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ATTORNEY WORK PRODUCTS NON-TECHNICAL SUMMARY OF THE OCTOBER 20,1992 DRAFT OF: "TOXICITY TESTING PLAN FOR LOW IGNITION-POTENTIAL CIGARETTES" The following is a brief, non-technical, summary of a draft report from the U.S.. Consumer Product Safety Commission (CPSC) and it's Expert Panel, in consultation with the U'.S. Department of Health and Human Services. The draft report provides information about a plan for assessing the potential health impact of cigarettes with low ignition potential. This summary only includes information present in the draft report and does not attempt to evaluate that information. Outline and General Purpose of the Draft Report This report was prepared in response to a requirement in the Fire-Safe Cigarette Act of 1990. This Act requires the CPSC "to develop information on changes in the toxicity of smoke and resultant health effect of cigarettes with a reduced ability to start fires." Due to a statutory limitation of $50,000 to develop this information the CPSC decided to develop a plan for the toxicological work needed and convened an expert panel to assist in the development of the plan. The draft report consists of seven parts: Section Title Author and A liatton Health Effects Assessment Plan Brian C. Lee, Ph.D. (Directorate for Health Sciences, US CPSQ Chapter A -- Overview and Major Jeffrey E. Harris, MD, Ph.D. (Internal Considerations in the Toxicity Testing of Medicine Associates, Massachusetts Low I ition-Potential Ci arettes General Ho ital ) Chapter B -- Smoking Machine Harold C. Pillsbury, Jr. (Cigarette Ti esting Parameters for Collection of Total Consultant). Particulate Matter and Gases from Low L ition-Potential Ci arettes Chapter C -- Assessing Changes in David M. Burns, MD (University of Topography (Inhalation Profile) and California at San Diego Medical Center) Biological Effects of Tobacco Smoke in Humans Chapter D -- Analysis of Toxic Smoke Dietrich Hoffmann, Ph.D. (American Constituents Health Foundation Chapter E -- Short-Term Tests for the C. Gary Gairola, Ph.D. (Tobacco and Evaluation of Cigarette Smoke Toxicity Health Research Institute, University of Kentuc ky at Lexin gton Chapter F-- In Vivo Bioassays for Dietrich Hoffmann, Ph.D. (American Carcino enici' y Health Foundation)'.

ATTORNEY WORK PR®DUCTt S Health Effects Assessment Plan The report states that there are several adverse health effects which form the basis for considering the toxicity tests: lung and throat cancer,, chronic obstructive lung disease, reproductive effects, fetal growth retardation, and addiction. Due to the lack of appropriate tests, expenses,, or time constraints not all of these effects can be addressed at this time. A sequential series of toxicity tests for low ignition potential cigarettes is proposed. The Federal Trade Commission (FTC) smoking machine method will be the initial way smoke is generated for testing. The first level of testing consists of analysis of cigarette smoke for various components which may relate to health effects associated with smoking. The second level consists of testing cigarette smoke tar in living cells. One of these tests detects changes in the genetic material of bacteria. Another test uses mouse cells grown in dishes to detect potential cancer-causing activity. The third level is to determine if people smoke low ignition potential cigarettes differently than the comparable brand or type currently on the market. If the way the cigarettes are smoked is different, then the first two levels of testing will be repeated with the smoking machines set to reflect the change in smoking behavior. The fourth level examines the response of animals to cigarette smoke or tar. One test will look for inflammation in the lungs of mice in response to: cigarette smoke. A second test will! look for tumor formation in the upper respiratory tract of hamsters exposed' to smoke. The third test will look for the cancer producing ability of cigarette smoke tar by applying the tar to the skin of mice. At each level of testing a cigarette with lowered ignition potential would be compared to its currently marketed counterpart. Both mainstream and sidestream smoke would be tested unless data were produced demonstrating that this was unnecessary. Cigarettes passing tests in the first level would proceed to the next level and so on. However, the report states that the definition of acceptable performance is "beyond the scope of this plan and: the direction given by the Act." As noted above, levels one and two would be repeated based on the outcome of level three testing. Also, of note is that the plan assumes that new additives or increased levels of current additives will not be in the low ignition propensity cigarettes. This plan was developed from the information contained in Chapters A-F. Chapter A This chapter provides a general overview of the major points to be considered for the toxicity testing of low ignition-potential cigarettes. During smoking both mainstream smoke (inhaled by the smoker) and sidestream smoke (mainly from the burning end of the cigarette) are generated. While mainstream

~.~TOR NEY WORK PRODUCTS and sidestc+eam smoke are qualitatively similar the quantity of specific components differs between the two. Additionally, modifications to the cigarette can independently affect the composition of sidestream and mainstream smoke. It is concluded, therefore, that testing of low ignition potential cigarettes needs to address changes to both mainstream and sidestream smoke. The major health effects attributed to smoking are briefly outlined. The following human diseases are listed as being increased by smoking: cancer at multiple sites, especially the lungs; non-cancerous lung diseases, such as chronic obstructive pulmonary disease, including emphysema; atherosclerotic cardiovascular disease; and negative effects on reproduction, such as lowered birth weightL Due the large number of diverse effects it is unlikely that each potential adverse effect can; be examined in a practical series of toxicity tests. Epidemiology is not a practical approach for addressing the issue of the health effects of changes in a cigarette to reduce ignition potential. Because people may smoke cigarettes designed to reduce ignition potential differently (ex.longer or faster puffs) than currently available cigarettes it may be important to consider whether these changes affect smoke chemistry and therefore toxicity. For example, the new cigarette type may result in a smoker taking longer puffs which may then change the smoke chemistry and toxicity. Testing can examine the effects on toxicity of a single design change in a cigarette or can examine the effects of a set of design changes compared to an unchanged control. Depending on the information available each approach is reasonable. Testing protocols can follow either a screening or a tradeoff approach. In the screening approach new designs are subjected to a series of tests each with criteria for passing or failing. Designs which fail are eliminated from further testing, while those passing are subjected to additional scrutiny. In the tradeoff approach the relative changes in each test would be assessed in light of other information about the particular design. . Changing cigarette additives can complicate toxicity testing. This is because new additives might introduce entirely new toxic endpoints which are not associated with current products. Chapter B This chapter presents information about the FTC smoking method. Very briefly, the FTC method describes: how cigarettes are to be prepared for smoking, the type of smoking machine to use, the way the smoking machine should be operated, the method for collecting smoke products, and ways to! measure moisture content, nicotine, carbon monoxide and tar. The author recommends the use of this method for studies of cigarette smoke chemistry and toxicity.

ATTORNEY WORK PRODUCTS The cost of analysis is estimated to be $3,000 to $4,000 per run. There is capability to make six runs per day at the Tobacco Institute Laboratory. Chapter C A summary of changes in human smoking behavior and the potential impact of those changes on toxicity is presented. The basis for concern in this area is that the toxicity of cigarette smoke is directly related to the composition of the smoke and that the composition of the smoke may be changed if the way the cigarettes are smoked is changed. No estimate of the cost or duration of these studies is given. Chapter D This chapter suggests a variety of chemical analyses which could be done to aid in the determination of the change in toxicity of a low ignition potential product. These analyses are proposed because the toxicity of smoke is related to its chemical composition. The following table lists the proposed analyses and the health effect associated with the component or property measured. Anai sis Health E ect Total Particulate Matter (M) Carcino gen pH Effect on nicotine toxici y Redox Potential Influence toxici y of whole smoke Carbon Monoxide Reduces abilit . of blood to carry ox en Nitrogen Oxides (NOX) Increase nitrosamine formation, inhibit enz rne function Hydrogen Cyanide Inhibits lung clearance, Lowers ability of bod to use ox en H drocarbons enzene butadiene Sus cted or known carcino ens Aldehydes (ex. formaldehyde, acrolein) Inhibits lung clearance, animal carcino . ens Volatile nitrosamines Stron animal carcino gens Tobacco-s ecific nitrosamines Stron animal carcino gens Nicotine Associated with cardiovascular disease Phenols Enhance carcino en action Catechol Major carcino en Poiynuclear Aromatic Hydrocarbons PNAs Major tumor initiators The direct costs of these analyses are estimated to be $ 8,100. No estimate of the time required was given.

;1.7TCP:ltEll WORK PRODUCTS Chapter E This chapter describes and proposes for use a set of three toxicity tests of relatively short duration: a bacterial mutagenicity test, an animal cell test to detect potential carcinogens, and a lung inflammation test in animals. The Ames test uses certain types of Salmonella bacteria to quantitatively assess the ability of a material to cause mutations. Mutations are involved in the process of carcinogenesis. In this test a solution of collected smoke particulates is mixed with the bacteria. Bacteria with the ability to grow in the absence of a particular nutrient are scored as mutants. It is estimated that testing four cigarette types would take 4-6 weeks with a cost of $1,500 -- $2,200 per type. The potential cancer-causing ability of chemicals can be evaluated using a cell transformation assay. In this assay solutions of smoke particulates are given to animal cells grown in dishes in the laboratory. After several weeks the cells are examined under the microscope. At this time the cells are scored for abnormal growth patterns. The number of clusters of abnormally growing cells are then compared among cigarette types. It would take about six months to test the particulates from one cigarette type at a cost of $7,000 -- $8,000. In the animal study inflammation of the lungs would be assessed. The changes measured in this test may be related to the development of chronic obstructive pulmonary disease. In these tests mice would be exposed to whole smoke two times per day. The number of days the mice would be exposed was not stated. At the end of the exposure period the animals would be killed and the lungs washed out to collect inflammatory cells. The numbers and kinds of the cells would be measured. These studies are estimated to take 8 - 10 months to test one cigarette type at a cost of about $50,000. Chapter F This chapter describes two long-term animal tests for cancer causing ability. In the first test cigarette tar is ~ applied to the back skin of mice. Skin tumors are then scored over the life of the animals. The use of this test is rationalized using two arguments. 1) In studies of tumor formation by smoke in hamsters whole smoke is active but smoke free of particulates is not. 2) A large number of known carcinogens are contained in the particulate portion of cigarette smoke. The direct cost (no overhead) of testing two cigarette types would be about $39,000. No estimate of the total duration of these studies is given. The second test examines the tumor forming ability of whole smoke in hamsters. Previous work is cited which describes a positive response in the larynx butnot the lungs of hamsters exposed over their lifetime to whole cigarette smoke. In this test the animals are exposed twice daily to the diluted smoke of one cigarette every day for their entire

qTTORhEY WOR4C PRODUCTS lives. Tumor formation is the endpoint measured in this assay. Because the test is so labor intensive it is recommended only as a last step in a series of tests. It is estimated that a test comparing two cigarette types would take 24 - 26 months to complete at a direct cost of $185,000! -- $250,000.