1. 1 Preliminary Information Concerning the Establishment of a List of Harmful and Potentially Harmful Tobacco Product Constituents Before the FDA Tobacco Product Constituents Subcommittee of the Tobacco Products Scientific Advisory Committee June 8, 2010 Michael W. Ogden, Ph.D. R. J. Reynolds Tobacco Company

2. 2 Summary Presentation Addresses the topics listed in the Federal Register Notice 75 (80) 22147 of April 27, 2010. Is intended to provide the Committee with preliminary information concerning the establishment of a list of harmful and potentially harmful tobacco product constituents, including smoke constituents, pursuant to section 904 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 387d), as amended by the Family Smoking Prevention and Tobacco Control Act (“the Act”) (Public Law 111-31). As requested by the FDA, representatives of multiple individual tobacco product manufacturers and others have contributed to this slide deck. My presentation does not necessarily represent the perspectives of individual tobacco product manufacturers. Some individual manufacturers have submitted their own written comments. I will be available to answer questions on behalf of R. J. Reynolds. Representatives of other individual tobacco product manufacturers are also available to provide their perspectives.

3. 3 Contributors to This Presentation Altria Client Services on behalf of: – Philip Morris USA – U.S. Smokeless Tobacco Co. Commonwealth Brands Inc. Japan Tobacco International King Maker Marketing Inc. Liggett Group LLC Lorillard Tobacco Co. R. J. Reynolds Tobacco Co. on behalf of itself and: – American Snuff Co. LLC – Lane Limited – R. J. Reynolds Tobacco (CI) Co. – Santa Fe Natural Tobacco Co. Swedish Match North America Inc. Vector Tobacco Inc.

4. 4 Overview Introduction Background information Fundamental considerations Scientific framework for selecting constituents Testing methods Conclusion

5. 5 Introduction A clear purpose for developing any list is critical. Tobacco is an agricultural product. – Tobacco and smoke constituents (i.e., chemicals appearing in tobacco or smoke) are subject to inherent variation. The framework for developing a list of harmful and potentially harmful constituents needs to be science- based. Any testing/reporting of constituents must be based on properly standardized methodologies that are validated and fit for purpose.

6. 6 Background Information

7. 7 Constituents* in tobacco – tobacco is an agricultural product – inherent natural variability – potential impact at the farm level Constituents in smoke – absolute and relative smoke yields depend on many variables – reduction of one constituent often results in elevation of another *For the purpose of this presentation, “constituents” are defined as chemicals appearing in tobacco or smoke.

8. 8 Classification Most of the commercial tobaccos produced in the world are Nicotiana tabacum L. – Based on the Tobacco Genome Initiative (NC State University), a conservative estimate of the size of the N. tabacum genome is 4.5 billion base-pairs, approximately 1.5 times larger than the human genome. Properties of tobaccos, and therefore their usabilities, depend on (among others): – Variety – Locality – System of production and curing method – Other (e.g., stalk position) 8 “Tobacco: production, chemistry and Technology” (1999). Eds. D.L. Davis, M.T. Nielsen. ISBN 0-632-04791-7.

9. 9 Sources of Tobacco Variability Tobacco variety Leaf stalk position Growing region Agronomic practices Weather and climatic conditions 9

10. 10 Field Practices Like most agricultural crops, tobacco plants are affected by such variables as seedling quality, plant populations, nutrition, plant-water relationships, and climatic factors. For tobacco, there are special requirements for topping (removing the inflorescence) and for control of suckers (axillary bud growths). Leaf quality and composition varies with position on the stalk. 10

11. 11 Curing Practices The two major curing methods, flue-curing and air- curing, produce quite different results, even if the same plant variety is used. During the curing process (also during aging and fermentation), chemical processes occur that form chemicals that are organoleptically important. 11

12. 12 Storage Practices Freshly cured tobacco leaf is not ready for use immediately and cured tobacco is typically stored for several years. Additional chemical changes occur as the tobacco ages. 12

13. 13 Tobacco Blends: Cigarettes American-blend cigarettes usually contain a mixture of: – Flue-cured (“Virginia” or “Bright”) tobacco – Burley tobacco (air cured) – Oriental (“Turkish”) tobacco (sun cured) – Expanded tobacco (“puffed”) – Reconstituted leaf (a process similar to that used to make paper) 13

14. 14 Tobacco Blends: Smokeless American smokeless products are primarily produced from fire-cured and/or air/sun- cured dark tobaccos. – “Dark” tobaccos are so named because they have a high chlorophyll content. – Flue-cured tobacco generally is not used. – Smoke from hardwood (usually hickory) fires is usually used in the fire-curing process. 14

15. 15 Tobacco Varieties Within each main tobacco type, there are large numbers of tobacco varieties (or cultivars). These varieties were often produced for resistance to diseases such as tobacco mosaic virus, and to tobacco pests such as nematodes. At least: – 1500 tobacco germplasms archived at USDA (1996) – 60 varieties each of flue-cured, Burley & Oriental – 120 countries growing tobacco commercially 15

16. 16 Total Variability* Short-term (days) – Variability in tobacco weight, filter ventilation, blend uniformity, etc., around targets Medium-term (months) – Components (papers, filters, ventilation), tobacco blend grades and sources Long-term (years) – Tobacco crop year inventories, component suppliers, cigarette design changes At least one manufacturer (PMUSA) has discussed specific constituent variability with CDC. *ISO Standard 8243-2006(E), Annex B

17. 17 Fundamental Considerations

18. 18 Define Purpose of the List As a first step in the process of developing a list of harmful and potentially harmful constituents in tobacco products, the Subcommittee should define clearly the purpose of the list. Without that, it will be very difficult to appropriately determine the criteria by which constituents would or would not be placed on the list. Establishing the purpose will also be critical in determining appropriate analytical methods and testing standards.

19. 19 Listing of Harmful Constituents: Possible Purposes? Evaluating product changes Product research to understand the relationship between constituents and health risk Setting product standards Consumer communication

20. 20 Consider Public Health Benefit Agency and industry efforts should be focused on activities that will have a meaningful impact on disease outcome. – How will the information and effort expended be used to advance the public health? How have previous reports to various public health agencies been used to advance the public health? – How will impact be verified?

21. 21 Scientific Framework for Selecting Harmful and Potentially Harmful Constituents

22. 22 Scientific Basis for Identifying Harmful and Potentially Harmful Constituents Cigarette smoking causes lung cancer, heart disease, emphysema and other serious diseases in smokers. Tobacco and smoke contain many chemical constituents. – Some of these chemicals have been identified as “toxic” using non-clinical testing and occupational exposures history. – Many of these chemicals are not unique to tobacco. There is inadequate evidence that specific constituents in cigarette smoke cause any specific smoking-related disease in cigarette smokers. There is also inadequate evidence that selective smoke constituent reduction reduces risk.

23. 23 Composition is Complex Tobacco: – Due to genetic and agricultural variables, tobacco is inevitably complex. Smoke: – Smoke from combusted tobacco is complex due to the inherent variability of the tobacco leaf and the influence of other factors, such as processing and inclusion of structural components of the cigarette (papers, filters, etc.). 23

24. 24 One Estimate of Composition Constituent ClassTobaccoSmoke Hydrocarbons3241,217 Oxygen-containing compounds 5,1493,568 Nitrogen-containing compounds 575675 Nitrogen heterocyclic compounds 6071,246 Miscellaneous1,434651 Total8,0897,357 “The chemical components of tobacco and tobacco smoke” (2009). A. Rodgman, T.A. Perfetti. ISBN 978-1-4200-7883-1.

25. 25 Key Questions for Establishing a Scientifically Sound Prioritized Constituent List Calculated Risk Hazard, Dose-Response (Biology): What are the toxic effects of a chemical? How much of a chemical does it take to cause the toxic effect(s)? Exposure (Chemistry): How are users exposed? Are they exposed to enough of the chemical for a duration adequate to cause a toxic effect? Risk Management

26. 26 Historical Context: Risk-Based Approaches Regulatory advocacy reports applying risk-based approaches – New Zealand Carcinogen List: The Chemical Constituents in Cigarettes and Cigarette Smoke: Priorities for Harm Reduction. A Report to the New Zealand Ministry of Health, March 2000. – WHO Technical Report Series 951: The Scientific Basis of Tobacco Product Regulation 2008. Other reports and publications – Vorhees et al., Report to The Medical Foundation (1997). – Rodgman and Green, Beitr Tabakforsch Int 20 (2003) 481. – Fowles and Dybing, Tobacco Control 12 (2003) 424. General qualitative agreement between lists, likely because nearly all use a modification of the “Exposure x Potency” approach with similar assumptions.

27. 27 Selection Criteria for Consideration – Hazard What are the hazards for the constituent? – cancer – what type? – route of exposure Does the constituent have the same hazard as the tobacco product? – assessment of chemicals in isolation vs. in a complex mixture e.g., benzene causes leukemia – smoking is not an established cause of leukemia How robust is the hazard data? (Degree of uncertainty) – in vitro studies, animal studies, human data other than in tobacco – standard practices about causation consistency of findings general weight of evidence

28. 28 Selection Criteria for Consideration – Exposure What is the strength of evidence that consumers receive a biologically meaningful amount of any given constituent? – found in tobacco/product/smoke – human yield under conditions of use – human exposure under conditions of use biomarker data Absorption, Distribution, Metabolism & Excretion What is the magnitude of exposure to the constituent from other sources? – confounding and relevance

29. 29 Quantitative Risk Assessment: A Possible Tool An established approach used in regulation of chemicals in other consumer products, food, and environmental matrices. Incorporates estimates of both biological potency and exposure in a unified cancer/non-cancer approach. Provides a framework for quantitative analysis of the uncertainty and variability inherent in the process required to establish a list of constituents. Flexibility—methods can be scaled to estimate absolute risk or to compare relative risk between constituents; can be easily updated as the science evolves. But…only as valuable as the input data allow.

30. 30 Beyond Establishing a List of Harmful and Potentially Harmful Constituents: Testing Methods

31. 31 Need for Standardization and Harmonization There are no standardized methods for measuring most of the constituents being considered. Methods standardization should be completed prior to generation of vast amounts of constituent data. The development of any new product testing regime(s) should be set according to internationally recognized standards (e.g., ISO) or, in the absence of such standards, on the basis of new standards developed and validated according to internationally recognized best practice. Such standardization and harmonization will ensure accepted tolerance values exist within which to compare test results. A clear understanding of the purpose for constituent testing will facilitate generation of the most useful information.

32. 32 Methodological Considerations Stability over time Sampling needs (representative) Extraction techniques – try to remove everything – try to represent (estimate) human exposure Smoking methods – try to estimate human exposure averages ranges maxima Quality standards (e.g., ISO, GLP) – should reflect intended use of measurement

33. 33 Testing Considerations: Laboratory Yield Most reproducible - permits comparisons over time Can measure many different chemicals Data from multiple machine regimens (for smoke) currently available: – Cambridge Filter Method (formerly FTC) – ISO – Massachusetts – Health Canada More limited data from extraction regimens (for smokeless) currently available: – CDC (nicotine, pH) – variety of in-house methods for other constituents (Gothiatek®) Difficult to mimic range of human use – No regimen proposed to date accurately predicts constituent yield under actual human use conditions Inter-individual variability in behavior is a key limitation when using laboratory yield data in risk characterization

34. 34 Testing Considerations: Yield in Use* Constituent yields estimated under actual human use conditions – Better than laboratory yield testing as an estimate of actual exposure Less reproducible than laboratory yield testing Data set is currently somewhat limited but growing When applied in a probabilistic risk assessment, YIU data can partially account for inter-individual variability in behavior *Yield in Use (YIU) - Filter testing for cigarettes; before/after use for smokeless.

35. 35 Testing Considerations: Biomarkers of Exposure Can provide an estimate of biological dose Limited number of biomarkers available Highly variable Disease relationship is still uncertain

36. 36 Testing Considerations 36 Members of the regulated industry have experience in this area and are willing to provide additional detailed presentations on: – Possible development of laboratory methods – Human use (YIU) studies – Uptake (biomarker) studies – Alternative smoking machine regimens

37. 37 Potential Technical Objectives – Smoke Constituents Develop an understanding of: – The intended purpose of a new smoking regime – The scope of relevant human smoking behavior studies – The scope of relevant uptake studies – The scope of “alternative” smoking machine regimens available – Repeatability and reproducibility characteristics of alternative smoking methods

38. 38 Historical Perspective Relevance of machine yields to smoke yields experienced by smokers: Both government and non-government bodies have rejected the idea that machine test yields based upon a single smoking regimen equate to what an “average” consumer obtains from smoking.

39. 39 Technical Capability vs. Promulgated Regulation

40. 40 Machine-based Smoking Regimes FTC Method ISO 3308 Mass- achusetts Canadian “Intense” Applicable In: United States (Historical) International Standard Mass., Texas Canada Stated Purpose: Cigarette Yield Ratings for Product Comparison Estimate Nicotine Yield for an “Average” Consumer Estimate “Maximum” Smoke Yields Under “Realistic” Conditions

41. 41 The FTC Method - 1967 Stated Purpose: Cigarette Yield Ratings for Product Comparison An example of technical capability preceding regulatory testing requirements: Interlaboratory harmonization conducted in 1964 Method variability determined – Within laboratory – Between laboratory Test results reported in accordance with observed method accuracy and precision – “tar” – whole (1) mg – nicotine – 1/10 (0.1) mg Method suitable for stated purpose

42. 42 The “Massachusetts Method” - 1997 Stated Purpose: Estimate Nicotine Yield for an “Average” Consumer An example of regulatory testing requirements preceding technical capability: No interlaboratory harmonization conducted prior to regulatory implementation Method variability unknown – Within laboratory – Between laboratory Results reported based on FTC method accuracy and precision – nicotine – 1/10 (0.1) mg

43. 43 Relevance of Massachusetts Machine Yields to Intended Purpose Stated Purpose: Estimate Nicotine Yield for an “Average” Consumer Nicotine yields generated under the Mass. machine test method do not indicate what an average consumer will inhale into their lungs and retain (i.e., smoke intake) when smoking a particular brand of cigarettes.* *Based on smoker YIU data compared to Mass. machine yields.

44. 44 The “Canadian Intense” Method – 1998 Stated Purpose: Estimate “Maximum” Smoke Yields Under “Realistic” Conditions Another example of regulatory testing requirements preceding technical capability: No interlaboratory harmonization conducted prior to regulatory implementation Method variability unknown – Within laboratory – Between laboratory

45. 45 Relevance of Canadian Intense Machine Yields to Intended Purpose Stated Purpose: Estimate “Maximum” Smoke Yields Under “Realistic” Conditions Intense method does approximate the maximum mouth-level exposure possible when smoking their usual brand of U.S. cigarette.* But how realistic is it? *Based on YIU data in smokers compared to Canadian Intense machine yields.

46. 46 Canadian Intense Method Compared to Smokers’ Actual Yields How realistic is it? Assumes smokers fully compensate for nicotine when switching from high to low ISO/FTC yield cigarettes. – Many studies show compensation is incomplete. – Many smokers of highly ventilated cigarettes are not switchers. Only meaningful if relative composition of smoke is similar for machine smoking and human smoking. – Unlikely to be true for highly ventilated cigarettes – as smokers do not block all vent holes. Unrealistic changes occur during tobacco combustion. – Peak temperatures during a puff, filter efficiencies, etc.

47. 47 Technical Capability Should Precede Promulgation of New Regulation

48. 48 Conclusion A clear purpose for developing any list is critical. Tobacco is an agricultural product. – Tobacco and smoke constituents (i.e., chemicals appearing in tobacco or smoke) are subject to inherent variation. The framework for developing a list of harmful and potentially harmful constituents needs to be science- based. Any testing/reporting of constituents must be based on properly standardized methodologies that are validated and fit for purpose.