Document yEpzGyMmv0omrd090NL911pX

r Pram Or B Bennett Sito Hedleal A4rlMr To Please see Circulation List attached lmp*M Chmical IndwcrtM PLC UilhoiM PQ Sox No 4 Thornton -Govotoys Blackpool PYS 4Q& Toiophona 02S3 SM1C1 Teh* 674B3 IdpUit Q(y Cop>*ta JUftf For Distribution hv CMA SPECIAL i`:iOGT.MS DIVISION From--------Hus Shah Ref. No. CJkr+A: Date-------*5______________ Ow nrf BVHO TO mxx 332 On 22 Kay 85 VCM XFXDBQOLOGICAL BKVIW Lost Thursday, l May, X sot with Sir Richard Doll at Oxford, in ordar to discuss with his his performing a critical review of all the VCM literature with reference to both carcinogenicity, mutagenicity, and all ether health effects associated with VCM, During ay discussion, we both decided on s protocol,which is as follows *Numerous studies of ths hsalth status and aortal!ty of workera in the vinyl chloride aonostr/pelyviny1 chloride induetry have been reported. It la the intent of this review to examine theae reports, in order to * determine their strengths and waaknaaaea, to look for eonsiatenciea and inconsistencies between them, and to draw conclusions about the existence or noo-exietenee of the vnrioua occupational baserds, from consideration of the total available evidence, Xt la iateadsd that the results of the review will be aede public, and will be published in the Scientific Literature in the normal way'. X then asked Sir Biehard whan ha expected the task to be completed, end be felt it would be March 1986, This ia due to the fact that he is greatly la dasand, sad has taken on other taake since X first approached his. At present, he is performing e study on Spanish toxic oils. After he has completed the project, it has been agreed that six people would review it for him, prior to its release, and ft was suggested that perhaps it eould be reviewed by individuals such as Julian Peto, Geoff Paddle and Tad Torkalsoo. X have also agreed that, at tha end of the day, X will apportion the coat of 15,000 (plus any expenses, which X expect to be adniaal), between the various participants who hava agreed to seat the cost. /Over t as i6fio BSV 0018854 froi Or B Itnatit to 22 May 85 As yon know, Sir Bichard and ayaelf have written a ftps* 00 tbs A&L Beginter, asking projections of total lumbers of caass, dna to VCM, that wo expect to occur in tha~world* tfs haws agreed that the AfiL Paper, which has gone for publication, should be reviewed in five years*, is order to see how correct the forecast is* B BEWICK RSV 0018855 9988100 ASH mm 'IYOIDCnoiKKZZdX HOA I o ** V1 r JM ****** d V ag uoummmm 9 X *a --Tim f n a *a uo^apW f <ta "TW f a *a aorcwog ft ag *T* H uSmg d ZH HIV TPP*d H D jg OMQ H < f Jta u*ppm 1 A 4g 91**l d *a ao#ugof )( H *a \uodac 0 *H ?Aa o r ZN ao^/vxD H <ZM onqg M ZH doq*T9 9 ag 5 aowTT0 8 ZZ abn Sli Toedatont szniAno-fioijracBi * *08 0 4 nw ~TOTE and *w"M fOT-- **" g ag Mi Reprinted pom British Jomnai of hukutriai UeSerne 1983;42:750-753 Copyright C 1983 MM Journal oflndusoial Mddw AM rights of npiurfuui'nH of Bus reprint or* reserved in oB eotmoios ofMu vrortd Jan e Exposure to vinyl chloride and angiosarcoma of the liver: a report of the register of cases D FORMAN. BENNETT, i STAFFORD. AND R. DOLL | British Medical Assodation, Tavistock Square, London WC1H 9JR I RSV 0018857 *ri>U flmiamml Mria* I9>5;<t730-7J3 Exposure to vinyl chloride and angiosarcoma of the liver: a report of the register of cases D FORMAN.1 B BENNETT,* J STAFFORD,* AND R DOLL* from tW Import* Cmr Research Fmd Cpidamioiogy md OUe* M Vmi.1 Infirmary. Oxford OX26HE. md Import* Omnia* bmbatria pie} Thorium Otorkyo. Bimkpo* FTS4Q0. UK asstoact The Association of Plastic Manufacturers m Europe maintains a register of all cases of angiosarcoma of the Ever (ASL) resulting from exposure to vinyl chloride monomer (VCM). This register has recorded all known VCM related cases of the flisrssr worldwide that have been histologically confirmed. Although likely to be incomplete, it is the moat comprehensive tabulation of such casm available and, by the end of 1984,118 men had been registered. The information from analysis of the cases currently on the register is used to make an approximate projection of die number ofcases to beexpected in the fixture. Thecoaduaou from this projection is that the industry is reaching the halfway stage in the appearance of VCM related ASL. The idea that vinyl chloride might cause cancer was first wuuiol by Viola in 1970 as a result of experi ments in rats.1 This was subsequently confirmed by MaJtoni at 1973 with bis comprehensive series of experiments m rets, mica, and hamsters.* Among the tumours that developed in three snimsh wss (he oormalty rare angiosarcoma of the fiver (ASL). It was not. however, until three cases ofASL were-observed m men who had been hrarfly expoeod to vinyl chloride a polyvinyl chloride (PVC) polymerisation plant in the United States that the realicy of the hazard was generally accepted.' ASL it normally so rare that only three or four cases occur each year in the whole of Britain (see bdow) so that the occurrence rtf three eases in a snail group of industrial employed m the United States was, m itself, reOriem to justify the belief that the chemical caused die dismse. If. bow* ever, any doubt has perwsted it was soon dispelled by the steady secretion of new industrial cases and the finding that sngioaarronias and various other tumours could be produced in eats by levels of exposure that were appreciably ten than those that had previously occurred m industry.* Steps were therefore quickly taken in the tnkM970s to reduce the aunt to wfcteb individuals could be apesad from levels of the order of several hundred ppm to 3 ppm <13 x 10* ngm/m*) or less.* This reduction followed Rmm4 23 FSr--i j 1913 23 Muc* IMS an earlier lowering ofexposure levels in Che mid-1960s after concern wee expressed about the narcotic effects of vinyl chloride and the risk of it producing aero* osteotysa. Before then exposure to some employees was often in the range of several thousand ppm. The rarity of ASL. even onder conditions of heavy exposure, has made it ****** to study its epi* demioloficalcharacteristics* and it aaemed. therefore, the! it might be of value to aamrin the data that have been recorded in the regtner of cnees that has been maintented by Imperial Chemical Industrie pic on behalf of the Assoaation of Plastics Manu facturers in Europe (APME). This tabulates informa tion about all the am of ASL known to have occurred in men exposed to vinyl chloride that have been reported by individual manufacturing compa nies, trade associations, and occupational health organisations m Europe. North America, and Japan. Tbs register is, doubtless, incomplete. It includes. TsMs I Msider* ofrmyt ddatidt toiatod ema of Miiemiiie ofpa *wr hy dor ofdm* Pin* - 1S33-4 IMO-4 IMS-9 I970-I 1973-4 I9S0-4 I93S-S4 . Mo*maim 1 4 9 3 44 M "Tim mm Orngamd a IM0-* won to* aim I Jewry 1*3- 730 RSV 0018858 Exfonrt to amyl chloride and mtgioaweema of the liver 75! Tsbls2 Nmmkm af tbtfi dderih rvloud tern of fiHVNMf ofliver byegeei degmeeh 4f *yarns) rjse--*u js-sa S3-* 440J--4447 re-t* Alasw tfafamas 2I1I7* IS 2170 S 2 ns hwnti, all the cue* known to the collaborating organisations and they win probably have been informed, in ooe way or another, about nearly all rewr that have baea among the relevant groups ofrenployees. Until the end of 1994, 1II eeen had been recorded as having vinyl chloride related ASL, of whoa three were still alive on I January 1915. AO the cue* had been confirmed hutologiaDy: 117 were reported to be hepatoangioeamwnee and one a cholanfioearcofaa. No cane* were mandad re women, but few women have been onploynd in manufacturing PVC. Table I tbert the breakdown of die eases by data of death, h should be noted that the register was begun in 1974 whan vinyl first hrxnrae firmly mrahlithed ua risk factor far ASL. Under-reporting is. therefore, lu fikely to be a problem after this date what serial anendoo began to be paid to the disease. Table 2 gives the age distribution ofthe 1II men at the time ofdfafncai*. The mean age at diagnosis is 52. Table 3 greet the number of cases diagnosed and the number of PVC producing factories in each of the 12 countries reporting at lean one case of ASL. Some countries have had cases in most of their factories (France. West Germany): others have had cases clus tered in s snail number of factories (United States. United Kingdom). Indeed, the United States has had 23 of its 33 cues in just two factories. Other countries that produce PVC but have not reported any cues are shown m table 4. Table 5 shows the numbers of case by time snee first exposure and maximum exposure time possible. It seems that the incidence of ASL reaches a peak 20-29 yean after first oposure but substantial num bers of case may still occur after more than 30 years. The table also gives hypothetical numbers for expected new cases based on the distribution of cases in men who could have experienced the maximum latency period. These calculations show that the occurrence of vinyl chloride related ASL fa not yet at the halfway stage and one might reasonably expect another ISO cues or so with an unknown number of farther cues occurring 35 years or more after first exposure. Table 6 shows the principal occupations of theJII effected nm At least 43% ofthe men (51 /118) had been --gg autoclave cleaners, an occupation that has been thought to have necessitated the highest exposure to vinyl chloride monomer. The reassuring feature ofthere results is that the num ber ofcun on the register is so mail, and, in partic ular. dial only10 new cues have best diagnosed since 1975. despite the large size of the industry. In the decade 1975-14. 19 cases were registered from the United Stares sad seven from the United Kingdom. In men aged over 15 about 3300 deaths a year are attributed to all types of liver cancer in the United Stats and about 550 a year in the United Kingdom. Many of there cancers are probably rec- Table 3 Dtnrgattiom sfmrri ddaridr rrietrd cases ofmsgit rmm ofliter by ternary. fNmmber offactories with duet Ciww Na aftma Sa afjmttmm Tm* Na afjacmwt fVC br--nra Prt-nea IMMSttw ~~--------] C--Sa Until Kiaedom Sms llah Yufntavia J-earn tOfiMM AS laiimriw report (w 33 2S IS 10 7 3 4 4 * r%e T US 10 (J) <3* 3 U 1 (1) 2 (!) 1 U) 4<--> tm ii--) n--) 11--i 11--j 34113) 44 0 7 4 2 II 3 31 T 122 21 7 3 3 4 7 2 l 7* mi hiiowmtt pte pradueimi a year ilMonmiiwi wpplwd by ICI ami by Mn|wi* at Ue n|mw|. Gipmy* m 1972 2070 1133 427 U 302 103 771 to 4S 1097 199 43 7442 RSV 0018859 752 Forman, Mermen. Stafford, md DoS Tabk 4 Cornu-m eritb PVCfoctorin operatioaot before 1974 o*b (mi repoittd to iwgister Ci i Iirj TeedHeef/enertrt Pn-mt Pre-ntd hoar* Anft 4 mum PMaU Crawa Hehaed ***** Span Sraahd Cwm Any* Catena lew C --iij Hea*dt hM USSK See* .tewto AcMdte mam c--m Mtoaraniae late X t 3 1 4 t t 2 t 2 9 3 3 2 t 2 3 t Ibyldaedbyi \ 1 1 3 1 _ 2 | 1 4 1 3 2 1 oodary fiver cancers originating m other organs, par* ticularly a men over 40. but if this is ignored it appears that only about 0-06% of Ever aacm in aduh aen in the United States (19/3300 x 10) arc attributable to vinyl chloride and about 0-13% in Britain (7/550 x 10). Two pieces of evidence suggest that an extremely high exposure to vinyl chloride may be needed to induce ASL. Firstly, the fiat that so many ofthe cases earn among men working as autodave cleaners in which da highest exposures arc thought id have emui ad: it was in these jobs that employees some* Table 5 >31 1994 ft times became bint and unconscious before the 1960s. when the main concern about vinyl chloride was its narcotic dfact Secondly, in some countries there b a remarkable clustering ofcues into a small number of factories This uim hi that the working conditions and hygiene standards varied in different factories. Fifteen of the 16 Japanese and 19 of the 28 United States factories operating before 1964 have reported no cues, and it would be helpful if it could be shown that the exposures in these factories was appreciably kss--unless, of course, da number of employees in these factories wen aO very It is the rarity of this th has enabled its rapid identification as an riea of iipnsurr to vinyl chloride. Butter r ot have ericnlaied that the back ground madcaps of ASL as dm United Kingdom is btrerxu two and mven mass a year that is. ones unattributabk to exposure to vinyl chloride or to tbo- rotrast. the ocher established aedologicil agent.* That bring so then the seven mdustriai.mms in the *--~-** 1975-44 r?|in x iir an mmasr in the utional figures of between 10% and 35%. The mean induction period (time from first exposure to initial diagnosis) for the 118 cases is 22-6 years. Most cues have attained 15 to 29 years after first expanse u a common with occupationally induced cancers. There are also, however, suhstamisl numbers ofcases occurring after longer time intervals. IS having been diagnosed 30 or more yean after first exposure. This means that new am are fikdy to be diagnoaed well into dm 1990a even ifit is asswned that exposures r signifiaab^mdiioed in the mid- 1960s when dm first m^or bapr/vaxau in standards of hygiene were made. The mean induction period ofthe cams currently on the rejpsur (22-6 years) must there* W '*<4 - tedetotod by yinJbomfuel i 1 to idtfi ekldride totem period), (ttmmher ofe flaw. ***> open ml! Qeintear M4 u 30-34 29-29 20-34 19-1* a-u Tecal *Nwater afcaw tiwapwieoarriili 'frem ifcrr redeem* to far efdoomed J- J- --2 _1 ,* m 3 12 1 12 o acne almlaad by ateairtthw f 19- 20-- 2S- 30-14 Tetdwmtm JlPMt iSfotre 1 . 4. W 19 2(+7) n<+ri ia 12 s 2(4-29) (IT) 32 (-442) 12 1 4(+n (+m (410 23(494) 7 1(44) (4)0 (422) MW (414) (<490 22 2T (44) . 23(410 21 (4*t> 3(434) (4lH -11014139) ? S(4?; I monin oiaw m H aepcawe aweary tfoatr ptrvtow k for 2S-2S *awaewant wpoaaf*ari 29-29 yn--awwhiwry OTTTTITTSTCTJI a (I2*T) 21 a 19 - I3J As Cm* cmm tea ibanli tern itemnnri r af ant wan to te opate man] a* wteiterite hazard cfaieytdUendc ia (hr Uuw a awaiter an tit tetaaiy tewaawWa 1904 a> ba dmaadem RSV 0018860 Lxposwt to amrt ekioridt md angiosarcoma of the if*rr 7S3 Table 6 ArcwdM wnfuiu ASL eon * mguur Ha* Fiwdsbea iwrkstepsswr A--dm sue flittMi Bnittl^BttlttfiMflF Otbwjebs Uitast a* SI 11 17 IS* A* mrai a^jw ma mom Omm am tab imetiad far item. taMteifenrtfitlll fere be expected to be materially tncrrssrd with the passage of tune. Any method to sness the number of expected new am a likely to be anpredse. Our method amply looks nt the proportions ofcum with different latent periods and*makes projections baaed on the distribu tion of ones that have occurred within different peri ods of maximum possible latency. In the absence of any information about the numbers of exposed amployemk is all that can be done. The results suggest that another 135 cases are fikdy to be diagnosed within 35 yuan after Ant exposure. Compared with the 110 asm in this rotcgory (tiagmrtrri so far, this means that the industry is approaching the halfway stage in the appearance of ASL The calculation of 155 more cases within 35 years of first exposure assumes that the hazard was essentially eftminacad in the late 1960s. If it was not a further 50 or 60 roses (something slightly less than the number expected to haw been mduced is men who could have been observer! for only 15 to 19 years by the end of 1984) must be added to the totaL Further cases must also be expected to occur 35 or more yron after fine nposure but it is, u yet, virtu ally impossible to esrimate the number to be expected with any p--It could, however, eerily be around 50. We nf" therefore, that it should be assumed that there sriD be another 200-250 deaths from vinyl chloride related ASL over the next 30 yean. This estimate is in pronounced contrast with that calculated by Nicholson et of who suggest that "within a lector of 2 or 3" there will eventually be a total'of350 ifniht (torn vinyl chloride related ASL in Ok United Stales and 1200 ill Western Europe alone.* Nicholson h of used a complex model to deduce these figures baaed on the assumption that the incidence of ASL at any point in time tnoeases in proportion to (0 the first power ofthe product of the population at risk and the degree of exposure and (ii) a higher power (most probably the third) of the time since exposure first occurred.* Knowledge ofthe distribution ofasm recorded by the National Institute of Occupational Health and Hygiene (1982) by year of first etposure and year of occurrence, the amount of vinyl chloride produced. --**m--* avenge exposures at work at different periods from before 1950 to 1970-4. and oortnal national mortality rates allowed them to make approximate **"*" of the variables in these equa tions and hence to calculate the number of cases that might be expected to occur in the future. Only rime will show which of the two methods will give the better wiumm of the number of rose that win eventually be observed. We are encouraged, how ever. to think that the lower estimate may be the nearer as die -rtfrr1 of Nicholson ti ai predicted an insense in the annual number of roses after 1979. whereas the number recorded to date has declined from an average of 9-2 in 1975-9 to an average of 6-8 in 1980-4. The tatter figures will, however, almost certainly, be mini upwards in the course of the next few years owing to delayed repotting. * Vfafc PL. ""`-Iiuji at amyi ttioridr, Mfa IFTfed(:fT4:S0. * MOW' C. OhsmmmI esaaofmteis ted lasrmfinnat Syw- paua oa Camr DMemik Fieiwuui. lotnfre. 1*74. Ik Adtmem k War pmn, dmcHorn, ad cUmnwlH Vat 1 A--iSkk tin him IHitra 1*77. * Cwcb JL. Mwm MW. Aowmi a(the Ew ii the mow fawidFVClOwMiW I*74;l4tl-M. 190-L. * MaJtaai C Lduaw G. CeraBOfcnncy btoanys at vteyt Sl ride. mmmm la l*74;TJ*7-40S. * leraee AW. Vfayl blonde wd (he prafaaiM at PVt eidsitffa XeyteSsWry ytete-is l*Tfc**-.2T7-. * Fee Ai. Cotter PF. Mortafity etyeiaet at works* eepaeed w ijejil rMnorte msiwi is ill seniifwiiei nf |idjiriwyl rtitnrirte ie Greet mete, * / Jte terd I*T7J*1-IB, 1 belter FJ. Aetheiy PP. MtOew RNM. Srheier FI. Aapownwan Ot (hr far. Madras aid eeuatep q Qtst gritein. d / ted ited t*nfcJTt}-21. * Nedotes WJ. IIim ilii[ge [ PK. Terr O. Trade ia oot mor tality asaag worhan ia tte eyaibrac pteywm iadaetry. Ik >merr* tesdt <^>farm m d jyttetfc rhwwn. Mew York: Lk. ISS4.-S5-7S. RSV 0018861