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E1t'V. YAK : 26- 3-53 : 1'U :1ti ; (i. t-. C. t.. - 44 Ut31 5ti8 7U21; # 2/ 7 lnternationai Center for a Scientific Ecology Is the aonoept of linear relation_ship between dose and effect still a valid model for assessi~ risk related to low doses of carcinogens? A restricted international scimt'Yf'ic cpaninar May 10, 1993 - Paris (France) BACKGROUND Assessing the risks to a population due to exposure to high doses of carcinogens has become routine practicr for toxicologists, cancerologists and epidemiologists. Although neither simple nor completely devoid of uncertainty, this practice is based on tested methodologies which lead to reliable predictions. Although experiments on animals provide valuable datK~t (whatever doubts may remain on the difficulty of extrapolating from animals to man), epidemiology, practised with the necessary rigour, takes us beyond hypotheses into the field' of incontestable facts. Occupation:.tl safety regulations use such facts as a rcference. Questions arise when decision centres, trade unions, associations and "environmentalists", in-short, lobbies as a whole, seizing on the observation that a substance is "carcinogenic in high concentrations", put increasingly heavy pressure on the scientific community (and on epidemiologists in particular) to obtain 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 cpid'emioiogical use of clinical observation of cffects on a representative population becomes inapplicable because of the size of the samples needed to validate the findings. While a few hv.ndred individuals suffice for a fairly accurate assessment (if the risk related to high doses, hundreds of thousands and even millions are needed to assess the potentihl risk when. the dose is a hundred times smaller. Such numbers, once the cuLurt.ti have been rid of possible bias (presence of c.o-c..arcinogeus, 1gc, sex, life style, manner and source of exposure, latency time, direct and indirect cxpusure, etc.) ttrc quite heyond our reach, technicall,y, materially and financially. ' I'hc need to know" - and among decision makers the need to know what to base their decisions on - remains. In 1959, dUring debates on tlie "Fcxxi, Drug and Cosmetics Act°', US cungre.samart Delaney` int.roduced an atnenc3rnent which postulated that :ir,y mulccul'e cf a carcinoge,aic sulist;tncc can causr cancer. • In 19,0. . dllrlng dcl)atC:± <1ntht? -F/lUd. L)1ui; :Sod Cf1~n1Yt.1(`.G {\ct ,USc()IIurH!tivftian I)C1k171vy introduced an ,.rnrndmenU which bore lri,c namc and which 1Nr,tulatcd the notion ti,xt. there is no d(,>:e without: an cffcct. 'I'hiF concept rlpiJlv wenC beyond tlic lsnrits of products iritAandWJ Cor hurna,n cnniirmption un(1 waS Oxt<`ndC(] to al66tlssm.•nt..in gc•I1crRl-`cithoUt referencc l<, the t70s(J - Vf all carcinogr_ns. "No dow is Delane,y ms.inc{ir.ed. "Onc fibtrr c,in kill~- l.rwin Sclikrfifreturtcd a fi•w yecu's It[Q„r. International Center to( a Scientilic Ecology 1'), ovenue de Messine. lS(X)EIIPiari;, Fionce PI iox'~e:;1J 1 45 fil 2U (Xl, tc-tx : 33 1~ 42 89CO 50

26- 3'-93 ; 10:28 ; G.F.C.C.-- 44 081 569 7021:R 3/ ~ dVV: PAR : This new notion had reverberations well beyond the United States, upsetting ideas held by the international community of Loxicologists wtuch had lyeen ba..~cd on a saying attributcd to Parucelsus: 2 Euerything is a poisc,n, nothing is a poison, the dose alone malurs tlw. poison_" At Llre same time, incredible advances were being made in physical and chemical measuring techniques, which meant that infir;itesitnal traces of substances eould be measured - traces of anything in everything- Epidemialol,ry, originally an experimental science, had to respond to this urgent demand and took the approach of the Delaney amendment: "No dose is safc." NumhPrfi of mathematical models were devised, perfected and used to assess substances with proven carcinogenic effects in high doses, by extrapolating from the eifects observed in high exposure towards low exposure. The principle chosen was linear: the etI'eet was proportional to the dase, starting from the principle that any dose - no matter how low it was - wotrld have some effect. This concept, which often yields very different result_5 froni onc study to another, is currently used as the basis for evaluating low exposure effects and, consequently, for drafting national and international rc:gulatioiis: Many epidemiologists themselves doubt the validity of these extrapolations but they use thern, for lack of anything bctter- For many substances omnipresent in man's environment, the application of the concept of linearity also poses an insurmountable prnblem concerning the elimination of natural sources of exposure. The combination~ of new developrncnts in methods of analysis and measurement and the very human desire to enjoy total protection (zero risk) seems to lead more and more often to dead-end or incoherent regulations. Iiow far can we legitimately push the principle of'prccaution? ' It was felt thaL this is art opportune time to pose the qucst.ion in its very principle now that we are ir% a position - for some substances at least - to compare predictions resulting from the linear mathematical approach with ohservable facts. This seminar, res[:rved for international speciaiists, will address the following quektion: must we persist with a principle crf asscssment, even if its predictions arYt 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 is "hio", a new approach ought to be proposed.

E7VV. PAR : 26- 3-93 ; 10 = 28 ; Provi.sional agenda Monday May 10, 1993 8/8.15 a.m. • Registration - Coffee. 8.1.ri/8 _10 a.m. - - Welcome address by Pierre Joly, Chairman of the International Center for Scientific h:cology. 8.30/'9 a.m. • Opening speech by the Chairman, Prof Bruce N. Ames (Riologist, Dir., Nat. Inst. of Environmental Health Sciences Center, Berkeley, U S.A.). 3 9/9.20 a.m. • Methodology of prediction studics through mathematical extrapolation. Dr. Moolgavkar (Epidemiologist, Fred Hutchinson Cancer Research Center). (to be confirmed). 9.20/9.40 a.m. • Critical approach of mathematical extrapolation. Prof Etienne Fournier (`foxicologi.st, Hopital Fernand-Widal, Paris, France). 9.40/10.00 H.m. •`1`ho Delaney amendment and its conscquences on the American regulation. Prof Fred S. Singer (Physicist, former Dir., US Weather Satellite Program; President, Science & Environmental Policy Project, 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, U.K.). - The Arsenic case. Prof. Gerhard Stfihrer (former chief, Dept. of chemical risk, Research Inst. Sloan-Kettering, U S..A.). - The case of chlorine and derivated products (VCM). Dr Werner Erreicsleben (Dir., European Council of Vinyl Manufacturers) - The DDT case. ProE Aaron Wildavsky (Uniuersity 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. Prof. P.N. Lee (Statistics and computing, Sutton, U.K.): 11.30 /y 2.1.5 a.m. • Questions / Answcrs. 12.15 a.mJ2 p.m. • Lunch. 2/4-30 p.m. • General discusqicn. 4.30/5 p.m. • Coffec/'I'ca break. G. F. C. C. ~ 44 081 569 7021; # 4/ ; ./

. F1W. PAEZ : 1b- 3-93 ;' 10=29 ; G. F. C. C. - 44 081 563 7021: # 5/ 7 6/6p.m. • Carrying of a consensus text. End of Seminar. 61'7p.m. • Special meeting with international scientific press for Q/A and interviews. ' (The panelists will receive well in advance a 5110 page text of each contribution, but the oral presentation should not exceed 10 minutes). 1'articzpants 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. Utgani.sation 4 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 1Vlichel Salomon, the coordinator of the Heidelberg Appeal. ...,<=~.: Zzanslation Lectures and comments may be either in English or French. Simultaneous trenslation will be provided in both languages throughout the seminar. Press Conference 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.m. on May 10, 1993. .../

- V UV - 1 U LUI u . ~ . i ni. -.. u. r. U. U. - 44 ubl oW 1U11 ;'; Eil 7 5 The International Center for a Sden#ific Ecology The Center has been created at the beginning of 1993 under thc 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 thc scientific community is confrontcd 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 living species, natural sites and the resources of the planet. The Association thus proposes to provide the most relevant scientific facts to the authorities responsible for developing environmental protection policies, to the Society which, under the principle of transpareney, is called upon to express its point of view, as well as to all socio-econornical partners who want tu contribute in both the conservation on the Earth and the long-term development of its populatiorjs." The Board of the Center includes in particular : - Mr Pierre Joly, President of the Association FranVaise pour Ia Itecherche 'I'herapeutiquc; ic,rracr I'residcnt of Llte International Federation of Pharmaceutical Manufacturers Associdtion; French nationality; - Mr Cdnstant Burg, honorary member of the State Council; honoraiy managing directur of ThTSF-.RM; President of the Tnstitut Curie; French nationality: - Mr Gilbert Itutman, chief mining engineer; President of the (;onseil National des Ingenieurs et des Scientifiques de France; French national'2ty; - ProL S. Fred Singer, Tbctor of Physical Science; President of the Science & Environmental Policy Project; former Director, US Wcather Satellite Program; Dean of the S<:hool of Environmental Sciences, University of Miami; Deputy Assistant Administrator of US Environmental Pr.otecLioa Agency (1?I'A);, Axnerican nationality; - Mr Gary Nash, Secretary General of the International Council on Metals and the Lnvironunent (ICME); former Director General in LI're Canndir llcpartment of Enert,ry, Mincs and Resources; Canadian nzticrnality; - Dr. Michel Salomon, coordinator of the Heidelberg Appeal; former science journalist; magazine editor; French nationality. 'fhe Seminly de%,oted to the linear dosehespornnse relationship is the first. event initiatcA by the. TnternationHl Center for a Scientific Foolt>gy. 17/219T Internofiona! Cent;e, toc a Scientific Ecology 10, C7vCnuc, de Me'ssiiie, 75~ PUris• franc:e, R 'none = 33, 1 i i1b 62 20 03'• rcix : 13 142 t3V 00 59