New Low-Nicotine Cigarettes Are Still as Harmful:Implications for FDA Regulation of Tobacco

University of Illinois at ChicagoInstitute for Health Research and PolicyChicago, Illinois

November 4, 2010

Andrew A. Strasser, Ph.D.

OutlineFocus: FDA Regulation and the Family Smoking Prevention and Tobacco Control Act

1) Regulatory Background

2) Smoking Topography: Measurement of Smoking Behavior, Human Smoking Variability and Toxin Exposure

3) Research Programa) Light cigarettes

Reliability of carbon monoxide (CO) boostPreferred brand cigarette study

b) Quest cigarettesSmoking topography, CO boost and filter tar stains as indices of exposurePREP advertisement features and smokers’ beliefs

c) Marketing and labeling of low nicotine cigarettesNovel PREP beliefsQuest ad manipulationBeliefs and eye-tracking

NICOTINE

1-HOP

NNAL

CO

EBC

ss 907

1. Regulatory Background

20th Century Smoking Rates in the United States

1

2

3

02468

1012141618202224

1968 1978 1988 1998

Year

Stan

dard

Tar

(mg)

Background of Tar Yields

The FTC cigarette test

Basic Smoking Machine

C. Filter-Pad traps Tar and Nicotine

cigarette

A."Syringe" Puffer takes One 2-sec Puff Per minute

B. Filter Vent Holes

35 ml puff

Tar

Nic

CO

How Low-tar cigarettes test low

1 ) Reduce the number of puffs by:– decreasing the cigarette length– increasing burn rate– increasing paper porosity– puffing up tobacco

2) Reduce the concentration of smoke in each puff by:– increasing paper porosity– adding filter ventilation holes.

Kozlowski et al., 2000 Cigarettes, Nicotine, and Health

Figure. Minimum percentage compensation C* necessary to obtain at least as great a dosage from a cigarette of the lower tar as the higher tar brand, per mg nicotine.

Harris JE (NTR 6(5); 2004

2. Smoking Topography: Measurement of Smoking Behavior, Human Smoking Variability and Toxin Exposure

Measures Include:

Number of Puffs

Puff Volume

Total Puff Volume

Puff Velocity

Puff Duration

Interpuff Interval

Peak Velocity

Total Time Lit

ReliabilityPu

ff V

olum

e (m

l)

Day

Lee et al., Nic Tob Res 2003; Strasser et al., Pharm Bio Beh 2005

20

10

0

50

40

30

2 3 41

Intraclass correlation coefficients: .66 - .75, p<.001

Physiological or biochemicalmeasure

Smoking condition

Topography NaturalCarbon monoxide (ppm) 4.6 + 0.6 5.1 + 0.8Plasma nicotine (mg/ml) 18.5 + 4.6 25.5 + 4.5

Time to smoke (s) 278 + 6.8 286 + 6.9

Number of puffs 11.2 + 0.8 10.3 + 0.7

Validity

TOPOGRAPHY MEASURE ICC 95% CI p value

NUMBER OF PUFFS .97 .95-.98 .001

INTERPUFF INTERVAL .93 .88-.97 .002

TOTAL TIME LIT .91 .84-.95 .008

Lee et al., Nic Tob Res. 2003; Strasser et al., Exp Clin Psych 2009

COMPARISON OF SMOKING TOPOGRAPHY AND AD LIB LABORATORY SESSIONS

Hecht, SS. et al. Cancer Epidem Biomarkers Prev 2005

Figure. Levels of (A) total NNAL, (B) 1-HOP, and (C) total cotinine, all per mg creatinine, in the urine of smokers of regular, light, and ultralight cigarettes (n = 175)

-1

0

1

2

3

4

5

6To

tal N

NAL

(pm

ol/m

g C

reat

inin

e)

1 2 3

Bo x Plo tGr o u p in g V ar iab le (s ): RL UL

REGULAR LIGHT ULTRALIGHT

Levels of NNAL/mg creatinine by cigarette type (N=113)

N=38 N=14N=61

Strasser et al., (under review)

PUFF VELO

CITY

Hecht, SS. et al. J Natl Cancer Inst 2004

Percent reduction in cigarettes per day (open bars) and total 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) per milligram of creatinine (solid bars) in smokers in the reduction group during weeks 4-6, 4-12, and 4-26.

3. Research Program

A. Light cigarettes (addressing FDA bill ss907: Product design)

1. Reliability of carbon monoxide (CO) boost:

The effect of filter vent blocking and smoking topography on carbon monoxide levels in smokers. Pharmacology Biochemistry and Behavior 2005; 82(2): 320-329.

2. Preferred brand cigarette study – 5 day:Behavioral filter vent blocking on the first cigarette of the day

predicts which smokers of light cigarettes will increase smoke exposure from blocked vents. Experimental and Clinical Psychopharmacology 2009; 17(6): 405-412.

Fig. 1. Mean CO boosts with standard errors for both ultralight (0.1 mg nicotine, 1 mg tar, 2 mg CO) and light (0.8 mg nicotine, 10 mg tar, 10 mg CO) cigarettes under both blocking conditions.

Fig. 3. Mean subjective ratings of heat with standard errors for both ultralight (0.1 mg nicotine, 1 mg tar, 2 mg CO) and light (0.8 mg nicotine, 10 mg tar, 10 mg CO) cigarettes under both blocking conditions.

Fig. 2. Mean subjective ratings of strength/harshness with standard errors for both ultralight (0.1 mg nicotine, 1 mg tar, 2 mg CO) and light (0.8 mg nicotine, 10 mg tar, 10 mg CO) cigarettes under both blocking conditions.

Kozlowski et al., 1997 Pharm. Bio. Beh.

Fig. 1. A. Study 1. The effect of cigarette type and filter vent blocking condition on CO boost. Significant main effects indicate blocking increased CO boost for both cigarette types. Light cigarettes had greater CO boost than ultra-light cigarettes.

Fig.1. B. Study 1. The effect of cigarette type and filter vent blocking condition on puff volume. Puff volume for unblocked ultra-light was significantly larger than puff volume for the three other conditions.

Strasser et al., 2005 Pharm. Bio. Beh.

1. Reliability of carbon monoxide (CO) boost

MEAN (SD)UNBLOCKED BLOCKED p value

SEX (% FEMALE) 73% 40% .11

AGE 47.6 (9.2) 40.0 (9.5) .07

BODY MASS INDEX 31.0 (8.8) 27.1 (4.9) .21

DAILY CIGARETTES 20.4 (4.8) 20.5 (2.5) .98

NICOTINE DEPENDENCE 5.1 (1.6) 5.7 (1.8) .42

ICC 95% CI p value

NUMBER OF PUFFS .97 .95-.98 .001

INTERPUFF INTERVAL .93 .88-.97 .002

TOTAL TIME LIT .91 .84-.95 .008

2. Preferred brand cigarette study – 5 day25 Marlboro Light smokers only; 1 session ST, 1 session VT; ad lib smoking.

Participant Descriptive Statistics:

Comparison of Smoking Behaviors between Session

UNBLOCKED BLOCKED IRR = .88

Filter ventilation in Light cigarettes

Strasser et al., 2009 Exp Clinical Psychopharm

Strasser et al., 2009 Exp Clinical Psychopharm

3. Research Program

B. Quest cigarettes (addressing FDA regulation of cigarette nicotine levels)

1. Smoking topography, CO boost and filter tar stains as indices of exposureNew lower nicotine cigarettes can produce compensatory smoking and

increased carbon monoxide exposure. Drug Alcohol Depend 2007; 86: 294-300.

Digital image analysis of cigarette filter stains as an indicator of compensatorysmoking. Cancer Epidemiol Biomarkers and Prevention 2006; 15(12): 2565-2569.

2. Extended PREP use, smoking behavior and exposure biomarkersNCI R01-120594, ongoing

Quest® 1 Quest® 2 Quest® 3

Reported nicotine level (mg) 0.6 0.3 0.05

Reported tar level (mg) 10.0 10.0 10.0

Cigarette length (mm) 82.5 82.8 82.2

Cigarette diameter (mm) 7.6 7.8 7.9

Tobacco rod length (mm) 57.6 57.8 57.5

Tobacco mass (g) 0.60 0.57 0.57

Tipping paper length (mm) 30.0 30.1 30.0

Filter length (mm) 24.9 24.8 24.7

Filer length – mouth end (mm) 12.1 12.0 12.5

Filter length – rod end (mm) 8.0 7.9 7.6

Total filter mass (g) 0.23 0.22 0.24

Filter mass - mouth end (g) 0.071 0.073 0.072

Filter mass – rod end (g) 0.068 0.068 0.065

Filter carbon mass (g) 0.100 0.102 0.108

Pressure drop (mm H2 O) 111.1 (1.1) 101.5 (1.4) 115.8 (0.9)

Ventilation (%) 1.1 (0.1) 1.4 (0.1) 1.3 (0.04)

Strasser et al., 2006 Cancer Epi Bio Prev

Descriptive Characteristics of Quest cigarettes.

1) Informed Consent

2) Review Procedures

3) Baseline Questionnaire

1) Pre-cigarette CO

2) Topography:

Quest cigarette A

3) Post-cigarette CO

4) Subjective Ratings

1) Pre-cigarette CO

2) Topography:

Quest cigarette B

3) Post-cigarette CO

4) Subjective Ratings

1) Pre-cigarette CO

2) Topography:

Quest cigarette C

3) Post-cigarette CO

4) Subjective Ratings

1) Pre-cigarette CO

2) Topography:

Usual brand

3) Post-cigarette CO

4) Subjective Ratings

Time (minutes)0 30 60 90 120

1. Smoking topography, CO boost and filter tar stains as indices of exposure

Overview of Study Design.

50 participants; single session; ad lib smoking.

Cigarette order of presentation was counter-balanced between subjects.

Cigarettes were color-coded and masked to double-blind researchers and participants to nicotine level.

Outcome measures: CO boost and smoking topography

0

100

200

300

400

500

600

700

0.6 0.3 0.05Quest cigarette nicotine level (mg)

Tota

l Puf

f Vol

ume

(ml)

0

1

2

3

4

5

6

7

CO

boo

st (p

pm)

The effect of cigarette nicotine level on total puff volume [(ml; solid bars; left y-axis); F(2, 47) = 5.73, p=.006] and mean carbon monoxide boost [(ppm; open bars; right y-axis); F(2, 47) = 5.43, p=.01]. Data presented as mean (± 95% CI).

Strasser et al., 2007 Drug and Alcohol Depend

-15% -- 59% -21% -- 60%

-23% -- 98%

% d-TPV

0.6 mg nicotine < 0.05 mg nicotine

1024 x 768 pixel resolution images.

CIELAB color space analyses for:L (lightness), a*(red-green), and b*(yellow-blue). Strasser et al., 2006 Cancer Epi Bio Prev

Digital Imaging of Filter Tar Stains (Quest)

TPV 0.6 – TPV 0.05

TPV 0.6 – TPV 0.05

Topography also refers to how people smoke over a period of time…

QUEST 1 (0.6 mg nic)

QUEST 2(0.3 mg nic)

QUEST 2(0.3 mg nic)

QUEST 3 (0.05 mg nic)

QUEST 2 (0.3 mg nic)

QUEST 2 (0.3 mg nic)

USUAL BRAND

QUEST 1 (0.6 mg nic)

USUAL BRAND

QUEST 1 (0.6 mg nic)

QUEST 1 (0.6 mg nic)

DAY 1 5* 10 15* 20 25 * 30 35 *

CONTROL OWN CIGARETTES

QUEST 3(0.05 mg nic)

QUEST 3(0.05 mg nic)

QUEST 3(0.05 mg nic)

* = denotes urine (NNAL, 1-HOP, cotinine) collection.smoking topography, carbon monoxide boost, daily cigarettes collected at each session.

2. Extended PREP use, smoking behavior and exposure biomarkers

0

100

200

300

400

500

600

700

800

Own Brand Quest 1 (0.6 mg nic) Quest 2 (0.3 mg nic) Quest 3 (0.05 mg nic)

Tota

l Puf

f Vol

ume

(ml)

N =62p = .01

The effect of cigarette nicotine level on Total Puff Volume: Initial Exposure

Days 1-5 Days 5-15 Days 15-25 Days 25-35

0

100

200

300

400

500

600

700

800

Own Brand Quest 1 (0.6 mg nic) Quest 2 (0.3 mg nic) Quest 3 (0.05 mg nic)

Tota

l Puf

f Vol

ume

(ml)

N =62p = .01

The effect of cigarette nicotine level on Total Puff Volume: Mean

Days 1-5 Days 5-15 Days 15-25 Days 25-35

0

5

10

15

20

25

30

Dai

ly C

igar

ette

Con

sum

ptio

n

Days 1-5 Days 5-15 Days 15-25 Days 25-35(own) (0.6 mg) (0.05 mg)(0.3 mg)

N =43r filters = .94

The effect of cigarette nicotine level on daily cigarettes: Own Brand

0

5

10

15

20

25

30

Dai

ly C

igar

ette

Con

sum

ptio

nThe effect of cigarette nicotine level on daily cigarettes: Nicotine Decrease

Days 1-5 Days 5-15 Days 15-25 Days 25-35(own) (0.6 mg) (0.05 mg)(0.3 mg)

N =62r filters = .98

The effect of cigarette nicotine level on toxin exposure: Nicotine

0

1000

2000

3000

4000

5000

Tota

l Nic

otin

e (n

gpe

r mg

Cre

atin

ine)

N =43; p=. 22

0

1000

2000

3000

4000

5000

DAY 5 DAY 15 DAY 25 DAY 35

N =62; p=.001

DAY 5 DAY 15 DAY 25 DAY 35

Tota

l Nic

otin

e (n

gpe

r mg

Cre

atin

ine)

CONTROL NIC DEC

The effect of cigarette nicotine level on toxin exposure: Cotinine

0

1000

2000

3000

4000

5000

Tota

l Cot

inin

e (n

gpe

r mg

Cre

atin

ine)

N =43; p= .15

0

1000

2000

3000

4000

5000

DAY 5 DAY 15 DAY 25 DAY 35

N =62; p=.001

DAY 5 DAY 15 DAY 25 DAY 35

Tota

l Cot

inin

e (n

gpe

r mg

Cre

atin

ine)

CONTROL NIC DEC

The effect of cigarette nicotine level on toxin exposure: NNAL

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Tota

l NN

AL

(ng

per m

g C

reat

inin

e)

N =43; p=. 28

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

DAY 5 DAY 15 DAY 25 DAY 35

N =62; p=.002

DAY 5 DAY 15 DAY 25 DAY 35

Tota

l NN

AL

(ng

per m

g C

reat

inin

e)

CONTROL NIC DEC

The effect of cigarette nicotine level on toxin exposure: 1-HOP

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

Tota

l 1-H

OP

(pm

olpe

r mg

Cre

atin

ine)

N =43; p=. 99

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

DAY 5 DAY 15 DAY 25 DAY 35

N =64; p=.065

Tota

l 1-H

OP

(pm

olpe

r mg

Cre

atin

ine)

DAY 5 DAY 15 DAY 25 DAY 35

CONTROL NIC DEC

The effect of cigarette nicotine level on toxin exposure: Carbon Monoxide

0

5

10

15

20

25

30

35

40

Car

bon

Mon

oxid

e (B

asel

ine,

ppm

)

N =43; p=. 91

0

5

10

15

20

25

30

35

40

DAYS 0 5 10 15 20 25 30 35

N =64; p=.001

Car

bon

Mon

oxid

e (B

asel

ine,

ppm

)

CONTROL NIC DEC

DAYS 0 5 10 15 20 25 30 35

The effect of cigarette nicotine level on subjective ratings

0

10

20

30

40

50

60

70

80

90

100

Stre

ngth

(mm

)

N =43; p=.09

0

10

20

30

40

50

60

70

80

90

100

OWN 0.6 MG 0.3 MG 0.05 MG OWN 0.6 MG 0.3 MG 0.05 MG

Sat

isfa

ctio

n (m

m)

N =60; p=.005

Summary of Low Nicotine (Quest) Results

Behavioral measures of Daily Cigarette Consumption and Smoking Topography initially increase as cigarette nicotine levels decrease, then return to approximate baseline.

Nicotine and Cotinine levels decrease as cigarette nicotine levels decrease.

Toxin exposure is not uniform: 1-HOP, CO increase, but NNAL decreases.

Subjective ratings decrease as a function of cigarette nicotine levels, similarto previous research, which may partly convey less harmfulness.

3. Research Program

C. Marketing and labeling of low nicotine cigarettes(addressing FDA regulation of cigarette nicotine levels ss.201)

1. PREP advertisement features and smokers’ beliefsEvaluating smokers’ reactions to advertising for new lower nicotine Quest

cigarettes. Psychology of Addictive Behaviors 2006; 20(1): 80-84.

PREP advertisement features affect smokers’ beliefs regarding potential harm. Tobacco Control 2008; S1: 32-38.

2. Effect of explicit and implicit information on smokers’ beliefsRobert Wood Johnson Foundation – Substance Abuse Policy Research

Program (2008-2010).

Shopping mall intercept study where participants completed demographic and smoking history questions, viewed the ad and answered 8 items related to beliefs about Quest cigarettes.

Participants smoked an average of 16.9 cigarettes per day (SD = 10.8) and had a mean nicotine dependence score of 4.6 (SD = 2.3)

Smokers made several specific false inferences about Quest cigarettes after exposure (i.e., lower in tar, healthier, less likely to cause cancer).

Those lower in education, having lower nicotine dependence and males tended to respond correctly less frequently. Need for cognition and perceived vulnerability moderated smokers’ beliefs.

Additionally, 25% of participants reported that Quest cigarettes would help them quit smoking, despite warnings to the contrary.

PREP advertisement features and smokers’ beliefs

Shadel, Lerman, Strasser et al., 2006 Psych Add Beh

NO TEXT (N=165)

RED (N=161)

ORIGINAL (N=174)

Advertisement Manipulation Web-TV recruitment.Descriptive and Smoking History.Randomization to Ad.8-item Quest beliefs.

Marlboro Red King smokers significantly preferred both the Marlboro Ultra Light Red cigarettes and package.

Marlboro Red King smokers viewed the cigarettes in the Blue pack as “too mild”, “not easy drawing”, and “burned too fast”.

Other low tar king smokers described the cigarettes in the Red pack as harsher than those in the blue pack

PM docs: Bates 20473870792048718182

Strasser et al., 2008 Tobacco Control

The effect of cigarette advertising on beliefs of potential harm

OR

3.5

2.0

3.0

2.5

2.1

3.31.5 (.1)

2.5

Strasser et al., 2008 Tobacco Control

The effect of cigarette advertising on beliefs of potential harm

OR

3.5

2.0

3.0

2.5

2.1

3.31.5 (.1)

2.5

Figure. Ad conditions: A) accurate explicit-accurate implicit; B) accurate explicit-misleading implicit; C) misleading explicit-accurate implicit; D) misleading explicit-misleading implicit.

A

DC

B

ACCURATE IMPLICIT

Figure. Ad conditions: A) accurate explicit-accurate implicit; D) misleading explicit-misleading implicit.

ACCURATE EXPLICIT

Project: False Inferences from Advertising of PREPs, Lights and CigarsRWJF: Substance Abuse Policy Research Program (2008-2010)

Regions of interest:

Explicit Correct Manipulation: Topographic Dwell Time

Figure 2. Explicit Incorrect Manipulation: Topographic Dwell Time

TIM

E (s

ec)

TIM

E (s

ec)

Quest cigarettes are lower in tar than regular cigarettes?

Quest cigarettes help people quit smoking?

P=.042

TIM

E (S

ECO

ND

S)

INCORRECT CORRECT

1.6 2.3

DWELL TIME IN WARNING LABEL (ROI)

TIM

E (S

ECO

ND

S)

P=.52INCORRECT CORRECT

0.91 0.77

DWELL TIME IN TAR STATEMENT (ROI)

2.3

1.6

0

0.5

1

1.5

2

2.5

3

0.810.91

00.10.20.30.40.50.60.70.80.9

11.11.2

l

.657 .428 1.536 2.359 .1246 1.929 .834 4.462-.129 .071 -1.824 3.328 .0681 .879 .766 1.010.594 .298 1.993 3.970 .0463 1.811 1.010 3.248

-.164 .295 -.556 .309 .5782 .849 .476 1.512.555 .314 1.766 3.120 .0773 1.741 .941 3.222

Coef Std. Error Coef/SE Chi-Square P-Value Exp(Coef) 95% Lower 95% Upper1: constant FTND explicit-acc: 1 implicit-acc: 1 sex 1=M: 2

Logistic Model Coefficients Table for tar correct

Log likelihood = -131.76, R2=0.04

l

0

.1

.2

.3

.4

.5

.6

.7

.8

0 10

.1

.2

.3

.4

.5

.6

.7

0 10

.1

.2

.3

.4

.5

.6

.7

.8

1 2

Percent correct

52 68 5264 6653

EXPLICIT SEXNICOTINE DEPENDENCE

Tar correct

l

Log likelihood = -119.74, R2=0.13

l

Percent correct

5366 5264 6653

WARNING LABEL DWELL HEADLINE DWELLNICOTINE DEPENDENCE

Warning label correct

-.604 .425 -1.423 2.024 .1549 .547 .238 1.256.108 .314 .343 .118 .7313 1.114 .602 2.060

-.058 .315 -.185 .034 .8530 .943 .509 1.748.413 .320 1.290 1.663 .1972 1.511 .807 2.832.414 .097 4.266 18.202 <.0001 1.512 1.251 1.829

-.158 .069 -2.281 5.205 .0225 .854 .745 .978

Coef Std. Error Coef/SE Chi-Square P-Value Exp(Coef) 95% Lower 95% Upper1: constant explicit-acc: 1 implicit-acc: 1 FTND-di: 1 6WarningLabelsonly 2Headline

Logistic Model Coefficients Table for correct warning label

0

.1

.2

.3

.4

.5

.6

0 10

.1

.2

.3

.4

.5

.6

.7

0 10

.1

.2

.3

.4

.5

.6

0 1

30 63 4837 3151

Summary of Advertising and Labeling

Embedding a correct statement (explicit accurate) in the advertisement significantly increased participant correct response that Quest had as much tar as a light cigarette.

However, explicit information in the warning label area did not lead to participants correctly understanding that the product would not help them quit smoking.

Eye-tracking data suggests overall, relatively little time was allocated to viewing the warning labels, suggesting participant incorrect responses may be attributable to no or little viewing time of the warning label. However, correct recall of warning label content was positively associated with increased dwell time of warning label.

Results suggest that accurate risk information in the body of the advertisement may increase retaining risk information more than in the warning labels.

General Concluding Statements to Apply to the FDA legislation:

Laboratory results suggest that smoking topography is an important component in assessing smoking behavior, and is associated with constituent exposure.-- Implementing a testing and evaluation paradigm that considers these variations is imperative, but complex.

Conventional low nicotine cigarettes have design elasticity which permits increased extraction of nicotine and other cigarette constituents. Blocking the filter vents on Light cigarettes can significantly increase toxin exposure. -- Filter vent blocking occurs in a significant proportion of smokers and ought to be banned as a design feature that harms the public health.

Novel low nicotine cigarettes (PREPs) are less elastic in design and initially may be smoked more intensely leading to increased toxicant exposure. Extended use patterns suggest compensation may occur in varying ways.-- Reducing cigarette nicotine levels may not reduce harm or improve the public’s health.

In extended examination of novel low nicotine cigarettes, nicotine (cotinine) levels likely decrease, but all toxin exposures may not.

-- What makes a product less harmful, both at a constituent level and on a population level?

Advertising helps formulate an initial expectation of product response and risk.-- What effect will an FDA stamp of approval have on smokers’ beliefs? -- Is it warning labels that should be regulated?