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International Center for a Scientific Ecology Centre International pour une Ecologie Scientifique Is the concept of linear relationship between dose and effect still a valid model for assessing risk related to low doses of carcinogens ? May 10, 1993 - Paris International Center for a Scientific Ecology 10, avenue de Messine, 75008 Paris. France Phone : 33 1 45 62 20 03, Fax : 33 1 42 89 00 59

International Center for a Scientific Ecology Centre International pour une Ecologie Scientifique Is the concept of linear relationship between dose and effect still a valid model for assessing risk related to low doses of carcinogens ? May 10, 1993 - Paris •Background Prof. Bruce N. Ames • The Causes and Prevention of Cancer Prof. Georg Luebeck • How biologically based models may help extrapolating cancer risk to low doses Prof. Etienne Fournier • A critical study of methods of assessment of effects of low doses Prof. Aaron Wildavsky - Do rodent studies predict human cancers ? Prof. S. Fred Singer • The Delaney Clause - Linchpin of the Environmental Policy Edifice Prof. Gerhard StShrer • Toxic Policy at Dead End. The case of Arsenic Prof. J. Corbett McDonald • The Asbestos example Dr Werner Freiesleben • The case of chlorine and derivated products Dr William Hazeltine • The DDT : Example Prof. Bernard L. Cohen • Test of the linear-no thershold theory of radiation carcinogenesis Dr. Clifford i. Chappel • Bladder cancer in rats fed sodium saccharin Prof. P.N. Lee • Environmental Tobacco Smoke and Lung Cancer Approaches to risk assessment Pr Erich Hecker • Endeavouring new shores in the estimation and assessment of the cancer risk by environmental materials (abstract) Prof. Douglas Liddell • Health effects ot Historical Exposures to Asbestos • Exposure-Response : Asbestos and Mesothelioma International Center for a Scientific Ecology 10. avenue de Messine. 75008 Paris. France Phone : 33 1 45 62 20 03. Fax : 33 1 42 89 00 59

International Center for a Scientific Ecology Centre International pour une Ecologie Scientifique Is the concept of linear relationship between dose and effect still a valid model for assessing risk related to low doses of carcinogens? Arestricted international scientific seminar May 10, 1993 - Paris (France) BACKGROUND Assessing the risks to a population due to exposure to high doses of carcinogens has become routine practice 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 data (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. Occupational safety regulations use such facts as a reference. 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 epidemiological use of clinical observation of effects on a representative population becomes inapplicable because of the size of the samples needed to validate the findings. While a few hundred individuals suffice for 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 cohorts 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.) are quite beyond our reach, technically, materially and financially. "The need to know" - and among decision makers the need to know what to base their decisions on - remains. In 1959, during debates on the "Food, Drug and Cosmetics Act", US congressman Delaney` introduced an amendment which postulated that any molecule of a carcinogenic substance can cause cancer. * In 1959, during debates on the "Food, Drug and Cosmetics Act", US congressman Delaney introduced an amendment which bore his name and which postulated the notion that there is no dose without an effect. This concept rapidly went beyond the limits of products intended for human consumption and was extended to assessment in general - without reference to the dose - of all carcinogens. "No dose is safe;" Delaney maintained. "One fiber can kill;" Irwin Selikoff retorted a few years later. - International Center for a Scientific Ecology 10, avenue de Messine, 75008 Pads. France Phone : 33 1 45 62 20 03. Fax : 33 1 42 89 00 59

2 This new notion had reverberations well beyond the United States, upsetting ideas held by the international community of toxicologists which had been based on a saying attributed to Paracelsus: "Everything is a poison, nothing is a poison, the dose alone makes the poison." 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 safe." Numbers of mathematical models were devised, perfected and used to assess substances with proven carcinogenic effects in high doses, by extrapolating from the effects observed in high exposure towards low exposure. The principle chosen was linear: the effect was proportional to the dose, starting from the principle that any dose - no matter how low it was - would have some effect. This concept, which often yields very different results from one study to another, is currently used as the basis for evaluating 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 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 combination of new developments 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. How far can we legitimately push the principle of precaution? It was felt that this is an opportune time to pose the 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 assessment, even if its predictions are 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 "No", a new approach ought to be proposed.