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1erU3 '93 18:02 Q32 2 2878069 P'.Y.C.S BRUSSELS ++4 FTR Neuchatel CH I&00b/012 r 0 1 Is the concept of linear relationship between dose and effect sctill a valid model for assessing risk related to low doses of carcinogens? A restrictred intemtiam al wdentire seminar May 10,1998 - Parig (Prance) RA4KGROILM As6essing the risks to a population due to exposure to high dc,$es of carcinogens has 1sQccaa4 rout.ine practice for r.oxioologists, cancerologists and epidemiologiata. Althouth neii.tier simple nor com letely devoid of uncertainty, this- p is bassd on tested methodologies which lead to reliat,le predictions. Althoug expenmEnt.f on azaimals provide valuable data (whatever doubts mav remain on the difficulty of extrapolating from animals to man), epidemiolrigy, practised with the necessary rigour, takes us loyozid hypotheaee into th• field of incontestable facts. Occupatton$l aafety r'qul2ttions use sueh faCls as a reference. Questions arise when decision centres, trade unions, associatioa3 and "enviropmentalists", in short, lobbies as a whole, seizing on the observation that a substance is "carr.nopnic in high concentretions", put increasingly hoavy pressure on the scientific community (ard on epidemiologists in particular) to obtain data asbessing the risk to populations who, at work or in their everyday life, are subjected to loer - even very low - concentrations of substances proran carcinogenic In high doses. The classic epidexniologwcal use of clinical observation of effkco on a repredentativepo pulatxon becomes inapplicable because of the size of the samplee needed to validate the findings. While a few hundred individuals .ui~'ica for aWrly accurate assessment of the risk related to high doses, hundreds of thousands and even millions are needed to assess the potential risk when the dose is a hundred timEs smaller. Such numbers, once the cohorts have been rid of possible bias (presdnce of co-carcinogens, age, ewr, life style, manner and source of exposure, latency timo, direct and Indirect exposure, etc.) are quitc beyond our reach, technically, materially and Sn$ncially. "The need to knovi" - and among decision makers the need to know what to basd their decisic,uti on - remains. In 1959, during debates on tttQ "Food, lirug and Cosmetics Act", US Senator 7Jelaney"3ntrodLced an amendment which postudated thae any molecule of a carcinogenic substance can cause caacer. * In 1959, durins dt batei oa the "Food. Drug and Cosmewcs Piet", US 4enator NIAnry itttroduced a.z amsndmen: which bora bis name and which nostaiated tlie notion that there is no dose vr+thout an e:fect_ This concept rapidly went beyond Lhe Iuwtft of products intended for human comutr.ption sad was extended to aasessment in genera: • arithoaL referenco to tlA dos; • ot' asl carcuiog.ns. --Stio 3ose v safe," Delaney mainta3rpd. "Onr Sber can kill," Irwin S¢likotrrEtortt+d 4 fwy years bLar.

leiuJ 'a3 1u:u3 IM3Y 2 1S7ltU68 Y.ri.C.S BRUSSELS ~++ rTR Neuchatel CH W1'vO8iU1Y 9 This new nction had reverberations well beyond the Umted Statea, upsetting ideas hold by the international community of toidcologista which had been based on z sayfng atUibuted to Faracelsus: "Euprytlurt,g is a poison, nothing is a poison, the dose al4ne makec the poison.. „ At the ss=ne tiou. incredihht advences ware being mzde in physical and chemical rniaturing techniques, which meant that fntinitesizuxl traces of substances could be measured - trbu.-ua of anythine in eve:ythinC. Epidemiology, originally an expcrimental science, had w raxxpond to this urgent demand and took the approach of the Delaney aInendrnont: "No dosa is safa." Numbers of mathematical models wera devised, perfecxed and used to assess substances with proven carcinoggextic effects in high doses, by extrapolating from the effects observed in high exposure towards low expwuure. The nrinciple chosen was linear: the effect wau proportional tu the dose, starting from the principle that any dose - no matter how low it was - would have some eft'ect. This concept, whiah often yieldr, very different rsau2ts from one study to another, is cuxseritly used as the basis for evaluazing low exposure effects and, consequently, for drafting national and international regulations. Many epidemiologists themselves doubt the validity of these extrapolations but they use them, for lack c,f anything better. For many substanczs o=ipresent in man's environment. the application of the concept of linearity also poses an insurmountable problem concerning the eiinodnatfon of natural sources of expoeure. The combination of now developments in methods of analysis and measurement and the very human desue to enjoy total protection (zero riek) seems to lead more and more often to dead-end or incoherent reguluLu,na. tlow far can we legitimately push the principle of precaution? It wae felt that this ig en opportusie tiiae to pose the question ia its very principle now that we are in a position - for some subatances at Ieast. - to compare predictions resulting from the linear mathem,alaral approach with observabie facts. This seminar. reserved for international spec.ialiets, will address the followir+g question: must we persist with a principle of assessment, even if its predictions are not confirmed by real events. if the answer is "Xes'", the limits of credibility of such a principle ought to ke defined. jy If the answer is "No", a new approach ought to be proposed. ~

laiua a3 ta:ua -a:fz 2 Z67ouaa r.r.C.B lsKUS59LS +++ F1K NeuGhatel Cfl W'uu7/u1z 3 Nmviaio»! Ageiula Sunday May 9,19St:1 x17 p.m • Welcome and regisLratiOn i1n pxnelixto H3ttd Hilton - Pkris 1$, aveoue de 5uffien - 75016 Paris ?l8 p.m. • Welr,onmo cocktail 8/10 p.ns. • D'umor Mnrday May 10, 1993 8/8.11i a.m. • ReBistration - Lpffca B.lbI8.S0 A.m. • Welcome address by Pierre My, Chairman of the lnternaLiotLal Center for 9cientific Ecology 8.M a.m " • Opening apeach by chairmpn, Prof. $tuce N. Ames ;Biologist, Dtr., Nat. Xnst. of Environnuntal Ilealth ,Sciences Center, Berkeley, U.S.A.1 b/0.84 a.ati. • MetluxioluKy tif prevision gLudies through mathematical extrapolation. $ug~sted speaker : Pro~ Julian Peto (Ep:a'.emiulq8ist, Dir., Section of Epid., l'nat. of Cancer Research, Londres, U.K.) 9.20/9.10 r..ta. • Critacal approxeb of mathemetieal exLtwpultdL'uru. Jk'roZ Etlenne Fburnier (lbxieptogist / cancdrologiat, HBpital Fernond Wtdal, 1aarts, France) 9.40/10.00 n.m. •'1'he De1aney amendinent and its cons,equences on the amerirsn regulation. PWL prod & Sitwc Thysicist. rormer Dir., US Weath.er Satellite Program; Prislrlent, Science & Enutronmental Policy 1'ra)ect. U.S.A.) 1lNl(1.f6 u_m. • Cuffe;c lrrr;zk Cr! ~

LOiYJ 7/JLO:V9 (jdL L LO/'OWOtl r.a.to.zi nxubblsi.a .++ P'1'K reucIIatel l:H iWUUfI/UlY 4 lU.lli/11.Si1 a.m. • Caees etudiea:l'revieiunr at roalitv. • mhe Asbesl,os case. Yia-.£ CorbOMMACDOMld l'Epidetruolagi4 Research Unit in Epid., Heart wed Lung lut„ Londres, IT.K.) • The Araenic cuR.. PruL «sr6uct! 8tbrrir (former chief. Ikpl. of chemical risk, Rtttarch inst. Sioan-Ifetterinr, U.S.A.1 - The cstw of cblorine and derivatad products (VCM). Suggested speaker : ProL Jean•Maric lxbn- NobeL Prize Wtnnar Chemistry, 1987, - Prof., Calltge dt Fra»tx, Lab. de Chin,ie Suprctniottculaire, Univerattt Louia PastQur, Strasbourg, Franct) - The ll13T cue. (not yet decided) • '1'ho Saccharine case.(tiot yet decided) - The cw of pllasive smoldng. Int r.N Le (8tattstum and computing, Sutton, UKJ ('i'he panelists will be sent well in advanoe a b/10 fold text frdsa each cblItribution, the oral pre3enutieL not exceding 10 minutes). 11.30 /1 2.15 a.m. • Questions / Anewarz 12.16/14.00 p.m. - Luiach 1411 R!iA ~s_m. • Genera! discugsion 16.3O117.0a p.as. • CufteeP!'ea break t 7h.8 p.m. • Curying of a cansenaus text. minrdr Ertd e,TSe 18/19 p.pt. - SAecial meeting with internatioatil press for Q/A nad interviewa. 19.30J9.00 p.m. • Llinncr srientific

la/v3 as 16:u5 7tY32 2 2678069 P.1[.C.S BRUSSELS -*++ FTR Nenchatel CH ImO09/012 b Parti4iiwntm Invitatioiu have been sent to the people listed in the appendix. We expect from twenty to thirty sdeUtim k, ruWwd. AudiQwe A number of personalitios truaa sndurtry, the administration and thc press will be permitted to nttend the saminar proceedings without intervening, except for personal contacts which may be made during meals, breaks and when sessions are not ia progress. They will be asked to makt a tlslanCial contribut;uu. S {)rgx nisation The seminar is organised by the internativnal Centre tor a Scientific Ecology (see Introduction to the Centre in the appendix). The seientiPc work is organised by Dr Michel Salomon, the coordinator of the Heidelberg Appeal. Translation The papers and coaaments made during debatss may be dolivqred in eithor English or French. ufmultaneotis txanelation will be eupplied iti both lenguages throughout the seirunar. Press Conference Kepresetitativts of the internatiuiwl scientific prm are asked to regiKter if they wish to attend the sesstons. A press conference wi1T be held by the members of the scientific panel at 6 p.m. on Mxy 10, 1993, to answer questioae i'irom journalists.

18/03 '93 18:05 1232 2 2678069 P.Y.C.S BRUSSELS +4+ P1'R Neuchatel CH 4D010/012 6 M~!t IIItsZ'2'1ahazal (i@Y'lter forA .4CIeI1tift C ILtVA(a The Center has been created at the beginning of 1998 under the french lsw for non-profit org~i~adors. The purpose is to answer a reque3t from a number of the Heidelberg Appaal aignatoriea in view to extend its impact in QxaMinusg 9otual issues the scientiflc communiry is confronted with. The purpose of the Center is exprlssed in the by-laws : "The purpuere of this Association is to pnomon a.rld facilttate the exchanPe of scientific knowledge, based on scientil'tc data, regarding the protection of mdctikind, other living species, natural sites, and the resources of the planee. The Aasocuctzon thus proposee to supply the most releuant scientific facts to the authorities responsible for deuelopir,,g environmental pratection policies, to society as a u-hate, which, so that decisions may be made opcnly, &a called uponn lu exf,ress tts point of view, as well as to all socto• eeonomic actors desirous of contribatiit,lt both to the conservation of tlcr L+'arth and the lond•term development of the human groups which pupid"Ir it. The Association is a non-proJii organ,iration," The Board of the Center indudes in particular : • Mr Picrre Joly, President of.' tbe Association r`ran;aise pour l& Recherche ThtrapeuriquQ; former President of the International Federation of Pharmaceutical 12anufacturera Association: of French ' uatioaality; - Mr Constast Burg, honorary merAber of the State Covruil; honorary managing diroctor of TNS1::R~tii; President of tle Institut Curde; of French nationality; - Mr Gilbert Rutman, chief mining cngine.er, President of the Conseil National des Ing6nieurs et des Scientifiques de France; of French uatianality; - PoL S. Fred Singer, Doctor of Physical Sdence; President of the Sdence & EavironmeAtal Policy Project; former : Director, US Weather Satellite L'rogram; Dean of the school of Environmental Sciences, C'nivexsity of lwiiami; deputy assistant Admiasatrator of US Environmental Protection Agency (EPA); of Ainerican nationality; - Mr Gaxq Nash, mining Enqir,eer. Secretary General of the Internarional Council on Metals and the Environment (TC*A12): former Director of the Mineral Rqaources of Canada; of Canadian nationaUty; - Dr. Michel Salomon. coordinator of the Heidelberg Appeal; former science journaliut; magazine editor; of li'rench nationalitv. The Sewiaar davoted to the linear doseJreeponse rPiatioashfp is the BreE event M*ated by the I~ra~tioaaL Center !br a 9cLent3Sc E441nzY-

18/03 '93 18:06 032 2 2878069 P.M.C.B BRUSSELS ++~ FPR Neuchatel CH 40011/012 . Invited panelists May 10th, 1893 Seminar Proe. Bw= N. AMEts, )baph"oMsr. 4qA. . IiAr ChatsMn r. AMMIN0M, 4yefpr, UWA. fk Aedk= /MC1111W. droOqy. a+qr. Prof. ./wa AVVA 06 OAAf)O. /iMWouler NaboY. 6lm Pha4. aeban W. lAt.pw/fN, C.nanko. UK. Prol. FNnA sI,YLAN, howwnwao. MM,t. rW. UiV9aM K. YkCKUME. Gao.n.ob,r. &O%ata. . W Wry 11tNACEMqAi. CfnON01oa1r. USA. Ur Tomfai YFsfit7tJC, amaeteqy. Olo.awti eot; .1aAe EI(iNW Pn.uwAlr+ptr. Frsea. . 5ir J.nnes W. &LACK Pnum.ouoW. UK Paf. P.a. $tJ<IN. f:rmy:un.ew/ war.rk, lJK. Praf. GtbriM YWICHWC WwWrroloW.'tanm. pret. walor 6ooMOi, c.,o=...>rtr. Urc. Prvf, AndesW f1=YVSK1. r.QOprapny. Polaiw P41of. P. DOR9T. CWmrolopy. f M NiliM»n+nda.. wot. Canwnt BuAM LArisita. F.anc.. • Pw, Dr. Adolph OtITENANDT. Ctronstrr. Ow*.any. • Pr9l. Thoom R. c:ffc:M. Vhonstry. u3.. Pro+. 18 OpuN CHPifeTltN. Mvlmonory IA.S"M. rnna fw [bmat0 L {:CtFtkN.l+thrWa, uf3A. 1Ar ctWrale V. eQU3. CoouP.dwitl Hyyierwe. Ausvaxa. Piof. Anarb CGIi.M 1. Ft.nee_ :N. Mvb Paolo COLOMIlc), U+oelopy. Wy. Sx. Pae10 M. COTAOOL/0. Ona.aw. h++r. Prof TA COMINfnAS. To/d00IM. UK. • 9w ,bohn INaroup CdqfYFORTM. ;,Mmicvy, UK Prot. M~ COMkJ. Claniatry. lyanow PSO1.1Nrrwn CQ?MiAU. Tos'walom. wMearwi 3w U"COOi, UL s Prof Jo1ta OEtSENMOFAA. f+oeftrsuM. USA. Prot fia+sid OCq.t. Epldeiwolopr. UK. hfnt: J+oqWt JYNMtGAM, Taalaalo&. Ci+utla. . fhat L1r. AAIhk~ lbAfeN. Clnwry. tirmuny, Or. GwQ ERDMAfvN, ta,exAw. tianwr.. . Prof. Rtatw0 !y. EMNST. Chanaaey. 5wawi+nif1+101. Mlyrt1o11Q tflkkARL1f.1, Vtwwury, fm+ew l+191. fi9f3f3M fOY1Mrl6i#, l0aaalomI f<rawe. . Ptel. f+iwr..QlM= dr OEAMVft Otwsks. Fr.aoe• Dr. Jama OOI.fSMkG. Cinoerola0!!. AarM. PIef. HeUrxct GRElK ToYio~1 Ge0nany. Mr Jade GF1099, Caae.rdeyy.lvaN. Prof. Toftuki HAMACftA. Onao+oWi. laPy+ • Prof. NeftrtlC MAtJPS1HAN. lo^crs. USA. Pnof. lk_ L7f. h.e. id&r4ld tw FIAU*fN. CNropak>91r. Cwmunr: . bk OUft R. liERSCMBACM. CtmrMfy. U" . or. [3r#vO HEFlZSENG. Ctafaitlf/. Canacf.i . Ptvf. AAW Hp'MMNN. CUemmiry. U5n. • Mr Noorxt Wt11PA beof-W. 4,..ma^r. Prd. J.n.t HWG}IE3. Epidemok191(.:75A Prof. LMOien 18RAfL, d.nawNo9y, frdno4 Ptot. Mud! JASAAIN. Cr4evlvqr. f+anex F+rat. l-neaAda JUNO. Tome+epr. rsnnany Nk fmtl F. KADW Mit. Toyimbgy, U9A. ,waf. Fual KALYONCU. MeCwlna.,luAwy. • Wln4erbme KAWL'e.OhM+rrery. USA Prof, Alorqoh! X icf:LLtcHEA, Carmlrolagy. tlul -wct. t . e_- t.c-

18/03 '9g 18:06 832 2 2878069 P.Y.C.S BRUSSELS ++-& FTR Neuchatel CH 1®012/012 . RM'M JeM KlliufirtW.1M01iW1oI llWuyy. UK • ht A..mn kl i Ifi. R'tMMlr'r. UK . Peat. fetlwrl d. KKElr, Eiooh.nifhy. USA. Wr L.on.ti T. KUMEJlno. Eo+Wnal%W, USA Pn/. rMrt..W wktAV6~.'S1MM 1lV. Pro. wyqa,a uYAaC;T. a..r"a .,y. Fme... • Mr ru.n t uEle, Wwm.y. tRi& IAr Palor K tiEE. UK • pWOt. J.an•Man.l.tMN. Gxmnrtry, heanOs. P+vt. Monri Lia7iiAMT. GpeqnuebQy. Fraaa FMOt. FA.K UD06LL, UfMa. Pro1. Tt+.nwr UON. CanoMebOY. Awm • Nlr YVIqI1fM1 K. LJP8CCII>B. ChOmimy. USA. Peel. JM~•kl.np W. hpidenrobw, Cfta Plof. JoFn COibMR MAC CONALD. lpbntfYaluyy, UK. Dr. Jafn J. MAC IQeTTA. Cllew:al MOr*.rr+q. UsA. Pr w. Mwb W. AAAFIJUAMU 1. 1 o.m4pY. twRnsay. tk waClw MAFWVAMA. th,oolopr..ld,wt. Ptol. danld VAF121N, ToadeoloQy. F+anee:. Mr r-iw. W-ApEA, Frwioe. Mre1f. ts. MIW"O. rawOdm, ifinm. Pre!, MieMd MOo4NY. Irblecular eonye:cs. Fnruo. Mf. ero01w 1: WI068MAN. PaaetOpy. USA. Or. F{oM WRRAY.7M"forW IMaoM. UK. Nk aab1iM N/IHAa, Tan0010py, M nUl. ,va clamdnn W. IvEWELL. Toriee"Wr, U" Dr. Meh A. NIaG. CYfk+^eleOY. gwinarrhnd Mr Choa+ N. QNO. To:-3lepr. Rwwpm• . Prot. LimA PAIJt]N0. L*Anuuy. USA • Prot. FMz F.dnan0PEPlUTZ.lWwv vry. t1K Prct. Jul=PETO. EOl- idom r. UK. . Prd. J.hn Ch.Ls PCt.AN1n. t.n.ndwy. Lw.da. • dnOf. GoqryP MCIH{MM. CHpnqky, lAC . Hrot. l. PiV00aiNlL Chantaqr. Edwn• Wi MtM-Y{ifA dl1 qECpN00.,C.lwolopy; XMM thof. An iREEOWK pqmmay. The Netaur4m. Dr. rWaM R0E9,WFWWopy. US. Or. NfWrl RALCIAGN.1A.aea.. frana. lir, Ai.KS EqIU18IN. Cwasrob&. Fynos Frof. J. 611r1oK P"n. fei~. Mrm. a. Fnd amGE7i. Physros, Usk rwot ftv ii1tAA8ANEK r-Fd.eWalayy,ltilsnd, kOr KFt: *UlAA1GlN, Ima+iwyt. Cr*J& Or. Abpawarunan. iSOW. tpacr+wkNY. A"'uw+r. IuV J. STJEMf111YARG. Cma"olom, Swittrrtu+d Dr. Gwhab STbHAEA, Chemftay„uV+1 W CWW4 TANG. RDrdwnlotoV. WA. Prof. li.,i 1NUFIAi7T. TaaiOplopy. kaf+as• Nnff. Maurios TUlIANA, Cwnunofurllr. Fsanuc. Arot. Feeor VAUC. OQCupwOnMt MrOok1C. Croatia PraR /Win+"owms VAW:~.,W*-Ta0moub"• rqnelr- Wrot. Fhdlnrck WA NNER. UK. PYAf, J>r. Aod. Hms M. WELLliGkE{L To,~4*". 3w+rsny, tx. EbzaCvnt WFIkWN, UyW atel. MNns-@r+q1 wIGhIWNN. fta.nrwMW. Gw=n,, Gr. Bm XUE. Tvxsawprr. L'suns. MM hW4PA LMu, Oca4pVonA'.Flrldlh: (:F.nn 7 • NCbN F'ru.r W.nf4r 26rf11.'3]