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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

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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.

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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.

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Overview

• Introduction• Background information• Fundamental considerations• Scientific framework for selecting constituents• Testing methods• Conclusion

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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.

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Background Information

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Background Information

• 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.

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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)

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“Tobacco: production, chemistry and Technology” (1999).Eds. D.L. Davis, M.T. Nielsen. ISBN 0-632-04791-7.

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Sources of Tobacco Variability

• Tobacco variety• Leaf stalk position• Growing region• Agronomic

practices• Weather and

climatic conditions

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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.

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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.

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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.

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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)

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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.

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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 growingtobacco commercially

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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

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Fundamental Considerations

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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.

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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

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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?

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Scientific Framework for Selecting Harmful and Potentially Harmful

Constituents

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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.

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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.).

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One Estimate of Composition

Constituent Class Tobacco SmokeHydrocarbons 324 1,217

Oxygen-containing compounds

5,149 3,568

Nitrogen-containing compounds

575 675

Nitrogen heterocyclic compounds

607 1,246

Miscellaneous 1,434 651

Total 8,089 7,357

“The chemical components of tobacco and tobacco smoke” (2009).A. Rodgman, T.A. Perfetti. ISBN 978-1-4200-7883-1.

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Key Questions for Establishing a Scientifically Sound Prioritized Constituent List

CalculatedRisk

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

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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.

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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

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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

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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.

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Beyond Establishing a List of Harmful and Potentially Harmful

Constituents:Testing Methods

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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.

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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

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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

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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.

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Testing Considerations:Biomarkers of Exposure

• Can provide an estimate of biological dose• Limited number of biomarkers available• Highly variable• Disease relationship is still uncertain

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Testing Considerations

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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

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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

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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.

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Technical Capabilityvs.

Promulgated Regulation

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Machine-based Smoking Regimes

FTC Method ISO 3308

Mass-achusetts

Canadian “Intense”

ApplicableIn:

United States

(Historical)

International Standard

Mass.,Texas

Canada

Stated Purpose:

Cigarette Yield

Ratings for Product

Comparison

Cigarette Yield Ratings for Product Comparison

Estimate Nicotine Yield for

an “Average” Consumer

Estimate “Maximum”

Smoke Yields Under

“Realistic” Conditions

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The FTC Method - 1967Stated 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

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The “Massachusetts Method” - 1997Stated 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

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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.

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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

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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.

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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.

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Technical Capability Should PrecedePromulgation of New Regulation

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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.