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i I I i ] I I 3 page 3 The CPSC staff recommends the following guidance plan after reviewing the considerations of its expert panel and DHHS. III. Assessment Plan This plan provides guidance for the development of data needed to evaluate the changes in toxicity associated with low ignition-potential cigarettes. Performance-based, rather than design-based, testing will be used to provide data specific to cigarette prototypes. A screening paradigm that requires acceptable performance levels by a candidate cigarette type at one tier of tests before proceeding with the next tier is recommended. This would allow early rejection of candidates evaluated as unacceptable. However, definition of acceptable levels of performance is beyond the scope of this plan and the direction given by the Act. Therefore, the tests.are presented in a sequence of tiers for screening without ascribing acceptable levels of performance at each tier. - Results of the recommended testing will be used to assess the relative toxicity of low-ignition potential cigarettes. The toxicity of a candidate low ignition cigarette should be compared to: 1) the specific marketed brand/type intended for replacement, or comparable marketed brands/types for a non- replacement candidate, and 2) standard reference cigarettes, such as the University of Kentucky standard cigarettes mentioned in Chapter E, for quality control. There are insufficient test methods and data on exposure to cigarette smoke and resultant effects for the direct translation of the results into absolute risks to humans. Since the overall health goal is to avoid the production of greater or perhaps new toxicities than that caused by existing cigarettes, a comparative approach of assessing toxicity is appropriate. Selection of the guidance plan tests assumes that no new additives would be present in the candidate cigarettes and that presently used additives would not exceed the levels in the current cigarettes. Since toxic effects not considered by this guidance plan could also occur, it is recommended that additives exceeding the current maximum levels of use on a per unit weight of tobacco basis must be disclosed to the U.S. Department of II Health and Human Services. Confidential business information status may be requested for the data disclosed. I

A. Smoking machine page 4 The FTC method described in Chapter B is the basis for the mechanical generation of smoke constituents. Puff volume, frequency, and draw velocity may be modified as dictated by behavioral data developed from human testing (Tier III), as described in Chapter C. Unless consistent correlation of testing results of mainstream and sidestream smokes can be shown, both must be separately collected and tested. B. Description of Tiers An outline of four tiers is presented in Table 1. A description of the tiers follows. Tier I_- Analyses of chemicals All constituents will be reported as per unit weight of tobacco burned and per cigarette. Moisture, nicotine, tar (total particulate matter- dry), and carbon monoxide will be measured according to the FTC method, as described in Chapter B. Nitric oxide will also be measured using the detector attachment to the smoking machine. The gaseous phase will be analyzed for acidity, reduction/oxidation potential, hydrogen cyanide, volatile hydrocarbons, aldehydes, and volatile nitrosamines, as described in Chapter D. The tar will be analyzed for phenols, catechols, polyaromatic hydrocarbons, and tobacco-specific nitrosamines (Chapter D). Tier II - In vitro tests The tar will be assayed for mutagenic activity with Ames' Salmonella test with strains TA98, 100, and 1535. The tar will also be assayed for malignant cell transforming activity, using C3H/10T1/2 mouse embryo fibroblast cells. Both mutagenicity and cell transformation assays are described in Chapter E. Tier III - Human smoking behavior Humans are typically the last experimental tier in testing products with potential human health effects. An example is the premarket testing of new drugs. Human testing to collect topographical data is limited to a couple of weeks of exposure. Smoking behavior, including puff volume, frequency, and draw velocity of a selected group of human volunteers would be monitored, as outlined in Chapter C. Carbon monoxide (breath or blood) and cotinine (urinary, salivary, or blood) will serve as biological markers of exposure to the smoke. If the smoking behavior data is significantly different from the FTC smoking machine settings such that an increase in exposure to the analyzed chemicals might result, then the machine must be set to I i r I I I 1:1 I I

~ reflect these data before generating smoke constituents for page 5 further Tier I and II testing and then animal testing. f Tier IV - Animal tests Inflammatory lung response to cigarette smoke in C57B1 mice will be assayed as described in Chapter E. Tumor formation in the upper respiratory tract of random-bred golden Syrian hamsters from inhalation exposure and the skin, lungs, and other tissues of Swiss albino Ha/ICR/Mil strain mice from skin painting exposure will be examined. These two carcinogenicity tests are described in Chapter F. All testing must conform to good laboratory practices, humane laboratory animal methods, and informed human consent procedures accepted within the scientific community. Evaluations of toxicity must be conducted by.scientists possessing appropriate toxicological qualifications. IV. First implementation step Table 2 is a collection of direct cost estimates for Tiers I, II, and IV. No estimates are available for Tier III. Completion of all four testing tiers by successful low ignition potential cigarette candidates might be considered expensive relative to the present level of testing required by FTC ($330,000 for Tiers I, II, and IV vs. $3,500 for FTC; Table 2). Therefore, a stepwise implementation of the plan is suggested.

page 6 Table 2 Estimated Direct Costs in 1993 U.S. Dollars per brand or prototype ~ Tier I - Analyses of chemicals = $9,500 3500 FTC-required tar, nicotine, and carbon monoxide 250 Whole smoke: = acidity (pH) 500 - reduction/oxidation potential 350 Gas phase gases hydrogen cyanide 400 nitric oxide 700 aldehydes 600 volatile hydrocarbons 800 V.clatile nitrosamines N-nitrosodiethylamine N-nitrosodimethylamine N-nitrosopyrrolidine Particulate phase 350 catechol 250 nicotine 500 phenols, as phenol 500 benzo(a)pyrene 800 tobacco specific nitrosamines Tier II- In Vitro Tests = $9,350 1850 Salmonella mutagenicity (Ames' assay) 7500 mouse embryo fibroblast cell transformation Tier IV - Animal Tests = $309,000 50,000 mouse inflammatory lung response assay 220,000 hamster upper respiratory tract carcinogenicity 39,000 mouse skin painting carcinogenicity ® $327,850total for Tiers I, II, and IV N ha r F f I I I I I I I I

page 7 I I I I I I j I I I I A practical selection of recommended tests should comprise a first step in the implentation of this health effects assessment plan. Subsequent steps should consider the testing recommended by this plan. The first step should include: Smoke and condensate generated by machine according to the FTC protocol Tier I $5,050 tar-FTC nicotine carbon monoxide whole smoke pH benzo(a)pyrene tobacc-o specific nitrosamines N'-nitrosonornicotine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone Tier II $1,850 Salmonella mutagenicity ("Ames") assay ® $6,900 Estimated total per brand or prototype The rationale for selecting these tests extends beyond cost and time duration considerations. Levels of specific chemicals (Tier I) as well as an indication of the genotoxicity of the mixture (Tier II) are needed. Tar, nicotine, and carbon monoxide are presently required by FTC. The pH of the whole smoke is relevant to nicotine uptake. Benzo(a)pyrene is a known animal and human carcinogen; however, cigarettes are not the only source of exposure. The tobacco-specific nitrosamines are potent animal carcinogens and tobacco is the only known source of human exposure. No data are available on the human carcinogenicity of these nitrosamines. J

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OVERVIEW AND MAJOR CONSIDERATIONS IN THE TOXICITY TESTING OF LOW IGNITION-POTENTIAL CIGARETTES Jeffrey Harris, M.D., Ph.D. Internal Medicine Associates - 2 Wang Ambulatory Care Center 605 Massachusetts General Hospital Parkman Street Boston, MA 02114 21 Aug 1992

page 1 ABSTRACT Both mainstream andsidestream cigarette smoke are complex chemical mixtures. In view of this chemical complexity, it should be no surprise that cigarette smoke has multiple, diverse effects on human health. Nor should it be unexpected that multiple chemicals in cigarette smoke contribute to any single adverse health effect. The diverse human health consequences of cigarettee smoking are briefly reviewed. Many experimental laboratory models have been developed to study the mechanisms of cigarette smoke-induced disease. These laboratory models are not always convertible into practical, standardized test systems that quantitatively compare one cigarette prototype with another. In view of the multiplicity of health effects and mechanisms of smoke-induced health damage, no single test or battery of tests can capture all possible health endpoints. While analyses of smoke constituents and studies in laboratory animals are feasible, human epidemiological studies are not practical for short-term assessment of small differences in the toxic effects of various cigarette prototypes. Cigarette smoke samples for chemical analysis and biological testing need to be collected in a manner that approximates human cigarette puffing as closely as technically feasible. In formulating a testing plan, the CPSC essentially has two options: a design-based testing plan, in which individuaL, pre-selected cigarette design parameters, such as paper porosity or percent expanded tobacco, are systematically varied and tested; and a performance-based testing plan, in which complete cigarette prototypes, and not individual design parameters, are evaluated. Some testing protocols entail a "screening paradigm." Multiple tests are performed in sequence. If a prototype fails any particular test in the sequence, the prototype is rejected and no further tests are performed. Other multi-test protocols allow for tradeoffs among costs and benefits. An unfavorable result at any point along the testing sequence does not necessarily result in rejection. The only governmentally-mandated, health-oriented testing of commercial cigarette brands is the measurement and reporting of "tar," nicotine and carbon monoxide in mainstream smoke by the Federal Trade Commission. With this exception, none of the toxicity tests described by the Expert Panel are routinely performed on existing cigarette brands by any governmental agency. The contents of currently marketed cigarettes are proprietary information. Specific additives, tobacco

page 2 composition, and other design features are not publicly disclosed.