FDA Advisory Committee Tobacco Constituents Subcommittee June 8 & 9, 2010 Gaithersburg, Maryland Recommendations for Measurement of Toxic Tobacco Constituents Star Scientific, Incorporated “Good science reducing tobacco-related harm at every level” Ryan K. Lanier, PhD Curtis Wright IV, MD MPH

Criteria for Selection To be selected for measurement, a tobacco constituent should meet three tests: 1.It must be known to be present in toxic amounts 2.There must be evidence it can be controlled 3.The anticipated benefits must be substantial This is a place for regulatory parsimony. Nothing on the list must be vulnerable to successful challenge by any responsible party.

Star Scientific Candidates 1.NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) 2.NNN (N’-nitrosonornicotine) 3.Total Tobacco-Specific Nitrosamines (TSNAs) (NNN + NNK + NAT+ NAB) 4. Benzo[a]pyrene (both as a primary carcinogen and as a marker of carcinogenic polycyclic aromatic hydrocarbon content)

NNK and NNN Known to be carcinogenic in animals (IARC 1985, 2007) NNK metabolite (NNAL) levels linked to cancer in humans (Yuan et al. 2009; Church et al. 2009) Found in both tobacco and smoke condensate (IARC) Broad range observed in smoked tobacco Very broad range observed in smokeless tobacco Strong evidence levels can be controlled Standard analytic methods available (TWT ) May be expressed “per unit” and “per mg nicotine” Completely defensible by any standard 1 Labstat International ULC (Kitchener, ON, Canada) LC-MS/MS analytical method

NNK Variability in Cigarettes Gray et al., Tobacco Control, 2000;9:

Total TSNAs Consists of NNN, NNK, NAT, NAB “One number” that covers tobacco-specific nitrosamines Very strong evidence linking total TSNAs with cancer Very large bibliography developed over decades Very broad range observed in smokeless tobacco Strong analytical methods available (TWT ) May be expressed “per unit” and “per mg nicotine” Resolves the problem of how to handle NAT & NAB 1 Labstat International ULC (Kitchener, ON, Canada) LC-MS/MS analytical method

TSNA Variability in Smokeless Ariva-BDL Application, February 2010

Benzo[a]pyrene Soot known to be carcinogenic for centuries B[a]P a paradigmatic carcinogenic hydrocarbon Found in both tobacco and smoke condensate (IARC) Broad range observed in smoked and smokeless tobacco Strong evidence levels can be controlled Standard analytic methods available (TWT ) May be expressed “per unit” and “per mg nicotine” Completely defensible by any standard 1 Labstat International ULC (Kitchener, ON, Canada) GC/MS analytical method

B[a]P Variability Data on file at Star Scientific, Inc.*Cigarette data are per unit

Criteria for Reporting Measurement and reporting of toxins in a commercial product should be designed to lead to positive health outcomes and should avoid risks of distortion through advertising. Trace contaminants like TSNAs and B[a]P should be reported per unit of use (cigarette, lozenge, pinch, sachet) AND per milligram of nicotine. This is similar to “Foods” labeling which reports both quantity data (calories per serving) and “percent of normal diet” data to the consumer.

Per Unit of Use Data on file at Star Scientific, Inc.

Per Milligram Nicotine Data on file at Star Scientific, Inc.

“Tobacco Facts” Labeling Tobacco Facts Portion Size: One pinch (1 g) Portions per package: 15 Nicotine 11 mg per pinch Per Portion Per mg Nicotine Total Tobacco-Specific Nitrosamines Benzo[a]pyrene NNK NNN xx PPB yy PPB xx PPB yy PPB xx PPB yy PPB xx PPB yy PPB Tobacco, corn syrup, licorice, EDTA, propylene glycol Manufactured under the authority of NONESUCH TOBACCO COMPANY, NOWHERE, USA, Warning: Smokeless tobacco is addictive.

In Conclusion We recommend as harmful constituents: NNK (4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone) NNN (N’-nitrosonornicotine) Total Tobacco-Specific Nitrosamines (NNN + NNK + NAT+ NAB) Benzo[a]pyrene (both as a major carcinogen and as an indicator of carcinogenic polycyclic aromatic hydrocarbons)