1. Preliminary Thoughts on Evaluating Harm Reduction Claims Based on the Mass SAB Experience 2003 National Conference on Tobacco or Health David Burns MD

2. Preliminary Thoughts Framework of Measures Cigarette design features Cigarette design features Smoke chemistry Smoke chemistry Measures of toxicity Measures of toxicity Measures of exposure Measures of exposure Measures of Injury Measures of Injury Measures of outcome Measures of outcome

3. Preliminary Thoughts Harm Reduction Cascade  Design  Smoke composition  Toxicity  Exposure  Injury  Disease incidence  Disease incidence

4. Preliminary Thoughts We Need to Test both the product We need to evaluate toxicity for both the product and for the product as it is used by the smoker We need to evaluate toxicity for both the product and for the product as it is used by the smoker We cannot assume that the only difference between smokers who use different products is the product they use We cannot assume that the only difference between smokers who use different products is the product they use

5. Preliminary Thoughts Design Examples Easily verified, but may convey claims of harm reduction Filter vs filtered Filter vs filtered Menthol Menthol Nicotine free Nicotine free

6. Preliminary Thoughts Smoke Chemistry Reproducible test methods Reproducible test methods Large, potentially incomplete, list of toxic constituents Large, potentially incomplete, list of toxic constituents Generation conditions must match conditions of use to be meaningful for dose of exposure estimates Generation conditions must match conditions of use to be meaningful for dose of exposure estimates

7. Preliminary Thoughts Tests of Toxicity The chain of scientific logic and evidence must be complete to link the testing as it is used in evaluating cigarettes to the outcomes (e.g. carcinogenicity). The chain of scientific logic and evidence must be complete to link the testing as it is used in evaluating cigarettes to the outcomes (e.g. carcinogenicity). It is not enough to assume that the name of the testing (mutagenicity, genotoxicity, cytotoxicity) applies to cigarettes if the tests are used differently. It is not enough to assume that the name of the testing (mutagenicity, genotoxicity, cytotoxicity) applies to cigarettes if the tests are used differently.

8. Preliminary Thoughts Tests of Toxicity Matrix What does the test measure What does the test measure What is the protocol What is the protocol What is its reproducibility within and across laboratories What is its reproducibility within and across laboratories How big a difference in the test measure is necessary to be considered a real difference How big a difference in the test measure is necessary to be considered a real difference Do real differences in the test values correspond to other measures of exposure or toxicity Do real differences in the test values correspond to other measures of exposure or toxicity

9. Preliminary Thoughts Tests of Toxicity Matrix Have differences been validated as a measure of toxicity as the test is used Have differences been validated as a measure of toxicity as the test is used Has a change in the measure been shown to correspond to a change in toxicity in animals or humans Has a change in the measure been shown to correspond to a change in toxicity in animals or humans Has a change in the measure been shown to a change in disease rates Has a change in the measure been shown to a change in disease rates

10. Preliminary Thoughts Mutagenicity as Used By Tobacco Companies

11. Preliminary Thoughts Mutagenicity Measures specific point mutations—substitution, addition, or deletion of one or a few DNA base pairs Measures specific point mutations—substitution, addition, or deletion of one or a few DNA base pairs Normally used to screen for carcinogenicity as a positive or negative test, as opposed to a quantitative measure of mutagenic potential Normally used to screen for carcinogenicity as a positive or negative test, as opposed to a quantitative measure of mutagenic potential Cigarette smoke is not mutagenic with all strains tested Cigarette smoke is not mutagenic with all strains tested Mutations for a single strain are likely at a specific site and are likely influenced by individual carcinogens or groups of carcinogens Mutations for a single strain are likely at a specific site and are likely influenced by individual carcinogens or groups of carcinogens If there is an increase in the number of mutations per mg tar, does that mean that the tar is more carcinogenic or simply that it contains a more of one chemical that the bacteria is sensitive to? If there is an increase in the number of mutations per mg tar, does that mean that the tar is more carcinogenic or simply that it contains a more of one chemical that the bacteria is sensitive to? Is the slope of the mutagenicity a measure of toxicity or a measure of smoke chemistry Is the slope of the mutagenicity a measure of toxicity or a measure of smoke chemistry

12. Preliminary Thoughts Current Utility of Tests Smoke Chemistry – Design Smoke Chemistry – Design Mutagenicity – Design Mutagenicity – Design Cytotoxicity -Design Cytotoxicity -Design Inhalation – Design Inhalation – Design Skin Painting – Toxicity Skin Painting – Toxicity Cotinine and CO – Exposure Cotinine and CO – Exposure Others - Developmental Others - Developmental

13. Preliminary Thoughts Human Exposure Studies Cautions

14. Preliminary Thoughts California Tobacco Survey: Current Smoking Status Compared to Smoking Status 1 Year Ago Daily Smokers 1 Year Ago, 25 Years and Older The test of marginal homogeneity is significant (chi-squared = 189.4 on 3 df, p < 0.0001). This suggests there is a slight downward trend in the intensity of smoking. Shift

15. Preliminary Thoughts Unanswered Questions on How We Measure Exposure Differences Do we need to express yield comparisons in mg’s per mg of nicotine? Do we need to express yield comparisons in mg’s per mg of nicotine? Do we need to express exposure measures per mg of cotinine? Do we need to express exposure measures per mg of cotinine? What do we do with those who quit or cut down in any comparison? What do we do with those who quit or cut down in any comparison? What else needs to be controlled? What else needs to be controlled?

16. Preliminary Thoughts SUMMARY Tests of smoke chemistry are not measures of exposure until we find a way to match machine measurements and actual smoking patterns, an achievable outcome. Tests of smoke chemistry are not measures of exposure until we find a way to match machine measurements and actual smoking patterns, an achievable outcome. Mutagenicity and cytotoxicity testing are screening tools and whether they can be used to assess relative toxicity is uncertain Mutagenicity and cytotoxicity testing are screening tools and whether they can be used to assess relative toxicity is uncertain Measures of exposure are available but we are uncertain how to appropriately compare human smokers who change brands Measures of exposure are available but we are uncertain how to appropriately compare human smokers who change brands