Document 2VJwrB29KGa29rqzkMBq0jo5

DCHN'S t MVWlf. THOMAS .1 MV<" * W. OAnMCM NUMAY aM**CO T. MUOMAT OCNMIt t HVI*T. jm. WWLMAM n. oaatl* MCH. M. oahochc I IIIATT M CeCMAAM. .*. Murray & Murray * ixoal M*erciONAb associatiom ATTOANCTS AT L.AW 00 etWTAL MNWt SAMOUSKV. OHIO 04070 Arrow* i samwtcb to --ctck m rcBCAM. eowro --e WTwCCOUTKOf owe, MtiMOAM. AstfcCTQ COUIllS'k CCKWMftO. fwOAlp, MM NCWTQH * SmTToOoWhaCaI nAMnOcCtftOWFMTXOOAAtAoLmC CSwiWff aovocato July 19, 1968 (*`S) 627-0700 f Robert A. Bunda, Esq FULLER fc HENRY One SeaGate, 17th Floor P.O. Box 2068 Toledo, OH 43603 In Re: Dendinoer t Wallace, etal.v^ Chrysler. et_aL Dear Bob: Pursuant to our telephone conversation yesterday, this letter is for the purpose of confirming your agreement to provide me with all of the articles and other information upon which Dr. Doll will base his expert opinions on the day prior to your taking of his deposition. Please be advised that I would like to review all of these materials at Dr. Doll's office beginning at 1:00 p.m., London time, on July 25, 1988. This assumes, of course, that the District Court will overrule my motion for a protective order and allows the videotaping to go forward on July 26. Very truly yours URL 11692 KJDB:sg v CAHCFR DEATHS AHOHG FORMER. WHITE HALE. CHRYSLER PLASTIC RROOUCT C0RPQBATI08 EHP1.0VEES Respiratory Cancer Observed Deaths Expected Deaths Coat ing/Finishing (Wa 11 ace) Inspect!on/Shi png (Dendinger) 4 2 1-40 1.17 total 6 2.57 Other Cancer Observed Expected Oeaths Deaths 3 2.47 5 1.95 8 4.42 Total Cancer . Observed Expected .Deaths Deaths 7 3.87 7 3.12 14 6.99 69 man l A ftediclna del LavowF Jl March 1970 (VoX. 61, n.3.1970)1 176-179 .PLAINTIFF'S 1 PLAINTIFF'S I I PLAINTIFF'S EXHIBIT I 1 EXHIBIT O*irM*\*l0 I I WKerier-H i-'-PlAINIVrSi IDCHIWt^ ".CfctifcAui ,r 1 MauittMaiauMivee. letitut cli Patologia General dall'Universlta di Perugia . Direttora: Prof. A. Caputo * PATHOLOGY OP VIKYL CHLORIDE P. L. Viol* "* URL 11694 During the last year* a syndrome characterised by alterations of the skeleton, teguments, nervous system and hepatie function1. 2, 3, 4, 5, 6 been observed among the wortenen associated with vinyl chloride polymerisation process. An experimental programme has been perforat'd in order to evaluate the toxic effect of -vinyl chloride on the animal organism, and in order to try to reproduce in rats the acroosteolytic lesions observed in man. MATERIALS AK> METHODS Twenty-five Kistar male albino rats, of average weight 150 gr., were exposed to vapours of vinyl chloride 4 hours a day for 5 days a week during 12 months. The animals were kept in a plastic air-tight container through which there was a constant flow of air containing 2% in weight, equal to 30,000 p.p.m. of vinyl chloride. At the end of treatment the surviving animals were killed at twenty-day intervals, and the paws, brain, liver, kidneys and thyroid were examined histologically after fixation, `inclusion and colouration by the ematoxylin-eosine. Van Gieson. PAS, Weighert, Bielschowsky-Gcmori methods. Twenty five rats of the same breed were set aside as a control. RESULTS During the period of exposure the animals were slightly soporific, but the first few months of treatment were well tolerated and the rats showed no change in body growth or behaviour and no organic alteration visible macroseopically or by radiological means. After ten months some of the animals began to show a decrease in weight., in agressiveness, in their reaction to external stimuli, and often a disturbed equilibrium. Thirteen animals died from cardio-respiratory complications. Two animals died from hematoperitoneum. Most of the animals showed pathological involvement -2- PathoJoav of Vinvl Chloride p. Ii. Viola * . .. of the brain, liver, kidneys, end thyroid. 6ix rats showed histo** pathological alterations of the skeleton. ' The small metatarsal bones showed an extensive periosfal proliferation of cartilage-like material apparently originating by metaplasia directly from.the bone. All around the newly .formed cartilage*the cellular components ware compressed and arranged tangentially to the cartilage itself, forming a perichondral layer. The isogenous certilagenous groups were irreg-V . ularly arranged and their nuclei were of varying sise and often number per cell. The edges of the cartilage were irregular, showing digital extroflexions resulting from a varying growth potential. Thera was also evidence of chondroid metaplasia in areas of mature compact bone, in which the cartilagineous elements were grouped around a central nucleus of bone, as in typical osteochondromatosic processes.. In the small bones the. chondroid metaplasia was often vary extensive end the boncts seemed to be impregnated with a mucoid substance Which altered the characteristic disposition of the bone tissue obliterating the. cement lines. The skin ef the paws showed areas of hypexkeratosis superficial thickening of the epidermis, vacuolization and degeneration of the basal layer, disappearance of the cutaneous adnexa and modest accentuation of the papillar layer of the derma. An almost constant state of edema was observed in the epidermic zone. The connective tissue showed dissociation of the collagen bundles and a diminution and fragmentation of the elastic retic ulum. The small arterial vessels showed signs of endothelial fibrosis with a thickening and dissociation of the elastic membrane, often accompanied by a partial hyaline degeneration and homogeniza tion of the walls and proliferation of the endothelium. Some of the vessels appeared completely blocked by a proliferation of the connective tissue in a formation not unlike that of onion skin. URL 11695 The small nerve bundles were often surrounded and invaded by fibrotic processes. A microscopic examination of the brain revealed diffuse degenerative lesions of the grey and white matter. The external granular layer was often reduced end in some areas this was true also the medium sized end giant cells. Kumerous examples were found of hypercoloured, atrophic*neurons with disappearance of the. nucleoli end sometimes also of the nucleus itself. At the level of the white matter there were tones ef intense, reactive gliosis consisting for the most part of cyto plasmic and fibrillar astrocytes, some of which were arranged in a concentric disposition around the blood vessels. There was evidence of neuronal phagokaryosis with satcllitosis and the deposition of neuroglial elements around the altered nerve cells. Pathology of Vinvl Chloride P. i. Viola There was modest proliferation of microglial elements, especially in areas of more intense gliosis and zenes of intense spongiosis showing an accumulation of astrocyte-type elements with.basophiiic cytoplasm and abounding in gemistocytic and microglial elements .similar in appearance to ."scavenger" cells. The cerebellum .showed signs of atrophy of the granular layer which was often ^represented only by a few isolated nuclei. The layer of Purkinje `cells was in some places profoundly modified, the cells appearing to be undergoing intense degeneration and all the various stages of this process were, observed, from the whole cell to the small' , homogeneous bodies with indistinct outlines which represent the most damaged form of the cell, except for mail and limited areas, the molecular layer seemed to be well preserved. he liver was often of increased volume, sometimes subicteric in colour, with a smooth surface and somewhat more brittle consistency than normal. A histological examination showed in the majority of cases signs of diffused interstitial hepatitis with numerous hepatic cells in the grip of regressive processes .varying from torbid degeneration of the cytoplasm'to necrosis with marked cytoplasmic and nuclear polymorphism. Some of the hepatocytes showed giant or double nuclei. In these areas of cellular necrosis a corpuscolar exudation was always present consisting of round cellular elements of the lymphocyte or plasmacellular type. There was evidence of an abnormal proliferation of the Kupffer's cells, which were often hypertrophic. The triangular spaces appeared to be increased by the infiltration of round and polynueleated cells and eosinophiles showing marked polymorphism. The portal capillaries, centrolobular veins and sinusoids were often blocked by numerous centrally-located areas of partial necrosis, often accompanied by a diffuse steatosis in the form of small drops with clearly-defined areas of acidophile necrosis and the formation of elements similar to the round acidophile bodies of viral hepatitis and the "Cauncilman" bodies of yellow fever. In certain cases evidence was found of an intense fibrosclerotic reaction alongside the degenerative processes. The kidneys did not appear to be excessively altered by the prolonged treatment with vinyl chloride, although they showed signs of tubulonephrosis, sometimes accompanied by chronic interstitial nephritis. The thyroid often showed e colloid goitre and e marked increase in parafollicular cells. v 969 m a n patholonv Of Vinvl cnionge p. L. Viola The control animals showed no histopat-.hological alterations of the skeleton or of the various organs. __ CONCLUSIONS r This research confirms that the animals are sensitive to the toxic setion of vinyl chloride. The lesions of the bone and connective tissue are similar to those noticed in experimental osteo*latyrism and to those described in a man affected with acroosteolysis of ^ the hands (Marin) It should be pointed out that the roentgen- * ological findings of skeleton in man rests on cartilaginous transformation of the bone tissue. Therefore according to raccomendation made at XVI International Congress on Occupational Health of Tokyo (1969) 2 should like some precautions to be takdn in the manufacturing plants polymerising vinyl chloride# such as reduction of the threshold limit value of monomer# and substitution of manual cleaning of autoclaves by automatic devices. .SUMMARY The results of this investigation show that animals exposed to vapours of vinyl chloride may show degeneration of the skeleton and connective tissue with histopathological pictures similar to those observed in human acroosteolysis of the hands. The bones in fact undergo processes of intense periostium growth and diffuse, chondroidmetaplasis. The connective tissue is dissociated into collagen bundles with a reduced number of cells# the plastic reticulum is markedly reduced and fragmentary# the small vessels of the deep layers of the derma ahow hypertrophy of the walls with a diminution and sometimes obliteration of the lumen, the nerve endings are surrounded and infiltrated by fibrous tissue. Degenerative processes of the parenchyma were observed in the brain# in the liver and in the kidneys. NOTE: Figures on available copy were not suitable for reproduction. They are as follows* . \ ?. - \\ 4 t*` * a Fig. 1 -- Periostal proliferation of metatarsal bone of a rat 16th months old, exposed to vinyl chloride vapours for 12 months Fig. 2 -- Periostal proliferation of metatarsal bone of a rat, 16th months old, exposed to vinyl chloride vapours for for 12 months :v URL 11697 t i i i i i \i i ' rainoiuav ui vnu* V11 P. L. Viola I Fig. 3 -- Feriostal proliferation of metatarsal bone of a rat, 16th months old, exposed to vinyl chloride vapours for 12 months. Fig. 4 -- Chondroid metaplasia in mature bone of metatarsus of a rat, 16th months old, exposed to vinyl chloride vapours for 12 months Fig. 5 -- Chondroid metaplasia in mature bone of metatarsus of rat, 16th month? old, exposed to vinyl ehloride vapours for 12 months Fig. 6 --. Chondroid metaplasia in mature bone of metatarsus of a rat, 16th months old, exposed to vinyl chloride vapours for 12 months j . * i . :i \ y 7 \ ' m>:muuakiium r Nmn.Ur 2), mi TO t Dr. C. II. tVrtmM. KYO*4 Mr. M. K. Ki*nluNiv( M' Mr, H. I. lUnon. Ml Dr. K. O. Hull, IN Mr. O. It. Krill, SU Dr. K. S. |At. NVO-4 l>r. W. H. Mintdne. Ml Dr. A. II. Merle. NYn.SA SUDjr.CTi MsmiUrttirinc A**M'ilini rkiu|>ilinMl llfklll< friHuiurr - Vinvl <*.lilTiilr (Umlrttftrr % I .I t '^ C"tpnit wilt. internet in vinyl rtilnrirt* rf( invited < tern) rtprtirnlilirti | rnnviilrr the fAltnwinc: 1. ('nh< nf llid A(riwilrlviir K'fiMry Projrrnm. 2. lUvinw the rrjmrlr nf Dr. 1*. I. Vinla *n it>e <)rvi-|M|mi-nl vt lutM<r in file rapn,f| m vinyl (blrridr rM<Nir>mrr tr. 3. C.nnridtr ipninrm( * rrrenrcK pm?ram in llm II.S. t<> rs*>>rirm nl in (irovMe aildilinnil dtU in rVirtnr Vi|'* Mncly nrn. Titf prn|ted firoprunt ruld cent v|iriuiklrly J U0. lino ycr ytf. *1 aii>'kiI.ih< m-m l*;ln will, ^l*l In wj.)c pmtni. A Kill tin* nf l),o*i- AIIi-imIoii; will ! **'! Jalrr If MCA. ('*iliinalii.ii ,.( dm l**einlrf f**.grn \v*;. <1 In fl*t VI**" I" 'Ml * ! I,. <|*}imiiIn|; <mi h>; rM<C |,>.*.!. Tlcf r> tiA* rMI V I.<nr ..................... iihhiIIi* i., ilair. A f.rin Ifmlprl for- Inlurr |irr(iii writ. Hm iiw. IJRL 11699 ft t : ft Kormb. r IT) r Cllintlillf all |hi*c |trim{ rtprtiifil a desire to ccMinuc Hit program ntw mppAriH kf ibnvi ten companle*. Individual ccmpenie* will kt contacted far further atrthrrlMlIia f fund*. Hm* Carbide iliunlil cm. Ilnur la participate In thia program at laaat until the physiological effect! f vinyl chloride are halter defined. \ Di. r L. Vinla. el at af ll*r lleplna Rleia Inttilwte for Cancer, huttrek. Rome. tuly. iinaioreriitffltilny M^. etarted aui la viudy ecroealoelyelt and lie attendant Raynaud'* phenomena. He originally ettrud working with manktya amt later twitched la rate ttecauen af cnet and other faciare. Doctor Viola aepoeed rale in varying cuncenlreltyoe af acetylene derived vinyl chloride and noted the fallowing incidence af turner*: Vinyl Otleride Cwneenfrntlnn Ineident^ofJJmnaf^ in. <niq ppm , to. noofiimi ID. 0IM1 |tpn },iiii(i pi**** <S, ftOO ppm M% ao*. IS' tn.tj>* Some lumen (Dr. M. O. >.r>*cvrr, Snlvny M.C.. Held laier that thr incidence of tumor* in coMrel group* of ihi* atrain of rate vu $11.) Doctor Viola's initial work involving exposure of ret* to )0.0C<0 ppm VC we* reported at the Tenth Intemalinnel Cancer Ccnprtii, tt"ton. Tern in hlay 1JW and wae later published in Cancer Research. kUy 1971. The re* maining date le unpublished el thia lime. After the sppraraner >.f Hoe m r Vinle'a paper at the Houston mooting tntrrealed rompnnVee. including UCC. paid Doctor Viola's expenses (nr a tr*lin( in Washington on hi ay $. 1971. PubliaMnc *? Doctor V.l*`s in the U.5. lent to serious problem* with regard to (hr. vinyl rhlnfide mopnfrw i end renin induftry. TMtt ere a* follow*: Thr IVUn<!y iMirmliiiRnl bans the war of ny materiel in fond that can ai*e rmirrr. nI X. A law nii* in Iwnnaylvania banning rarritmeent from thi* oir: i. r, . thr allnwaltle thrrshuM limit is r.ert*. URL 11700 pll > I November 2). iqyj ), The prfum |w)ilicki clltult in lit* It. S. la awch that CMipiltA lif Mr. II. Ntdcr and othrri could lore* ik iMuitrUI upheaval vli new liwi nr etrlct Interpretation nf pollution and occupational hullli Uwa,. There her keen ka ftovernmani reaction tn Vlnla*e work. id date. The ACC11I plkni tn diitm It Ihi* week of their merlins. Dr* T. .ft. Terkleaon reviewed tle prepeitd ktf.A*|eMArt<l iiimtl rivdf. 4|tli |>r|Hnt inmWtd eepoeurc. if ret* n<1 mie* In three Invela of vinyl ctilorlde $*' concentration* S.dOO. I.Wtfl. end 00 ppm. The vinyl chloride would V* derived from ethylene end front acetylene.. The rtt aludy would rover 24 niunlha whilu the ilml}* would cover 12 month*. The cnet of the *uidy weam*iimeted tn hr 5)8). 000 by Indursr;*! nioleet. Chic-ego. Illinei*. Depending on thr reiiilm of (hi* ol*ly. an cfirirmrelppril ttvdy the IftduAtry could b required. 1/ vln^ l.rhlnfitlo were exonerated in the proposed tnimil rturiy. then n aludy of (fie effeetr of <Jt material on progeny might he .required. The need for two tnurett of vinyl chloride end the ehorsn cxpoiurc concentrations er questioned, but no action wo* token *i tM timt. 'Dr. M. 2. ]r*vrc. Selvay |.l. C. . diarusard the work of hU Company In Europe * well * hit ofen knowledge recording physiological e/iect* of vinyl chloride. Jtem^ of interest arc a* /ollm-i: 1. Rumanian work hwed ln% liver tnltrgrmtm 0* well *a a c reoatcolya It. Y.'nrknra lit S|in showed unnatural wr;aritr>. pnaaiMy indittling llvvr iiwelvrnicrl. Thia waa nol nnleil in Krenrh or llelglan wnrkrri. ^RL 117oi 2. Doctor Viola (nmol 2* im|ttirilir* in Iti* vinyl chloride im lmlinj: methyl rltlrrUlr. 'J'hia could be a major factor. yi i"\ 4 A tI 1 iI 4 12. 1*71 3* The bene (umori noted by ViAit wc i pr*lat|y trr*A*(rulyi. |We*r l#Krvvr aeen Insieiis In that Kn*' kml in Ih* pelvis a fra nf Urn bark. 4. N* I'rM'ilriilynii ht* keen (mind in ituwomtt md CMit|wuMl pia Ml wnrhers. N* iumvri in reactor dcenerA el Jfinlvey M. C ptsnle. 5. Doctor U*rf Ihenrlnne Kill vinyl chloride la ibaarbad In body iui and 1a urriad la Ike brain. It icli nn the centeri cnnlrnlllng rirrwUtien nf b]nvd la Ike entrcmliiee. Anlrleiian el Uif blind lie* lavica the ptl si Ike bant MriifUrri In move fr*m * anrmit bealc rssdllltn where inlncrsli ere deposited i an eridic eondi* linn ce^slnc raninral nf minerals frnin liie benea. Acre* naieelysis is reused by gfntral aipuurr end inhalation ei vinyl chleritlr; nn( jtial espnanrat of (he hand*. I, Dnclnr Visit'* work la lieinj di^rknl end expanded. ntrapesh Indira underway involve rKpotir of snlmsla i* ceurmirntiuna el 20, non, ID. non, 5.000. 2,000, SOfl. and peritap* lull ppm. Vinyl (lilrriilr. av<l "ill be a mixture ei in* acetylene and 10% ethylene dcrivrd. The afiernmin discussion eriEinally |ilaniir0 to rryanlrt industry a upperI for the MCA prnsrsm shewed lhai many juration* existed an<J would have in he answered llfnr, s program riMild hr presented iff industry, support. .Ivint of the principal items discussed were: I. Acciylrnn*baaed vinyl ililariilr innnniuer could pnaslhly he '! from the study rar^fi li< eanfirm Doetor Viola's wurkai ilit V non ppm >|nf{ irvcl. 2. |v*wer cwni entraiivn e*p,,"urr IfirU. suuliaaSri ppm. ahnuld clu-ilmd. S. The animal ludy pi*f*.tl *'i still (*! '.unplrlvly sail Suit H lt<il'l uni overlap tiir Kiirapr.au study mentioned by Ikncmr l<rvrr. 4. Human epWIvminlMcicsl studies si mu )>l lie made. URL 11702 > c"> VJJl . )' I'Op* 1 I. ft. 7. j; rrhOl *J. r All iAtlinlry |wmnri kmiH |M> ihrir pro rtli chart; but wkai i * pr nu >Imm^' The ri9rrMm,i| ilnmlil Aptmeor Ik* iludp l!vf if .....Mfdavmrahle. they |W dnw-n m {Hihtatry nf Cliil Vinyl rhlnridf mnnmnrr I* fall ml ImparUitl. and one f Ihea* ntMil k a cirrin*(a. Vhta ll kccimc tlul moro clndy required, an IwUnUf in study iImi problem* tiul make rrrmn>cndi> iImi la l)i Occupational llnljk OimmltUt of MCA. 11n committee itMiili nf: | 4* H. J. M'krkr. Jr.. Ckirnuit Union Garhldr Curporilinn Herman C. White. Mi. I). filirll Ckmird r.<ini|Miiv M. V. AnUicny Sutiifftr Chcminl Company URL 11703 The Committee i In aeeh opinion* and iUia from induitry mernbtn and lomecl with Hr. K. I). .lohnann. MCA Aaririant Technical Director* Occupational Health, on December M, 1071 to prepare a program. The Cummillcr in In recanimem! a program induatry win awrport and.recommend prncodurca fur, funding the prueram. Qucdiona n( study acope. aentylune va ethylene derived vinyl chloride. and significant Im* puriliea in vinyl chloride will hr reawlved. The MCA will survey n.mtl.rri nf U- huUiairy regarding ilirir willinpitcaa In aupiuirt a yicn.OIH! prr yenr sandy will, erpt* allneMetl t * ipnnian Ua*ed on publish'-d lapi.'liifi nf ami pn1yiMr. htnnn.ner proriuerr* Kill hr ashml fr representative Miilyic* if tl.r.r mnnmner and llielr motlmUs of analysis. AaauMtiiic i'M'J iniliintr) |urlii'i|*AlMHia Union Carbide** aharc of the program enal It* apprnaimatrly per year. Thif rosl ahnultl he ell her Imme dire, tty l.y I It.* <*>*( raf inn *r eha rend in Vinyl Ke Ine. Dyne]. Amt h'lufOta rl** p,<fi< renters n the IvAii. nf their vinyl riilnride Consumption.  Papa d* l'2vCMtb*-i ij. J97J t ktttd tMiii M<vln(i I. Tht Muftty H*i a ruiMmilliilUf !* lu rwi>lyt *ul (uilemeri In take any np.fMtir rtii^n 10 pralacl (kfin. |in{"ft Ctrhld* Carpnrailan I* a tfftpontlblt mimkir mt that Mutlry and will kir Iti (hire ( Ihr cast. f\ ^2* tlalan Cirkldf )ai a fare* atakc la ilia tui innt j llbalf ta b ilftcttd ftdi i land, land (wrk|ihc, 'te'. fiber, iad mviiiIi nd w*ld bt aerlauilf hart by arbltra ry f k. UnUn CtrUilt ha* a frikthara *f hftvwktAtc and tittrltnee Ikat t*a ailil |p the ivtcr.i* a/ Hit ^rp^ied *tudy anrt Ihal can {uidt Mtk a ilndy to rcnoned crjicluaion*. URL 11704 KNWJr/ra PLAINTIFF'S EXHIBIT*--< &&h? u mm imtea PLAINTIFF'S . EXHIBIT CAKCEROGEWIC EFFECT OF VINYL CHLORIDE P. L. Viola (Regina Elena Institute for Cancer Research) Rome, Italy ___ Presented at the Tenth International Cancer Congress Houston, Texas Hay 22-29, 1?70 *1 1 E*. t lifcSi'; FIAINTIFFS l^-pCHiBIt ! ganceroacnic Effect jpf Vipyl_Chlori_de p. b. Viola pumors of the respiratory.tract Even if as far *'*r**tge is concerned these occur in a smaller numbir, thei? .t;-. **ic appearance is mainly'of an adenocarcinoma; only ir. tr..: ml -1 nas been observed a tumor of the epidermoid.type. ..v-* /:;*" . tumor showed an .earl developmental stage and cor. .eminently of cubie o: columnar cells arranged as i*-. a- ui irregular tubular and papillary elements supported by poorly developed fibrous stroma. Tutnori of the bo^es - ., . ' . * ' s Zn the metaphysical region of the four limbs a large proliferation of cartilaginous tissue arises outwardly to the periostitm and seems to derive directly out of the osseous cortical by the growth of its cells. The cartilagenous growth is dishomogeneous as it is shown by the extension of finger-like prolongations into the boundary of neoformed tissue. Beside the chondroblastic, chondroeytic and angiomatous areas, manifestation of noticeable growth power, there are cartilaginous zones with regressive features, as fibrosis and hyalinosis. The results reported above indicated that vinyl chloride is an effective carcinogenic agent for the rat. As for many carcinogenesis studies, where multiple tumors arise at different sites, in different tissues and organs, the data obtained need to be evaluated considering a more prompt positive response according to the ideal concentration of the carcinogenic. It is noteworthy to emphasize that the cutaneous system represents an impressive pattern of susceptibility to the vinyl chloride. Another point to be considered ie that all the cutaneous tumors developed in the same site, i.e., the region including the area in which submaxillary and parotid gland are located. .Ho implications to human pathology can be extrapolated from the experimental model reported in this paper. v EXHIBIT 3i.s^sfwr!?7ir i J Oncogenic Response of Rat Skin, Lungs, and Bones to Vinyl Chloride1 >, L. Viola, A. Bipotti, and A. Caputo iegOm Dim iaxkmefo* Ci*Hr ftoawdk, Home, tmfy PLAINTIFF* EXHIBIT,* row* ***? a* PLAINTIFF!* [EXHIBIT ihiinKBmrss SUMMARY to vinyl chloride follows s singular l^amm for the difftn^ tissues and organs of the rau IUu (ArflRE Wuur strata) txpoaad for 12 month* to vapors of vinyl chloride developed tumor* of the skin, lungs, and bones. The cutanaous tumors, which alwiyt appeared la MATERIALS AND METHODS the am in which submixiUary and parotid glands are located, have been histologically recoptized as epidermoid carctaomas, papillomas, and mucoepidermoid carcinomas. The morphological characteristics of lung tumors, which occurred in a lower percentage, were mainly of the adenocarcinoma type, with the exception of a single epidermoid tumor originating from the epithelial covering cells. In a minor number of rats, a Urge proliferation of cartilaginous tissue diagnosed as osteochondroma developed in the metacarpal and metatarsal regions of the four limbs. The experiments were performed with vinyl cKanS (CH*QiCI, the mooohalofcnatc derivative of ethylene; e$ commercial grade (99% purity)' assumed to ccs insignificant amounts of various noncarcinjjeT? contaminants. 4 Three-month-old Wistar (Ar/TR) male albino rata (sbwi 150 g body weight) were exposed to vinyl chloride vipers fo: 4 hr a day, 5 days a week, for 12 months. The animal: wen kept in metal or plastic, air-tight cages in which a cotsuSl flow of air, containing 3% v/v (equal to 30,000 ppm) of risri INTRODUCTION chloride, was introduced. Twenty-five rats of the same risa were the control group. At the end of the treatmer.i, 'tt The oncogenic properties of some chemical organic compounds used for the preparation of "plastics" have been widely investigated,! and their limits and effectiveness have surviving animals were kitted at 2(May intervals, and the mo2 important tissues and organs were examined histologically by standard methods. During the period of exposure, the irinai were slightly soporific; however, the first few monvvj o' been well established.. Detailed information on this subject treatment were well tolerated and no changes in pow.h a may he found in the literature (5, B); however, all behavior were noticed. After 10 months of treatment, sotre information and references are exclusively related to highly animals began to show a hard mass in the paraauriculir repo: polymerized compounds of roughly the same size as used in which became progressively larger until it reached the the of various industries. walnut or slightly larger. In most cases, the twellinj wi Oneogenic polymers produce sareomstous tumors, with the unilateral; It was bilateral in only s few animals. After I or exception of polyurethans which, as reported by Hueper (6), months, the growing masses became ulcerated and duc^t-T also induee adenocarcinomas. Recently, It has been demonstrated that sarcomatous turnon (1-4, 7) are transplantable, and It has been suggested that they may originate from the (issues of the capsule that gradually coven the plastic Him. Thus, Brand er mi. (2-4) have observed premalignant areas made of poorly differentiated fibroblasts which were firmly attached to the plastie film up to the moment of malignant transformation. This Invtsliption demonstrates that even the monomer vinyl chloride possesses oncogenic properties when used with necrotic debris, while a certain amount of tumorous tis* began to form on their surfaces. In addition, we ebrnvd th the mases were an Integral part oT the paraaurieular regie and eould not be distinguished from the local tissues. Ctwo necrotic zones were found. Pleura and pericardium oft showed diffuse inflammation of a fibrous nature and, ir mu cases, the lungs were covered with a number of wh. formations as large as pains of rice or even larger and sard than the hings themselves. In 2 cases, the lungs * hemorrhagic with milky, thick fluid in the pleural cavitia T an appropriate model different from the models previously liver was sometimes increased in size and very fragS*- T reported by even) authorsg-12). The carcinogenic response animals were subjected to X-ray analyses at different ir.rere from the beginning of treatment in order to control the 1A preliminary reperl of (he remit* reported here (>** at the Tenth Inicmaborvai Cutti CMptu, Houston, Teams, May 22-34, 1970. Received July 197Q' ftcie6 January t2. I97j of the skeletal bones. ** 3 All the animals that inhaled vinyl chloride showed 1 *? of parenchymal lesions. Among ihese, most promine'r.: w th^di&appearance f yanular and Purkinje cells, degenmt CANCER RESEARCH V"L the cerebellum, severe chronic hepatitis, interstitial Warty subaurieuUr growths occurred in some rats. The mfnyinonii, and moderate swelling of the kidney parenchyma, histological picture showed papillar epithelial proliferation, Ufien assuming the pattern of tubuloncphrosis. with progressive increase in (he thickness of the epidermis j^SULTS (FiM). The papillary warn of exophytic type had a fibrous vaseular Stroma and various degrees of Inflammatory luaphocyiie The ntes of survival and the main findings on summarised 5fTsble l. Almost all the animals developed tumors of the and lungs. Very few animals developed bone tumors; in 'cse cases, the tumors wen localized In the metacarpal and gatsianal bones of all 4 extremities. Skin tumors were by far Ac most frequent, amounting to 65 or 70%. rat | VSkin Tumors. The tumor that developed most frequently in Ac paraaurkular ngion was the epidermoid carcinoma, but we Uo observed papillomas and nrely mucoepidermoid lareinomas. In atl cases, the neoplasms wen of epithelial Stun. The 3 patterns noticed cannot be compand to various Uttorypet but nther to a transition of one type into the other Ik, end which is move likely, to diffennt stages of the same j^obfcrtlivt type. infiltration, marked hyperkeratosis,parakeratosis, acanthosis, and anas of Individual dyskeratosis or pcarMike horny formations. * The epithelial cells of the penetrating columns (Fig. 2) were Irregularly arranged and wan frequently accompanied by an Inflammatory infiltration of the dermis. The typical features of the Malpighian layer and of the stntum comeum of the prickle cells and of germinal layers wen casiy recognized (Fig. 3). The homy layer was composed largely of cell nests, which appeared at certain points within the epithelial masses and assumed the well-known appearance of "homy parts'* (Fig. 3, arrows); they wen made of flattened and compressed prickle cells without nuclei and wen located around a central core of Itdratin. ^ Table t r Ontogrnh tfftett ofMohti viny/ shiondt m t function oftin* I The animals were iipead le vinyl chloride vapors for 4 hr day, 9 4ay a week, for lout of 12 months, A a eonstent flow of air conteming J% Wv vinyl chloride. - Tumorr Rat Survival rate Skin Lungs Sonet J 3.3 4 5 ( 7 t 14 16.17 31 33 3} 24 25 26 >00 310-300 310 333 337 347 347 334 359 >iio MO MO sto 3S0 330 Mucoepidermoid carcinoma Epidermoid arcinoma, kentiniiint type Epidermoid carcinoma, km* tinisinc type Papilloma, fcemiotie type Epidermoid earcinoma Epidermoid ateinoma Mucoepidermoid ateinoma Epidermoid ateinoma Epidermoid ateinoma Epidermoid aictnoma Epidermoid mrcinoma Epidermoid areifioma Epidermoid atcinoma Epidermoid ateinoma Epidermoid arcinoma Adcnoaanthoma No fumor Adenoatcinoma No amor No tumor No rumor No amor No amor Adenocarcinoma No amor Adenocarcinoma No amor Mucus-produeuig adenocarcinoma (alveolar all carcinoma?) No amor Seuamour all arcinoma Osteochondroma No tumor No tumor Oiteochondroroa Oneodiondroma No amor Osteochondroma No tumor No amor No tumor Osteochondroma No amor No amor No tumor No tumor s son nun H- .197] 517 fm U. Viola. A. tf/gnni. and A. Capnto Kerstinization wu irregular and often parakeratosis was cartilaginous tones possessing regressive fcaiures. such ebiervtd in the areas of (he ttimor in which (he cell* were fibrous and hyalinodt. The perichondrium appeared often a* ,f ioowly it|re|iitd and undergoing an individual tathet than a compressed and structurally altered fibrous lissue. _ collective type of kcniinizatlon (Fig. 4). In dyikeritoiic areas, In some esses, the tumor growth was related to the stage of? few epithelial cells tended to form pearls. The tumor seldom the endochondral eaificalion occurring betewthe "epiphytal! showed an ondifferentiaied growth with cellular plate.** Ossification was irregiptr, so that osseous trabeculaef pteomoiphism and several mitotic figures (Fig. 5). A few varied greatly in thickness and contours. In other cases, foci oft tumor* showed tittle nests of belated pale cells (Figs. 6 and 7) active caliular proliferation. Cartilaginous areas, chondroidj of 3 types: mucinproducing cells (originating from the duct developmental nests, and calcified bones occurred in thjj epithelium of sweat glands or salivary glands); squamous celts; deeper portions of the trabeculae (Fig. 18). Z and intermediate cells with minor tendencies Cowards The new formation appeared to be an osteoehondromi and* differentiation. conristed essentially of a bony protuberance capped bn Respiratory Tract. These tumors, although occurring rarely, cartilage and a fibrous layer, q^hieh eepresenied thjj were mainly adenocareinomatoua. Only in 1 rat did we observe perichondrium. an epidermoid tumor originating from the ephheiiumovering The fibrous layer was continuous with the periosteum oa celts. Sometimes, the tumors were seen in their early the adjacent cortical bone and extended inward to form sepuj development and consisted predominantly of cubic or separating and enclosing lobules of cartilage. j( columnar cells arranged as regular or irregular tubular and Control Animats. The control rats wart kept under the sun? papillary elements (Fig. 8) and supported by poorly developed conditions as tht experimental rats and at the appropriate iim? fibrous stroma (Fig. 9). were subjected to a constant flow of air without vin^ In other esses, glandular structures were often imperfectly chloride. None of these animals developed tumors or the typer formed and appeared n sheet-like proliferations of of parenchymal lesions developed by the rat* that inhiiri undifferentiated or pieomorphie character. The cells showed a vinyl chloride. In a very few of the control rats, there was! tendency to extend into the pulmonary parenchyma, thus swelling of the liver and kidneys. simulating (he microscopic features of the so-called alveolar 1 cell carcinoma (Fig. 10). Sometimes, this was the prevailing patiem. The pulmonary air sacs were limited by 1 or more DISCUSSION layers of cubic, columnar, or polyhedral cells with abundant cytoplion that was faintly eosinophilic (Fig. 11); frequently, A* in many eareinogenesi* studies in which multiple turnon denoptpiUaiy excrescence* spreading into the alveolar spaces arise in different tissues and organs, the data must be evaluated were present. in term* of a more prompt positive response to be obtained In some areas, foci of cellular polymorphism with with the ideal concentration of the carcinogenic compound hyperchromaiic nuclei were noticed; mucin was produced in The eutaneous system is the most susceptible to the oncogen* vaiying amounts and secreted into the lumen of the tubules effects of vinyl chloride. $ and acini. There were small pools of mucin In which signet ring Our experimental date do not explain why the eutanrou cells occurred, cither alone or in small clusters (Fig. 12). The tumors developed in the same site, ic, the region indudin jjveolar walls were often quite thick and, at limes, showed an the area in which the submixiliary and parotid glands at inflammatory infiltration. located. It is possible that the salivary glands may by involve As mentioned before, a single tumor showed squamous in the concentration or excretion of vinyl chloride or sor-e c tinctures and appeared to have been formed mainly by iu active decomposition products. This hypothesis is strong' spindle and oval undifferentiated cell* (Fig. 12). supported by morphological findings showing the spf:if Bones. In the mctacsrpal and metatarsal region* of the 4 tendency of the developed tumor to appear as 4 limb*, a large proliferation of cartilaginous tissues arose mucoepidermoid carcinoma, which indicates the a:tr outward from the periosteum and, from the appearance of its contribution of the mueus glandular cells to the tumoro cells, seemed to derive directly from the cortical bone (Fig. growth. Such kinds of hisiotypes are often related to son 14). The periosteum also grew and in some sreas spread as glandular aggregates, and, therefore, the histogenesis of hum. finger-like prolongations Into the newly formed cartilage (Fig. mucoepidermoid carcinoma has been restricted to the ceils 15). In these places, a gradual transition between fibrous intercalated duets. This hypothetical interpretion mu*: cartilage, periosteum, and bone could be noticed. confirmed by future experiments in which the action eft The newly formed cartilage appeared irregular with atypical vinyl chloride should be restricted to the salivary system.-; areas; the cells, which had nuclei larger than the normal the concentrations used, saturation and wetting of the i chondrocytes, lay in well-formed, capsulsted lacunae. The cells might well be expected. Under these circumstances, l occurred singly, in pairs, or in tetrads and, although of natural cleansing habit of the rat might add a signify different site and shape, (hey usually contained a single, ingestion problem with subsequent concentration of w dtrkly stained nucleus. The cartilaginous growth was not chloride in the nlivary glands. The local ex:* homogeneous, as shown by the extension of the finger-like concentration could be the result of the difficulty o' prolongation* into the boundary of newly formed tissue. complete cleansing by the rat. Besides the chondroblaslic, ehondrocytic, and angiomatous The neoplastic response of ..the lower respiratory :n areas which indicated a rapid growth, there were also although of lesser magnitude, is of relevant interest, sine: c 5ll CANCER RESEARCH VC-C 33 too S, well 4\ J often os* thttispc *t "epiphysial i itabevubt l*f. ftK"f III , chondinid ued in ihr iht tumors were morphologically similar to those described jff.th* *kin. The hypothesis that mucus-produeing cells may ^'capable or retaining vinyl chloride or its decomposition Spdvcu teems to be relevant once more. Obviously, a JjTtrent interpretation is acquired for the pathogenesis of the tumors and for their simultaneous incidence at the level [fill 4 limbs. ferences mdroma and capped b> eitttci) tfcir tttorteam >! to form tept* ndn the tatm propriaic Umc Kfitfcovi vm>l nor the types S that tnhsle* u. their wi < rhMjtt, M.. end Bams, B. Pvevatenee Heiervpioldy ta Plastic ^filnMvod Primary Sirsms BriL J. Queer, 20; 553-541, 1934. G, and Bmm, L Nysnr Tumorigcnerit: Multiple rpRMoybitic Oenas in Prierttr Order *hk Clonal Inhibition. Proc. Eaptl. Biot Med, 721. 1131-1t5t.I94L grand, C., Ivwn, L, and Brand. I. Malignant Tranifarmatieii and iiiuaiiN in NsadWdMH Cells during Potymer Tumorigeneus. rae.SK.EapU. BioL MtL,/J*473 -471. 1947. 9|iud, C, Buoen. L. and Brand, I. Carctaotenrsn from Potymar [letplants: New Apicu 6am Quomammal and Trupinutian Smdin during rrunalignanrr t NaiL fanter Imu7P 441-479, 1970. 4. Druckrey, It Cxperimemclle Bcitratge wum Mcchanimui a. CarcinegeMn Wirkung. ArtneirmNeiroiseh.. /. 1*1-395. I9i 4. Muepct, C. Cancer Induction by Folywiethan and Polyt'dieor flanks. J. Natl. Cancer |na., 32: 1005-1037.194a. 7. Johnaon, K.. Buoen, L.. Brand. I, and Brand, C. Polytru Tumorigcncds Oonal Deteimination of Histopathologic. Oiartctctistics during Early franeoplasia: Balaiionthtpi i Karyotype. Mourn Strain, and Sea. J. "Natl. Cancer Inst., 7*5-79), 1970. -e I. Kogan, A. Experimental Blattomogentsts Caused by Syniheti Potymcrs (Plastics). McdHains. Moscow. f. 215-317.1945. f. Marnefnatteo. E.. Ffcha*. A. M, Omni. II.. and Danaiger. Acute Inhalation Toxicity of Vinyl Chloride to liberator Animals. Am. Ind. Hyg. Assoc. 1.21; 194-197, I960 10. Torkenon.T. B.. Oycn, F,, and Bow*, V. K. The Toxicity of Vi> Chloride as Determined by Reported Expeiura of Uboraier Animals. Ind. Hyg. J, 354-141. OetSber 196!. 11. Van Duren. B. U Sivak. A.. Goldschmidt. W.. Kats. C-. an< Mekhienae, S. Carcinogenicity of HalmEshers. J. Natl. Cance Inst, 4/ 4||-4g4, (969. 11. Viola, P. L. Pathelogy of Vinyl Oileridc. 14th Imemittoni Congress of Oecopaiional Health. (Communication No. 38) Tokyo.1949. ' ivjhiplc tuii*i<*i si be evaluate.* io be ohioinr.' tic comjv*uiu i the oncitgvni. the CBtanr.v> rgion iruhijj;. Diid glanU a>< nay by involve.: >ride or some hesis is strong!' ng the *pe*nV. appear as a tej the actm o the tumuiowi related to hw Thesis oflutftue d to the cells * ration must hr he action of the avkty system. 4* rting of the fc' rumsiances. tk dd a tigmfuV tration of wv local (xwr difficulty of * TSpiratory *" siru't *** C ID <=>* I. II. 10 ]I. All motions were siairwd with H4E. . [.Squamous aril popiiioma of (ha akin. X 25, St/^Ximritional stage from papilloma to bifUtntNe type of eanaei. x 10. 5; FmpR^ikc arabcculac branch to form aeconduy prooemet showing homy pearl formation (arrow*), x 25. I.' Dyrientotic area. Few epithelial cells with a wndeney to form whorls. Little capacity to develop into horny purls x 250. 5. Atypical eeOi partly locking prickles end showing considerable variation in sue, shape and many mitotic figures, x 250. I Mamrpirif mttiiri skin tumor. Ouuntno of hydropic epidermoid dells, basal mils, columnar mils, and oxyphilic mils in virio X 100. 7; Muoocpidermeid aUn tumor, Blowing differentiation of mamas of squamous epithelium from columnar mils, lining and proliferating in tubular ipaeev X 100. [`Mimonodular adenoonresnoma of the King arising from a ragmcnial btonchus. X 25. 'DcmS of Fig ahowbig tubular aggregates made up by mill with hypcrchtomatk nuekv I.0- Modular bronehiolar aNootv mueueooeiedng sdesracareinoma. X 100. 11' Demil of Fig. 10, showing an ahreologcnic pattern. X 250. Mucus-produang milt with hyperehromatte tad pleomorphic nuclei and oeeuncnm of signet ring mils, x 250. [l-Sqmous mil ardnena of the lung. X 100. [4. Oaaochendroosa developing at a protuberenm from the small bones of metacarpus and metatarsus, x 25. j? M^tifiation of Fig. 14. The protuberance conosts of bone trabeculae, mpped by cartiUgc, and a fibrous layer functioning sdriumx 100. '. Otwochondroma. Cartilaginous growth chareetcruod by ringer-like ptolifcrstion. x 100. y L5 Orioochondroma. Area of endochondral ossification. X 100. i II. CeAuUs area of an osteochondroma showing the transition from mrtilagc to osteoid. X 100. ABCH VOL. ` 171 it' uanun ( AM'I-U <* *' aR< u v('i0 ,. i V. c JD --J `HY l*m J^Sfe^ovl*l^!i^.^.-v>.rC* 2 ^'2ty 5i: C-AM'I-K KtSl AKHl VOL S* j 522 RICHARD DOLL CURRICULUM VilAt - & r .1 . C+tA' BORN 28 October, 1912 GRADUATED St. Thomas's Hospital Medical School, University of London, M.B., B.S.* 1937 * OTHER DEGREES M.D., London, 1945 D.Sc., London, 1958 D.M., Oxford, 1969 HONORARY' DEGREES - PROFESSIONAL AWARDS D.Sc., Newcastle 1969; Belfast 1972; Reading 1973; Newfoundland 1973; D.M.* Tasmania 1975* F.R.C.P. London, 1957; Honorary F.R.C.G.P.# 1978. F.R.S., 1966. Honorary member of the American Association for Cance Research, the American Gastroenterological Assoc iation, the American Epidemiological Society, the American Academy of Arts and Sciences, the Italian Oncological Society, and the Norwegian Academy of Sciences. HONOURS Kt. 1971 O.B.E. 1956 MILITARY SERVICE R.A.M.C. 1939-45: Battalion Medical Officer, France, 1939-40, Medical Specialist Middle East, 1941-44. POSTS HELD Casualty Officer and House Physician, St. Thomas's Hospital, 1938-39. House Physician, Royal Postgraduate Medical School, Hammersmith, 1939. Junior Assistant, Medical Unit, St'TN^homas's Hospital 1945. Research Assistant to Dr Avery Jones, Central Middlesex Hospital, 1946-47. Member MRC's Statistical Research Unit, 1948-69 Deputy Director 1956-60 Director " 1961-69 Deputy Director of MRC's Clinical Research Centre, 1966-69. Honorary Associate Physician, Central Middlesex Hospital, 1949-69. Honorary Lecturer in Epidemiology, London School of Hygiene and Tropical Medicine, 1956-62, and University College Hospital Medical School, 1962-69. POSTS HELD PRESENT POST AWARDS COMMITTEES Regius Professor of Medicine, Ui..varsity of Oxford, *nd Honorary Physician, Radcliffe Infirmary, 1969-79. Honorary Director, Imperial Cancer Research Fund's Cancer Epidemiology and Clinical Trials Unit, 1978-63. Warden, Green College, Oxford, 1979-83. Acting Director, Imperial Cancer Research Fund's Cancer Epidemiology and Clinical Trials Research . Unit. william Julius Mickle Fellow, University of London, 19S5 David Anderson Berry Prise, Royal Society of Edinburgh (jointly, with W.M. Court Brown), 1958. Bisset Hawkins Medal, Royal College of Physicians, 1962. United Nations Award for Cancer Research, 1962. Gairdner Award, Toronto, 1970. Buchanan Medal of the Royal Society, 1972. Nuffield Medal, Royal Society of Medicine, 1973. Presidential Award, New York Academy of Sciences, 1974. Prix Griffuel, Paris, 1975. John Snow Award, Epidemiology Section, American Public Health Association, 1976. Gold Medal, Royal Institute of Public Health, 1977. Charles, S. Mott Prize for Cancer Reserch, New York, 1979. Gold Medal, British Medical Association, 1983. Wilhelm Conrad Rdntgen Prise, Accademia del Lincei, Rome, 1984. Johann-Georg-2immermann Praise, Hannover, 1965. Founders' Award, Chemical Industry Institute of Toxicology, 1986. Royal Medal, The Royal Society, 1986* Chairman, Management Committee, institute of Cancer Research, 1976 to date. Member, Council of Institute of Occupational Medicine, 1981 to date. Chairman, Medical Research Council's Cancer Coordinating Committee, 1973-77. a Adverse Reactions Sub-Committee of the Committee on Safety of Medicines, 1970-77. Sometime member. Royal Commission on Environmental Pollution. Commission on Energy and the Environment. " Council of the Royal Society. Medical Research Council. Council of the Royal College of physicians. Advisory Committee on Medical Research, World Health Organisation. Scientific Council of the International Agency for Research on Cancer. Council of the International Union against Cancer. LIST OP PUBLICATIONS RICHARD DOLL 1936 X. DOLL. k. (1936), Medical statitw-js. St Thomas * Hospital Gazette, 294-297 1937 2. DOLL, R. (1937). Motes on the Merger rhythm and the electro-encephalogram, St Thomass Hospital Gazette. 157159 1939 3. RICHARDSON, J.S. end DOLL, R. <1939). The juvenile form of the adreno-genital syndrome. Brit, med. J.. 2,* 501 1946 4.* DOLL, R. <1946). Helium in the treatment of asthma. Thorax. 1. 30-38 1948 5.+ DOLL, R. and SCHNEIDER, R. (1946). The effect of paludrine on human gastric secretion. Brit. J. Pharmacol, a Chemo., J5, 352-353 URL 1171 7 1949 6. DOLL, R. and JONES, F.A. (1949). Environmental factors in the aetiology of peptic ulcer. The Practitioner. 162 44-50 7. DOLL, R. and BUCKATZSCH, M.M. (1949). Sickness absence due to peptic ulcer. Brit. J. industr. Med.. 100-102 8. DOLL, R., JONES, F.A. and MACLAGAN, N.F. (1949). .-Gastric secretion and subsequent dyspepsia. Lancet. 2, 984 1950 9.* BISHOP, P.M.F., RICHARDS, N.A. and DOLL, R. (1950). Habitual abortion. Brit, med. J.. 2.' 130 I 10. DOLL, R. (1950). Occupational factors in peptic ulcer. Medical Research Council. Proceedings of a Conference on Application of Scientific Methods to Industrial Medicine and Service Medicine. London, HMSO, pp.16-19 I 11. DOLL, R. (1950). perforated carcinoma of the stomach simulating perforated gastric ulcer. Brit, med. J., 1., 215 12. DOLL, R. and HILL, A.B. (1950). Smoking and carcinoma of I the lung. Brit, med. J.. 2, 739 13, * DOLL, R. and BUCK, J. (1950). Hereditary factors in peptic ulcer. Ann. Eugenics, 15, 135-146 I 1950 14 * DOLL contd Prac.. (1950). Peptic ulcer. 504 (Interim Suppl.) ~it. tncyclopaed. md. 1951 15. JONES. F.A., DOLL, R., FLETCHER, C. And RODGERS. Jt*W. (1951). The risks of gastroscopy. Lancet, l, 647 16. DOLL, R., JONES, F.A. end BUCKAT2SCH, M.M. (1951). Occupational factors in the aetiology of gastric and duodenal ulcers. Med. Res. Council Spec. Rep. Ser. No. $76. HMSO, London 17.* DOLL, R. and XELLOCX, T.D. (1951). The separate inheritance of gastric and duodenal ulcers. Ann. Eugenics. 16. 231-240 18.* DAFF, M.E., DOLL, R. and XENKAWAY, X.L. 11951). Cancer of the lung in relation to tobacco. Brit. JL, Cancer. 5. 1-20 1952 1920. DOLL, F. (1952). Peptic ulcers 1. Endeeiology. in: Modern Trends in Gastroenterology. London, Butterworth, p.361 DOLL, R. and PYGOTT, F. (1952). factors influencing the rate of healing of gastric ulcer. Lancet. 1, 171 c F5 --j 03 21. DOLL, R. (1952). Causes of death among gas-workers with special reference to cancer of the lung. Brit. J. industr. Med., 9, 180 22.* DOLL. R. and HILL. A.B. (1952). A stu% of aetiology of carcinoma of the lung. Brit, mad. J.. A. 1271 23. BUCKAT2SCH, J. and DOLL, R. (1952). Aaasperimental factor analysis of cancer mortality in England w) Wales, 1921-30. J. Hvoiene. SO. 384-390 1953 24.* MFC WORKING PARTY OF ANTIBIOTICS CLXNX96TRIALS COMMITTEE (incl. R. DOLL) (1953). Antibiotic andAw>therapeutic agents in the treatment of infaa&il* dlesiBnea and vomiting. Lancet. 2_, 1163 25. JONES, F.A. and DOLL, R. (1953). TraatMrit and prognosis of acute perforated peptic ulcer* Brit.--J. . 1, 122 26. DOLL, R. (1953). Mortality from lung cm among non-smoke; Brit, j. Cancer, 2* 303 27.* DOLL, R. (1953). Bronchial carcinoma* dfcidence and aetiology. Brit, med. J.. 2, 521-S21 A'5B5-590 1953 26. DOLL . (1953). Smoking and Cf 'noma of the lung, contd Acta n. internat. contr. Cancer. ^# 495 1954 29. DOLL, R. (1954). The scientific approach. Ann, phys, Med.. 2. 85 30. KRC COMMITTEE ON ANALGESIA (incl. R. DOLL) (1954). The ue of trilane by mldvives. Medical Research Council Memorandum Mo. 30. London# KMSO 31. TRUELOVE, S.C., HITTS, L.J., TUNBRIDGE# R.E., WATKINS ON, G., JONES# F.A., DOLL# R.# HARDY# T.L.# ST JOHNSTON# C.R.# CARD# W.X.# WILSON# M. and TAYLOR# J. (1954). Cortisone in ulcerative colitis (preliminary report). Brit, med. J.. 2, 375 32. DOLL# R. and PYGOTT, F. (1954). Clinical trial of Robaden and of cabbage juice in treatment of gastric ulcer. Lancet. 2# 1200-1204 33. DOLL# R. and HILL# A.B. (1954). The mortality of doctors in relation to their smoking habits. Brit, med. J.# 1., 1451 34. DOUL# R. (1954). Cancer of the respiratory tract. Brit. j. industr. Med.. 11# 305 35. ARMITAGE# P. and DOLL# R. (1954). The age distribution of cancer and a multi-stage theory of carcinogenesis. Brit, j. cancer, 8, 1-12 36. BOYD, J.T. and DOLL, R. (1954). Gastro-intestinal cancer and the use of liquid paraffin. Brit. J. cancer, 231-237 URL 11719 1955 37. TRUELOVE, S.C.# WITTS# L.J., TUNBRIDGE, R.E., WATKINSON# G.. JONES# F.A.# DOLL# R.. HARDY# T.L.# ST JOHNSTON, C.R.. CARD, W.I.# WILSON# M. and TAYLOR# J. (1955). Cortisone in ulcerative colitis (final report). Brit, med. J. # 2_, 1041 38. DOLL# R. (1955). Etiology of lung cancer. In: Advances in Cancer Research, 3. New York# Academic Press 39. DOLL# R. (1955). Mortality from lung cancer in asbestos workers. Brit. J. industr. Med., 12, 61-86 J74 DOLL# R. (1955). Medical statistics. Middlesex Hospital journal, 40, 190 1956 40. DOLL, . PRICE, R.V., PYGOTX, F -nd SANDERSON, P.H. Conti. ,,wus intragastric milk drij. a treatment of uncomplicated gastric ulcer. Lancet. 1, 70-73 41. DOLL, R., FRIEDLANDER, P. and PYGOTT, F. (1956). Dietetie treatment of peptic ulcer. Lancet. I, 5-9 42.* HILL, A.B. end DOLL, R. (1956). Lung cancer and tobacco. Brit, mad. J.. m1--, 1160 43. DOLL, R. end HILL, A.B. (1956). Lung cancer and other causes of death in relation to smoking. Brit, med. J.. 2,, 1071 44. DOLL, R. (1956). Environmental factors in the aetiology of cancer of the stomach, castroenterolooia. 86. 320-326 URL 11720 1957 45. COURT BROWN, K.M. and DOLL, R. (1957). Leukaemia and aplastic anaemia in patients irradiated for ankylosing spondylitis. Med, Res. Council Spec. Rep. Ser. No. 295. London, HMSO 46. DOLL, R. and HILL, A.B. (1957). Deaths from poliomyelitis among British doctors. Brit, med. J.. ,1, 372 47. DOLL, R. (1957). Aetiology of cancer of the stomach. In: Modern Trends in Gastroenterology. London, Butterrorth. pp.53-64 48.* DOLL, R., JONES, F.A., PYGOTT, F, and STUBBE, J.L. (1957). The risk of gastric cancer after medical treatment.for gastric ulcer. Gastroenterologia. 88. 1 49. ARMITAGE, P. and DOLL, R. (1957). A two-stage theory of carcinogenesis in relation to the age distribution of hurr.an cancer. Brit. J. Cancer. 11. 161 50. DOLL, R. (1957). Lung cancer and smoking. Rov. Soc. Hlth j. 77, 247-254 51 .*DOLL, R., HILL, A.B. and KREYBERG, L. (1957). The significance of cell type in relation to the aetiology of lung cancer. Brit. J. Cancer, 11. 43-48 1958 52 .* DOLL, R. and JONES, F.A. (1958). Smoking and peptic ulcer. Allqemeine pathologic und Bakteriolooie. 21, 209-313 53. HILL, A.B., DOLL, R., GALLOWAY, T.MeL. and HUGHES, J.P.Q. (1958). Virus diseases in pregnancy and congenital defects. Brit. J. prev. soc. Med.. 12, 1-7 1956 54. C0UR7 JWN, W.M. and DOLL. R. ( -) . Expectation of contd life and mortality from cancer among British radiologists. Brit, med. J.. 2( 181-187 55. DOLL. F. (1958). Cancer of the lung and nose in nickel workers. Brit. J. industr. Med.. 15. 217-223 56. DOLL.- F. (1958) Assessment of therapy for gastric ulcer by naans of controlled elinieal trials, cs. oaetroenterologi .2.22 57. * DOLL. F.. JOKES. F.A. and PYGOTT, T. (1958). Effect of smoking on the production and maintenance of gastric and duodenal ulcers. Lancet. 1. 657-662 URL 11721 1959 58 * DOLL. F*. HILL. A.B.. GRAY. P.G. and FARR, E.A. (1959). Lung cancer mortality and the length of cigarette ends: an international comparison. Brit, med. J.`. .1. 322-325 59. DOLL. R. (1959). Smoking and lung cancer: report to the sub-committee for the study of the risks of cancer from air pollution end the consumption of tobacco. Acta. 15. 1283 60. * DOLL. F. (1959). Lung cancer and cigarette smoking. Acta t)n. internet, contr. Cancer. 15. 417 61. DOLL. R. (1959). Occupational lung cancer: a review. Brit. J. industr. Med.. 16. 1B1-190 62. * DOLL. R. (1959). The concurrent assessment of several treatments. In: controlled Clinical Trials. Oxford. Blackwell 63. * DOLL, F. (1959). Retrospective and prospective studies. In: Medical Surveys and Clinical Trials. Oxford University Press, pp.64-89 64. * DOLL. R. (1959). Cancer. In: Medical Surveys and Clinical Trials. Oxford University Press, pp.296-310 65. ARMITAGE, P., COURT BROWN, W.M. and DOLL, R. (1959). Doseresponse ralationship in radiation leukaemia. Nature. 184. 1669-1670 66. COURT BROWN, W.M. and DOLL, R. (1959). The expectation of life and cancer mortality of British radiologists. Progress in Nuclear Energy. Series VII. 2^, 21-27 (Pergamon) 67. COURT BROWN, W.M. and DOLL, R. (1959). Adult leukaemia: trends in mortality in relation to aetiology. Brit, med. J. 1, 1063-1069 .^4^, <%: 1960 68.* DOLL, (I960), The carcinogen* -isk of radiation human leukt...ia. Acta Un. internet. co,,,r. cancer, 16. 418-421 69. COURT BROWN, W.M. and DOLL, R. (1960). Radiation hazards. In: Modern Trends in Occupational Health. London. Butterworth-, pp. 133-142 70. COURT BROWN, W.M., SPIERS, F.W., DOLL, R., DUFFY, B.J. and MeHUGH, M.J. (I960). Geographical variation in.leukaemia mortality in relation to background radiation and other factors. Brit, med. J.. 1,, 1753-1759 71* COURT BROWN, W.M., DOLL, R. and RILL, A.B. (1960). Incidence of leukaemia after exposure to diagnostic radiation in utero. Brit, med. J.. 2., 1539-1545 72. DOLL, R., SWYNNERTON, B.P. and NEWELL, A.C. (1960). Observations on bloodgroup distribution in peptic ulcer and gastric cancer. Gut, ^1, 31 73 .* ARMITAGE, F. and DOLL, R. (1960). Stochastic models for carcinogenesis. In: Proc. 4th Berkeley Symposium on Mathematical Statistics and Probability, 4, 19. University of California Press 74. DOLL, R., HILL, A.B. and SAKULA, J. (1960). Asian influenza in pregnancy and congenital defects. Brit. J. prey, soc. Med., 14, 167-172 URL 117, 75. COURT BROWN, W.M., JACOBS, P.A. and DOLL, R. (1960). Interpretation of chromosome counts made on bone-marrow cells. Lancet, 1, 160-163 1961 76.* DOLL, R. and RANINGTON, E. (1961). International survey of eclampsia and pre-eclampsia, 1956-59: epidemiological aspects, path. Microbiol.. 24, 531-541 (7th International Conference of Society of Geographical pathology, London) 77. COURT BROWN, W.M. and DOLL, R. (1961). Leukaemia in childhood and young adult life: trends in mortality in relation to aetiology. Brit, med. J.. 1, 981-988 78.* MACKENZIE, A., DOLL, R., COURT BROWN, W.M. and SISSONS, H.A. (1961). Mortality from primary tumours of bone in England and Wales. Brit, med, J.. 1^ 1782-1790 79.* COURT BROWN, W.M., DOLL, R., HEASMAN, M.A. and SISSONS, H.A. (1961). Geographical distribution of primary tumours of bone in England and Wales. Brit, j. prey, soc. Med., 15. 167-170 r" 1961 80. *DOLL, DRAKE, H. and NEWELL, A ^1961). Secretion contd of blooo group substances in duodenland stomal ulcer, gastric carcinoma and diabetes mellitus. Gut, 2, 352 81. JACOBS, P.A., COURT BRWN, W.M. and DOLL, R. (1961)T Distribution of human chromosome counts in relation to age. Nature. 191. 1178-1180 URL 11723 1962 82. DOLL, R. (1962). Age differences in susceptibility to carcinogenesis in man. Brit. J, Radiol.. 35. 31-36 83. BUCKTON, K.E., JACOBS, P.A., COURT BROWN, W.M. and DOLL, R. <1962). Cancer subjects and abnormal cell division. Nature, 193. 591 84. DOLL, R. (1962). Susceptibility to carcinogenesis at different ages. Geront. clin.. 4,, 211-221 B5. HOLLAND, W.W., DOLL, R. and CARTER, C.O. (1962). The mortality from leukaemia and other cancers among patients with Down's syndrome (mongols) and among their parents. Brit. J. Cancer. 16, 177-186 86. BUCKTON, K.E., JACOBS, P.A., COURT BROWN, W.M. and DOLL, R. (1962). A study of the chromosome damage persisting after X-ray therapy for ankylosing spondylitis.- Lancet. 2., 676682 " B7.*D0LL, R., HILL, I.D., HUTTON, C. and UNDERWOOD, D.J, (1962). Clinical trial of a triterpenoid liquorice compound in gastric and duodenal ulcer. Lancet. , 793-796 6B.*D0LL, R. (1962). Information sought on somatic effects. In: The Use of Vital and Health Statistics for Genetic and Radiation Studies. United Nations Publication Sales No. 61. XVII.8.. New York, pp.11-18 1963 89 .*JACOBS, P.A., BRUNTON. M., COURT BROWN, W.M., DOLL, R. and G01DSTEIN, H. (1963). Change of human chromosome count distributions with age: avidenca for a sex difference. Nature. 197. 1080-10B1 8 90. *MRC WORKING PARTY ON EVALUATION OF DIFFERENT METHODS OF THERAPY IN LEUKAEMIA (incl. R. DOLL) (1963). Treatment of acute leukaemia in adults: comparison of steroid therapy at high and low dosage in conjunction with 6-mercaptopurine. Brit, med. J.. 1, 7-14 91. *D0LL, R. (1963). Investigation into cigarette smoking and atmospheric pollution in the aetiology of lung cancer. Methods of Information in Medicine. 2, 13-19 1963 93. CAMPr* \, H., DOLL, R. and LETCH'***, J. (1963). Incidence contd of ti.^oid cancer in England anc. ,les. Brit. med. J.. 2, 1370-1373 7 2 * DOLL, R. (1963). Interpretation! of epidemiologic data. Cancer Research. 23, 1613-1623 * ttm iw n 1964 94. INTERNATIONAL WORKING PARTY OF THE ORGANIZATION MONDIALE DE GASTRO-ENTEROLOGIE RESEARCH SUB-COMMITTEE (incl. R.DOLL) (1964). Die epidemiology of gastro-intestinal cancer with special reference to causation. Gut, , 196-200 95. ACHESON, E.D. and DOLL, R. (1964). Dietary factors in carcinoma of the stomach: a study of lOO cases and 200 controls. Gut. , 126-131 96.*DOLL, R. (1964). Medical treatment of gastric ulcer. Scot, med. J.. 9, 1B3-196 97. DOLL, R. and HILL, A.B. (1964). Mortality in relation to smoking: ten years* observations of British doctors. Brit, med. J.. 1, 1399-1410 and 1460-1467 98. HAYHOE, F.G.J., QUAGLINO, D. and DOLL, R. (1964). The cytology and cytochemistry of acute leukaemias. Med. Res, Council Spec. Rep. Ser. No. 304. London, HMSO 99.*DOLL, R. (1964). Epidemiological observations on susceptibility to cancer in man with special reference to age. Acta Un. internet, contr. Cancer. 20, 747-752 100. BOYD, J.T. and DOLL, R. (1964). A study of the aetiology of carcinoma of the cervix uteri. Brit. J. cancer. 18, 419-434 101. DOLL, R. (1964). Aetiology of cancer of the cervix uteri. In? Revista del Instituto Nacional de Cancerolooia. UICC Symposium on Cancer of the Uterus, Mexico city, 1964, pp.358-367 102. COURT BROWN, W.M., DOLL, R. and HILL, A.B. (1964). Leukaemia in Britain and Scandinavia. Path. Microbiol., 27, 644-654 (8th Conference of the International Society of Geographical Pathology, Milan, 1963) 19__5 103 .* DOLL, , FISHER, R.E.W., GAMMON, J., GUNN, W., HUGnta, G.O., ryRER, F.H. and WILSON, V. U965). Mortality of gasworkers with speeial reference to cancars of the lung and bladder, chronic bronchitis, and pneumoconiosis. Brit. J. industr. Med.. 22, 1-12 104. * D01X, R. (1965). Cancer: the possibilities. Brit, med. J., 1, 471-473 105. DOLL, R., HILL, l.D. and HUTTON, C.F. (1965). Treatment of gastric ulcer with carbenoxolone sodium and oestrogens. Cut. 6, 19-24 106 * DOLL, R. (1965). Clinical trials. Xn: Evaluation of Hew Drugs in Man. Proc. 2nd International Pharmacol. Meeting, Prague, 1963. Czechoslovak Medical press, pp.159-164 107.*DOLL, R. (1965). The epidemiological picture. Xn: Current Research in Leukaemia. Ed. F.6.J. Hayhoe. Lc.idon, Syndics of Cambridge University Press, pp.280-299 108.*PIKE, M.C. and DOLL, R. (1965). Age at onset of lung cancer: aignificance in relation to effect of smoking. Lancet. 1. 665-668 109.*ZANGMAN, M.J.S. and DOLL, R. (1965). ABO blood group and secretor status in ralation to clinical characteristics of peptic ulcer. Gut. 6, 270-273 110. COURT BRCWN, W.M. and DOLL, R. (1965). Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis. Brit, med, J.. 2^, 1327-1332 111.*KNOX, J.F., DOLL. R. and HILL, l.D. (1965). Cohort analysis of changes in incidence of bronchial carcinoma in a textile asbestos factory. Ann. N.Y. Acad. Sci.. 132, 526-535 112. ARMXTAGE, P., DOLL, R. and PIKE, M.C. (1965). Somatic mutation. Brit, med. J.. 1,. 723 1966 113. HILL, I.D., DOLL, R. and KNOX, J.F. (1966). Mortality among asbestos workers. Proc. rov. Soc. Med.. 59, 59-60 114.*DOLL, r. and HILL, A.B. (1966). Mortality of British doctors in relation to smoking: observations on coronary thrombosis. In: Study of Cancer and Other chronic Diseases National Cancer Institute Monograph No. 19. Bethesda, Maryland URL 11725 1966 115. INTER*' 10NAL COMMISSION ON RADIC '.ICAL PROTECTION contd COMMIT*;E I (incl. R. DOLL) (1966). The evaluation of risks from radiation. Health Physics, 12. 239*302 H6.#MRC WORKING PARTY ON THE EVALUATION OF DIFFERENT METHODS OF THERAPY-IN LEUKAEMIA (incl. R. DOLL) (1966)_*_ Treatment of aeute leukaemia in adults: comparison of steroid and mercaptppurine therapy, alone and in conjunction (2nd Report) Brit, med. J., 1., 1383-1389 117.*LANGMAN. M.J.S., DOLL, R. and WILSON, J. (1966). Plasma and salivary thiocyanate in gastric cancer. Gut. 7.* 549*552 S' H8.*dOLL, R. (1966). Cancer bronchigue et tabac. Les Bronches. li' 313-324 119. DOLL. R., PAYNE, P. and WATERHOUSE, J. (Eds) (1966). Cancer Incidence in Five Continents. UICC, Springer-verlag, Berlin 120.* DOLL, R. (1966). Mechanism of carcinogenesis: evidence from epidemiological data. In: Fifteenth Yearbook for Cancer Research and Fight Against Cancer in the Netherlands. Amsterdam, Vereniging het Nederland* Ranker Znstituut, pp.13-31. (wassink Lecture given by R. Doll, October 1965) 1967 121. LANGMAN, DOLL, R. and SARACCI. R. (1967). ABO blood group and secretor status in stomal ulcer. 8. 128-132 Gut, 122 .* MEDICAL RESEARCH COUNCIL SUBCOMMITTEE (incl. R.DOLL) (1967). Risk of thromboembolic disease in women taking oral contraceptives: a preliminary communication to the Medical Research Council by a Subcommittee. Brit, med. J.. 2_t 355-359 URL 11726 123. DOLL, R. and COOK, P. (1967). Summarising indices for comparison of cancer incidence data. Int. j. Cancer, 2_* 269-279 124.*DOLL, R. (1967). Statistical approach to the evaluation and prediction of possible carcinogenic action of drugs. In: Potential Carcinogenic Hazards from Drugs. Ed. R. Truha UICC Monograph Series, Vol. 7. Springer-verlag, Berlin, pp.53-58 125.* DOLL, R. (1967). Worldwide distribution of gastrointestinal cancer. In: Tumors of the Alimentary Tract. National Cancer Institute Monograph No. 25, pp.173-190 1967 126 .*TILL, M., HARDISTY, R.M.* PIKE, C. end DOLL, R. (1967). contd Child>.-^d leukaemia in Greater L> jn: a search for evidence of clustering. Brit. med. 3. . 3. 755-758. 127.*D0LL, R. (1967). controlled clinical trials and their evaluation? introduction. In: Proc. ixth Int^r Cancer Congress. UICC Monograph Series Vol. 10. Ed. R.J.C. Harris Springer-Verlag. Berlin* pp.193-194 126. DOLL* R. (1967). Prevention of Cancer: pointers from Epidemiology. Nuffield Provincial Hospitals Trust* London 129.+DOU** R. (1967). The statistical approach to industrial lung cancer. In; Some Aspects of Carcinoma of the Bronchus and Other Malignant Diseases of the Lung (A Symposium held on 4 and 5 July 1966). Ed. D. Tears and J. Penning. King Edward VII Hospital* Midhurst, pp.5-18 130. COURT BROWN, W.M., DOLL, R. and SMITH* P. (1967). Neoplasia in patients treated with x-rays for ankylosing spondylitis or metropathia haemorrhagica. In: Proc. IXth Int. Cancer Congress. UICC Monograph Series vol. 10. Ed. R.J.C. Harris. Springer-Verlag* Berlin, pp.119-126 1966 131. BLACKBURN, E.K.* CALLENDER, S.T.* DACIE, J.V.* DOLL, R.* GIRDWOOD. R.H.* MOLLIN* D.L.* SARACCX, R.* STAFFORD, J.L., THOMPSON, R.B., VARADI. S. and WETHERLEY-MEIN, G. (1966). Possible association between pernicious anaemia and leukaemia: a prospective study of 1,625 patients with a note on the very high incidence of stomach cancer.. Int, J. Cancer. 2' 163-170 URL 11727 132 .*MRC WORKING PARTY FOR THERAPEUTIC TRIALS IN LEUKAEMIA (incl. R. DOLL) (196B). Chronic granulocytic leukaemia: comparison of radiotherapy and busulphan therapy. Brit, med. J.. 1, 201-208 133.*SPEI2ER, F.E., DOLL, R. HEAF, P. and STRANG, L.B. (1968). Investigation into use of drugs preceding death from asthma. Brit, med. J., 2* 339*343 134. SPEIZER, F.E., DOLL* R. and HEAF, P. (1968). on recent increase in mortality from asthma. 1* 335-339 Observations Brit, med. j.. 135. DOLL, R., LANGMAN, H.J.S. and SHAWDON* H.H. (196B). Treatment of gastric ulcer with carbenoxolone: antagonistic effect of spironolactone. Gut, 2* 42-45 136.*DOLL, R., LANGMAN, M.J.S. and SHAWDON, H.H. (1968). Treatment of gastric ulcer with estrogens. Gut, 9, 46-47 contd of X irradiation in patients treated for metropathia haemc agica. Brit. J. Radiol.. 1, 362-368 /?V VESSEY, M.P. and DOLL, R. (196B). Investigation of relation between use of oral contraceptives and thrombo embolic disease. Brit, med. J., 2, 199-205 __ i3f SPEIZER, F.E. and DOLL, R, (1966). A century of asthma deaths in young people. Brit, med. J.. 3, 245-246 e y.- DOLL, R. (1968). Hospital records in the computer age. Proc. rov. Soc. Med.. 61, 709-715 H/ DOLL, R. (1968). Epidemiology of cancer. Proc. toy. Soc. Med.. 61, 731-732 /r* DOLL, R. (1968). Introductory remarks. A Symposium on Carbenoxolone Sodium (held November 1967). Ed. J.M. Robson and F.M. Sullivan. Butterworth, London, pp.47-49 DOLL, R. (1968). TTie age distribution of cancer in man. Ins Cancer and Aoinq (Thule Symposium, held September 1967). Ed. Engel and Larsson. Nordiska Bokhandelns Forlag, pp.15-36 >7 AHLUWALIA, H.S. and DOLL, R. (1966). Mortality from cancer of the cervix uteri in British Columbia and other parts of Canada. Brit, J prev. soc. Med.. 22, 161-164 URL 11728 tut DOLL, R. (1968). Carcinogens in the environment: human evidence. T. norske Laeoeforen, 88, 1187-1194 Hi DOLL, R. (1968). The geographical distribution of cancer. T. norske Laeoeforen, 88. 1160-1165 /*-> KNOX, J.F., HOLMES, S., DOLL, R. and HILL, I.D. (1968). Mortality from lung cancer and other causes among workers in an asbestos textile factory. Brit. J. industr. Med.. 25. 293-303 RESEARCH COMMITTEE OF BTA (incl. R. DOLL) (1968). Aspergillus in persistent lung cavities after tuberculosis. Tubercle, 49. 1-11 1969 COOK, F., DOLL, R. and FELLXNGHAM, S.A. (1969). A mathematical model for the age distribution of cancer in man. Int. J. Cancer. , 93-112 If'* BOYD, J.T., DOLL, R., HILL, G.B. and SISSONS, H.P. (1969), Mortality from primary tumours of bone in England and Wales, 1961-63. Brit. J. prev. soc. Med.. 23, 12-22 1969 151.*STUK0N. M. and DOLL, R. (1969). strie cancer in man contd and physical activity at work. Int. J. Cancer. . 248-254 153.*KRC WORKING PARTY (incl. R. DOLL) (1969). Hypogamma globulinemia in the United Kingdom. Lancet. ,1, 162-168 154.*D0LL, R. (1969). Recognition of unwanted drug effects. Brit.med. J.. 2, 69-76 155. DOLL. R. (1969). The geographical distribution of cancer. Brit, j. cancer. 23, 1-8 156.DOLL, R. (1969). Comparison* of cancer incidence: statistical aspects. Cancer in Africa. 14. 1-6 157.BURNS-CttC, C.J., DOLL, R. and BAU.. X.P. (1969). Sugar intake and myocardial infarction. Brit. Heart J.. 31. 485-49C 158.*VESSEY, M.P. and DOLL, R. (1969). Investigation of relation between use of oral contraceptives and throniboembolic disease. A further report. Brit, med, j., 651-657 159.*D03X, R. et al (1969). Summarising statement on results of treatment. U1CC Monograph Series Vol. 12, Thyroid Cancer. Ed. C. Hedinger. Springer-Verlag, Berlin, pp.309-312 160.*FLETCHER, C. and DOLL, R. (1969). A survey of doctors' attitudes to smoking. Brit, J. prev. soc, Med.. 23. 145-153 ttoA boll. R. (1969). Kezelesek ertekelese (evaluation pf treatment). Orvoskepzes. 44, 384-394 161.*D0LL, R. and VESSEY, M.P. (1969). Effects on the vascular system and blood: epidemiological studies. In: Metabolic Effects of Gonadal Hormones and contraceptive Steroids, plenum Press, pp.563-579 162. DOLL, R. (1969). Documentazione ospedaliera nell'epoca dei caleolatori elettronici (hospital records in the computer age). Appllcazioni bio-mediche del calcolo elettronico, 2, 61-72 1970 163.*D0LL, R. and VESSEY, M.P. (1970). Evaluation ef rare adverse effects of systemic contraceptives. Brit, med. Bull. 26. 33-38 164.*B0YD, J.T., DOLL, R.. FAUIDS, J.S, and 1EIPER, J. (1970). Cancer of the lung in iron ore (haematite) miners. Brit, j. industr. Med., 27, 97-105 1970 165.*BENNTJ A.E., DOLL, R. and HCMEL R.w. (1970). Sugar eontd consumption and cigarette smoking. Lancet. 1.. 1012-1014 166. *rc COMMITTEE ON NITROUS OXIDE & OXYGEN ANALGESIA IN MIDWIFERY (incl. R. DOLL) (1970). Clinical trials of different concentrations of oxygen and nitrous oxide for obstetric analgesia. Brit, med. j.. 1. 709-713 167. *VESSEY, M.P., DOLL, R., FAXRBAIRN, A.S. and GLOWER, G. (1970). Postoperative thromboembolism and the use of oral contraceptives. Brit, mefl. j.. 123-126 168. *D0LL, R. (1970). The long-term effects of steroid contraceptives. J, biosoc. Sci.. , 367-389 RESEARCH COMMITTEE OF STA (incl. R.DOLL) (1970). Aspergilloma and residual tuberculous cavities - the results of a resurvey. Tubercle, 51. 227-245 169. *D0LL, R. (1970). Practical steps towards the prevention of bronchial carcinoma. Scot, med. J.. 15, 433-447 170. *DOLL, R. and KINLEN, L.J. (1970). Immunosurveillance and cancer: epidemiological evidence. Brit, med. J.. A_, 410-421 1-rcA DOLL, R., MUIR, C. and WATERHOUSE, J. (eds) (1970). Cancer Incidence in Five continents. II. Springer-Verlag, Berlin, for UICC i i in n 1971 171 .*DOLL. R. (1971). Unwanted effects of drugs. Brit! med. Bull.. 27, 25-31 172 .* DOLL, R., MORGAN, L.G. and SPEIZER, F.E. (1971). of the lung and naSal sinuses in nickel workers. Cancer. 24, 623-632 Cancers Brit, j. 173.*FRASER, P. and DOLL, R. (1971). Geographical variations in the epidemic of asthma deaths. Brit, j. prev. toe, Med., 25. 34-36 174 .* FRASER, SPEIZER, F.E., WATERS. S.D.M.. DOLL, R. and MANN, N.M. (1971). The circumstances preceding death from asthma in young people in 1968 to 1969. Brit. J. Pis. Ches- 65, 71-B4 175.*D0LL, R. and FRASER, p. (1971). An epidemic of asthma deaths and its relation to drug therapy. Proc. XII Mtg. Europ. Soe. Study Drug Toxicity (Uppsala, 1970). Excerota Medica Internat. Cong. Ser. No. 220. pp.133-137 1971 176. DOLL, (1971). The *ge distril *on of cancer: contd implications for models of carcinogenesis. J. rov. statist. Soc. Series A. , 134. 133-166 177 .* GLOBER, G., DOLL, R., FAIRBAIRN, A.S. and VESSEY, M.P. (1971). peptic ulceration and the use of oral contraceptives Brit. J. prev. soc. Med.. 25. 144-146 178 .* GLOBER, G.A., CANTRELL. E.C., DOLL. R. and PETO> It. (1971). Interaction between ABO and Rhesus blood groups, the site of origin of gastric cancers, and the age and sex of the patient. Gut. 12. 570-573 179.*VESSEY, M.P., DOLL, R. and SUTTON, P.M. (1971). Investigation of the possible relationship between oral contraceptives and benign and malignant breast disease. Cancer. 2B, 1395-1399 DOLL, R. (1971). Cancer and aging: the epidemiologic evidence. Oncology 1970. ,5. 1-28. Year Book Medical Publishers, Chicago *->*& DOLL, R. (1971). Cancer following therapeutic external radiation. Oncology 1970. J5, 96-102. Year Book Medical publishers, Chicago V C L llT U n 1972 doll, R. (1972). Cancer in five continents. Proc. rov. Soc. Med.. 65. 49-55 180.*d0LL, R. and PIKE, M.C. (1972). Trends in mortality among British doctors in relation to their smoking habits. J. rov. Coll. Physcns London. G, 216-222 IDOLL, R. (1972). The Epidemiology of Leukaemia. Leukaemia Research Fund, London 182. DOLL, R. (1972). Der ewert epidemiologischer Melhoden fur die Aufdeckung unerwunschte Araneimittelwirkungen. Der Internist. 13. 301-309 (translation of article in Brit, med. Bull.. 27, 25-31, 1971) 183.*FRASER, P.M., DOLL, R., LANGMAN, M.J.S., MISIEWICZ, J.J. and SHAWDON, H.H. (1972). Clinical trial of a new carbonenoxolone analogue (BX24), sine sulphate, and vitamin A in the treatment of gastric ulcer. Gut. 13. 459-463 in4 DOLL, R. (1972). Cancers related to smoking. In: Proceedings of the Second World Conference on Smoking and Health. Ed. R.F. Richardson. Pitman Medical, London, pp.10-23 197 2 184 .* DOLL, (X972). Retrospective 'dies. Ins AKAPI eontd Sympo.um on Adverse Drug Reactic . Ed. D.J. Richards and R.X. Rondel. Churchill Livingstone 185.* VESSEY, K.P., DOLL, R. and SUTTON, P.M. (1972). Oral contraceptives and breast neoplasia - a retrospective study. Brit, wed. J.. 2* 719-723 186.* VESSEY, M.P., DOLL, R., PETO, R. and REDMAN, C..W.G. (1972). Characteristics of women using different methods of contraception - some preliminary findings from a prospective study. Int. J, Epidem.. 1, 119-123 1B7. DOLL. R., VESSEY, M.P., BEASLEY, R.W.R., BUCKLEY, A.R., FEAR, E.C., FISHER, R.E.W., GAMMON, E.J., GUNN. W., HUGHES. G.O., LEE, X. and NORMAN-rSMlTH, B. (1972). Mortality of gasworkere - final raport of a prospective study. Brit. J. industr. Med., 29. 394-406 1*74 VESSEY, M.P. and DOLL, R. (1972). Thymectomy and cancer a follow-up study. Brit, j. Cancer. 26. 53-68 1973 MRC WORKING PARTY ON THERAPEUTIC TRIALS IN LEUKAEMIA (incl. R. DOLL) (1973). Report on the first myelomatosis trial, part 1. Analysis of presenting features of prognostic importance. Brit, J, Haematol.. 24, 123-139 186. DOLL, R. (1973). Hazards of the first nine months: an epidemiologist's nightmare. J. Irish med. Ass.. 66, 117-126 URL 11732 189.* DOLL. R. (1973). Monitoring the National Health Service. Proc. rov. Soc. Med., 66. 729-740 (Nuffield Lecture) 190.* DOLL, R. (1973). Oral contraceptives: a medical audit. Community Health. 2' 32-48 (Harben Lecture, 1972) 191.* DOLL, R. (1973). Osier's English School (Osier Oration, 197 Medical History. 2 217-222 192.* BOYD, J.T., DOLL, R. and GURU, C.H. (1973). Cancer incident in Fiji. Int. J. Epidem.. 2, 177-187 193.* KINLEN, L.J. and DOLL, R. (1973). Trends in mortality from cancer of the uterus in Canada and in England and Kales Brit, j. prev, soc. Med.. 27. 146 DOLL. R. and VODOPIJA, I. (1973). (Eds). Host Environment Interactions in the Aetiology of cancer in Man. 1ARC Scientific Publications No. 7. IARC, Lyon 1973 tfiA DOLL, 1* 4 973). Age. In: Host ronment Interactions contd in th rtiology of Cancer in^Mar. Bu. r. do IT ana 1. Vodopija. 1ARC Scientific Publications No. 7. IARC, Lyon 1974ff6 POLL. R. (1974). The causes and prevention of oesophageal cancer. Annual of the Faculty of Medicine (Aristotelian University-of Thessalonikii, Vol.X. (Symeonidss Memorial Volume) DOLLAR. (2974). The Open Arms. Osier Library Newsletter. No. 15. McGill University, Montreal t til OOLL.R. (1974) Smoking, lung cancer, and Occam's razor. Wes Scientist. 21 February (<J1 DOLL,R. (1974). Oesophageal cancer: a preventible disease? In: Monograph 1, International Seminar on Epidemiology of Oesophageal Cancer. Indian Cancer Society. Bombay HP VESSEY.M.P. JOHNSON,B., PETO,R. and DOLL,R. (1974). Outcome Of pregnancy in women using an intrauterine device. Lancet. lt 495-498. ,4f4*MRC WORKING PARTY ON THE USE OF ANTI-D IMMUNOGLOBULIN FOR THE PREVENTION OF ISOIMMUNISATION OF Rh-NEGATIVE WOMEN DURING PREGNANCY (incl. R. DOLL) (1974). Controlled trial of various anti-D dosages in suppression of Rh sensitization following pregnancy. Brit, med. J.. 2, URL 11733 *ARMSTRONG,B., STEVENS,N. and DOLL,R. (1974). A retrospective study of the association between use of rawolfia derivatives and breast cancer in English women. Lancet. 2, DOLL,R. (1974). To measure NHS progress. Fabian occasional paper 8. Fabian Society, London f4f7 *DOLL,R. (1974). Surveillance and monitoring. Int. J, Epidem.. 3, 305-313 *doll,R. (1974). Public benefit and personal privacy: the problems of medical investigation in the community. Proc. roy. Soc. Med., 67, 1281-1286 ARMSTRONG, B. and DOLL,R. (1973). Bladder cancer mortality in England and Wales in relation to cigarette smoking and saccharin consumption. Brit, J.Prev. soc. Med.. 28., 233-240 2*2. DOLL,R. (1974). Measuring the progress of a health service. N.Z. med. J.. 80, 325 DOLL,R. (1974). Oral contraception: a medical audit. N.Z. med. J., 80, 253-257 1975 204. ARMSTF , B. and DOLL, R. (1975) Environmental factors and cancar incidence and mortality n different countries, with special reference to dietary practices. Int. J. Cancer. 15, 617-631 205. VESSEY, M.P,, DOLL, R. and JOKES, K. (1975). ral contraceptives and breast cancer. Progress report of an epidemiological study. Lancet. _1, 941 % 206.+P0LL, R. (1975). The effect of changes in the environment on the health of the community - an epidemiologist's view. J. rov. Coll. Gen. Pract., 25. 326-334 207. ARMSTRONG, B. and DOLL, R. (1975). Bladder cancer mortality in diabetics in relation to saccharin consumption and smoXing habits. Brit. J. prey, soc. Med., 29, 73-81 208.+MANN, J.X.. VESSEY, M.P., THOROGOOD, M. and DOLL, R. (1975). Myocardial infarction in young women with special reference to oral contraceptive practice. Brit, med. J.. 2., 241-245 209t DOLL, R. (1975). Pott and the prospects for prevention. Brit. J. Cancer. 32. 263-272 210. MRC WORKING PARTY ON LEUKAEMIA IN ADULTS (incl. R. DOLL) (1975). The relation between morphology and other features of acute myeloid leuKaemia and their prognostic significance. Brit. J, Haemat.. 31. 165-179 211. DOLL, R. (1975). Medical research in the public interest. In: Health Care Teaching and Research. Ed. W.C. Gibson. University of British Columbia Press URL 11734 211a .* DOLL, R. (1975). Discussion paper. N.Y. Acad. Sci.. 246 320-321 212.* DOLL, R. (1975). Pott and the path to prevention. Arch. Geschwulstforsch.. 45/6. 521-531 213. DOLL, R. (1975). The epidemiology of cancers of the breast and reproductive system. Scot, med. J.. 20. 305 214.* ARMSTRONG, B., GARROD, A. and DOLL. R. (1975). A retrospective study of renal cancer with special reference to coffee and animal protein consumption. Brit. J. cancer, 33, 127 1976 4A0. f ** * V* *U t\ m . irrad *on in patients treated i Brit. J. Radiol.. 49. 224-232 metropathia haemorrhagic; 216.* DOLL, R, (1976)* The contribution of epidemiology to knowledge of cancer. Revue d*epidemiologic et de sante oublique. 24, 107. r*. 1 ___ 217. ARMSTRONG, B., SKEGG, D., WHITE, C. and DOLL, R. (1976). Rauwolfia derivatives and breast cancer in hypertensive women. Lancet, 2, 8 216. MANN, J.X., DOLL, R., THOROGOOD, M., VESSEY, M.P. and WATERS, W.E. (1976). Risk factors for myocardial infarction in young women. Brit. J. prev. eoc. Med.. 30. 94-100 219. VESSEY, M.P., DOLL, R.. PETO, R., JOHNSON, B. and WIGGINS, P. (1976). A long-term follow-up study of women using different methods of contraception: an interim report. J. biosoc. Sci B, 373-425 220. DOLL, R. (1976). Epidemiology of cancer: current perspectives. Am. J. Epidcm.. 104. 396-404 221.*VESSEY, M.P. and DOLL. R. (1976). Is "the pill" safe enough to continue using? Proc. rov. Soc. Lond. B. 195, 69-BO 222 ."DOLL, R. and PETO, R. (1976). Mortality in relation to smoking-. 20 years' observations on male British doctors. Brit, med. J., 2, 1525-1536 set n w 1977 223. DOLL, R. and PETO. R. (1977). Mortality among doctors in different occupations. Brit, med. J.. 1>, 1433-1436 224 .*SKEGG, D.C.G., DOLL, R. and PERRY, J. (1977). Use of mtdicines in general practice. Brit, med. J.. 1., 1561-1563 225/ DOLL, R., MATHEWS, J.D. and MORGAN, L.G. (1977). Cancers of the lung and nasal sinuses in nickel workers; a reassessment of the period f risk. Brit. J. prev. soc. Med.. 34, 102 226."SMITH, P.G., DOLL, R. and RADFORD, E.P. (1977). Cancer mortality among patients with ankylosing spondylitis not given X-ray therapy, Brit. J. Radiol.. 50. 72B-734 227."DOLL, R. (1977). The prevention of cancer, j. rov. Coll. Phvcns.. 11. 125 m 36 1$77 228. DOLL, ~ (1977). Strategy tor oc w*.***,, eontd to man. Nature, 265, 589-596 _ 229.*RADFORD, E.P., DOLL, R. and SMITH, F.C. (1977). Mortality among patients with ankylosing spondylitis not given x-ray therapy. Hew Engl. J. Med.. 297, 572-576 230.*D0LL, R. (1977). Smoking and disease; prospects for control. Royal Society of Health. August 1977 231.*SKEGG, D.c.c. and DOLL, R. (1977). Frequency of eye complaints and rashes among patients receiving practolol and propranolol. Lancet. , 465-478 232 .*PET0, J.. DOLL, HOWARD, S.V., KINLEH, L.J. and LEWXNSOHN, H.C. (1977). A mortality study among workers in an English asbestos factory, Brit. J. industr. Med.. 169-173 233. DOLL, R. (1977). Ganeral epidemiology. In: Topics in Gastroenterology. S. Cancer of the Large Bowel. Ed. S.C. Truelove and . Lee. Blackwell Scientific Publications. Oxford, pp.3- 234 *SXEGG, D.C.G. and DOLL, R. (1977). The case for recording events in clinical trials. Brit, med. J., 2,, 1523-1524 235.*DOLL, R. (1977). Introduction. In: Origins of Human Cancer Cold Spring Harbor Laboratory, Hew York, pp.1-12 236. DOLL, R. and XINLEN, L.J. (1977). Fluoridation of water and cancer mortality in the USA. lancet, 1, 1300-1302 1976 237. MRC WORKING PARTY ON LEUKAEMIA IN CHILDHOOD (incl. R. DOLL) (1978). Immunotherapy of acute myeloid leukaemia. Brit. J. Cancer. 37. 1-14 238.-*dOLL, R. (1978). Atmospheric pollution and lung cancer. Environmental Health Perspectives. 22. 23-31 239* CEDERLOP, R., DOLL, R., FOWLER, B., FRXBERG, L., KELSON, N. and VOUK, V. (1978). Air pollution and cancer: risk assessment methodology and epidemiological evidence. Environmental Health Perspectives. 22, 1-12 240.* SMITH, P.G. and DOLL, R. (1978). Age and time dependent changes In the rates of radiation-induced cancers in patie with ankylosing spondylitis following a single course of X-ray treatment. In: Late Biological Effects of Ionizing Radiation, vol. I. International Atomic Energy Agency, Vienna, 1978 1977 228. DOLL, R .977). Strategy for det *on of cancer hazards contd to man. Nature, 265, 589-596 229.`RADFORD, E.P., DOLL, It. end SMITH, P.C. (1977). Mortality among patients with ankylosing spondylitis not given X-ray therapy. Hew: Engl, 3. Med. 297. 572-576 -- 230.`DOLL, R. (1977). Smoking and disease: prospects for control. Royal Society of Health. August 1977 231.*SKEGG, D.C.G. and DOLL, R. (1977). Frequency of eye coinplaints and rashes among patients receiving practolol and propranolol. Lancet, 2. 465-478 232 .* PETO, J., DOLL, A., HOWARD, S.V., KINLEN, L.J. and XEWINSOHN, H.C. (1977). A mortality study among workers in an English asbestos factory. Brit, J. industr. Med., 34,, 169-173 233. DOLL, R. (1977). General epidemiology. 2n: Topics in Gastroenterology. 5. Cancer of the Large Bowel. Ed. S.c. Truelove and E. Lee. Blackwell Scientific Publications, Oxford, pp.3- 234.*SKEGG, D.C.G. and DOLL, R. (1977). The case for recording events in clinical trials. Brit. med. J.. 2,, 1523-1524 235.`DOLL, R. (1977). Introduction. In? Origins of Bumafi Cancer. Cold Spring Harbor laboratory. Hew York, pp.1-12 236. DOLL, R. and KINLEN, L.J. (1977). Fluoridation of water and cancer mortality in the USA. Lancet. 1,, 1300-1302 URL 11737 1978 237. MRC WORKING PARTY ON LEUKAEMIA IN CHILDHOOD (incl. R. DOLL) (1978). Immunotherapy of acute myeloid leukaemia. Brit. J. Cancer. 37. 1-14 238-*DOLL, R. (1978). Atmospheric pollution and lung cancer. Environmental Health Perspectives. 22. 23-31 239* CZDERLOF, R.. DOLL, R., FOWLER, FRIBERG, L., KELSON, N. and VOUX, V. (1978). Air pollution and caneeri risk assessment methodology and epidemiological evidence. Environmental Health Perspectives. 22, 1-12 240.* SMITH, P.G. and DOLL, R. (1978). Age and time dependent changes in the rates of radiation-induced cancers in patients with ankylosing spondylitis following a single course of X-ray treatment. In: Late Biological Effects of Ionizing Radiation, vol. I. international Atomic Energy Agency, Vienna, 1978 1978 241 WRIGHT,N.H. , VXSSEY,M.P., , McPHERSON,K. , and eostd DOI . (1978). Neoplasia and tplasia of the cervix ute*x and contraception: a poss.~le protective effect of the diaphragm. Brit. J. Cancer. 38, 274-279 242 DOLL.R. (1978). Prevention: some future perspectives. Prev. Med.. 7, 486-497 -- 243 DOLL,R. (1978). Geographical variation in cancer incidence: a clue to causation. World J. Sure.. 2, 595-602 (Grey Turner Lecture, Kyoto, Japan, >977)"* 244 DOLL, R. (1978). An Epidemiological Perspective of the Biology of Cancer. Cancer Research. 36, 3573*3583 245 D0LL,R. and Peto.R. (1978). Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non-smokers. J. Epiden. A Community Health, 32. 303-313 URC WORKING PARTY ON LEUKAEMIA IN CHILDHOOD (1978) (Incl. R.DOLL) Effect of varying radiation schedules, cyclo phosphamide treatment, and duration of treatment In acute lymphoblastic leukaemia. Brit. Med. J.. 2. 787-791 1979 246 VESSEY,M.P., DOLL,R., NORMAN-SMITH,B., and HILL,I.D. (1979). Thymectomy and Cancer: A further report. Br. J. Cancer, 39, 193-105 247 SKEGG,D.C.G., RICHARDS,8.M., and DOLL,R. (1979). Minor tranquillisers and road accidents. BMJ, 1_, 917-91-9 eum un 248 VESSEY,M.P., DOLL,R., JONES, KEENA, McPHERSON,K., and YEATES,D. (1979). An epidemiological study of oral contraceptives and breast cancer. BMJ, 1, 1757-1760 249 DOLL.R. (1979). Contraception and cardiovascular accidents. INSERM, 83, 17-30 250 D0LL,R. (1979). The pattern of disease in the post infection era: national trends. Proc. Roy. Soc.. 205, 47-61. (also Preface, Proc. Roy. Soc. . 20b'. 3-4) 251 DOLL,R. (1979). Nutrition and cancer: a Review. Nutrition and Cancer. 1, 35-45 252 DOLL,R. (1979). Epidemiology of cervix cancer. Advances In Medical Oncology, Research and Education. voi. 8. ed. N.ThatcherT Pergamon Press, oxiord. 253 DOLL.R., (1979). Smoking, Industrial Pollutants and their interactions. Advances in Medical Oncology. Research and Evaluation." vol. 11. ed. P.M. Wilkinson pp 9-14. Pergamon Press, Oxford. 254 MEDICAL RESEARCH COUNCIL WORKING PARTY ON LEUKAEMIA IK ADULTS (incl. R.DOLL) (1979) Chemotherapy of acute myeloid leukaemia in adults. Brit. J. Cancer, 39, 69-66 ------------------------------ " 255 DOLL.R. (1979). Epidemiological Enquiry - power and limitations. In: Environmental Carcinogenesis Ed. p. Enmelot and E. Rriek, Elsevier, Amsterdam 256 KINLEN,L. J.SHEIL.A.G.R., PETO,J. and DOLL.R. _1079) Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs. Brit. -Med. J.. 2, 1461-1466. 257 MEDICAL RESEARCH COUNCIL'S WORKING PARTY FOR LEUKAEMIA IN ADULTS AND THE OXFORD LYMPHOMA GROUP (1976). Light chain isotype associated suppression of normal plasma cell numbers In patients with multiple myeloma. Int. J. Cancer. 24, 385-393 1680 258 DOLL.R., GRAY,R., HAFNER.B., and PETO,R. (1980) Mortality in relation to smoking: 22 years' observation on female British doctors. Brit. Med. J. 260. 967-971 259 DOLL,R. (1980). The epidemiology of cancer.' Cancer. 45, 2475-2485. 260 HARRIS,R.W.C., BRINTON,L.A., COWDELL,R.H., SKEGG.D.C.G., VESSEY.M.P., and D0LL,R. (1980). Characteristics of women with dysplasia or carclnoma-ln-sltu of the cervix uteri. Brit. J. Cancer. 42, 359-369 1981 261 DOLL,R. (1980) The interface between epidemiology and cancer control policy. Cancer. 1., 35-50 262 DOLL,R., (1981). Relevance of epidemiology to policies for prevention of cancer in Nickel Toxicology Ed. G.S. Brown pp 3-8 Academic tress, ^iew York 263 CUCKLE,H., DOLL.R., and MORGAN,L.G, (1981) Mortality studies of men working with soluble nickel compounds in Nickel Toxicology. Ed. G.S. Brown, pp 10-14, Academic tress. New York 264 DOLL,R. (1981). Radiation hazards: 25 years of collaborative research. Brit. J, Radiol.. 54, 179-186 265 SMITH,P.G., and DOLL,R. (1981) Mortality from cancer and all causes among British radiologists. Brit. J. Radiol.. 54, 187-194 266 DOLL.R., and ARMSTRQNG.B. (1981) Environmental factors of certain diseases: %^mmmes. in Western Diseases: their emergence and prevention. Ed. V.c. Trowell and D.P. Burkett, pp 93-110, Arnold, London 267 PET0,R., DOLL.R., BUCKLEY,J.D., and SPORN.M.B. (1981) Can dietary beta-carotene materially reduce human cancer rates? Nature. 290. 5803-5810 . 268 WALD,N., DOLL.R., and COPELAND,G. (10B1) Trends in tar nicotine, and carbon monoxide yields of U.K. cigarettes manufactured since 1934. Brit. Med. J. 282, 763-765 URL 11739 193 1 contd. 269 DOLL, fi. (19B1) Problems of interpreting the epidemiology of oral contraceptive associated liver tjrj-r* in Drug Reactions and the Liver* Eds. Devis,.M., Tredger, J.M., and Williams, R. pp. 31c -- 312 Pitman Medical, Bath. -- URL 11 MO 270 .VESSEY, M.P., McPHERSON, K.t and DOLL,.*. (1981) -Breast cancer and oral contraceptives: findings in Oxford - Family Planning Association contraceptive study. Brit. Hed. J., gS2. 2092-209* 271 DOLL, F. and PETO, R. (1981) The causes or cancer. Quantitative estimates of avoidable risks of cancer in the United States today. J. Natl. Cancer. Instg., 66, 1196-1308 and aasaseed published by Oxford University Press. 272 DOLL, R. (1981) Relevance of epidemiology to policies for the prevention of cancer. J. Occup. Med., 23. 601-609 273 COX, J.E., DOLL, R., SCOTT, W.A., and SMITH, S. USED Mortality of nickel workers: experience of men working with metallic nickel. Brit. J. Industr. Med., 36. 235-239. 27* COOK-MOZAFFARI, P., BULUSU. L., and DOLL, R. (1981) Fluoridation of water supplies and cancer mortality. 2. A search for an effect in the U.K. on risk of death from cancer. J. Epidem. Community Hlth.. 35. 227-232. 275 COOK-MOZAFFARI, P., and Doll, R. (1981) II. Mortality trends after fluoridation. j. Epidem. Community Hlth., 35, 233-236. 276 K2NLEN, L., and Doll, R. (1961) III. A re-examinatior of mortality in cities in the U.S.A. J. Epidem. Community Hlth., 35, 239-2**. 277 BUCKLEY, J.D., HARRIS, R.W.C., DOLL, F., VESSEY, M.P., and WILLIAMS, P.T. (1961) Case-control study of the husbands of women with dysplssia or carcinoma of the cervix uteri. Lancet. 2, 1010-1012 276 MANNING, K.P., SKEGG, D.C.G., STELL, P.M., and DOLL, F. (1981) Cancer of the larynx and other occupational hazards of mustard gas workers. Clin. Otolaryngol.. 6, 165-170. 279 DOLL, R. (1981) The smoking-induced epidemic. Canad. J. Publ. Hlth.. 72, 372-381. (1981) 280 SKEGG, D.C.G., and DOLL, R. 1 Record linkage for drug monitoring. 0. Epidem. Community Hlth., 25-31. 281 SKEGG, D.C.G., RICHARDS, S., and DOLL, R i^ssessment of the 'E1 book as a tool for drug monitoring. J. Epidem. Community Hlth.. 35, 32-3*. 19E? 283 ShiTH, P.G., and DOLL, R. (H_*) Mortality among patients with ankylosing spondylitis after a single treatment course with x-rays. Brit. Med. J.. 264. 449-460. 284 VE55CY, H.P., McPKERSON, K., YEATE5, D., and DOLL, R. (1962) Oral contraceptive use and abortion before first tens pregnancy in relation to breast cancer risk. Brit. 0. Cancer. 46. 327-331. 285 SKEGG, D.C.C., CORWIN, P.A., PAUL. C.f and DOLL, R. t (1962) laportanee of the aale factor In cancer of the cervix. Lancet. Z% 561-583. 286 DOLL, R., and PETO, R. (1962) Morbidity versus mortality (letter) J. Nat. Cancer Inst.. 69. 549-550. 287 DOLL. R. (1962) Oesophageal carclnoaa, epldealology in Topics in Gastroenterology, 10. Eds. D.P. 4ewell and V.S. 5lby. Blackwell scientific Publications, Oxford. 268 DOLL, R. (1962) Green College, Oxford: its contrlbutlor to clinical medicine. Brit. Hed. J.. 285. 1805-1606. 289 DOLL, R. (1962) Clinical trials: retrospect and prospect. Statistics in Med. . J., 337-344. 290 DOLL, R. (1982) Prospects for prevention. I Royal College of Physicians, London, reprinted Brit. Med. J. (1983), 286, 445-453 and (abbreviated) in World Health forum. 4, 219-227. URL 11 Ml 1963 291 DOLL, R. (2982) Underlying concepts of cancer control in the future. In: Cancer Prevention in Developing Countries. Eds. Aoki, K., Tomlnaga, S., Hirayama, J., and ttiroto, J. University of Nagoya Praaa, Nagoya. 292 KINLEN, L., DOLL, R., and PETO, J. (1963) The Incidence of tumors in human transplant recipients. Transplantation Proceedings. 15. 1039-1042. 293 VESSEY, BARON, J., DOLL, R., McPKERSON, K,, and YEATES, D. (1983) Oral contraceptives and breast cancer: final report of an epidemiological study. Brit. J. Cancer. 47. 455-462. 294 DOLL, R. (1983) Cancer control. Symposium on Medical Management of Malignant Disease. Royal College of Physicians of Edinburgh, Edinburgh. 295 CUZICK, J., VELEZ, R., and DOLL, R. (1983) International variations and temporal trends in mortality from multiple myeloma. Int. J. Cancer. 32, 13-19. --------------------------- 1963 296 FORMAN, Dr DOLL, R., ftnd PETO, R. (1983) cont'd Trends In mortality from carcinoma of the liver and the use of oral contraceptives. Brit. J. Cancer. 48. 349-354. __ 297 DOLL, R. (1963) Prospects for the prevention of cancer. Clin. Radiol., 34. 609-623. 298 PRANCESCHI, S., DOLL, R., GALLWET, J., LA VECCHIA, C., PETO, R. and SPRIGGS, A.I. (1983) Genital warts and cervical neoplasias an epidemio logical study. Brit. J. Cancer, 48, 21-628. 1984 299 WALD, N., BOREHAM, 3., DOLL, R., and BONSALL, J. (1984) Occupational exposure to hydrazine and subsequent risk of cancer. Brit. J Industr. Ned., 41, 31-34. 300 DOLL, R. (1984) Smoking and death rates. 3. Amer. Med. Ass., 231, 2854-2857. 301 DOLL, R. (1984) Prevention of cancers practical prospects. Ann. Acad. Ned. (Singapore), 13(2), 194-205. URL 11742 302 DOLL, R. (1984) Epidemiological discovery of occupational cancers. Ann. Acad. Ned. (Singapore), 13(2) (Suppl), 331-339. 303 DOLL, R. (1984) Occupational cancers problems in interpreting human evidence. Ann. Occup. Ned., 28, 291-305. 304 PETO, R. and DOLL, R. (1984) Keynote address: the control of lung cancer. In: Lung Cancer: Causes and Prevention. Verlag Chemie International Inc. 305 DOLL, R. (1984) ..The controlled trial. PostQrad. Ned. J., 60, 719-724. 306 DOLL, R. (1984) Nickel exposure: a human health hazard. 1ARC Scientific Publication No. 53. ed. F.H. Sunderman. pp.3-21 307 PETO, J., COCKLE, H., DOLL, R., RERMON, C. and MORGAN, L.G. (1984) Respiratory cancer mortality of Welsh nickel refinery workers. IARC Scientific Publication No. 53. ed. F.W. Sunderman. pp.37-46. 1985 30B FORMAN, D., AL-DABBAGH, S., and DOLL, R. (1985) Nitrates, nitrites and gastric cancer in Great Britain. Nature. 313. 620-625. 19B5 309 DOLL, R. (1985) cont`d Occupational cancer: a hazard for epidemiologists. Int. j, Fpide-iol., 14, 22-31. 310 DOLL, R. ( 1.965) ---- Relevance of epidemiology to policies for the prevention of cancer. Human Toxicol,, 4, 79-116. 311 DOLL, R, and PETO, J. (1985) Asbestos: Effects on Health of Exposure to Asbestos. A Report to the Health and safety commission, HMSO, London* 312 GREENBERG, E.R., VESSEY, H.P., MCPHERSON, K., DOLL, R. and YEATES, D. (1965) Body sise and survival in premenopausal breast cancer. Br. J. Cancer, 51,, 691-697. 313 PETO, R. and DOLL, R. (1985) The control of lung cancer. New Scientist, 24 January, 1985. 314 PETO, J., DOLL, R., HERMON, C., BZNNS, W., CLAYTON, R. and GOFF, T. (198S) Relationship of mortality to measures of environmental asbestos pollution in an asbestos textile factory. Ann. Occup Hvq., 29, 305-355. URL 11743 315 FORMAN, D., BENNETT, B., STAFFORD, J. and DOLL, R. (1985) Exposure to vinyl chloride and angiosarcoma of the liver: a report of the register of cases. Brit. J. industr. Med., 42, 750-753. 316 FORMAN, D., AL-DABBAGH, S, and DOLL, R. (1985) Nitrate and gastric cancer risks, (letter) Nature, 312# 675-676. 317 DOLL, R. (1985) Richesses de la Difference. Recherche Medicale, Sante. Societe. Collogue organise a ^'occasion du XXerae anniversaire de L'Xnstitut Nationale de la Sante et de la Recherche Medicale, 27 6 28 Octobre 1984. 1NSERM, Paris. 318 DARBY, S.C., DOLL, R. and PIKE, M.C. (1985) Detection of late effects of ionising radiations: why deaths of A-bomb survivors are a valuable resource. Int. J. Epidemiol,. 14, 637-636. 1986 319 McCANCE, D., KALACHE, A., ASHDOWN, K., ANDRADE, L., MENE2ES, F., SMITH, P. and DOLL, R. (1985) Human papillomavirus types 16 and 18 in carcinoma of the penis from Brazil. Int. J. Cancer, 37, 55-S9. lm 320 NEUBERGER, J., FORMAN, D., DOLL, R. and WILLIAMS, R. cont'd (1966) Oral contraceptives and hepatocellular carcinoma. Brit. Med. . 292, 1355-1357. -- 321 FORMAN# D., VINCENT# T.J. and DOLL# R. (1986) Cancer of the liver and the uae of oral contraceptives. ' Brit. Med. J.. 292# 1357-1361. 322 HARRIS# R.W.C., FORMAN# D. # DOLL# R., VESSEY# M.F. and WALD# N.J. (1966) Cancer of the cervix uteri and vitamin A. Brit. J. Cancer# 53, 653-659. 323 AL-DABBAGH# 6.# FORMAN# D. # BRYSON# D.. STRATTON, 1. and DOLL# R. (1966) Mortality of nitrate fertiliser workers. Brit. 3. industr. Med., 43. 507-515. 324 DOLL# R. (1986) The quantitative significance of asbestos fibres in the ambient air. In: Advances in Aerobiology, Proceedings of the 3rd International Conference on Aerobiology. Eds. G. Boehm and R.M. Leutschner. Birkhaeuser Verlag, Basel. L ilia n 325 DOLL, R. (1986) Implications of epidemiological evidence for future progress. In: Banbury Report 21: Viral Etiology of Cervical Cancer. Eds. R. Peto an^H. tur Hausen, dp.321-326. Cold Spring Harbor Laboratory, 1986. 326 DOLL, R. (1966) Cancer: a world-wide perspective. In: Biochemical and Molecular Epidemiology of Cancer, UCLA Symposium on Molecular and Cellular Bioloov. New Series.vol. 40. Ed. cTc. Harris. pp7lll-125. Alan rTlTss, New York. 327 DOLL, R. (1986) Possibilities for the prevention of cancer. A lecture for the public gi7en on 13 November 1966, The Royal Society, 1986. 326 PETO, J. and DOLL, R. (1986) Passive smoking. Br. J. Cancer, S4. 381-383. 329 DOLL, R. (1986) Cancer: a preventable disease? Royal Society of Medicine, London. 1966 330 DOLL, It. (1986) cont * d Tobaccos an overview of health effects. In* Tobaccos A Major international Health Hazard. Eds. D. Zaridse and R. peto. IARC Scientific --7 Publications No. 74* International Agency for Research on Cancer, Lyon. 331 KALDOR, J., PETO, J., EASTON, D., DOLL, It., BERfcON, C. and MORGAN, L. (1986) Models for respiratory cancer in nickel refinery workers. J. Natl. Cancer Inst., 77, 641-846. 1987 332 DARBY, 6.C., DOLL, R., GILL, 6.K. and 6MITB, P.G. (1987) Long tern nortality after a single treatment course with s-rays in patients treated for ankylosing spondylitis. Br. J. Cancer. 55, 179-190. 333 DOLL, R. (1987) Future prospects for population health research. Transactions of the Menties Foundation, 13, 227-229. 334 DOLL, R. (1987) The role of epidemiology in the detection and reduction of cancer risks. Cancer Risks* Strategies for Elimination. Ed. p. Bannasch. pp.14-23. Springer-Verlag, Berlin. URL 11745 335 DARBY, S.C. and DOLL, R. (1987) Fallout, radiation doses near Dounreay, and childhood leukaemia. Brit. Med. J., 294, 603-607. 336 DOLL, R. (1987) Environmental chemicals and cancer. Chemistry in Britain, 23, 847-849. 337 FORMAN, D., COOK-MOZAFFARZ, P., DARBY, 6., DAVEY G., STRATTON, I., DOLL, R. and PIKE, M. (1987) Cancer near nuclear Installations. Nature, 329, 499-505. 338 DARBY, S.C. and DOLL, R. (1987) Childhood leukaemia, fallout and radiation doses near Dounreay. In* Radiation and Health. Eds. R. Russell Jones and R. Southvood. pp7 221-231. John Wiley & Sons Ltd., 1987. 339 MCPHERSON, K. , VESSEY, M.P., NEIL, A., DOLL, R., JONES, L. and ROBERTS, M. (1987) Early oral contraceptive use and breast cancers results of another case-control study. Brit J. Cancer, 56, 653-660. 340 DOLL, ft. (1987) Medicine and Geography. Ini Orography ind it Neighbours, School of Geograp>EyT""0nIveriTty'"o7""0x7r3','fte search Papers. r Ed. A.p. Treadgold. 341 DOLL, ft. and PETO, J. (1987) Other eebeetos related neoplasms. In* Asbsstos-relstsd Malignancy. Eds. K. Anman and J. Aiener. pp. 81-96. Crune a Stratton, Orlando. 342a DOLL, ft. (1987) Major epidemics of the 20th century* from coronary thrombosis to AIDS. J. roy. Stat, Boc.. Series A, 150, 373-395. 342b DOLL, ft. (1988) Major epidemics of the 20th century* thrombosis to AIDS. Social Trends. 18, 13-22. from coronary 343a DARBY, S.C., KENDALL, G.M., FELL, T.P., O'HAGAN, J.A., MU2RHEAD, C.K., ENNIS, J.R., BALL, A.M., DENNIS, J.A. and DOLL, ft. (1988) Mortality and cancer incidence in UK participants in UK atmospheric nuclear weapon tests and experimental programmes. Report R214 National Radiological Protection Board, Chilton. 343b DARBY, S.C., KENDALL, G.M., FELL, T.P., O'HAGAN, J.A., MUXRHEAD, C.X., ENNIS, J.R., BALL, A.M., DENNIS, J.A. and DOLL, ft. (1988) A summary of mortality and incidence of caneer in men from the United Kingdom who participated in the United Kingdom's atmospheric nuclear weapon tests and experimental programmes. Brit, med. J.. 296, 332-336. 344 PETO, ft., GRAY, R., COLLINS, R., WHEATLEY, K., KENNEKENS, C., JAMROZIX, X., WARLOW, C., HAFNER, B., THOMSON, E., NORTON, S., GILLILAND, J. end DOLL, R* (1986) Randomised trial of prophylactic daily aspirin in British mala doctors. Brit, med. J., 296, 313-316. REVIEWS SMntf y If'tw* Environ Health 14 (1988) 61--78 >| c-juA Effects of exposure to vinyl chloride An MMtiiMnt of tho ovMonco by Sir Richard Doll, FRS1 DOLL ft. Effects of exposure to vinyl chloride: As wHprm of the evidence. Scaitd J Work Environ Htohh 14 (1988)61--71. This paper review* the possible effects of vinyl chloride on the mortality of oc cupationally exposed meo and the cardoogenk effect* that might be observed in the general population as a result of environmental pollution with vinyl chloride. The remits of four studies fulfilling the criteria of providing substantial numbers of observations more than 23 yaars after first exposure mod covering a period long enough for more than 10 % of the workers to have been expected to die constitute the basis for the assessment of the occupational hazards. Other studies provide only supplementary information. The data permit two conclusions. First, men occupationally cxpoaad to vinyl chloride have experienced a specific hazard of angiosarcoma of the liver. Second, any other occupational hazards that may have existed have been small. No positive evidence of a hazard of any nomnalignant disease or any type of cancer other than angiosarcoma of the liver has been found except possibly for a small hazard of hing cancer when exposure was heavy. More definite conchmom might he reached if those who have studied exposed employees could present their results in appropriate and comparable ways. A very small risk of angiosarcoma may have occurred as a result of vinyl chloride into the environment arok.id plants handling vinyl chloride in the pan, but the evidence indicates that the current risk to the general public (if any) must be negligible. Key terms: angiosarcoma of the liver, cancer, hug cancer, mortality, polyvinyl chloride, review, vinyl chloride monomer. For many years the inhalation of large amounts of vinyl chloride has been recognized as potentially haz ardous. Concentrations of the order of 10 000 ppm in the air induce unconsciousness and cardiac arrhyth mia. while prolonged exposure to concentrations an order of magnitude lower have been liable to cause a specific pathological syndrome. This "vinyl chloride illness" has been characterized by four cardinal signs, namely, enlargement or the liver and spleen with a specific histological appearance, patchy infiltration of the skin resembling scleroderma, bony changes in the tips of the fingers described as acroosteolysis, and peripheral circulatory changes identical with the clas sical picture of Raynaud's disease. These pathologi cal reactions may occur singly or together and may pos sibly be accompanied by other less characteristic ef fects. They can, however, be completely avoided if ex posure never exceeds the level of a few hundred parts per million, ie, the level to which exposures were generally reduced in the mid-1960s. One other serious effect has, however, been observed that may not be avoidable in the same relatively easy way, namely, the production of angiosarcoma of the liver. It must, indeed, be presumed that some risk of developing the disease will persist from exposure to ' Imperial Cancer Research Fund. Cancer Epidemiology and Clinical Trials Unit, Radcliffe Infirmary, Oxford. United Kingdom. Reprint requests to: Sir R Doll, Imperial Cancer Research Fund. University of Oxford, Gibson Building. The Radcliffe Infirmary , Oxford OX2 6HE. United Kingdom. doses that are even lower than the current industrial levels of S ppm or less, as vinyl chloride has been shown to act as a mutagen (23), and it cannot be assumed that a threshold exists below which no carcinogenic risk persists. Moreover, the possibility has to be considered that vinyl chloride may cause some cancers other than angiosarcoma of the liver, partly because laboratory studies have shown that it causes other cancers in animat experiments and partly because 'the initial studies demonstrating the production of angiosarcoma of the liver in humans were inadequate in size to ex clude a materia] increase in the risk of cancer in com mon sites, such as the lung and large bowel. Since no threshold dose can be postulated, it also follows that some cancers may have been produoed in the genera! public by the small amounts that have escaped into the general environment. Consideration also needs to be given to the possi bility that exposure to vinyl chloride over a long pe riod may have noxious effects on humans that cannot be seen easily in animal experiments (by, for example, producing chronic respiratory disease), and, as it is a mutagen, there is also a possibility that it may act as a teratogen and cause congenital malformations in offspring. In this review I have not examined the possibility that vinyl chloride acts as a teratogen or that it causes mutations in germ cells, as there is too little serious evidence to justify inclusion. Reviews carried out for sections of the industry by Downs et al (unpublished report to the Society of Plastic Industries Inc in 1977) 1 61 URL 11748 and by MacMahon (unpublished report to the Chemi sure). These requirements do noL introduce any new cal Manufacturers Association in 1977) concluded that complexity, as both are, of course, also required if cor- the few reports of positive effects could not be sub rea conclusions are to be drawn from the results of stantiated. and do additional evidence was found in the individual studies when they are examined on their a similar later review by Ban (unpublished report to own. Air Products and Chemicals Inc In 1961), apart from a report that embryos were absorbed and skeletal os sification was produced when pregnant rats were ex posed to doses appreciably lower than those that had been used by ocher workers without any such effects being observed. Hie report of absorbed embryos (34) could not be evaluated thoroughly, however, as the ex periment was inadequately described. 1 have, therefore, ecamined only the possible effects on the personal health of men occupationally exposed to vinyl chlo ride. ocher than those related to their reproductive capacity, and the carcinogenic effects that might con ceivably be observed in the general population as a result of the widespread distribution of vinyl chloride as a pollutant. Sources of information Four studies meet the aforementioned requirements, namely, two large national surveys, one reported by Jones (23) for the United Kingdom (UK) and the other by Environmental Health Associates (14) for the United States (US), and studies of individual plants in Canada, reported by TMriault & Allard (46) and in Italy, reported (ns span ofa national study) by Belli ct a) (4). AD four include observations on men more than 23 years after their first exposure, and the ex pected number of deaths is, in each case, greater than 10 of the total number' of employees, a value indi cating a long average period at risk. Earlier observa tions on UK and US employees (6, 9, 12, 16, 20, 36, 39,40,43,30) have been subsumed in the national sur Occupational hazards veys and now serve only as sources of hypotheses and of some detailed information not included in the na Many studies of workers exposed to vinyl chloride in tional reports. Studies of German (49), Norwegian the manufacture of vinyl chloride monomer (VCM) (22), Swedish (7), French (41, and unpublished report and polyvinyl chloride (PVC) have been undertaken of Laplancbe et al), Japanese (33, 37), and some other since it was first found that vinyl chloride could cause Italian (4) workers provide some supplementary infor cancer in animals (28,48) and man (10). These inves- ' mation, but, in genera), the periods of observation tigations have confirmed that exposure causes a haz have not been long enough for useful epidemiologic ard of angiosarcoma of the liver and, in several in data to be obtained about diseases that are unlikely stances, have shown excess incidence or mortality rates to occur within 20 years of first exposure, or they that were conventionally statistically significant for report only seleaed results which are difficult to in other diseases. Conventional tests of statistical signifi terpret, as only excess rates tend to have been selected. cance are. however, designed to help answer single Studies of makers of PVC produas have not been questions defined beforehand, and several findings that included, as the workers have had much less exposure might be expected to occur by chance alone once in to vinyl chloride than those employed in the manufac (say) 20 times must be expeaed to occur if dozens of ture of VCM or PVC and any occupational hazard to rates are examined in each of several sets of indepen which they may have been exposed is more likely to dent data. Scientists have, therefore, been faced with have been produced by PVC dust. the problem of deciding whether the excess rates that have been observed in individual studies are due to oc US study. The study carried out by Environmental cupational hazards or to the vagaries of chance. Health Associates (14) on behalf of the US Chemical This problem can be solved in part with an exami Manufaaurers Association is the largest and most in nation of the results of a sumation of data from com formative investigation thus far undertaken. It cov parable studies, that is, by a comparison of the sums ered 10 173 men who had worked in 37 plants owned of the numbers of deaths observed and expeaed in each study. This procedure does not require the as sumption that the exposures have been the same in each study any more than the same assumption is required for each individual when the results of each study are considered alone. It does require however that each exposed population has been observed over a period when its members were at risk of developing disease (if a genuine hazard existed) and that in each study the reference population from which the expeaed num bers of deaths were derived was appropriate (that is, at the same risk of developing disease as the exposed population would have been in the absence of expo by 17 companies -- 1 214 men in 11 plants that produced only VCM, 6 848 men in 18 plants that produced only PVC, 935 men in three plants that produced both, and I 176 men in five plants that produced homopolymers and copolymers, with or without VCM or PVC. Twenty-two of the plants were in the southern pan of the country, 14 were in the northeastern or north central parts, and one was in the west. Men were included if they had been exposed to vinyl chloride for at least a year before 31 December 1972 and had been employed in 1942 or subsequently (the first year depending on the date the plant began making 62 r or using vinyl chloride tad the earliest date that per* sonnel records were deemed to be complete, whichever was the later). Individuals who met these criteria were identified from company records by company per* sonnel. Racial characteristics were known only for 686 men, 97 % of whom were white, and it was presumed, for the purpose of *"*ting the number of expected deaths, that all 10 173 men were white. Follow-up data were obtained from plant and So da! Security Administration records and (for men who died after 1979) from the National Death Index. Five plants did not collaborate in the extension of Cooper's (9) earlier study, which had been subsumed in the present investigation, and the 933 employees in these plants who were known to be alive on 31 December 1972 were not followed any further. For the rest, follow-up was attempted to death or 31 December 1982, whichever was the earlier. On this basis 92.7 9* of the men were successfully traced. Those who were untraced were excluded from the last date of contact, which was usually the date when employment ceased. Almost half of the men (46 9) were first employed before 1933. A large proportion was, therefore, ob served more than 23 years after first exposure (and in many cases for more than 30 years) when diseases with e long latency period might be expected to be seen. Short-term workers had been excluded from the cohort, and most of the men had continued in em ployment for many years, two-thirds being employed for 10 years or more and the average duration of em ployment being 16 years. Fifteen hundred and thirty-six men were found to have died. In 1 439 cases, the cause of death was ob tained from the death certificate, but no cause was ob tained for the other 97 persons (6.3 *7). The numbers of deaths expected from each of 38 causes or groups of causes were obtained by multi plying the person-years at risk by the disease-specific national rates for white males, for the corresponding age groups and five-year periods of the study. This important study is open to three minor criti cisms, which are unlikely to have had any material effects on the results. First, the lists of employees were compiled by company personnel from company re cords without any independent check. Second, the as sumption that all the employees were white will have caused the expected deaths to have been very slightly underestimated, as the few black employees are likely to have had higher mortality rates and there is no reason for supposing that the small sample from which the proportion of black employees was estimated was necessarily representative. Third, an element of uncer tainty was introduced by the failure to trace as many as 7.3 of the employees. Two other criticisms are more important. First, the expected numbers of deaths were calculated on the as sumption that the men would have experienced the same mortality rates as the white male population of the whole country at the corresponding dates. The use of national rates is common practice in studies of in dustrial populations and tends to result in an overestimation of the expected numbers of deaths so that the employees appear to be unusually healthy. This "healthy worker effect" is well known and has been taken into account in my discussion of the results. A more serious objection to the use of national rates is the way mortality varies from one part of the country to another, due to differences in the prevalence of en vironmental and social factors unrelated to the occu pation ofinterest. It is, therefore, generally preferable to use state (if not county) rates, in place of national rates. With 37 plants, however, h might be thought that their geographic distribution would be sufficiently wide to make the use of national rates appropriate. Unfortunately 22 of the plants were located in the eouth, and a check would have been desirable to see whether their location could have caused any material distortion of the results. Second, causes were not obtained for 97 of the 1 336 deaths. This deficiency was allowed for in the calcu lation ofthe overall mentality by the inclusion of deaths due to unknown causes. It was not allowed for, how ever, in the calculation of the disease-specific mortality rates and will have caused the standardized mortality ratios to be underestimated by an average of 6.3 9e. For the present purpose, therefore, the numbers of deaths attributed to specific diseases have each been multiplied by 1.0674 [100/(1--97/1536)] and rounded off to the nearest integer. UK study. The study reported by Jones (23 and un published) on behalf of the British Health and Safety Executive covered 5 498 men who were employed for at least one year in jobs that involved potential expo sure to VCM for at least 23 9* of the work week and who were first employed in the period 1940--1974. De tails of the men were compiled from the personnel records of nine chemical plants manufacturing or poly merizing vinyl chloride, and the vital status of the men was determined at the end of 1984 from the records of the National Health Service Central Register. Five thousand four hundred and ninety-eighi men were traced (98.9 9). Seven hundred and eighty deaths were identified, and copies of the death certificates [coded to the eighth revision of the International Classifica tion of Diseases (1CD) if they occurred before 1979 and to the ninth revision if they occurred later] were sent to the investigators. Several specific points about the study need to be noted. First, national mortality rates for England and Wales were calculated for five-year age groups over quinquennia] periods for 66 causes of death, and these rates were used in the estimation of the numbers of deaths that might have been expected in Ihe cohon by multiplying them by the corresponding numbers of person-years under observation. Some difficulty which could have been related to the causes of death being 63 4 coded according to the eighth and ninth revisions of presumed that the expected numbers of deaths in the the ICD was, however, experienced in obtaining suit* first two exposure categories are likely to have been able rates for all cause; of death, and rates for a rela overestimated. tively late period had to be used for estimating the numbers of deaths from many dsseaset that might have been expected to occur in earlier periods. For two categories the earbest available rates were 1960--1964, for one they were 1965--1969, for 34 they were 1970-- 1974, and for one they were 1975--1979. Canadian study. The Canadian study (46) was limited to employees of a single plant in Shawinigan, Quebec. The plant, which was situated in an industrial com plex, was opened in 1943. VCM and PVC were both made until the late 1960s, when the production of Second, an attempt was made to classify men ac VCM ceased, while the production of PVC continued. cording to whether they had high, intermediate, or low An attempt was made to trace all the production work exposure to VCM or PVC dust, and each man's em ers whose names appeared on the unions' lists or the ployment history was recorded according to 12 job payrolls ofthe companies in the whole industrial com titles with advice from the plants concerned. The men plex, including the vinyl chloride plant, between I I were then grouped according to whether exposure to January 1948 and 31 December 1972, and contact was VCM was likely to have been high (group A), expo made with the worker or his next-of-kin in 1 611 out sure to PVC dust was likely to have been high with of 1 659 instances (97.1 %). Detailed occupational and exposure to VCM low (group B), or exposure to VCM histories were *****< by questionnaire, and and PVC dust was intermediate and intermittent 156 men who had been employed by the companies (group C). All other men, who would generally have for less than five yean were excluded. The remaining had low exposure to both VCM and PVC dust, were men were categorized as (i) exposed to V CM if they classed as group D. Within all the groups, exposure had worked on the production of VCM or PVC for to VCM was likely to have been higher if it had begun at least five years (451 men), (ii) unexposed to VCM before 1956. if they had worked similarly for less than six months URL 11750 The study makes an important contribution to the knowledge concerning the long-term effects of vinyl chloride. The use of national rates to calculate the ex pected numbers of deaths may be justified on the grounds that the men were employed in nine plants, which were presumably distributed about the country, but no details of their location are given. In general, mortality rates tend to be higher in the parts of Britain where heavy industry is located than in other pans of (870 men), and (iii) other men (134 in total). The last group was excluded from the study. Follow-up was closed on 31 December 1977. Copies of the death cer tificates were obtained, and the causes for all who had died (59 exposed and 233 unexposed) were coded ac cording to the eighth revision of the ICD. Informa tion was also sought for histological or cytological con firmation of all the diagnoses for all the exposed men who had died of cancer. the country so that the expected numbers of deaths are The results were examined in two ways. First, the more likely to be biased downwards than upwards; but mortalities of the exposed and unexposed men were whether this is so or not needs to be shown. compared after standardization for five-year periods The use of recent rates to calculate expected num bers of deaths from many specific causes of death was presumably necessary if the diseases were to be studied individually and will have done no harm if (he inci dence and fatality of the diseases in question remained stable. It would have been desirable, however, for the to have been specified so that the reader would know which were liable to be distoned. of the study and five-year age groups. Second, the mor tality of the exposed men was compared w ith that ex pected if the men had had the sex- and age-specific mortality rates recorded in Quebec for the year 1971. In both comparisons the causes of death used were those specified on the death certificate, and the addi tional pathological information was used later onh for interpretation of the results. The system used to classify the men into four expo sure groups is the son of system that is commonly used If precise measures of exposure are not available. It creates some difficulties in the statistical analysis if men Most of the exposed men were exposed for more than 10 years (75 ^), the average length of exposure was approximately 17 years, and 44 were observed more than 25 years after first exposure. move from one job to another and are classed (as in Although small, the study makes a useful contribu this instance) as having had high exposure if they have tion to the overall results. The histological review of ever had a particular type of employment (eg, ever been the cancer cases is particularly helpful. It showed that employed as an autoclave worker). No evidence is pro all eight cancers diagnosed as liver cancer (including i vided to show that the person-years at risk before a two specified as hepatoma and one specified as angio- man entered the category have been subtracted and sarcoma) were angiosarcomas of the liver, as well as ; added to another exposure group before the numbers one that had been diagnosed as angiosarcoma of the of expected deaths were calculated. Movement from peritoneum. Two other cases of angiosarcoma of the one job to another was said to have tended to be out liver were found to have been certified as hepatic cir of groups A and B into D, but even so it must be rhosis. It is also helpful to have a comparison between 64 URL 11151 the exposed and "unexposed" employees of the same companies as it shows that the low mortality observed for all nonmalignam diseases could be attributed to a healthy worker effect and was not due to bias in the recording of exposure (relative risk for all nonmalignant causes compared to that of the `imexposed" men 0.95). One aspect of the study has to be criticized however, fe, the use of provincial rates for one year (1971) to calculate expected mortality spread over a 30-year period (1948 to 1977 indusive). Deaths will have leaded to bunch up towards the end of the period of obser vation so that the rates for this particular year may have been fairly representative, but it must have caused some distortion of the expected numbers of deaths, the size (and even the direction) of which is impossible to estimate. For most disease groups the distortion is un likely to have been large. Italian study. A study of all men employed in the pro duction of vinyl chloride and PVC in nine Italian plants was begun in 1983. All men were included who were employed for at least six months at any time from the start up of the plant to the end of 1981. The study is still incomplete, but results are now available for men in three plants (4). Two plants (in Ferrara and Rougnana) began operation in 1953. Four hundred and thirty-seven men were employed in one plant and 181 in the other. All but three (from the Ferrara plant) were followed to the end of 1984. Expected deaths were esti mated by multiplying the person-years at risk by the corresponding national mortality rates for each fiveyear age group and each five-year period of the study. The total expected deaths in each case amounted to more than 10 of the employees in the two plants (12.4 and 12.8 *). Clinical information was sought about the cause of death of all the 55 employees of the Ferrara plant who had died. Revised diagnoses, which were not used for comparison with the expected deaths, revealed four deaths from cancers of the liver in place of one. The Ravenna plant did not begin operation until 1959. Six hundred and thirty-right men were employed. All but four were traced to the end of 1983, and 17 were found to have died. No man could have been fol lowed for more than 24 years, and only 25.1 deaths (3.9 of the work force) were expected. The data for this plant have not, therefore, been used in the prin cipal analyses. It may be noted, however, that one death was attributed to liver cancer when 0.1 was ex pected. Other sources. The Norwegian study (22) provided ob servations on 454 men who had been employed in a plant in Telemark where VCM had been manufactured from 1950 to 1971 and PVC from 1950 to the end of the study period. Every man was included whose name was recorded in the company's personnel register and health department records whd~Ead ever been em ployed from the start of production to the end of 1969 and had worked for at least one year. The men were followed from 1953 to 1979 inclusive. Deaths and cases of cancer were identified from the records of the Cen tral Bureau of Statistics and the national cancer regis try. No reference was made to any men being lost to follow-up, but it can be assumed that the number (if not aero) was small, as all citizens have an identity number which is used by both employers and central tenors. Fifty men were found to have died against 59.34 expected if the sex-, age-, and quinquennium^sedftc national mortality rates had operated. Twentyooc men were found to have developed 23 cancers against 20.16 cancers *p****4 from the comparable national incidence rates, the use of which was justi fied by the finding that the incidence in the county in which the plant was situated was between 90 and 95 of the rate of the country as a whole. One man who had been employed in PVC production developed an giosarcoma of die liver. The observed and expected numbers of cases were given for cancers of the lung, colon, and thyroid, for melanomas, and for all can cers, but no expected numbers were given for other types of cancer. It is evident that several other types of cancer must have been in deficit, as there were eight eases in all against 14.93 expected, and it is difficult to know what weight to give the excesses observed for the reported types of cancer, as they seem likely to have been reported specifically because the numbers were in excess of those expected. The authors noted that one further case of melanoma had occurred after the closure of the study and that one "incipient case" was also known to them. The German study (49) included the following three groups: (i) 7 021 men who had been exposed to VC in the course of their employment in any of the 11 plants in which VC and PVC had been produced in the Federal Republic of Germany, (ii) 4 820 men who had been employed in seven chemical plants without having had any exposure to vinyl chloride, and (iii) 4 007 men employed in two other plants where PVC was processed. Employees were included only if they were of German or Austrian nationality, and they were regarded as exposed to vinyl chloride if they were production workers or other skilled workers or laborers assigned regularly to the plants, but not if they were employed in them only occasionally. All the men were included from the time of opening of the plants to the end of 1974, and they were followed to the end of 1974. Many of the men were therefore observed for only a few years after first employment, and only 14, 36, and 19 ^.respectively, of the three groups were first em ployed before 1954 and were therefore capable of con tributing person-years at risk more than 20 years after first employment, when an occupational hazard of can cer could be expected to be observed. 65 Of the exposed group 93.2 9k were successfully fol lowed, and causes of death were discovered for 92.3 9k of the 414 men discovered to have died. The propor tions for the other two groups were respectively 39.8 and 88.7 9k for the unexposed and 92.1 and 86.9 * for the PVC process workers. The failure to obtain causes of death for an the men who had died was allowed for is the subsequent analysis by the weight ing of the numbers attributed to each cause by a sys tem which took account of the age group and calen dar period in which death with an unknown cause oc curred. The ripened numbers of deaths from each cause was by multiplying the person-years at risk by the sex-, age-, and cause-specific mortality rates for the Federal Republic of Oennany. National data before 1968 used an idiosyncratic classification system, and the 1968 rates had to be used to multiply all the person-years at risk up to the end of 1968. For subsequent yean (1969 to 1974) the person-years at risk were multiplied by the corresponding rates for the same calendar year. Epidemiologic studies are more difficult to carry out in the Federal Republic of Germany than in North America, the United Kingdom, or Scandinavia because the medical cause of death is not recorded publicly, and there is no central system which can be used for checking whether an individual is alive or dead. In these circumstances, the German authors have made valiant efforts to obtain reliable data, and the propor tions of men in the exposed groups who were not suc cessfully followed (6.8 9) and the proportions of deaths for which the cause was not obtained (7.2 9) were similar to those in the study of the Environmental Health Associates (14). Two defects, however, make the data less useful. First, no national mortality rates were available before 1968, and the use of the 1968 rates to estimate the num bers of deaths in and before 1968 will have overesti mated the numbers attributable to diseases that were becoming more prevalent or were being diagnosed more often and underestimated those due to diseases that were becoming less prevalent. Second, and more importantly, a large proportion of the men had been first employed less than 10 years before the follow-up ended. Therefore the useful observations on the few men who had been exposed long enough to have had much chance of developing an occupational disease with a long latency period must have been swamped by a mass of other observations that had little to con tribute. The expected deaths amounted to only 6.2 9k of the exposed men, and there is, therefore, little to be gained, and something to be lost, by including the German data in the overview. It may be noted, how ever, that 12 deaths were attributed to cancer of the liver among the workers exposed to vinyl chloride against 0.9 expected and that smaller excesses were also observed among the unexposed chemical workers (4 observed against 1.1 expected) and the PVC process workers (3 deaths against 0.8 expected). Two Swedish plants have produced VCM and PVC, one since 1943 and the other since 1971, and employees of the first plant have been studied by Byren et al (7). All persons who had ever been employed when expo sure to VCM oould occur were listed from the per sonnel files of the factory. Twenty-one were excluded because they were foreigners who left the country after a short period of employment. The remaining 730 were followed to October 1974. Expected numbers of deaths were estimated by multiplying the person-years at risk by the corresponding age-specific mortality rates for the whole country, and the expected numbers of can cer cases from 1958 to 1971 Inclusive (during which period all cancer cases had been registered nationally) were wrimated by multiplying by dm national agespedfic cancer incidence rates. In both instances, the rates aaad were those recorded in 1969. Fifty-eight deaths were found, but no figure was given for the ex pected number. Detailed figures wer* given only foT die numbers of deaths and cases observed and expected for cancer of the lung and for cancers of the liver and pancreas combined and for the numbers of deaths from brain cancer and three categories of cardiovas cular disease. Two men known to have angiosarcoma of the liver were certified as having died of liver can cer or pancreatic cancer, and a third man died of angiosarcoma of the liver 17 months after the close of the follow-up. Two French studies provide the results of a long term follow-up of men employed in one plant (41) and of a short-term follow-up of men employed in 12 plants (Laplanche et al, unpublished). The first provided ob servations on 1 311 men exposed to vinyl chloride in the production of VCM and PVC and in selected an cillary operations from the opening of the Tavaux plant in 1933 to the end of 1976 (41). Six other employees were excluded from the study because of lack of oc cupational histories and 160 men because their vital status at the end of the study period was undetermined. Twenty-five men were found to have died against 48.75 expected from contemporaneous sex- and age-specific national mortality rates (3.7 9k of the men at risk). One death was attributed to angiosarcoma of the liv er, in a man who had been exposed for more than 15 years. The reported data are so incomplete and cover such a relatively short period from the opening of the plant that they add nothing of epidemiologic value to the results of the other studies, apart from the addition of a further case of angiosarcoma. The second study provided observations on 1 100 men aged 40 to $3 years who, in 1980, were exposed or had been exposed to vinyl chloride in 12 plants, which constituted "most of the French VCM polym erisation plants" (Laplanche et ad, unpublished I. Many of 4hc men were, or had been, employed at Tavaux and were presumably survivors of the cohort siudied by Pierre et al (41). The men were followed for five years, and their morbidity and monality were com pared with those observed for 1 100 men of the same 66 est.it nan ages ( 2 yean) who were employed in the same plants but who had never been exposed to VCM. The men in both groups were interviewed personally, and in formation was obtained about their smoking and drinking habits, which were found to be similar in the two groups. The men in the exposed group bad been first exposed for an average of about 14 years and had first been employed in the plant about 18 yean previ ously. Morbidity and mortality data were recorded an nually by the plant physidan, who successfully traced 98 9b of the exposed men and 96 % of the referents. One ofthe exposed men, but none of those unexposed, developed an angiosarcoma of the Hver. Data were not given separately for different periods after first em ployment, and it is impossible to assess the significance of the finding that six of the exposed men developed hing cancer against two of the referents, which may well reflect a chance occurrence of unusually few cases in the reference group, as the proportion of all lung cancers in that group (2 out of 15) was unusually low. One exposed man developed a cancer of the lympbobematopoietic system against none of the referents, but none of the men in either group were known to have developed melanomas or canccT of the brain or thy roid. A Japanese study has reported the mortality ex perience of 4 524 men employed for at least one year before 1965 in 25 Japanese plants which began pro ducing VCM or PVC between 1949 and 1964 inclu sive (37). The men were followed to 31 October 1975. Twenty-eight percent of the men were observed more than 20 years after first employment, but none was ob served more than 26 years. Only 0.6 Vi of the men were umraced. and copies of the death certificates were ob tained for all the 209 men who had died (4.6 9# of the initial cohort). Individuals were classified according to the job in which they had been longest employed at the termination of their follow-up, and data were given separately for the 2 546 men classed as employed in PVC production and 1 978 others (including 900 classed as VCM production workers). If this study is continued for another 10 years, it should provide useful additional information, but the present data include too few observations on men more than 20 years after first exposure to be of any material use. They confirm the evidence of a hazard of liver cancer with six deaths among the PVC production workers against 2.54 expected from national rates, while only one such death was observed among the other workers against 1,82 expected. One of the six deaths from liver cancer among the PVC production workers was certified as due to angiosarcoma of the liver, and at least one of the other liver cancer deaths was due to the same cause. Lung cancer deaths were not in excess (2 observed in PVC workers against 2.33 expected). No data were given for cancers of the lym phatic and hematopoietic systems, for cancer of the brain or thyroid, or for melanomas. The mortality reported by Masuda (33) for 305 Japanese vinyl chlo ride workers has presumably been subsumed in Na kamura's (37) later and larger study. Hoards of cancer The results of the four most useful studies are listed individually in tables 1 and 2. The overall results for all causes, liver cancer, and three broad groups of con ditions are shown in table 3, and those for 10 types, or daises, ofcancer are presented in table 4. Data have not been reported for each type of cancer in each study, and the sources of the data are, therefore, specified separately for each type. Additional information ob tained from four other less informative studies (4,7, 22,49) is given in table 5 for seven types or classes of cancer. Table 3 shows that, apart from cancer of the liver, the overall mortality is what would be anticipated for an industry without any major hazard of accident or disease. In particular the standardized mortality ratio (SMR) of 84 for diseases other than cancer is typical of the ratios that are commonly observed for groups of employed men. A low SMR of this order refleas the "healthy worker effect," which results from the seieaion process that inevitably excludes some of the least healthy members of the population from indus trial employment. This effect does not, however, nor mally affect the mortality from cancer beyond that ob served in the first few years after the start of employ ment, and an SMR of 102 for cancers other than can cer of the liver is compatible both with the absence of hazard and with SMR values of 84 for other diseases and 77 for accidents, poisonings, and violence. Angiosarcoma. Death certificates are an unreliable source of information about the histology of cancers that cause death, but there is no reason to suppose that the excess mortality attributed to liver cancer (or, in the US series, liver and gallbladder cancer) is not entire ly accounted for by the known hazard of angiosar coma- Fifteen of the 37 deaths3 attributed to cancers of the liver and gallbladder in the US series are known to have been due to angiosarcoma of the liver (14). In the UK series, seven of the 11 deaths attributed to liver cancer, not specified as secondary, were known to be angiosarcomas, and they all occurred in auto clave workers against 0.38 expected liver cancers of all types <P<lCrJ) (25). In the Canadian series, histo logical review showed that seven of the eight so-called liver cancers were angiosarcomas (one had been de scribed as an angiosarcoma on the death certificate, two as hepatomas, and five as unspecified liver can cers). One so-called liver cancer death was found to have been due to cancer of the sigmoid colon, while one death attributed to angiosarcoma of the perito-1 1 Increased to 39 in table I to take account of the 97 extra deaths from an unknown cause. 67 Table i. Observed and expectad number* ol deaths from deferent cancer* report#0 in tne four principal studies (4. 14, 25, 4ft). (O obaarved number of Oaaths, E expected number of deaths) Typa or class of cancer Ouocai eavfty and pharynx Esophagus Stomach Large tmastin* Rectum Uver Uw and galtbiaddsr Pancreas Other gigaaWva Larynx Umg Other rtpirstory Sons Melanoma Prostata Testis Bladder Kidney Other and unspecified urinary Brain Eye and central narvous eyatem Thyroid Lymphb' and tatieuloaarcema Hodgkin's dieses* Leukemia Muiiipi* myeloma | Other iymphetie Other j Ml cancer* United Stales o E 13 1135 T 6.07 11 1601 21 28.79 N 8.77 17 18.40 116 11537 6 638 2 131 6 736 16 1530 6 646 12 636 35 1676 12 736 3 5.45 14 13.04 837 46 40.50 383 341.73 United Kingdom OE 4 338 6 1434 26 23.01 13.04 11 1049 11 1.04 7 636 4 231 1 212 2 1.74 12 650 2 136 U 600 8 4.10 3 430 4 616 2 043 4 235 3 230 7 6.16 2 235 16 8.12 235 228.60 Canada OE 0 0.64 8 0.14 6 538 2 8.78 133 1 137 2 0 05 20 16.37 Italy 0E 1 08 1 0.6 3 3.0 0 13 i 06 6 0.7 i. 12 0.9 6.1 o 0.2 i 0.7 i 0.7 o 04 0 07 b 4.5 X 2V1 Obeerved death* multiplied by 14)674 and rounded off to the nearest inteper to allow for death* without discovered cause. Table 2. Number* of death* from nonmahgnant and all cause* reported in the tour principal studies (4.14,25,46). (0 = observed number of deaths. E expected number of deaths) SeniQn and other unspecified tumors Cerebrovascular disease ltch*mic heart disease Other circulatory disease Bronchitis6 Pneumonia Other respiratory disease Cirrhosis of the liver Other digestive disease Disease of the genitourinary system Other diseases Suicide Accidents and other violence Mi nonmaiignent causes Ail causa* United Statas O* E United Kingdom OE 4 5.06 75 01.03 521 597.73 157 123 55 44 2233 16 31.04 15 32.64 37 56-06 27 39 52 11 X41 67 iiS3a 40 82.76 IX 173.19 1153 1363.54 1536 170537 276 105 36 1 40 5 43 1 40 545 780 268 141 * 4614 l1 51 f 76 X 665 894 Canada 0E 25 31.67 \ i 6 331 ) 335 r 5.40 2 1035 39 54 76 59 71.07 Italy 0E . 0 0.5 19 27.4 3 5.0 4 S3 3 27 2 7.0 1 0.9 4 7.7 X 56 4 66 77.5 * See footnote to table 1. 6 Emphysema in data from the United States. * includes two eases certified as cirrhosis of the liver which proved to be angiosarcoma of the liver * includes one case with cause unknown. t?SL VVI t t f l neum was found to have been due to angiosarcoma of the liver (46). In the Italian study, further evidence revealed that three further deaths should have been at tributed to cancer of the liver (for a total of four), but only one of the four was described as an angiosarcoma <<). 68 URL 11755 Tafets 3. Mortality from cancer of the liver and othar easiest among vinyl chloride workers in 49 plants to the four principal studies combined (4,14.2$. 49). <0 observed numbar of death*, E expected number of deaths. SMR * standardised mortality ratio) Causa of death 0 E SMR Cancer of the liver Cancer of othar alles Olhar diaaaaas Accidents, poisonings, and vlolanea 69 909 1647 226 9.45 699.35 1 944.89 296.15 All cauaai 2 441 2 74744 Including cancan of tha gallbladder m tha series from tha UnMad States. 99 102 94 77 9 Table 4 Mortality from various eaneen among vinyl eMorlda workers In 49 plants In tha four principal studies combined. <0 m observed number of deaths, exposed numbar of deaths. SMR standardised mortality ratio) Typt or etaea of cancar OE SMR Source of information* Mouth and pharynx Digestive tystam (othar than Uver) Respiratory system Lung Genitourinary system Melanoma Brain Thyroid Lymphalic and hematopoietic system Other All other than of tha liver 19 1947 125 164.69 223 22946 211 214.06 70 92.61 2 1.94 29 19.54 2 0.43 97 50.67 3 63-24 90S 699.35 109 1. 2. 3, 4 91 1.2. 3,4 97 1. 2. 3, 4 99 1. 2, 4 111 1, 2. 3, 4 2, 4 146 1,2.3 2 112 1.2. 3,4 131 1,2. 3,4 102 1. 2, 3, 4 It United States study (14). 2 * United Kingdom study (25), 3 * Canadian study (46), and 4 = Italian study (4) Table V Mortality* from various canctrs among vinyl chiorfda workara: Supplementary evidence (4, 7, 22, 49). (0 = observed number of deaths, Eu expected number of deaths, $Mft> standardized mortality ratio) Type or claas of cancer federal Republic of Germany (tl plants) 0E Norway (1 plant) OE Sweden (1 plcnt) 0E Italy (1 plant) OE four countries combinsd (14 planis) O E SMR Digestive eystem (excluding the liver) Lung Melanoma Brain Thyroid Lymphatic and hemato poietic eystem Other (excluding the liver) All excluding the liver 35.0 31.6 23.5 24.6 2.1 14 16.5 7.7 10.7 244 67.9 69.7 3* 1.44* 5 2.84 4 0.79 2 0.16 8 14.93 22 20.19 3 1.78 2 043 5* 2.1V 1 14 0 1.5 0 0.1 0 0.7 4 2.0 6 5.7 39.0 314 4.0 4.1 2.0 194 22.7 1194 34 44 30.72 0.69 143 0.16 6.4 41.43 117.67 113 103 196 55 102 incidence and cases In the Norwegian study. * Cancer of the intestine only c Cancer of the lung and brain only. Further evidence that the excess mortality from liver cancer (or liver and gallbladder cancer in the US series) can be attributed principally ir not wholly to the known hazard of angiosarcoma is obtained in a comparison of the excess deaths with the numbers of deaths from angiosarcomas recorded in the Register of Liver Angio sarcoma Cases (maintained on behalf of the Associa tion of Plastics Manufacturers in Europe by the Im perial Chemical industry PLC) before the end of the follow-up period (Bennett, unpublished). Fifty-one ex cess liver cancers are recorded in the combined data, and 49 angiosarcoma are recorded in the Register for 69 .Table 6 Mortality from King eaneer In the eerie* from tha United States (US) (14) mo tt>a Unltad Kingdom (UK) (25) by characteristics relevant to an occupational hazard. (Oa ob served number of deaths, E expected number of death*. SMR a atandardtzad modality ratio) Data characteristic* Category 1 0* E MR Category 2 O* E MR Observed 20 yaw* or more after lint employment (t), Other* (2) Employed 10 year* or more tn the US <13, Other* tn tha U$ (2) Employed betor* 1866 In the UK (1), others (nth*UK(2) Ever employed aa autoclave worker in the UK (1), others (n the UK (21 114 113J6 100 66 62.45 106 62 61J6 101 te 17*16 4 6 SJ3 01 ES 63-44 0 to 40J0 72 6 74S2 7 The number* In parenthood* designate the category * Sat footnote to table 1 for obearvad death* in tha US. the relevant period* for the three countries and the two Italian plants1 that are covered by the survey. None of the 120 cases yet recorded in the Register were in men who were first exposed after 1969, and none of the 45 men affected in North America were first exposed after 1964. All may, therefore, have been exposed to concentrations of several hundred parts per million, and many may have been exposed to concen trations appreciably higher (unpublished report by Barr to Air Products and Chemicals Inc in 1981). Lung cancer. The idea that exposure to vinyl chloride might cause cancer of the lung was suggested by Monson et al in 1974 (36), when they noted 13 cases against an expected number of 7.9 in a study of proportional mortality. The combined data shown in table 4 do not provide any support for the hypothesis, either for res piratory cancer as a whole (SMR 97) or for the speci fied data for lung cancer in the US, the UK, and Italy (SMR 99). There are, however, consistently higher risks in the subgroups of men in the US and UK series, in which occupational hazards would be more likely to 1 Twenty-nine were registered as occurring in the United States against an excess of 33; only 20, however, were iden tifiable in both aerie*. Inquiry has, as ya, failed to reveal information about the histology of the remaining 13 in the cohort study and the origin ofthe nine extra deaths in the register. Nine deaths were registered at occurring in the United Kingdom against an excess of nine, but one of the registered cases was certified as due to a benign hemangioma and not related to the liver (code 227 in the eighth revision of the International Classification of Diseases). Ten cases were registered as occurring in Canada against an excess of eight; two were recorded as being in men who had been employed for five years, and it is possible that the actual duration had been slightly leu than five years with con sequent exclusion from the Canadian cohort One case was registered as occurring in one of the two Italian plants against an excess of leu than one. be seen than in other groups. This circumstance is illustrated by table 6, which shows that the SMR values are slightly higher for men observed 20 years or more after first exposure than for men observed earlier, for men employed before 1956 in the UK than for men first employed after 1955 (when exposure levels are believed to have been lower), for men employed for longer than for shorter periods in the US, and for autoclave workers in the UK (among whom the angio sarcoma eases have mostly occurred) than for other workers. The differences are all small or very small. They are, however, all in the same direction, and the probability that the rates should al) be higher in the groups fat which aa occupational hazard is more like ly to be seen la each of the four pain of groups is 1 In 16. Additional information from other sources is given In table 5. A total of 30 deaths (or cases) was observed, and this figure Increases to 31.5 when allowance is made for the number of deaths due to unidentified causes in the German study (SMR becoming 103). In the German study the SMR was higher for the men who bad been exposed for 10 years or more than for those who had been exposed for shorter periods (111 against 79), and, in the Norwegian study, four of the five eases observed occurred in men whose occupations were regarded as involving high exposure against 1.82 of the 2.84 expected. Both the German and the Swed ish studies derived the expected numbers of deaths from national mortality rates for a single year towards the end of the study period. The expected numbers of deaths are likely, therefore, to have been overestimated and the SMR values correspondingly underestimated as the mortality from lung cancer had been rising throughout the period of Observation. Brain cancer. The idea that vinyl chloride might cause brain cancer was also suggested by Monson et al (36) when they reported five cases against 1.2 expected. The combined data that are shown in table 4 provide some support for this hypothesis. The cases of Monson et al (36) were, however, observed in US workers and must be presumed to be included in the toial reported by Environmental Health Associates (14); therefore they will have contributed a substantial proportion of the total in table 4. As a test of the hypothesis the data of Monson et al ought, therefore, to be subtracted from those in the table. Their investigation was noi a cohort study, and their expected deaths do not cor respond exactly to those in table 4. If, however, the observed and the expected cases are both subtracted from the totals, twenty-four observed deaths remain against approximately 16.3 expected, a difference which might easily occur by chance (P one-tailed = O.l).4 * If the study of Waxweiler et al (50) is regarded as the origin of the hypothesis, 26 deaths are left against 18.94 expected (P one-tailed-0,07). 70 <w.inHn ? i URL 1175? Additional information from two other sources is given in table 5. The small excess reported provides little further evidence of an occupational hazard, as ooe of the two deaths observed in the Swedish study occurred in a young man who had been employed for less than a year when the diagnosis was made, while the access death rate for brain cancer observed in the German study was less than that observed among chemical workers not exposed to vinyl chloride (2.9 deaths after allowance for deaths from unknown causes g*'"** 1*6 expected) and among workers in the PVC fabrication industry <5.9 deaths after allowance for deaths from unknown muses against 1.1 expected). Cancers oflymphatic and hematopoietic tissues. The idea that vinyl chloride might cause cancer of the lym phatic and hematopoietic tissues -- more specifically the lymphatic tissue -- was suggested by Tabershaw A Gaffey (45) and by Waxweiler et a! (50) in two cohort studies, when they found, respectively, five deaths from lymphomas in the most heavily exposed workers against 2.S4 expected and four deaths from cancers of the lymphatic and hematopoietic tissues against 2.5 ex* pected. These small excesses might have been ignored if the laboratory findings had not been interpreted as suggesting that lymphomas were produced experimen tally in animals exposed to vinyl chloride by inhala tion (29). The idea that similar exposure might also cause lymphomas in humans, therefore, merits seri ous consideration. The data from the four principal studies that are summarized in table 4 provide little support for the hypothesis when all cancers of the lymphatic and hematopoietic tissues are considered to gether (57 deaths against 50.87 expected, SMR 112) and very little more is obtained from the separate data for cancers of the lymphatic system (Tabershaw & Gaffey's definition of 1CD list numbers, eighth revision, 200--203 and 205 being used) that are shown in table I (35 deaths against 29.40 expected). The position is, moreover, hardly altered if the data in Tabershaw A Gaffey's initial report are subtracted (29 deaths against 23.36 expected. SMR 124). Little additional information is provided by the results of the German study (49). (See table 5.) This study obtained an SMR of 214 for exposed workers (based on 15 observed deaths, increased to 16.5 when allowance is made for the number of deaths from un known causes) against SMR values of 77 and 34 for an unexposed group of chemical workers and a group of PVC fabricators. It showed that the excess of the exposed workers was present only for men who had been exposed for more than one year and that this ex cess was most marked for men who had been exposed for five years or more (10.7 deaths after allowance for the number of deaths from unknown causes against 4.0 expected, SMR 268, P one-tailed <0.0l). Melanoma. An excess of melanoma was reported for Norwegian workers by Held&as et a) (22), who raised the possibility that vinyl chloride-might have produced the disease. Four eases were observed when 0.79 were expected, and three ofthe four were in men whose oc cupations involved the highest exposures (against 0.51 expected). At the time of the writing of their report, one further case had been detected with onset three years after the closure ofthe study. Subsequent studies in other countries have, so far, reported only two deaths against 2.0 expected. (See tables I and 5.) Thyroidcancer. An excess of thyroid cancer was also reported in the Norwegian Body (22), in which two caseswo* observed against 0.16expected. The inves tigators were not aware of any other studies indicating an excess of tids type ofcaaoer, and they drew no condurian from their ohstmeiinn Two of the three major mudtet that have been reported since the Norwegian observation was made gave no data for thyroid can cer; the third reported two deaths against 0.43 ex pected. (Sec table 1.) One death from thyroid cancer, it may be noted, was reported in the US by Monson et al (36). Cancan of the digestive tract. Suggestions that vinyl chloride might cause cancers of the digestive tract in genera] have sometimes been made, but they have not taken adequate account of the contribution of cancers of the liver to the total number of cancers of the digestive system, particularly when it is borne in mind that some liver cancers are likely to be misdiagnosed as cancers of other organs. The combined data from the four principal studies shown in table 4 weigh heavily against the idea that any such effect has been produced. Other cancers. One of the remaining types, or classes, of cancer listed in table 4 shows statistically signifi cant excess, namely, the heterogeneous group of "other cancers" (83 observed deaths against 65.24 ex pected, P two-sided <0.05). This excess is only mar ginally significant and may be a chance observation. The most likely explanation is, however, that a few angiosarcomas of the liver were not recognized and were diagnosed as secondary liver cancer or carci nomatosis, she unknown, the number of deaths in this category therefore being increased. Hazards of nonmalignant disease No previous study has suggested that any nonmalignant cause of death other than cirrhosis of the liver would be likely to be increased as a result of exposure to vinyl chloride, and cirrhosis of the liver is presumed to be increased only because of the liver changes that were observed as pan of the "vinyl chloride illness" (24, 31, 33). Two other possibilities have, however, been raised, namely, the production of nonmalignant respiratory disease, because of the changes in lung function and radiographic appearances that have been 71 I AS/ 11 W i TeMe 7. Mortality from selected nonmalignant cmmi and ail flamat h the four principal ttudle* combined. (0 * ebaarvad number el daalha, E expected numbar of deaths, SMR standardized mortality ratio} Type ottltaaaae O E BMA Source of informallor* Bronchitis, omphyeomt* Other reeptratory Oteeeee 0 8643 120 1.2 71 125.78 06 1.2 Mmpinieiy taehamte heart dtaava Othar etfoutatory AM circulatory dtaaaaa* OtnhooU of tha Mvor Othar rttaaaaa 190 797 352 1103 46 836 30042 85.73 3*446 130945 9626 30407 All nonmalignant Oaaaat All axtamai cauaaa 1647 134440 226 395.15 Alt nonmalignant eauaas Alieauaa* 1773 2139.65 3 441 3 74745 0 1, 2,3, 4 0 U 6 12 81 1.2, 3. 4 80 1.2,4 06 1,2, 3.4 *4 1.2, 3,4 77 1.13.4 6 1. 1 3. 4 89 1.2. 3,4 * 1 United States study (14), 2 United Kingdom study (25), 3 * Canadian study (46), and 4 Italian study (4). * Bronchitis in the United Kingdom study, emphysema m in* United States study * Include* cerebrovascular dieses* m the United Kingdom end Italian studies. Table 6. Mortality from chronic obstructive lung disease* In the senes from the Untteo States <US)(14) and the United King dom (UK) (2S) by characteristics relevant to an occupational hazard (O observed number of deaths, E expected number of deaths, 8MR a standardized mortality ratio) Data characteristice Category 1 O E BMR OOftrvad 20 years or mom attar first amptoymem in tna US (1). oihars in tna US (2) Employed 10 yaart or more in tna US (1), Othar* In tha US (2) Employed before 1956 in tha UK (1). othar* in the UK (2) Ever amployad a* an autoclave worker in the UK (1). Othar* in the UK 30 16 26 3 154 100 10.9 147 30.17 06 6.05 46 Category 2 O E SMR 11 7.0 157 2$ 124 208 10 13.60 74 33 3722 69 * Described as emphysema In the US study and as bronchlii* In the United Kingdom study. * The numbers In parentheses designate the category. * Man ever employed as a bagger or drier, occupations which would have caused the greatest occupational exposure to polyvinyl ehlorioa dust, experienced one death from bron chitis against 4.96 expected recorded for men exposed m pyr dust (2,26,27,44), and acute cardiac death, from analogy with the effect of other halogenated hydrocarbons (25) and the ob servation of an increased mortality from myocardial infarction in the few years following the cessation of exposure in the Swedish PVC processing industry (35). Relevant figures for the numbers of deaths from these and other nonmalignant causes that are obtainable from the four principal studies were given in table 2, and they have been summarized in table 7. Cirrhosis of the liver. Three of the four principal studies gave separate figures for cirrhosis of the liver, one of which showed #n increased mortality (table 2); in combination they gave an SMR of 69 based on 46 deaths. The fourth study, which did not give sepa rate data for drrbosis of the liver, reported four deaths from all *!--* of the digestive system combined against 3.85 expeaed and noted that the four included two that were certified as due to cirrhosis of the liver, but actually due to angiosarcoma (46). In the two sup plementary studies in which data were given for this disease, the SMR was 82 in one, based on 15.1 deaths after allowance for the number with unknown causes (49), and 133 in the other, based on seven deaths (37). Nonmalignant respiratory disease. The data for nonmalignant respiratory disease are confusing in that the total SMR from the combined data for the four prin cipal studies is 80 and is the sort of figure that is com monly found in healthy industrial populations, yet the US study recorded a substantially increased mortality from emphysema (41 deaths and an SMR of 160 be fore any allowance was made for deaths from un known causes). No such excess was found in the UK, where 36 deaths from bronchitis gave an SMR of 82. International comparisons of chronic nonmalignant respiratory disease are complicated by the usage of dif ferent terms to describe what it is now agreed is best called chronic obstructive lung (or pulmonary) disease, but which in the past tended to be called emphysema in the US and chronic bronchitis in the United King dom. It must, therefore, be presumed that the two categories of "emphysema" and "bronchitis" used re spectively in the two large national studies were meant to describe the same thing. One must assume, there fore, that the experiences in the two countries were very different, despite the fact that both related to cohorts that had very similar experiences of angiosarcoma of the liver and so, presumably, fairly similar exposures to vinyl chloride. Separate figures are shown in table 8, where a\ ailable, for the monaliiy observed among men with dif ferent durations and intensities of exposure. Unlike the data for cancer of the Jung that were shown in table 6, they provide no consistent evidence of a greater risk in the groups in which an occupational hazard would 72 be expected to be concentrated. The authors of the En vironmental Health Associates report (14) were unable to five any explanation for the increased mortality from emphysema, and they point out that it could hardly be due to excess dfarettc smoking, as there was no overall excess for cancer of the lung. It is striking, however, that the excels is more than compensated for by deficiencies m the other categories of oonmalignant respiratory disease (pneumonia 15 deaths,' SMR 47.0; other respiratory dirrase 14 deaths, SMR 42.6), and the Question arises whether the emphysema excess could be a dassifieatory artifact. Environmental Health Associates (14) list all the 41 deaths which show that they were coded under ICD number 527 which, m the out-of-date seventh revision that was used for the coding of all deaths m the study, was the code for "other respiratory disease not otherwise classified'* and included emphysema. Under that revision, however, emphysema that was associated with bronchitis should be classified with bronchitis under ICD numbers 500 to 502, and the possibility may be considered that some of the emphysema deaths should have been classified in some category of respiratory disease other than 1CD number 527. If this were the situation, it could account for both the excess mortality from emphysema and the grossly deficient mortality from other nonmalignant respiratory diseases. No excess mortality from "bronchitis, emphysema, and asthma" was observed in the German study (SMR 44 with 6.3 deaths observed after allowance for the number of deaths from an unknown cause) (49). Cardiovascular disease. Data for ischemic (or arterio sclerotic) heart disease (which may be presumed to in clude the vast majority of all deaths certified as due to acute cardiac disease) were given only by the two big national studies, and they provide no evidence of an increased mortality. The SMR values of 90 for this group of diseases and of 91 for all cardiovascular dis ease recorded in the four principal studies are typical of the SMR values of healthy industrial populations, and there is no suggestion of any occupational hazard in the subsidiary analyses provided by the two national studies. In particular, there is no evidence of an in creased mortality within one month of leaving em ployment in the UK study either for all workers (52 deaths. SMR 61) or for the most heavily exposed auto clave workers (9 deaths, SMR 42). A slight increase in ischemic heart disease mortal ity was recorded for the exposed workers in the Ger man study (49), but it was less than that recorded for * The deaths attributed to different groups of respiratory dis eases and the corresponding SMR values that are cited in this section for the US study are as given by the Environ mental Health Associates (14) and have not been adjusted to account for the number of deaths from an unknown cause. To take account of these deaths, the observed deaths and SMR values can both be multiplied by 1.0674. the unexposed chemical workers and the PVC fabri cators (SMR values of 127,131, and 156 based on 97.2, 126.7, and 109.7 deaths, respectively, after allowance for the number of deaths from unknown causes). Discussion The information that has now been obtained about the long-term health of men occupationally exposed to vinyl chloride is massive and compares favorably with that available for any other occupational group. Two fans are outstanding. First, the men have experienced a specific hazard of a type of cancer that is normally esucmcly rare, namdy, angiosarcoma of the liver. The rarity of this disease under other conditions made the detection of the hazard easy; but the long latency period before the disease appears after first exposure (almost always more than 10 years and usually more than 15 years) meant that a large number of men had been exposed before the hazard was delected and that It will still be many years before the extent of the pro tection provided by the reduction in exposure in the 1960s and that of the further reduction that followed die recognition of the hazard in 1974 are known. There is, unfortunately, no effective treatment for the dis ease, and the number of cases is reflected in the num ber of deaths. Some SO deaths have occurred among the 16 740 men who were followed in the four prin cipal studies that have been reviewed in this report, so that approximately 1 in 33$ men have been affected, 2 4b of the deaths having been due to this one cause. Eventually many more men must be expected to de velop the disease. One estimate (38) suggests that the total may be increased 10 times, but a more realistic estimate is two to three times (19). The second outstanding observation is that the mor tality of the exposed men, other than that due to angiosarcoma of the liver, is typical of the normally healthy industrial worker -- that is not to say that no other hazard exists, but that the effect of any other hazard is small. The massive data that are now available provide no reason for thinking that any hazard other than one of cancer has been overlooked. It is, however, still dif ficult to decide whether vinyl chloride produces a risk of developing cancer other than angiosarcoma of the liver which might be small compared to the risks produced by nonoccupational causes, but yet abso lutely almost as large as the risk of developing the nor mally very rare angiosarcoma. One of the many hazards suggested can be dismissed, as there is no evidence to support it, namely, that of vinyl chloride as a cause of any cancer of the diges tive tract other than angiosarcoma of the liver. Two hazards (of melanoma and cancer of the thyroid) have been suggested only very recently, and few of the avail able studies have provided information about them. There is no good theoretical reason or laboratory evi dence to suggest that either should be produced by 73 vinyl chloride, and, in light of present evidence, the simplest explanation is that the reported excesses are the chance effects that must be expected when many different types of cancer are studied in several different populations. So far as melanoma is concerned, ft has to be remembered that the disease has become much more common in recent years in Scandinavia (where die excess was reported) due, ft is believed, to the popularity of sunbathing and the increased oppor tunities for Scandinavians to travel to the wanner pans of Southern Europe and North Africa. The extent to which this change may have affected the observation in Norway needs to be examined. Two other hazards (oflymphoma and brain cancer) were suggested by the early results of some of the US studies. That vinyl chloride might produce a hazard of lymphoma was initially supported by the prelimi nary results of animal studies, but the complete results of the many investigations that have been undertaken (see reference 29) do not suggest that lymphoma or any other cancer of the hematopoietic system is liable to be produced. There is, however, some evidence that brain tumors can be produoed in rats (29). The hypoth eses that lymphomas and brain cancers might be produced by vinyl chloride have been supported by the observation that both these types of cancer have caused death more often than might be opened from national mortality rates, but the excesses observed in the com bined data from the four principal studies in this re view are small and not statistically significant, and the hypotheses remain unproved. The small excess of brain cancer is particularly difficult to evaluate, as mortal ity rates from this disease have changed rapidly over time as methods of diagnosis have improved and the suspicion of an occupational hazard (which was raised in 197S) could have influenced the findings. What ex cess has occurred has been limited to the US and Ger many, and the German ftndings carry little weight, as the excess was found in each of the three occupational groups studied, irrespective of the chemicals to which they were exposed. The supplementary data from the German study showing an increased mortality from lymphatic and hematopoietic cancers are more impres sive, particularly as the excess was the most marked for men who had been employed for at least five years. In these circumstances, judgment must still be sus pended until the data for each study are analyzed for each specific type of cancer, by intensity and duration of exposure, and by time since exposure began. There remains the suggestion that vinyl chloride might cause lung cancer. At first sight, this possibil ity is ruled out by the SMR of 97 for the combined data for respiratory cancer for the four principal studies. Lung cancer is, however, normally so com mon (accounting for about 8 * of the expected deaths) that an increase in mortality that was half as impor tant (numerically) as the increase in mortality from angiosarcoma of the liver might easily be overlooked (95 ft confidence limits of the SMR 85--112). The in 74 cidence of the disease varies moreover within a coun try, and there must be doubts as to whether the na tional cxpaiaice provides a suitable icfeence for men employed in plants that are not evenly distributed about the country. In these circumstances one cannot exclude an occupational hazard unless it can be shown that the mortality of the exposed men is independent of the factors that might be expected to influence it if some of ft woe occupational in origin, namely, the intensity and duration ofeeposure and the time since exposure began. It is not possible to examine these relationships In detail, as the reports do not provide all the necessary faformatiou. Such information as they do provide, which was summarized in table 6. supports the idea that exposure to vinyl chloride involves a small haard of long cancer. Taken in conjunction with the knowledge that long turnon have been produced in sev eral species of animals exposed to vinyl chloride by in halation (29), ft would seem that a small hazard of lung cancer probably did occur. The evidence is not, how ever, strong enough to conclude that it definitely did. If it did, the hazard was evident only for men who had been employed for many years at a time when expo sures of several hundred pans per million or more were common, and any persisting risk can be only minute and incapable of detection. The questions that have been left unanswered by this discussion might well be answered definitely if (i) all the exposed men could be followed to (say) the end of 1984, (ii) the investigators could present their data in comparable ways, taking account of duration of employment and time since first employment and presenting data separately for men first employed be fore (say) 1965 and between 1965 and 1974, and (iii) estimates could be made of the effect of correcting the results for each group of employees for the locality in which they lived and worked. Hazards to the ganaral population As vinyl chloride has been proved to cause cancer in man and is a mutagen in laboratory experiments, it jnust be presumed that even the minute doses that Escaped into the general environment from production plants or (in the early days of manufacture) from PVC materials will have caused some risk of cancer to the general public. These risks must, however, have been very small, as air concentrations of vinyl chloride, even within a kilometer of plants handling vinyl chloride, used to be (in or around 1975) of the order of 10 to 40ppb(l, 3,15), and this level is about one-ten thou sandth of the concentration that has caused an occu pational hazard. It is obvious, therefore, that it would be impossible to detect the risk of any cancer that might be produced by vinyl chloride other than a risk of angiosarcoma of the liver, as it has proved so diffi cult to detect any other risk among men who were ex posed occupationally. The position with regard to an- URL 11760 URL 11761 giosarcoma of the liver It different. Tbis disease is nor mally so rare that, in the absence of specific exposure lo one of the known causes (vinyl chloride, thorium dioxide, and arsenic in pesticides and medicines), the annual modencc is on the order of 1--2 I0~7 (5, S).` lo these circumstances the discovery of even one case in a man living dose to a factory in which vinyl chlo ride was used in the days before exposure was tightly cootroUed may be retarded as presumptive evidence of the effect of environmental polhiUoa. Several surveys have been undertaken to determine whether any such cases have occurred. Saric et al (43) and Elinder A Pcrthagen (13) sought for cases tat the vicinity of plants handling vinyl chloride in Yugoslavia and Sweden and found none. In Holland Daldenip et el (11) found eight confirmed eases not attributable to thorotrast or arsenic and could trace "no contact with vinyl chloride," but they made no specific men tion of the patient's place of residence. Baxter et al (3) found 14 confirmed cases in Greet Britain over a 12-year period, one of which was in a man who had lived half a kilometer from a PVC manufacturing plant, and, in New York State over an 18-year period, Brady et al (5) found 19 cases that could not be at tributed to any known cause, five of which were in peo ple living within a mile of plants manufacturing or using vinyl chloride. The overall incidence rates in these last two studies were not unduly high, but the occur rence of as many as six cases among people living so close to manufacturing plants is surprising. Brady and his colleagues, moreover, compared their series of pa tients with matched referents and found that none of the referents lived equally dose to a plant. Two of these six neighborhood cases (one in England and one in New York State)cannot be attributed to environmental pollution with vinyl chloride, as the men who devel oped the disease had lived near the plants for six and eight years, respectively, before developing the disease, and this period is too short to allow for the necessary latency. The other four cases, however, all occurred after IS or more years of local residence, and the dis covery of these cases strongly suggests that pollution of the environment around plants manufacturing VCM or PVC may have caused a minute hazard to the gen eral public. Current concentrations around plants handling vinyl chloride are certainly much lower than those reported previously by the US Environmental Protection Agency. Recent British measurements made within a few hundred meters of the VCM areas have given aver age values below the daily limit of detection (5 ppb) for three of five plants, the readings at the two others being 20 ppb (ICO m outside the boundary fence) and 68 ppb (just inside it) (47), although substantially higher values were recorded on two occasions asso ciated with putting one plant into operation and with * The figure of 1.4 I0-* died by Heath ei al (21) seems to have been a misprint for 1.4 io-\ an accident at the other. According to any reasonable criterion the hazard to the genera] public (if there is any at all) must be negligible U2)._ No other hazard to the general population, other than a hazard of cancer, can reasonably be postulated. Summary This paper reviews (i) the possible effects of vinyl chloride mi the personal health of men exposed by virtue of their occupation (other than the early effects of the very high concentrations to which men were ex posed when the Industry was first developed -- uncon sciousness, cardiac arrhythmia, and the characteristic "vinyl chloride illness") and 00 the carcinogenic effects that might cooeeivabty be observed in the gen eral populatiooasa result ofthe widespread distribu tion of vinyl chloride as a pollutant. The possibility that vinyl chloride might act as a teratogen or might cause mutations fat the germ cells has not been exam ined, as the little evidence that has been adduced relating to sod) possible effects hes been reviewed else where and the conclusion was readied that no such ef fects have been demonstrated. Many groups of workers exposed to vinyl chloride in the manufacture of VCM or PVC have been studied since the carcinogenic potential of vinyl chloride was first recognized. Some results have shown that occu pational exposure can cause angiosarcoma of the liver, and others have suggested that it may cause several other types of cancer as well. The actual situation can be determined only in an examination of all the evi dence, especially the combined results of those studies that include a substantial proportion of observations on men more than 25 yean after their first exposure and cover a iong enough period for more than 10 4% of the employees to have been expected to die. The results of four studies can be usefully combined for this purpose. They are two national studies, one from the US and the other from the UK, and two studies of employees in one plant in Canada and two plants in Italy. The results of other studies from the Federal Republic of Germany, Norway, Sweden, Italy, France, and Japan can be used only to provide sup plementary information. The many earlier repons of exposed workers in the US and the UK concern men covered more completely in the two recent national studies, and their results serve only as sources of hy potheses. Minor criticisms can be made of three of the four most useful studies. They do not seriously affect the value of the results, except that allowance has to be made for the failure to determine the cause of 6.3 *7e of the deaths recorded in the US study. Three of the studies use national rates to estimate the numbers of deaths thai might have been expected to occur in the absence of any special occupational hazard, and the founh (Canadian) uses rates for the province in which 75 v: the plant was situated. It must, therefore, be kept in tion is the observation of an increased mortality from fi mind that the rates used may not have been wholly ap cancers of the lymphatic and hematopoietic systems tl propriate for the localities in which the plants were in the supplementary study from the Federal Republic d situated. This circumstance is potentially important for of Germany. P the US study, which covered workers in 37 plants, 22 Two types of cancer were reported to be in excess U of which were situated in the southern part of the in the Norwegian study, namely, thyroid cancer and ft country. The other'less informative studies are, for the melanoma. The significance offliis finding is difficult tl most part, open to more serious criticism, and the value to assess because very little information about these P of each set of results needs to be assessed separately cancers has been provided by other studies. b in relation to each disease. Suggestions that vinyl chloride might cause cancers o The combined results of the four principal studies of the digestive tract have failed to account for the w show that the SMR vahie^ reflecting the ratios between contribution of angiosarcoma of the liver. When this ii the numbers of deaths observed and those expected in disease is excluded, the mortality from digestive tract the absence of an occupational hazard multiplied by cancer decreases to below the average (SMR 82 for the w 100, have been 0) 77 for accidents and other violence, four principal studies). ct (ii) 84 for diseases other than cancer, and (lii) 102 for A snail excess mortality from the heterogeneous o cancers other than cancer ofthe liver. All these results group of "other cancers*' in the combined results of s are what might be anticipated for an industry devoid the four principal studies was statistically marginally o of any specific occupational hazard. The low ratio for significant (83 deaths against 65.25 expected, f><0.05). <i dhraiei other than cancer reflects the "healthy worker Soane ofthe excess was likely to have been due to the effect/* which results from the selection process that utisdasslfication of angiosarcomas as secondary can b heritably excludes tome of the less heahhy members cers of the Hvcr or carcinomatosis, the unknown. h of the population from industrial employment and is The following three nonmaligntnt causes of death e compatible with a higher ratio for cancer, as the mor have requited special examination: cirrhosis of the Bver P tality from cancer is not normally subject to such an because of damage to the liver in "vinyl chloride ill 0 effect, apart from the first two or three yean imme ness, '' myocardial infarction (from analogy with the d diately following the start of employment. effect of cither hatogenated hydrocarbons and because IT The mortality from cancer of the liver was nearly of some observations from Swedish PVC fabricators), b seven times that expected. Most of the 51 excess deaths and nonmalignant respiratory disease because of vi were known to be due to angiosarcoma, even though changes in lung function and the radiographic appear h this diagnosis was not recorded on the death certifi ance of the lungs observed in men exposed to PVC e cate. The excess corresponds closely with the 49 deaths dust. Far from being raised, the mortality from cir it due to angiosarcoma reported to the International rhosis of the liver was less than expected in the three ti Register of Angiosarcoma Cases as occurring in em principal studies and in one of the two supplementary ct ployees of the plants concerned during the periods studies which gave separate figures for the disease ir under observation. All the men who developed the dis (SMR values of 69, based on 46 deaths, and 82, based Cl ease were likely to have been exposed to concentrations on IS deaths), while in the other supplementary study ir of vinyl chloride of several hundred parts per million the increase was trivial. tl or more. Data for myocardial infarction have not been re S' Three other types of cancer which have been sug ported separately. But myocardial infarction accounts tl gested to occur as a result of exposure to rinyl chlo for most of the deaths attributed to ischemic heart dis c ride are cancers of the lung, brain, and lymphatic and ease, and there is no evidence that either ischemic heart ly hematopoietic systems. The combined data for the disease or cardiovascular disease as a whole was un si mortality from respiratory cancer fail, at first sight, duly common (SMR values of 90 and 92, respective ft to support the hypothesis regarding lung cancer (SMR ly) or related to occupational exposure. If 97). Higher ratios for lung cancer have, however, been The data for the third category of nonmalignant dis P* observed consistently in the subgroups in which the ease (nonmalignant respiratory disease) are confusing, ti effect of an occupational hazard would be most like because the two large national studies give conflicting 01 ly to be seen (that is, men employed for more than 10 results. The combined data for the four principal years, exposed to higher than average concentrations, studies show the low mortality that is commonly found m or observed more than 20 years after first exposure). in heahhy industrial populations (SMR 80). This fig h In two of the supplementary studies it was also noted ure hides, however, an increased mortality from d that the mortality from lung cancer was specifically chronic obstructive lung disease (SMR 120), which in ct increased among the most heavily exposed workers. dudes emphysema and is due to a grossly increased ir The combined data show small excesses in the mor mortality attributed to emphysema in the US study tl tality from cancers of the brain and of the lymphatic (SMR 193). The corresponding mortality in the British ti and hematopoietic systems. The excesses are, however, study, which was preferentially described as due to ai not statistically significant, and there is nothing to sug bronchitis, was less than expected (SMR 82), as was (S gest that they are occupational in origin. An excep the mortality from pneumonia (SMR 50) and other res- 7Q / U in n 7 76 piratory ditetm (SMR 46) in the US study. There is no consistent evidence that the mortality from emphysema.or brooch!tis was specifically occupational, and it seems possible that the repotted excess is the US study was an artifact due to nosolofica] difficul ties with the use of the seventh revision of the ICD. Review of the massive data now available on the long-term health of men occupationally exposed to vinyl chloride leads to two dear conclusions. First the men have experienced a specific hazard ofthe normally extremely rare angiosarcoma of the liver. Approxi mately 1 in 333 of the men exposed hi the 49 plants studied died of the disease, and approximately 2 % of the obsmvad deaths were attributed to it. la the course of tune the numbers of cases of angiosarcoma must be expected to increase two to three times. Second, the mortality from all other causes has been typical of that of normally healthy industrial workers. Ifany hazard has existed, its effect has been small. The data provide no reason to think that any haz ard other than one of cancer hat been overlooked. It is, however, still difficult to decide whether vinyl chlo ride produces small risks of cancer, compared to those due to nonoccupational causes, at sites other than the liver, and, If so, whether, in total, these risks might cause almost as many deaths as angiosarcoma of the liver. There is too little evidence either to confirm or refute the suggestion that vinyl chloride might cause mela noma or cancers of the thyroid, brain, and lymphatic and hematopoietic systems. None of the small excesses that have been recorded point specifically to an occu pational hazard, apart from that attributable to can cers of the lymphatic and hematopoietic systems in the German study reviewed, and most are likely to be the sort of chance effect that is certain to be observed when irony types of cancer are examined in many different studies. The lack of any increased mortality from lung can cer m the combined results of the four principal studies reviewed does not exdude the potability that there may have been a small occupational hazard of developing the disease, as geographic variations in the incidence of the disease throw doubt on the validity of using national rates for estimating the expected numbers of deaths. The greater mortality in groups of workers who would be more likely to show an occupational hazard than otheT groups suggests that a small hazard may have existed. The evidence is, however, weak, and the existence of a hazard has not been proved. Clearer answers to some of the questions that have been posed in this review might be obtained if the various groups of investigators could present their results in more appropriate and comparable ways. As vinyl chloride is a mutagen in laboratory experi ments and a proved human carcinogen, the minute doses that have escaped into the general environment as pollutants must be presumed to have caused com parably minute risks to the general public. No such 2 risk could possibly be detected, other than one of angiosarcoma of the liver which is normally an ex tremely rare disease. Several surveys have sought evi dence of the existence of such an effect, and sugges tive evidence that such an effect may have occurred at a time when environmental pollution was much greater than it is now has been found in one. fMwanoao 1. Ab Products and Chsodcals, lac. Commas* on the pro posed sandord for vinyl chloride. Letter to DR Goodwin, Bavfcuamsutol PioswUnii Agency. Washing ton, DC 23 fapwnbsr 1976. (Chad is as unpublished rqon by Rare to Air Product* end Chemicals, Inc, in 19*1). 2. Baser ME, Tockman MS, Kennedy TP. Pulmonary function sod imfiiiciory symptom* in polyvinyl chlo ride fabrication worker*. Am Rev Reaptr Du 131 (1935) 203--201. 3. Baxter PJ, Anthony FP.MacSweeeNM.ScbeuerPJ. Angweartoma of the km in Gnat Britain. 1963--73. Br Med J 2 (1977) 919-921. 4. BeQi S, Benazri PA, Combe P, Foe V, MaJtoni C, Marina A, Pirastu R, Regianni A, Vigotti MA- indagine nils mortaliu dei produttori di PVC in Italia: Disegno ddlo audio e primi risuhoti. Cancer Leu (in press). 5. Brady J, Liberalore F, Harper P, Greenwald P, Bur nett W, Davie* TN, Bishop M, Polan A, Vienna N. Angiosarcoma of the liver: An epidemiologic survey. J Natl Cancer Intt 39 (1977) 1333--I3SS. - 6. Buffler PA, Wood S. Eifler C. Suarez L, Kiliane DJ. Mortality experience of workers in a vinyl chloride monomer production plant. J Occup Med 21 (1979) 195--203. 7. Byren D, Enghobn G, Enghind A, Westerholm P. Mor tality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environ Health Pcnpeci 17 (1976) 167--170. I. Byren D, Hoimberg B. Two possible cates of angiosar coma of the liver in a group of Swedish vinyl chloride workers. Ann NY Acad Sri 246 (1975) 249--250 9. Cooper WC. Epidemiologic study of vinyl chloride workers: Mortality through December 31,1972. Environ Health Penned, 41 (1961) 101--106. 10. Creech JL, Johnson MN. Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Occup Med 16 (1974) 150--151. 11. Daldcnip LM, Freni SC. Bras C, Bronckhursi FB. An giosarcoma of the liver. Lancet ] (1976) 246. 12. Duck BW, Carter JT, Coombes EJ. Mortality study of workers in a polyvinylchloride production plant. Lancet 2 (1975) 1197--1199. 13. wiiiitof CG, Pershagen G- Pilot study concerning the mortality in Njurunda Community. Swedish Nature Conservancy Board, 1973. (Ched in an unpublished report by Barr to Air Products and Chemicals, Inc. in 1931). 14. Environmental Health Associates. An update of an epi demiological study of vinyl chloride workers 1942--82: Final report to the Chemical Manufacturers Association. Environmental Health Associates, Oakland, CA 1986. 15. Environmental Protection Agency. Standard support document and environmental impact statement: Emisrion standard for vinyl chloride. Environmental Protec tion Agency, Washington. DC 1975. (EPA 450/2-75009). 16. Equitable Environmental Health. Epidemiological study of vinyl chloride workers: Final report to Manufacturing Chemists Association. Rockville. MD 1978. 77 URL 11763 17. Falk H. Tetta NC, lihak KG, Thomas LB, Popper H. Epidemiology of tborotnst-iaducad hepatic aogiosaranas Environ Ret IK (1979)65--73. II. Ffecbtner J. Reyes C, Rentmertter K, ct at. Epidemi ologic notes and reports: Angiosarcoma of the hver -- Wisconsin. Morb Mortal Wkly Rep 25 (1976) 57-5K. 19. Fcnnap D. Bennett R, Sufford J, Doll R. Exposure to vinyl chloride end angiosarcoma of the liver: A report of the ngtaar of cases. 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