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Short Proposal: Low Ignition-Potential Cigarettes 1 PREFACE Page i It is conceivable that at least some possible modifications to reduce the ignition po- tential of cigarettes could be connected with a change in the biological activity of the smoke of these products. The objective of the industry therefore is to assure that these modifications do not lead to an increase (or arise) of an unwanted biological activity, which is harmful to the consumer. An increase in the biological activity can be measured either indirectly by chemical/- physical analyses or directly in biological systems. As epidemiological studies from the practicable point of view are not capable to help in this respect, guidance can only be expected from chemical/physical analyses, in vitro and in vivo studies. It is obvious that, not only in view of the limited scientific resources, these assays should only deal with these parameters which have shown that they are directly or at least tightly associated with a possible negative impact on the consumer. That means, these parameters have shown that they, in the context of the objective, are relevant. In order to detect changes in the biological activity between the customary and the new, low ignition-potential product the assays need to have proven their reproducibi- lity, which means, for at least, they are established. As a comparison between two products is required, a major prerequesite of each assay is its ability to give not only qualitative data (yes/no answere) but also being quantitative. Furthermore the assays to be applied should have shown, that they are able to detect differences between the biological activity of cigarettes which are extremely diffe- rent with respect to their filler content. Although this is not necessarily a prerequesite with respect to the objective, these assays would be judged as more sensitive than others which have not shown that they are discriminative. N O ~ ~ ~ W ~ N,. ~

Short Proposal: Low Ignition-Potential Cigarettes Page 2 2 CONCEPT Conceptually there are two approaches to investigate the influence of a cigarette modification on the biological activity of its smoke, Following the so called performance-based approach, one would investigate the biological activity of a cigarette prototype, which is identical to the cigarette intended to put on the market place. The shortcomming of this approach is that the informa- tion gained from the investigations would be only valid for that special prototype. Each change in that cigarette, e.g. minor variations in the filler composition, would therefore implicate the necessity of a reevaluation. Furthermore, and most impor- tant, this approach would not give any insight into the biological importance of the modification itself. A scientificly more valid approach, which gives the information about the impact of the modification itself, would be a design-based investigation. This means, investigated will be a series of cigarettes which differ in the ext~nd of that modification, which is intended to reduce the ignition potentia of cigarettes. If evidence is given, that effects or the absence of effects are not restricted to a given cigarette type but is rather an intrinsic consequence of that modification, than that information can be taken for the decision to give or to give not a general permission for that modification. The decision to accept a modification or not requires two elements: a comparison and a decision rule. As a first step, the results of the investigations have to be compared with some kind of a reference. This reference could be •#he biological activity of the cigarettes alrea- MKa dy on the market place or a defined segment of these. However, if a design-based investigation has been choosen, this choice of reference results in the undesirable situation, that the outcome of the comparison depends on the basic construction of the cigarette type used to investigate the consequences of the modification. If this basic construction leads to a rather low activity of the unmodified cigarette, than the modification will probably not result in a biological activity which is higher than the reference. The opposite is true, when using a high biological activity cigarette on top of which a modification is placed.

Short Proposal: Low Ignition-Potential Cigarettes Page 3 More appropriate seems the comparison of the modified j with the unmodified cigarette, ~ 'k which inherently underlies the design-based approach. Taking the unmodified ciga- rette as a reference, the actual decrease or increase in the biological activity due to the modification can be assessed quantitatively. More problematic than the choice of the type of comparison seems the choice of the decision rule, especially when more than one parameter are to be judged. In that situation there are in principle only two alternatives: 1. Any increase in the biological activity of a single parameter due to the modification leads to a rejection of that modification. 2. Increases in the biological activity of one parameter can be compensated by a decrease of another parameter. Decision rule 1 takes a more conservative approach and, at first sight, seems to protect the consumer more than the alternative. But considering the situation when only one parameter is minimally increased and all the other parametersinvestigated are drastically decreased, then this decision rule is in fact detrimental to the consu- mer. Therefore increases in the biological activity should be weighed against decreases. There are obviously no conclusive criteria to perform such a balance. A reasonable approach, however, seems to use the variation of the single parameters in those cigarettes already on the market place as a guidance (the mathematical context for this approach is given in the appendix).

Short Proposal: Low Ignition-Potential Cigarettes Page 4 3 CHEMICAL/PHYSICAL ANALYSES

Short Proposal: Low Ignition-Potential Cigarettes Page 5 4 IN VITRO STUDIES 4.1 Proposed Assays One aspect which should be covered by in vitro investigations is the cytotoxicity of the smoke. An assay which deals with this aspect and has proven to give reliable, dose dependent responses for a lot of substances is the neutral uptake assay. This test is, to our experience, not only sensitive to cigarette smoke but also capable to discriminate between different cigarette types. As the direct application of cigaret- te smoke, as in other in vitro systems, poses major disadvantages, the particle phase and the gas phase of the smoke should be assayed seperately. This can be done by applying either condensate of the smoke or saline through which filtered (particle free) smoke was bubbled. An other aspect to be investigated is the genotoxicity of the smoke. An exceptional reliable test system with this respect is the Salmonella plate incorporation assay. This assay, commonly called the Ames assay, has shown for cigarette smoke con- densate to be able to discriminate between differrent cigarette types. For the gas phase of the smoke we recommend the Salmonella microsuspension assay, which is an variation of the incorporation assay. Also here smoke bubbled saline should be applied to the test system. 4.2 Costs 4.3 Further Considerations additional assays with the same endpoints additional assays with different endpoints