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

Preliminary Thoughts Preliminary Thoughts on Evaluating Harm on Evaluating Harm Reduction Claims Reduction Claims Based on the Mass Based on the Mass

SAB ExperienceSAB Experience2003 National Conference on Tobacco 2003 National Conference on Tobacco

or Healthor HealthDavid Burns MDDavid Burns MD

Preliminary Thoughts

Framework of MeasuresFramework of Measures

Cigarette design featuresCigarette design features Smoke chemistrySmoke chemistry Measures of toxicityMeasures of toxicity Measures of exposureMeasures of exposure Measures of InjuryMeasures of Injury Measures of outcomeMeasures of outcome


Harm Reduction CascadeHarm Reduction Cascade

DesignDesignSmoke compositionSmoke composition

ToxicityToxicityExposureExposure

InjuryInjury

Disease incidenceDisease incidence


We Need to Test both the We Need to Test both the productproduct

We need to evaluate toxicity for both We need to evaluate toxicity for both the the productproduct and for the product as it and for the product as it is is usedused by the smoker by the smoker

We cannot assume that the only We cannot assume that the only difference between smokers who use difference between smokers who use different products is the product different products is the product they usethey use


Design ExamplesDesign ExamplesEasily verified, but may convey claims of Easily verified, but may convey claims of

harm reductionharm reduction

Filter vs filteredFilter vs filtered MentholMenthol Nicotine freeNicotine free


Smoke ChemistrySmoke Chemistry

Reproducible test methodsReproducible test methods Large, potentially incomplete, list Large, potentially incomplete, list

of toxic constituentsof toxic constituents Generation conditions must match Generation conditions must match

conditions of use to be meaningful conditions of use to be meaningful for dose of exposure estimatesfor dose of exposure estimates


Tests of ToxicityTests of Toxicity

The chain of scientific logic and The chain of scientific logic and evidence must be complete to link the evidence must be complete to link the testing as it is used in evaluating testing as it is used in evaluating cigarettes to the outcomes (e.g. cigarettes to the outcomes (e.g. carcinogenicity).carcinogenicity).

It is not enough to assume that the It is not enough to assume that the name of the testing (mutagenicity, name of the testing (mutagenicity, genotoxicity, cytotoxicity) applies to genotoxicity, cytotoxicity) applies to cigarettes if the tests are used cigarettes if the tests are used differently.differently.


Tests of Toxicity MatrixTests of Toxicity Matrix

What does the test measureWhat does the test measure What is the protocolWhat is the protocol What is its reproducibility within What is its reproducibility within

and across laboratoriesand across laboratories How big a difference in the test How big a difference in the test

measure is necessary to be measure is necessary to be considered a real differenceconsidered a real difference

Do real differences in the test Do real differences in the test values correspond to other values correspond to other measures of exposure or toxicitymeasures of exposure or toxicity


Tests of Toxicity MatrixTests of Toxicity Matrix

Have differences been validated as Have differences been validated as a measure of toxicity as the test is a measure of toxicity as the test is usedused

Has a change in the measure been Has a change in the measure been shown to correspond to a change shown to correspond to a change in toxicity in animals or humansin toxicity in animals or humans

Has a change in the measure been Has a change in the measure been shown to a change in disease ratesshown to a change in disease rates


Mutagenicity as Used By Mutagenicity as Used By Tobacco CompaniesTobacco Companies

0

100

200

300

400

500

600

700

800

0 100 200 300 400 500 600micro grams of tar per picoliter

Re

ve

rta

nts

(M

uta

tio

ns)

TA 1538 1R4F Kentucky Reference Cigarette(12.6 mg TPM per cigarette)

TA 1538 Commercially available Ultra-low Tar(1.6 mg TPM per cig)

Linear (TA 1538 Commercially available Ultra-low Tar (1.6 mg TPM per cig))

Linear (TA 1538 1R4F Kentucky ReferenceCigarette (12.6 mg TPM per cigarette))

Doolittle et al. Environmental and Molecular Mutagenesis 15:93-105, 1990

LowTar Cigarette

Full FlavoredCigarette


MutagenicityMutagenicity Measures specific point mutations—substitution, Measures specific point mutations—substitution,

addition, or deletion of one or a few DNA base pairsaddition, or deletion of one or a few DNA base pairs Normally used to screen for carcinogenicity as a Normally used to screen for carcinogenicity as a

positive or negative test, as opposed to a quantitative positive or negative test, as opposed to a quantitative measure of mutagenic potentialmeasure of mutagenic potential

Cigarette smoke is not mutagenic with all strains Cigarette smoke is not mutagenic with all strains testedtested

Mutations for a single strain are likely at a specific Mutations for a single strain are likely at a specific site and are likely influenced by individual site and are likely influenced by individual carcinogens or groups of carcinogenscarcinogens or groups of carcinogens

If there is an increase in the number of mutations per If there is an increase in the number of mutations per mg tar, does that mean that the tar is more mg tar, does that mean that the tar is more carcinogenic or simply that it contains a more of one carcinogenic or simply that it contains a more of one chemical that the bacteria is sensitive to?chemical that the bacteria is sensitive to?

Is the slope of the mutagenicity a measure of toxicity Is the slope of the mutagenicity a measure of toxicity or a measure of smoke chemistryor a measure of smoke chemistry


Current Utility of TestsCurrent Utility of Tests

Smoke Chemistry – DesignSmoke Chemistry – Design Mutagenicity – DesignMutagenicity – Design Cytotoxicity -Cytotoxicity -DesignDesign Inhalation – DesignInhalation – Design Skin Painting – ToxicitySkin Painting – Toxicity Cotinine and CO – ExposureCotinine and CO – Exposure Others - DevelopmentalOthers - Developmental


Human Exposure Studies Human Exposure Studies CautionsCautions


California Tobacco Survey: Current California Tobacco Survey: Current Smoking Status Compared to Smoking Smoking Status Compared to Smoking

Status 1 Year AgoStatus 1 Year Ago Daily Smokers 1 Year Ago, 25 Years and OlderDaily Smokers 1 Year Ago, 25 Years and Older

1-4 72.2 9.3 9.3 1.7

5-14 10.5 82.6 6.3 0.6

15-24 3.8 10.9 82.3 3.1

25+ 2.7 4.9 15.5 77.4

25+

Cigarettes Smoked 1Year Ago

1-4 5-14 15-24

Current Smoker: Cigarettes Smoked per Day

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


Unanswered Questions on Unanswered Questions on How We Measure Exposure How We Measure Exposure

DifferencesDifferences Do we need to express yield Do we need to express yield

comparisons in mg’s per mg of comparisons in mg’s per mg of nicotine?nicotine?

Do we need to express exposure Do we need to express exposure measures per mg of cotinine?measures per mg of cotinine?

What do we do with those who quit What do we do with those who quit or cut down in any comparison?or cut down in any comparison?

What else needs to be controlled?What else needs to be controlled?


SUMMARYSUMMARY

Tests of smoke chemistry are not measures Tests of smoke chemistry are not measures of exposure until we find a way to match of exposure until we find a way to match machine measurements and actual smoking machine measurements and actual smoking patterns, an achievable outcome.patterns, an achievable outcome.

Mutagenicity and cytotoxicity testing are Mutagenicity and cytotoxicity testing are screening tools and whether they can be screening tools and whether they can be used to assess relative toxicity is uncertainused to assess relative toxicity is uncertain

Measures of exposure are available but we Measures of exposure are available but we are uncertain how to appropriately compare are uncertain how to appropriately compare human smokers who change brandshuman smokers who change brands

Documents

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