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2001 Planning Guidance - Tier 1 - Understandins S&H/Harm Reduction CANCER CVD COPD REPRODUCTIVE ALL OTHER . EXPOSURE . , . Determine if cigarette burn (continued) time can be used to . . accurately estimate smoke . exposure In humans by - . _ comparing actual exposure (TES like study) with predicted exposure from , , cigarette burn times. . [Lipowicz] - . Determine if changes can be made to the normal . nicotine to tar ratio in cigarettes which would , result in a product with , reduced constituent . . exposures (Fading - . Studies). [Takada] . . - Determine if an - enhancement of nicotine's . sensory response in adult smokers can be used to . develop products with - . reduced constituent exposures. [Gullotta] . Determine if the GAG device can be used to - answer research questions such as: 1) how Important . is the rapid adsorption of nicotine for smoking behavior; 2) can the CAG device deliver nlcotine to , the lungs in a manner . similar to a conventional cigarette; 3) what , . compounds might be relevant for a reduced . harm product ; 4) can the . device be developed into a reduced harm product? [Davies] , Develop an RFP to . examine the importance of . ~ . the rapid nicotine bolus . - (nicotine spike effect) -- hi d h i ff , - ~ c occurs ur w ng a pu , I on smoking behavior. - s 895go£$QZ } _11 . [Takada] DRAFT FOR DISCUSSION PURPOSES Page 3 of 4 11-15-00

2001 Planning Guidance - Tier 1- Understanding S&H/fIarm Reduction CANCER CVD COPD REPRODUCTIVE ALL OTHER EXPOSURE . Compensation/Low-Tar . (continued) - Consensus Group. [continued, Kinser] . . . Execute the TES Study In US. [Walk] - . - ' Plan ScoR human . , exposure/effect study. , . [Walk] . . Plan OASIS human . . exposure/effect study in . , Japan. [Takada] . Biomarker Working Group. ' [Tricker] . ETS Working Group. [Lau] Smoking Behavior . . Working Group. [Davies] OTHER: Carcinogenicity Index. CVD.index, in vivo. Lung Inflammation Index, in Conduct work to assess GENERAL HARM . vivo. the best basis of REDUCTION Promotion Index, in vivo. comparison of a new cigarette to the market. . . _ Complete and refine the weighting approach for. , constituents on the current . smoke chemistry list. - - C oxici Index, in vitro. ~s ~- iggg980E80Z DRAFT FOR DISCUSSION PURPOSES Page 4 of 4 11-15-00

2001 Plannine Guidance - Tier 1- Understanding S&H/Harm Reduction CANCER CVD COPD REPRODUCTIVE ALL OTHER HAZARD Causation Consensus Dose-response, variability, COPD Biomarker Identification NHa Consensus Caroup (continued) Group. [continued, and correlation analysis for Group (relevance of human - (Cigarette chemistry of - Dempsey] C-reactive protein (tissue biomarkers in animal models). ammonia in relation to injury, inflammation, [Dempsey?] - _ nicotine delivery/Uptake of ' , LuC Biomarker neoplasm) thromboxane B2, nicotine as a consequence .. , Identification.Group. , 8-epi-PGF2alpha, HDL, LDL COPD Target Compounds in of ammonia . - [Tricker] . and fibrinogen Smoke Identification Group. . concentration). . . . (atherosclerosis, lipid [Kinser?] , [Podraza/Andriot] . " _ LuC target compounds in peroxidation) in TES and . . . ~ . smoke identification cessation study. - . Group. [Haussmann] . . CVD Target Compounds in . . " TSNA Consensus Group Smoke Identification Group. . , ' (Understanding of Smoke [Sanders] . . - " - Nitrosamine Sources). . Kinser ASSAYS Definitiveavaluation of Development of in vivo Development of in vivo Complete repro study Conduct work to determine Method Development, . Mouse Skin Painting- models. , models. at IITRI. , if smoke constituents are - Biochemistry. . , generated in proportion to Definitive evaluation of Development of in vitro Development of in vitro one another under a wide Method Development, Cell . A/J Mouse. models. . models. variety of smoking Biology. " . ' regimens. Study of increasing Method Development, CVD . sensitivity in the rat model Understanding Cytotox, Lab. by choice of Strains. histopathology methods , for the lung. . Understanding Signal . . - ' Transduction, TrX/TrXR. . " - ' Understanding Apopotosis/Necrosis, - , Single Components. _ EXPOSURE - Develop and document a Addiction Consensus Group. - complete assessment of [Takada] . , . - our knowledge of . , biomarkers of exposure for - constituents Identified by , target identification groups, to use in subsequent exposure studies. [Tricker , . -BWG] . Develop a scientific consensus for the adoption of permissable exposure , I - limits (PEL's) for ETS . ~ t'$9980E80Z I _---- -- -_- 1 based on ETS consensus evaluation.[Lau-EEWG] DRAFT FOR DISCUSSION PURPOSES Page 2 of 4 11-15-00

2001 Planning Guidance -15er 1 - Understanding S&H/Harm Reduction CANCER CVD COPD REPRODUCTIVE ALL OTHER _ EPIDEMIOLOGY Complete analysis of Complete analysis of Carry out detailed analysis of ' Design a molecular . , existing data relating . smoking/CVD . COPD epidemiological studies epidemiology study that adenocarcinoma epidemiological data in order in order for us to obtain a might confirm harm . increases with "low, tar" to identify possible - meaningful understanding of reduction for Oasis cigarettes to possibly be susceptible populations and the relationship of active smokers in Japan- able to guide Product possibly provide guidance in smoking with COPD. Such .. Development with respect assay and reduced harm information could possibly Design a molecular - to the development of product development. provide guidance in assay and , - epidemiology study that reduced-harm filters that . reduced harm product might confirm harm , . can change the . '. development. , reduction for Project ScoR distribution of smoke . . products- (This project is delivered to the lung. . noted in order to be . .- , . complete; however, work is Analyze lung cancer . not planned to start until literature with respect to . . 2002). - . either regions or ethnic .. types that appear to be at Cessation Study - design a . greater or lesser risk for molecular epidemiological - lung cancer. (This study , study that will look at will certainly focus on effects in smokers who Japan in 2001. The . - have stopped smoking. ' addition of other such Such a study will provide regions or groups will base line information as to depend on the ability to the maximum effects that locate outside research - could be achieved in assistance). This ' - - , molecular epidemlological . information is important in studies on reduced harm . . identifying the existence , products. , of populations that might - . be sensitive or resistant ' W hat is the relative . to cigarette smoking- - , importance of ETS/SS in, caused lung cancer and " . harm reduction? . thereby provides mechanistic insight. Design epidemiological . . , . , study on the association of lung cancer with ultra . . - low tar cigarettes (1 -5 . mg) to understand the - implications of low tar , - delive on reduced harm. HAZARD State of the science, State of the science, State of the science, including ETS Health Effect . Assessment of role of irritation including a review of Including a review of literature a review of literature on Consensus Group. to establish ETS exposure literature on molecular on molecular epidemiological molecular epidemiological , [continued, Sanders] management level. [continued, , , epidemiological studies, . studies, of potential studies, of potential Lau] of the potential mode/mechanism(s) mode/mechanism(s) including . IITRI . mode/mechanism(s) including disease endpoints disease endpoints and host Understand lactate effects. Including disease and host factors for ischemic factors of emphysema and LSRO endpoints and host heart disease. [von Holt] chronic bronchitis [look at factors of LuC (initiation . studies by UNC Center of Parameter Studies and promotion). [Tricker] CVD Biomarker Identification Environm- Med. [Dempsey?] [continued, Roemer] , ' Grou . von Holt? McKinne DRAFT FOR DISCUSSION PURPOSES F.8998US8UZ ~ Page 1 of 4 11-15-00