11/6/03LSRO presentation Draft for discussion PM USA Mission Our goal is to be the most responsible, effective and respected developer, manufacturer and marketer of consumer products, especially products intended for adults. Our core business is manufacturing and marketing the best quality tobacco products to adults who use them … Exceed Consumer Expectations Provide Smoking Pleasure/Reduced Harm — Respect our adult consumers by meeting or exceeding their preferences, providing them with smoking pleasure and continuously developing new methods and technologies with the potential to reduce harm associated with our products. (PMUSA.com)

11/6/03LSRO presentation Draft for discussion Cigarette Ingredients and Smoking Behavior Outline: The potential role of cigarette ingredients in smoking behavior A simple model of smoking behavior The range of potential effects on nicotine retention – an example from the literature Testing for specific effects Conclusion

11/6/03LSRO presentation Draft for discussion Cigarette Ingredients and Smoking Behavior Cigarette ingredients should not increase harm in the population of adult smokers by changes in smoking behavior (increased exposure by e.g., smoking more cigarettes, increase in puff volume)

11/6/03LSRO presentation Draft for discussion those ingredients, which are not processing aids or humectants, are intended to make a product more appealing however a less appealing product does not necessarily reduce exposure, but might result in rejecting that product and switching to another more appealing product Cigarette Ingredients and Smoking Behavior

11/6/03LSRO presentation Draft for discussion Ingredients might decrease exposure by providing sensory cues e.g., increased irritation in the lower respiratory tract might reduce depth of inhalation Cigarette Ingredients and Smoking Behavior

11/6/03LSRO presentation Draft for discussion Do we have evidence that ingredients change smoking behavior in that way that exposure is increasing?

11/6/03LSRO presentation Draft for discussion Case Study Comparison of 2 cigarettes: 1. Reference cigarette 2. Test cigarette Same FTC tar delivery, different taste

11/6/03LSRO presentation Draft for discussion Mean + SD

11/6/03LSRO presentation Draft for discussion Cigarette Design Smoke Chemistry Puff Intake Topography Inhalation Pneumotachogram ADME Biomarkers Biological Effects short-, long-term Behavior Incidental, occasional, repetitive smoker Choice Puff Duration, Volume etc. Depth of Inhal., Ret. Time Sociological, Psychological Influence Puff Frequency, Number ? Genotype Our Model of Smoking Behavior

11/6/03LSRO presentation Draft for discussion Frost BE, Mariner DC, Sinclair NM. Factors Relating To Nicotine Physio-Chemistry And Retention In Human Smokers. Coresta, Effects of Depth of Inhalation

11/6/03LSRO presentation Draft for discussion Testing of Cigarette Ingredients Ingredients have to pass toxicological acceptability testing In an early rapid screening process “flavor systems” (perceivable ingredients) can be tested for their effects on smoking topography and inhalation

11/6/03LSRO presentation Draft for discussion Different Types of Cigarette Ingredients Vanillin at low levels probably does not change smoking behavior resulting in a significantly increased exposure Is this assumption true for menthol (effect on nicotine metabolism, sensory effects) or ammonium-salts (possible effect on nicotine pharmacokinetics)?

11/6/03LSRO presentation Draft for discussion Does menthol have a local anaesthetic effect?

11/6/03LSRO presentation Draft for discussion Interaction between Menthol and CO 2 CO 2 Menthol 3 conc. Negative Mucosal Potential during CO 2 stimulation Psychophysics Odor Cooling Pain Rhinoklack Kobal&Renner 11 CO2 stimulation during

11/6/03LSRO presentation Draft for discussion Kobal&Renner

11/6/03LSRO presentation Draft for discussion Rating of CO 2 : Pain 14 Kobal&Renner

11/6/03LSRO presentation Draft for discussion Conclusions There are different types of ingredients Ingredient testing is necessary when there is some evidence for potential increase of exposure, e.g. –Significant effects on topography or inhalation –Significant effects on metabolism

11/6/03LSRO presentation Draft for discussionConclusion Ingredients have to pass toxicological acceptability testing Observation (surveillance) of a product when marketed has to be in place to capture changes in smoking behavior and to plan appropriate investigations of the effects