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. F.h'V. PAR = 26 - 3-93 ; 10 :28 ; G. F. C. C. - 44 081 569 7021;# 2/ 7 International Center for a Scientific Ecology Is the concept of linear relationship between dose and effoct still a valid model for assesdl>g risk related to low doses of ets? A restricted internatioaal scienfifie cPminar May 10, 1993 - Paris (France) BACKGROUND Assessing the risks to a population due to exposure to high doses of carcinogens has become routine practicx for toxicologists, cancerologists and epidcmiologists. Although neither simple nor completely devoid of uncertainty, this practice is Uased on tested' methodologies which lead to reliable predictions. Although experiments on animals provide valuable data (whatever doubts may remain on the difficulty of extrapolating from animals to man), epidemiology, practised with the neccssary rigour, takes us beyond hypotheses into the field of incontestable facts. Occupationzt safety regulations use such facts as a rcfcrence. Questions arise when decision centres, trade unions, associations and "cnvironmentalimts", in'short, lobbies as a whole, seizing on the observation that a substance is "carcinogenic in high ccmcentrations", put increasingly heavy pressure on the scientific community (and! on epidemiologists in particular) to ubtain data assessing the risk to populations who, at work or in their everyday life, are subjected to low - even very low - concentrations of substances proven carcinogenic in high doses. The classic epidemiological usc of clinical observation of effects on a representative population becomes inapplicable because of the si7e of the samples needed to validate the findings. While a few hu.ndred individuals sutY`iccr fiar a fairly 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 cuhoris have been rid of possible bias (presence of co-carcinogens, age, sex, life style, manner and source of exposure, latency time, direct and indirect exposure, etc.) arc: quite beyond our reach, technicall,y, materially and financially. "The need to know" - and among decision makers the need to know what to base their decisions on - remains. In 1959, dtrring debates on the "hood, Drug and Cosmetics Act", US congresgmari Delaney` introduced an amendment which postulated that any molecule c,f a carcinogenic Sub.tancc can cause cancer. . In 1959, durirrg dcbatcs on thP "Fbud„ Drug and ('.c,srnrt;irs Act ; US corrgr-rsvman llelnrrry introdtticed an xrnendmcnt which bore hirs name and which Ixtstulated the notion lhxt there is no d<r-:<• wiuhout an rffcct_ 'I'hi- concept rapii3ly went beyond the lineits of products in1AmdNd ior hua,um cnn-umption und K•:rs cxtendau' to ussescmi~nt in gr:ncrul - without referencc ta the d.ise - uf ull <arcinogens. "hdh d<rie is safe,' Delaney rnaiiaLar.ed. "Ono fibor c„n kill,: lrwin Sc?ikoff rrtorted a few ye:lr:: l rttAar.. , -J Internolional Center tor a Scientific Ecology lf), Uver,ue de Messine„ ?5008 Poriu. France Ptxxie : as 14562 20 (Xi. FOK : 33 142 89 C1Cl .`f)

h]W. PAR: 26- 3-93 ; 10:28 ; G.F.C.C.- 44 081 569 7021;: 3/ -1 This new notion had reverberations well beyond the United States, upsetting ideas held by the international community of toxicologists which had been ba..~cd on a saying attributed to Paracxslsus: 2 ELerythirg is a poison, nothing i.s a poison, th:e dose alone rnu.kes the poi.son. " At the same time, incredible advances were being made in physical and chemical measuring techniques, which meant that infinitesimal traces of substances could be measured - traces of anything in everything. Epidemiology, originally an experimental science, had to respond to this urgent demand and took the approach of the Delaney amendment: "No dose is safa.' Numbers of mathematical models were deviscd, perfected and used to assess substances with proven carcinogenic effects in high doses, by extrapolating from the eirects observed in high exposure towards low exposure. The principle chosen was linear: the etlect was proportional to the dose, starting from the principle that any dose - no matter how low it was - would have some effect. This coiicept, which often yields very diffErent results from oiie study to another, is currently used as the basis far evaluating low expnsure effects and, consequently, for drafting national and international regulations. Many epidemiologists themselvcs doubt the validity of these extralmlatiomi but they use thctn, for lack of anything better. For many substances omnipresent in man's environment, the application of the concept of linearity also poses an insurmountable problem concerning the elimination of natural sources of exposure. The comtiination of new developments in methods of analysis and measurement and the very human desire t<) enjoy total protection (zero risk) seems to lead more and more often to dead-end or incoherent regulal,ions. ' iiow far can we legitimately push the principle of precaution? It was felt that this is an opportune time to pose thee question in its very principle now that we are in a position - for some substances at least - to compare predictions resulting from the linear mathematical approach with observable facts. This seminar, reserved for international specialists, will address the following question: must we persist with a principle of a::scssmont, even if its pn!dictions atre not confirmed by real events. If the answer is "Yes", the limits of credibility of such a principle ought to be defined.. If the answer ic "Nb", a new approach ought to be prulmed. !'

pNV, pAR: 267 3-93 ; 10 = 28 ; G. F. C. C. -+ 44 081 569 7021: # 4/7 3 Provisional agenda Monday May 10, 1993 8/8.15 a.m. • Registration - Coffee. 8.151fi -30 a.m. - - Welcome address by Pierre Joly, Chairman of the Intcruational Center for Scientific )!:cologyr. 8.301'9 a.m. • Opening speech by the Chairman, ProL Bruce N. Ames (Riolqgist, Dir., Nat. Inst. of Environmental Health Sciences Center, Berkeley, U.S.A.). 919.20 a.m. • Methodology of prediction atudics through mathematical extrapolation. Dr. Moolgavkar (Epiderniologist, Fred Ilutchinson Cancer Research Center). (to be confirmed). 9.20/9.40 a.m. • Critical approach of mathematical extrapolation. Prot Etienne Fournier ('L'oxicologist, Hopital Fernand-Widal, Paris, France). 9.40/10.00 a.m. -'1`ho Delaney amendment and its conscquences on the American regulation. Proi; Fred S. Singer (Physicist, former IJin, US Weather Satellite Program; President, Science & Environmental Policy Projeet, U.S.A-). 10/10.15 a.m. • Coffee break. 10.15/11.30 a.m. • Case studies: Predictions and reality. - The Asbestos case. Prof, J. Corbett MacDonald (Epidemiologist, Research Unit in Epid., Heart and Lung Inst., Londres, II.Kj. - The Arsenic case. Prof. Gerhard StBhrer (forMer chief, Dept. oF chemical risk, Research Inst. Sloan-Kettering, US.EL.). - The case of chlorine and derivated prod.ucbs (VCM). Dr Werner F'reieslcben (Dir., European Council of Vinyl Manuf acturers) - The DDT case. Prot Aaron Wildavsky (University of Berkeley) (to be confirmed). - The Saccharine case. Prof. Samuel Cohen (Chair, Dept. of Pathology, Nebraska Un.) (to be confirmed) ~~ - The case of passive smoking, ProL P.N. Lcc (Stati,ctics and ~ computing, Sutton, U.K). 11.30 /7 2.1:5 a.m. • Questions / Answcrs. 12.15 a.mJ2 p.m. - LuncE 2/43i)p.m. • General discussion. 4.30/5 p.m. • Co(fcc/'i'ca brcak. ...I

-pW: pA[i : 26- 3-93 ; 10 :29 ; G. F. C. C. - 44 081 569 7021: # 5/ 7 4 516p.m. • Carrying of a consensus text. End of Seminar. 6/7p.m. • Special meeting with international scientific press for fa/A and interviews. (The panelists will receive well in advance a 5/I0 page text of each contribution, but the oral presentation should not exceed 10 minutes). Fazticzpanta Invitations have been sent to the people listed in the appendix. We expect twenty to thirty scientists to attend: Audience A number of personalities from industry, the administration and the press will attend the seminar as observers only. Organisation The seminar is organised by the International Centre for a Scientific Ecology (see Introduction to the Centre in the appendix). The scientific work is organised by Dr Michel Salomon, the coordinator of the Heidelberg Appeal. Translation Lectures and comments may be either in English or French. Simultaneous transldtiun will be provided in both languages throughout the seminar. Press Confereuce International scientific journalists are asked to register if they wish to attend the sessions. A press conference will be held by the members of the scientific panel at 6 p:rn. on May 10,1993. ...J

EW; t'AR : 26- 3-93 ; 10 : 29 ; G. F. C. C. - 44 0$1 569 ?02i ;-- 6/ 7 5 The Internafional Center for a Scienfz!"ic Eoolagy The Center has been created at the beginning of 1993 under the French law for non-profit organizations. The purpose is to answer the request from a number of the Heidelberg Appeal signatories in view to extend its* impact in examining actual issues the scientific community is confronted with. The purpose of the Center is expressed in the by-laws : "The purpose of the Association is to promote and facilitate exchange of scientific knowledge, based on scientific data, regarding the protection of mankind, other lioireg species, natural sites and the resources of the planet. The Association thus proposes to provide the most relevant scientif `u facts to the authorities responsible for developing environmental protection policies, to the Society which, under the principle of transparency, is called upon to express its point of view, as well as to all sociu-economual partreers who want to contribute in both the conservation on the Earth and the long-term development of its populalior~.~s." The Board of the Center includes in particular : - M.r Pierre Joly. President of the Association FranCaise pour la ILecherche 7'herapeutique; forruer 1'resident of the International Federation of Pharmaceutical Manufacturers Association; French nationality; - Mr Constant Burg, honorary member of the State Council; honorary managing director o(' TNTSF.RM; President of the Institut Curie; French nationality; - Mr Gilbert ftutman, chief mining engineer; President of the Conseil' National des Ingenieurs et des Scientifiques de France; French nationality; - Prof. S. Fred Singer, Doctor of Physical Science; President of the Science & Environmental Policy Project; former Director, US Weather Satellite Program; Dean of the School of Environmental Sciences, University of Miami; Deputy Assistant Administrator of US Environmenta) T'r.otectiorl Agency (Ea-'A); American. nationality; - Mr Gary Nash, Secretary General of the Iuteriiational Council on Metals and the Environment (ICME); former Director (aenrral in the CanldrI Department of Energy, Mines and Resources; Canadian nationality; -1)r. Michel Salomon, coordinator of the Heidelberg Appeal; former science journalist; magazine editor; French nationality. The Seminar devoted to the linear dose/response relationship ist.he firsit event initiatc~d by thc International CentQ.r for a Scientific F.orak-ogy. 17/2!`A3 International Cenier for a Scientific Ecoiogy 10, avCnuC d6 Messine. 750(3ti Paris. frani:e . R xu,e : 33 1 n562 2003. r(i x :33 142 89 00 59