISON, EXPOSURE TO VC J_N UTERO ALONE INDUCED LIVER ANGIOSARCOMA IN 1 OF 71 RATS AND HEPATOCELLULAR CARCINOMA IN 11 OF 71. TREATMENT-RELATED MALIGNANT TUMORS INCLUDED ANGIOSARCOMA IN THE LIVER, LUNG AND MUSCLE,, AND CARCINOMA IN THE LIVER, BILE DUCT AND MAMMARY TISSUE. AP00022278 INTRODUCTION Chronic exposure to vinyl chloride monomer (VC) induces ANGIOSARCOMA IN THE LIVER OF BOTH HUMANS (1) AND LABORATORY ANI MALS (2). IN A COMPREHENSIVE INVESTIGATION OF VC CARCINOGENICITY, MALTONI ET AL. (5) TESTED THE TRANSPLACENTAL EFFECTS OF VC BY EX POSING PREGNANT SPRAGUE-DAWLEY RATS 4 HRS/DAY TO 10,000 OR 6,000 PPM VC FROM THE 12TH JO THE 18TH DAY OF GESTATION*. In COMPARISON TO HISTORICAL CONTROLS, AN INCREASE WAS OBSERVED IN ZYMBAL GLAND CARCINOMAS AND NEPHROBLASTOMAS. THESE INVESTIGATORS ALSO DEMON STRATED THAT NEWBORN RATS ARE MORE SENSITIVE.THAN ADULTS TO VC CARCINOGENICITY. LlVER ANGIOSARCOMA DEVELOPED IN 40.5% (6,000 PPM VC) AND IN 34.1% (10,000 PPM) OF NEWBORN S-D RATS EXPOSED 4 HRS/DAY, 5 DAYS/WEEK FOR 5 WEEKS 3). IN THIS LABORATORY, 5% ETHANOL IN THE DRINKING WATER OF RATS WAS SHOWN TO POTENTIATE THE EFFECTS OF CHRONIC INHALATION OF VC (600 PPM, 4 HRS/DAY, 5 DAYS/WEEK, 1 YEAR). IN COMPARISON TO VC- TREATMENT ALONE, CONCOMITANT INGESTION OF ETHANOL MORE THAN DOUBLED THE INCIDENCE OF LIVER ANGIOSARCOMA (4), These inhalation studies were designed to examine 1) the TRANSPLACENTAL EFFECTS AND SENSITIVITY OF NEWBORN RATS TO A LOWER CONCENTRATION OF VC (600 PPM) AND 2) THE TRANSPLACENTAL ACTION OF ETHANOL AND VC-TREATMENT ON CARCINOGENESIS IN OFFSPRING. SUPPORTED BY USEPA 68-03-2402 AND USPHS ES-00159. AP00022279 METHODS Five groups of Sprague-Dawley pregnant rats were used IN A STUDY OF THE EFFECTS OF INGESTED ETHANOL AND POST-NATAL EX POSURE TO VC ON OFFSPRING OF DAMS EXPOSED BY INHALATION TO VC FROM THE 9TH THROUGH THE 21ST DAY OF GESTATION. GROUP DESIGNATIONS AND EXPOSURE PROTOCOLS ARE GIVEN IN TABLE I. DURING EXPOSURE TO VC* FOOD AND WATER WERE WITHDRAWN EXCEPT WATER WAS PROVIDED FOR LACTATING MOTHERS. ANIMAL CAGES WERE ROTATED IN THE CHAMBER WHICH WAS MONITORED FOR VC CONCENTRATION EVERY FIVE MINUTES WITH a Baseline Industries automatic air sampling gas chromatograph. \ At birth the number of animals per litter was randomly reduced AS NEWBORN ANIMALS WERE SACRIFICED FOR EXAMINATION OF SOFT TISSUE AND SKELETAL ABNORMALITIES. THE REMAINING ANIMALS IN EACH LITTER WERE OBSERVED FOR LIFE FOR THE DEVELOPMENT OF TUMORS OR MORIBUND CONDITIONS. OBSERVATIONS WERE RECORDED AT AUTOPSY AND TISSUES WERE PREPARED FOR HISTOPATHOLOGICAL EXAMINATION. AP00022280 TABLE I, GROUP DESIGNATIONS AND EXPOSURE PROTOCOL Group Designation vc vc + PN vc + EtOH FA + EtOH FA Exposure Protocol Number of Dams Inhalation of 600 ppm VC, A HRS/DAY, 9-21ST DAY OF GES TATION. Inhalation of 600 ppm VC, 4 HRS/DAY, 9th DAY OF GESTATION THROUGH WEANING OF PUPS 30 DAYS AFTER BIRTH. PUPS WERE EXPOSED TO VC WITH MOTHERS. Inhalation of 600 ppm VC, 4 HRS/DAY, 9-2l$T DAY OF GES TATION. Virgin females were GIVEN SX ETHANOL (V/V IN DRINKING WATER 8 WEEKS PRIOR TO BREEDING, THROUGHOUT GES TATION AND UNTIL WEANING OF PUPS. 8 7 18 INHALATION OF FILTERED AIR THROUGHOUT EXPERIMENT. VIRGIN FEMALES WERE GIVEN SX ETHANOL IN WATER 8 WEEKS PRIOR TO BREEDING AND CONTINUED THROUGH WEANING OF PUPS. 15 Inhalation of filtered air THROUGHOUT EXPERIMENT. 8 No. OF Offspring Retained for Life 71 72 80 74 71 AP0002228f RESULTS The average body weight of offspring of dams chronically INGESTING ETHANOL WAS HIGHER THAN THAT OF OTHER GROUPS FOR MORE THAN 12 months: VC + EtOH > FA + EtOH > VC > FA > VC + PN. The WEIGHT DIFFERENCE BETWEEN THE VC + EtOH GROUP AND THE VC + PN GROUP WAS 75-100 GRAMS UNTIL ABOUT 18 MONTHS. MEAN SURVIVAL TIME OF THE VC + PN GROUP WAS SIGNIFICANTLY DIFFERENT (p< 0.005) WHEN COMPARED TO SURVIVAL OF THE FA GROUP (TABLE II). SURVIVAL TIMES OF OTHER TREATMENT GROUPS DID NOT DIFFER SIGNIFICANTLY FROM CONTROLS. IN ALL GROUPS; SURVIVAL OF ANIMALS WITH LIVER TUMORS WAS LONGER THAN THAT OF THEIR RESPECTIVE TREATMENT GROUPS (Table II). THE TOTAL NUMBER OF ANIMALS WITH NEOPLASMS (BENIGN + MALIG NANT) WAS HIGH IN ALL GROUPS (TABLE III) WITH THE VC AND VC + PN GROUPS EXHIBITING THE LARGEST NUMBER OF ANIMALS WITH MALIGNANCIES. A NUMBER OF MALIGNANT LESIONS WERE NOT RELATED TO TREATMENT (LYMPHOMA; PITUITARY; LUNG; AND KIDNEY CARCINOMAS; AND INDIVIDUAL TUMORS AT OTHER SITES). THE INCIDENCE OF TREATMENT RELATED MALIGNANCIES INDICATES THAT VC IS A TRANSPLACENTAL CARCINOGEN NOT ONLY BECAUSE OF THE INCREASED INCIDENCE OF CARCINOMAS IN THE LIVER; BILE DUCT; AND MAMMARY GLAND (TABLE IV). EVEN THOUGH THE INCIDENCE WAS LOW; THE DEVELOPMENT OF RARE ANGIOSARCOMAS ONLY IN OFFSPRING OF VC-EXPOSED DAMS INDICATES THE TRANSPLACENTAL POTENTIAL OF INHALED VC. OF PARTICULAR INTEREST IS THE TENFOLD INCREASE IN LIVER ANGIOSARCOMAS IN THE VC + PN GROUPS. AP00022282 TABLE 11. MEAN SURVIVAL (WEEKS) OF ALL RATS AND THOSE WITH TREATMENT-RELATED MALIGNANT TUMORS Group M Litters/ # Offspring VC VC f pn VC + EtOH FA + EtOH 8/71 7/72 18/80 15/74 FA 8/71 Angiosarcoma Liver Lung Muscle 121,1 92,1 106,6 63.4 76,6 76.6 Liver 105.1 82.2 107.5 103.1 110.7 Carcinoma . Bile Duct Mammary 100.6 86.6 26.9 98.5 81.0 89.9 All Animals 93,5 78.8a 87.0B 90.5 95.4 Statistically significant from FA survival time (p< 0.005). Borderline significance (0.025 > p > 0.005), AP00022283 Group VC VC + PN VC + EtOH FA + EtOH FA TABLE III. TOTAL NEOPLASMS PER TREATMENT GROUP Number of Litters Number of Offspring Retained Number Animals with Malignant Tumors (Z) Number Animals with Benign Tumors (Z) 8(7)a 71 29(41) 28(39) 7(7) 72 56(78) 20(28) Total Number Animals with Neoplasms (Z) 49(69) 57(79) 18(13) 80 25(31) 19(24) 39(49) 15(11) 8(7) 74 71 20(27) 17(24) 19(26) 25(35) 35(47) 39(55) AlN PARENTHESIS/ THE NUMBER OF LITTERS HAVING ANIMALS WITH MALIGNANT TUMORS. AP00022284 i r Group VC VC + PN VC + EtOH TABLE IV. INCIDENCE OF TREATMENT-RELATED MALIGNANT TUMORS # Litters/ # Offspring ANGIOSARCOMA Liver Lung Muscle Liver CARCINOMA Bile Duct Mammary Other . Malignancies 8/71 11 11 7/72 10 1 48 18/80 1 1 1 15 1 6 6 7 5 19a 11 11B FA + EtOH FA 15/74 ( 8/71 71 5 13c 12 AP00022285 AlNCLUDES 7 PITUITARY CARCINOMAS. BIncludes 2 pituitary carcinomas. cIncludes 3 pituitary carcinomas. t i CONCLUSIONS 1) In Sprague-Dawley rats* VC (600 PPM).IS A trans placental CARCINOGEN INDUCING ANGIOSARCOMA OF THE LIVER* LUNG,, AND MUSCLE AND AN INCREASE IN HEPATOCELLULAR CARCINOMA IN OFF SPRING EXPOSED TO VC ONLY IN UTERO. 2) INGE5TION OF 5% EtOH IN WATER BY PREGNANT RATS EX POSED BY INHALATION TO 600 PPM VC DURING GESTATION (9TH TO 21ST DAY) DOES NOT AFFECT THE OCCURRENCE OF VC-TREATMENT-RELATED MALIGNANCIES -IN OFFSPRING. 3) Post-natal exposure of pups to VC (in addition to in UTERO EXPOSURE) INDICATES THAT THE RAPIDLY GROWING RATS ARE QUITE SENSITIVE TO THE CARCINOGENIC EFFECTS OF INHALED VC. IN COMPARISON TO THE TUMOR INCIDENCE IN OFFSPRING EXPOSED IN UTERO* POST-NATAL EXPOSURE OF PUPS TO VC CAUSED A 10-FOLD IN CREASE IN LIVER ANGIOSARCOMA* A 4-FOLD INCREASE IN HEPATOCELLULAR CARCINOMA* AND A 6-FOLD INCREASE IN BILE DUCT CARCINOMA. AP00022286 REFERENCES 1. Creech, J.L., Jr., and Johnson/ M.N. Angiosar coma OF LIVER IN THE MANUFACTURE OF POLYVINYL CHLORIDE, J. OCCUP. MED./ 16:150 (1974). 2. Viola, P.L., Bigotti, A., and Caputo, A. Onco genic RESPONSE OF RAT SKIN, LUNGS/ AND BONES TO VINYL CHLORIDE. CANCER RES./ 31:516 (1971), 3. Maltoni, C., Lefemine, G., Ciliberti, A., Cotti, G./ and CarrettI/ D. Carcinogenicity bioassays of vinyl CHLORIDE MONOMER: A MODEL OF RISK ASSESSMENT ON AN EXPERIMENTAL BASIS. ENVIRON. HlTH. PeRSPEC./ 41:3 (1981). 4. RaDIKE, M.J., STEMMER, K. L., AND BINGHAM, E. EFFECT OF ETHANOL ON VINYL CHLORIDE CARCINOGENESIS. ENVIRON. Hlth. Perspec./ 41:59 (1981). AP00022287