This seminar aims to unravel the role of flavoring agents in enhancing the appeal of inhalable tobacco and nicotine products. Flavors are present in almost all tobacco/nicotine products and play a crucial role in their appeal and use behaviors but are poorly regulated. Dr. Krishnan-Sarin will discuss the sensory processes underlying the perception of flavoring agents, known pharmacological targets for flavor chemicals, and evidence of the potential toxicity of flavoring agents. She will also highlight the implications of the state of the science of flavoring agents for future research and regulation.

1. Flavors in Tobacco and Nicotine
Products
Science Based Regulation?
Suchitra Krishnan-Sarin, Ph.D.
Professor of Psychiatry, and of Public Health
Chair, IRB
Yale University

2. Tobacco Products and Flavors

3. Tobacco Products and Flavors
Krüsemann et al., 2019
Cigar Inspector, 2013

4. Flavors always
used in Tobacco
Product
Innovation
Extensive advertising
and marketing of flavors
(colors, descriptors) on
product packaging
•Flavorants within the tobacco casing, as top
flavoring (sprayed on),
•In the filter, wrapping papers and mouthpieces, foil
liner of tobacco packaging.
Strategic placement of
sweeteners/flavors in
product to enhance
appeal
•Cigars/cigarillos, heated tobacco products
•Flavor capsules in filter of cigarettes, flavor inserts
•E-liquids
Novel products and new
modes of including
flavors
•Sweeteners
•Cooling agents
•Concept flavors
Novel Flavors

5. Global Regulation of Flavors in Tobacco Products
• Eleven countries and the 28 EU Member States
restrict flavor in some tobacco products.
• The most common tobacco products covered by
existing flavor policies are cigarettes, with only
the EU regulating a small portion of e-cigarette
liquid flavors.
• The EU, Moldova and Turkey prohibit flavors in
cigarette capsules.
• Menthol is included in the flavor ban policies of
eight countries and the EU.
• Six countries explicitly prohibit the use of flavor
terms or imagery on tobacco product packaging;
none of these countries explicitly prohibit flavors
in e-cigarettes.

6. Epidemiology of Flavored Tobacco Product Use
Behaviors
Lack of systematic
worldwide
evidence
High rates of use
of Flavored
tobacco products

7. Flavored Nicotine/Tobacco Product Use
Rates in US
0
10
20
30
40
50
60
70
80
90
100
Any
tobacco
Cigarettes Cigars Pipe Hookahs ENDS Smokeless
Tobacco
Proportion,
% Proportion of Current Tobacco Product Users >18 Who
Reported Using Flavored Products, TUS-CPS, 2014-2015
Odani S, Armour B, Agaku IT. NTR 2020

8. Use of Flavors in ENDS
US PATH study, 2015-2016
0
10
20
30
40
50
60
70
Adult Past 30-day ENDS User N = 1809
Youth Past 30-day ENDS User N = 226

9. Flavors used in non-cigarette tobacco products
US National Adult Tobacco Survey, 2013-2014
Michèle G Bonhomme et al. Tob Control doi:10.1136/tobaccocontrol-2016-053373

10. Heated Tobacco Products
2018 ITC Japan Survey
Sutanto E, Miller C, Smith DM, et al., 2019

11. Flavors Appeal to Youth
Villanti et al., 2017

12. To decide how best to regulate flavors it is important to
understand how they influence use behaviors and perceptions!!
How to regulate Flavors

13. PACKAGING and ADVERTISING
Colors, images, descriptors
Regulation of Flavors

14. Tobacco Products and Flavors

15. Menthol medicates
Menthol Health effects!
Cool!
Fresh!
Happy!
Pleasure!

16. New “non-menthol” Newport cigarettes introduced in CA
Newport non-menthol Green (RJ Reynolds)
Introduced in December 2022, after CA flavor ban took effect

17. New “non-menthol” Newport cigarettes introduced in CA

18. Kool non-menthol green/blue
(ITG Brands)
New “non-menthol” Kool cigarettes introduced in CA

19. ZYN “unflavored” ONPs

20. CHEMISTRY
Regulation of Flavors

21. E-liquids in US in 2019 > 15,000 flavors
Benzaldehyde
Cinnamaldehyde
Acrolein
Furfural
Diacetyl
β-damascone,
δtetradecalactone
γ-decalactone
citral
dipentene
ethyl maltol
ethyl vanillin
ethyl vanillin PG
acetal
linalool
piperonal
Dipentene
ETC….

22. Flavor chemicals in Camel Crush Oasis capsule
γ-Octalactone (coconut)
Linalool (floral/lavender)
Acetophenone (floral/sweet) Anethole (anise)
Vanillin Ethylvanillin
(vanilla)
Menthol

23. Statement from the Flavor and Extract Manufacturers
Association of the United States
• “The Flavor and Extract Manufacturers Association of the United States (FEMA) has for more than
50 years sponsored an extensive program, the FEMA GRAS program, to assure the safety of flavor
ingredients added to food through state-of-the-art safety evaluations conducted by the FEMA Expert
Panel (Hallagan et al., 2020). The Expert Panel operates under the authority of the GRAS
(“generally recognized as safe”) provision in the statute that governs the safety and labeling of
foods, the Federal Food, Drug, and Cosmetic Act (“FFDCA”). The primary route to regulatory
authority to use flavor ingredients in the U.S. for addition to food is the GRAS determinations made
by the FEMA Expert Panel.”
• “The FEMA Expert Panel evaluates the safety of flavor ingredients only under their
conditions of intended use in food and does not evaluate flavor ingredients for use
in vaping products, or any other uses that are intended for inhalation. FEMA does
not support the use of flavors in vaping products in the absence of rigorous safety
assessments performed by vaping product manufacturers and marketers that
demonstrate safety.”

24. CHEMISTRY
Levels and Toxicity
Regulation of Flavors

25. High levels of flavor compounds in tobacco products

26. Brown JE et al. N Engl J Med 2014;370:2250-2252.
Levels and Patterns of Chemicals in Various Brands of Cherry-Flavored
Candies, Kool-Aid Drink Mix, and Tobacco Products.

27. Flavor Chemicals and Health effects
Much more research is needed!
Khlystov A, Samburova V, 2016
• Flavors are composed of aldehydes
and other chemicals
• Formaldehyde is a human carcinogen
0
5
10
15
20
25
30
35
formaldehyde acetaldehyde acrolein propionaldehyde
Concentration
of
aldehydes
(µg/puff)
No flavor Bubble Gum Pina Colada
Blueberry Tutti Fruity Caramel Mocha
• Flavor additives can be toxic to cells
• Diacetyl increases the risk of
“popcorn lung” disease
0
100
200
300
400
500
600
Diacetyl 2,3-Pentanedione Acetoin
mass
(μg/e-cig
Cherry Crush Classic Java Jolt Menthol
Peach Schnapps Pina Colada Vanilla
Allen JG, Flanigan SS, LeBlanc M, Vallarino J, MacNaughton P, Stewart JH, Christiani DC, 2016

28. Erythropel, Jabba, et al. Nicotine and Tobacco Research, 2018, https://doi.org/10.1093/ntr/nty192
Flavor aldehydes form acetal adducts in e-liquids which can
be more toxic than the parent aldehydes
28
Commonly used flavor aldehydes in e-liquids include vanillin, ethylvanillin (both in vanilla flavor), benzaldehyde (cherry),
cinnamaldehyde (cinnamon), and citral (citrus)
aldehyde
A

29. Currently known toxicity mechanisms in affected respiratory
cells upon flavorant exposure
(Kaur, Muthmalage, Rahman, Toxicol. Lett. 2018)

30. CHEMISTRY
Sensory Effects
Regulation of Flavors

31. Temperature
• Release of volatile molecules from
flavors in tobacco products
Touch
• Oral feel in lips and mouth
• Dryness, astringency caused by
inhaled/oral tobacco products
Chemesthesis
• Stimulation of receptors in
response to pain, temperature
• Harshness of nicotine, acrolein
• Coolness of menthol
Sensory systems that contribute to Tobacco Flavors
Somatosensation (Chemicals, thermal and tactile)

32. Flavorant Receptors Relevant to Tobacco
Products
• Sweet and Bitter receptors (GPCR family)
• Irritation/Harshness/Coolness receptors (TRP family)
• Olfactory receptors

33. Flavorant Receptor Targets
• TRP channel receptors
• TRPA1 is the receptor for noxious aldehydes in tobacco smoke
• eliciting burning and irritating sensations.
• TRPA1 also mediates the irritating effects of nicotine and flavorant aldehydes.
• TRPM8 is the receptor for menthol
• mediating its cooling and soothing effects
• is essential for menthol to suppress the irritating and aversive effects of tobacco smoke and
nicotine
• Bitter and Sweet Receptors

34. Menthol and Nicotine activate TRP channels
Nicotine Menthol
Activates / inhibits TRPA1
Activates TRPM8
Activates TRPA1
Sensitizes TRPV1

35. Synthetic cooling agent in CA-marketed “non-menthol” cigarettes
Developed by Wilkinson Sword (WS) in the 1970s, initially for use in
shaving products.
Present in e-cigarette liquids (Juul, Puffbar etc.)
=> Cooling effect, but no minty smell, less irritating than menthol
N-ethyl-p-menthane-3-carboxamide
is WS-3, a synthetic cooling agent
Other Synthetic Coolants also activate TRP channels

36. Contain WS compounds
Activate TRPM8 receptors
Newer Tobacco Products may have synthetic coolants

37. DEFINITION of Flavor
Regulation of Flavors

38. EU Definition of Flavors
• Flavor is the sensory experience produced when something is
ingested or inhaled through the mouth
• “Characterizing flavor” as a “clearly noticeable smell or taste other
than one of tobacco, resulting from an additive or combination of
additives, including, but not limited to, fruit, spice, herb, alcohol,
candy, menthol or vanilla, which is noticeable before or during the
consumption of the tobacco product.” (EU Tobacco Product Directive,
2014)

39. US FDA Definition of Flavors in Cigars
This rule would provide that a cigar or any of its components or parts (including the tobacco, filter, or
wrapper, as applicable) must not contain, as a constituent (including a smoke constituent) or additive,
an artificial or natural flavor (other than tobacco) or an herb or spice, including, but not limited to,
strawberry, grape, orange, clove, cinnamon, pineapple, vanilla, coconut, licorice, cocoa, chocolate,
cherry, coffee, mint, or menthol, that is a characterizing flavor of the tobacco product or tobacco
smoke. Among the factors that FDA believes are relevant in determining whether a cigar has a
characterizing flavor are:
• The presence and amount of artificial or natural flavor additives, compounds, constituents, or
ingredients, or any other flavoring ingredient in a tobacco product, including its components or
parts;
• The multisensory experience ( i.e., taste, aroma, and cooling or burning sensations in the mouth
and throat) of a flavor during use of a tobacco product, including its components or parts;
• Flavor representations (including descriptors), either explicit or implicit, in or on the labeling
(including packaging) or advertising of a tobacco product; and
• Any other means that impart flavor or represent that a tobacco product has a characterizing flavor.

40. Even Low Menthol concentrations improve the taste of E-liquids
• Human E-
cigarette
Exposure
Paradigm
• E-cig puff
exposure
in young
adult e-cig
users
0
5
10
15
20
25
30
No Menthol Low
Menthol
High
Menthol
Dislike/Like
Taste
of
E-
cigarettes
(-100
to
100)
Like Taste of E-cigarettes
(Menthol main effect, p<0.001)
-20
0
20
40
60
No Menthol Low MentholHigh Menthol
Dislike/Like
Taste
of
E-cig
(-100
to
100)
Like Taste of E-cigarettes
(Menthol*Nicotine, p<0.05)
0 mg Nicotine 6 mg/ml Nicotine
p<0.05
Krishnan-Sarin et al., Drug and Alcohol Dependence, 2018

41. Canada and Brazil Definition of Flavors
• 5.1 (1) No manufacturer shall use an additive set out in column 1 of Schedule 1 in the manufacture of a tobacco
product set out in column 2.
• 5.2 No manufacturer shall sell a tobacco product set out in column 2 of Schedule 1 that contains an additive set
out in column 1.
• additives identified as flavouring agents by the Joint FAO/WHO Expert Committee on Food Additives in the
Committee’s evaluations, as published from time to time in the WHO Technical Report Series
• additives identified as generally recognized as safe (GRAS) flavouring substances by the Flavor and Extract
Manufacturers Association (FEMA) Expert Panel in its lists of GRAS substances referred to as “GRAS 3” to
“GRAS 24” and subsequent lists of GRAS substances, as published from time to time, if any

42. Recommendations on evidence needed to support
Regulatory efforts
• Global Use Rates
• Need Surveillance systems worldwide
• Need to identify and use similar measures to assess use of flavored products
• Need to focus on all flavors; not just menthol
• Perceptions about the appeal and addictive potential of flavored products.
• Need more information on flavors other than menthol
• Human Behavioral Testing
• Identify what aspect of the appeal of product is altered by the flavor
• Are these alterations concentration specific?
• Identify how flavors interact with nicotine and/or tobacco
• Chemical and Toxicological testing
• Levels and stability of chemicals in tobacco products
• What is actually delivered to the consumer (e.g. in smoke or vapor)
• Toxicity of chemical in products and what is delivered
WHO Tob Reg reports; Krishnan-Sarin et al., 2019; El-Hellani et al., 2021