Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44619

Annex 

Nicotine in Cigarettes and Smokeless Tobacco 

Is a Drug and These Products Are Nicotine Delivery Devices 

Under the Federal Food, Drug, and Cosmetic Act: 

Jurisdictional Determination 

August 1996 

DEPARTMrnNTOFH~THANDHUMANSER~C~ 

U.S. Food and Drug Adroi.'l'lictration 
44620 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

SUMMARY TABLE OF CONTENTS 

EXECUTIVE SUMMARY 

INTRODUCTION 

L CIGARETTES AND SMOKELESS TOBACCO "AFFECT THE 

STRUCTURE OR ANY FUNCTION OF THE BODY'' WITHIN THE 

MEANING OF THE ACT 

IL CIGARETTES AND SMOKELESS TOBACCO ARE "INTENDED" TO 

AFFECT THE STRUCTURE AND FUNCTION OF THE BODY WITHIN 

THE MEANING OF THE ACT 

IlL CIGARETTES AND SMOKELESS TOBACCO ARE COMBINATION 

PRODUCTS CONSISTING OF "DRUG" AND ''DEVICE COMPONENTS 

IV. FDA'S ASSERTION OF JURISDICTION OVER CIGARETTES AND 

SMOKELESS TOBACCO AT THIS TIME IS JUSTIFIED 

V. CONGRESS HAS NOT PRECLUDED OR PREEMPTED FDA FROM 

REGULATING CIGARETTES AND SMOKELESS TOBACCO 

VL FDA EMPLOYED PROCEDURES THAT PROVIDED AN 

OPPORTUNITY FOR FULL PUBLIC PARTICIPATION AND 

EXCEEDED ALL LEGAL REQUIREMENTS 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44621

DETAILED TABLE OF CONTENTS 

EXECUTIVE SUMMARY ................................................................................................................... ix 

INTRODUCTION ................................................................................................................................ 1 

L CIGARETTES AND SMOKELESS TOBACCO "AFFECT THE STRUCTURE OR 

ANY FUNCTION OF THE BODY" WITHIN THE MEANING OF THE ACT ................... 8 

A. THE PHARMACOLOGICAL EFFECTS OF THE NICOTINE IN CIGARETTES 

AND SMOKELESS TOBACCO ON THE BODY ARE SIGNIFICANT ......................... 9 

B. RESPONSE TO COMMENTS ...................................................................................... 14 

1L CIGARETTES AND SMOKELESS TOBACCO ARE "INTENDED" TO AFFECT 

THE STRUCTURE AND FUNCTION OF THE BODY WITHIN THE MEANING 

OF THE ACT .......................................................................................................................... 30 

A. A REASONABLE MANUFACTURER WOULD FORESEE THAT 

CIGARETIES AND SMOKELESS TOBACCO WILL CAUSE ADDICTION 

AND OTHER PHARMACOLOGICAL EFFECTS AND WILL BE USED BY 

CONSUMERS FOR PHARMACOLOGICAL PURPOSES ........................................... 34 

1. "Intended Use" May Be Established on the Basis of Foreseeable 

Pharmacological Effects and Uses ....................................................................... 35 

2. The Significant Pharmacological Effects and Uses of Cigarettes and 

Smokeless Tobacco Are Foreseeable ................................................................. .42 

3. Nicotine Is Widely Recognized as Addictive, and It Is Foreseeable That 

Consumers Will Use Cigarettes and Smokeless Tobacco To Satisfy an 

Addiction .......................................................................................................... 45 

a. Scientific Consensus ............................................................................... 45 

b. Definition of Addiction ........................................................................... 50 

c. Data Establish That Nicotine Is Addictive and That Consumers Use 

Cigarettes and Smokeless Tobacco To Satisfy an Addiction .................... 56 

i. Laboratory Studies Establish That Nicotine Produces 

Pharmacological Effects Similar to Those of Other Addictive 

Substances .............................................................................................. 56 

ii. Epidemiological Data Establish That Many Tobacco Users Are 

Addicted ................................................................................................. 7 4 

4. It Is Foreseeable That Consumers Will Use Cigarettes and Smokeless 

Tobacco for Other Pharmacological Purposes ..................................................... 83 

5. Cigarettes and Smokeless Tobacco Deliver Pharmacologically Active 

Doses ofNicotine ............................................................................................... 88 

6. Conclusion ......................................................................................................... 94 

7. Response to Additional Comments ..................................................................... 95 

a. Comments on the Professional Consensus That Nicotine Is Addictive ..... 95 

b. Comments on the Defmition of Addiction ............................................... 96 

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c. General Comments on Laboratory Evidence of Addictive Potential ....... l04 

d. Comments on Tests ofPsychoactivity ................................................... 106 

e. Comments on Self-Administration and Reinforcement ........................... 114 

f. Comments on Withdrawal, Tolerance, and Nicotine Replacement.. ........ l20 

g. Comments on Epidemiological Studies .................................................. 133 

h. Comments on Nicotine's Other Significant Pharmacological Effects ...... 141 

i. Comments on Whether Cigarettes and Smokeless Tobacco Deliver 

Pharmacologically Active Doses of Nicotine .......................................... 142 

B. CONSUMERS USE CIGARETTES AND SMOKELESS TOBACCO TO 

OBTAIN THE PHARMACOWGICAL EFFECTS OF NICOTINE AND 

TO SATISFY THEIR ADDICTION ............................................................................ 151 

1. "Intended Use" May Be Established on the Basis of Actual 

Consumer Use ................................................................................................... 152 

2. Consumers Use Cigarettes and Smokeless Tobacco for the Pharmacological 

Effects of Nicotine ............................................................................................ 155 

a. Epidemiological Evidence Shows That Consumers Use Cigarettes 

and Smokeless Tobacco for Pharmacological Effects ............................. 156 

b. Experimental Evidence Shows That Consumers Use Cigarettes 

and Smokeless Tobacco for Pharmacological Effects ............................. 159 

c. The Data Do Not Support the Industry's Claim That Consumers 

Seek Nicotine for Its Sensory Effects Rather than Its 

Pharmacological Effects ........................................................................ 161 

3. Other Factors Associated with Tobacco Use Are Secondary to 

Pharmacological Effects .................................................................................... 167 

4. Responses to Additional Comments .................................................................. 172 

a. General Comments on Consumer Use ................................................... 172 

b. Comments on Tobacco Use To Satisfy Addiction .................................. 175 

c. Comments on Tobacco Use for Effects on Mood and Weight.. .............. 181 

d. Comments on Nonpharmacological Factors Associated with 

Tobacco Use ......................................................................................... 182 

C. THE STATEMENTS, RESEARCH, AND ACTIONS OF THE CIGAREITE 

MANUFACTURERS SHOW THAT THE MANUFACTURERS INTEND THEIR 

PRODUCTS TO AFFECT THE STRUcnJRE AND FUNCTION 

OF THE BODY ........................................................................................................... 191 

1. "Intended Use" May Be Established on the Basis of the Statements, 

Actions, and Research of the Manufacturers ..................................................... .195 

2. The Cigarette Manufacturers Understand That Nicotine Has Addictive 

and Other Pharmacological Effects and That Smokers Use Cigarettes To 

Obtain These Effects ......................................................................................... 198 

a. The Statements and Research of Philip Morris ....................................... 198 

i. The Views of Senior Researchers and Officials ...................................... 199 

ii. Research into Nicotine Pharmacology ................................................... 202 

iii. Project Table ......................................................................................... 209 

b. The Statements and Research of R. J. Reynolds ..................................... 211 

i. The Teague Memoranda ....................................................................... 211 

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ii Other Statements and Research of RJR Scientists and Officials .............. 215 

iii. RJR's Alternative Tobacco Products ..................................................... 221 

iv. RJR's I..egal Briefs ................................................................................ 223 

c. The Statements and Research of Brown & Williamson .......................... 225 

i. Statements and Research in the 1960's .................................................. 226 

ii Statements and Research in the 1970's and 1980's ................................ 230 

iii Statements and Research in the 1990's .................................................. 235 

iv. The Wigand Deposition .......................................................................... 237 

d. The Statements and Research of Other Cigarette Manufacturers ........... 238 

e. Three Decades of Statements and Research by Cigarette 

Manufacturers Are Sufficient to Establish Intent ................................... 256 

3. The Cigarette Manufacturers Have Conducted Extensive Product 

Research and Development To Optimize the Delivery ofNicotine ..................... 259 

a. Philip Morris' Product Research and Development Efforts .................... 261 

b. RJR' s Product Research and Development Efforts ................................ 269 

c. Brown & Williamson's Product Research and Development Efforts ...... 272 

i. Product Research and Development in the 1960's ................................. 273 

ii. Product Research and Development to Maintain 

Pharmacologically Satisfying Doses of Nicotine 

while Lowering Tar ............................................................................... 276 

iii Blending and "Y-1" .............................................................................. 281 

iv. Chemical Manipulation ........................................ ~ ................................ 283 

v. "Elasticity" Technologies ...................................................................... 284 

d. Other Cigarette Manufacturers' Product Research and 

Development Efforts ............................................................................. 285 

i. American Tobacco Company ................................................................ 285 

ii Lorillard Tobacco Company .................................................................. 287 

e. Filter and Paper Suppliers' Product Research and Development 

Efforts .................................................................................................. 288 

f. These Product Research and Development Efforts Were Undertaken 

for Commercial Reasons ....................................................................... 290 

4. The Cigarette Manufacturers Design Commercially Marketed Cigarettes 

To Provide a Pharmacologically Active Dose of Nicotine ................................. 294 

a. The Manufacturers Use Nicotine-Rich Tobacco Blends in 

I...ow-Tar Cigarettes ............................................................................... 295 

i. The Use of Nicotine-Rich Tobacco Blends in the 1950's ....................... 296 

ii The Use of Nicotine-Rich Tobacco Blends Today ................................. 297 

iii The Use of Nicotine-Rich Tobacco Blends Is Not Due to Accident 

or Taste ................................................................................................ 301 

b. The Manufacturers Use Filtration and Ventilation Technologies 

That Selectively Remove More Tar than Nicotine and That Allow 

Smokers To Inhale More Nicotine than the Measured I..evels ................ 307 

c. The Manufacturers Use Chemical Additives to Increase the 

Delivery of "Free" Nicotine ................................................................... 314 

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d. Nicotine Deliveries Have fucreased in Recent Years by Design, 

Especially in Low-Tar Cigarettes .......................................................... .319 

e. The Manufacturers Precisely Control Nicotine Deliveries ...................... 324 

i. Tobacco Growing ................................................................................. 325 

ii Leaf Purchasing .................................................................................... 326 

iii Leaf Blending ........................................................................................ 327 

iv. Reconstituted Tobacco .......................................................................... 328 

f. Satisfying Consumer Preferences Requires Controlling and 

Manipulating Nicotine Deliveries To Satisfy Addiction and 

Provide Other Phannacological Effects .................................................. 330 

5. Conclusion ....................................................................................................... 336 

6. Response to Comments .................................................................................... 339 

a. Comments on Statements and Research on Nicotine's Drug Effects ...... 339 

i. Comments on Specific Philip Morris Statements and Research 

Projects ................................................................................................. 339 

ii Comments on Specific RJR Statements and Research 

Projects ................................................................................................. 370 

iii Comments on Specific Brown & Williamson Statements aild 

Research Projects .................................................................................. 376 

iv. Other Comments ................................................................................... 381 

b. Comments on Product Research and Development To Optimize 

and Manipulate Nicotine Delivery .......................................................... 389 

i. Comments on Specific Philip Morris Product Research and 

Development Projects ........................................................................... 389 

ii Comments on Specific RJR Product Research and Development 

Projects ................................................................................................. 395 

iii Comments on Specific Brown & Williamson Product Research 

and Development Projects ..................................................................... 401 

iv. Other Comments ................................................................................... 406 

c. Comments on Nicotine Manipulation and Control ................................ .409 

i. Comments on the Use of High-Nicotine Blends in 

Low-Yield Cigarettes ............................................................................ 409 

ii Comments on Nicotine Deliveries and Nicotine-to-Tar Ratios .............. .411 

iii Comments on Chemical Manipulation. ................................................. .419 

iv. Comments on Flavorings and Casings.~ .................................................. 427 

v. Comments on the Consistency of Nicotine Deliveries ........................... .428 

vi. Comments on Breeding ......................................................................... 429 

vii. Comments on Leaf Purchasing .............................................................. 434 

viii Comments on Reconstituted Tobacco .................................................. .436 

ix. Other Comments ................................................................................... 437 

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D. THE STATEMENTS, RESEARCH, AND ACTIONS OF THE SMOKELESS 

TOBACCO MANUFACTURERS SHOWTHATTHEMANUFACTURERS 

INTEND THEIR PRODUCTS TO AFFECT THE STRUCTURE AND 

FUNCTION OF THE BODY ...................................................................................... 442 

I. The Smokeless Tobacco Manufacturers Understand That Nicotine Has 

Addictive and Other Pharmacological Effects and That Consumers 

Use Smokeless Tobacco To Obtain These Effects ............................................. .444 

2. The Smokeless Tobacco Manufacturers Manipulate Nicotine Deliveries 

from Smokeless Tobacco in a Manner That Promotes Tolerance and 

Addiction in Users ............................................................................................ 452 

a. Evidence of Graduated Nicotine Deliveries .......................................... .454 

b. Evidence that Teenage Users Graduate from Smokeless Tobacco 

with Low Nicotine Deliveries to Products with High Nicotine 

Deliveries ...... : ....................................................................................... 460 

c~ Documentary Evidence of UST's Deliberate "Graduation Process" ...... 464 

3. Conclusion ....................................................................................................... 469 

4. Response to Comments .................................................................................... 470 

a. Comments on pH Manipulation ............................................................. 470 

b. Comments on the Graduation Process .................................................. .484 

c. Other Comments ................................................................................... 492 

E. THE "INTENDED USE" OF A PRODUCT IS NOT DETERMINED ONLY 

ON THE BASIS OF PROMOTIONAL CLAIMS ....................................................... .495 

1. The "Intended Use" of a Product May Be Established on the Basis of 

All Relevant Objective Evidence of Intent ........................................................ .496 

a. The Plain Meaning of the Statute Authorizes FDA To 

Consider All Evidence of Intent ............................................................ 498 

b. FDA's Regulations Authorize FDA To Consider All 

Evidence of Intent ................................................................................. 501 

c. Judicial Decisions Authorize FDA To Consider All Evidence 

of Intent ................................................................................................ 504 

i. Pharmacological or Physical Effects ......................... : ............................ 506 

ii Consumer Use .................................................. ~ ................................... 507 

iii Other Evidence ..................................................................................... 508 

d. The Agency's Administrative Precedent Supports the Agency's 

Consideration of More Than Promotional Claims .................................. 510 

e. Policy Considerations Also Weigh Strongly in Favor of the 

Agency's Interpretation ......................................................................... 512 

2. Consideration of Tobacco Manufacturers' Promotional 

Claims Supports the Agency's Position .............................................................. 515 

3. Response to Additional Comments on Legal Theory ........................................ 522 

a. General Comments ............................................................................... 522 

b. Comments on Administrative Precedents .............................................. 529 

F. RESPONSE TO ADDITIONAL COMMENTS ........................................................... 536 

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44626 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

G. CONSIDERED CUMULATIVELY, Tiffi EVIDENCE OVERWHELMINGLY 

DEMONSTRATES THAT CIGARETTES. AND SMOKELESS TOBACCO ARE 

INTENDED TO AFFECT Tiffi STRUCTURE AND FUNCTION OF 1HE BODY ... 547 

Ill. CIGARETTES AND SMOKELESS TOBACCO ARE COMBINA T.ION PRODUCTS 

CONSISTING OF "DRUG" AND "DEVICE" COMPONENTS ....................................... .549 

A. NICOTINE IN CIGARETTES AND SMOKELESS TOBACCO IS A DRUG ........... .551 

B. CIGARETTES AND SMOKELESS TOBACCO CONTAIN DELNERY 

DEVICES AND ARE COMBINATION PRODUCTS UNDER THE ACT ................ .552 

1. Cigarettes Are Combination Products ............................................................... 553 

2. Smokeless Tobacco Is a Combination Product .................................................. 557 

C. RESPONSE TO COMMEN1'S .................................................................................... 560 

IV. FDA'S ASSERTION OF JURISDICTION OVER CIGARETTES AND 

SMOKELESS TOBACCO AT THIS TIME IS JUSTIFIED ............................................... 563 

A. FDA HAS ALWAYS EXERCISED AUTHORITY TO REGULATE TOBACCO 

PRODUCTS WHEN THE EVIDENCE ESTABLISHED THAT TiffiY FELL 

WITHIN THE DRUG OR DEVICE DEFINffiONS ................................................... 566 

B. A CHANGE IN THE EVIDENCE BEFORE THE AGENCY NOW 

ESTABLISHES "INTENT'' TO AFFECT Tiffi STRUCTURE AND FUNCTION 

OF THE BODY ........................................................................................................... 567 

1. Previous Agency Position and the Evidence on Which It Was Based ................. 567 

2. New Evidence Supporting the Agenct s Change in Position .............................. 570 

a. Since 1980, a Scientific Consensus Has Emerged That Nicotine Is 

Addictive and Has Other Significant Pharmacological Effects 

and Uses ............................................................................................... 572 

b. Since 1980, Evidence Has Become Available That Consumers Use 

Tobacco Predominantly for Its Pharmacological Effects ....................... .577 

c. Since 1980, Evidence Has Become Available Demonstrating That 

Tobacco Manufacturers Actually Intend Their Products To Affect 

the Structure and Function of the Body ................................................. 579 

C. NEW EVIDENCE 1HAT NICOTINE ADDICTION IS A PEDIATRIC 

DISEASE PERMITS EFFECTNE REGULATORY INTERVENTION .•.•........ ~ ......... 582 

1. New Information Shows that Cigarette and Smokeless Tobacco Use 

Begins Almost Exclusively in Childhood and Ado1escence ................................ .583 

2. New Information Shows that Effective Restrictions on Access and 

Advertising to Children and Adolescents Can Decrease Tobacco Use 

by Children ........................................................................................................ 587 

3. New Information Indicates that Regulatory Interventions Can Reduce 

Tobacco-Related illness If They Focus on Preventing Children from 

Becoming Addicted ........................................................................................... 591 

D. RESPONSE TO COMMEN1'S .................................................................................... 593 

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V. CONGRESS HAS NOT PRECLUDED OR PREEMPTED FDA FROM 

REGULATING CIGARETTES AND SMOKELESS TOBACC0 ..................................... 597 

A. THE PLAIN LANGUAGE OF 1HE FEDERAL FOOD, DRUG, AND 

COSMETIC ACT DOES NOT PRECLUDE FDA JURISDICTION OVER 

TOBACCO PRODUCTS ............................................................................................. 597 

B. THE LEGISLATIVE HISTORY OF 1HE FEDERAL FOOD, DRUG, AND 

COSMETIC ACT DEMONSTRATES THAT FDA'S JURISDICTION OVER 

TOBACCO PRODUCTS IS NOT PREEMPTED OR PRECLUDED .......................... 599 

C. OTHER STATUTES DO NOT PRECLUDE OR PREEMPT FDA'S 

JURISDICTION OVER TOBACCO PRODUCTS ...................................................... 605 

D. RESPONSE TO COMMENTS .................................................................................... 610 

VL FDA EMPLOYED PROCEDURES THAT PROVIDED AN OPPORTUNITY 

FOR FULL PUBLIC PARTICIPATION AND EXCEEDED ALL LEGAL 

REQUIREMEN'I'S ................................................................................................................. 614 

A. ADEQUACY OF 1HE RECORD ................................................................................ 618 

1. The Administrative Record the Agency Assembled for This Proceeding 

Surpassed the Requirements of the APA. ........................................ ~ ................. 619 

2. The Agency's Use of Confidential Documents .................................................. 623 

a. Confidential Documents on Which the Agency Did Not Rely ................. 623 

b. Confidential Documents on Which the Agency Relied ........................... 625 

3. The Claim that FDA Relied on "Unknown" Undisclosed Data .......................... 630 

4. The Claim that FDA Failed To Include in the Record NDA Data on 

Which It Relied ................................................................................................ 631 

a. The Agency's Reference to Five NDA's ................................................ 632 

b. The Agency's Reference to Nineteen Smoking Cessation Studies .......... 635 

5. The Agency's Reliance in the Final Jurisdictional Determination on 

New Materials .................................................................................................. 637 

B. ADEQUACY OF 1HE NOTICE ................................................................................. 639 

1. The Agency Provided Adequate Notice of the Key Legal and 

Factual Issues ................................................................................................... 641 

2. The Agency Provided a "Reasoned Explanation" for Its Current Position ......... 648 

C. ADEQUACY OF THE COMMENT PERIOD ............................................................. 651 

D. THE NEED FOR "ADDffiONAL PROCEDURES" ................................................... 654 

E. CONCLUSION ........................................................................................................... 662 

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EXECUTIVE SUMMARY 

This document explains the basis for the Food and Drug Administration's assertion 

of jurisdiction over cigarettes and smokeless tobacco under the Federal Food, Drug, and 

Cosmetic Act (the Act). FDA regulates a diverse range of products under the Act, 

including foods, drugs, medical devices, and cosmetics. The distinguishing feature that 

characterizes these products is their intimate and potentially harmful relationship with the 

human body. The products that FDA regulates include those that are ingested, inhaled, 

implanted, or otherwise used in close contact with the human body. 

Cigarettes, which deliver a pharmacologically active dose of nicotine to the body 

through inhalation, and smokeless tobacco, which delivers a pharmacologically active dose 

of nicotine to the body through buccal absorption, share this distinguishing feature. Like 

the products that FDA traditionally regulates, cigarettes and smokeless tobacco are 

inhaled or placed within the human body; like many of these products, they deliver a 

pharmacologically active substance to the bloodstream; and like these products, they have 

potentially dangerous effects. Indeed, no products cause more death and disease than 

cigarettes and smokeless tobacco. 

FDA is asserting jurisdiction over cigarettes and smokeless tobacco under the drug 

and device provisions of the Act. Specifically, FDA has concluded that cigarettes and 

smokeless tobacco are combination products consisting of nicotine, a drug that causes 

addiction and other significant pharmacological effects on the human body, and device 

components that deliver nicotine to the body. FDA last considered whether cigarettes 

were drugs or devices in the late 1970's. See Action on Smoking and Health v. Harris, 

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655 F.2d 236 (D.C. Cir. 1980). Since that time, substantial new evidence has become 

available to FDA. This evidence includes the emergence of a scientific consensus that 

cigarettes and smokeless tobacco cause addiction to nicotine and the disclosure of 

thousands of pages of internal tobacco company documents detailing that these products 

are intended by the manufacturers to affect the structure and function of the human body. 

This new evidence justifies the Agency's determination that cigarettes and smokeless 

tobacco are delivery systems for the drug nicotine. 

Under the Act, a product is a drug or device if it is an article (other than food) 

"intended to affect the structure or any function of the body." Sections 201(gXIXC), 

20l(h)(3). The statutory defmition is "intended to define 'drug' far more broadly than 

does the medical profession." United States v. An Article of Drug ... Bacto-Unidisk, 394 

U.S. 784, 793, 798 (1969). The legal question of whether cigarettes and smokeless 

tobacco are subject to FDA jurisdiction is one that "FDA has jurisdiction to decide with 

administrative fmality." Weinberger v. Bentex Pharmaceuticals, Inc., 412 U.S. 645, 653 

(1973). 

After intensive investigation and careful consideration of the public comments, 

FDA concludes that cigarettes and smokeless tobacco meet the statutory definition of a 

drug and a device. This conclusion is based on two determinations: (1) nicotine in 

cigarettes and smokeless tobacco does "affect the structure or any function of the body," 

and (2) these effects on the structure and function of the body are "intended" by the 

manufacturers. 

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The Agency's determination that nicotine in cigarettes and smokeless tobacco does 

"affect the structure or any function of the body" is based on three central fmdings: 

1. Nicotine in cigarettes and smokeless tobacco causes and 

sustains addiction. 

2. Nicotine in cigarettes and smokeless tobacco causes other 

psychoactive (mood-altering) effects, including 

tranquilization and stimulation. 

3. Nicotine in cigarettes and smokeless tobacco controls 

weight. 

The Agency's determination that the manufacturers of cigarettes and smokeless 

tobacco "intend" these effects is based on five central fmdings: 

1. The addictive and other pharmacological effects of nicotine 

are so widely known and accepted that it is foreseeable to a 

reasonable manufacturer that cigarettes and smokeless 

tobacco will cause addiction to nicotine and other 

significant pharmacological effects and will be used by 

consumers for pharmacological purposes, including 

sustaining their addiction to nicotine. 

2. Consumers use cigarettes and smokeless tobacco 

predominantly for pharmacological purposes, including 

sustaining their addiction to nicotine, mood alteration, and 

weight loss. 

3. Manufacturers of cigarettes and smokeless tobacco know 

that nicotine in their products causes pharmacological 

effects in consumers, including addiction to nicotine and 

mood alteration, and _that consumers use their products 

primarily to obtain the pharmacological effects of nicotine. 

4. Manufacturers of cigarettes and smokeless tobacco design 

their products to provide consumers with a 

pharmacologically active dose of nicotine. 

5. An inevitable consequence of the design of cigarettes and 

smokeless tobacco to provide consumers with a 

pharmacologically active dose of nicotine is to keep 

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consumers using cigarettes and smokeless tobacco by 

sustaining their addiction to nicotine. 

This document is divided into six sections. Section I describes the evidence and 

legal basis supporting the Agency's fmding that cigarettes and smokeless tobacco "affect 

the structure or any function of the body." Section II describes the evidence and legal 

basis supporting the Agency's finding that the manufacturers "intend" these effects on the 

structure and function of the body. Section ill explains the Agency's conclusion that 

cigarettes and smokeless tobacco are combination products that contain a "drug" and a 

"device." Section IV explains why the Agency's decision to assert jurisdiction over 

cigarettes and smokeless tobacco is justified by the new evidence now available to the 

Agency. Section V demonstrates that Congress has not precluded or preempted the 

Agency's assertion of jurisdiction over cigarettes and smokeless tobacco. Section VI 

addresses procedural issues relating to the Agency's assertion of jurisdiction over 

cigarettes and smokeless tobacco. These sections are summarized below. 

I. Cigarettes and Smokeless Tobacco "Affect the Structure or any Function of the 

Body" Within the Meaning of the Act 

The nicotine delivered by cigarettes and smokeless tobacco has significant 

pharmacological effects on the structure and function of the body. 

First, the nicotine in cigarettes and smokeless tobacco causes and sustains 

addiction. Nicotine exerts psychoactive, or mood-altering, effects on the brain that 

motivate repeated, compulsive use of the substance. These pharmacological effects create 

dependence in the user. The pharmacological processes that cause this addiction to 

nicotine are similar to those that cause addiction to heroin and cocaine. 

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Second, the nicotine in cigarettes and smokeless tobacco produces other important 

pharmacological effects on the central nervous system. Under some circumstances and 

doses, the nicotine has a sedating or tranquilizing effect on mood and brain activity. 

Under other circumstances and doses, the nicotine has a stimulant or arousal-inducing 

effect on mood and brain activity. 

Third, the nicotine in cigarettes and smokeless tobacco affects body weight. 

These effects on the structure and function of the body are significant and 

quintessentially drug-like. Moreover, these effects are the same as the effects of other 

drugs that FDA has traditionally regulated, including stimulants, tranquilizers, appetite 

suppressants, and products, such as methadone, used in the maintenance of addiction. For 

these reasons, the Agency finds that cigarettes and smokeless tobacco "affect the structure 

or any function of the body'' within the meaning of the Act. 

II. Cigarettes and Smokeless Tobacco Are "Intended" to Affect the Structure and 

Function of the Body Within the Meaning of the Act 

To determine whether effects on the structure or function of the body are 

"intended" by the manufacturer, the Agency must objectively evaluate all the relevant 

evidence of intent in the record before it. "The FDA is not bound by the manufacturer's 

subjective claims of intent," but rather can find actual intent "on the basis of objective 

evidence." National Nutritional Foods Ass'n v. Matthews~ 557 F.2d 325, 334 (2d Cir. 

1977). In the case of cigarettes and smokeless tobacco, the Agency finds that three types 

of objective evidence provide independent bases for fmding that the manufacturers intend 

to affect the structure and function of the body: ( 1) the evidence of the foreseeable 

pharmacological effects and uses of cigarettes and smokeless tobacco; (2) the evidence of 

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the actual consumer use of cigarettes and smokeless tobacco for pharmacological 

purposes; and (3) the evidence of the statements, research, and actions of the 

manufacturers themselves. Considered independently or cumulatively, this evidence 

convincingly demonstrates that cigarettes and smokeless tobacco are intended to be used 

for pharmacological purposes. 

A. A Reasonable Manufacturer Would Foresee that Tobacco Products Will 

Cause Addiction and Other Pharmacological Effects and Will Be Used by 

Consumers for Pharmacological Purposes 

When Congress enacted the current definition of "drug" in 1938, it was well 

understood that "[t]he law presumes that every man intends the legitimate consequences 

of his own acts." Agnew v. United States, 165 U.S. 36, 53 (1897). Consistent with this 

common understanding, FDA's regulations provide that a product's intended 

pharmacological use may be established by evidence that the manufacturer "knows, or has 

knowledge of facts that would give him notice," that the product is being widely used for 

a pharmacological purpose, even if the product is not being promoted for this purpose. 

21 CFR 201.128, 801.4. Thus, FDA may find that a manufacturer intends its product to 

affect the structure or function of the body when it would be foreseeable to a reasonable 

manufacturer that the product will (1) affect the structure or function of the body and (2) 

be used by a substantial proportion of consumers to obtain these effects. For example, 

when it is foreseeable to a reasonable manufacturer that a product will produce drug 

effects in consumers and be purchased by a substantial proportion of consumers for drug 

purposes, FDA may consider the product a "drug." 

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In the case of cigarettes and smokeless tobacco, no reasonable manufacturer could 

fail to foresee that these products will have significant pharmacological effects on 

consumers and be widely used by consumers for pharmacological purposes. All major 

public health organizations in the United States and abroad with expertise in tobacco or 

drug addiction now recognize that the nicotine delivered by cigarettes and smokeless 

tobacco is addictive. The first major organization to do so was the American Psychiatric 

Association, which in 1980 defmed the "tobacco dependence disorder'' and the "tobacco 

withdrawal syndrome." Since 1980, nicotine in tobacco products has also been 

recognized as addictive by the U.S. Surgeon General (1986 and 1988), the American 

Psychological Association (1988), the Royal Society of Canada (1989), the World Health 

Organization (1992), the American Medical Association (1993), and the Medical Research 

Council in the United Kingdom (1994). Every expert medical organization that submitted 

comments to FDA on whether nicotine is addictive concluded that it is. The tobacco 

industry's public position that nicotine is not addictive is simply not credible in light of this 

overwhelming scientific consensus. 

The scientific consensus that cigarettes and smokeless tobacco cause addiction to 

nicotine makes it foreseeable to a reasonable manufacturer that these products will affect 

the structure and function of the body. This scientific consensus also makes it foreseeable 

that cigarettes and smokeless tobacco will be used by a substantial proportion of 

consumers for a pharmacological purpose-namely, to satisfy their addiction. 

It is also foreseeable that the nicotine in cigarettes and smokeless tobacco will 

cause, and be used for, other significant pharmacological effects. It is well established that 

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the nicotine in cigarettes and smokeless tobacco has psychoactive or mood-altering effects 

in the brain. Under some circumstances, nicotine can have a sedative or tranquilizing 

effect on the brain; under other circumstances, nicotine can have a stimulating or arousalinducing effect. In this regard, nicotine is similar to other addictive drugs such as opiates, 

which can have both stimulating and sedating effects. In addition, nicotine plays a role in 

weight regulation, with substantial evidence demonstrating that cigarette smoking leads to 

weight loss. 

Because a reasonable manufacturer would foresee that cigarettes and smokeless 

tobacco will cause and be used for these well-established pharmacological effects in a 

substantial proportion of consumers, the Agency finds that these drug effects and drug 

uses are intended by the manufacturers. 

B. Consumers Use Tobacco Products to Obtain the Pharmacological Effects 

of Nicotine and to Satisfy Their Addiction 

A second basis for establishing that a product is intended to affect the structure or 

function of the body is evidence showing that consumers actually use the product for 

pharmacological purposes. In fact, courts have recognized that even in the absence of any 

other evidence of intent to affect the structure or function of the body, such an intent may 

be established by evidence showing that consumers use the product "predominantly'' for 

pharmacological purposes. ASH, 655 F.2d at 239-240. 

In the case of cigarettes and smokeless tobacco, the evidence establishes that 

consumers do use these products "predominantly" for pharmacological purposes. Major 

recent studies have concluded that 77% to 92% of smokers are addicted to nicotine in 

cigarettes. The U.S. Department of Health and Human Services estimates that 75% of 

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young regular users of smokeless tobacco are addicted to nicotine in these products. The 

comments from the American Heart Association, the American Lung Association, and the 

American Cancer Society, whose member physicians provide health care for tobacco users 

in the United States, confirm that ''the vast majority of people who use nicotine containing 

cigarettes and smokeless tobacco do so to satisfy their craving for the pharmacological 

effects of nicotine; that is, to satisfy their drug dependence or addiction." 

In addition, a large proportion of consumers also use cigarettes and smokeless 

tobacco for other pharmacological pwposes. A recent survey found that over 70% of 

young people 10 to 22 years old who are daily smokers reported that they use cigarettes 

for relaxation. The same survey found that over 50% of young people who are daily users 

of smokeless tobacco reported that they use smokeless tobacco for relaxation. Other 

surveys show that between one-third and one-half of young smokers report that weight 

control is a reason for their smoking. 

This evidence that consumers actually use cigarettes and smokeless tobacco 

predominantly to obtain the pharmacological effects of nicotine leads FDA to fmd that 

cigarettes and smokeless tobacco are intended to affect the structure and function of the 

body. 

C. The Statements, Research, and Actions of the Cigarette Manufacturers 

Show that the Manufacturers Intend to Affect the Structure and Function 

of the Body· 

A third basis for establishing that a manufacturer intends to affect the structure or 

function of the body is evidence from the statements, research, and actions of the 

manufacturer that reveals that the manufacturer knows that its product will, or designs its 

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product to, affect the structure or function of the body. It is a canon of statutory 

construction that words used by Congress should ordinarily be interpreted in accordance 

with their plain meaning. The plain meaning of "intend" includes "to have in mind" or "to 

design" for a particular use. The American Heritage Dictionary, for instance, defmes 

"intend" as: "1. To have in mind; plan. 2.a. To design for a specific purpose. b. To 

have in mind for a particular use." Consistent with the plain meaning of "intend," FDA 

may consider whether the statements, research, and actions of the manufacturer show that 

the manufacturer "has in mind" that its product will, or "designs" its product to, affect the 

structure or function of the body. 

The administrative record contains three decades of documents and other evidence 

from the major cigarette manufacturers. This evidence, most of which has only recently 

become available, establishes that the manufacturers do "have in mind" that their products 

will have and be used for pharmacological effects. First, the evidence shows that the 

cigarette manufacturers know that nicotine is a pharmacologically active drug. In internal 

documents, for instance, researchers for Philip Morris Inc. call nicotine "a powerful 

pharmacological agent with multiple sites of action" and "a physiologically active ... 

substance ••. [which] alters the state of the smoker by becoming a neurotransmitter and a 

stimulant"; a researcher for RJ. Reynolds Tobacco Co. (RJR) calls nicotine "a potent 

drug with a variety of physiological effects"; and researchers for Brown & Williamson 

Tobacco Corp. and its parent company, BAT Industries PLC (formerly the BritishAmerican Tobacco Co.) (BATCO), call nicotine "pharmacologically active in the brain" 

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44638 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

and "an extremely biologically active compound capable of eliciting a range of 

pharmacological, biochemical, and physiological responses." 

Second, the evidence establishes that the cigarette manufacturers have conducted 

extensive research to understand precisely how nicotine affects the structure and function 

of the body. In one year alone, Philip Morris conducted 16 different studies on the effects 

of nicotine, including 5 experiments to determine the pharmacological effects of nicotine 

on the human brain. RJR's similarly extensive research found that the nicotine in 

cigarettes produces measurable changes in brain wave activity, such as "a significant 

increase in beta2 magnitude" (an effect associated with anxiety relief) and "a significant 

decrease in delta magnitude" (an effect associated with improved mental condition). 

Through the Council for Tobacco Research, an organization formed by the major tobacco 

companies, the manufacturers funded dozens of sophisticated investigations concerning 

nicotine, including numerous studies that demonstrate nicotine's ability to alter the 

function of the human brain. 

Third, the evidence shows that the manufacturers know that one of the 

pharmacological effects of nicotine is to cause and sustain addiction. Researchers and 

senior officials of Brown & Williamson and BA TCO expressly acknowledge this fact in 

their internal documents, stating that "smoking is a habit of addiction" and that "nicotine is 

addictive." Philip Morris scientists also know of nicotine's addiction potential. They 

conducted a series of nicotine "self-administration" experiments using the tests used by the 

National Institute on Drug Abuse to determine whether a substance has addiction 

potential. These studies found that rats would self-administer nicotine, which is one of the 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44639

hallmark characteristics of an addictive drug. Moreover, through the Council for Tobacco 

Research, the cigarette manufacturers funded research that reported that "smoking is a 

form of dependence no less binding than that of other addictive drugs." 

Fourth, the evidence shows that the manufacturers know that consumers smoke 

cigarettes primarily to obtain the pharmacological effects of nicotine. This point is 

repeatedly acknowledged in internal company documents. For example, researchers for 

Philip Morris have stated that nicotine is "the primary reason why people smoke" and that 

nicotine is "the physiologically active component of smoke having the greatest 

consequence to the consumer''; researchers for RJR have stated that ''the confirmed user 

of tobacco is primarily seeking the physiological 'satisfaction' derived from nicotine" and 

that "[ w ]ithout any question, the desire to smoke is based upon the effect of nicotine on 

the body"; and BATCO's director of research has stated that "[t]he tobacco smoking habit 

is reinforced or dependent upon the psycho-pharmacological effects mainly of nicotine." 

This knowledge of the central role of nicotine in cigarette smoking was communicated to 

the highest levels of the companies. In 1969, for instance, Philip Morris' vice president for 

research and development told the Philip Morris board of directors that ''the ultimate 

explanation for the perpetuated cigarette habit resides in the pharmacological effect of 

smoke upon the body of the smoker." 

Fifth, the evidence shows that in their internal documents, the cigarette 

manufacturers expressly refer to cigarettes as devices for the delivery of nicotine. For 

instance, researchers for Philip Morris have described cigarettes as a "dispenser for a dose 

unit of nicotine" and as a "nicotine delivery device"; a senior researcher for RJR has 

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44640 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

described cigarettes as a "vehicle for delivering nicotine"; and researchers for BATCO 

have described cigarettes as the "means of providing nicotine dose in a metered fashion" 

and as a device that provides the smoker "very flexible control over titrating his desired 

dose of nicotine." 

This evidence establishes that cigarettes are intended by the manufacturers to 

affect the structure and function of the body. It demonstrates that the manufacturers 

know that nicotine is pharmacologically active; that consumers smoke primarily to obtain 

the pharmacological effects of nicotine; and that cigarettes function as devices for the 

delivery of nicotine. The evidence thus shows that when the manufacturers offer 

cigarettes for sale, they "have in mind" that their products will be used for the particular 

purpose of affecting the structure and function of the body. 

In addition to the evidence showing that cigarette manufacturers "have in mind" 

the use of cigarettes for pharmacological purposes, the record shows that the 

manufacturers "design" cigarettes to ensure the delivery of a pharmacologically active 

dose of nicotine to the smoker. The evidence in the record shows that the manufacturers 

have conducted extensive product research and development to fmd ways to maintain 

adequate nicotine levels in low-tar cigarettes. According to one former senior official at 

Philip Morris, "a key objective of the cigarette industry over the last 20-30 years" was 

"maintaining an acceptable and pharmacologically active nicotine level" in low-tar 

cigarettes. Internal industry documents in the record disclose research to determine the 

dose of nicotine that must be delivered to provide "pharmacological satisfaction" to the 

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smoker, as well as estimates by industry scientists of the minimum and optimum doses of 

nicotine that cigarettes must deliver. 

Among the many examples in the record of product research and development to 

enhance relative nicotine deliveries, Philip Morris conducted extensive research to identify 

''the optimal nicotine/tar ratios for cigarette acceptability of relatively low-delivery 

cigarettes"; RJR developed alternative tobacco products that provide a "more efficient and 

direct way to provide the desired nicotine dosage than the present system involving 

combustion of tobacco"; and Brown & Williamson investigated chemical manipulation to 

raise smoke pH, thereby increasing "free" nicotine delivery, and used genetic engineering 

to breed a high-nicotine tobacco plant called Y -1. 

The record before the Agency shows that several methods of enhancing nicotine 

deliveries are used in the manufacture of commercial cigarettes. Tobacco blending to raise 

the nicotine concentration in low-tar cigarettes is common. As the vice chairman and chief 

operating officer of Lorillard Tobacco Co. has stated, ''the lowest tar segment is 

composed of cigarettes utilizing a tobacco blend which is significantly higher in nicotine." 

Another common technique for enhancing nicotine deliveries in low-tar cigarettes is the 

use of filter and ventilation systems that by design remove a higher percentage of tar than 

nicotine. Yet a third type of nicotine manipulation is the addition of ammonia compounds 

that increase the delivery of "free" nicotine to smokers by raising the alkalinity or pH of 

tobacco smoke. These ammonia technologies are widely used within the industry. 

The record establishes that an important reason why the manufacturers design 

cigarettes that provide pharmacologically active doses of nicotine is to satisfy the demands 

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44642 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

of users. The manufacturers concede in their comments that their "intent is to design, 

manufacture and market ... cigarettes to meet the preferences of adult smokers." The 

preferences of most smokers, however, include obtaining sufficient nicotine to sustain 

their addiction and to experience nicotine's mood-altering effects. What the cigarette 

manufacturers describe as producing cigarettes that satisfy consumer preferences is, in 

reality, producing cigarettes that provide the pharmacological effects of nicotine sought by 

consumers. The effect of maintaining a pharmacologically active dose of nicotine in 

cigarettes is to keep consumers smoking by sustaining their addiction. 

The evidence that the manufacturers "design" cigarettes to provide a 

pharmacologically active dose of nicotine is further proof that the manufacturers intend 

cigarettes to affect the structure and function of the body. Taken together, the evidence 

shows that the cigarette manufacturers: (1) "have in mind" the use of cigarettes for the 

particular purpose of delivering the pharmacological effects of nicotine, and (2) "design" 

their products to provide these effects. This evidence convincingly demonstrates that the 

pharmacological effects of cigarettes are "intended" by the manufacturers. 

D. The Statements, Research, and Actions of the Smokeless Tobacco 

Manufacturers Show that the Manufacturers Intend their Products to 

Affect the Structure and Function of the Body 

The administrative record also contains evidence of the statements, research, and 

actions of the smokeless tobacco manufacturers. Like the evidence of the statements, 

research, and actions of the cigarette manufacturers, this evidence establishes that the 

smokeless tobacco manufacturers intend to affect the structure and function of the body. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44643

First, the evidence in the record shows that the smokeless tobacco manufacturers 

know that nicotine is a phannacologically active drug and that consumers use smokeless 

tobacco to obtain the phannacological effects of nicotine. As a senior vice president for 

United States Tobacco Co. (UST) stated, "virtually all tobacco usage is based upon 

nicotine, 'the kick,' satisfaction." Researchers affiliated with Brown & Williamson 

acknowledge that "nicotine ... absorbed through ... the lining of the nose or mouth ... 

will quickly enter a direct route, in the blood, to the brain." 

Second, the evidence shows that the smokeless tobacco manufacturers manipulate 

the nicotine delivery of their products in a manner that promotes tolerance and addiction 

to nicotine. This manipulation is accomplished through the use of chemicals that alter the 

pH of the smokeless tobacco. Moist snuff brands that are marketed as "starter'' brands 

have a low pH and consequently deliver a low level of ''free" nicotine to the user, limiting 

the absorption of nicotine in the mouth. The low nicotine deliveries allow the new user to 

develop a tolerance to nicotine without experiencing adverse reactions such as nausea and 

vomiting. In contrast, moist snuff brands that are marketed to experienced users have a 

high pH and consequently deliver a high level of "free" nicotine to the user, increasing the 

amount of nicotine available for absorption~ The increased nicotine deliveries provide 

sufficient nicotine to sustain the user's addiction. 

Third, the evidence shows that smokeless tobacco use and addiction to nicotine _ 

has substantially increased among teenagers since the manufacturers began to manipulate 

nicotine deliveries. Before the introduction of starter brands with low levels of nicotine 

delivery, virtually no teenagers and young adults used smokeless tobacco. After the 

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44644 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

smokeless tobacco manufacturers began to market low-nicotine "starter'' brands in the 

1970's, however, use of smokeless tobacco by teenagers rose dramatically. Use of 

smokeless tobacco by adolescent males aged 18 to 19, for instance, increased almost 

1,500% between 1971 and 1991. Most of the regular teenage users of smokeless tobacco 

graduate to higher nicotine brands. An analysis by the Centers for Disease Control and 

Prevention found that the pattern of smokeless tobacco use by teenagers "support[s] the 

hypothesis that snuff users in earlier stages of tobacco use and nicotine addiction use 

brands with low levels of free nicotine and then 'graduate' to brands with high levels." 

This evidence of: (1) knowledge of nicotine pharmacology, (2) manipulation of 

nicotine deliveries, and (3) graduation to higher nicotine brands among young users is a 

sufficient basis to establish that the smokeless tobacco manufacturers intend to affect the 

structure and function of the body. 

In addition to this industry-wide evidence of intended use, the record contains 

numerous documents from the nation's largest smokeless tobacco manufacturer, UST. 

The UST documents in the record show that: 

• UST officials in the early 1970's recommended the development of products 

with ''three different ... strengths of nicotine[:] ... a. High nicotine, strong 

tobacco flavor ... b. Medium strength of nicotine ... c. Low nicotine, sweet 

product." In particular, UST officials recommended the development of a 

product that provided "mild" nicotine satisfaction targeted at "new users ... 

age group 15-35." 

• Shortly after these recommendations, UST began aggressively to market lownicotine products, targeted "for you guys just starting out." Marketing 

techniques included free sampling on college campuses and at sports events. 

Advertisements included instructions on use for new users. 

• Numerous UST documents and statements refer to an explicit "graduation 

process" in which users of smokeless tobacco are encouraged to start with lownicotine starter brands and then progress to higher nicotine brands. For 

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instance, a UST vice president has stated that Skoal Bandits, one of UST' s lownicotine brands, "is the introductory product, and we look towards establishing 

a nonnal graduation process." 

These UST documents confmn that smokeless tobacco manufacturers deliberately 

produce brands with a range of nicotine deliveries in order to allow users to progress (or 

"graduate") from low-delivery products to high-delivery products. They thus corroborate 

the Agency's fmding that smokeless tobacco is intended to affect the structure and 

function of the body. 

E. The "Intended Use" of a Product Is Not Determined Only on the Basis of 

Promotional Claims 

The principal legal argument of the tobacco industry is that the intended use of a 

product must be detennined exclusively on the basis of the promotional claims made by 

the manufacturer. Under the industry's legal theory, the Agency must disregard the 

voluminous internal tobacco industry documents showing that the manufacturers have in 

mind, and design their products to provide, the pharmacological effects of nicotine. The 

tobacco industry also urges the Agency to disregard the evidence of the foreseeable 

phannacological effects and uses of cigarettes and smokeless tobacco, as well as the 

evidence of the actual consumer use of these products for pharmacological purposes. 

The Agency rejects the industry's legal argument First, the industry's position is 

contrary to the plain language of the Act The Act does not say that only products 

"promoted" to affect the structure or function of the body are drugs or devices. Rather, 

the Act says that products "intended" to affect the structure or function of the body are 

drugs or devices. The plain meaning of "intend" is significant! y broader than the meaning 

of "promote." As summarized above, the plain meaning of "intend" includes "to have in 

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44646 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

mind" and ''to design" for a particular use. The evidence that is relevant to determining 

the uses that a manufacturer "has in mind" or "designs" includes not just the promotional 

claims of the manufacturer, but also the internal statements of the manufacturer, as well as 

the manufacturer's research and actions. Moreover, the ordinary meaning of "intend" also 

encompasses the reasonably foreseeable consequences of the manufacturer's actions, 

thereby making consideration of the foreseeable pharmacological effects and uses of a 

product relevant to its intended use. 

Second, the industry's position is contrary to FDA's regulations. These 

regulations provide that the term "intended use" refers to the "objective intent" of the 

manufacturer. Under these regulations, the Agency determines the intent of the 

manufacturer objectively by evaluating all of the relevant evidence in the record from the 

perspective of a reasonable fact-fmder. FDA's regulations expressly direct the Agency to 

consider the manufacturer's "knowledge" of the use of the product; the manufacturer's 

"expressions" and "oral or written statements"; and the "circumstances surrounding the 

distribution of the article." 21 CFR 201.128, 801.4. Thus, the regulations expressly 

provide that the Agency should consider a broad range of evidence in determining 

intended use, not merely the manufacturer's promotional claims. 

Third, the industry's position is contrary to judicial decisions interpreting the Act. 

These decisions have applied the Act's defmitions of drug and device to two different 

types of products. The first type of product is one that contains no known drug 

ingredients and has no known pharmacological effects or uses. In cases involving such 

products, the courts recognize that a manufacturer's promotional claims have a crucial 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44647

role in establishing intended use. Even a product like mineral water can be brought within 

FDA's jurisdiction by advertisements that make pharmacological claims. See Bradley v. 

United States, 264 F. 79 (5th Cir. 1920). 

The situation is fundamentally different, however, when the product contains a 

known drug ingredient like nicotine that has known pharmacological effects and uses. 

When a product is pharmacologically active, the courts have recognized that "a fact fmder 

should be free to pierce ... a manufacturer's misleading ... labels to fmd actual 

therapeutic intent on the basis of objective evidence." National Nutritional Foods Ass'n 

v. FDA, 504 F.2d 761, 789 (2d Cir. 1974). Thus, contrary to the industry's contention, 

the courts have recogniZed that in determining intended use, FDA may consider a wide 

range of evidence beyond the manufacturer's promotional claims, including evidence of 

the pharmacological effects of the product, e.g., United States v. Undetermined Quantities 

... "Pets Smellfree," 22 F.3d 235, 240 (10th Cir. 1994); the purposes for which 

consumers actually use the product, e.g., ASH, 655 F.2d at 239-240; the medical use of 

the product, e.g., United States v. An Article of Device ... Toftness Radiation Detector, 

731 F.2d 1253, 1257 (7th Cir. 1984); and how the product was formulated, e.g., 

American Health ProdUcts Co. v. Hayes, 574 F. Supp. 1498, 1508 (S.D.N.Y. 1983). 

Fourth, the industry's position is contrary to FDA's administrative precedent In a 

broad range of instances, FDA has asserted jurisdiction over products based on the likely 

pharmacological effects and uses of the product-not express promotional claims. 

Indeed, in many of these instances, the manufacturer's promotional claims were designed 

to disguise the actual intended use of the product. 

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44648 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

Fifth, the industry's position is contrary to the public health objectives of the Act. 

If promotional claims alone determined the intended use of a product, virtually any 

manufacturer of drugs or devices could avoid the Act's reach by simply refraining from 

making pharmacological claims for the product. For instance, under the industry's 

interpretation, a company could market a potent tranquilizer or amphetamine for its 

"pleasurable" effect and escape FDA regulation. To protect the public from the 

unregulated distribution of products with pharmacologically active ingredients, the Agency 

must be able to look beyond a manufacturer's promotional claims when determining 

whether to regulate such products. 

For these reasons, the Agency rejects the tobacco industry's legal theory that 

intended use is determined exclusively on the basis of promotional claims. The Agency 

also rejects the premise of the industry's position-namely, that their promotional claims 

demonstrate that cigarettes and smokeless tobacco are not intended to affect the structure 

and function of the body. To the contrary, as internal tobacco company documents 

indicate, promises of "satisfaction" in tobacco advertisements imply that cigarettes and 

smokeless tobacco will provide consumers with desired pharmacological effects of 

nicotine. These implied drug claims lend support to the Agency's fmding that cigarettes 

and smokeless tobacco are intended to affect the structure and function of the body. 

F. Response to Additional Comments 

This section responds to additional comments regarding the evidence of the 

intended use of cigarettes and smokeless tobacco and the Agency's use of this evidence. 

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G. Considered Cumulatively, the Evidence Overwhelmingly Demonstrates 

that Cigarettes and Smokeless Tobacco Are Intended to Affect the 

Structure and Function of the Body 

As summarized above, the evidence in the record provides several independent 

bases for the Agency's fmding that cigarettes and smokeless tobacco are "intended" to 

affect the structure and function of the body. Independently, each of these distinct 

categories of evidence is a strong and sufficient basis for the Agency's conclusion that the 

manufacturers of cigarettes and smokeless tobacco intend the pharmacological effects and 

uses of their products. Considered together, they are mutually corroborating. Both 

independently and taken as a whole, therefore, the evidence in the administrative record 

overwhelmingly establishes that cigarettes and smokeless tobacco are "intended to affect 

the structure or any function of the body" within the meaning of the Act. 

Ill. Cigarettes and Smokeless Tobacco Are Combination Products Consisting of 

"Drug" and "Device" Components 

The Agency's findings in sections I and II establish that the nicotine in cigarettes 

and smokeless tobacco is a "drug" under section 201(g)(l)(C) of the Act. These fmdings 

show that the nicotine in cigarettes and smokeless tobacco "affect[s] the structure or any 

function of the body" and that these effects are "intended." These fmdings thus 

demonstrate that the nicotine in cigarettes and smokeless tobacco meets the statutory 

defmition of a "drug." 

Cigarettes and smokeless tobacco are not simply packaged nicotine, however. 

They also include delivery devices that deliver nicotine to the body. Section 201(h)(3), 21 

U.S.C. 321(h)(3). In the case of cigarettes, the device components work together upon 

combustion outside the body to form a nicotine-containing aerosol, which then delivers 

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44650 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

nicotine to the body when inhaled by the smoker. In the case of smokeless tobacco, the 

device components function by presenting nicotine to the consumer in a fonn that is 

palatable and absorbable by the buccal mucosa. Unlike the drug nicotine, these device 

components achieve their primary intended purpose without chemical action in or on the 

body and without being metabolized. 

The presence of both drug and device components in cigarettes and smokeless 

tobacco make these products "combination products" under section 503(g) the Act, 21 

u.s.c. 353(g)(l). 

W. FDA's Assenion of Jurisdiction Over Cigarettes and Smokeless Tobacco at This 

Time Is Justified 

FDA has always exercised jurisdiction over tobacco products when there is 

sufficient evidence in the record to establish that these products are "intended" to treat or 

prevent disease or to affect the structure or function of the body. Over thirty years ago, 

for instance, the Agency asserted jurisdiction over a brand of cigarettes when the evidence 

established that the brand was intended to reduce body weight. United States v. 354 Bulk 

Cartons . .. Trim Reducing-Aid Cigarettes, 178 F. Supp. 847 (D.N.J. 1959). 

The Agency last considered whether to regulate cigarettes in the late 1970's, when 

the Agency rejected petitions by Action on Smoking and Health (ASH) urging the Agency 

to regulate cigarettes as drugs or devices. The Agency agreed with ASH that "objective 

evidence other than manufacturers' claims can be material to a determination of intended 

use" and that "evidence of consumer use can be one element of objective evidence to be 

weighed in determining if the intended purpose of a product subjects it to regulation under 

the Act." However, the Agency concluded that the evidence presented by ASH in the 

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petition was insufficient to establish that cigarettes and smokeless tobacco were in fact 

intended to affect the structure and function of the body. The court deferred to the 

Agency's determination not to regulate cigarettes as drugs but expressly left open the 

possibility that FDA might, at a later date, revisit its decision and determine that it did 

indeed have jurisdiction over cigarettes. ASH v. Harris, 655 F.2d 236 (D.C. Cir. 1980). 

The evidence regarding the intended use of cigarettes and smokeless tobacco has 

changed dramatically since ASH. First, a scientific consensus has emerged since 1980 that 

nicotine is addictive and has other significant pharmacological effects and that cigarettes 

and smokeless tobacco are used by consumers to obtain pharmacological effects. As 

summarized above, no major public health organization had determined that nicotine was 

an addictive drug before 1980. Between 1980 and 1994, however, every leading scientific 

organization with expertise in addiction concluded that nicotine is addictive. This new 

evidence thus shows that the pharmacological effects and uses of cigarettes and smokeless 

tobacco have become foreseeable. 

Second, scientific evidence accumulated since 1980 has shown that the vast 

majority of people who use cigarettes and smokeless tobacco use these products to satisfy 

addiction or to obtain other pharmacological effects. As summarized above, this new 

evidence now shows that 77% to 92% of smokers are addicted to nicotine and provides a 

basis for estimating that 75% of young regular smokeless tobacco users are addicted to 

nicotine. This new evidence establishes that consumers use cigarettes and smokeless 

tobacco predominantly for pharmacological purposes. 

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Third, FDA, congressional, and other investigations have recently uncovered a 

wealth of documents from a wide range of tobacco companies that show that the 

manufacturers have long known of the pharmacological effects and uses of nicotine and 

have designed their products to provide pharmacologically active doses of nicotine to 

consumers. Virtually none of this information was available to FDA in 1980. 

Information developed since 1980 also demonstrates that the Agency has a unique 

public health opportunity to reduce substantially the more than 400,000 deaths from 

tobacco use each year in the United States. This information shows that for most people 

tobacco use and nicotine addiction begin in childhood and adolescence, and that an 

increasing number of American children and adolescents are using cigarettes and 

smokeless tobacco. The data now suggest that if children and adolescents can be 

prevented from initiating tobacco use during their teenage years, they are unlikely to begin 

tobacco use later in life, thereby preventing the onset of tobacco-related disease and 

premature death. 

Before the importance of youth-centered interventions was identified, most of the 

regulatory approaches available under the Federal Food, Drug, and Cosmetic Act to 

address tobacco-related disease and death, such as removal of the products from the 

market, were not believed to be feasible solutions. It is now apparent, however, that 

FDA's authority to restrict the sale, distribution, and use of cigarettes and smokeless 

tobacco to people under the age of eighteen is an effective tool to reduce the adverse 

health consequences of tobacco use. Thus, asserting jurisdiction over cigarettes and 

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smokeless tobacco now presents an opportunity to use the Agency's resources effectively 

for substantial public health gains. 

The court in ASH specifically recognized that FDA was permitted to modify its 

position and that any new FDA position would be accorded deference by the courts. /d. 

at 242 n.lO. In light of the substantial new information, FDA has reviewed its earlier 

determination not to assert jurisdiction over tobacco products. The new evidence 

persuades the Agency to conclude that its previous position is no longer consistent with 

the relevant facts and should be changed. The evidence before the Agency is now 

sufficient to establish that cigarettes and smokeless tobacco are in fact intended to affect 

the structure and function of the body. 

V. Congress Has Not Precluded or Preempted FDA from Regulating Cigarettes and 

Smokeless Tobacco 

FDA disagrees with the comments of the tobacco industry that assert that 

Congress has precluded or preempted FDA from regulating cigarettes and smokeless 

tobacco. The plain language of the Act does not exclude cigarettes or smokeless tobacco 

from FDA jurisdiction. Tobacco products are expressly excluded from the jurisdiction of 

the Consumer Product Safety Commission under the Federal Hazardous Substances Act 

and from the jurisdiction of the Environmental Protection Agency under the Toxic 

Substances Control Act The absence of any similar exclusion in the Federal Food, Drug, 

and Cosmetic Act demonstrates that Congress has not chosen to exclude cigarettes and 

smokeless tobacco from FDA jurisdiction. 

The legislative history of the Act confirms that the Act should not be interpreted to 

preclude FDA jurisdiction over tobacco products. Congress has long known that FDA 

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44654 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

will assert jurisdiction over cigarettes when the evidence establishes that the cigarettes are 

intended to affect the structure or function of the body. For instance, FDA asserted 

jurisdiction more than 30 years ago over cigarettes that were intended to reduce weight. 

This demonstrates that Congress has not "ratified" or "acquiesced in" an interpretation of 

the Act that would preclude FDA from regulating tobacco products intended to affect the 

structure or function of the body. 

Moreover, even if Congress had acquiesced in such an interpretation of the Act, 

congressional acquiescence in a prior agency interpretation does not prevent an agency 

from changing its interpretation. Motor Vehicle Mfrs. Ass'n v. State Farm Mut. Auto Ins. 

Co., 463 U.S. 29, 45 (1983). In the case of cigarettes and smokeless tobacco, a change in 

interpretation would be justified by the new evidence in the record-evidence never 

previously before either the Agency or Congress. 

The Agency also disagrees that other federal statutes preempt FDA jurisdiction 

over cigarettes and smokeless tobacco. Both the Federal Cigarette Labeling and 

Advertising Act and the Comprehensive Smokeless Tobacco Health Education Act have 

provisions that expressly specify the limited extent to which these laws preempt FDA and 

other federal agencies from regulating cigarettes or smokeless tobacco. In the Federal 

Cigarette Labeling and Advertising Act, for instance, federal agencies are preempted only 

from requiring "statement[s] relating to smoking and health ... on any cigarette package." 

15 U.S.C. 1334(a). The narrow preemption provisions that Congress expressly included 

in these statutes do not apply to FDA's assertion of jurisdiction over cigarettes and 

smokeless tobacco. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44655

No other federal statutes contain provisions preempting FDA regulation of 

tobacco products. In the absence of an express preemption provision, one federal statute 

preempts another federal statute only where there is an irreconcilable conflict between the 

two laws. Connecticut Nat'l Bank v. Germain, 503 U.S. 249, 253 (1992). There is no 

irreconcilable conflict between FDA jurisdiction and other federal statutes. 

VI. FDA Employed Procedures That Provided an Opportunity for Full Public 

Participation and Exceeded All Legal Requirements 

FDA went to great lengths to involve the public in the process by which the 

Agency made its fmal jurisdictional determination. The Commissioner made public his 

intention to investigate the role of nicotine in tobacco products, testified twice before 

Congress on the Agency's findings, wrote to all the major cigarette and tobacco 

companies requesting information on the role of nicotine in their products, and held a 

public advisory committee meeting on the abuse potential of nicotine. Although the 

Agency is not required to undertake rulemaking to establish jurisdiction over new 

products, the Agency published in the Federal Register its initial jurisdictional fmdings and 

comprehensive legal analysis in a 325-page document, supported by over 600 footnotes, 

and sought public comment on those fmdings. The Agency placed over 210,000 pages of 

supporting documents in a public docket. FDA received over 700,000 comments on the 

Jurisdictional Analysis and the accompanying proposed rule. The Agency has responded 

to substantive comments in this Annex and in the preamble to the Final Rule. 

FDA disagrees with the comments of the tobacco industry that the record 

supporting the Jurisdictional Analysis or the procedures the Agency followed were 

inadequate. The procedures the Agency employed in reaching its fmal determination 

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44656 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

exceeded the requirements of the Administrative Procedures Act (AP A) and the Agency's 

own procedural requirements. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44657

INTRODUCTION 

On August 11, 1995, the Food and Drug Administration (hereinafter FDA or the 

Agency) announced the results of its extensive investigation and comprehensive legal 

analysis regarding the Agency's jurisdiction over cigarettes and smokeless tobacco in a 

document entitled, "Nicotine in Cigarettes and Smokeless Tobacco Products Is a Drug 

and These Products Are Nicotine Delivery Devices Under the Federal Food, Drug, and 

Cosmetic Act" (hereinafter referred to as the "Jurisdictional Analysis"). 60 FR 41453-

41787 (Aug. 11, 1995). The Agency reported that its investigation and analysis supported 

a finding at that time that nicotine in cigarettes and smokeless tobacco is a drug and that 

these products are drug delivery devices within the meaning oflhe Federal Food, Drug, 

and Cosmetic Act (hereinafter the Act). Because of the unique importance of the 

jurisdictional issue, the Agency invited comment on this fmding. 

The public comment period closed on January 2, 1996. 60 FR 53620 (Oct. 16, 

1995). On March 20, 1996, the Agency published in the Federal Register notice of an 

additional 30 day comment period, until April 19, 1996, limited to specific documents the 

Agency added to the docket in support of the Agency's analysis of jurisdiction. 61 FR 

11419 (Mar. 20, 1996). The Agency received over 700,000 colnments on its 

Jurisdictional Analysis and its Proposed Rule restricting the sale and distribution of 

cigarettes and smokeless tobacco to protect children and adolescents. The Agency has 

carefully considered these comments. 

This fmal jurisdictional detennination responds to the public comments and reports 

the Agency's conclusion that the nicotine in cigarettes and smokeless tobacco is a drug 

and that cigarettes and smokeless tobacco are drug delivery devices whose purpose is to 

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44658 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

deliver nicotine to the body in a manner in which it can be readily absorbed. These 

products, therefore, are subject to FDA regulation under the Act. 

The legal question of whether cigarettes and smokeless tobacco are drugs and 

devices subject to FDA regulation is one that "FDA has jurisdiction to decide with 

administrative finality." Weinberger v. Bentex Pharmaceuticals, Inc., 412 U.S. 645, 653 

(1973). The Act defmes a "drug" as (1) an article "intended for use in the diagnosis, cure, 

mitigation, treatment, or prevention of disease in man or other animals," or (2) an article 

(other than food) "intended to affect the structure or any function of the body of man or 

other animals." Section 201(g)(l)(B) and (C), 21 U.S.C. 321(g)(l)(B) and (C) (emphasis 

added). The Act's device defmition parallels the drug definition and provides that an 

instrument, apparatus, or other similar article is a "device" if it is ( 1) "intended for use in 

the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other 

animals," or (2) "intended to affect the structure or any function of the body of man or 

other animnls;" Section 20l(h)(2) and (3), 21 U.S.C. 321(h)(2) and (3) (emphasis 

added). These definitions are intended to be broad in scope and to encompass products 

that are not within the ordinary medical defmitions of drugs and devices. See United 

States v. An Article of Drug . .. Bacto-Unidisk, 394 U.S. 784, 793 (1969) ("we think it 

plain that Congress intended to defme 'drug' far more broadly than does the medical 

profession"). 

In applying these legal standards to cigarettes and smokeless tobacco, the Agency 

has focused on the second prong of the definition of drug and device: whether cigarettes 

and smokeless tobacco are "intended to affect the structure or any function of the body." 

Historically, the Agency has regulated tobacco products whenever the evidence before the 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44659

Agency was sufficient to establish that the products were intended to affect the structure 

or function of the body. FDA last considered whether cigarettes were drugs or devices in 

the late 1970's, determining that the limited evidence then before the Agency was 

insufficient to demonstrate that these products were intended to affect the structure or 

function of the body. See Action on Smoking and Health v. Ha"is, 655 F.2d 236 (D.C. 

Cir. 1980). Since that time, substantial new evidence has become available to FDA This 

evidence includes the emergence of a scientific consensus that cigarettes and smokeless 

tobacco cause addiction to nicotine and the disclosure of thousands of pages of internal 

tobacco company documents detailing that the manufacturers intend to affect the structure 

and function of the human body. 

The determination whether a product is subject to FDA jurisdiction often requires 

the Agency to make difficult factual judgments, including judgments regarding the 

intended use of the product. The Agency must have enough evidence to show that these 

factual judgments are rational and not "arbitrary, capricious, an abuse of discretion, or 

otherwise not in accordance with law." 5 U.S.C. 706(2)(A); see National Nutritional 

Foods Ass'n v. Weinberger, 512 F.2d 688, 700-701 (2d Cir. 1975), cert. denied, 423 U.S. 

827 (1975). The Agency must provide some evidentiary suppoit for its factual judgments, 

and there must be a rational connection between these judgments and the conclusions 

reached. Motor Vehicle Mfrs. Ass'n of the United States, Inc. v. State Farm Mur. Auto. 

Ins. Co., 463 U.S. 29, 42-43 (1983). The Agency should also have considered all the 

relevant data and the relevant aspects of the issue. /d.; Citizens to Preserve Overton Park, 

Inc. v. Volpe, 401 U.S. 402, 416 (1971). An agency's factual judgments made in the 

context of an informal agency action ordinarily need only be supponed by a record that 

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44660 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

shows a "rational basis" for the agency's decision, Natural Resources Defense Council, 

Inc. v. EPA, 16 F.3d 1395, 1401 (4th Cir. 1993), or by a record consisting of ''some 

evidence" in support of the agency's decision. Aman v. FAA, 856 F.2d 946, 950 n.3 (7th 

Cir. 1988) (while an agency determination need only have "some evidentiary basis to avoid 

being held 'arbitrary and capricious,' [t]he difference between 'some' and 'substantial' 

probably cannot be precisely stated except in the context of particular cases .... "). 

Several courts, however, have held that an agency's factual judgments must always be 

supported by "substantial evidence,'' even though that standard is intended to be applied 

only to formal "on the record" agency actions, see 5 U.S.C. 706(2)(E).1 

In this case, the Agenct s evidentiary record exceeds these standards. That is, 

FDA has concluded that the evidence now before the Agency supports a finding of 

jurisdiction over these products. In assessing the new evidence, FDA has used a two-step 

approach, evaluating first whether the nicotine in these products "affects the structure or 

1 See, e.g., Ass'n of Data Processing Service Organizations, Inc. v. Board of Governors, 745 F.2d 677, 

683-684 (D.C. Cir. 1984) (Scalia, J) ("When the arbitrary or capricious standard is performing that 

function of assuring factual suppon, there is no substantive difference between what it requires and what 

would be required by the substantial evidence test. since it is impossible to conceive of a 'nonarbitrary' 

factual judgment supponed only by evidence that is not substantial in the APA sense .... "). Contra 

Corrosion Proof Fillings v. EPA, 947 F.2d 1201, 1213-1214 and n.17 (5th Cir. 1991) (declining to find 

that the substantial evidence standard and the arbitrary and capricious standard .. are in fact one and the 

same"); Am. Paper /nst. ''·Am. Elec. Power Serv. Corp., 461 U.S. 402,412 n.7 (1983) (in the absence of 

a specific command in the statute to employ a particular standard of review, the Coun of Appeals should 

have applied the more lenient arbitrary and capricious standard in evaluating the factual basis supporting 

an agency's informal rulemaking}. 

The difference in the case law, however, is of no consequence here because FDA's evidentiary record 

exceeds the "substantial evidence" standard-the more stringent of the two standards. Substantial 

evidence is •·such relevant evidence as a reasonable mind might accept as adequate to suppon a 

conclusion," Consolo v. Federal Maritime Commission, 383 U.S. 607,619-620 (1966) (quoting 

Consolidated Edison Co. ''· NU?.B, 305 U.S. 197, 229 (1938)), even if two inconsistent conclusions might 

be inferred from the san1e evidence. See Consolo, 383 U.S. at620; NU?.B v. Nevada Consolidated 

Copper Corp., 316 U.S. 105. 106 (1942). Under the substantial evidence standard, an agency's factual 

determinations are conclusive even if supponed by "something less than the weight of the evidence .... " 

Consolo, 383 U.S. at 620 (emphasis added). 

4 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44661

any function of the body" and second whether these effects are "intended." FDA has 

determined that the evidence overwhelmingly demonstrates that (1) nicotine in cigarettes 

and smokeless tobacco has significant effects on the structure and function of the body 

and (2) these effects are intended by the manufacturers of these products. 

The Agency's determination that nicotine in cigarettes and smokeless tobacco 

~·affect[s] the structure or any function of the body" is based on three central findings: 

1. Nicotine in cigarettes and smokeless tobacco causes and 

sustains addiction. 

2. Nicotine in cigarettes and smokeless tobacco causes other 

psychoactive (mood-altering) effects, including 

tranquilization and stimulation. 

3. Nicotine in cigarettes and smokeless tobacco controls 

weight. 

These findings demonstrate that nicotine in cigarettes and smokeless tobacco has 

the same pharmacological effects as other drugs that FDA has traditionally regulated, 

including tranquilizers, stimulants, appetite suppressants, and products used in the 

maintenance of addiction such as methadone. Thus, the effects of nicotine in cigarettes 

and smokeless tobacco on the structure and function of the body are within FDA's 

jurisdiction. 

FDA's determination that the manufacturers of cigarettes and smokeless tobacco 

"intend" the effects of nicotine on the structure and function of the body is based on five 

central findings: 

1. The addictive and other pharmacological effects of nicotine 

are so widely known and accepted that it is foreseeable to a 

reasonable manufacturer that cigarettes and smokeless 

tobacco will cause addiction to nicotine and other 

significant pharmacological effects and will be used by 

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44662 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

consumers for phannacological pwposes, including 

sustaining their addiction to nicotine. 

2. Consumers use cigarettes and smokeless tobacco 

predominantly for phannacological purposes, including 

sustaining their addiction to nicotine, mood alteration, and 

weight loss. 

3. Manufacturers of cigarettes and smokeless tobacco know 

that nicotine in their products causes phannacological 

effects in consumers, including addiction to nicotine and 

mood alteration, and that consumers use their products 

primarily to obtain the phannacological effects of nicotine. 

4. Manufacturers of cigarettes and smokeless tobacco design 

their products to provide consumers with a 

pharmacologically active dose of nicotine. 

5. An inevitable consequence of the design of cigarettes and 

smokeless tobacco to provide phannacologically active 

doses of nicotine is to keep consumers using cigarettes and 

smokeless tobacco by sustaining their addiction to nicotine. 

Each of these findings provides an independent basis for establishing that the 

manufacturers of cigarettes and smokeless tobacco "intend" to affect the structure and 

function of the body. Taken together, the cumulative weight of the evidence convincingly 

supports the determination that the effects of nicotine on the structure and function of the 

body are "intended" by the manufacturers. 

FDA's assertion of jurisdiction over cigarettes and smokeless tobacco is consistent 

with the Agency's assertion of jurisdiction over other similar products. FDA regulates a 

diverse range of products under the Act. These products-foods, drugs, devices, 

cosmetics, and radiation-emitting electronic products-all ''affect the health and wellbeing of the public." United States v. Park, 421 U.S. 658,672 (1975). The common 

feature that distinguishes these products is their intimate and potentially harmful contact 

6 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44663

with the human body. See id. at 668. FDA-regulated products include those that are 

intended to be ingested, inhaled, applied to the skin, implanted, or otherwise used in close 

contact with the body. Cigarettes, which deliver a pharmacologically active dose of 

nicotine to the body through inhalation, and smokeless tobacco, which delivers a 

pharmacologically active dose of nicotine through buccal absorption, share this 

distinguishing feature and thus are properly subject to FDA jurisdiction. 

The detenninations that ( 1) the nicotine in cigarettes and smokeless tobacco 

"affects the structure or any function of the body" and (2) these effects are "intended" by 

the manufacturers satisfy the legal requirements under the Act for FDA jurisdiction. FDA 

has also detennined that cigarettes and smokeless tobacco contain both a "drug" and a 

"device" and are thus combination products within the meaning of the Act. Accordingly, 

the Agency has concluded that the nicotine in cigarettes and smokeless tobacco is a drug 

and that cigarettes and smokeless tobacco are drug delivery devices under the Federal 

Food, Drug, and Cosmetic Act. 

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44664 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

I. CIGARETTES AND SMOKELESS TOBACCO "AFFECT THE 

STRUCTURE OR ANY FUNCTION OF THE BODY" WITHIN THE 

MEANING OF THE ACT 

In the Jurisdictional Analysis, FDA found, based on the evidence available to it at 

the time, that nicotine in cigarettes and smokeless tobacco is "highly addictive, causes 

other psychoactive effects, such as relaxation and stimulation, and affects weight 

regulation." See Jurisdictional Analysis, 60 FR 41464 (Aug. 11, 1995). The Agency 

found that the nicotine in these products "has pharmacological effects on both the 

structure and function of the central nervous system, particularly the brain," and that 

"[a ]ddiction is a direct result of nicotine's effects on the structure and function of the 

body." /d. at 41470. Based on these fmdings of pharmacological effects, the Agency 

found that cigarettes and smokeless tobacco "affect the structure or any function of the 

body." /d. (emphasis added). 

As described more fully below, the Agency received comments that agreed and 

disagreed with the Agency's position.2 After considering the evidence in the 

I. 

administrative record,3 including the public comments, the Agency finds that cigarettes and 

2 The Agency received a consolidated comment of the cigarette industry (Brown & Williamson Tobacco 

Corp., Liggett Group Inc., Lorillard Tobacco Co., Philip Morris Inc., RJ. Reynolds Tobacco Co., Tobacco 

Institute Inc.) (Jan. 2, 1996) (hereinafter Joint Comments of the Cigarette Manufacturers). See AR(Vol. 

535 Ref. 96). The Agency also received a consolidated comment of the smokeless tobacco industry 

(Smokeless Tobacco Council. Inc., Brown & Williamson Tobacco Corp., Con wood Co., L.P., National 

Tobacco Co., L.P., the Pinkerton Tobacco Co., RC. Owen Co., Swisher International, Inc., United States 

Tobacco Co.) (Jan. 2, 1996) (hereinafter Joint Comments of the Smokeless Tobacco Manufacturers). See 

AR (Vol. 526 Ref. 95). 

3 In the footnotes of this doqunent, cites tQ the 1ldministrative record (AR) specify both the number of the 

reference and the volume of the AR in which d:.e reference is found The reference may contain the full 

document or a partial document Where the reference contains a partial document, the full document may 

be found elsewhere in the AR In a small number of cases, a reference will occupy several volumes of the 

AR, for example, the Joint Comments of the ~igareue Manufacturers. In these cases, tbe cite will specify 

the volume of the AR in which the reference begins. 

8 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44665

I. A 

smokeless tobacco do indeed "affect the structure or any function of the body" within the 

meaning of sections 201(gXl)(C) and 201(h)(3) of the Act, 21 U.S.C. 321(g)(l)(C), 

321(h)(3). 

To interpret the Federal Food, Drug, and Cosmetic Act in a manner that excludes 

the effects of these products from the scope of the structure-function prong of the drug 

and device definitions would be inconsistent with the plain meaning of the Act, its 

legislative history, case law interpreting the structure-function prong, and the Agency's 

past applications of that provision. The Agency's conclusions are summarized in section 

I.A., followed by a detailed discussion of the comments and the Agency's respon.ses to 

them in section LB. 

A. THE PHARMACOWGICAL EFFECTS OF THE NICOTINE IN 

CIGARETTES AND SMOKELESS TOBACCO ON THE BODY 

ARE SIGNIFICANT 

Cigarettes and smokeless tobacco contain nicotine, an addictive and 

pharmacologically active drug. See section II.A, below. Nicotine is the active ingredient 

in several products regulated as drugs by the Agency, including nicotine transdermal 

patches, nicotine chewing gums, nicotine nasal spray, and Favor, a hollow paper tube with 

nicotine impregnated in the mouthpiece. See Jurisdictional Analysis, 60 FR 41482, 41549-

41550. The effects of the nicotine in cigarettes and smokeless tobacco greatly exceed 

those exerted by the nicotine-containing products already regulated by the Agency.4 

Nicotine in cigarettes and smokeless tobacco produces significant pharmacological 

effects on the human body. First, nicotine causes and sustains addiction. The processes 

4 Nicotine-use cessation products are discussed in section II.A.5., below. 

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44666 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

LA. 

that lead to addiction to nicotine in cigarettes and smokeless tobacco are similar to those 

that lead to addiction to products such as morphine and opium. See section II.A.2., 

below. Like other addictive substances, nicotine in cigarettes and smo~less tobacco 

achieves its addictive effects by exerting psychoactive, or mood-altering, effects on the 

brain and by producing chemical reactions in the brain that motivate repeated, compulsive 

use of the substance. See section II.A3., below. These pharmacological effects create 

dependence in the user. /d. 

In addition to creating and sustaining addiction, cigarettes and smokeless tobacco 

produce other significant pharmacological effects. For example, under some 

circumstances, nicotine in cigarettes and smokeless tobacco has a sedating or tranquilizing 

effect on mood and brain activity. See section II.A.4., below. Under other circumstances, 

nicotine in cigarettes and smokeless tobacco has a stimulant or arousal-increasing effect on 

the body. /d. 

Nicotine in cigarettes and smokeless tobacco also controls body weight. /d. 

Clinical and animal studies indicate that nicotine administration causes weight loss and that 

cessation of nicotine administration results in weight gain. /d. 

These effects on the structure and function of the body are significant and 

quintessentially drug-like. They produce immediate pharmacological changes in the 

function of the brain (depressing or stimulating arousal); they change the physical 

structure of the body (increased growth of nicotine receptors in the brain, weight loss); 

and they cause drug dependence (addiction). /d. 

10 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44667

LA 

The tobacco industry comments argue that "remote" or "insignificant" 

pharmacological effects are not subject to FDA jurisdiction. Although "remote physical 

effect[s] upon the body" may not be covered by the structure-function provision, see E.R. 

Squibb & Sons, Inc. v. Bowen, 870 F.2d 678,682 (D.C. Cir. 1989), the pharmacological 

effects of cigarettes and smokeless tobacco are not "remote" or insignificant. Indeed, they 

are powerful and immediate pharmacological effects that are not qualitatively or 

quantitatively different from the effects of other drugs subject to FDA jurisdiction. 

In fact, the effects of cigarettes and smokeless tobacco-addiction, sedation, 

stimulation, and weight loss-are precisely the types of effects the Agency traditionally 

regulates. It is well established that the Agency has the authority to regulate, and has 

regulated, products that sedate, tranquilize, or reduce anxiety (e.g., Valium and other 

benzodiazepines); products that stimulate or restore mental alertness (e.g., caffeinecontaining pills such as NoDoz, see Stimulant Drug Products for Over-the-Counter 

Human Use, Final Monograph, 53 FR 6100 (February 29, 1988); 21 CFR Part 340);5 

products that cause weight loss (see Weight Control Products for Over-the-Counter 

Human Use, Certain Active Ingredients, 56 FR 37792 (August 8, 1991); 21 CFR 

310.545(a)(20); see also United States v. 354 Bulk Cartons ... Trim Reducing-Aid 

Cigarettes, 178 F. Supp. 847, 851 (D.N.J. 1959)); and products that are used for 

maintenance treatment of addiction (e.g., methadone and other "narcotic drugs [used] in 

the medical treatment of narcotic addiction," 21 CFR 291.501). The approved uses of 

these products include uses to "affect the structure or any function of the body" under 

5 A more detailed discussion of the Agency's regulation of caffeine and caffeine-containing products is 

contained in section LB., below. 

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44668 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

LA 

section 201(g)(1XC) of the Act Thus, cigarettes and smokeless tobacco have the same 

effects as products that are undeniably within FDA's jurisdiction. 

Indeed, internal tobacco company documents reveal that tobacco industry 

scientists understand that the nicotine in tobacco produces pharmacological effects no 

different from those produced by approved drugs. These industry scientists viewed 

prescription drugs as competing products.6 Over three decades ago, the British American 

Tobacco Company (BA TCO), the parent of Brown & Williamson Tobacco Corporation, 

commissioned a study to compare the effects of nicotine with those of tranquilizers, 

"which might supersede tobacco habits in the near future." 7 The study concludeq that 

nicotine was "more beneficial or less noxious-than the new tranquilizers" because it 

reduced stress and regulated weight. 8 

Philip Morris and R.I. Reynolds Tobacco Company (RJR) also have repeatedly 

compared the effects of nicotine from tobacco to the effects of drugs regulated by FDA. 

For example, Philip Morris researchers and officials have concluded that smokers use 

cigarettes as "a narcotic, tranquilizer, or sedative"9 and that "[nicotine] is a physiologically 

active, nitrogen containing substance. Similar organic chemicals include ... quinine, 

6 These documents, and the conclusions the Agency has drawn from them, are described in detail in 

sections IT. C. and n.D., below. 

7 Haselbach CH, Libert 0, Final Repon on Project HIPPO II (Geneva: Battelle Memorial Institute, 

International Division, Mar. 1963), at 1. See AR (VoL 64 Ref. 321). 

8 /d. at 2. 

9 Udow A. Why People Start to Smoke (Jun. 2, 1976), in 141 Cong. Rec. H7664 (daily ed. Jul 25, 1995). 

See AR (VoL 14 Ref. 175a). 

12 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44669

I. A 

cocaine, atropine and nwrphine. While each of these substances can be used to affect 

human physiology, nicotine has a particularly broad range of influence. "

10 

Similarly, RJR scientists have reported that smokers who inhale lightly appear to 

use tobacco to achieve "mental activation and perfonnance enhancement" whereas those 

who inhale more deeply show brain effects that "may reflect the anxiolytic properties of 

benzodiazepines,"11 prescription drugs used to alleviate anxiety. Another RJR researcher 

has stated: 

[l]n different situations and at different dose levels, nicotine appears to act as a 

stimulant, depressant, tranquilizer, psychic energizer, appetite reducer, antifatigue agent, or energizer . ... Therefore, in addition to competing with.products 

of the tobacco industry, our products may, in a sense, compete with a variety of 

other products with certain types of drug action.12 

Thus, the industry's own documents acknowledge that the pharmacological effects 

of their products are the same as the effects the Agency has considered to be structurefunction effects within the meaning of section 20l(g)(lXC). Notwithstanding the views of 

their own scientists, the tobacco industry comments publicly assert that cigarettes and 

smokeless tobacco do not affect the structure or any function of the body within the 

meaning of the Act because their effects are too "remote" or not therapeutic or beneficial. 

The ramifications of the tobacco industry's position are far-reaching. If the 

Agency were to determine that the pharmacological effects of cigarettes and smokeless 

10 Philip Morris Inc., Draft Report Regarding a Proposal for a "Safer" Cigarette, Code-named Table 

(emphasis added). See AR (Vol 531 Ref. 122). 

11 Pritchard WS, RJ. Reynolds Tobacco Co., Electroencephalographic effects of cigarette smoking, 

Psychopharmacology 1991;104:485, at488. See AR(Vol 3 Ref. 23-2). 

12 Teague CE, RJ. Reynolds Tobacco Co., Research Planning Memoraru:lum on the Nature of the Tobacco 

Business and the Crucial Role of Nicotine Therein (Apr. 14, 1972), at 1-2 (emphasis added). See AR 

(Vol. 531 Ref. 125). 

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44670 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

I. B. 

tobacco are not effects on the structure and function of the body, or are not significant 

effects, the Agency's authority to regulate other products with like phannacological 

effects-sedation, stimulation, weight loss, and satisfaction of addiction-would be called 

into question. Under the industry's characterization of the effects of their products, even 

if the pharmacological effects of sedation, stimulation, weight loss, or satisfaction of 

addiction were expressly promoted or otherwise intended, products producing the same 

effects could not be regulated under section 201(g)(l)(C) or 201(h)(3) because, by the 

industry's definition, these products would not "affect the structure or any function of the 

body." This view, if accepted, could undermine the Agency's ability to regulate Orugs and 

devices that are not used in the diagnosis or treatment of disease, but significantly affect 

the structure or any function of the body. Further, such an interpretation would be 

inconsistent with over 50 years of Agency practice since passage of the Act in 1938. 

In sum, cigarettes and smokeless tobacco do affect the structure and function of 

the body within the meaning of the Act. The pharmacological effects of nicotineContaining tobacco products are significant and the same as the effects of other products 

traditionally regulated by FDA Because these effects are "intended" within the meaning 

of the Act-the issue discussed in section II., be1ow~igarettes and smokeless tobacco 

fall within the jurisdiction of the Agency under the Act. 

B. RESPONSE TO COMMENTS 

1. As noted in section LA, above, tobacco industry comments and others 

argue that the effects of nicotine delivered from cigarettes and smokeless tobacco are too 

remote or insignificant to be subject to the Act. These comments minimize nicotine's 

14 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44671

LB. 

effects and argue that nicotine-containing tobacco products "stimulate the senses" and 

"calm[] feelings of stress," more like the effects of "hammocks [and] gardening tools" than 

those of products within FDA's jurisdiction.13 The industry comments urge the Agency to 

follow the holding of FTC v. Liggett & Myers Tobacco Co., 108 F. Supp. 573 (S.D.N.Y. 

1952), aff'd, 203 F.2d 955 (1953), where the court concluded that the "soothing" effects 

of cigarettes do not affect the structure and function of the body. 

FDA disagrees with these comments. As described earlier in this section, 

nicotine's effects on the structure and function of the body are comparable both in quality 

and quantity to those of tranquilizers, stimulants, weight control products, and products 

for long-term maintenance of addiction. These effects have long been recognized as 

effects on the structure or function of the body that are within FDA's jurisdiction. In 

addition, the Act's legislative history and case law interpreting the Act provide ample 

support for the conclusion that nicotine's effects are significant and within the scope of the 

Act. While "remote physical effect[s] on the body" may not be sufficient to invoke the 

Act's jurisdiction, see Squibb, 870 F.2d at 682, nicotine produces significant 

pharmacological and physiological effects on the structure and function of the body, and 

these effects clearly fall within sections 201(g)(1XC) and 201(hX3). 

The courts have held that effects much less significant than those of nicotine are 

effects on the structure or function of the body and are within FDA's jurisdiction. 

13 Joint Comments of the Smokeless Tobacco Manufacturers, Comment (Jan. 2, 1996), at 241. See AR 

(Vol. 526 Ref. 95). 

Joint Comments of the Cigarette Manufacturers, Comment (Jan. 2, 1996), vol.II, at 65-66. See AR (Vol. 

535 Ref. 96). 

15 
44672 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

LB. 

Products whose effects have been found sufficient to fall within the scope of sections 

201(g)(1)(c) and 201(h)(3) include those for temporary smoothing of wrinkles, United 

States v .... "line Away, Temporary Wrinkle Smoother," 284 F. Supp. 107 (D. Del. 

1968), aff'd, 415 F.2d 369 (3d Cir. 1969); United States v .... "Sudden Change," 409 

F.2d 734 (2d Cir. 1969); and products that deliver low levels of oxygen for recreational 

use to enhance athletic performance, United States v .... "Sports Oxygen," Civ. No. 89-

2085 (D.N.J. Oct. 27, 1992), reprinted in Federal Food, Drug, and Cosmetic Act: A 

Judicial Record, 1991-92, 110-119. These effects are plainly less significant than the 

potent psychoactive, addictive, and weight-regulating effects of nicotine. 

Weight loss is one of the effects of cigarettes and smokeless tobacco. See section 

II.A4., below. Courts have held that this type of effect alone is sufficient to make 

cigarettes a drug when the product is "intended to affect the structure and functions of the 

human body by ... achieving a reduction in the body's weight." United States v. 354 

Bulk Cartons .. . "Trim Reducing-Aid Cigarettes," 178 F. Supp. 847, 851 (D.N.J. 1959). 

Similarly, the legislative history of section 201(g)(l)(C) also demonstrates that weight 

loss alone is an effect on the structure and function of the body within the meanfng of the 

Act. Indeed, one of the principal reasons cited by Congress for broadening the definition 

of "drug" to include products that affect the structure or function of_the body was to bring 

weight control products within FDA's jurisdiction. See 78 Cong. Rec. 8960, 73d Cong., 

2d Sess. (May 16, 1934) (statement of Senator Copeland), reprinted in A Legislative 

History of the Federal Food, Drug, and Cosmetic Act and Its Amendments (hereinafter 

Legislative History), vol. 2, at 831. 

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LB. 

The Agency disagrees that the effects of nicotine in cigarettes and smokeless 

tobacco are comparable to those produced by hammocks, gardening tools, or other similar 

articles. First, such articles do not introduce chemical ingredients into the body. By 

contrast, cigarettes and smokeless tobacco deliver a potent chemical ingredient, nicotine, 

whose significant pharmacological effects on the human body are widely recognized in the 

scientific community. Second, the powerful psychoactive effects produced by nicotine in 

cigarettes and smokeless tobacco are comparable to those produced by tranquilizers, 

stimulants, weight management agents, and drugs used for long-term maintenance of 

addiction, all of which are indisputably within FDA's jurisdiction. Third, as described in 

section I.A., above, tobacco industry officials have acknowledged that nicotine's effects 

are comparable to those of prescription drug products. 

FDA also disagrees that the 1952 decision, Liggett & Myers, 108 F. Supp. 573, 

represents a controlling determination that cigarettes do not affect the structure or 

function of the body within the Act's meaning. Much less was known about the addictive, 

psychoactive, and weight-regulating effects of nicotine when the court decided Uggett in 

1952 than is known today. The kinds of effects that were alleged in li.ggett (lack of 

irritation to the respiratory system and "soothing" effects) are far different from the 

addicting and other psychoactive and weight-regulating effects now known to be caused 

by nicotine in cigarettes. See sections II.A.l. and IV., below. Moreover, li.ggett was 

decided before FDA regulated nicotine. The Agency now regulates nicotine-containing 

products such as nicotine transdermal patches and nicotine nasal spray intended to treat 

nicotine addiction. If nicotine were not a powerful pharmacological agent with addictive 

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44674 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

I. B. 

properties, nicotine cessation products would be unnecessary. Further, the liggett 

opinion does not suggest that the definition of "drug" would preclude treating cigarettes 

as drugs if new evidence concerning cigarettes' effects became known. See section IV., 

below. 

Accordingly, FDA concludes that nicotine's significant pharmacological effects are 

effects on the structure or function of the body within the Act's meaning. 

2. Tobacco industry comments contend that Congress intended to limit the 

drugs and devices covered by sections 201(g)(l)(C) and 20l(h)(3) (products "intended to 

affect the structure or any function of the body") to products with ''therapeutic" Qr 

"medical" uses. One industry comment further elaborates that the structure-function 

provision was added to the Federal Food, Drug, and Cosmetic Act in 1938 only as a result 

of concern that certain ''therapeutic" products used for weight management purposes had 

escaped regulation under the 1906 Pure Food and Drug Act because obesity and leanness 

were not considered to be diseases. Consequently, this comment argues, the structurefunction provision encompasses only products intended for "therapeutic" or "medical" use 

in "disease-treatment" eonditions.14 

This industry comment also makes a related argument that effects on the structure 

or function of the body must be "beneficial," or "drug-like," and not "destructive or 

toxic." According to this c6mment, "FDA views 'addictiveness' as an undesirable 

characteristic, not as a beneficial effect, and therefore more as a form of toxicity."15 This 

14 Joint Comments of the Smokeless Tobacco Manufacturers, Comment (Jan. 2, 1996), at 145-146. See 

AR (Vol. 526 Ref. 95). 

IS /d. at 151. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44675

LB. 

comment argues that the effects of cigarettes and smokeless tobacco are therefore outside 

the scope of the Act. 

Conversely, one public interest group comment argues that construing sections 

20l(g)(l)(C) and 201(h)(3) as requiring a ''therapeutic" effect would make these sections 

redundant of sections 20l(g)(l)(B) and 20l(h)(2), which defme drugs and devices as 

products "intended for use in the diagnosis, cure, mitigation, treatment, or prevention of 

disease." According to this comment, such an interpretation would violate basic rules of 

statutory construction. 

The Agency disagrees with the tobacco industry's narrow reading of the-~tructurefunction provision. Neither the language of the statute, its legislative history, nor the case 

law supports the position that drugs and devices must have "therapeutic," "medical," or 

"beneficial" effects or purposes in order to "affect the structure or any function of the 

body." 

The plain language of the statute provides no support for the tobacco industry's 

position. The terms, "therapeutic," "medical," and "beneficial," or words of similar 

import, do not appear anywhere in section 20l(gXl)(C) or 20l(hX3). FDA agrees with 

the comments that assert that construing the "structure or any function" language to 

require a therapeutic or medical effect would make these provisions essentially identical in 

scope and meaning to sections 20l(g)(l)(B) and 20l(h)(2). To do so would violate the 

well-accepted principle that "a legislature is presumed to have used no superfluous 

words." Bailey v. United States, 116 S.Ct. 501, 507 (1995). 

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44676 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

I. B. 

The legislative history is also inconsistent with the tobacco industry's position. 

Congress added sections 201(g)(l)(C) and 20l(h)(3) to broaden the coverage of the Act 

to include a "comprehensive class of preparations which were intended to affect the 

structure or function of the body." "line Away," 284 F. Supp. at 110 (citations omitted). 

The Act's legislative history makes clear that Congress intended to expand the Act's 

jurisdiction, rather than merely "close a loop-hole" in subsection 201(gX1XB). See, e.g., 

H.R. Rep. No. 2139, 75th Cong., 3d Sess. 2 (1938), reprinted in 6 Legislative History 

301 ("Drugs intended ... for remedying underweight or overweight or for otherwise 

affecting bodily structure or function are subject to regulation"}( emphasis added); see 

also American Health Products Co. v. Hayes, 574 F. Supp. 1498, 1506 (S.D.N.Y. 1983) 

(The structure-function provision was enacted to "reach those products ... which evaded 

regulation altogether because they were neither foods nor therapeutic agents') (emphasis 

added). 

The inclusive nature of the structure-function provision was raised several times 

during the hearings that led to enactment of the 1938 Act. See Hearings on S. 1944, 

Senate Subcomm. of the Comm. on Commerce, 73d Cong., 2d Sess. 15 (1933), reprinted 

in 1 Legislative History 107 ("The definition of the term 'drug' has been widened"); 

Hearings on S. 2800, Senate Comm. on Commerce, 73d Cong., 2d Sess. 516 (1934), 

reprinted in 2 Legislative History 519 ("This definition of 'drugs' is all-inclusive"); 

Hearings on S. 5, Senate Comm. on Commerce, 74th Cong., 1st Sess. 352 (1935), 

reprinted in 3 Legislative History 546 ("There is a universal recognition that the definition 

of the term 'drug' in the third subdivision is inclusive"). Congress consistently rejected 

20 
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LB. 

suggestions to limit the drug definition to products with medical or medicinal purposes. 

See,-e.g., Hearings on S. 2800, Senate Comm. on Commerce, 73d Cong., 2d Sess. 515-

516 (1934), reprinted in 2 Legislative History 518-519. 

Judicial decisions and Agency practice also conflict with the narrow interpretation 

urged by the manufacturers. As the Supreme Court has stated: 

Viewing the structure, the legislative history, and the remedial 

nature of the Act, ... it [is] plain that Congress intended to defme 

"drug" far more broadly than does the medical profession .... 

. . . the word "drug" is a term of art for the purposes of the Act, 

encompassing far more than the strict medical definition of that 

word. If Congress had intended to limit the statutory definition to 

the medical one, it could have so stated explicitly. 

United States v. An Article of Drug ... Bacto-Unidisk, 394 U.S. 784,793 (1969). 

The structure-function provision has been applied since 1938 to a wide assortment 

of products with a range of uses and effects, many of which cannot be considered 

"therapeutic." For example, products that have been found to be within this provision 

include those with cosmetic, recreational, economic, or other nontherapeutic purposes. 

These products include tanning booths; sunscreens; breast implants; injectable collagen; 

birth control pills; products purporting to remove wrinkles temporarily, e.g., "line 

Away," "Sudden Change",· products intended to eliminate pet odors, e.g., United States 

v. Undetermined Quantities . .. "Pets Smellfree," 22 F.3d 235, 240 (lOth Cir. 1994); 

products intended to grow hair, e.g., United States v. Kasz Enterprises, Inc., 855 F. Supp. 

534, 540 (D.R.I.), modified on other grounds, 862 F. Supp. 717 (D.R.I. 1994); products 

intended as aphrodisiacs, see 54 FR 28780 (July 7, 1989), 21 CFR 310.528; products 

intended to enhance athletic performance by delivering a low, non-therapeutic level of 

21 
44678 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

LB. 

oxygen, e.g., "Sports Oxygen"; and veterinary products intended to increase milk 

production, e.g., United States v. Pro-Ag, Inc.; 796 F. Supp. 1219 (D. Minn. 1991), aff'd, 

968 F.2d 681 (8th Cir. 1992). 

In the case of tanning booths, the Agency considers the product to be a "device" 

intended to affect the structure or any function of the body despite the fact that the 

American Academy of Dermatology considers tanning booths to be a potential health 

hazard and discourages their use.16 FDA even regulates veterinary products intended to 

induce death in animals by humane means-an intended use that is indisputably not 

therapeutic. See United States v. Articles of Drug ... "Beuthanasia-D Regular,." Civ. 

No. 77-0-396 (D. Neb. August 1, 1979), reprinted in Federal Food, Drug, and Cosmetic 

Act: A Judicial Record, 1978-80, 83-89. 

The nature of a product's effect on the structure or function of the bodytherapeutic or non-therapeutic, beneficial or adverse-thus does not determine FDA's 

jurisdiction. The relevant inquiry is simply whether a product has an effect on the 

structure or any function of the body. Cigarettes and smokeless tobacco do have such 

effects and, moreover, the effects are achieved through pharmacological means. The 

tobacco industry comments admit that products with "drug-type characteristics" (i.e., 

pharmacological action) are within the Act's jurisdiction. 

16 Photobiology Task Force of the American Academy of Dermatology, Risks and benefits from highintensity ultraviolet A sources used for cosmetic purposes: special report, Journal of the American 

Academy of Dermatology 1985;12:380-381. See AR (Vol 711 Ref. 17). 

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LB. 

The argument that a product's effects must be therapeutic or medical is also 

inconsistent with FDA's assertion of jurisdiction over products with cosmetic, 

recreational, and economic uses. Notably, the comments that contend that effects on the 

structure or function of the body must be therapeutic or medical and also beneficial do not 

claim that FDA incorrectly applied the structure-function provision to products with 

cosmetic, recreational, or economic uses. Instead, these comments attempt to avoid the 

inconsistency between their arguments and these precedents by expansively interpreting 

"therapeutic" and "medical" to encompass products with cosmetic, recreational, 

economic, and other apparently non-therapeutic purposes or effects. Moreover, ~hese 

comments do not provide any rationale to support the position that products regulating 

weight are subject to the Act, but that nicotine-containing cigarettes and smokeless 

tobacco, which also affect weight regulation, are not. Instead, the comments assert that 

the weight control effects of cigarettes and smokeless tobacco are too minor to be subject 

to the Act's jurisdiction. This argument is refuted in section II.A4., below. 

The Agency rejects the legal premise that effects on the structure or function of the 

body must be therapeutic or beneficial. However, even if the Agency were to accept the 

manufacturers' legal premise, this would not change the Agency's decision with respect to 

cigarettes and smokeless tobacco. As noted previously, cigarettes-and smokeless tobacco 

produce pharmacological effects on the structure and function of the body that are 

indistinguishable from the effects of a wide range of products regulated by FDA, including 

sedation, stimulation, weight loss, and sustaining addiction. These pharmacological 

effects are as "therapeutic" or "beneficial" as many effects currently regulated under the 

23 
44680 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

LB. 

Act, and would be sufficient to satisfy a requirement that products regulated as drug 

delivery devices have beneficial or therapeutic effects. Tobacco-industry scientists have 

themselves argued that tobacco products provide "needed psychological benefits 

(increased mental alertness; anxiety reduction, coping with stress)"17 and that "nicotine is a 

very remarkable beneficent drug."18 

Indeed, if a new product with the powerful pharmacological effects of cigarettes 

and smokeless tobacco-sedation, stimulation, weight loss, and sustaining addictionsuddenly began to be distributed in the United States, there would be no question that the 

product would be subject to regulation under the Act because it "affect[s] the s~cture or 

any function of the body" within the Act's meaning. For example, the Agency has 

regulated gamma hydroxybutrate and gamma hydroxybutyric acid (collectively, GHB), a 

product intended to affect the structure or function of the body by promoting weight loss 

and muscle gain. The product is also used as a relaxant and sleep aid. GHB emerged as a 

steroid alternative after anabolic steroids became controlled substances. Very little was 

known about the product when GHB first entered the market because it was manufactured 

in clandestine laboratories (e.g., basements and kitchens), obtained from other black 

market sources, and usually distributed at health and sporting stores and clubs without 

labeling. The use of GHB as a steroid alternative and body-building aid is not 

"therapeutic"; nonetheless, the Agency successfully undertook regulatory actions against 

17 Robinson JH, Pritchard WS, The role of nicotine in tobacco use, Psychopharmacology 1992;108:397-

407, at 398. See AR (Vol66 Ref. 31-1). 

18 Ellis C, Science Advisor to the BATCO Board, The Smoking and Health Problem, presented at the 

BA TCO Research Conference, Southampton, England ( 1962), at 15. See .AR (Vol 15 Ref. 190). 

24 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44681

I. B. 

GHB pursuant to the Act's drug authorities. See United States v. Wood, Nos. 92-50512, 

92-50514 (9th Cir. Oct. 21, 1993); 58 FR 33690, 33699 (Jun. 18, 1993); FDA Quarterly 

Activities Report, First Quarter, FY 1991 (Oct.-Dec. 1990). 

3. One comment contends that the structure-function provision is limited to 

products that "purport to change the physical structure of the body.»~ 9 The Agency 

disagrees. Although the provision covers products that change a structure or function of 

the body, it is not limited to such effects. Courts have rejected the view that section 

20l(g)(l)(C) requires an actual "change [in] the physical structure or function of the [] 

body." "Pets Smellfree," 22 F.3d at 237. Moreover, cigarettes and smokeless tpbacco 

do in fact change the physical structure of the body by, for example, affecting brain 

chemistry and electrical activity in the brain, reducing weight, and increasing the growth of 

nicotine receptors in the central nervous system. 

4. One comment asserts that the structure-function provision "is not intended 

to authorize the regulation of products solely because FDA believes their use is harmful 

and undesimble."20 The Agency agrees. However, if a particular product meets the 

statutory definition of drug or device, the fact that it is also associated with harms to 

health is a reasonable consideration for the Agency in deciding to regulate the product. 

The Act's legislative history supports this view. As noted, concern about weight loss 

products that escaped regulation in the 1906 Pure Food and Drug Act was an impetus for 

19 Joint Comments of the Cigarette Manufacturers, Comment (Jan. 2., 1996), vol. II, at 83 (emphasis 

added). See AR (Vol535 Ref. 96). 

20 Joint Comments of the Smokeless Tobacco Manufacturers, Comment (Jan. 2., 1996), at 152. See AR 

(Vol. 526 Ref. 95). 

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44682 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

LB. 

broadening the definition of "drug" to include products that affect the structure or 

function of the body. Congress was concerned not so much with the weight-reduction 

effects of weight loss products but with the serious and undesirable hamtS to health that 

resulted from their use. See, e.g., Hearing on H.R. 6906, H.R. 8805, H.R. 8941, and S. 5 

Before a Subcomm. of the House Comm. on Interstate and Foreign Commerce, 74th 

Cong., 1st Sess. 55 (1935) (statement of FDA Chief Walter Campbell), reprinted in 4 

Legislative History 370. 

5. Some comments state that FDA's determination that cigarettes and 

smokeless tobacco are "drugs" and "devices" would obligate tile Agency to regu~te 

caffeine and caffeine-containing products as drugs or drug delivery devices. These 

comments assert that for this reason the Agency should not regulate tobacco products as 

drugs or devices. The Agency disagrees that a comparison to caffeine provides a reason 

not to regulate nicotine-containing cigarettes and smokeless tobacco. 

Caffeine is the active ingredient in several products regulated as drugs by the 

Agency. For instance, caffeine is the active ingredient in NoDoz, an over-the-counter 

stimulant that is regulated for its effects on the structure and function of the body. 

Caffeine is also an ingredient in internal analgesics and menstrual discomfort relief · 

products. 

Although these products are regulated as drugs, the effects of these caffeinecontaining products on the structure and function of the body are significantly less than 

those of nicotine. See section II.A3.c.i., below. For instance, unlike nicotine, caffeine is 

not recognized at this time as an addictive drug by health organizations such as the 

26 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44683

LB. 

American Psychiatric Association or the World Health Organization. Indeed, even an 

internal Philip Morris report comparing smoking and caffeine found that nicotine has a 

stronger stimulant effect than caffeine and that the stimulant effects of caffeine are "more 

like those of ... placebo" than of nicotine.21 The implication for nicotine-containing 

cigarettes and smokeless tobacco is clear: if caffeine in products such as NoDoz "affect[s] 

the structure or any function of the body within the meaning of the Act," then a fortiori 

nicotine-containing cigarettes and smokeless tobacco "affect the structure or any function 

of the body" as well. 

Caffeine naturally occurs in coffee, tea, and other foods, and is used as a11: 

ingredient in soft drinks. The Act defines "food" as "articles used for food or drink for 

man or other animals." See section 201(t)(l) of the Act, 21 U.S.C. 321(t)(l). The 

statutory definition "includes articles used by people in the ordinary way most people use 

food-primarily for taste, aroma, or nutritive value." Nutrilab v. Schweiker, 713 F.2d 

335, 338 (7th Cir. 1983). When caffeine is used in soft drink products in accordance with 

section 402 ofthe Act, 21 U.S.C. 342, and when it naturally occurs in other products that 

are foods, such as coffee, the product is a "food" under section 201(t)(l) of the Act, 21 

U.S.C. 321(t)(l), and is explicitly excepted from the definition of drug in section 

201(g)(l)(C), 21 U.S.C. 321(g)(l)(C) ("articles, other than food, intended to affect the 

structure or any function of the body") (emphasis added). The Agency's treatment of 

caffeine in beverages consequently has no bearing on how cigarettes and smokeless 

tobacco should be regulated. 

21 Memorandum from Scbori TR to Dunn WL, Smoking and CaffeilU!: A Comparison of Physiological 

Arousal Effects (May 17, 1972), at 1-2. See AR (Vol 15 Ref. 189-7). 

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44684 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

LB. 

6. Several comments assert that if FDA regulates nicotine-containing 

cigarettes and smokeless tobacco, it must also regulate the nicotine that occurs naturally in 

food products such as tomatoes, potatoes, eggplant, and cauliflower. Tne Agency 

disagrees. As noted above in response 5, section 20l(g)(l)(C) specifically excludes from 

its coverage products that are "foods" under the Act. Tomatoes, potatoes, eggplant, and 

cauliflower are "foods" within the meaning of the Act because they are "articles used for 

food ... for man." See section 201(0(1), 21 U.S.C. 321(t)(l). While these vegetables 

do contain trace amounts of nicotine, a person would have to consume 206 pounds of 

tomatoes, 309 pounds of potatoes, 22 pounds of eggplant, or 355 pounds of cauliflower 

to obtain the same amount of nicotine as in one cigarette.22 Thus, these products are 

appropriately regulated as foods. 

7. Some comments question whether applying the structure-function 

provision to nicotine-containing cigarettes and smokeless tobacco might provide 

precedent for applying the provision to a wide range of products that have effects on the 

structure or function of the body-including guns and other weapons, products that 

prevent injury, such as airbags, and chemical sprays used for self-defense or law 

enforcement pwposes. 

The Agency has never construed the structure-function provision to include 

products such as guns, airbags, and chemical sprays, and applying the structure-function 

provision to nicotine-delivering tobacco products will not provide any precedent for doing 

22 Chart Y, prepared in conjunction with the testimony of David Kessler before the Subcommittee on 

Health and the Environment. Committee on Energy and Commerce, U.S. House of Representatives 

(Mar. 25, 1994). See AR (VoL 296 Ref. 4175). 

28 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44685

I. B. 

so. Moreover, there are fundamental distinctions between these products and nicotinedelivering tobacco products. Cigarettes deliver a pharmacologically active dose-of the 

drug nicotine to the body through inhalation. Smokeless tobacco delivers a 

pharmacologically active dose of the same drug through buccal absorption. Collectively, 

tobacco products achieve their effects on the structure and function of the body through 

nicotine's pharmacological effects. These include sedation, stimulation, weight control, 

and maintenance of addiction. Tobacco products are thus indistinguishable from products 

that the Agency has traditionally regulated as drugs and devices. In contrast, guns, 

airbags, and chemical sprays are markedly different and distinguishable from such 

products. 

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44686 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

IL CIGARETTES AND SMOKELESS TOBACCO ARE "INTENDED" TO 

AFFECT THE STRUCTURE AND FUNCTION OF THE BODY WITHIN 

THE MEANING OF THE ACT 

Cigarettes and smokeless tobacco clearly "affect the structure or any function of 

the body." The principal issue before the Food and Drug Administration (FDA) is thus 

whether these effects are "intended" within the meaning of the Federal Food, Drug, and 

Cosmetic Act (the Act). 

The Act's drug and device definitions provide in pertinent part that an article is a 

drug or device if it is "intended to affect the structure or any function of the body." 

Sections 201(g)(l)(C) and 201(h)(3), 21 U.S.C. 321(g)(l)(C) and (h)(3) (emphasis 

II. 

added). In deteimining whether an article is "intended" to affect the structure or function 

of the body, "the FDA is not bound by the manufacturer's subjective claims of intent," but 

rather can fmd actual intent "on the basis of objective evidence." National Nutritional 

Foods Ass'n (NNFA) v. Mathews, 551 F.2d 325,334 (2d Cir. 1977). That is, the Agency 

determines the intent of the manufacturers objectively by evaluating all of the relevant 

evidence in the record from the perspective of a reasonable fact fmder. See 21 CFR 

201.-128,801.4. In deteimining intended use, the Agency may "examine a wide range of 

evidence." United States v. Two Plastic Drums ... Black Currant Oil, 761 F. Supp. 70, 

72 (C. D. ill. 1991), aff'd, 984 F.2d 814 (7th Cir. 1993). 

In the Jurisdictional Analysis, 60 FR 41453-41787, the Agency determined, based 

on the evidence then available to it, that cigarettes and smokeless tobacco are "intended" 

to affect the structure and function of the body. This determination was based on three 

grounds: 

30 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44687

II. 

(1) The addictive, psychoactive, and other significant pharmacological effects 

of cigarettes and smokeless tobacco are so widely known and foreseeable 

that these effects may be deemed to have been intended by the 

manufacturers, see Jurisdictional Analysis, 60 FR 41483-41490; 

(2) Such a large percentage of consumers use cigarettes and smokeless 

tobacco to satisfy their addiction or to obtain other pharmacological effects 

that the manufacturers may be deemed to intend that their products will be 

used for such purposes, see Jurisdictional Analysis, 60 FR 41490-41491; 

and 

(3) The statements, research, and actions of the tobacco manufacturers show 

that the manufacturers actually intend their products to affect the structure 

or any function of the body, see Jurisdictional Analysis, 60 FR 41491-

41520. 

FDA received comments on its fmdings from the tobacco industry, public health 

organizations, and other interest groups and members of the public. 

In this section, the Agency considers, in light of the public comments, the objective 

evidence in the administrative record relevant to whether cigarette and smokeless tobacco 

manufacturers intend their products to affect the structure or any function of the body, 

including new evidence that has become available since the issuance of the Jurisdictional 

Analysis. The Agency also discusses the legal standard for establishing the intended use of 

cigarettes and smokeless tobacco, and respondS-to the substantive comments received by 

the Agency on the evidence and the legal standard. Specifically: 

• Section II.A. discusses the evidence supporting FDA's fmding that it is foreseeable to 

a reasonable tobacco manufacturer that the nicotine in cigarettes and smokeless 

tobacco will cause pharmacological effects and will be used by consumers for those 

effects and responds to comments on this issue; 

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44688 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II. 

• Section II.B. discusses the evidence supporting FDA's finding that consumers use 

eigarettes and smokeless tobacco predominantly to obtain the phannacological effects 

of nicotine and responds to comments on this issue; 

• Section II.C. discusses the evidence supporting FDA's fmding that cigarette 

manufacturers' statements, research, and actions show that they intend their products 

to be used for the phannacological effects of nicotine and responds to comments on 

this issue; 

• Section II.D. discusses the evidence supporting FDA's fmding that smokeless tobacco 

manufacturers' statements, research, and actions show that they intend their products 

to be used for the phannacological effects of nicotine and responds to comments on 

this issue; 

• Sections II.E. and F. respond to comments, not already addressed in the foregoing 

sections, on the legal standard for evaluating intended use; and 

• Section II. G. discusses the cumulative evidence of intended use. 

Except as modified below, FDA confirms its prior fmdings and incorporates them 

by reference. FDA concludes that the evidence on the foreseeability of nicotine's effects, 

actual consumer use of tobacco for those effects, and evidence of intended use based on. 

industry statements, research, and actions each provides an independent basis for the 

detennination that the manufacturers of cigarettes and smokeless tobacco intend their 

products to affect the structure of function of the body. 

Although the evidence thus provides several independent bases for establishing 

that cigarettes and smokeless tobacco are intended to affect the structure and function of 

the body, the Agency also looks at the objective evidence of intent as a whole. The 

32 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44689

II. 

Agency fmds that, both independently and cumulatively, the evidence of foreseeable 

pharmacological effects and uses, actual consumer use for pharmacological purposes, and 

manufacturer intent as revealed through the statements, research, and ar-tions of the 

manufacturers convincingly supports the Agency's determination that cigarettes and 

smokeless tobacco are intended to affect the structure and function of the body. 

33 
44690 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

A. A REASONABLE MANUFACTURER WOULD FORESEE 

THAT CIGARETTES AND SMOKELESS TOBACCO WILL 

CAUSE ADDICTION AND OTHER PHARMACOLOGICAL 

EFFECTS AND WILL BE USED BY CONSUMERS FOR 

PHARMACOLOGICAL PURPOSES 

II. A. 

FDA may conclude that a product is intended to affect the structure or function of 

the body if a reasonable person in the position of the manufacturer would foresee that the 

product will have phannacological effects and that a substantial proportion of consumers 

will use the product for those effects. In the Jurisdictional Analysis, the Agency made 

extensive findings, based on the evidence then available, regarding the pharmacological 

effects of tobacco on the human body. See Jurisdictional Analysis, 60 FR 41534-41575. 

FDA received comments on these fmdings from the tobacco industry, many medical and 

public health organizations and medical practitioners, and from other members of the 

public. The administrative record includes extensive, publicly disseminated evidence from 

scientific studies and expert panels on the subject of tobacco's pharmacological effects on 

the human body. 

After considering the administrative record and reviewing public comments, the 

Agency fmds that the evidence clearly demonstrates that a reasonable tobacco 

manufacturer would foresee that cigarettes and smokeless tobacco will cause and sustain 

addiction, produce other psychoactive effects, and control weight and be used by 

consumers for these effects. This fmding provides an independent basis for the Agency's 

conclusion that cigarettes and smokeless tobacco are intended to affect the structure and 

function of the body. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44691

II.A.l. 

In section ll.A.1., below, FDA describes the legal basis for considering evidence of 

the foreseeable effects and uses of a product. FDA presents its major fmdings and 

responds to significant comments in sections ll.A.2. through II.A.6. In section ll.A. 7 ., 

FDA responds to the remaining relevant substantive comments. 

1. "Intended Use" May Be Established on the Basis of Foreseeable 

Pharmacological Effects and Uses 

The Agency's legal authority to establish intended use based on the foreseeable 

effects and the foreseeable uses of a product comes from the plain language of the Act, as 

well as from FDA's regulations, case law, administrative precedent, and the public health 

purposes of the Act. 

The plain language of the Act provides that a drug or device is an article "intended 

to affect the structure or any function of the body." Sections 201(g)(l)(c) and 201(h)(3) 

of the Act, 21 U.S.C. 321(g)(l)(C), 321(h)(3) (emphasis added). It is a widely accepted 

legal principle that persons can be held to "intend" the reasonably foreseeable 

consequences of their actions. In 1938, when Congress defined drugs and devices as 

articles "intended" to affect the structure or any function of the body of man, it was well 

established that "[t]he law presumes that every man intends the legitimate consequences of 

his own acts." Agnew v. United States, 165 U.S. 36, 53 (1897); accord Fanning v. 

United States, 72 F.2d 929, 932 (4th Cir. 1934) (''the law imputes an intent to accomplish 

the natural results of one's own act") (citations omitted); Eastern Drug Co. v. BieringerHanauer Co., 8 F.2d 838, 839 (1st Cir. 1925) ("presumption that one intends the natural 

and probable consequences of his acts"); see also 4 Wigmore on Evidence 3388-3390 

35 
44692 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.A.l. 

( 1904-1905) (intent is "a volition having consequences which ought reasonably to have 

been foreseen"), quoted in Rushmore v. Saxon, 158 F. 499,506 (C.C.S.D.N.Y. 1908). 

In accordance with this well-accepted legal principle, FDA may establish that a 

manufacturer "intends" that its product affect the structure or function of the body when it 

is foreseeable that the product will in fact affect the structure or function of the body in a 

drug-like manner. The case for establishing intent through foreseeability is especially 

strong when a reasonable manufacturer would foresee that a product will both act like a 

drug and be commonly used like a drug. Where it is foreseeable that a product will have 

phannacological effects on a significant proportion of consumers and will be used by these 

consumers to obtain these phannacological effects, the statute allows FDA to recognize 

reality and fmd that the manufacturer "intends" its product to be used as a drug. 

Consistent with this well-established understanding of"intent," FDA's regulations 

defining "intended use" contemplate that foreseeability can be a basis for establishing the 

objective intent of the manufacturer. These regulations require product labeling to include 

adequate directions for all "intended uses." 21 CFR 201.5 (drugs); 21 CFR 801.5 

(devices). The intended uses of a drug or device that must be included on the label are 

defmed to include those that are, or that reasonably can be, anticipated by the 

manufacturer. 

The defmition of "intended uses" for drugs establishes an "objective 

intent" standard. Specifically, the regulations provides: 

The words "intended use" or words of similar import ... refer to 

the objective intent of the persons legally responsible for the 

labeling of drugs. The intent is determined by such persons' 

expressions or may be shown by the circumstances surrounding the 

distribution of the article. This objective intent may, for example, 

36 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44693

be shown by labeling claims, advertising matter, or oral or written 

statements by such persons or their representatives. It may be 

shown by the circumstances that the article is, with the knowledge 

of such persons or their representatives, offered and used for a 

purpose for which it is neither labeled nor advertised. The intended 

uses of an article may change after it has been introduced into 

interstate commerce by its manufacturer. If, for example, a packer, 

distributor, or seller intends an article for different uses than those 

intended by the person from whom he received the drug, such 

packer, distributor, or seller is required to supply adequate labeling 

in accordance with the new intended uses. But if a manufacturer 

knows, or has knowledge of facts that would give him notice, that a 

drug introduced into interstate commerce by him is to be used for 

conditions, purposes, or uses other than the ones for which he 

offers it, he is required to provide adequate labeling for such a drug 

which accords with such other uses to which the article is to be put. 

21 CFR 201.128 (emphasis added). The definition of"intended uses" for devices is 

II.A.l. 

essentially identical. 21 CFR 801.4. Thus, under these regulatory provisions, objective 

intent can be established by evidence showing that the manufacturer "knows" or "has 

knowledge of facts that would give him notice," i.e., that a reasonable manufacturer would 

foresee that consumers will use a product for drug or device uses. 23 

Other parts of the regulations also provide that foreseeable pharmacological uses 

should be considered to be intended by the manufacturer. Section 201.128, for instance, 

23 The Agency disagrees with the tobacco industry's suggestion that this foreseeability test must be 

interpreted to apply only to products that are already classified as "drugs" or "devices." The Agency 

regularly uses the regulatory defmition of "intended uses" to determine whether products should be 

classified as drugs or devices. See, e.g., United States v. Articles of Drug, 625 F.2d 665, 668 n.5 (5th Cir. 

1980); United States v. Undetermined Quantities of An Article or Drug Labeled as "Exachol," 716 F. 

Supp. 787, 791 (S.D.N.Y. 1989); United States v. 22 ... devices ... "The Ster-o-lizer MD-200," 714 F. 

Supp. 1159, 1165 (D. Utah 1989); United States v. Kasz Enterprises, 855 F. Supp. 534,539 (D.RI. 1994}, 

modified on other grounds, 862 F. Supp. 717 (D.R.I. 1994); United States v. Articles of Food and Drug 

Consisting of ... Apricots, 444 F. Supp. 266, 273 (B.D. Wis. 1977). Thus, the Agency relies on the test 

of objective intent in the regulation (including the foreseeability standard described above) to establish: 

(1) in the case of products already classified as drugs or devices, the intended uses that must appear on the 

product labeling; and (2) in the case of products not yet classified as drugs or devices, the intended uses 

that determine whether the product should be classified as a drug or device. The Agency's interpretation 

of its own regulation is reasonable and entitled to "controlling weight" Thomas Jefferson Univ. 114 S. 

Ct 2381, 2386 (1994). 

37 
44694 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

Il.A.l. 

further provides that "objective intent ... may be shown by the circumstance that the 

article is, with the ktwwledge of such persons or their representatives, offered and used for 

a purpose for which it is neither labeled oor advenised."24 21 CFR 201.128 (emphasis 

added). 

The case law and administrative precedent interpreting the Act recognize that the 

foreseeable pharmacological effects and uses of a product are proper grounds for 

establishing intent These precedents recognize that the Agency may consider evidence of 

the likely consumer use of a product in determining intended use. See, e.g., Two Plastic 

Drums, 761 F. Supp. at 72; Kasz, 855 F. Supp. at 539. They also recognize that a 

foreseeable drug effect is generally persuasive evidence that the product is intended to 

affect the structure and function of the body. For example, the court in United States v. 

Undetermined Quantities ... "Pets Smellfree" found that the presence of 

chlortetracycline, a drug ingredient, at doses sufficient to reduce the level of bacteria in 

animal intestines was evidence that the product was intended to affect the structure and 

function of the body. 22 F.3d 235, 240 (lOth Cir. 1994). 25 Indeed, the court found this 

evidence to be relevent even though the dose of chlortetracycline in the product was 

"subtherapeutic"-that is, the dose was sufficient to reduce bacteria levels, but not to cure 

24 The tobacco industry contends that the requirement that the product must be "offered" as well as used 

for an unlabeled or unadvertised use means that there must be a specific marketing representation 

promoting the use. The Agency does not so interpret the regulation. The ordinary defmition of the word 

"offer" means simply "[t]o present for acceptance or rejection." American Heritage Dictionary of the 

English Language (3d ed. 1992) at 1255. Moreover, the tobacco industry's interpretation conflicts with 

the language in the regulation that provides that the use for which the product is offered is a use "for 

which it is neither labeled nor advertised." Consistent with the language of the regulation, the Agency 

interprets the requirement that the product be "offered" to mean simply that the product be presented to 

the consumer for purchase. 

25 See section II.E., below, for an additional discussion of the relevant case Jaw and administrative 

precedent. 

38 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44695

II.AJ. 

or treat a disease. ld. Administratively, the Agency has asserted jurisdiction over 

products such as khat, imitation cocaine, honnone-containing skin creams, and fluoridecontaining toothpastes based primarily, if not exclusively, on evidence that these products 

have foreseeable drug effects and drug uses. See section Il.E.l.e., below. 

Cases interpreting other public health statutes establish a test for determining 

intended use that is the same as the one used by FDA and that pennits reliance on 

foreseeable uses. InN. Jonas & Co. v. EPA, 666 F.2d 829 (3d Cir. 1981), for example, 

the court held that a product was "intended for use" as a pesticide under the Federal 

Insecticide, Fungicide, and Rodenticide Act (FIFRA) based on its foreseeable consumer 

use--even though the manufacturer did not promote the product as a pesticide (and even 

disclaimed use as a pesticide on the label). The court stated: 

The Act [and] the regulations ... focus inquiry on the intended use, 

implicit or expressed. We take this to mean the use which a 

reasonable consumer would undertake .... In determining intent 

objectively, the inquiry cannot be restricted to a product's label 

and to the producer's representations. Industry claims and general 

public knowledge can make a product pesticidal notwithstanding 

the lack of express pesticidal claims by the producer itself. 

ld. at 833 (emphasis added). 

Similarly, in United States v. Focht, 882 F.2d 55, 60 (3d Cir. 1989), the court held 

that under the Federal Hazardous Substances Act (FHSA), "[i]ntended use ... , 

objectively defmed, necessarily encompasses foreseeability." In this case, the Consumer 

Product Safety Commission sought to take action against fireworks components that 

could be assembled to make banned fireworks. The court found that the testimony that 

90% of consumers who order the components will use the components to make illegal 

fireworks "makes it foreseeable that the components in question will be used to build 

39 
44696 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.A.l. 

banned fireworks. Such knowledge must be attributed to [the defendants]." Id.; accord 

United States v. Articles of Banned Hazardous Substances . .. Baby Rattles, 614 F. Supp. 

226 (E.D.N.Y. 1985). 

The tobacco industry argues that the Agency may not rely on the interpretation of 

"intended use" in other statutes to interpret "intended use" under the Federal Food, Drug, 

and Cosmetic Act. The fact that FDA's interpretation of "intended use" under the Federal 

Food, Drug, and Cosmetic Act parallels the interpretation under other public health 

statutes, however, strongly supports the reasonableness of the Agency's analysis. Indeed, 

the court in Jonas relied in part on cases interpreting intended use under the Federal Food, 

Drug, and Cosmetic Act in holding that intended uses encompass readily foreseeable 

consumer uses, specifically citing National Nutritional Foods Ass'n (NNFA) v. Mathews, 

557 F.2d 325, 334 (2d Cir. 1977), for the proposition that "FDA [is] not bound by 

manufacturer's subjective claims of intent in assessing whether product is intended as a 

drug," and Bacto-Unidisk, 394 U.S. 784 (1969), for the proposition that ''the defmition of 

drug [is] to be given liberal interpretation in light of remedial purpose of Federal Food, 

Drug and Cosmetic Act." 666 F.2d at 833. 26 

Moreover, contrary to the tobacco industry's contention, the FHSA and FIFRA 

cannot be distinguished from the Federal Food, Drug, and Cosmetic Act on the ground 

that foreseeability principles are alien to the Federal Food, Drug, and Cosmetic Act. 

Several other provisions of the Act contemplate foreseeability principles. See, e.g., 21 

26 Similarly, courts interpreting the Federal Food, Drug, and Cosmetic Act rely on interpretations of 

analogous consumer protection statutes. See, e.g., "Sudden Change," 409 F.2d 734, 741 n.8 (2d Cir. 

1969) (citing a case interpreting the Federal Trade Commission Act because .. the remedial purpose of the 

Federal Trade Commission Act is sufficiently analogous"). 

40 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44697

II.A.l. 

U.S.C. 321(n) (an article may be misbranded if its labeling and advertising fail to reveal 

"consequences which may result from ... such conditions of use as are customary or 

usual"); 21 U.S.C. 360h (FDA authorized to recall devices that "present[] an unreasonable 

risk of substantial harm"). 

Indeed, in United States v. Park, 421 U.S. 658 (1975), the Supreme Court 

concluded that the Federal Food, Drug, and Cosmetic Act imposes "requirements of 

foresight and vigilance" on manufacturers, stating: 

the Act imposes not only a positive duty to seek out and remedy 

violations when they occur but also, and primarily, a duty to 

implement measures that will insure that violations will not occur. 

The requirements of foresight and vigilance imposed on 

responsible corporate officials are beyond question demanding, and 

perhaps onerous, but they are no more stringent than the public has 

a right to expect of those who voluntarily assume positions of 

authority in business enterprises whose services and products affect 

the health and well-being of the public that supports them. 

Id. at 672 (emphasis added). 

Compelling policy reasons support the Agency's interpretation that it may establish 

that a product is intended to affect the structure or function of the body when it is 

foreseeable that a product will produce significant pharmacological effects in consumers 

and be widely used by consumers for these effects. The manufacturers' position is that 

they may ignore overwhelming scientific evidence that their product will have and be used 

for pharmacological effects so long as they avoid promoting their product for these 

pharmacological effects. Under this interpretation, however, the manufacturer of virtually 

any drug or device could avoid regulation under the Act-no matter how substantial and 

well-established the pharmacological effects and uses of the product-by simply avoiding 

making certain claims in the product's labeling and advertising. For example, it is not 

41 
44698 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.A.2. 

difficult to imagine a manufacturer of a generic version of a drug like Proza.c (fluoxetine 

hydrochloride), an antidepressant drug currently available only by prescription, seeking to 

avoid FDA regulation by advertising its product as intended solely for the "pleasure" of its 

consumers. See section II.F.l.e., below. 

Accepting the manufacturers' position would leave the public vulnerable to the 

unregulated distribution of products with known pharmacologically active ingredients. 

Moreover, it would reward manufacturers who deny the obvious pharmacological effects 

and uses of their products in their public statements, labeling, and advertising. Thus, the 

Agency concludes that the public health objectives of the Act require the Agency to 

regulate as "drugs" or "devices" products that can be foreseen to have widespread 

pharmacological effects and uses. 

2. The Significant Pharmacological Effects and Uses of Cigarettes and 

Smokeless Tobacco Are Foreseeable 

The evidence in the administrative record establishes that the pharmacological 

effects and uses of cigarettes and smokeless tobacco are so widespread and well-known 

that a reasonable manufacturer would foresee them. Since the Agency last considered the 

issue of whether cigarettes are drugs over 15 years ago, a scientific consensus has 

emerged that nicotine is addictive and has other significant pharmacological effects. 

Nicotine-the essential ingredient in cigarettes and smokeless tobacco-is a 

pharmacological agent that substantially alters the structure and function of the brain and 

other systems of the body. After a single puff inhaled from a cigarette, nicotine enters the 

mouth, passes into the lungs, is absorbed from the lungs into the bloodstream, and diffuses 

42 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44699

II.A.2. 

from the blood into the brain. This process takes about 11 seconds. 27 When consumed in 

smokeless tobacco, nicotine is absorbed through the lining of the mouth into the 

bloodstream and flows to the brain. 

Once inside the human brain, nicotine binds to unique receptors on the swfaces of 

brain cells. These nicotinic receptors normally interact with a natural chemical messenger 

called acetylcholine, but can also be stimulated by nicotine to alter mood, alertness, and 

cognition. Exposure to nicotine causes the number of nicotinic receptors on the swfaces 

of brain cells to increase28 and significantly alters the brain's normal electrical and 

metabolic activity.29 Nicotine's actions on the central nervous system produce both 

27 Department of Health and Human Services, Office on Smoking and Health, The Health Consequences 

of Smoking: Nicotine Addiction, a Report of the Surgeon General (Jul. 29, 1988), DHHS Publication No. 

(CDC) 88-8406 (Washington DC: GPO, 1988), at 13-14 (hereinafter cited as Surgeon General's Report, 

1988). See AR (Vol 129 Ref. 1592). 

Benowitz NL, Clinical Pharmacology of Inhaled Drugs of Abuse: Implications in Understanding Nicotine 

Dependence, NIDA Research Monograph 99 (Rockville MD: National Institute on Drug Abuse, 1990), at 

17. See AR (Vol 3 Ref. 18). 

28 Benwell :MEM, Balfour DJK. Anderson JM, Evidence that tobacco smoking increases the density of 

(-)-eH]nicotine binding sites in human brain, Journal of Neurochemistry 1988;50: 1243-1247. See AR 

(Vol. 136 Ref. 1570). 

29 Surgeon General's Report, 1988, at 79-123. See AR (Vol 129 Ref. 1592). 

43 
44700 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.A.2. 

sedating and stimulating effects, depending on dose and circumstances. 30 Nicotine also 

plays a role in weight regulation.31 

In addition to its sedating and stimulating effects, nicotine causes and sustains 

addiction. Nicotine directly affects an intrinsic brain system, known as the mesolimbic 

system, that signals pleasure and reward and modulates emotions. When stimulated by an 

addictive substance, the mesolimbic system responds by rewarding the repeated 

consumption of the substance.32 It is widely believed that amphetamine, cocaine, and 

nicotine all cause the compulsive drug-seeking behavior of drug addiction through the 

same mechanism: increasing the activity of the neurotransmitter dopamine within the 

meso limbic system. 33 

30 Pritchard WS, Gilbert DG, Duke DW, Flexible effects of quantified cigarette-smoke delivery on EEG 

dimensional complexity, Psychopharmacology 1993;113:95-102. See AR (Vol 3 Ref. 23-1). 

Pritchard WS, Electroencephalographic effects of cigarette smoking, Psychopharmacology 1991;104:485-

490. See AR (Vol 105 Ref. 965). 

Norton R, Brown K., Howard R, Smoking, nicotine dose and the lateralisation of electrocortical activity, 

Psychopharmacology 1992;108:473-479. See AR (Vol 3 Ref. 22). 

Golding JF, Effects of cigarette smoking on resting EEG, visual evoked potentials and photic driving, 

Pharmacology, Biochemistry and Behavior 1988;29:23-32. See AR (Vol3 Ref. 23-3). 

31 Surgeon General's Report, 1988, at 431-432. See AR (Vol 129 Ref. 1592). 

32 Pomerleau OF, Pomerleau CS, Neuroregulators and the reinforcement of smoking: towards a 

biobehavioral explanation, Neuroscience and Biobehavioral Reviews 1984;8:503-513. See AR (Vol 3 

Ref. 20-l). 

Wise RA, Rompre PP, Brain dopamine and reward, Annual Review of Psychology 1989;40:191-225. 

See AR (Vol3 Ref. 19-1). 

Clarke PBS, Mesolimbic dopamine activation-the key to nicotine reinforcement? CIBA Foundation 

Symposium 1990;152:153-168. See AR (Vol 3 Ref. 19-2). 

33/d. 

Pontieri FE, Tanda G, Orzi F, et at., Effects of nicotine on the nucleus accumbens and similarity to those 

of addictive drugs, Nature 1996;382:255-257. See AR (Vol 711 Ref. 51). 

44 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44701

II.A.3. 

Extensive scientific evidence demonstrating the significant effects of nicotine in 

tobacco products on the structure and function of the body is discussed in detail in the 

remainder of this section. The magnitude and wide dissemination of the scientific evidence 

demonstrates that it is foreseeable to a reasonable person in the position of tobacco 

manufacturer that many consumers will use tobacco products for these phannacological 

effects. 

3. Nicotine Is Widely Recognized as Addictive, and It Is Foreseeable 

That Consumers Will Use Cigarettes and Smokeless Tobacco To 

Satisfy an Addiction 

Nicotine's effects on the brain are the biological basis of nicotine addiction-an 

addiction that has been proven by a wealth of laboratory and epidemiological evidence and 

recognized by every major independent medical organization that has studied the question. 

Nicotine's widely recognized addictive properties make it foreseeable to any reasonable 

person that a substantial proportion of users of tobacco products will consume these 

products to satisfy their addiction. 34 

a. Scientific Consensus 

Overwhelming scientific evidence and broad recognition that nicotine is an 

Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine 

concentrations in the mesolimbic system of freely moving rats, Proceedings of the National Academy 

of Sciences of the United States of America 1988;85:5274-5278. See AR (VoL 66 Ref. 26). 

Corrigall W A, Franklin KBJ, Coen KM. et al., The mesolimbic dopaminergic system is implicated in the 

reinforcing effect<; of nicotine, Psychopharmacology 1992;107:285·289. See AR(VoL 8 Ref. 93-4). 

34 FDA's conclusion that the pharmacological effects and uses of nicotine in cigarettes and smokeless 

tobacco are foreseeable rest<; on published literarure, including widely disseminated government reporu. 

FDA's conclusion that the tobacco industry knows that nicotine has substantial pharmacological effects 

and that consumers use tobacco for these effects, see section n.c., below, is based largely on internal 

company document<;. 

45 
44702 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

addictive, dependence-producing substance emerged in the 1980's.35 All leading 

expert and public health organizations in the United States and the international 

community with expertise in tobacco or drug addiction now recognize that 

nicotine is addictive. The first major organization to do so was the American 

Psychiatric Association in 1980, when its Diagnostic and Statistical Manual of 

Mental Disorders, Third Edition (DSM-III), defmed the Tobacco Dependence 

Disorder and the Tobacco Withdrawal Syndrome.36 Since 1980, nicotine in 

tobacco products has also been recognized as addictive by the U.S. Surgeon 

General ( 1986 and 1988)37 American Psychological Association ( 1988), 38 the Royal 

Society of Canada (1989),39 the World Health Organization (WHO) (1992),40 the 

II.A.3. 

35 The tfmlS "addictive" and "~deuce-producing" are used interchangeably among experts and scientific 

ocganizations and generally refec to the persistent and repetitive intake of a psychoactive substance despite 

evidence of harm and a desire to quit In this document, FDA also uses both tfmlS interchangeably. The term 

"abuse liability'' also refers to a subitance' s ability to produce dependence <1: addiction. 

36 American Psychiatric Association, Diagnostic and Statistical Ma:nual of Mental Disorders, 3d ed 

(Washington DC: American Psychiatric Association, 1987), at 159-160, 176-178. See AR (Vol 535 

Ref. 96, vol ID.A). 

37 Department of Health and Human Secvices, Office on Smoking and Health, The Health Consequences 

of Using Smokeless Tobacco, A Report of the Advisory Committee to the Surgeon Genecal (Apr. 1986), 

NIH Publication No. 86-2874 (Bethesda, MD:l986). See AR (Vol. 128 Ref. 1591) 

Surgeon General's Report, 1988. See AR(VoL 129 Ref. 1592). 

38 Hearings Before the Subcommittee on Health and the Environment of the Committee on Energy and 

Commerce, U.S. House ofRepresentatives, tOOth Cong., lstSess. 1 (Jul. 29, 1988) (statement of the 

American Psychological Association). See AR (Vol 5 Ref. 43-5). 

39 Royal Society of Canada, Tobacco, Nicotine, and Addiction: A Committee Report, prepared at the 

request of the Royal Society of Canada for the Health Protection Branch, Health and Welfare Canada 

(Aug. 31, 1989), at v-vi See AR (Vol 62 Ref. 814). 

40 WHO, The /CD-I 0 Classification of Mental and Behavioural Disorders: Clinical Descriptions and 

Diagnostic Guidelines (Geneva: World Health Organization, 1992), at 76. See AR(Vol43 Ref. 175). 

46 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44703

II.A.3. 

American Medical Association (1993),41 and the Medical Research Council in the 

United Kingdom (1994).42 Every expert organization that has commented on 

whether nicotine is addictive has concluded that it is. 

Recognition of nicotine addiction is now so universal that even the vast 

majority of scientists who have received funding from the tobacco industry believe 

that nicotine is addictive. In a survey of principal investigators of research projects 

funded by the tobacco industry in 1989, 83.3% agreed strongly and an additional 

15.3% agreed somewhat that cigarette smoking is addictive.43 Moreover, as 

demonstrated in section n.c., below, the tobacco industry itself, despite public 

pronouncements to the contrary, has long known nicotine to be addictive. 

Salient findings that reflect nicotine's addictiveness include the following: 

Epidemiological Evidence. 

• Persons who have smoked at least one cigarette are about twice as likely to develop 

dependence as are persons who have ever tried cocaine or alcohol.44 

41 American Medical Association, Ethyl alcohol and nicotine as addictive drugs, in 1993 AMA Policy 

Compendium (Chicago: AMA. 1993), at 35. See AR (Vol37 Ref. 2). 

42 Medical Research Council, The Basis of Drug Dependence, MRC Field Review (London: Medical 

Research Council, 1994 ), at 11. See AR (Vol 41 Ref. 1 05). 

43 Cummings KM, Sciandra R, Gingrass A, et al., What scientists funded by the tobacco industry believe 

about the hazards of cigarette smoking, American Journal of Public Health, 1991;81(7):894-896. See 

AR (Vol. 5 Ref. 44). 

44 Anthony JC, Warner LA, Kessler RC, Comparative epidemiology of dependence on tobacco, alcohol, 

controlled substances and inhalants: basic f'mdings from the National Comorbidity Survey, Experimental 

and Clinical Psychopharmacology 1994;2:244-268. See AR (Vol37 Ref. 4). 

47 
44704 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.A.3. 

• More than half of people presenting for treatment of alcohol or drug abuse who also 

smoke cigarettes report that quitting smoking would be harder than giving up their 

other drug of abuse.45 

• Despite the interest of 70% of smokers in quitting smoking, fewer than 3% succeed per 

• About two of every five users of smokeless tobacco have attempted to quit and failed,47 

and 68% of smokeless tobacco users who have attempted to quit report an average of 

four such attempts.48 

• About 50% of smokers recovering from surgery for a smoking-related disease (e.g., 

lung cancer) and whose prognosis and symptoms would be improved by abstinence 

resume smoking.49 

Evidence from Animal and Human Laboratory Studies. 

• Nicotine has been determined to have significant potential to produce addiction in 

humans on the basis of the same screening tests used to evaluate the addictive potential 

of any drug by the World Health Organization, the Drug Enforcement Administration, 

45 Kozlowski LT, Wilkinson A. Skinner W, et al., Comparing tobacco cigarette dependence with other 

drug dependencies, Journal of the A~rican Medical Association 1989;261(6):898-901. See AR (Vol 41 

Ref. 92). 

46 Centers for Disease Control and Prevention, Cigarette smoking among adults-United States, 1993, 

Morbidity and Mortality Weekly Report 1994 (Dec. 23);43:925-930. See AR (Vo136 Ref. 616-1). 

47 Novotny TE, Pierce JP, Fiore MC, et al., Smokeless tobacco use in the United States: the adult use of 

tobacco surveys, Monographs/National Cancer Institute 1989;8:25-28. See AR (Vol 41 Ref. 109). 

48 Severson HH, Enough snuff: ST cessation from the behaviora1. clinical. and public health perspectives, 

in Smokeless Tobacco or Health, An International Perspective, Smoking and Tobacco Control 

Monograph 2, NIH Publication No. 93-3461 (Washington DC: DHHS, 1993), at 281-282. See AR (Vol. 

18 Ref. 5-l). 

49 Surgeon General's Report, 1988, at 150. See AR (Vo1129 Ref. 1592). 

48 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44705

II.A.3. 

the National Institute on Drug Abuse (NIDA), the College on Problems of Drug 

Dependence, pharmaceutical companies, and FDA's Drug Abuse Advisory Committee 

(the Committee).50 See section II.A.3.c.i., below. 

• Nicotine's effects in the brain have been shown to be critical in the self-administration 

of nicotine by both animals and humans. 5

1 (The tendency of a substance to be selfadministered demonstrates its ability to cause an animal or human to seek repeated 

doses of the substance.) This finding is a key element of addiction. 

• The ability of nicotine to produce strong physiological and behavioral effects, including 

death at high doses, is no less than that of amphetamine or morphine. 5

2 

Other Biological Evidence. 

• Nicotine increases dopamine activity in the mesolimbic system of the brain. As with 

cocaine, amphetamine, and other drugs, this effect is believed to contribute to the 

compulsive drug-seeking behavior of addiction. 5

3 

• Chronic nicotine exposure causes the number of nicotinic receptors on the surfaces of 

brain cells to increase. This phenomenon is associated with tolerance to the effects of 

nicotine and has been well documented in animals and people. 54 

50 /d. at 270. 

51 /d. at 166, 173-175, 182-192. 

Corrigan W A, Coen KM, Nicotfu.e maintains robust self-administration in rats on a limited access 

schedule. Psychopharmacology 1989;99:473-478. See AR (Vol 136 Ref. 1561). 

52 Surgeon General's Report, 1988, at 272-274,594. See AR (Vol129 Ref. 1592). 

53 Corrigall W A, Franklin KBJ, Coen KM, et al., The mesolimbic dopaminergic system is implicated in 

the reinforcing effects of nicotine. Psychopharmacology 1992;107:285-289. See AR(Vol8 Ref. 93-4). 

54 Marks MJ, Burch JB, Collins AC, Effects of chronic nicotine infusion on tolerance development and 

nicotine receptors, Journal of Pharmacology and Experimental Therapeutics 1983;226:817-825. See AR 

(Vol. 41 Ref. 103). 

49 
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II.A.3. 

Commercial Evidence. 

• Non-nicotine-containing tobacco products have never proved successful substitutes for 

tobacco despite the sophistication of some of them (e.g., Philip Morris' Next) in 

mimicking the non-nicotine-mediated effects of conventional cigarettes. 

These data are just a few selections from the overwhelming evidence that has led 

the world's health authorities to classify nicotine as addictive. The following sections 

describe in detail the definition of addiction and how the widely known scientific evidence 

would lead any reasonable manufacturer to foresee that a significant proportion of tobacco 

consumers will become addicted to nicotine and will use tobacco products to satisfy their 

addiction. 

b. Definition of Addiction 

The tobacco industry is virtually alone in publicly contending that nicotine is not 

addictive. Its primary argument for rejecting the massive body of research and the expert 

opinion of every authoritative medical organization that has considered the issue is to 

claim that the entire scientific community is using the wrong defmition of addiction. 55 

According to the tobacco industry, the ''traditional criteria" of addiction are "meaningful 

Surgeon General's Report, 1988, at 53-54. See AR (VoL 129 Ref. 1592). 

Benwell MEM, Balfour DJK, Anderson JM, Evidence that tobacco smoking increases the density of 

(-)-eH]nicotine binding sites in human brain, Journal of Neurochemistry 1988;50:1243-1247. See AR 

(Vol. 136 Ref. 1570). 

55 The tobacco industry cites the opinions of several physicians and scientists to support the contention 

that nicotine is not addictive. In most cases, as described below, the opinions have been taken out of 

context, and the cited individuals are on record as believing that nicotine is addictive. Those individuals 

who agree with the industry that nicotine is not addictive comprise a .. handful of scientific supporters." 

Hwang SL, Ono Y, Tobacco dream team: experts who insist nicotine isn't addictive, Wall Street Journal 

(Mar. 23, 1995). See AR(Vol. 711 Ref. 29). 

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II.A.3. 

intoxication, withdrawal, and tolerance." Although withdrawal and tolerance are still 

considered criteria for addiction, "intoxication" has not been considered a necessary 

criterion for over thirty years. The industry cites no medical dictionary, expert panel, or 

scientific organization for this specific definition; the "criteria" are instead extracted from 

portions of a defmition developed in the 1950's and used by the editors of the 1964 

Surgeon General's Report on tobacco. 5

6 This defmition was premised on the nowdiscarded, early twentieth-century conception of drug addiction as a personality disorder 

characterized by weakness of will, immaturity of character development, and immorality.57 

Within months of publication of the Surgeon General's Report in 1964, its 

definition of addiction was cast aside by the scientific community. In a major report, the 

World Health Organization (WHO) recognized that intoxication was not a distinguishing 

characteristic of dependence for any drug under its purview.58 Indeed, people dependent 

on stable daily doses of opiates may display no observable signs of intoxication. 5

9 

Conversely, it is widely known that nonaddicting drugs such as antihistamines and 

atropine and scopolamine preparations can produce intoxication.60 Moreover, under the 

56 Department of Health, Education, and Welfare, Public Health Service, Smoking and Health: Repon of 

the Advisory Committee to the Surgeon General of the Public Health Service (Washington DC: GPO, 

1964), at 349-352. See AR (Vol43 Ref. 156). 

57 Surgeon General's Report, 1988, at 248. See AR (VoL 129 Ref. 1592). 

58 WHO Expert Committee on Addiction-Producing Drugs, WHO 1964, World Health Organization 

Technical Report Series No. 273, Thirteenth Report (Geneva: World Health Organization, 1964), at3-20. 

See AR(VoL 43 Ref. 169). 

59 Surgeon General's Report, 1988, at 251. See AR (Vol. 129 Ref. 1592). 

60 Garrison JC, Histamine, bradykinin, 5-hydroxytryptamine, and their antagonists, in Goodman and 

Gilman's The Pharmacological Basis ofTherapeutics, 8th ed. (New York: Pergamon Press, 1990), chap. 

23, at 584, 586. See AR (Vol. 711 Ref. 14). 

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II.A.3. 

old definition, cocaine and amphetamines would not clearly have been considered 

addictive because of lack of evidence at the time demonstrating physical dependence.61 

The scientific community thus rejected the old definition of addiction because of new 

scientific insights about the nature of addiction, more than 15 years before finding nicotine 

to be addictive. 

Today, drug addiction has been defmed by scientific organizations from both 

laboratory and clinical perspectives. The laboratory perspective assesses experimentally 

whether a substance alters the central nervous system in a manner that can produce 

characteristic addictive behavior in humans. 

While the laboratory perspective focuses on the chemical substance, the clinical 

perspective on drug addiction assesses whether an individual in society consumes the 

substance in a manner that demonstrates addiction. Consensus clinical criteria for 

diagnosing addiction have been developed by the American Psychiatric Association and 

were most recently published in the Diagnostic and Statistical Manual of Mental 

Disorders (DSM-IV) in 1994: 

Criteria for Substance De.penctence 

A maladaptive pattern of substance use, leading to clinically significant 

impairment or distress, as manifested by three (or more) of the following, 

occurring at any time in the same 12-month period: 

(I) tolerance, as defmed by either of the following: 

Brown JH, Atropine, scopalomine, and related antimuscarinic drugs, in Goodman and Gilman's The 

Pharmacological Basis ofTherapeutics, 8th ed. (New York Pergamon Press, 1990), chap. 8, at 157. 

See AR (Vol 711 Ref. 14). 

61 WHO Expert Committee on Addiction-Producing Drugs, WHO 1964, World Health Organization 

Technical Report Series No. 273, Thirteenth Report (Geneva: World Health Organization, 1964), at 3-20. 

See AR(Vol. 43 Ref. 169). 

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(a) a need for markedly increased amounts of the substance to 

achieve intoxication or desired effect 

(b) markedly diminished effect with continued use of the same 

amount of the substance 

(2) withdrawal, as manifested by either of the following 

(a) the characteristic withdrawal syndrome for the substance ... 

(b) the same (or a closely related) substance is taken to relieve or 

avoid withdrawal symptoms 

(3) the substance is often taken in larger amounts or over a longer period 

than was intended 

( 4) there is a persistent desire or unsuccessful efforts to cut down or 

control substance use 

(5) a great deal of time is spent in activities necessary to obtain the 

substance (e.g., visiting multiple doctors or driving long distances), use 

the substance (e.g., chain-smoking), or recover from its effects 

( 6) important social, occupational, or recreational activities are given up or 

reduced because of substance use 

(7) the substance use is continued despite knowledge of having a persistent 

or recurrent physical or psychological problem that is likely to have 

been caused or exacerbated by the substance (e.g., current cocaine use 

despite recognition of cocaine-induced depression, or continued 

drinking despite recognition that an ulcer was made worse by alcohol 

consumptiont2 

Clinicians rely on these criteria to identify addictive behavior in patients. 

II.A.3. 

In 1988, the U.S. Surgeon General used the most up-to-date laboratory tests and 

clinical criteria to develop the following consensus set of criteria for drug dependence: 

Criteria for Drug Dependence. 

Primary Criteria 

• Highly controlled or compulsive use 

• Psychoactive effects 

• Drug-reinforced behavior 

Additional Criteria 

• Addictive behavior often involves: 

62 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994), at 181. See AR (Vol 37 Ref. 8). 

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-stereotypic patterns of use 

-use despite harmful effects 

-relapse following abstinence 

-recurrent drug cravings 

• Dependence-producing drugs often produce: 

-tolerance 

-physical dependence 

-pleasant (euphoriant) effects63 

II.A.3. 

The laboratory and clinical perspectives on drug addiction embodied in the criteria 

of the U.S. Surgeon General and the American Psychiatric Association are entirely 

consistent. Moreover, the definitions of addiction used by all other world scientific 

authorities, such as WH064 and the Royal Society of Canada, 65 share the same principles, 

differing from each other only in wording and emphasis. 

To assess whether nicotine is addictive and whether consumers are addicted to 

nicotine, FDA utilized these modem laboratory and clinical perspectives on addiction 

supported in principle by every relevant medical authority in the world. 

The modem conception of addiction is not hazy. It does not-as the tobacco 

industry asserts in its comments-encompass food ingredients, activities, or daily rituals. 

The scientifically accepted method of identifying addictive drugs emphasizes the 

pharmacological basis of addiction, rather than the simple observation of compulsiveappearing behavior. Addictive drugs are now known to exert "psychoactive" or mood63 Surgeon General's Report. 1988, at 7. See AR (Vol 129 Ref. 1592). 

64 WHO, The JCD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and 

Diagnostic Guidelines (Geneva: World Health Organization, 1992), at 75-76. See AR (Vol. 43 Ref. 

175). 

65 Royal Society of Canada, Tobacco, Nicotine, and Addiction: A Committee Report, prepared at the 

request of the Royal Society of Canada for the Health Protection Branch, Health and Welfare Canada 

(Aug. 31, 1989), at v. See AR (Vol 62 Ref. 814). 

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Il.A.3. 

altering effects and to affect the structure and function of certain key portions of the brain 

that motivate repeated, compulsive use of the substance. By activating, inhibiting, or 

mimicking normal central nervous system processes, dependence-producing drugs exert 

control over the behavior of users. Consumers are strongly compelled to consume these 

substances for the pharmacological effect of satisfying addiction. Methods used to 

identify addictive drugs effectively exclude jogging, eating chocolate, playing computer 

games, or similar activities because these activities do not depend upon an exogenously 

administered drug. 

Contrary to the suggestion of the tobacco industry, application of the criteria for 

identifying addictive drugs by the expert organizations responsible for this task66 shows 

remarkable consistency across organizations and has resulted in the current identification 

of a very small number of truly dependence-producing drugs and drug types. These are 

cocaine, amphetamines, nicotine/tobacco, alcohol, hallucinogens, inhalants, cannabis, 

phencyclidine, opioids (including morphine and heroin), and the class of sedatives, 

hypnotics, and anxiolytics.67 Application of the criteria has not led to the classification of 

66 These organizations include the World Health Organization's Expert Committee on Drug Dependence, 

the U.S. Drug Enforcement Administration, the National Institute on Drug Abuse, and the Food and Drug 

Administration. 

67 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994), at 175-177. See AR (Vol37 Ref. 8). 

WHO, The /CD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and 

Diagnostic Guidelines (Geneva: World Health Organization, 1992), at 75-76. See AR (Vol43 Ref. 

175). 

Since no two of these substances are chemically or biologically identicaL no two addictions are exactly the 

same. The observation that dependence on nicotine can be distinguished in some respects from other 

addictions (as repeatedly asserted by tobacco industry comments) is thus irrelevant to whether nicotine 

should be classified as addictive. 

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II.A.3. 

carrots or jogging or any of the other activities claimed by the tobacco industry in its 

comments as "addictive drugs." A key reason for the reliability and validity of the modem 

definition of drug addiction is that scientific organizations rely upon the convergence of 

results from several different test procedures before determining that a substance is 

addictive. In assessing whether nicotine is addictive, FDA examined a wide range of such 

laboratory evidence, as well as epidemiological evidence of whether consumers are 

addicted to tobacco products. 

c. Data Establish That Nicotine Is Addictive and That Consumers 

Use Cigarettes and Smokeless Tobacco To Satisfy an Addiction 

Animal and human studies demonstrate that nicotine is a powerful psychoactive 

agent that can cause dependence by producing effects in the brain characteristic of other 

addictive substances. These findings have been widely published and presented and discussed 

at major international scientific and medical meetings since the 1980's. Numerous laboratories 

throughout the world have replicated the core findings using a variety of techniques and have 

produced convergent resu1ts, demonstrating that the findings are reliable and valid. A weahh 

of epidemiological studies complements these 1aboratory data by showing that smokers and 

users of smokeless tobacco display clinical signs and symptoms of addiction. The evidence 

that has led to the nearly universal scientific conclusion that nicotine is addictive is 

discussed in the following sections. 

i. Laboratory Studies Establish That Nicotine Produces Pharmacological 

Effects Similar to Those of Other Addictive Substances. The tests used by the U.S. 

Surgeon General to develop its consensus definition of drug dependence are the following: 

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II.A.3. 

• Animal and human "drug discrimination" tests, which assess a substance's ability to 

produce psychoactive effects that can be distinguished from those of other 

psychoactive substances; 

• Tests of human psychoactive or "subjective" effects, which assess a substance's ability 

to produce changes in perception, mood, and behavior; 

• Human and animal drug "self-administration" tests, which assess a substance's ability 

to induce repeated, compulsive use by functioning as a "positive reinforcer''; and 

• Tests for physiological dependence, which assess a substance's ability to produce 

tolerance and a withdrawal syndrome. 

These tests of an addictive drug are widely accepted for their validity.68 They are 

the screening tests for addictiveness used most commonly by pharmaceutical 

manufacturers and regulatory agencies, as evidenced by their prominence in reports by 

WHO, reviews by the National Institute on Drug Abuse (NIDA) and the College on 

Problems of Drug Dependence, and deliberations by the Drug Abuse Advisory 

Committee, which primarily serves FDA. 69 

Thus, these tests were not invented or selectively used to evaluate nicotine. 

Rather, they have been used to screen drugs of abuse for more than two decades before 

FDA's current deliberations concerning nicotine. Upon review of the evidence in the 

68 Surgeon General's Report, 1988, at 270-296. See AR (Vol 129 Ref. 1592). 

Balster RL, Drug abuse potential evaluation in animals, British Journal of Addiction 1991;86:1549-1558. 

See AR (Vol 8 Ref. 89). 

69 Surgeon General's Report, 1988, at 269-270. See AR (Vol 129 Ref. 1592). 

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II.A.3. 

administrative record, FDA concludes that nicotine tests positive in all relevant laboratory 

tests for addictive potential. 

Testing for psychoactivity. Psychoactivity is a hallmark characteristic of all 

dependence-producing drugs. Psychoactive effects (sometimes also referred to as "subjective 

effects") are changes in mood or feelings that resuh from the pharmacological effects of the 

substance on the central nervous system Changes in mood or feelings that are not produced 

phannacologically are not considered psychoactive effects. The psychoactivity of a drug is 

evaluated in "drug discrimination" studies and "subjective effects" studies. 

Drug discrimination studies. Drug discrimination studies evaluate the psychoactivity of 

a drug by testing whether animal or human subjects can reliably differentiate the drug from 

placebo. A drug that can be so differentiated is considered a "discriminative stimulus." The 

tests allow direct comparisons of a drug's effects to known dependence-producing drugs.70 

The drug discrimination paradigm is routinely used in preclinical assessment of the abuse 

potential of a drug and is considered to be an animal model for human subjective reactions to 

drugs.71 

Like other dependence-producing drugs, including cocaine, amphetamine, morphine, 

marij113.ru4 and alcohol, nicotine tests positive in animal drug discrimination tests. fDA 

referred to numerous studies documenting this resuh in the Jurisdictional Analysis and its 

appendix. 72 Using a variety of drug discrimination paradigms, researchers have shown that 

70 Balster RL, Drug abuse potential evaluation in animals, British Journal of Addiction 1991;86:1549-

1558. See AR (Vol 8 Ref. 89). 

71 Surgeon General's Report, 1988, at 274-275. See AR (Vol 129 Ref. 1592). 

72 See appendix 1 to Jurisdictional Analysis at 23-25. See AR (Vol 1 Appendix 1). 

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II.A.3. 

nicotine can serve as a discriminative stimulus in rats73 and squirrel monkeys.74 Comparative 

studies have demonstrated that, although nicotine's stimulus effects are unique, they more 

closely resemble the stimulus effects elicited by amphetamine75 than those of opioids, 

sedatives, or hallucinogens. 76 

Nicotine's positive resuhs in these drug discrimination tests are a consequence of its 

action in the central nervous system Mecamylamine, a nicotine antagonist that acts in the 

brain, attenuates nicotine's ability to serve as a discriminative stimulus, whereas the peripheral 

antagonist hexamethonium-which does not enter the b~oes not affect nicotine 

73 Morrison CF, Stephenson JA, Nicotine injections as the conditioned stimulus in discrimination learning, 

Psyclwpharmacologia 1969;15:351-360. See AR(Vol41 Ref. 107). 

Chance WT, Murfin D, Krynock GM, et al., A description of the nicotine stimulus and tests of its generalization 

to amphetamine, Psyclwpharmacology 1977;55: 19-26. See AR (Vol 37 Ref. 22). 

S tolerman IP, Discriminative stimulus effects of nicotine in rats trained under different schedules of 

reinforcement, Psychopharmacology 1989;97:131-138. See AR (Vol42 Ref. 152). 

Craft RM, Howard JL, Cue properties of oral and transdermal nicotine in the rat, Psychopharmacology 

1988;96:281-284. See AR (Vol 74Ref. 115). 

Stolerman IP, Garcha HS, Pratt JA, et al., Role of training da;e in discrimination of nicotine and related 

compounds by rats, Psyclwpharmocology 1984;84:413-419. See AR(Vol8 Ref. 90-5). 

Garcha HS, Goldberg SR, Reavill C, et al., Behavioral effects of the optical isomers of nicotine and nomicotine, 

and cotinine, in rats, British Journal of Pharmacology 1986;88:298. See AR (Vol. 38 Ref. 44). 

74 Takada K, Swedberg MDB, Goldberg SR, et al., Discriminative stimulus effects of intavenous !-nicotine and 

nicotine analogs or metabolites in squirrel mOnkeys, Psychopharmacology 1989;99:208-212. See AR (Vol. 43 

Ref. 153). 

75 Chance wr, Murfin D, Krynock GM, et al., A description of the nicotine stimulus and tests of its 

genexalization to amphetamine, Psychopharmacology 1977;55:19-26. See AR(Vol37 Ref. 22). 

76 Ra5ecrans JA, Meltzer LT, Central sites and mechanism of action of nicotine, Neuroscience and 

Biobehavioral Reviews 1981;5(4):497-501. See AR (Vol. 42 Ref. 127). 

Pratt JA, Stolerman IP, Garcha HS, et al., Discriminative stimulus properties of nicotine: further.eviden.ce for 

mediation at a cholinergic receptor, Psychopharmacology 1983;81:54-60. See AR (Vol 8 Ref. 90-2). 

59 
44716 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.A.3. 

discrimination.77 These studies demonstrate that nicotine's psychoactive effects are the direct 

results of its actions in the brain. 

Human drug discrimination tests for nicotine are also positive. Using a drug 

discrimination procedure analogous to those employed with animals, Kallman and colleagues 

originally demonstrated that nicotine, as delivered by the inhalation of tobacco smoke, acts as 

a discriminative stimulus in humans. 78 Recently, Perkins et al. demonstrated that intranasally 

administered nicotine also functions as a discriminative stimulus in hwnan volunteers. This 

resuh from a product that produces no sensory effects from smoke confirms that the 

pharmacological action of nicotine-rather than the taste or flavor of tobacco smokeproduces these hallmark psychoactive effects. 79 

Psychoactive effects. Psychoactive or subjective effects produced by addictive 

drugs may range from very mild relaxation to intense intoxication or impaired cognitive 

abilities. 80 Assessment in humans of the subjective effects of addictive drugs involves 

giving either drug or placebo to volunteers and then asking them to report what they feel. 

77 R.ooecrans JA, Chance wr, Cholinergic and noo-cholinergic aspects of the disai.minative stimulus properties 

of nicotine, in Discriminative Stimulus Properties of Drugs, ed. Lal H (New Y <Xk Plenum Press, 1977), at 

155-185. See AR(Vol 42Ref. 126). 

R.ooecrans JA, Meltzer LT, Central sites and mechanism of actioo of nicotine, Neuroscience and 

Biobehavioral Reviews 1981;5(4):497-501. See AR (Vol 42 Ref. 127). 

Meltzer LT, R.ooecrans JA, Aceto MD, et al., Disaiminative stimulus properties of the optical isomers of 

nicotine, Psychopharmacology 1980;68:283-286. See AR(Vol.. 41 Ref. 106). 

78 Kallman WM, Kallman MJ, Harry GJ, et al., Nicotine as a discriminative stimulus in human subjects, 

in Drug Discrimination: Applications in CNS Pharmacology, eds. Colpaert PC, Slangen JL 

(Amsterdam: Elsevier Biomedical Press, 1982), at 211-218. See AR (Vol 41 Ref. 89). 

79 Perkins K, Grobe J, Scierka A, et al., Discriminative Stimulus effects of nicotine in smokers, in 

International Symposium on Nicotine: The Effects of Nicotine on Biological Systems II, eds. Clarke PBS, 

Quik M, Thurau K, Adlkofer F (Basel: Birkbauser Verlag, 1994), at 111. See AR (Vol 42 Ref. 111). 

80 Surgeon General's Report, 1988, at 270. See AR (Vol. 129 Ref. 1592). 

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II.A.3. 

Individuals with histories of addictive drug use report what drug, if any, the test drug feels 

like. This testing helps determine whether the test drug produces any effects on mood and 

feeling that resemble those of previously studied drugs. Individuals with histories of using 

a variety of addictive drugs and who report "liking" the effects of several types of drugs 

help assess the addictiveness of the test drug. These individuals are asked to evaluate the 

ability to feel a drug effect, to rate how much they "like" the drug effect, and to attempt to 

identify the drug that was given from a list of widely used and abused drugs. Results that 

show consistent kinds of effects across drugs confirm that these drugs are appropriately 

categorized together as addicting drugs.81 _ 

Nicotine produces significant psychological sensations whether inhaled or injected. In 

one study, smokers with histories of abuse of other drugs identified intravenous or inhaled 

nicotine as being a euphoriant similar to cocaine or amphetamine.82 With a common measure 

of the subjective effects of addictive drugs (the Addiction Research Center Inventory), nicotine 

produced dose-related increases in the "euphoria" scale (also known as the MorphineBenzedrine Group Scale or MBG) and the "liking" scale, showing that nicotine produces 

subjective effects similar to those of other addictive drugs. This study essentially extended 

the original fmding of Johnston in 1942, who had argued from the premise that "smoking 

tobacco is essentially a means of administering nicotine, just as smoking opium is a means 

of administering morphine.'.s3 In his study, Johnston administered intravenous injections 

81 /d. at 271-272. 

82 Benningfield JE, Miyasato K, Jasinski DR, Abuse liability and pharmacodynamic characteristics of 

intravenous and inhaled nicotine, Journal of Pharmacology and Experimental Therapeutics 1985;234: 1-

12. See AR (Vol. 39 Ref. 69). 

83 Johnston LM, Tobacco smoking and nicotine, Lancet 1942;2:742. See AR (Vol 278 Ref. 3947). 

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II.A.3. 

of nicotine, in doses comparable to those that people obtain from cigarettes or smokeless 

tobacco, to cigarette smokers to determine both nicotine's effects and its potential 

usefulness in helping people abstain from tobacco. He found that the nicotine injections 

produced "psychic" effects that "closely resembled" those of cigarette smoke inhalation, 

were pleasant for smokers, and left the smokers "disinclined to smoke." See also section 

II.C.6.b. (comment 1). 

Similar fmdings were also obtained in a study by Jones et al., who found that 

intravenous nicotine injections in doses comparable to those that people obtain from 

cigarettes or smokeless tobacco produced "a pleasurable stimulant-like sensation that 

many of them termed a 'rush."' Half of the subjects tested requested substantially higher 

doses.84 More recently, these early results have been confirmed by Pomerleau and 

Pomerleau, Perkins et al., and Sutherland et al., who have found that nicotine delivered 

from cigarettes, intravenous injection, and intranasal spray produces psychoactive and 

mood-altering effects consistent with those of other addictive drugs.85 

84 Jones RT, Farrell TR III, Heming Rl, Tobacco smoking and nicotine tolerance, in Self-Administration 

of Abused Substances: Methods for Study, ed. Krasnego NA, NIDA Research Monograph 20 (Rockville 

MD: National Institute on Drug Abuse, 1978), at 202-208. See AR (Vol 41 Ref. 88). 

85 Pomerleau CS, Pomerleau OF, Euphoriant effects of nicotine in smokers, Psychopharmacology 

1992;108:460-465. See AR (Vol 87 Ref. 426). 

Perkins KA, Grobe JE, Epstein LH, et al., Effects of nicotine on subjective arousal may be dependent on 

baseline subjective state, Journal of Substance Abuse 1992;4:131-141. See AR (VoL 348 Ref. 5516). 

Perkins KA, Grobe JE, Epstein LH, et al., Chronic and acute tolerance to subjective effects of nicotine, 

Pharmacology, Biochemistry and Behavior 1993;45:375-381. See AR (Vol 271 Ref. 3728). 

Sutherland G, Stapleton J A, Russell MAH, et al., Randomised controlled trial of nasal nicotine spray in 

smoking cessation. Lancet 1992;340:324-329. See AR (VoL 91 Ref. 527). 

Sutherland G, Russell MA, Stapleton J, et al., Nasal nicotine spray: a rapid nicotine delivery system, 

Psychopharmacology 1992;108:512-518. See AR (Vol 91 Ref. 526). 

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II.A.3. 

The tobacco industry contends that tobacco is used for pleasure. So, too, is 

cocaine used for pleasure. These data establish, however, that receiving nicotine through a 

route that does not provide any sensory qualities of tobacco use (e.g., through the venous 

system) also is pleasurable. Thus, the pharmacological effects of nicotine administered 

through non-inhalation routes are able to produce the characteristic psychoactive effects 

of tobacco use. 

Self-administration testing. In self-administration testing, human or animal subjects 

are given access to a drug and then evaluated for their tendency to seek repeated doses of the 

drug. The self-administration test determines the ability of a drug to sustain drug-seeking 

behavior-one of the key distinguishing features of drug dependence. The self-administration 

test is widely used to determine whether a drug can control behavior; a drug whose intake 

leads to more consumption is called a "positive reinforcer." It is generally accepted in the 

scientific community that the ability of addictive drugs to serve as positive reinforcers is the 

core property that promotes the development and maintenance of addiction. 86 

Self-administration procedures using primates and rats have been shown to be valid and 

reliable predictors of the potential for a compound to resuh in drug dependence. There is a 

strong correlation between the types of drugs that serve as reinforcers in animals and the drugs 

associated with addiction in humans. 87 

Benningfield JE, Miyasato K. Jasinski DR, Abuse liability and pharmacodynamic characteristics of 

intravenous and inhaled nicotine, Journal of Pharmacology and Experimental Therapeutics, 

1985;234(1):1-12. See AR (Vol39 Ref. 69). 

86 Balster RL, Drug abuse potential evaluation in animals, British Journal of Addiction 1991;86: 1549-

1558. See AR(Vol8 Ref. 89). 

87 Griffiths RR. Bigelow GE, Benningfield JE, Similarities in animal and human drug-taking behavior, 

Advances in Substance Abuse 1980;1:1-90. See AR(Vol8 Ref 91-2). 

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44720 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.A.3. 

Animal self-administration studies, using a variety of administration schedules and 

controls, have shown that nicotine functions as a positive reinforcer across several species.88 

Nicotine is more avidly self-administered when available on an intermittent schedule than when 

freely available.89 Since tobacco users self-administer intermittent doses of nicotine per 

cigarette or pinch of smokeless tobacco, the schedule of nicotine administration that is most 

reinforcing in animals corresponds to the pattern of actual tobacco consumption. 

Consistent with animal self-administration studies, analogous studies with humans in 

the 1980's demonstrated that nicotine serves as a positive reinforcer under controlled 

laboratory conditions.90 Subjects self-administered intravenous nicotine in a regular and 

Woolverton WL, Nader MA. Experimental evaluation of the reinforcing effects of drugs, in Modern Metlwds in 

Pharmacology, eds. Adler MW, Cowen A(New York Wiley-Liss, 1990), 6:165-192. See AR(VoL 535 

Ref. 96, vol. ill.N). 

88 Goldberg SR, Spealman RD, Goldberg DM, Persistent behavior at high rates maintained by intravenous selfadministration of nicotine, Science 1981;214:573-575. See AR (Vol 5 Ref. 35-2). 

Goldberg SR, Spealman RD, Maintenance and suppression of behavior by intravenous nicotine injections in 

squirrel monkeys, Federation Proceedings 1982;41(2):21(r220. See AR (Vol39 Ref. 52). 

Spealman RD, Goldberg SR, Maintenance of scheduled-controlled behavior by intravenous injections of 

nicotine in squirrel monkeys, Journal of Pharmacology and Experimental Therapeutics 1982;223(2):402-408. 

See AR (Vol 42 Ref. 146). 

Risner ME, Goldberg SR, A comparisoo of nicotine and oocaine self-administration in the dog: fixed-ratio and 

progressive-ratio schedules of intravenous drug infusion, Journal of Pharmacology and Experimental 

Therapeutics 1983;224(2):319-326. See AR(Vol42 Ref. 119). 

Cox BM, Goldstein A. Nelson wr, Nicotine self-administration in rats, British Journal of Pharmacology 

1984;83:49-55. See AR(VoL 8 Ref. 93-1). 

Slifer BL, Balster RL, Intravenous self-administration of nicotine: with and without schedule-induction, 

Pharmacology, Biochemistry and Behavior 1985;22:61-69. See AR (Vol 8 Ref. 93-3). 

Corrigall W A. Coen KM, Nicotine maintains robust self-administration in rats on a limited access 

schedule, Psychopharmacology 1989;99:473-478. See AR (Vol347 Ref. 5495). 

89 Surgeon General's Report, 1988, at 182-189. See AR (Vol. 129 Ref. 1592). 

90 Henningfield JE, Miyasoto K, Jasinski DR, Cigarette smokers self-administer intravenous nicotine, 

Pharinacology, Biochemistry and Behavior 1983;19:887-890. See AR (Vol 8 Ref. 97). 

64 
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II.A.3. 

orderly pattern, giving themselves amounts of nicotine comparable to those they were 

accustomed to receiving from their cigarettes. These studies demonstrate that the 

pharmacological effects of nicotine can explain why people engage in compulsive consumption 

of tobacco. 

At a molecular level, nicotine's reinforcing effects are widely believed to be a 

consequence of its actions on specific areas in the central nervous system Within the scientific 

community, a consensus has emerged that nicotine, like other addictive drugs such as cocaine, 

amphetamine, and morphine, causes addiction by increasing the activity of the neurotransmitter 

dopamine within the meso limbic system of the brain. 91 A very recent study, which expands on 

and confirms earlier studies, has demonstrated that nicotine, at doses known to be selfadministered, mimics the effects of cocaine, morphine, and amphetamines in the meso limbic 

system, by selectively increasing dopamine transmission and energy metabolism in a specific 

region of the nucleus accumbens previously shown to be imponant in mediating the addictive 

effects of these drugs. 92 

Surgeoo General's Report. 1988, at 192 See AR (VoL 129 Ret: 1592). 

91 Clarke PBS, Mesolimbic dopamine activation-the key to nicotine reinforcement? CIBA Foundation 

Symposium 1990;152:153-168. See AR (VoL 3 Ref. 19-2). 

Corrigall W A. Coen KM, Selective dopamine antagonists reduce nicotine self-administration, 

Psycfwpharmacology 1991;104:171-176. See AR(VoL 66 Ret: 30). 

Corrigall W A, Franklin K.BJ, Coen KM, et al., The mesolimbic dopaminergic system is implicated in the 

reinforcing effects of nicotine, Psychopharmacology 1992;107:285-289. See AR (VoL 8 Ref. 93-4). 

Iverson LL, ... harmful to the brain, Nature 1996;382:206-207. See AR (Vol. 711 Ref. 51). 

92 Pontieri FE, Tanda G, Orzi F, et al., Effects of nicotine on the nucleus accumbens and similarity to 

those of addictive drugs, Nature 1996;382:255-257. See AR (VoL 711 Ref. 51). 

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II.A.3. 

Observing that food, water, and salt also increase dopamine activity in the 

meso limbic system, the tobacco industry comments that nicotine's action is not unique. 

FDA's finding, however, is not that nicotine's role in this system is unique, but that it is 

significant. Indeed, the tobacco industry's own observation on food, water, and salt 

reflects the significance of nicotine's action. As researchers have noted, the mesolimbic 

"reward" system of the brain naturally reinforces the intake of essential substances (such 

as food, water, and salt) because these substances are necessary for human existence. 

Without an intrinsic reward for eating and drinking, humans would perish. Researchers 

believe that addictive substances such as nicotine, amphetamine, cocaine, and morphine 

are so powerful precisely because they activate and even control this natural system of 

reward. Indeed, the same scientists quoted by the tobacco industry state that "nicotine 

could substitute for food or other reinforcers" in the mesolimbic system.93 That nicotine 

can mimic life-sustaining substances and alter such a pivotal neurological system 

demonstrates its substantial effect on the structure and function of the human body. 

Withdrawal and tolerance. Documentation of a drug withdrawal syndrome is the 

primary method of establishing that a substance causes physical dependence. According to the 

Surgeon General, "[m]easurement of drug withdrawal phenomena entails recording 

physiological, subjective, and behavioral responses that occur when drug administration is 

terminated."94 Numerous studies document a characteristic withdrawal syndroll)e, 

93 Mifsud JC, Hernandez L, Hoebel BG, Nicotine infused into the nucleus accumbens increases synaptic 

dopamine as measured by in vivo microdialysis, Brain Research 1989;478(2):365-367, at 367. See AR 

(Vol. 535 Ref. 96, vol. IILJ). 

94 Surgeon General's Report, 1988, at 291. See AR (Vol. 129 Ref. 1592). 

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II.A.3. 

including both physiological and psychological symptoms, associated with nicotine 

abstinence.95 Widely used criteria for diagnosing withdrawal come from the American 

Psychiatric Association's DSM-IV, which defines Nicotine Withdrawal Syndrome as four 

(or more) of the following symptoms within 24 hours after cessation of use: dysphoric or 

depressed mood; insomnia; irritability, frustration, or anger; anxiety; difficulty 

concentrating; restlessness; decreased heart rate; increased appetite or weight gain.96 

Although nicotine withdrawal is not as life-threatening as withdrawal from alcohol or 

some barbiturates, it is comparable to or stronger than withdrawal from such other 

stimulants as cocaine and can be highly disruptive to personallife.97 After several weeks 

of nicotine exposure, users who are deprived of nicotine for more than a few hours can 

develop withdrawal symptoms.98 Withdrawal symptoms after quitting tobacco use can 

persist for months. 99 

The tobacco industry contends that nicotine withdrawal is associated only with 

psychological changes; the evidence, however, demonstrates that tobacco abstinence also 

causes significant physiological effects on the body. These effects include decreased heart 

95 Id. at 197-207. 

96 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994), at 244-245. See AR (VoL 37 Ref. 8). 

97 Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of North America 

1992;76(2):415-437. See AR (VoL 535 Ref. 96, vol. Ill.A). 

98 Jaffe JH, Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of 

Therapeutics, 8th ed. (New York: Pergamon Press, 1990), chap. 22 (522-573), at 548. See AR (VoL 535 

Ref. 96, VOL m.G). 

99 Ryan FJ, Cold turkey in Greenfield, Iowa: a follow-up study, in SrMking Behavior: Motives and 

Incentives, ed. Dunn WL (Washington DC: VH Winston & Sons, 1973), at 231-234. See AR (VoL 8 

Ref. 105). 

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II.A.3. 

rate at rest and after standing, alteration of the electroencephalogram (EEG, a measure of 

brain electrical activity), skin temperature changes, and disruptions in sleep patterns. 100 

Studies have also demonstrated that tobacco withdrawal can cause an increase in weight. 

This weight increase may be attributed to increased caloric intake, decreased metabolism, 

and decreased energy expenditure during nicotine withdrawal. 101 The physiological signs 

of nicotine withdrawal are substantially reversed when nicotine is given in a form other 

than tobacco.102 

Significant behavioral and subjective symptoms common to nicotine withdrawal 

include depression, anger, irritability, anxiety, poor concentration, and restlessness.103 

100 West RJ, Jarvis MJ, Russell MAH, et al., Effect of nicotine replacement on the cigarette withdrawal 

syildrome, British Journal of Addiction 1984;79(2):215-219. See AR (Vol 8 Ref. 102-1). 

Hughes JR, Hatsukami D, Signs and symptoms of tobacco withdrawal, Archives of General Psychiatry 

1986;43:289-294. See AR (Vol 8 Ref. 102-2). 

Hughes JR, Higgins ST, Hatsukami D, Effects of abstinence from tobacco: a critical review, Research 

Advances in Alcohol and Drug Problems 1990;10:317-398, at 382. See AR (Vol535 Ref. 96, vol. III.G). 

101 Wack JT, Rodin J, Smoking and its effect on body weight and the systems of caloric regulations, 

American Journal of Clinical Nutrition 1982;35(2):366-380. See AR (Vol 8 Ref. 103-1). 

Glauser SC, Glauser EM, Reidenberg MM, et al., Metabolic changes associated with the cessation of 

cigarette smoking, Archives of Environmental Health 1970;20:377-381. See AR (Vol8 Ref. 103-2). 

102 Surgeon General's Report. 1988, at 208. See AR (Vol129 Ref. 1592). 

103 See, e.g., Hughes JR, Hatsukami D, Signs and symptoms of tobacco withdrawal, Archives of General 

Psychiatry 1986;43:289-294. See AR (Vol 8 Ref. 102-2). 

Centers for Disease Control and Prevention, Reasons for tobacco use and symptoms of nicotine 

withdrawal among adolescent and young adult tobacco users-United States, 1993, Morbidity and 

Mortality Weekly Report 1994;43(41):745-750. See AR (Vol 7 Ref. 86). 

Hughes JR, Nicotine withdrawal, dependence, and abuse, in DSM-N Sourcebook., eds. Widiger T, 

Frances A, et al. (Washington DC: American Psychiatric Association, 1994), 1:109-116. See AR (Vol. 

535 Ref. 96, vol. III.F). 

West RJ, Jarvis MJ, Russell MAH, et al., Effect of nicotine replacement on the cigarette withruawal 

syndrome, British Journal of Addiction 1984;79(2):215-219. See AR (Vol 8 Ref. 102-1). 

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II.A.3. 

Dependent smokers also show substantial withdrawal symptoms within a day of nicotine 

abstinence. 104 These psychological symptoms are substantially reversible or preventable 

by providing nicotine in the form of conventional cigarettes or by providing equivalent or 

lower doses of nicotine in other forms (e.g., nicotine gum) including forms without the 

taste of nicotine (e.g., nicotine patches). 105 

Withdrawal from smokeless tobacco also causes physiological changes attributable 

to nicotine abstinence. Hatsukami and colleagues showed the following changes in users 

deprived of chewing tobacco: (1) decreased heart rate at rest and after standing; (2) 

increased craving for tobacco; (3) increased confusion score on the Profile of Mood States 

(POMS) (this measures tension/anxiety, depression/dejection, confusion, anger/hostility, 

vigor, and fatigue); (4) increased eating; (5) increased number of sleep interruptions; and 

(6) increased total scores on a withdrawal symptom checklist for both self-rated and 

observer-rated measures.

106 

104 Jaffe JH, Drug addiction and drug abuse. in Goodman and Gilman's The Pharmacological Basis of 

Therapeutics, 8th ed. (New York Pergamon Press, 1990), chap. 22 (522-5-73), at 548. See AR (Vol 535 

Ref. 96, vol III.G). 

105 Surgeon General's Report, 1988, at 470-485. See AR (Vol 129 Ref. 1592). 

Robinson JH, Pritchard WS, Davis RA, Psychopharmacological effects of smoking a cigarette with typical 

"tar'' and carbon monoxide yields but miniinal nicotine, Psychopharmacology 1992;108:466-472. See 

AR (Vol. 59 Ref. 236). 

Fagerstrom KO, Sa we U, Tonnesen P, Therapeutic use of nicotine patches: efficacy and safety, Journal of 

Drug Development 1993;5:191-205. See AR (Vol 76 Ref. 156). 

Fiore MC, Jorenby DE, Baker TB, et al., Tobacco dependence and the nicotine patch, Journal of the 

American Medical Association 1992;268:2687-2694. See AR (Vol351 Ref. 5609). 

106 Hatsukami DK, Gust SW, Keenan RM, Physiologic and subjective changes from smokeless tobacco 

withdrawal, Clinical Pharmacology and Therapeutics 1987;41:103-107. See AR (Vol 7 Ref. 73). 

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44726 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.A.3. 

A second key test of a substance's ability to produce physical dependence is 

whether it promotes tolerance.107 Tolerance occurs when responses produced by an initial 

dose are diminished with repeated doses, so that increasing doses are necessary to 

reproduce the initial effects. Tolerance to some effects of a substance can be acute, 

occurring within hours to days, while tolerance to other effects develops chronically as a 

result of long-tenn substance exposure. 

Tobacco users become tolerant to nicotine both acutely and chronically.108 After a 

single night of abstinence, the nervous system109 and the cardiovascular system110 

are 

highly responsive to small doses of nicotine. But after the administration of the equivalent 

of a few cigarettes, the responsiveness of the human body to nicotine declines markedly. 

Thus, a cigarette smoked in the middle of the day may not elicit the same psychological or 

physiological response in a cigarette smoker as one smoked earlier in the morning. This 

severe degree of acute tolerance seems to greatly exceed that produced by cocaine and to 

be more comparable to that produced by morphine. 111 

Tolerance to other effects of nicotine develops over weeks and months. For 

example, new smokers often experience nicotine-related effects such as dizziness, nausea, 

intoxication, vomiting, and headaches-symptoms that disappear eventually as the 

107 Surgeon General's Report, 1988, at 50-54. See AR (Vol 129 Ref. 1592). 

108 Perkins KA, Grobe JE, Epstein LH, et al., Chronic and acute tolerance to subjective effects of nicotine, 

Pharmacology, Biochemistry and Behavior 1993;45:375-381. See AR (Vol 271 Ref. 3728). 

!09 ld. 

110 Surgeon General's Report, 1988, at 47-48. See AR (Vol 129 Ref. 1592). 

111 Jaffe JH, Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of 

Therapeutics, 8th ed. (New York Pergamon Press, 1990), chap. 22 (522-573), at 533, 543, 548. See AR 

(Vol 535 Ref. 96, vol. III.G). 

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II.A.3. 

smokers' bodies adapt to nicotine and tolerance to these effects develops. 112 These and 

other examples of chronic tolerance (such as faster nicotine metabolism among 

experienced smokers) are consistent with laboratory evidence of long-term structural 

changes in the brain and other parts of the body from nicotine use.

113 

There is also epidemiological evidence that the vast majority of smokers and 

smokeless tobacco users increase their consumption and usage of tobacco products over 

time. See section ll.A.3.c.ii., below. This escalation of dose is an additional 

demonstration of the development of tolerance. Like users of other addictive drugs, 

tobacco users eventually reach a stable level of consumption.114 

Laboratory studies on drug discrimination, psychoactive/subjective effects, selfadministration, and withdrawal and tolerance thus demonstrate that nicotine has the 

properties of an addictive drug. 

Nicotine compared to saccharin and caffeine. In its comments, the tobacco 

industry attempts to discount a multitude of laboratory studies of nicotine by selectively 

pointing to a single test used to screen for addictive substances and arguing that, in that 

test, nicotine's effect was similar to saccharin's. From this premise, the industry-concludes 

that nicotine is no more addictive than saccharin. This argument misrepresents the 

. published data on saccharin's and nicotine's properties and overlooks fundamental 

112 Department of Health and Human Services, Office on Smoking and Health, Preventing Tobacco Use 

Among Young People: A Report of the Surgeon General (Washington DC: Government Printing Office, 

1994), at 138. See AR (Vol133 Ref. 1596). 

113 See section II.A3.i. and ii., below, for a more detailed discussion. 

114 Jaffe JH, Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of 

Therapeutics, 8th ed. (New York Pergamon Press, 1990), chap. 22 (522-532). See AR (Vol. 535 Ref. 

96, vol III.G). 

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II.A.3. 

differences between saccharin and nicotine. Contrary to the tobacco industry's argument, 

saccharin has not been shown to meet the most fundamental test of an addictive drug, 

namely, psychoactive effects in the brain that account for its appeal to humans and 

animals. Nicotine has been shown to have these effects. 

In contrast to nicotine, which can be pleasurable even when injected intravenously, 

saccharin is liked primarily because of its taste. For example, rats can be trained to selfadminister oral doses of saccharin in preference to water, demonstrating only that rats 

prefer the taste of saccharin to that of water. FDA is unaware of any studies, and the 

tobacco industry cites none, in which rats have self-administered saccharin intravenously. 

Such a study would be an essential step in proving that saccharin's appeal lies in its effects 

on the brain. Moreover, there is no evidence that saccharin produces any psychoactive 

effects. In contrast, nicotine, which produces no such pleasant taste, demonstrates all of 

the properties of an addictive drug, including self-administration and psychoactivity, 

through its actions on the central nervous system. 

The tobacco industry also argues that nicotine is similar to caffeine in tests of 

addictive potential. FDA disagrees. In comparison to the more orderly pattern of selfadministration observed with nicotine and stimulant drugs, the pattern of caffeine selfadministration is generally weak and sporadic in animals.115 Hence, in comparison to known 

115 Heishman SJ, Henningfield JE, Stimulus functions of caffeine in humans: relation to dependence potential, 

Neuroscience and Biobehavioral Reviews 1992;16:273-287. See AR (Vol 79 Ret: 230). 

Griffiths RR, Woodson PP, Reinforcing properties of caffeine: studies in humans and laboratory animals, 

Pharmacology, Biochemistry and Behavior 1988;29(2):419-427. See AR (Vol 535 Ret: 96, vol III.E). 

Jaffe JH, Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of 

Therapeutics, 8th ed. (New York Pergamon Press, 1990), chap. 22 (522-573), at 524. See AR (Vol. 535 

Ref. 96, vol Ill.G). 

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II.A.3. 

drugs of dependence (e.g., cocaine, morphine, and nicotine), caffeine has a lower relative 

dependence potential as well as a low risk of adverse effects in amounts currently pennitted in 

foods and beverages.116 Unlike nicotine, caffeine is not recognized as a dependence-producing 

substance by the American Psychiatric Association117 and the World Health Organization.118 

The laboratory differences between nicotine and caffeine are reflected in the different 

patterns of substance consumption. Neal Benowitz, a prominent addiction researcher, noted 

that, "[i]n contrast to coffee drinkers, the vast majority of cigarette smokers exhibit addictive 

behavior."119 The wide acceptance of decaffeinated beverages demonstrates a much more 

general ability to control intake and minimize _undesirable effects of caffeine. Moreover, while 

nicotine/tobacco addiction is estimated to be one of the leading causes of premature death in 

the United States, 120 caffeine at customary doses poses few risks to the individual or to society. 

116 Heishman SJ, Benningfield JE, Stimulus functions of caffeine in humans: relation to dependence potential. 

Neuroscience and Biobehavioral Reviews 1992;16:273-287. See AR(Vol 79 Ref 230). 

Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of North America 

1992;76(2):415-437. See AR (Vol 535 Ref. 96, vol. III.A). 

117 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994), at 176. See AR (Vol 37 Ref. 8). 

118 WHO, The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions 

and Diagnostic Guidelines (Geneva: World Health Organization, 1992), at 75-76. See AR (Vol 43 

Ref. 175). 

119 Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of North America 

1992;76(2):415-437, at430. See AR (Vol 535 Ref. 96, vol. ill.A). 

120 McGinnis JM, Foege WH, Actual causes of death in the United States, Journal of the American 

Medical Association 1993;270(18):2207-2212. See AR (Vol 2 Ref. 15-1). 

Hearing on Preventive Health: An Ounce of Prevention Saves a Pound of Cure, Before the Special 

Committee_ on Aging, U.S. Senate, 103d Cong., 1st Sess. 2 (May 6, 1993) (statement of Roger Herdman, 

Maria Hewitt, Mary Laschober, on smoking-related deaths and financial costs: Offtce of Technology 

Assessment estimates for 1990). See AR (Vol 17Q Ref. 2024). 

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44730 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.A.3. 

Thus, the average tobacco conswner--but not the average coffee drinker-uses tobacco 

despite severe health risks, a clinical sign of addiction. 121 

In summary, widely publicized laboratory studies show that tobacco use, like heroin 

and cocaine use, is a behavioral-phannacological process in which the individual's 

continued consumption of tobacco is controlled by a psychoactive and reinforcing drug 

that exerts its control through the central nervous system. Thus, nicotine is similar to 

other addictive drugs in every relevant aspect For this reason, every scientific authority 

that has reviewed the results of the laboratory evidence has concluded that nicotine is 

addictive. 

ii Epidemiological Data Establish That Many Tobacco Users Are Addicted. 

Numerous well-publicized studies and health surveys have documented the characteristics 

of nicotine dependence among tobacco users. In the United States, clinical criteria to 

assess addiction come from the DSM-IV published by the American Psychiatric 

Association. 

Several large studies have confmned that most cigarette smokers qualify for a 

diagnosis of nicotine dependence. As described in depth in the appendix to the 

Jurisdictional Analysis, and discussed further in section II.B.2.a., below, as many as 92% 

of smokers are addicted to cigarettes.122 Smokers are more likely to become addicted than 

121 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994), at 181. See AR (Vol 37 Ref. 8). 

122 See appendix 1 to Jurisdictional Analysis, at42-47. See AR (Vol. 1 Appendix 1). 

In the Jurisdictional Analysis (60 FR 41576), FDA referred to rates of dependence among "frequent 

smokers" as being in the range of 75% to 90%. In this document, FDA does not use "frequent" but rather 

describes the,defmition of smokers used in each study. See section IlB.2., below. 

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II.A.3. 

users of other dependence-producing drugs, including cocaine, alcohol, marijuana, 

inhalants, and heroin. 123 Consistent with the results from these large studies, which 

assessed the prevalence of nicotine dependence as defmed by meeting three or more of the 

seven criteria for addiction, are the fmdings of other studies that assessed the proportion 

of tobacco users meeting individual criteria. Of the seven criteria listed in section II.A.3.b., 

above, DSM-IV observes that six are readily apparent among tobacco users: desire to 

quit or unsuccessful efforts to cut down, use continued despite medical problems, a great 

deal of time spent using, use of substance in larger amounts and longer than intended, 

withdrawal, and tolerance.124 These results strongly support the conclusion that addiction 

to nicotine is widespread among smokers. 

Although there have been no population-based studies using criteria from the 

Diagnostic and Statistical Manual of Mental Disorders (DSM) to assess rates of 

addiction to smokeless tobacco, substantial evidence demonstrates that a high proportion 

of smokeless tobacco users meet individual DSM criteria for addiction. This evidence 

strongly supports the conclusion that a substantial proportion of such users are addicted. 

In 1992, the Inspector General of the Department of Health and Human Services 

estimated that approximately 75% of young regular users of smokeless tobacco are 

addicted. 125 

123 Anthony JC, Warner LA, Kessler RC, Comparative epidemiology of dependence on tobacco, alcohol, 

controlled substances and inhalants: basic findings from the National Comorbidity Survey, Experimental 

and Clinical Psychopharmacology 1994;2:244-268. See AR (Vol 37 Ref. 4). 

124 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association. 1994), at 243. See AR (Vo137 Ref. 8). 

125 Department of Health and Human Services, Office on Smoking and Health, Spit Tobacco a;w Youth 

(Washington DC:_ GPO, 1992), at 8. See AR (Vol. 7 Ref. 76). 

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44732 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.A.3. 

Data demonstrating that a high proportion of smokers and users of smokeless 

tobacco meet individual DSM criteria for addiction are now discussed. 

Desire to quit or unsuccessful efforts to cut down. Each year, more than 15 

million people in the United States-almost one-third of all daily smokers-try to quit 

smoking. Fewer than 3% of smokers achieve 1 year of abstinence.126 

Quitting smokeless tobacco is also difficult In one study, only 2.3% of smokeless 

tobacco users at a cessation clinic were able to remain abstinent for 6 months; the study 

concluded that using smokeless tobacco may be more addicting than cigarette smoking.127 

The Centers for Disease Control and Prevention (CDC) found that the greater the 

level of use of the tobacco product, the more likely young people were to report that "it's 

really hard to quit." This increase in difficulty quitting as the amount of tobacco consumed 

increases demonstrates a dose-response relationship, one of the characteristic features of 

pharmacological effects. This dose-response relationship holds true for both cigarettes 

and smokeless tobacco used by 10- to 22-year-olds. For example, 74% of young people 

who used smokeless tobacco every day reported that it was very difficulno quit, 

compared to only 11% who used smokeless tobacco 1 to 14 days a month.128 

126 Centers for Disease Control and Prevention, Smoking cessation during previous year among adultsUnited States, 1990 and 1991, Morbidity and Mortality Weekly Report 1993;42(26):504-507. See AR 

(Vol. 66 Ref. 2). 

127 Glover ED, Glover PN, Smokeless tobacco cessation and nicotine reduction therapy, in Smokeless 

Tobacco or Health, an International Perspective, Smoking and Tobacco Control, NIDA Research 

Monograph 2, NIH Publication No. 93-3461 (Rockville MD: Government Printing Office, 1993), at 291-

295. See AR (VoL 7 Ref. 79-1). 

128 Centers for Disease Control and Prevention, Reasons for tobacco use and symptoms of nicotine 

withdrawal among adolescents and young adult tobacco users-United States, 1993, Morbidity and 

Mortality Weekly Report 1994;43(41):745-750. See AR (VoL 7 Ref. 86). 

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II.A.3. 

Additional studies on the common desire to quit and the failure of the vast majority 

of attempts can be found in appendix 1 to Jurisdictional Analysis. 129 

Use continued despite medical problems. As many as 90% of smokers know that 

tobacco products are harmful to their own health, 65% of current smokers believe that 

smoking "has already affected" their health, and 77% of smokers believe that they could 

"avoid or decrease serious health problems from smoking" if they quit.130 Yet they keep 

smoking. 

Consumers of smokeless tobacco also recognize the health risks of their tobacco 

use, but do not stop. In one study, 96% of young men who regularly used smokeless 

tobacco agreed that chewing tobacco and snuff can cause cancer.131 Another study of 

users age 17 and over revealed that 77.4% believe that smokeless tobacco is a health 

haza.rd.l32 

People even continue tobacco use in the face of life-threatening, tobacco-related 

illnesses. For example, studies have shown that about half of smokers who have had 

129 See appendix 1 to Jurisdictional Analysis, at 52-55. See AR (Vol. 1 Appendix 1). 

130 Gallup GH. Smoking Prevalence, Beliefs, and Activities by Gender and Other Demographic Indicators 

(Princeton NJ: Gallup Organization, r993). See AR (Vol 38 Ref. 43a). 

131 Department of Health and Human Services, Office on Smoking and Health, Preventing Tobacco Use 

Among Young People: A Report of the Surgeon General (Washington DC: Government Printing Office, 

1994), at 101. See AR (Vol133 Ref. 1596). 

132 Novotny TE, Pierce JP, Fiore MC, et al., Smokeless tobacco use in the United States: the adult use of 

tobacco surveys, Monographs/National Cancer Institute 1989;8:25-28. See AR (Vol41 Ref. 109). 

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44734 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.A.3. 

surgery for lung cancer resume smoking133 and that almost 40% of smokers who have had 

their larynxes removed try smoking again.134 

Additional data on the use of tobacco products despite the health problems they 

have caused are presented in appendix 1 to the Jurisdictional Analysis.135 

Great deal of time spent using. Studies have demonstrated that tobacco users 

consume tobacco regularly and compulsively. For example, 90% of smokers consume five 

or more cigarettes every day.136 Over two-thirds of smokers who consume five cigarettes 

a day smoke their first cigarette within the first half-hour after awakening;137 according to 

many experts, this need is a key symptom indicating a very significant level of 

dependence.138 

Among users of chewing tobacco and moist snuff over 18, half use the products 

every day, and the proportion of daily users rises with age.139 The Inspector General of 

133 Davison G, Duffy M, Smoking habits of long term survivors of surgery for lung cancer, Thorax 

1982;37:331-333. See AR (Vol 6 Ref. 58). 

134 West R. Himbury S, Smoking habits after laryngectomy, British Medical Journal1985;291:514-515. 

See AR (Vol 6 Ref. 59). 

135 See appendix I- to Jurisdictional Analysis, at 56-58. See AR (Vol. 1 Appendix 1). 

136 Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of North America 

1992;76(2):415-437. See AR (Vol 535 Ref. 96, vol. Ill.A). 

Henningfield JE, Cohen C, Slade JD, Is nicotine more addictive than cocaine? British Journal of 

Addiction 1991;86:565-569. See AR {Vol 277 Ref. 3904). 

137 Giovino GA, Zhu BP, Tomar S, et al., Epidemiology of Tobacco Use and Symptoms of Nicotine 

Addiction in the United States: A Compilation of Data from lArge National Surveys, presentation of the 

Centers for Disease Control and Prevention to the FDA's Drug Abuse Advisory Committee (Aug. 2, 

1994), slide 19 (from National Health Interview Survey 1987). See AR(Vol 459 Ref. 7820). 

138 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994), 245. See AR (Vol 37 Ref. 8). 

139 Department of_Health and Human Services, National Center for Health Statistics, Vital and Health 

Statistics: Smoking and Other Tobacco Use: United States, 1987, Series 10: Data from the National 

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II.A.3. 

the U.S. Department of Health and Human Services reported that "our 1986 and 1992 

users typically held their dip or chaw 25 to 30 minutes, with most keeping it in over 30 

minutes, and often up to one hour."140 

Use of substance in lar~er amounts or lon~er than intended. Few beginning 

smokers plan to become daily smokers. Yet 90% of current smokers consume at least five 

cigarettes a day. 141 Smokers also smoke for longer periods than they intend. Among high 

school seniors from the Monitoring the Future Project (1976--86), almost half of the daily 

smokers reported that they would either probably or definitely not be smoking 5 years 

after graduation. 142 In a follow-up study conducted 5 to 6 years after graduation, more 

than two-thirds were smoking as frequently or more frequently than they had in high 

school (26% were smoking at the same level, and 40% were smoking more).143 

Other evidence that users of cigarettes and smokeless tobacco consume more than 

they intend comes from surveys demonstrating that many people try to quit but fail. For 

Health Survey, No. 169, Sep. 1989, DHHS Publication No. (PHS) 89-1597 (Washington DC: 

Government Printing Office, 1989), at 24, 26. See AR (Vol 711 Ref. 9). 

140 Department of Health and Human Services, Office on Smoking and Health, Spit Tobacco and Youth 

(Washington DC: Government Printing Office, 1992), at 7. See AR (Vol 7 Ref. 76). 

141 Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of Nonh America 

1992;76(2):415-437. See AR (Vol. 535 Ref. 96, vol. ID.A). 

Henningfield JE, Cohen C, Slade JD, Is nicotine more addictive than cocaine? British Journal of 

Addiction 1991;86:565-569. See AR (Vol 277 Ref. 3904). 

142 Elders MJ, Perry CL, Eriksen MP, et al., The repon of the Surgeon General: preventing tobacco use 

among young people, American Journal of Public Health 1994;84(4):543-547, at 544. See AR (Vol38 

Ref. 39). 

143/d. 

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II.A.3. 

example, two of every five adult users of smokeless tobacco have tried to quit. 144 

Additional studies are discussed in detail in appendix 1 to the Jurisdictional Analysis. 145 

Withdrawal. In addition to experimental evidence of withdrawal from nicotine 

described in section IT.A.3.c.i., above, persuasive data from epidemiological studies also 

demonstrate that the vast majority of consumers who abstain from tobacco products 

experience withdrawal symptoms.146 

Studies show that the symptoms of irritability, nervousness, restlessness, and 

increased appetite each affect over half of abstinent smokers; indeed, about half of 

abstinent smokers qualify for a formal diagnosis of Nicotine Withdrawal Syndrome under 

the Diagnostic and Statistical Manual of Mental Disorders, 3d ed., revised (DSM-lllR). 147 Withdrawal symptoms show a dose-response relationship; heavier smokers are 

more likely than light smokers to experience the symptoms of difficulty concentrating, 

hunger, irritability, restlessness, and sadness when they try to quit. 148 A similar doseresponse relationship between the likelihood of withdrawal symptoms and the level of 

144 Novotny TE, Pierce JP, Fiore MC, et al., Smokeless tobacco use in the United States: the adult use of 

tobacco surveys, Monographs/National Cancer Institute 1989;8:25-28. See AR (Vol 41 Ref. 109). 

145 See appendix 1 to Jurisdictional Analysis, at 48-55. See AR (Vol. 1 Appendix 1). 

146 See appendix 1 to Jurisdictional Analysis, at 58-61. See AR (Vol. 1 Appendix 1). 

147 Breslau N, Kilbey MM, Andreski MA. Nicotine withdrawal symptoms and psychiatric disorders: 

fmdings from an epidemiologic study of young adults, American Journal of Psychiatry 1992;149(4):464-

469. See AR (Vol 37 Ref. 18). 

148 Giovino GA. Zhu BP, Tomar S, et al., Epidemiology of Tobacco Use and Symptoms of Nicotine 

Addiction in the United States: A Compilation of Data from lArge National Surveys, presentation of the 

Centers for Disease Control and Prevention to the FDA's Drug Abuse Advisory Committee (Aug. 2, 

1994), slides 27-32. See AR(Vo1459 Ref. 7820). 

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II.A.3. 

nicotine intake was found among British schoolgirls149 and other populations studied.150 

Most people who quit smoking relapse within 1 week, 151 when withdrawal symptoms are 

at or near their peak 152 

Smokeless tobacco users typically experience withdrawal symptoms similar to 

those reported by smokers. In a study of young smokeless tobacco users, over 90% of 

daily users reported at least one symptom of nicotine withdrawal when trying to 

discontinue use. Restlessness and irritability were reported by half of daily users during 

abstinence. 153 

Tolerance. In addition to laboratory measures of tolerance to nicotine described in 

section Il.A.3.c.i., above, epidemiological studies show that users of tobacco products 

require increasing amounts to maintain the same effects. The 1991 and 1992 National 

Household Survey on Drug Abuse found that 12% of smokers 25 years or older and 20% 

of smokers 12 to 24 years of age who smoke 16 to 25 cigarettes per day report feeling the 

need for an increased number of cigarettes over time to obtain the desired effects.154 

149 McNeill AD, West RJ, Jarvis M, et al., Cigarette withdrawal symptoms in adolescent smokers, 

Psychopharmacology 1986;90(4):533-536. See AR (Vol 95 Ref. 683). 

150 Surgeon General's Report, 1988, at 206-207. See AR (Vol129 Ref. 1592). 

151 Hughes JR, Gulliver SB, FenwickJW, et·al., Smoking cessation among self-quitters, Health 

Psychology 1992;11:331-334. See AR (Vol348 Ref. 5512). 

152 Hughes JR, Gust SW, Skoog K, et al., Symptoms of tobacco withdrawal: a replication and extension, 

Archives of General Psychiatry 1991;48:52-59. See AR (Vol129 Ref. 1404). 

153 Centers for Disease Control and Prevention, Reasons for tobacco use and symptoms of nicotine 

withdrawal among adolescents and young adult tobacco users-United States, 1993, Morbidity and 

Mortality Weekly Report 1994;43(41):745-750. See AR(Vol 7 Ref. 86). 

154 Giovino GA, Zhu BP, Tomar S, et al., Epidemiology of Tobacco Use and Symptoms of Nicotine 

Addiction in the United States: A Compilation of Data from lo.rge National Surveys, presentation of the 

Centers for Disease Control and Prevention to the FDA's Drug Abuse Advisory Committee (Aug. 2, 

1994), slide 24. See AR(Vol459 Ref. 7820). 

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II.A.3. 

Among those who have tried an addictive substance at least once, people who have tried 

cigarettes are more likely to report the need for larger doses to get the same effect than 

people who have tried cocaine, marijuana, and alcohol.155 

Most consumers of tobacco products escalate their doses over time. Whereas few 

cigarette smokers initially plan to be regular daily users, approximately 90% of them 

consume more than five cigarettes every day.156 

Smokeless tobacco users also increase their dose of nicotine. One study showed a 

positive relationship among the number of years of smokeless tobacco use, the number of 

minutes per day of reported use, and urinary nicotine and cotinine levels. 157 (Cotinine is a 

major metabolite of nicotine and an indicator of nicotine absorption.) Other studies on 

dose escalation of tobacco products can be found in appendix 1 to the Jurisdictional 

Analysis. Iss 

The epidemiological data demonstrate that a large proportion of tobacco users are 

dependent on nicotine and that overwhelming numbers of users show signs of addiction. 

These data complement laboratory evidence proving that nicotine is an addictive substance 

and have led to _the nearly universal scientific recognition of nicotine as a drug whose 

155 Henningfield JE, Clayton R. Pollin W, Involvement of tobacco in alcoholism and illicit drug use, 

British Journal of Addiction 1990;85:279-292. See AR (Vol 39 Ref. 66). 

156 Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of North America 

1992;76(2):415-437. See AR (Vol535 Ref. 96, vol. lli.A). 

Henningfield JE, Cohen C, Slade JD, Is nicotine more addictive than cocaine? British Journal of 

Addiction 1991;86:565-569. See AR (Vol 277 Ref. 3904). 

157 World Health Organization, Smokeless Tobacco Control: Report of a WHO Study Group, WHO 

Technical Report Series No. 773 (Geneva: WHO, 1988), 36. See AR(Vol 7 Ref. 83). 

158 See appendix 1 to Jurisdictional Analysis, at 48-51. See AR (Vol. 1 Appendix 1). 

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II.A.4. 

pharmacological effects compel continued use. These widely disseminated public fmdings 

establish that a reasonable person in the position of a tobacco manufacturer would foresee 

that tobacco products would be consumed to satisfy an addiction to nicotine.159 

4. It Is Foreseeable That Consumers Will Use Cigarettes and Smokeless 

Tobacco for Other Pharmacological Purposes 

In addition to its foreseeable addictive effects, nicotine produces a range of other 

well-known and foreseeable significant pharmacological effects of importance to tobacco 

users. Evidence demonstrating that consumers actually use tobacco products for these 

effects is discussed in section II.B.2., below. 

Central Nervous System Effects: Sedation. Stimulation. Mood. and Cognition. 

Nicotine significantly alters the structure and function of the brain. At the molecular level, 

nicotine acts by stimulating receptors on the surfaces of brain cells intended for natural 

neurotransmitters such as acetylcholine and by stimulating the release of other key 

substances such as dopamine.160 Nicotine also changes the brain's molecular structure. 

Extensive animal research by both the tobacco industry and other researchers shows that 

nicotine exposure, ranging from a few days to a few weeks, within the range of doses 

equivalent to those received from smoking cigarettes, increases the number and changes 

the functional activity of nicotine receptors in the brain.161 In one study, doses of nicotine 

159 FDA notes that at least one major tobacco company appears to agree that information about the 

"addicting" properties of cigarettes is so widely disseminated that it must be considered foreseeable. In 

a lawsuit brought against RJR by a smoker, RJR argued that the "alleged habitutating or 'addicting"' 

qualities of cigarette smoking are so well known that smokers must be held to have foreseen them. 

See section II.C.2.b.iv., below. 

160 See the discussion of dopamine in the mesolimbic system, section II.A3.c.i., above. 

161 Marks MJ, Burch JB, Collins AC, Effects of chronic nicotine infusion on tolerance development and 

nicotine receptors, Journal of Pharmacology and Experimental Therapeutics 1983;226:817-825. See AR 

(Vol. 41 Ref. 103). 

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II.A.4. 

considered equivalent to those received by a fetus of a smoking mother increase the 

number of nicotine receptors in the brains of newborn rats.162 Consistent with animal data, 

cigarette smokers show clear evidence of increased numbers of cerebral nicotine receptors 

as a consequence of their smoking.163 

The result of these molecular actions is that nicotine clinically affects arousal, 

attention, mood, and, under certain conditions, cognition. Depending on the dose and the 

circumstances, nicotine delivered by cigarette smoking can have an arousal-increasing or 

arousal-reducing effect.164 This is another respect in which nicotine is similar to such 

other addictive drugs as opiates, which can have both stimulating and sedating effects. 

Nicotine's effects on mood and arousal have been confirmed using 

electroencephalographic (EEG) analysis, a measurement of electrical activity in the 

brain.165 When smokers are placed in a stressful situation, smoking can have a depressant 

Surgeon General's Report. 1988, at 53-54. See AR (Vol 129 Ref. 1592). 

Department of Health and Human Services, Office on Smoking and Health, Preventing Tobacco Use 

Among Young People: A Report of the Surgeon General (Washington DC: GPO, 1994), at 32-33. See 

AR (Vol. 133 Ref. 1596). 

162 Slotkin T A, Orband-Miller L, Queen KL, Development of eH)nicotine binding sites in brain regions 

of rats exposed to nicotine prenatally via maternal injections or infusions, Journal of Pharmacology and 

Experimental Therapeutics 1987;242:232-237. See AR (VoL 140 Ref. 1656). 

163 Benwell MEM, Balfour DJK, Anderson 1M, Evidence that tobacco smoking increases the density of 

(-)-eH]nicotine binding sites in human brain, Journal of Neurochemistry 1988;50:1243-1247. See AR 

(Vol. 136 Ref. 1570). 

164 Norton R, Brown K, Howard R, Smoking, nicotine dose and the lateralisation of electrocortical 

activity, Psychopharmacology 1992;108:473-479. See AR(VoL 3 Ref. 22). 

165 Pritchard WS, Gilbert DG, Duke OW, Flexible effects of quantified cigarette-smoke delivery on EEG 

dimensional complexity, Psychopharmacology 1993;113:95-102. See AR (Vol 3 Ref. 23-1). 

Pritchard WS, Electroencephalographic effects of cigarette smoking, Psychopharmacology 1991;104:485-

490. See AR (VoL 105 Ref. 965). 

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II.A.4. 

effect on the EEG profile.166 When smokers are placed in conditions of low arousal 

induced by mild sensory isolation, cigarette smokffig can have a stimulant effect. 167 In 

other words, smoking can have a relaxing effect in stressful situations and a stimulating 

effect in otherwise nonstimulating circumstances. 

The tobacco industry correctly observes that many substances affect the EEG. But 

what is significant is not that nicotine affects the EEG, but how nicotine does so. 

Nicotine's impact on the EEG: (1) is reproducible, (2) is clinically significant, (3) 

corresponds to other physiological and psychological changes of smoking, and ( 4) is 

similar to certain EEG changes associated with other addictive drugs such as 

benzodiazepines. 168 Altered electrical activity of the brain as demonstrated by EEG is 

convincing evidence of nicotine's significant pharmacological effects on the structure and 

function of the body. 

Smokers perform better on some cognitive tests than do deprived smokers, but 

nicotine does not improve general learning or make smokers generally perform better than 

nonsmokers.169 One leading researcher noted that, after a few hours of abstinence, 

"[P]eople are reporting they can't concentrate as well, they can't get the tasks done as 

Golding JF, Effects of cigarette smoking on resting BEG, visual evoked potentials and photic driving, 

Pharmacology, Biochemistry and Behavior 1988;29:23-32. See AR (Vol 3 Ref. 23-3). 

166 Pritchard WS, Electroencephalographic effects of cigarette smoking, Psychopharmacology 

1991;104:485-490. See AR(Vol 105 Ref. 965). 

167 Golding J, Mangan GL, Arousing and de-arousing effects of cigarette smoking under conditions of 

stress and mild sensory isolation. Psychophysiology 1982;19(4):449-456. See AR (Vol 48 Ref. 101). 

168 Pritchard WS, Electroencephalographic effects of cigarette smoking, Psychopharmacology 

1991;104:485-490, at 485, 488. See AR (Vol 105 Ref. 965). 

169 Surgeon General's Report. 1988, at441. See AR (Vol 129 Ref. 1592). 

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II.A.4. 

well, and our objective perfonnance batteries confirm that. They're right ... it's not just a 

psychological effect. They really aren't functioning as well."170 

Evidence on nicotine's effects on mood and cognition is strongly supported by the 

work of tobacco industry researchers, who concur that people use tobacco for the 

psychoactive effects of nicotine. These researchers contend that nicotine delivered by 

tobacco produces psychoactive effects comparable to the effects of prescription 

tranquilizers. For example, a researcher for the R.J. Reynolds Tobacco Company (RJR), 

W. S. Pritchard, reported that smoking cigarettes could produce "an EEG effect that in 

the benzodiazepine literature is associated with anxiety relief," leading him to conclude 

that "an important smoking motive for deep inhaling smokers might be anxiety reduction" 

and that his results were consistent with the theory that smoking provides beneficial 

psychological effects ("psychological tools" or "resources").171 

In a significant extension of this work, Robinson et al. concluded that ''the 

beneficial effects of smoking on cognitive performance are a function of nicotine absorbed 

from cigarette smoke upon inhalation."172 These RJR researchers performed their study 

because they thought that, although earlier work with various nicotine preparations was 

consistent with the hypothesis that people smoked for "psychopharmacological effects," 

170 Henningfield J, Transcript to the FDA Drug Abuse Advisory Committee, Meeting 27, "Issues 

Concerning Nicotine-Containing Cigarettes and Other Tobacco Products" (Aug. 2, 1994), at 309. 

See AR (Vol 255 Ref. 3445). 

171 Pritchard WS, Electroencephalographic effects of cigarette smoking, Psychopharmacology 

1991; 104:485-490, at 485, 488. See AR (Vol. 105 Ref. 965). 

172 Robinson JH, Pritchard WS, Davis RA, Psychopharmacological effects of smoking a cigarette with 

typical "tar" and carbon monoxide yields but minimal nicotine, Psychopharmacology 1992;1<>8:466-472. 

See AR (Vol 59 Ref. 236). 

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II.A.4. 

the role of nicotine in cigarettes was inconclusive. They therefore compared standard 

nicotine-delivering cigarettes to cigarettes that were similar in all other relevant 

characteristics (e.g., similar gases, tar, etc.) but that provided only "trace" or "minimal" 

levels of nicotine. The regular cigarettes provided psychopharmacological effects, while 

the minimal nicotine cigarettes did not. 

One of the leading tobacco industry-funded proponents of the contention that 

nicotine is not addictive, D. M. Warburton, is also one of the leading proponents of the 

view that people smoke because of the pharmacological actions of nicotine in the brain, 

rather than in the mouth.173 Warburton argues that nicotine is a ''therapeutic agent" that is 

self-administered by smokers to "control their bodily state"174 and that ''the rapid 

absorption and rapid metabolism make this substance suitable for hour-by-hour selfmedication because of the personal control [over dosage needs] that can be exercised. In 

this respect nicotine is superior to other compounds for medication."175 Thus, the 

conclusions oftobacco industry-funded researchers support FDA's finding that a 

reasonable manufacturer would foresee that nicotine in tobacco products produces 

significant pharmacological effects important to users. 

Other Effects: Wei~ht Re~ulation. Nicotine also plays a role in weight regulation. 

The 1988 Surgeon General's Report summarized the available data: 

In summary, there is substantial evidence of an inverse relationship 

between cigarette smoking and body weight. Of 71 studies 

reported since 1970,62 (87%) collectively indicate that smokers 

173 Warburton DM, Nicotine: an addictive substance or a therapeutic agent, Progress in Drug Research 

1989;33:9-41. See AR (Vol 140 Ref. 1657). 

174 /d. at 11. 

175 /d. at 37. 

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weigh less than nonsmokers and that people who quit smoking gain 

weight ... 

Animal studies indicate that nicotine administration results 

in weight loss or decreased weight gains and that cessation of 

nicotine results in body weight gains greater than those of controls 

[animals that did not receive nicotine] .... 

Recent research on nicotine polacrilex gum with humans 

corroborates the role of nicotine in body weight effects.176 

II.A.5. 

Numerous studies show that many tobacco consumers use tobacco to control their 

weight. For example, in two surveys, between one-third and one-half of young people 

reported that controlling weight was one of their reasons for smoking.177 

An extensive discussion of the physiological and central nervous system effects of 

nicotine is available in the 1988 Surgeon General's Report. 178 

Thus, aside from addiction, there are other foreseeable pharmacological effects of 

nicotine use that are important to users; that these effects are actual reasons for 

consumption is discussed in section II.B.3., below. 

5. Cigarettes and Smokeless Tobacco Deliver Pharmacologically Active 

Doses of Nicotine 

Currently marketed cigarettes and smokeless tobacco deliver sufficient doses of 

nicotine to cause addiction and lead to other significant pharmacological effects that cause 

continued use of the products. This robust conclusion is supported by published research 

presented in section II.A., above, and thus is foreseeable to a reasonable tobacco 

manufacturer. For example, laboratory studies using commercial cigarettes demonstrate 

that the products contain pharmacologically active levels of nicotine; epidemiological data 

176 Surgeon General's Report, 1988, at 431-432. See AR (VoL 129 Ref. 1592). 

177 /d. at 438-440. 

178 /d. at381-458. 

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II.A.5. 

show that actual tobacco consumers do become addicted. Four additional types of 

evidence conclusively demonstrate that tobacco products deliver sufficient doses of 

nicotine: (1) measurements of blood nicotine levels after consumption of tobacco 

products; (2) laboratory studies using doses of nicotine that are equivalent to those 

imparted by tobacco use; (3) studies demonstrating that nicotine levels control tobacco 

consumption behavior (known as "compensation"); and ( 4) studies of nicotine 

replacement therapy. 

Measurement of Blood Nicotine Levels. Evidence demonstrates that tobacco 

users receive pharmacological doses of nicotine when they consume cigarettes and 

smokeless tobacco. A currently marketed cigarette typically delivers about 1 mg of 

nicotine to the bloodstream of a smoker,179 with individual intake ranging from 0.3 to 3.2 

mg of nicotine per cigarette. 180 Studies have also revealed that, with regular use 

throughout the day, the levels of nicotine in the blood of smokeless tobacco users are 

similar to those observed in cigarette smokers. Data demonstrating that these products 

deliver substantial, pharmacologically active doses of nicotine are summarized in the 

Jurisdictional Analysis. See 60 FR 41571-41575. 

Laboratory Studies. Long before evidence emerged that nicotine is addictive, 

studies demonstrated that the quantitative and even qualitative nature of the effects of 

179 Benowitz NL, Henningfield JE, Establishing a nicotine threshold for addiction, New England Journal 

ofMedicine 1994;331:123-125. SeeAR(Vol 12Ref.l30). 

Gori GB, Lynch CJ, Analytical cigarette yields as predictors of smoke bioavailability, Regulatory 

Toxicology and Pharmacology 1985;5:314-326. See AR (Vol 12 Ref. 142). 

180 Benowitz NL, Henningfield JE, Establishing a nicotine threshold for addiction, New England Journal 

ofMedicine1994;33l:I23-l25. SeeAR(Vol 12Ref.130). 

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II.A.5. 

nicotine were dependent on the dose.181 In the 1980's, particularly important discoveries 

provided indisputable proof that the nicotine dose levels produced by cigarette smoking 

affect the structure and function of the body, and that many of these effects are similar to 

those of prototypic addictive drugs. For example, nicotine, administered in doses 

considered biologically equivalent to those from tobacco use, was found to affect the 

brain's use of energy (cerebral glucose utilization).182 Additionally, nicotine exposure at 

doses equivalent to those from tobacco use altered the brain so that excess nicotine 

receptors appeared on the surfaces of brain cells; this structural change was associated 

with altered responsiveness to nicotine.183 

In addition, nicotine administered to animals in doses and at intervals comparable 

to those humans obtain from smoking produces one of the hallmark effects of addictive 

drugs: brain-mediated reinforcement of self-administration behavior. In the early 1980's, 

Goldberg and colleagues at Harvard and the National Institute on Drug Abuse provided 

unequivocal evidence that nicotine in doses comparable to those obtained in humans could 

181 See Surgeon General's Report, 1988, chaps. 2-6. See AR (VoL 129 Ref. 1592). 

182 Id. at 85-88. 

183 Marks MJ, Burch JB, Collins AC, Effects of chronic nicotine infusion on tolerance development and 

nicotine receptors, Journal of Pharmacology and Experimental Therapeutics 1983;226:817-825. See AR 

(Vol. 41 Ref. 103). 

Surgeon General's Report, 1988, at 53-54. See AR (VoL 129 Ref. 1592). 

ld. at 32-33. 

Benwell MEM, Balfour DJK, Anderson JM, Evidence that tobacco smoking increases the density of 

(-)-eH]nicotine binding sites in human brain, Journal of Neurochemistry 1988;50:1243-1247. See AR 

(Vol. 136 Ref. 1570). 

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II.A.S. 

function powerfully to engender repetitive drug-seeking behavior in monkeys.184 In the 

late 1980'S, Corrigan and Coen developed a rat model utilizing key dosing parameters of 

cigarette smoking and smokeless tobacco use. This model provided for the delivery of 

very rapid and small doses and led the animals to repeatedly administer nicotine to 

themselves.185 

Nicotine Control of Tobacco Use. Nicotine's key pharmacological role in actual 

tobacco products is also confirmed by evidence that tobacco users adjust their 

consumption based on the products' nicotine levels. Manipulation of nicotine levels in 

cigarettes while holding the tar content constant has shown that nicotine is responsible for the 

maintenance of cigarette smoking behavior. Cigarette smokers given cigarettes with a high 

nicotine content decrease the number of cigarettes smoked.186 Modifying the amount of 

nicotine available by varying the length of cigarette smoked will influence the amount of the 

cigarette smoked187 and the characteristics of smoking (e.g., number of puffs, puff duration, 

puff size, depth of inhalation, amount of tobacco smoked).188 When cigarettes are shorter, 

184 Goldberg SR., Speal.man RD, Goldberg DM, Persistent behavior at high rates maintained by 

intravenous self-administration of nicotine, Science 1981;214:573-575. See AR(VoL 5 Ret: 35-2). 

185 Corrigan W A. Coen KM, Nicotine maintains robust self-administration in rats on a limited access 

schedule, Psychopharmacology 1989;99:473-478. See AR (VoL 347 Ref. 5495). 

186 Goldfarb T, Gritz ER. Jarvik ME, et al., Reactions to cigarettes as a functioo of nicotine and "tar," Clinical 

Pharmacology and Therapeutics 1976; 19:767-772. See AR (VoL 39 Ret: 53). 

187 Jarvik ME, Popek P, Schneider NG, et al., Can cigarette size and nicotine content in:flumce smoking and 

puffing rates? Psychopharmacology 1978;58:303-306. See AR (VoL 41 Ret: 86). 

188 Surgeoo General's Report, 1988, at 158-163. See AR (VoL 129 Ret: 1592). 

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II.A.5. 

people smoke more of them 189 Nemeth-Coslett and Griffiths showed that puff duration and 

puff volume are inversely proportional to the length of the cigarette.190 

Studies conducted by Stolennan, 191 Nemeth-Coslett et al., 192 and Pomerleau et al. 193 

provide convincing evidence that tobacco products provide pharmacologically active doses of 

nicotine. Pretreatment of cigarette smokers with mecamy1amine, an antagonist to nicotine that 

enters the brain, produced a dose-dependent increase in cigarette smoking (ie., increases in 

puffs per cigarette, puff duration, and cigarettes per session and decreases in intercigarette 

interval and interpuff interval) that resembled what one would expect to see if the nicotine dose 

in the cigarette had been decreased. An increase in nicotine plasma levels also accompanied the 

increase in cigarette consumption. Pretreatment with another nicotine antagonist that did not 

enter the brain had no such effects. These studies clearly demonstrate that obtaining a 

pharmacologically active dose of nicotine in the brain motivates the amount of tobacco 

consumed on a daily basis. 

Evidence from Nicotine Replacement Products. As described in the Jurisdictional 

Analysis, 60 FR 41565-41566, the ability of nicotine nasal spray to produce some of the 

classic characteristics of addiction to nicotine supports the position that tobacco users 

189 Jarvik ME, Popek P, Schneidel' NG, et al., Can cigarette size and nicotine oontent influence smOOilg and 

puffing rates? Psychopharmacology 1978;58:303-306. See AR (Vol 41 Ret: 86). 

190 Surgeoo General's Rep<rt, 1988, at 161. See AR (Vo1129 Ret: 1592). 

191 Stolerman IP, Goldfarb T, Fink R. et al., Influencing cigarette smoking with nicotine antagonists, 

Psychopharmacologia 1973;28:247-259. See AR (Vol. 42 Ref. 149). 

192 Nemeth-Coslett R. Henningfield JE, 0' Keffe MK, et al., Effects of mecamylamine on human cigarette 

smoking and subjective ratings, Psychopharmacology 1986;88:420-425. See AR (Vol. 41 Ref. 108). 

193 Pomerleau CS, Pomerleau OF, Majchrzak MJ, Mecamylamine pretreatment increases subsequent 

nicotine self-administration as indicated by changes in plasma nicotine level, Psychopharmacology 

1987;91:391-393. See AR (Vo142 Ref. 112). 

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II.A.5. 

seek nicotine primarily for its systemic pharmacological effects and not for its acute 

sensory effects. In contrast to cigarette smoke, aqueous nicotine spray does not provide 

the user any pleasing sensory characteristics. In fact, the spray can be irritating and 

unpleasant to use, and excessive use can cause ulcerations of the nasal mucosa. 

Notwithstanding the unpleasantness of the nicotine delivery mechanism and the presence 

of painful ulcerations that were further aggravated by its continued use, the spray was 

used to maintain nicotine dependence for some participants in clinical trials submitted to 

FDA.t94 

Studies of nicotine replacement therapies also demonstrate efficacy in maintaining 

abstinence from smoking.195 The ability of nicotine to promote abstinence, even when 

delivered through the skin, without any taste or flavor, demonstrates its key role as a 

reinforcer of tobacco consumption. Based on these data, among others, organizations 

with expertise in pharmacology and addiction have determined that cigarettes and 

smokeless tobacco deliver pharmacologically active doses of nicotine. In the 1986 

analysis of smokeless tobacco, the Surgeon General determined that smokeless tobacco 

use can be addictive.196 In 1988, after an even more extensive consideration of the 

potential addictiveness of nicotine, the Surgeon General determined that (1) "cigarettes 

and other forms of tobacco are addicting;" (2) "nicotine is the drug in tobacco that causes 

194 FDA Drug Abuse Advisory Committee Background Information (Aug. 1, 1994), Joint Abuse Liability 

Review of Nicotine Nasal Spray. See AR (Vol 9 Ref. 117). 

195 See appendix 1 to Jurisdictional Analysis. See AR (Vol 1 Appendix 1). 

196 Department of Health and Human Services, Public Health Service. The Health Consequences of Using 

Smokeless Tobacco: A Report of the Advisory Committee to the Surgeon General, 1986, NIH_Publication 

No. 86-2874 (Bethesda MD: DHHS, PHS, 1986) (hereinafter cited as Surgeon General's Report. 

Smokeless Tobacco, 1986), at viii. See AR (Vol 128 Ref. 1591). 

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44750 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.A.6. 

addiction;" and (3) "the pharmacological and behavioral processes that determine tobacco 

addiction are similar to those that determine addiction to drugs such as heroin and 

cocaine."197 On August 2, 1994, FDA's Drug Abuse Advisory Committee, an independent 

group composed primarily of experts on addiction science, concluded that nicotine as 

delivered by commonly used tobacco products can produce strong physiological effects, 

including addiction.198 

6. Conclusion 

Nicotine is addictive and produces foreseeable psychoactive and pharmacological 

effects in a substantial proportion of tobacco users. This conclusion is so robust-and the 

evidence for it is so voluminous-that every major public health organization and relevant 

scientific authority in the world is in agreement. It is FDA's responsibility to base its 

regulatory actions on well-founded and accepted scientific facts. In this case, FDA 

believes that a very strong scientific basis exists on which to conclude that it is foreseeable 

that nicotine will produce pharmacological effects in a substantial number of tobacco 

consumers and that those consumers will use tobacco products to satisfy their addiction 

and to obtain the other pharmacological effects of nicotine. To conclude otherwise would 

not be credible. 

197 Surgeon General's Report, 1988, at 13-17. See AR(Vol129 Ref. 1592). 

198 Transcript to the FDA Drug Abuse Advisory Committee, Meeting 27, "Issues Concerning NicotineContaining Cigarettes and Other Tobacco Products" (Aug. 2, 1994), at 336-342. See AR (Vof 255 Ref. 

3445). 

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7. Response to Additional Comments 

a. Comments on the Professional Consensus That Nicotine Is Addictive 

1. More than 150 professional health organizations or chapters, representing 

over 600,000 individuals and organizations, commented on whether nicotine is addictive. 

Virtually all concluded that it is. These groups include the following: 

• The American Cancer Society 

• The American College of Physicians 

• The American Heart Association 

• The American Lung Association 

• The American Medical Association 

• The American Psychiatric Association 

• The American Psychological Association 

• The American Society of Addiction Medicine 

• The College on Problems of Drug Dependence 

• The Society of General Internal Medicine 

• The Society for Head and Neck Surgeons 

• The Society for Research on Nicotine and Tobacco 

• The Virginia Society of Hospital Pharmacists 

FDA also notes that, of the more than 1,100 physicians, pharmacists, and other health 

professionals who commented on whether nicotine is addictive, virtually all agreed that 

it is. 

The Agency concurs with the unanimous conclusion of these organizations, most 

of which have expertise in this area. FDA notes that organizations with vast experience 

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II.A.7. 

examining other addictive drugs reached the same conclusion as organizations with vast 

experience studying nicotine. The former organizations include the American Psychiatric 

Association, the American Society of Addiction Medicine, the National Institute on Drug 

Abuse, and the World Health Organization. The latter include the American College of 

Chest Physicians and the Surgeon General's expert committees on tobacco. 

2. The tobacco industry disputes the process by which the American 

Psychiatric Association concluded that nicotine is addictive. The industry quotes several 

critical comments about the Diagnostic and Statistical Manual to suggest that the entire 

DSM structure of classifying all psychiatric diagnoses is flawed. This position, held by a 

small minority of psychiatrists, has been decisively rejected by the profession as a whole. 

The DSM-IV is now used throughout the world to classify psychiatric disorders, including 

drug dependence. 

FDA notes that, aside from this argument against the American Psychiatric 

Association, the industry does not dispute the expertise or decision-making capabilities of 

any of the other medical authorities originally cited by FDA. These authorities-which 

unanimously have concluded that nicotine is addictive-include the U.S. Surgeon General, 

the World Health Organization, the American Medical Association, the American 

Psychological Association, the Royal Society of Canada, and the Medical Research 

Council of the United Kingdom. 

b. Comments on the Definition of Addiction 

1. Several tobacco industry comments argue that cigarettes and smokeless 

tobacco are not addictive under a now-discarded definition of addiction developed in the 

1950's and used by the U.S. Surgeon General in 1964. 

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II.A.7. 

FDA disagrees with these comments. First. the tobacco industry borrows only 

selectively from the 1950's definition of addiction, emphasizing only certain criteria from 

that definition. Second, while the scientific community has rejected this historical 

defmition in part because it failed to clearly classify cocaine and amphetamines as 

addictive, see section ll.A.3.b., above, subsequent evidence has shown that nicotine would 

now qualify as addictive even by this outdated definition. The criteria cited by the 

Surgeon General,199 which were not met by nicotine on the basis of data available in the 

early l%0's, are all met on the basis of data available today. These include the following: 

• Surgeon General's 1964 conclusion: No overpowering compulsion to use the drug. 

Subseguent data: Ample documentation exists today that persons dependent upon 

cocaine, heroin, or alcohol fmd it as difficult to abstain from tobacco as from these 

other drugs and that persons who know that their lives are in imminent danger from 

smoking nevertheless continue to smoke. 200 

• Surgeon General's 1964 conclusion: No tendency to increase the dose. 

199 Departtnent of Health, Education, and Welfare, Public Health Service, Smoking and Health: Report of 

the Advisory Committee to the Surgeon General of the Public Health Service (Washington DC: GPO, 

1964), at 349-352. See AR (Vol 43 Ref. 156). 

200 Henningfield JE, Cohen C, Slade JD, Is nicotine more addictive than cocaine? British Journal of 

Addiction 1991;86:565-569. See AR (Vol277 Ref. 3904). 

Kozlowski LT, Wilkinson DA, Skinner W, et al., Comparing tobacco cigarette dependence with other 

drug dependencies, Journal of the American Medical Association 1989;261:898-901. See AR (Vol84 

Ref. 350). 

West R, Himbury S, Smoking habits after laryngectomy, British Medical Journal1985;291:514-515. See 

AR (Vol. 6 Ref. 59). 

Davison G, Duffy M, Smoking habits of long term survivors of surgery for lung cancer, Thorax 

1982;37:331-333. See AR (Vol6 Ref. 58). 

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Subsequent data: We now know that only about 10% of cigarette smokers are able to 

sustain a level of intake of five or fewer cigarettes per day. For example, one study 

found that 90o/o of people who smoke escalate to daily doses of five or more 

cigarettes. 201 Cigarettes are similar to morphine-like drugs in that, when either 

substance is readily available to the user, intake often escalates over a period of 

months or years and then stabilizes at a level that may vary little from day to day for 

many years. 202 

• Surgeon General's 1964 conclusion: No physical dependence on the effects of the 

drug. 

Subsequent data: The documentation that nicotine produces physical 

dependence has now been provided by scores of clinical treatment studies 

and laboratory studies with humans and animals. 203 There is a characteristic 

201 Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of North America 

1992;76(2):415-437. See AR (Vol 535 Ref. 96, vol. ill.A). 

Henningfield JE, Cohen C. Slade JD, Is nicotine more addictive than cocaine? British Journal of 

Addiction 1991;86:565-569. See AR (Vol277 Ref. 3904). 

202 Jaffe JH, Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of 

Therapeutics, 8th ed. (New York: Pergamon Press, 1990), chap. 22 (522-573). See AR (Vol535 

Ref. 96, vol lli.G). 

203 Henningfield JE, Cohen C, Slade JD, Is nicotine more addictive than cocaine? British Journal of 

Addiction 1991;86:565-569. See AR (Vol 277 Ref. 3904). 

Kozlowski LT, Wilkinson DA, Skinner W, et al., Comparing tobacco cigarette dependence with other 

drug dependencies, Journal of the American Medical Association 1989;261:898-901. See AR (Vol84 

Ref. 350). 

Surgeon General's Report, 1988, at 145-240. See AR (Vol. 129 Ref. 1592). 

Corrigan W A, Herling S, Coen KM, Evidence for a behavioral deficit during withdrawal from nicotine 

treatment, Pharmacology Biochemistry and Behavior 1989; 33:559-562. See AR (Vol. 139 Ref. 1626). 

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tobacco withdrawal syndrome that has been recognized by leading medical 

organizations. 204 

• Surgeon General's 1964 conclusion: Detrimental effects on society are not well 

documented. 

Subsequent data: The detrimental effects on smokers themselves were recognized in 

1964; however, it was not until the 1980's that the direct adverse effects of smoking 

upon nonsmokers and the fetuses of pregnant smokers were unequivocally 

documented.205 Moreover, it is now recognized that nicotine has a severe adverse 

economic impact on many aspects of society.206 

In addition to these four specific criteria, the Surgeon General in 1964 mentioned 

several other reasons for failing to categorize nicotine as addicting. These conclusions and 

the current data are as follows: 

• Surgeon General's 1964 conclusion: Cigarette smokers did not become intoxicated. 

Levin ED, Morgan MM, Galvez C, et al., Chronic nicotine and withdrawal effects on body weight and 

food and water consumption in female rats, Physiology and Behavior 1987; 39:441-444. See AR (Vol. 

278 Ref. 3932) 

204 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association. 1994), at 244-245. See AR (Vo137 Ref. 8). 

205 Department of Health and Human Services, Office on Smoking and Health, The Health Consequences 

of Involuntary Smoking: A Repon of the Surgeon General (Atlanta: DHHS, 1986) (hereinafter cited as 

Surgeon General's Report, Involuntary Smoking, 1986). See AR (Vo1128 Ref. 1591). 

206 McGinnis 1M, Foege WH, Actual causes of death in the United States, Journal of the American 

Medical Association 1993;270(18):2207-2212. See AR (Vol 2 Ref. 15-1). 

Hearing on Preventive Health: An Ounce of Prevention Saves a Pound of Cure, Before the Special 

Committee on Aging, U.S. Senate, 103d Cong., 1st Sess. 2 (May 6, 1993) (statement of Roger Herdman, 

Maria Hewitt, Mary Laschober on smoking-related deaths and fmancial costs: Office of Technology 

Assessment Estimates for 1990). See AR (Vol. 170 Ref. 2024). 

Hodgson T A, Cigarette smoking and lifetime medical expenditures, National Center for Health Statistics, 

Milbank Quarterly 1992;70(1):81-125. See AR (Vo119 Ref. 22). 

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Subsequent data: It is now well understood that nicotine can intoxicate, intoxication is 

a sign of nicotine overdose, and first-time users often become intoxicated.207 The 

ability of nicotine to produce strong physiological and behavioral effects, including 

death at high doses, is no less than that of amphetamine or morphine. 208 In practice, 

intoxication is rarely evident in regular users because they have developed an 

extremely high level of tolerance to this effect of nicotine.209 

• Surgeon General's 1964 conclusion: Subjective effects of nicotine itself were not well 

documented. The 1942 study by Johnston showing that intravenous nicotine could 

mimic the effects of smoking210 

was apparently given little weight because the study 

did not have the appropriate control conditions to rule out bias. 

Subsequent data: By the 1980's and 1990's, many properly controlled studies using 

nicotine delivered intravenously, intranasally, and by inhalation essentially confirmed 

Johnston's fmdings. 211 

207 Surgeon General's Report, 1988, at 593-594. See AR (Vol 129 Ref. 1592). 

208 /d. at 272-274, 594. 

209 /d. at 593-595. 

210 Johnston LM, Tobacco smoking and nicotine, lAncet 1942;2:742. See AR (Vol 278 Ref. 3947). 

211 See, e.g., Jones RT, Farrell TR III, Heming Rl, Tobacco smoking and nicotine tolerance, in SelfAdministration of Abused Substances: Methods for Study, ed. Krasnegor NA, NIDA Research 

Monograph 20 (Rockville MD: National Institute on Drug Abuse, 1978), at 202-208. See AR (Vol 41 

Ref. 88). 

Henningfield JE, Miyasato K, Jansinski DR, Abuse liability and pharmacodynamic characteristics of intravenous 

and inhaled nicotine, Journal of Pharmacology and Experimental Therapeutics 1985;234:1-12. See AR (Vol. 

39 Ref. 69). 

Pomerleau CS, Pomerleau OF, Euphoriant effect of nicotine in smokers, Psychopharmacology 

1992;108:460-465. See AR (Vol. 87 Ref. 426). 

Perkins KA, Grobe JE, Epstein LH, et al., Chronic and acute tolerance to subjective effects of nicotine, 

Pharmacology, Biochemistry and Behavior 1993;45:375-381. See AR (Vol. 271 Ref. 3728). 

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• Surgeon General's 1964 conclusion: No well-controlled demonstration that nicotine 

substitution could facilitate tobacco abstinence. 

Subsequent data: The absence of a nicotine-delivering medication effective in helping 

people to achieve abstinence was also noted in the 1964 report. There is now 

powerful evidence that products devoid of any tobacco constituent except nicotine are 

effective aids to smoking cessation and to providing relief of withdrawal symptoms.212 

• Surgeon General's 1964 conclusion: Personality deficit criteria did not appear 

satisfied. 

Subsequent data: It was noted that not categorizing tobacco use as an addiction 

avoided the inference that smokers would be considered to have "serious personality 

defects" under the definition of addiction then in place. We now understand that many 

people who develop addictions to cocaine, heroin, alcohol, or nicotine have no 

documented underlying personality disorder. Rather, the major cause of addiction is 

Perkins KA. Grobe JE, Epstein LH, et al., Effects of nicotine on subjective arousal may be dependent on 

baseline subjective state, Journal of Substance Abuse 1992;4:131-141. See AR(Vol348 Ref. 5516). 

Sutherland G, Stapleton 1 A, Russell MAH, et al., Randomised controlled trial of nasal nicotine spray in 

smoking cessation, lAncet 1992;340:324-329. See AR (VoL 91 Ref. 527). 

Sutherland G, Russell MA, Stapleton I, et al., Nasal nicotine spray: a rapid nicotine delivery system, 

Psychopharmacology 1992;108:512-518. See AR(VoL 91 Ref. 526). 

212 Fagerstrom KO, Sa we U, Tonnesen P, Therapeutic use of nicotine patches: efficacy and safety, 

Journal of Drug Development 1993;5:191-205. See AR (Vol 76 Ref. 156). 

Fiore MC, Smith SS, Iorenby DE, et al., The effectiveness of the nicotine patch for smoking cessation: a 

meta-analysis, Journal of the American Medical Association 1994;271: 1940-1947. See AR (Vol. 6 Ref. 

64-1). 

Fiore MC, Iorenby DE, Baker TB, et al., Tobacco dependence and the nicotine patch, Journal of the 

American Medical Association 1992;268:2687-2694. See AR (VoL 351 Ref. 5609). 

Surgeon General's Report, 1988, at 208. See AR (VoL 129 Ref. 1592). 

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the presence of a psychoactive, reinforcing drug and adequate access to the drug to 

enable the development and sustenance of addiction. 

Thus, it is virtually certain that tobacco use would be considered an addiction under the 

definition used by the Surgeon General in 1964. Indeed, FDA notes that a study 

sponsored by the tobacco industry in 1963 concluded that tobacco was addictive under the 

same definition used by the Surgeon General in 1%4.213 

2. The tobacco industry observes that defmitions of addiction from several 

medical authorities are not identical, quotes several experts stating that whether tobacco is 

addictive depends on the defmition of addiction, and presents excerpts from several 

scientific publications to suggest that no precise definition of addiction exists. The 

industry also argues that the use of the word "addiction" rather than "dependence" is 

political and claims that the modem defmition of addiction is motivated by public health 

goals, morality, and lawsuits. The industry concludes that the modem definition of 

addiction is inappropriate for use in considering whether a product is a drug under the 

Act. 

FDA disagrees. As discussed in section II.A3.b., above, there is remarkable 

consensus among medical authorities around the world on the meaning of addiction. The 

subtle variations among written definitions reflect wording and emphasis, not significant 

differences in concepts; such variations are not surprising, given that medical organizations 

often write their own defmitions of diseases and disease progression. International 

consistency on the meaning of addiction is demonstrated by the fact that all relevant 

213 Knapp PH, Bliss CM, Wells H, Addictive aspects in heavy cigarette smoking, American Journal of 

Psychiatry 1963;119:966. See AR (Vol. 528 Ref. 97, appendix 16). 

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II.A.7. 

scientific bodies have concluded that nicotine is addictive. Indeed, the tobacco industry 

fails to suggest any reason to believe that the current international understanding of 

nicotine as addictive will change in the future. 

The industry's quoting of addiction experts on the importance of defining 

addiction is not an argument against FDA's position. It is axiomatic that whether nicotine 

is addictive depends on the definition of addiction. The industry fails, however, to show 

that nicotine would not be considered addictive under any of the current defmitions of 

addiction. 

The industry's use of an article from the Journal of the American Medical 

Association to show that the definition of addiction is imprecise is equally unpersuasive.214 

The article describes how a national panel was appointed in 1983 to try to settle variations 

in definitions relating to substance abuse. The panel surveyed dozens of experts from 

major scientific organizations and produced a consensus defmition of addiction: "A 

chronic disorder characterized by the compulsive use of a substance resulting in physical, 

psychological, or social harm to the user and continued use despite that harm.'m5 This 

defmition again is entirely consistent with the modern defmition of addiction relied on by 

FDA, not the tobacco industry's preferred version from the 1950's. 

The industry selectively quotes from several scientific publications that discuss 

subtle arguments over the precise definition of addiction. But these debates occur within a 

214 Rinaldi RC, Steindler EM, Wilford BB, et al., Clarification and standardization of substance abuse 

terminology, Journal of the American Medical Association 1988;259(4):555-557. See AR (Vol. 535 Ref. 

96 vol. III.L). 

215 ld. 

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broad understanding of addiction that has garnered overwhelming consensus. This 

understanding universally considers nicotine to be addictive. 

II.A.7. 

FDA, like many scientific and public health authorities, uses "addiction" and 

"dependence" interchangeably. Regardless of the terminology used, the concept that 

nicotine has substantial pharmacological effects on the brains of users that cause people to 

use tobacco compulsively is the same. Furthermore, any implication that the modem 

scientific understanding of addiction is motivated by public health goals, morals, or 

lawsuits is mistaken. As discussed in section II.A.3.b., above, the tobacco industry's 

preferred definition was discarded on scientific grounds in 1964, 15 years before nicotine 

was first considered addictive. 

Thus, there is no basis upon which to conclude that FDA's fmding that nicotine is 

addictive-a conclusion with nearly universal scientific backing-is not useful in 

determining whether nicotine is a "drug" under the Act. The fact that nicotine meets all 

currently accepted scientific defmitions of a dependence-producing drug and that these 

defmitions include as a criterion psychoactive effects on the brain is highly relevant to the 

Agency's inquiry. 

c. General Comments on Laboratory Evidence of Addictive Potential 

1. Comments from numerous heahh professionals and scientists agree with FDA 

that 1aboratory data in animals and humans provide compelling evidence that nicotine in 

cigarettes and smoke1ess tobacco is a phannacologically active agent that causes addiction. 

For example, the American Medical Association stated that it "concurs with the scientific 

rationale and legal basis for the FDA proposed action," and that it "strongly supports the 

scientific basis regarding nicotine ... and its essential role in maintaining demand for tobacco 

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II. A.?. 

products." Similarly, the Coalition on Smoking OR Heahh-an organization representing the 

American Heart Association, American Lung Association, and American Cancer Societycarefully reviewed the Jurisdictional Analysis ''for accuracy, objectivity, and completeness" and 

concluded that ''the FDA documents represent the most comprehensive, objective and 

scientifically accurate analysis of the impact of nicotine containing cigarettes and smokeless 

tobacco on the body ever conducted." 

2. The tobacco industry repeatedly comments that evidence from one laboratory 

test by itself is not enough to justify the conclusion that nicotine is addictive. For example, the 

industry argues that positive resuhs in drug discrimination tests in animals are not sufficient to 

prove that nicotine is addictive, as some nonaddictive substances also test positive. The 

industry repeats this same argument for subjective effects testing and animal self-administration 

studies. On several occasions, the industry uses quotations from addiction experts to support 

these arguments. 

FDA agrees that evidence from each test alone may not prove conclusively that 

nicotine is addictive. But addiction authorities around the world determine whether a 

substance is addicting by considering resuhs from all of the tests together. Nicotine tests 

positive in animal and human drug discrimination tests, subjective effects tests, and animal and 

human self-administration tests. Considering such evidence, the scientific community has 

overwhelmingly concluded that nicotine is addictive. 

The tobacco industry's selective use of quotations from addiction experts illustrates the 

point. On several occasions, the industry tries to make it appear that the individuals quoted 

believe that addiction testing methods are not reliable or that nicotine is not addictive. In fact, 

these individuals are on record as reaching the opposite conclusions. For example, the 

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II.A.7. 

tobacco industry selectively quotes from the work of Balster that "[t]he results of selfadministration studies should not be used alone for evaluating abuse potential. A number 

of drugs which probably possess minimal or no abuse potential have been shown to 

function as reinforcers in preclinical drug self-administration studies." 216 The industry 

also culls a quote from Woods that "[i]t should be clear that the proposition, viz., 

that the drugs that serve as reinforcers in animals are abused by humans, is greatly 

oversimplified."217 In both cases, however, the authors believe that demonstrating that a 

drug tests positive in both self-administration studies and drug discrimination studies is 

sufficient evidence of its abuse liability.218 Nicotine has repeatedly proved positive in both 

tests. 

d. Comments on Tests of Psychoactivity 

1. The tobacco industry disputes FDA's analysis of drug discrimination tests in 

animals. The industry argues that the purpose of drug discrimination studies is merely to 

demonstrate that the test subject "recognizes" or "identifies" a substance that has been 

administered. The industry further claims that laboratory animals have been able to 

216 Balster RL, Drug abuse potential evaluation in animals, British Journal of Addiction 1991 ;86: 1549-

1558, at 1555. See AR (VoL 8 Ref. 89). 

217 Woods J, Some thoughts on the relations between animal and human drug-taking, Progress in Neuropsychopharmacology and Biological Psychiatry 1983;7:577-584, at 582. See AR (VoL 535 Ref. 96, 

vol. III.N). 

218 Balster RL, Drug abuse potential evaluation in animals, British Journal of Addiction 1991;86: 1549-

1558, at 1555. See AR (VoL 8 Ref. 89). 

Woods J, Some thoughts on the relations between animal and human drug-taking, Progress in Neuropsychopharmacology and Biological Psychiatry 1983;7:577-584, at 582. See AR (VoL 535 Ref. 96, 

vol. III.N). 

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II.A.7. 

discriminate nicotine in the studies cited by FDA because researchers used amounts of nicotine 

that vastly exceed the nicotine yields in commercial cigarettes. 

FDA disagrees. Drug discrimination studies are not just a measure of whether or not 

the subject can "recognize" or "identify'' a substance; these studies assess the psychoactivity of 

a drug. Drugs that can be successfully discriminated from placebo are psychoactive. 219 

FDA also disagrees that animals can discriminate nicotine's stimulus properties only 

when receiving doses that vastly exceed those absorbed by human smokers. It is misleading to 

make a direct comparison between the training dose administered to animals and the nicotine 

yields of commercial cigarettes. Phannacological effects elicited by a drug are the resuh of its 

plasma concentration and the amount of drug at the receptor site (ie., site of action), not 

necessarily of how much drug is in the product or the amount of drug administered per 

kilogram of body weight. This distinction becomes critical when comparing animals with 

different abilities to metabolize drugs. The same amount of drug per kilogram administered to 

two species may lead to radically different plasma concentrations, for example, if one species 

breaks down and excretes the drug faster than the other. 

A study by Pratt et al. 220 cited by the comment actually deiOOnstrates that doses of 

nicotine that can be discriminated by rats yieJd a plasma concentration of nicotine that is 

comparable to the plasma concentration of nicotine in human SIOOkers. Accordingly, rats can 

learn to discriminate a dose of nicotine physiologically comparable to the dose received by 

219 Surgeon General's Report, 1988, at 170-171. See AR (Vol 129 Ref. 1592). 

220 Pratt J A, Stolennan JP, Garcha HS, et al., Disaiminative stimulus properties of nicotine: further evidence 

for mediation at a cholinergic receptor, Psychopharmacology 1983;81:54-60. See AR (Vol 8 Ret: 90-2). 

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~cigarette smokers and smokeless tobacco users. Two studies by Stolennan et al.221 also 

,demonstrated that rats can discriminate from saline a dose of nicotine that is comparable to the 

dose delivered to human tobacco users. 

2. The tobacco industry argues that nicotine's action as a discriminative stimulus 

is not exactly the same as that of cocaine and amphetamine. 

It is well known that nicotine does not behave identically to cocaine and amphetamine 

in drug discrimination experiments. This difference does not mean that nicotine is not an 

addictive drug, however. Amphetamine, morphine, alcoho~ and nicotine can all be 

differentiated from one another by animals and humans because of their unique effects. The 

fact that nicotine is not identical to cocaine is no more relevant than the fact that cocaine is not 

identical to morphine. What is critical is that all of these drugs are psychoactive because of 

their effects on the brain. The published data have shown that there are qualitative differences 

in these drugs' discriminative stimulus effects and that nicotine produces effects more 

amphetamine-like than morphine-like in animals and humans.222 Thus, while nicotine's 

discriminative stimulus effects are unique, they resemble the effects of stimulants more closely 

than those of sedatives. These data confinn that nicotine produces-critical discriminative and 

subjective effects shared by dependence-producing drugs. 

221 Stolerman IP, Garcha HS, Pratt JA. et al., Role of training dare in discrimination of nicotine and related 

compounds by rats, Psychopharmocology 1984;84:413-419. See AR(Vol. 8 Ret: 90-5). 

Stolerman IP, Discriminative stimulus effects of nicotine in rats trained under different schedules of 

reinforcement, Psychopharmacology 1989;97:131-138. See AR(Vol9 Ref. 90-6). 

222 Pratt JA. Stolerman IP, Garcha HS, et al., Discriminative stimulus properties of nicotine: further evidence 

for mediation at a cholinergic receptor, Psychopharmacology 1983;81:54-60. See AR (Vol. 8 Ref. 90-2). 

Stolerman IP, Garcha HS, Pratt J A. et al., Role of training dare in discrimination of nicotine and related 

compounds by rats, Psychopharmocology 1984;84:413419. See AR(Vol. 8 Ret: 90-5). 

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3. The tobacco industry contests FDA's interpretation of three studies on drug 

discrimination in humans cited in the Jurisdictional Analysis. The industry concludes that there 

is no evidence to suggest that nicotine functions as a discriminative stimulus in humans. 

Upon review of these studies and the administrative record, FDA concludes that there 

is convincing evidence that nicotine tests positive in human drug discrimination studies. The 

industry disputes the conclusion that a study by Kallman et al. proved that discrimination 

occurred in the central nervous system223 FDA, however, never drew this conclusion. FDA 

cited this study to demonstrate that smokers can differentiate between high- and low-nicotine 

cigarettes, a finding conceded by the industry. Much other evidence in the administrative 

record, described in section II.A3.c.i ofthis document and in the 1988 Surgeon General's 

report, 224 demonstrates that the discrimination occurs in the central nervous system 

The industry also claims that a study by Perkins et al. did not demonstrate 

discrimination.225 Noting that male subjects identified 2 uglkg of nicotine (administered by 

nasal spray) versus placebo correctly 50% of the time, the industry claims that this is 

exactly the percentage that would do so by chance. The industry concludes that the drug 

discrimination demonstrated by this study was due purely to chance and was not due to 

any effects of nicotine in the brain. 

223 Kallman WM, Kallman MJ, Harry GJ, et al., Nicotine as a disaiminative stimulus in human subjects, 

in Drug Discrimination: Applications in CNS Pharmacology, eds. Colpaert FC, SlangenJL (Amsterdam: 

Elsevier Biomedical Press, 1982), at 211-218. See AR (Vol 41 Ref. 89). 

224 Surgeon General's Report, 1988, at 176-178. See AR(Vol129 Ref. 1592). 

225 Perkins K, Grobe J, Scierka A, et al., Discriminative stimulus effects of nicotine in smokers, in 

International Symposium on Nicotine: The Effects of Nicotine on Biological Systems II, eds. Clarke PBS, 

Quik M, Thurau K, et al. (Basel: Birkbauser Verlag, 1994), at 111. See AR(Vol42 Ref. 111). 

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II.A.7. 

Upon review of the Perkins study, FDA notes that the industry has seriously 

misinterpreted its results. The study's objective was to determine whether subjects could 

differentiate the low dose of 12 uglkg of nicotine versus placebo, and its finding was that 

100% of all subjects correct! y identified nicotine at this dose at least 80% of the time. The 

authors concluded, "These findings indicate that humans are able to discriminate among 

low doses of nicotine."226 (The dose of 12 ug/kg of nicotine is less than the typical dose 

of nicotine received from a cigarette.227

) Having demonstrated this finding, the authors 

went on to test even smaller doses to determine the lowest dose of effective 

discrimination, that is, the dose at which subjects discriminated nicotine at least 50% of 

the time. That such a dose exists does not disprove nicotine's role as a discriminative 

stimulus, as implied by the tobacco industry; a minimal dose that cannot be differentiated 

from placebo exists for all psychoactive drugs. 

Finally, the industry contends that a study by Goldfarb et al. 228 is not a formal 

"discrimination" study. The Goldfarb study was cited not as a discrimination study but to 

demonstrate that humans can differentiate between cigarettes with different nicotine yields, 

a conclusion conceded by the industry. 

4. The tobacco industry argues that studies of the "subjective effects" of nicotine 

have vague methods and use subjects who are not representative of all smokers. These 

226 /d. at 111. 

227 Perkins KA, Grobe JE, Epstein LH, et al., Chronic and acute tolerance to subjective effects of nicotine, 

Pharmacology, Biochemistry and Behavior 1993;45:375-381. See AR (Vo1271 Ref. 3728). 

228 Goldfarb 1L, Gritz ER, Jarvik ME, et al., Reactions to cigarettes as a functioo of nicotine and "tar," Clinical 

Pharmacology and Therapeutics 1976;19:767-772. See AR(Vol. 39 Ret: 53). -

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comments criticize a study by Benningfield et al. 229 which was cited by the Agency. The 

industry further argues that the "subjective effects" of cigarettes could be secondary to tar and 

cites a study to suggest that nicotine-free cigarettes cause "Iiking."230 The industry thus 

disputes FDA's conclusion that nicotine produces subjective effects that are similar to those of 

other addictive drugs. 

FDA disagrees. A wide range of evidence, discussed in section II.A3.c.i, above, 

demonstrates that nicotine, whether administered alone or in a cigarette, behaves like other 

addictive drugs in "subjective effects" testing. Upon review of this evidence, FDA notes that 

the industry criticized only one of its cited studies. 

FDA further concludes that the Benningfield study is accurate and consistent with the 

findings of other researchers. The study design used by Benningfield et al. is a standardized _ 

procedure for qualifying the abuse liability of drugs in humans; it is used nationally and 

internationally by addiction researchers. 231 The use of subjects with histories of drug abuse is 

also standard practice in such studies; indeed, as described in section II.A3.c.i, above, these 

subjects are employed because they can use their history to distinguish the psychoactive effects 

of different drugs. Thus, for this type of abuse liability testing, it is critical that the population 

be composed of smokers with experience with other addictive drugs to enable them to 

compare the effects of nicotine to those of other drugs. 

229 Henningfield JE, Miyasato K, Jasinski DR. Abuse liability and pharmacodynamic characteristics of 

intravenous and inhaled nicotine, Journal of Pharmacology and Experimental Therapeutics 1985;234:1-

12. See AR (Vol 39 Ref. 69). 

230 See section II.A3.c.i., above, for a description of the term "liking." 

231 Jasinski DR, Henningfield JE, Human abuse liability assessment by measurement of subjective and 

physiological effects, in Testing for Abuse liability ofDrugs in Humans, eds. Fischman MW, Mello NK, NIDA 

Research Monograph 92 (Rockville MD: National Institute en Drug Abuse, 1989). See AR (Vol. 76 Ret: 172). 

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II.A.7. 

The resuhs from the study by Henningfield et al. demonstrate that nicotine, delivered 

by intravenous injection or by inhalation of tobacco smoke, produces similar subjective effects. 

These effects include dose-related elevation in the Morphine-Benzedrine Group Scale and the 

"liking" scale. There is no possibility that the subjects were responding to the ''flavor'' of 

nicotine or tar when they were able to discriminate nicotine injected intravenously. Nicotine 

produced resuhs similar to those of other dependence-producing drugs (e.g., morphine, 

cocaine, and amphetamine) on the scales used in this study. 

Furthermore, researchers who preceded and followed Henningfield obtained consistent 

findings. Researchers other than Henningfield et al., using methods other than the MBG and 

the "liking" scale, also confirmed that nicotine produces positive subjective effects after 

intranasal and intravenous administration. 232 Subjects in these studies used the following 

adjectives to describe the positive subjective effects of nicotine: "head rush," ''feeling good," 

or "high." This evidence strongly demonstrates that nicotine-and not tar-is responsible 

for the "subjective effects" of cigarettes. 

232 Sutherland G, Stapleton JA, Russell MAH, et al., Randomised controlled trial of nasal nicotine spray 

in smoking cessation, lAncet 1992;340:324-329. See AR (Vol 91 Ref. 527). 

Sutherland G, Russell MA, Stapleton J, et al., Nasal nicotine spray: a rapid nicotine delivery system, 

Psychopharmacology 1992;108:512-518. See AR (Vol 91 Ref. 526). 

Perkins KA, Grobe JE, Epstein LH, et al., Chronic and acute tolerance to subjective effects of nicotine, 

Pharmacology, Biochemistry aiul Behavior 1993;45:375-381. See AR (Vol 271 Ref. 3728).~ 

Perkins KA, Grobe JE, Epstein LH, et al., Effects of nicotine on subjective arousal may be dependent on 

baseline subjective state, Journal of Substance Abuse 1992;4: 131-141. See AR (Vol. 348 Ref. 5516). 

Johnston LM, Tobacco smoking and nicotine, Lancet 1942;2:742. See AR (Vol 278 Ref. 3947). 

Jones RT, Farrell TR III, Heming Rl, Tobacco smoking and nicotine tolerance, in Self-Administration of 

Ab~sed Substances: Methods for Study, ed. Krasnegor NA, NIDA Research Monograph 20 (Rockville 

MD: NationallnstituteonDrug Abuse, 1978), at202-208. See AR(Vol 41 Ref. 88). 

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Finally, the industry cites a study by Butschky et al. 233 to suggest that nicotine-free 

cigarettes cause "liking" too. What the industry does not mention is that the study was 

conducted in newly abstinent smokers and that these nicotine-free cigarettes were "liked" 

only when compared to lettuce cigarettes that the researchers acknowledged to be 

unpalatable. As described in section ll.B.3., below, the repeated association of 

pharmacological effects and sensory effects over thousands of repetitions causes the 

sensory aspects of addictive behaviors (such as taste) to come to be associated with the 

pharmacological effect (such as "liking") of addictive substances. Much as Pavlov's dog 

salivated at the sound of the bell (a conditioned response), individuals addicted to drugs 

actually experience some of the effects of the psychoactive drug by conditioned cues 

associated with the act of self-administering the drug in the early stages of abstinence. 234 

This phenomenon has been described for many drugs, including heroin.235 Just as a heroin 

addict may experience a rush simply by injecting a saline solution, a cigarette smoker may 

experience pleasure when smoking a denicotinized cigarette. Thus, the fmding that a 

denicotinized cigarette can trigger "liking" during withdrawal does not call into question 

the conclusion that nicotine has "subjective effects" in humans. 

233 Butscbky MF, Bailey D, Heriningfield JE, et al., Smoking without nicotine delivery decreases 

withdrawal in 12-hour abstinent smokers, Pharmacology, Biochemistry and Behavior 1995;50(1):91-96. 

See AR (Vol 442 Ref. 7484). 

234 0' Brien CP, Testa T, Ternes J, et al., Conditioning effects of narcotics in humans, in Behavioral 

Tolerance: Research and Treatment Implications, NIDA Research Monograph 18 (Washington DC: 

Government Printing Office No. 017-024-00899-8, Jan. 1978), at 67-71. See AR (Vol 535 Ref. 96, 

vol. III.L). 

235 Surgeon General's Report, 1988, at308-311. See AR(Vol 129 Ref. 1592). 

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II.A.7. 

e. Comments on Self-Administration and Reinforcement 

1. The tobacco industry argues that nicOtine's reinforcing effects are different 

from those of heroin and cocaine, that animals need to be trained to self-administer nicotine, 

that the reinforcing efficacy of nicotine is more like that of caffeine, and that in one study cited 

by FDA a light stimulus associated with nicotine was required for self-administration. The 

industry concludes that animal self-administration studies do not support the finding that 

nicotine is addictive. 

FDA disagrees. Upon review of the evidence in the administrative record, FDA notes 

that there are over ten studies demonstrating self-administration of nicotine by animals. 236 Only 

one of these is specifically contested by the tobacco industry. Furthermore, none of the 

industry's arguments seriously call into question FDA's finding that animals self-administer 

nicotine in a manner consistent with other addictive substances. 

It is true that the reinforcing effects of nicotine do differ from those of cocaine and 

heroin; all dependence-producing drugs are not alike. In fact, FDA noted that the range of 

environmental conditions under which nicotine functions as a positive reinforcer appears more 

limited than for cocaine.237 The limited conditions under which animals self-administer 

nicotine, however, closely correspond to the conditions of human tobacco use. That is, animals 

self-administer nicotine when it is given intermittently-in a fashion similar to nicotine delivery 

from cigarettes and smokeless tobacco. 

236 See appendix 1 to Jurisdictional Analysis. See AR (Vol. 1 Appendix 1). 

237 /d. 

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FDA agrees that animals can be trained to self-administer nicotine. This method is 

widely accepted as standard practice in self-administ:riltion testing in animals. What is 

important is that, under these conditions, nicotine is self-administered significantly more than 

placebo and in a manner consistent with other addictive substances. 

The tobacco industry cites-a review chapter in a textbook on psychopharmacology to 

suggest that caffeine and nicotine self-administration are similar. The review article cited 

focuses on whether caffeine is a drug of abuse and, while casually noting similarities between 

some data on nicotine and caffeine, does not purport to analyze the studies on nicotine at all. 238 

Indeed, caffeine self-administration in animals is weak and sporadic.239 FDA further notes that 

the chapter on nicotine in this same textbook unequivocally concludes that nicotine is 

addictive. 240 

Finally, FDA agrees that the study by Goldberg et al. 241 showed that squirrel monkeys 

self-administer nicotine most actively when associated with a light stimulus. The tobacco 

238 Griffiths RR, Mumford GK, Caffeine--A drug of abuse?, in Psychopharmacology: The Fourth 

Generation of Progress, eds. Bloom FE, Kupfer DJ (New York Raven Press, 1995), at 1699-1713. 

See AR (Vol 535 Ref. 96, vol. IILE). 

239 Heishman SJ, Henningfield JE, Stimulus functions of caffeine in humans: relatim to dependence potential, 

Neuroscience and Biobehavioral Reviews 1992;16:273-287. See AR(Vol. 79 Rd 230). 

Griffiths RR, Woods<Jl PP, Reinforcing properties of caffeine: studies in humans and laborata:y animals, 

Pharmacology, Biochemistry and Behavior 1988;29(2):419-427. See AR(Vol535Ret: 96, vol. III.E). 

Jaffe JH, Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of 

Therapeutics, 8th ed. (New York Pergamon Press, 1990), chap. 22 (522-573), at 524. See AR (Vol 535 

Ref. 96, vol ID.G). 

240 Henningfield JE, Schuh LM, Jarvik ME, Pathophysiology of tobacco dependence, in 

Psychopharmacology: The Fourth Generation of Progress, eds. Bloom FE, Kupfer DJ (New York 

Raven Press, 1995), at 1715-1729. See AR (Vol 39 Ref. 72). 

241 Goldberg SR, Spealman RD, Goldbel:g DM, Persistent bcl:lavior at high rates maintained by intravenous selfadministratim of nicotine, Science 1981;214:573-575. See AR(Vol 5 Ref 35-2). 

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industry implies that this finding means that the light stimulus-not nicotine-was responsible 

for nicotine self-administration in this study. FDA diSagrees. Rates of self-administration of 

nicotine with the light stimulus l-Vere markedly higher than rates of self-administration of 

placebo with the light stimulus. Indeed, the monkeys' self-administration of nicotine was so 

intense that it resembled cocaine use. Thus, the conclusion that nicotine was not selfadministered is incorrect; the correct conclusion is that nicotine self-administration was most 

dramatic when associated with environmental cues that had been linked to nicotine injections. 

2. The smokeless tobacco industry claims that its products provide a constant 

dose of nicotine, a regimen that animals did not self-administer. This claim is contrary to the 

evidence. As described in section ll.D., below, moist snuff and chewing tobacco do not 

provide uniform release of nicotine from the products. In fact, each pinch of smokeless 

tobacco provides nicotine that is absorbed rapidly for the first 5 minutes; the rate of absorption 

then tapers off until the next pinch is consumed. This pattern of nicotine consumption is similar 

to the regimen that was self-administered by animals. 

3. The tobacco industry criticizes the human self-administration study conducted 

by Henningfield et al. 242 

on the grounds that the number of subjects used in the study was too 

small, that the study should have been conducted with subjects without a history of drug abuse, 

and that the subjects also self-administered saline. 

FDA believes that the study's design was sound and that the results are reliable. 

The procedure utilized by these researchers is the standard procedure utilized by all 

investigators evaluating the abuse liability of a compound in humans. This well242 Henningfield JE, Miyasato K, Jasinski DR, Cigarette smoktn self-administf'I intravenous nicotine, 

Pharmacology, Biochemistry and Behavior 1983;19:887-890. See AR(Vol39 Ref. 71). 

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established procedure has been used to examine the abuse potential of a variety of 

compounds, such as alcohol, marijuana, heroin, and sedatives, in both inpatient and 

outpatient settings. In the evaluation of a new molecular entity (NME) that shows some 

structural and/or pharmacological similarities to known drugs of abuse, FDA requires that 

studies similar to this one be conducted in order to reach a regulatory decision on the 

abuse potential of the NME being considered for drug approval. 243 

In response to the concerns of the tobacco industry about the study methodology, 

the sample size of six is acceptable and the use of volunteers with histories of drug abuse 

is a valid method of conducting such research, according to the National Institute on Drug 

Abuse. 244 Human studies evaluating the abuse potential of a compound in subjects 

without a history of drug abuse do not produce valid results. Such tests in non-drug 

abusers could lead to the conclusion that drugs, including heroin, have a low potential to 

produce dependence because frrst-time users may not fmd them pleasant.245 

With respect to the self-administration of saline, the comment overlooks major 

distinctions between nicotine and saline: (1) "subjective effects" were not associated with 

the saline deliveries, thus saline was not psychoactive; (2) in comparison to the orderly 

pattern of self-administration observed with the nicotine injections, the pattern of saline 

deliveries was highly variable; (3) the number of self-administered saline injections 

243 See Surgeon General's Report, 1988, at 270. See AR (VoL 129 Ref. 1592). 

244 Jasinski DR, Benningfield JE, Human abuse liability assessment by measurement of subjective and 

physiological effects, in Testing for Abuse liability of Drugs in Humans, eds. Fischman MW, Mello NK, NIDA 

Research Monograph 92 (Rockville MD: National Institute on Drug A~ 1989). See AR (Vol 76 Ref 172). 

245 Jaffe JH, Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of 

Therapeutics, 8th ed. (New York: Pergamon Press, 1990), chap. 22 (522-573), at 529. See AR (Vol. 535 

Ref. 96, vol III.G). 

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II.A.7. 

decreased across sessions while nicotine injections were constant in those subjects who 

were tested repetitively with saline and nicotine; and ( 4) when saline and nicotine were 

simultaneously available in a follow-up study, the volunteers self-administered nicotine 

almost exclusively and not saline.246 Thus, saline was not psychoactive and did not 

function as a "positive reinforcer." 

4. The tobacco industry argues that caffeine, rapid eye movement (REM) 

sleep, magnetic fields, and stress increase dopamine levels in the brain. According to the 

industry, then, nicotine's effect on dopamine activity is shared by several other compounds 

or experiences. 

This argument is based on a mischaracterization of the relationship between 

addictive substances and dopamine activity. FDA found that nicotine and other addictive 

substances do more than increase dopamine levels in the brain; they increase dopamine 

activity in a specific system that signals reward and pleasure, thus leading to reinforcing 

behavior. Nicotine's effect in this system is similar to that of other dependence-producing 

substances. These conclusions are based on reproducible studies and are widely accepted 

in the scientific community. Indeed, none of the industry's cited studies casts any doubt 

on the profound effects of nicotine on this brain system. 

One study, cited by the industry as proof of the effect of caffeine on dopamine 

levels, actually examined the effect of caffeine on aggressive behavior of rats. Dopamine 

levels were not even measured. The authors merely speculated at the end of the article 

246 Surgeon General's Report, 1988, at 192. See AR (Vol129 Ref. 1592).-

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that caffeine may affect rat aggression via dopamine. Moreover, they did not extend their 

speculation to reward or reinforcement. 247 

Another study, cited by the industry as proof of the effect of REM sleep and 

magnetic fields on dopamine, actually described two patients treated with magnetic 

fields-without any control group. The authors merely speculated that REM sleep 

deprivation and magnetic fields may affect dopamine in the mesolimbic system. But 

without a control group, it is impossible to assess whether there was any true response to 

magnetic fields. 248 

The industry cites a third study to suggest that stress increases dopamine levels. 249 

This study delivered severe stimuli such as electric shocks to mice and studied dopamine 

responses. The authors concluded that a dopamine-based reward pathway exists and is 

altered under conditions of severe stress. This conclusion casts no doubt on the finding 

that nicotine also critically affects this pathway. 

5. In a footnote, the tobacco industry argues that "it is not clear that 

nicotine's effects on dopaminergic mechanisms play a significant role in smoking 

behavior." This argument refers to a study by Corrigan and Coen.250 

247 Petkov VV, Rousseva S, Effects of caffeine on aggressive behavior and avoidance learning of rats with 

isolation syndrome, Methods and Findings in Experimental and Clinical Pharmacology 1984;6(8):433-

436. See AR (Vol 535 Ref. 96, vol III.L). 

248 Sandyk R, Tsagas N, Anninos P A, et al., Magnetic fields mimic the behavioral effects of REM sleep 

deprivation in humans, International Journal of Neuroscience 1992;65(1-4):61-68. See AR-(Vol 535 

Ref. 96, vol. III.L). 

249 Puglisi-Allegra S, Kempf E, Cabib S, Role of genotype in the adaptation of the brain dopamine system 

to stress, Neuroscience and Biobehavioral Reviews 1990;14(4):523-528. See AR (Vol. 535 Ref. 96, 

vol. III.L). 

25° Corrigan W, Coen K, Dopamine mechanisms play at best a small role in the nicotine discriminative 

stimulus, Pharmacology, Biochemistry and Behavior 1994;48(3):817-820. See AR(Vol. 535 Ref. 96, 

vol. III.B). 

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Il.A.7. 

FDA has reviewed the study in question and concludes that the tobacco industry's 

conclusion seriously misrepresents the research. In this paper, the authors suggested that 

dopamine activity may not explain why smokers recognize low doses of nicotine in their 

brain, but the authors never doubted that dopamine activity is essential to the reward 

associated with smoking. The same article cited by the industry includes the statement that 

"the reinforcing effects of nicotine have a dopaminergic substrate, likely the ascending 

mesolimbic dopamine system"251-exactly the finding of FDA. These researchers, 

misrepresented by the industry to suggest a small role for dopamine in smoking behavior, 

have demonstrated in their own laboratory that dopamine activity significantly affects 

nicotine consumption.252 

f. Comments on Withdrawal, Tolerance, and Nicotine Replacement 

1. The tobacco industry argues that the effects of withdrawal from nicotine 

are not substantial. This argument is based upon multiple overlapping and sometimes 

contradictory contentions: (1) nicotine withdrawal is not as severe as withdrawal from 

certain other drugs, and some people quit smoking easily; (2) physical and psychological 

symptoms experienced during nicotine withdrawal are not the same among all abstinent 

users; (3) withdrawal from nicotine produces psychological but not physical symptoms; 

( 4) the psychological symptoms of abstinence may actually be a psychopathological 

condition previously suppressed by nicotine or may be frustration with losing a pleasurable 

activity; (5) what is thought to be nicotine withdrawal may actually be caffeine withdrawal 

251 ld. at 817. 

252 Corrigan W A, Franklin KBJ, Coen KM, et al., The mesolimbic dopaminergic system is imPlicated in 

the reinforcing effects of nicotine, Psychopharmac~logy 1992;107:285-289. See AR (Vol 8 Ref. 93-4). 

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II. A.?. 

or caffeine toxicity; (6) the severity of withdrawal symptoms does not always correlate 

with relapse; and (7) epidemiological studies cited by FDA do not prove a substantial 

withdrawal syndrome. 

Upon careful review of the industry's comments and the administrative record, 

FDA finds that nicotine clearly produces a withdrawal syndrome among abstinent tobacco 

users. This syndrome-which includes both psychological and physiological symptomsis described in numerous scientific articles and reviews cited by FDA, 253 only a few of 

which were criticized by the tobacco industry. Of the studies on withdrawal from 

smokeless tobacco cited by FDA, none is contested by the industry. The tobacco industry 

also accepts FDA's fmding that tobacco withdrawal causes many significant autonomic 

changes, such as changes in heart rate. Several of the industry's arguments do not 

seriously contest the fact that nicotine has a substantial withdrawal syndrome. The 

remaining arguments contradict each other. The Agency's specific responses to the major 

industry contentions are as follows: 

• Nicotine withdrawal is not as severe as withdrawal from certain other drugs, and some 

people quit smoking easily. 

FDA agrees that withdrawal from nicotine is not as acutely life-threatening as 

withdrawal from certain addictive drugs such as alcohol or short-acting barbiturates. But 

the severity of nicotine withdrawal is comparable to that of other addictive drugs such as 

253 See Jurisdictional Analysis, 60 FR 41560-41562 

See also Surgeon General's Report, 1988, at 197-207. See AR (Vol129 Ref. 1592). 

American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4tli ed. 

(Washington DC:_ American Psychiatric Association, 1994), at 244-245. See AR (Vol 37 Ref. 8). 

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cocaine.254 Medical authorities around the world have recognized the existence of a 

nicotine withdrawal syndrome that causes "clinically significant distress or impainnent in 

social, occupational, or other areas of functioning." 255 

FDA agrees that some people quit tobacco products easily. Similarly, some people 

quit cocaine and other addictive substances easily.256 However, for most addicted users of 

tobacco, quitting is very difficult See section II.A.3.c.ii., above. The characteristic 

feature of an addictive substance is that it is difficult for most people to quit Thus, the 

fact that some people can quit smoking easily is irrelevant to nicotine's addictiveness and 

to the scientific consensus supporting a nicotine withdrawal syndrome. Moreover, it may 

actually be easier to quit other powerful substances than to quit nicotine. Smokers who 

consume about a pack or more of cigarettes per day are more than twice as likely to report 

withdrawal symptoms during abstinence as people who consume five or more drinks on 

five or more occasions in a month, people who repeatedly use cocaine, and people who 

repeatedly use marijuana.257 

• Physical and psychological symptoms experienced during nicotine withdrawal are not 

the same among all abstinent users. 

254 Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of North America 

1992;76(2):415-437, at 429. See AR (VoL 535 Ref. 96, vol. ill.A). 

255 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders~ 4th ed. 

(Washington DC: American Psychiatric Association, 1994), at 245. See AR (Vol. 37 Ref. 8). 

256 Kleber H, Don't you believe that nicotine isn't addictive, New York Times, Apr. 4, 1994. See AR 

(Vol. 196 Ref. 2497). 

Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of North America 

1992;76(2):415-437, at 429. See AR (VoL 535 Ref. 96, vol. lli.A). 

257 Henningfield JE, Clayton R, Pollin W, Involvement of tobacco in alcoholism and illicit drug use, 

British Journal of Addiction 1990;85:279-292, at 280-281. See AR (VoL 39 Ref. 66). 

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FDA agrees that there is variation among tobacco users' physical and 

psychological responses to abstinence. But, as described in section II.A.3.c.i., above, and 

in reviews cited by the Agency, several symptoms are so common as to be part of a 

defined syndrome?58 These symptoms include depressed mood, insomnia, irritability, 

anxiety, difficulty concentrating, restlessness, decreased heart rate, and increasci:l appetite. 

Thousands of individuals around the world have reported these symptoms in studies of 

tobacco abstinence. 

• Withdrawal from nicotine produces psychological but not physical symptoms. 

The tobacco industry goes on to quote selectively from some researchers to 

suggest that nicotine withdrawal does not produce physical symptoms. This argument is 

at odds not only with the consensus understanding of nicotine withdrawal, but also with 

other quotations used by the tobacco industry in the same comment, which suggests that 

common withdrawal symptoms include, for example, "headache."259 

Indeed, the very sources cited by the tobacco industry clearly agree with FDA's 

fmding of a substantial tobacco withdrawal syndrome. For example, Balfour, who is 

quoted by the industry to suggest that withdrawal is mainly psychological, states that 

"many habitual smokers experience significant and unpleasant withdrawal effects when 

they frrst stop smoking which can be ameliorated by giving nicotine in another form."260 

258 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994), at 244-245. See AR (VoL 37 Ref. 8). 

259 Clark WG, Brater DC, Johnson AR, Drug abuse and dependence, in Goth's Medical Pharmacology 

(Baltimore: Mosby), 336-352, at 347. See AR (VoL 535 Ref. 96, vol. ill. B). 

260 Balfour DJK, The neurochemical mechanisms underlying nicotine tolerance and dependence, in The 

Biological Bases of Drug Tolerance and Dependence, ed. Pratt JA (New York: Academic Press, 1991), 

121-151, at 123 (citation omitted) (emphasis added). See AR (VoL 535 Ref. 96, vol. ill.A). 

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Similarly, a quotation culled from a review by Hughes et al. is used to support the 

conclusion that the effects of nicotine withdrawal are not substantial. In fact, Hughes et 

al. attribute multiple physical and psychological symptoms to nicotine withdrawal and 

conclude that some symptoms can be so severe that they may "prevent smoking 

cessation."261 

• The psychological symptoms of abstinence actually may be a psychopathological 

condition previously suppressed by nicotine or may be frustration with losing a 

pleasurable activity. 

The tobacco industry cites the Diagnostic and Statistical Manual of Mental 

Disorders of the American Psychiatric Association for this assertion, but offers no 

evidence to suggest that any significant number of quitting smokers have psychiatric 

diagnoses or are just frustrated. Nor does the DSM. Its actual text merely alerts 

clinicians not to mistake symptoms of abstinence for psychopathology or frustration "in 

any given case."262 

• What is thought to be nicotine withdrawal may actually be caffeine withdrawal or 

caffeine toxicity. 

FDA agrees that some symptoms are common to caffeine and nicotine withdrawal, 

and some are common to nicotine withdrawal and caffeine toxicity. Withdrawal from 

nicotine and cocaine also causes common symptoms of depressed mood, increased 

261 Hughes JR. Higgins ST, Hatsukami D, Effects of abstinence from tobacco: a critical review, Research 

Advances in Alcohol and Drug Problems 1990;10:317-398, at 381. See AR (VoL 535 Ref. 96, vol. ID.G). 

262 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 3d ed., 

revised (Washington DC: American Psychiatric Association, 1987), at 150. See AR (Vol 535 Ref. 96, 

vol. III.A). 

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appetite, and insomnia. 263 Such overlap has not led any credible scientific source to 

conclude that nicotine withdrawal has been confused with another drug's syndrome and 

therefore does not exist. 

• The severity of withdrawal symptoms does not always correlate with relapse. 

On several occasions in its comments, the tobacco industry claims that the severity 

of withdrawal does not directly predict relapse. Based on this observation, the industry 

concludes that the symptoms of withdrawal from tobacco are not significant and that 

physical dependence to nicotine is not real. 

FDA disagrees. Severity of withdrawal does predict relapse; most people who quit 

smoking relapse within 1 week, 264 when withdrawal symptoms are at or near their peak. 265 

Moreover, studies indicate that light smokers, who are less likely to suffer withdrawal 

symptoms, are more likely to succeed in quitting than are heavier smokers.266 

The industry's argument is based on the mistaken assumption that, if withdrawal 

symptoms were significant, their presence would perfectly correlate with relapse. But, as 

described in depth in the 1988 Surgeon General's Report, multiple confounding factors 

are associated with relapse to use of any addictive substance, no matter how significant 

the withdrawal syndrome.267 These factors include psychiatric impairment, expectations, 

263 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994). See AR (Vol535 Ref. 96, vol. ffi.B). 

264 Hughes JR, Gulliver SB, FenwickJW, et al., Smoking cessation among self-quitters, Health 

Psychology 1992;11:331-334, at333. See AR.(Vol348 Ref. 5512). 

265 Hughes JR, Gust SW, Skoog K, et al., Symptoms of tobacco withdrawal: a replication and extension, 

Archives of General Psychiatry 1991;48:52-59, at 56. See AR (Vol 129 Ref. 1404). 

266 SurgeonGeneral'sReport, 1988,at315-316. SeeAR(Vol129Ref.1592). 

267 !d. at 315-324. 

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demographics, enrollment in treatment programs, peer influence, and social support. Even 

life-threatening withdrawal symptoms associated with drugs such as alcohol do not 

necessarily lead to relapse. After a complete review of available evidence, the Surgeon 

General concluded that nicotine's pharmacological role in relapse is similar to the role of 

opioids and alcohol.268 Thus, the absence of a perfect correlation between withdrawal 

severity and the precise timing of a relapse does not compel the conclusion that 

withdrawal symptoms are insignificant or that physical dependence to nicotine is not real. 

• Epidemiological studies cited by FDA do not prove a substantial withdrawal syndrome. 

The tobacco industry criticizes several studies cited by FDA in support of a 

tobacco withdrawal syndrome. Upon review of these studies, FDA fmds that the 

industry's comments take quotations out of context and make inappropriate inferences 

from researchers' findings. For example, the industry objects to a study by Hughes 

et al. 269 on the grounds that the researchers tabulated withdrawal symptoms on only 105 

of the 315 subjects. In fact, the analysis of withdrawal appropriately included every 

subject in the study who was abstinent from both tobacco and nicotine. The other 210 

subjects received nicotine gum to reduce their withdrawal symptoms; these subjects were 

thus inappropriate for research on the severity of withdrawal. 

Similarly, the industry claims to provide data to contradict FDA's citation of the 

1991 and 1992 National Household Surveys. But FDA's data reported the prevalence of 

withdrawal symptoms for smokers who consume sixteen to twenty-five cigarettes per day. 

268 ld. at 323. 

269 Hughes JR. Gust SW, Skoog K. et al., Symptoms of tobacco withdrawal: a replication and extension, 

Archives ofGene'l"al Psychiatry 1991;48:52-59. See AR (Vol129 Ref. 1404). 

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The industry's data are based on a different set of smokers and, at any rate, are hardly 

different from FDA's. 

Such arguments cannot seriously challenge the scientific consensus that led the 

American Psychiatric Association to defme Tobacco Withdrawal Syndrome in 1980 and to 

ratify its decision again as recently as 1994 in DSM-IV. 

2. The tobacco industry argues that nicotine does not induce pharmacological 

tolerance. This conclusion is based upon several arguments: ( 1) tolerance can be both 

pharmacological and nonpharmacological; (2) smokers and users of smokeless tobacco do 

not continue to increase their tobacco consumption over the course of their lives and thus 

do not escalate their dose; (3) FDA's studies on dose escalation are not persuasive; and 

(4) a study on low-nicotine snuff disproves tolerance. 

FDA disagrees with the industry's analysis and conclusion. Much uncontested 

evidence in the administrative record demonstrates conclusively that nicotine causes 

tolerance in tobacco users. For example, the industry does not dispute evidence of 

diminished cardiovascular and nervous system responses to nicotine over the course of a 

day. Nor does the industry deny that many cigarette smokers escalate their doses of _ 

nicotine to daily use270 or that the age of young consumers of smokeless tobacco 

correlates with the amount of use. 271 Furthermore, the arguments that the industry does 

make are not persuasive, as discussed below. 

270 Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of North America 

1992;76(2):415-437. See AR (Vol 535 Ref. 96, vol. ID.A). 

Henningfield JE, Cohen C. Slade JD, Is nicotine more addictive than cocaine? British Journal of 

Addiction 1991;86:565-569. See AR (Vol 277 Ref. 3904). 

271 World Health Organization, Smokeless Tobacco Control: Report of a WHO Study Group, WHO 

Technical Report Series No. 773 (Geneva: WHO, 1988), at 36. See AR (Vol 7 Ref. 83). -

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II.A.7. 

The industry's description of two kinds of tolerance is irrelevant Sources in the 

administrative record cited by FDA refer exclusively to pharmacological tolerance. See 

sections II.A.3.c.i. and II.A.3.c.ii., above. 

The tobacco industry makes the observation that smoking behavior reaches a 

plateau as the smoker grows older. Similarly, the smokeless tobacco industry points out 

that middle-aged users may consume less than young adults. But these observations do 

not disprove the existence of tolerance, which does not require forever-increasing 

consumption of a substance. Tolerance is a phenomenon that develops rapidly, leads the 

vast majority of beginning tobacco users to escalate their dose, and then can eventually 

result in a stable pattern of consumption. Some heroin addicts also eventually reach a 

level of consumption that may remain constant for years.

272 

The tobacco industry asserts that a study cited by FDA on the proportion of 

smokers who report needing more cigarettes to obtain desired effects does not support the 

idea of tolerance to nicotine and also does not prove that such tolerance is widespread or 

marked. FDA disagrees with these assertions. The industry cites no data or references to 

explain why the study does not demonstrate tolerance. In fact, the study's findings 

perfectly fit the tobacco industry's awn defmition of tolerance that "more drug is necessary 

to produce the desired effect." People who have tried cigarettes at least once are more 

likely to report the need for larger doses to get the same effect than people who have tried 

272 Jaffe JH, Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of 

Therapeutics, 8th ed. (New York: Pergamon Press, 1990), chap. 22 (522-573), at 531-532. See AR 

(Vol535 Ref. 96, vol. III.G). 

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II. A.?. 

cocaine, marijuana, and alcohol at least once.273 Moreover, FDA notes that 

epidemiological data are just one demonstration of tolerance; most of the evidence on 

tolerance to nicotine presented by FDA is uncontested by the tobacco industry. 

Finally, the smokeless tobacco industry cites a study that measures the response of 

oral tobacco users to a low-nicotine snuff. In the study, users increased their consumption 

of tobacco to compensate for its lower nicotine content. The industry's argument here 

confuses tolerance with compensation. FDA addresses the industry's comments on 

compensation in section II.A.7.i., above. 

3. The tobacco industry cites research on nicotine replacement therapies to 

argue that nicotine is not a key reason for tobacco use. According to the industry, if 

nicotine were central to tobacco consumption, providing nicotine replacement should 

eliminate smoking behavior and all withdrawal symptoms. The industry contends that 

nicotine replacement trials cited by FDA do not demonstrate either efficacy of replacement 

therapy or elimination of withdrawal symptoms. The industry disputes FDA's summary of 

nicotine replacement trials and makes multiple objections to individual studies. The 

industry also contends that the study population is not generalizable to the entire smoking 

population. 

Upon review of the industry's detailed comments and the data in the administrative 

record, FDA disagrees with the industry's position on nicotine replacement therapies. 

Scientific consensus supports the view that such therapies not only reduce withdrawal 

symptoms but increase abstinence. An extensive preapproval evaluation of such therapies 

273 Henningfield JE, Clayton R. Pollin W, Involvement of tobacco in alcoholism and illicit drug use, 

British Journal of Addiction 1990;85:279-292. See AR (Vol 39 Ref. 66). 

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II.A.7. 

by FDA also concluded that they were safe and effective, and even sources cited by the 

tobacco industry agree. The efficacy of nicotine replacement therapies is strong proof of 

the central role of nicotine in tobacco consumption. The industry's position is based upon 

mistaken assumptions, misinterpretation of clinical trials, and misuse of FDA reviews. 

According to the tobacco industry, replacing one form of an addictive substance 

with another form should completely eliminate the addict's desire to use the substance. If 

this assumption were correct, then no methadone user would ever relapse to heroin. In 

fact, providing oral methadone in substance abuse clinics helps only some opioid users to 

remain totally abstinent/74 and abstinence rates of former heroin users on methadone are 

similar to those of former smokers receiving nicotine replacement therapy. 275 The 

industry's simplistic formulation ignores many factors, such as the importance of the route 

and speed of drug administration. Just as a heroin addict may want a "rush" from injection 

and reject the steady dose of oral methadone, a tobacco user may prefer the "rapid, 

peaking" dose of inhaled nicotine over the more steady dose from replacement therapy.276 

Given the strength of addiction to tobacco products, it is noteworthy that there is a 

274 Jaffe JH, Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of 

Therapeutics, 8th ed. (New York: Pergamon Press, 1990), chap. 22 (522-573), at 531-532. See AR 

(Vo1535 Ref. 96, voL ill.G). 

275 Henningfield JE, Griffiths RR, Jasinski DR, Cigarette smoking and opioid dependence: common 

factors, Presented at the meeting of the American Psychological Association (Sep. 2, 1980). See AR 

(Vol. 80 Ref. 254). 

Surgeon General's Report, Smokeless Tobacco, 1986, at 155. See AR (Vo1128 Ref. 1591). 

Gorelick D, Transcript to the FDA Drug Abuse Advisory Committee, Meeting 27, "Issues Concerning 

Nicotine-Containing Cigarettes and Other Tobacco Products" (Aug. 2, 1994), 292. See AR (VoL 255 

Ref. 3445). 

276 Research and Development/Quality, Transderma.l Nicotine, at3. See AR(Vol. 531 Ref. 124). 

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II.A.7. 

significant increase in abstinence with replacement therapy, but it is not surprising that 

these products are not always effective. 

The industry also argues that replacing an addictive substance with another form 

should eliminate all withdrawal symptoms. In fact, providing nicotine does dramatically 

reduce physiological withdrawal symptoms.277 Psychological withdrawal is reduced butnot eliminated, primarily because users have associated tobacco conswnption with certain 

stimuli, such as taste and ritual. Such "conditioned" cues become part of the tobacco 

conswnption experience, and the denial of such cues can lead to behavioral symptoms. In 

this sense, nicotine is like other addictive drugs. 278 

The industry misinterprets data on the efficacy of nicotine replacement therapies. 

First, the industry argues that FDA's data do not support the conclusion that the initial 

quit rate is "about 50%." The actual studies cited 1-month quit rates of 35%, 61%, 50%, 

50%, 26%, 57%, 47%, and 36%. The overall average for all studies was 49%.279 

Second, the industry argues that some individual studies do not show a statistically 

significant increased quit rate with nicotine replacement therapy. The Jurisdictional 

Analysis, however, included a chart showing the overwhelming consistency among 

nineteen studies on nicotine replacement therapies in demonstrating efficacy. 280 

277 Surgeon General's Report. 1988, at 208. See AR (Vol 129 Ref. 1592) .. 

278 Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of North America 

1992;76(2):415-437, at 418. See AR (Vol 535 Ref. 96, vol. ill.A). 

279 See appendix 1 to Jurisdictional Analysis. See AR (Vol. 1 Appendix 1). 

280 ld. 

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A definitive meta-analysis on the efficacy of the nicotine patch was cited by FDA, 

and its methods and results were not disputed by the tobacco industry. This study, 

published in the Journal of the American Medical Association, reviewed seventeen studies 

involving over 5,000 patients and concluded that "this meta-analysis provides compelling 

evidence that the nicotine patch is a consistently effective aid to smoking cessation. 

Individuals wearing the active nicotine patch were more than twice as likely to quit 

smoking as were individuals wearing a placebo patch."281 

Third, the industry makes multiple objections to individual studies on nicotine 

replacement therapy. These objections dispute fme points of methodology and often cite 

FDA reviewers' own criticisms of the studies. To the extent that the industry heavily 

relies on FDA's critique of the studies, the industry should accept FDA's conclusion that 

the studies demonstrate the efficacy of nicotine replacement therapy. Indeed, FDA has not 

only the statutory authority but also the expertise to determine whether a new drug 

therapy is efficacious. After extensive premarket review, FDA concluded that nicotine 

replacement therapies are efficacious. FDA's conclusion is consistent with scientific 

consensus. 

The tobacco industry also argues that the subjects in trials on nicotine replacement 

therapy are not representative of all smokers. But FDA's reason for citing the research 

was to demonstrate that providing nicotine by another means enhances abstinence and 

reduces withdrawal where it has been studied. These results show the critical 

281 Fiore MC, Smith SS, Jorenby DE, et al., The effectiveness of the nicotine patch for smoking cessation: 

a meta-analysis, Journal of the American Medical Association 1994;271:1940-1947, at 1945 (emphasis 

added). See AR (Vol. 6 Ref. 64-1). 

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II.A.7. 

phannacological role of nicotine in tobacco use. Indeed, if the tobacco industry were 

correct that nicotine's only important role in tobacco is for "flavor," then there should be 

absolutely no benefits in any study of transdennal nicotine replacement therapy. That 

nicotine replacement is effective is conclusive evidence of nicotine's role as a 

phannacological reinforcer. 

4. The tobacco industry argues that studies on nicotine replacement therapy 

cannot be relied upon to demonstrate that a high proportion of smokers are addicted. 

FDA agrees with this comment. Other studies, cited in section II.B.2.a., below, 

however, do demonstrate that a high proportion of smokers are addicted. 

g. Comments on Epidemiological Studies 

1. The tobacco industry claims that studies of individual DSM criteria do not 

demonstrate that any group of smokers satisfied sufficient criteria to qualify for the 

diagnosis of addiction. 

FDA cited these studies as support for the conclusion that a significant proportion 

of tobacco consumers are addicted to nicotine. This conclusion is primarily demonstrated 

by population-based studies, including the DSM-IV field trial, which show that the vast 

majority of smokers do meet sufficient DSM criteria to be considered nicotine dependent, 

discussed in more detail in section II.B., below. The field trial was a large, multicenter 

study conducted in 1991 and 1992 at five sites across the country (Burlington, VT; 

Philadelphia, PA; Denver, CO; St. Louis, MO; and San Diego, CA).282 The population 

282 Woody GE. Cottier LB, Cacciola J, Severity of dependence: data from the DSM-IV field trials, 

Addiction 1993;88:1573-1579. See AR (Vol 13 Ref. 150). 

Cottier L, Comparing DSM-III-R and ICD-10 substance use disorders, Addiction 1993;88:689-696. 

See AR (Vol 13 Ref. 149). 

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studied represented a diverse sample and included African-Americans, women, others 

randomly selected from the general population, and still others with a range of diagnoses 

and substance use patterns. The field trial documents that 80% to 87% of smokers 

studied qualified for the diagnosis of nicotine dependence. In its comments, the American 

Psychiatric Association concurs with the Agency's fmdings: "DSM based studies also 

found that 80% to 90% of adult smokers are nicotine dependent."283 

The tobacco industry's comments on population-based studies are addressed in 

section ILB.4.b., below. It is relevant to mention here that, if the industry's assertion that 

these population-based studies are not representative of all smokers is correct, then large 

surveys of whether all smokers meet individual DSM criteria would show inconsistent 

results. But this is not the case. Overwhelming evidence, cited in section Il.A.3.c.ii., 

above, conclusively demonstrates that the vast majority of tobacco consumers meet 

individual criteria for addiction. 

2. The tobacco industry disputes that use of tobacco products persists longer 

and in greater amounts than the user intends. According to the industry, studies cited by 

FDA demonstrate that, at most, 30% of people who have ever tried tobacco become 

"dependent" by FDA's defmition. The industry also argues that the desire to quit is not 

evidence of intent to cut down. 

FDA disagrees with the industry's position. It is widely accepted that users of 

tobacco products consume more than they originally intended.284 Longitudinal data, cited 

283 American Psychiatric Association, Comment (Jan. 2, 1996), at 2. See AR (VoL 700 Ref. 1 020). 

284 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994), at 243. See AR (VoL 37 Ref. 8). 

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in section II.A.3.c.ii., above, demonstrate that smokers frequently underestimate how 

much they will be smoking in the future. As many as 90% of current users smoke more 

than five cigarettes a day/85 despite the evidence that nearly half of young consumers do 

not intend to become daily smokers.286 Although estimates vary from study to study, 

persons who have smoked at least one cigarette are about twice as likely to develop 

dependence as are persons who have ever tried cocaine or alcohol.287 

If an individual wants to quit smoking but cannot, then the individual is smoking 

more than he or she intends. The overwhelming evidence presented in section ILA.3.c.ii., 

above, that many would-be quitters cannot attain abstinence supports the contention that 

consumers use cigarettes longer and in greater amounts than intended. 

3. The tobacco industry disputes that tobacco use continues despite attempts 

to quit. The industry observes that 90% of cigarette smokers who quit succeed by 

themselves, and the smokeless tobacco industry suggests that 75% of successful quitters 

find it easy to quit. The tobacco industry also alleges that FDA mischaracterizes data on 

self-reports of dependence from the National Household Surveys and misrepresents 

285 Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of Nonh America 

1992;76(2):415-437. See AR (VoL 535 Ref. 96, vol. ID.A). 

Benningfield JE, Cohen C. Slade JD, Is nicotine more addictive than cocaine? British Journal of 

Addiction 1991;86:565-569. See AR (Vol 277 Ref. 3904). 

286 Elders MJ, Perry CL, Eriksen MP, et al., The report of the Surgeon General: preventing tobacco use 

among ymmg people, American Journal of Public Health 1994;84(4):543-547, at 544. See AR (Vol 38 

Ref. 39). 

287 Anthony JC, Warner LA, Kessler RC, Comparative epidemiology of dependence on tobacco, alcohol, 

controlled substances and inhalants: basic imdings from the National Comorbidity Survey, Experimental 

and Clinical Psychopharmacology 1994;2:244-268. See AR (VoL 37 Ref. 4). 

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II.A.7. 

abstinence failure rates from a CDC study. The industry further argues that smokers may 

lie on surveys about their desire to quit. 

After reviewing industry comments and the administrative record, FDA concludes 

that there is overwhelming evidence that tobacco use continues despite attempts to quit. 

Indeed, this fact is well known to the tobacco industry. For example, Brown & 

Williamson's data show that, while 32 million Americans attempted to quit each year from 

1981 to 1983, fewer than a third were successful for 6 months. See Jurisdictional Analysis, 

60 FR 41668. Philip Morris' data show similar success rates.288 

The argument that most smokers and users of smokeless tobacco who quit do so 

without assistance relies on surveys of the small proportion of tobacco users who are able 

to quit each year. This population is not representative of the vast majority of current 

tobacco users, who have tremendous difficulty quitting. Furthermore, the fact that some 

smokers are able to quit without assistance does not reveal the difficulty experienced by 

these individuals or the extent to which they have previously relapsed. More than half of 

people presenting for treatment of alcohol or drug abuse who also smoke cigarettes report 

that quitting smoking would be harder than giving up their other drug of abuse.289 Twothirds of smokers who try to quit on their own relapse within 2 days, and approximately 

288 Ryan FJ (Philip Morris Inc.), Cold turkey in Greenfield, Iowa: a follow-up study, in Smoking 

Behavior: Motives and Incentives, ed. Dunn WL (Washington DC: VH Winston & Sons, 1973), at 231-

234. See AR (VoL 8 Ref. 1 05). 

289 Kozlowski LT, Wilkinson A, Skinner W, et al., Comparing tobacco cigarette dependence with other 

drug dependencies, Journal of the American Medical Association 1989;261:898-901. See AR(VoL 41 

Ref. 92). 

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90% relapse within 3 months?90 Sixty-eight percent of smokeless tobacco users who have 

attempted to quit have tried to do so an average of four times.291 

The industry disputes FDA's analysis of 1991 and 1992 National Household 

Survey data, which reveal that 83% to 87% of moderate to heavy smokers feel addicted. 

The industry first argues that the question to smokers has no validity; FDA disagrees and 

notes that the industry cited the same survey result from the 1985 survey at another point 

in its comments. The industry then suggests that FDA's analysis of the 1991 and 1992 

data is inconsistent with published reports. This is not true. The Substance Abuse and 

Mental Health Services Administration (SAMHSA) conducted two National Household 

Surveys, one in 1991 and another in 1992. The data referred to in the Proposed Rule 

were a calculation by the Centers for Disease Control and Prevention (CDC) of raw data 

obtained in the 1991 and 1992 surveys and presented at FDA's Drug Abuse Advisory 

Committee meeting in August 1994.292 The CDC pooled the raw data from both surveys, 

weighted them accordingly, and then evaluated the data using parameters different from 

those outlined in the main findings of each survey. The CDC used the data to look at 

different age groups of users and different numbers of cigarettes smoked per day than did 

SAMHSA. Even if the calculations performed by SAMHSA had been used, the data 

290 Hughes JR, Gulliver SB, Fenwick JW, et al., Smoking cessation among self-quitters, Health 

Psychology 1992;11:331-334. See AR (VoL 348 Ref. 5512). 

291 Severson HH, Enough snuff: ST cessation from the behavioral, clinical, and public health 

perspectives, in Smokeless Tobacco or Health, an International Perspective, Smoking and Tobacco 

Control Monograph 2, NIH Publication No. 93-3461 (Washington DC: GPO, 1993), at 281-282. See AR 

(Vol. 18 Ref. 5-1). 

292 Giovino GA, Zhu BP, Tomar S, et al., Epidemiology of Tobacco Use and Symptoms of Nicotine 

Addiction in the United States: A Compilation of Data from lArge National Surveys, presentation of the 

Centers for Disease Control and Prevention to the FDA's Drug Abuse Advisory Committee (Aug. 2, 

1994). See AR (VoL 459 Ref. 7820). 

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would still show that, among those who smoke about a pack or more of cigarettes per 

day, 81% report feeling dependent. 293 

The tobacco industry also argues that FDA mischaracterized a 1993 report from 

the CDC that FDA cited in the Jurisdictional Analysis for the statement that more than 15 

million Americans "tried to quit" each year and about 3% ultimately succeeded.294 The 

industry contends that the survey did not ask specifically whether smokers had tried to 

quit, but whether smokers did not smoke at least 1 day during the preceding year. The 

industry concludes that this report is not relevant to whether smokers try to quit. 

FDA disagrees. For daily smokers, the CDC counted one day of abstinence only if 

the smokers stated "they quit for at least 1 day."295 The CDC logically interpreted these 

results as showing that 17 million daily smokers who reported not smoking for at least 1 

day made an attempt to quit. According to the report, ''the fmdings from this survey 

indicate that, in 1990 and 1991, approximately 42% of daily smokers abstained from 

smoking cigarettes for at least 1 day but that approximately 86% of these persons 

subsequently resumed smoking. The high rate of relapse is likely because of the addictive 

nature of nicotine. "

296 FDA accepts CDC's interpretation of its survey. 

293 Departtnent of Health and Human Services, Substance Abuse and Mental Health Services 

Administration, Office of Applied Studies, National Household Survey on Drug Abuse: Main Findings, 

1991, DHHS Publication Number(SMA)93-1980 (Rockville MD: DHHS, Public Health Service, 1993), 

at 127. See AR (Vol535 Ref. 96, vol.lll.M). 

294 Centers for Disease Control and Prevention, Smoking cessation during previous year among adultsUnited States, 1990 and 1991, Morbidity and Mortality Weekly Report 1993;42(26):504-507. See AR 

(Vol. 66 Ref. 2). 

295 1d. at 504. 

296 1d. at 504-507. 

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II.A.7. 

FDA also notes that CDC's estimate is consistent with other published estimates297 

and the tobacco industry's own tabulations of long-term quit rates. For example, a 

tobacco company has estimated that fewer than 4% of smokers who attempt to quit are 

able to quit permanently. See Jurisdictional Analysis, 60 FR 41668-41669. 

FDA disagrees that survey results significantly distort the numbers of smokers who 

want to and have tried to quit. This method of data collection is a scientifically 

recognized and accepted mode of inquiry for prevalence studies, which is relied upon to 

determine the population prevalence of other disorders, including alcohol dependence, 

cocaine dependence, and depression. 298 Some of these are disorders for which, compared 

to tobacco use, interview methods would be less likely to reveal accurate results because 

of the criminal consequences associated with illicit drug use. Moreover, the authors of a 

study on this subject cited by the tobacco industry merely speculate that some smokers 

who say they want to quit may be dissembling, primarily on the basis of evidence that 

some smokers who claim to have quit smoking have been shown to be still smoking. At no 

time do these authors suggest that most smokers do not want to quit. 299 

4. The tobacco industry disputes that tobacco consumers continue to use 

despite knowledge of physical problems attributable to tobacco. The industry notes that, 

in one survey, a majority of smokers rated their overall health as good or excellent and 

297 See, e.g., Hughes JR, Gulliver SB, FenwickJW, et al., Smoking cessation among self-quitters, Health 

Psychology 1992;11:331-334. See AR (Vol348 Ref. 5512). 

298 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994), at 175-272. See AR (Vol 535 Ref. 96, 

vol. Ill.B). 

299 Kozlowski LT, Herman CP, Frecker RC, What researchers make of what cigarette smokers say: 

filtering smokers' hot air, lAncet 1980;1(8170):699-700. See AR (Vol. 535 Ref. 96, vol III. I). 

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concludes from this that the smokers were not suffering ill health from tobacco use. The 

industry also criticizes studies cited by FDA that document high rates of smoking after 

catastrophic illness on the basis that (1) the sample sizes were small; and (2) some fraction 

of the subjects in the studies were able to quit. 

After reviewing the evidence in the administrative record, FDA disagrees with the 

industry's position. To argue that a majority of smokers generally believe themselves in 

"good" or "excellent" health, the industry cites a Gallup poll originally cited by FDA.300 

In fact, contrary to the industry's argument, this Gallup poll demonstrates that smokers 

continue to use tobacco despite health problems. Sixty-five percent of smokers in the 

survey admitted that "smoking has already affected their health." Moreover, the data 

reveal that: (1) significantly fewer smokers than nonsmokers rated their health as 

"excellent"; and (2) smokers rated their overall condition as significantly less healthy than 

nonsmokers did. Thus, this survey supports FDA's contention that smokers persist in 

using tobacco despite knowledge that their health has been harmed by smoking. 

The industry's criticism of data cited by FDA on smokers continuing to use 

tobacco after myocardial infarction, lung cancer, and laryngeal cancer is not persuasive. 

The industry offers no contradicting evidence, nor does it suggest any reason why the 

studies cited by FDA might not be generalizable to the larger population. In the absence 

of such reasons, FDA believes that the sample sizes were adequate to permit such 

generalization. 

300 Gallup GH, Smofdng Prevalence, Beliefs, and Activities by Gender and Other Demographic Indicators 

(Princeton NJ: Gallup Organization, 1993), at 20, 37. See AR (Vol86 Ref. 1165). 

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The industry finally makes the argument that some people with devastating disease 

from tobacco are able to quit smoking. This contention misses the point. Even in the 

most drastic of circumstances, when patients have lost part of their body to cancer from 

smoking or had part of their heart muscle die from smoking, many still cannot stop. That 

any significant number of people return to smoking after such devastating tobacco-related 

disease is a powerful illustration of the addictiveness of nicotine. 

h. Comments on Nicotine's Other Significant Pharmacological Effects 

1. The tobacco industry argues that many substances and activities 

tangentially affect the brain, but that a reliable criterion for a "substantial" pharmacological 

effect is intoxication. According to the comment, nicotine does not produce intoxication, 

and therefore its pharmacological effects are not substantial. 

FDA disagrees. FDA has presented dozens of scientific studies and reviews to 

show that nicotine has numerous substantial pharmacological effects on the human body. 

The most significant of these is addiction, discussed at length in section II.A.3., above. 

Other examples of substantial effects include significant molecular changes in the brain, 

effects on weight regulation, and substantial alterations of mood, alertness, and cognition, 

none of which the industry contests. The vast majority of drugs that FDA already 

regulates, whose pharmacological effects are indisputable, do not produce intoxication. 

FDA notes that nicotine can cause intoxication. Indeed, fJISt-time users often become 

intoxicated.301 Regular users do so rarely because they have developed an extremely high 

level of tolerance to this effect of nicotine. 302 

301 Surgeon General's Report, 1988, at 594. See AR (Vol 129 Ref. 1592). 

302 /d. at 593-596. 

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i. Comments on Whether Cigarettes and Smokeless Tobacco Deliver 

Pharmacologically Active Doses of Nicotine 

1. Several professional organizations with expertise in pharmacology and 

addiction comment on the ability of cigarettes and smokeless tobacco to provide addictive 

doses of nicotine. These comments uniformly agree with the conclusion that cigarettes 

and smokeless tobacco do provide pharmacologically active doses of nicotine capable of 

producing addiction. These organizations include the College on Problems of Drug 

Dependence, which states: 

Nicotine is appropriately categorized as an addictive drug. Data 

from both animals and humans indicate that nicotine produces 

tolerance, physical dependence, reinforcing psychoactive effects 

and it thus has the potential for becoming an abused substance. 

Regular cigarette smokers and habitual smokeless tobacco users 

obtain sufficient quantities of nicotine to produce these effects .... 

Cigarettes and smokeless tobacco serve as highly effective and 

efficient drug delivery devices. They provide nicotine in quantities 

and patterns that enable users readily to develop and sustain 

dependence. 303 

The American Society of Addiction Medicine concludes that "nicotine in 

cigarettes and in smokeless tobacco is a pharmacologically active agent that causes 

addiction in a high proportion of users. "304 

Similar conclusions were reached by the American Psychological Association, 

which observes that "[c]igarettes and smokeless tobacco serve as highly effective and 

303 College on Problems of Drug Dependence, Comment (Nov. 6, 1995), at 1 (emphasis added). See AR 

(Vol. 700 Ref. 1021). 

304 American Society of Addiction Medicine, Comment (Dec. 29, 1995), at 1 (emphasis added). See AR 

(Vol. 528 Ref. 97). 

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II.A.7. 

efficient drug delivery systems, which by their very design enable people to readily 

develop and sustain nicotine addiction. "305 

FDA agrees with these independent scientific bodies. 

2. The tobacco industry takes issue with FDA's citations of studies to show 

that certain levels of nicotine cause pharmacological effects. 

The tobacco industry argues that three studies cited by FDA to estimate the 

minimum pharmacological dose of nicotine do not show that tobacco products cause 

significant pharmacological effects. The industry also contends that two studies cited by 

FDA to show that smokers can control their nicotine intake do not reflect common 

tobacco consumption behavior. 

The industry mischaracterizes FDA's reasons for citing the studies. FDA did not 

cite animal research and a study on the nicotine nasal spray to prove that cigarettes cause 

pharmacological effects in humans. Rather, the studies were cited to demonstrate that a 

very low blood level of nicotine that is easily attainable with cigarettes produces 

pharmacological effects across species. This observation complements overwhelming 

evidence from clinical, epidemiological, and laboratory studies showing that cigarettes and 

smokeless tobacco cause significant pharmacological effects in humans. 

Similarly, FDA did not cite studies on the extremes of nicotine intake to 

demonstrate exactly how much nicotine every smoker obtains. Rather, the studies were 

cited to demonstrate that nicotine intake from cigarettes has the potential to vary widely 

across a range of levels that produce significant pharmacological effects in humans. 

305 American Psychological Association, Comment (Dec. 28, 1995), at 2 (emphasis added). See AR 

(Vol. 531 Ref. 123). 

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II.A.7. 

FDA also notes that the industry offers no data contradicting FDA's studies. The 

industry also fails to contest other sources cited by FDA-including some from the 

tobacco industry-that clearly support the conclusion that nicotine levels in commercial 

tobacco products produce significant pharmacological effects in consumers. See 

Jurisdictional Analysis, 60 FR 41571-41572,41632-41640. 

Finally, FDA notes that the industry misinterprets a study by Perkins et al. 306 on 

nicotine nasal spray. See section II.A.7.d., above. 

3. The industry contends that nicotine doses provided by cigarettes produce 

only a "minimal response in laboratory animals and a small number of human subjects" and 

that, therefore, FDA has not established that nicotine doses delivered by cigarettes 

produce substantial phannacological effects. 

FDA disagrees. Many studies demonstrate such significant effects as systemic 

cardiovascular reactions in nontolerant humans and animals, 307 sickness produced by a 

single tobacco exposure in nontolerant individuals,308 and changes in brain electrical 

activity comparable to those produced by other addictive drugs.309 As described in 

sections II.A.4., above, and II.B.2., below, use of tobacco also produces significant effects 

on attention, mood, cognition, and weight regulation. These are not minimal effects. 

306 Perkins K, Grobe J, Scierka A. et al., Discriminative stimulus effects of nicotine in smokers, in 

International Symposium on Nicotine: The Effects of Nicotine on Biological Systems II, eds. Clarke PBS, 

Quik M, Thurau K, Adlkofer F (Basel: Birkhauser Verlag, 1994), at 111. See AR (Vol42 Ref. 111). 

307 Surgeon General's Report, 1988, at47. See AR (Vol129 Ref. 1592). 

308 /d. at 594. 

309 Pritchard WS, Electroencephalographic effects of cigarette smoking, Psychopharmacology 

1991;104:485-490, at485, 488. See AR (Voll05 Ref. 965). 

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Nicotine's capacity to produce and sustain addiction, as described in section ll.A.2., 

above, is another example of a significant pharmacological effect. 

II.A.7. 

Because the vast majority of chronic smokers are highly tolerant to nicotine, not all 

of the pharmacological effects of nicotine are evident with every cigarette and pinch of 

smokeless tobacco. As described in section II.A.3.c.i., above, the severe degree of 

tolerance produced by nicotine seems to greatly exceed that produced by cocaine and to 

be more comparable to that produced by morphine in the reduction of responsiveness to 

acute doses after a period of repeated exposure. 

4. The tobacco industry argues that there is no "addictive level" of nicotine. 

This contention is partly based on the claim that nicotine intake is not well correlated with 

quitting success. The industry also argues that FDA's Drug Abuse Advisory Committee 

did not identify a threshold addictive dose of nicotine. Without such an "addictive level," 

the industry concludes, the nicotine in tobacco products cannot have a substantial 

pharmacological effect. 

FDA disagrees. The tobacco industry misinterprets the scientific literature on 

cessation studies, the actual conclusion reached by the Committee, and the concept of 

"addictive level." 

A large body of literature has shown that nicotine dependence level is among the 

strongest general predictors of withdrawal severity and duration of abstinence. See 

section ILA.7.f., above.310 These data support the conclusion that the relationship 

between level of drug intake and dependence level is similar to that observed with other 

310 Surgeon General's Report. 1988, at315-321, 522-523. See AR(Vol 129 Ref. 1592). 

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II.A.7. 

forms of drug addiction, namely that level of drug intake is generally but not precisely 

correlated positively with dependence level and that there is wide individual variability.311 

It is because drug intake alone is not a perfect measure of dependence that diagnostic 

instruments such as the DSM are necessary for clinical practice. 

The industry also misrepresents the findings of the FDA Committee, which 

concluded that all currently marketed cigarettes contain an addictive dose of nicotine, but 

that the data were not sufficient to determine a threshold dose below which the product 

would not pose a risk of addiction. 312 The main concern of the Committee was that, in 

attempting to set a lower limit, any error on the high side would permit the industry to 

market products that would be addictive to some persons. The Committee was 

particularly concerned that persons who have not developed tolerance to nicotine, such as 

children, might find even the doses posed by Benowitz and Benningfield (approximately 

one-tenth of the delivery of a typical cigarette) to be addictive.313 

FDA concurs with the Committee that all currently marketed cigarettes contain 

addictive levels of nicotine. 

5. The tobacco industry argues that any compensation occurring in response 

to cigarettes with lower yields of tar and nicotine is limited and of short duration. Thus, 

according to the industry, smokers of low-yield cigarettes do not obtain pharmacologically 

active doses of nicotine. The industry contends that this proposition is supported by an 

311 /d. at 315-321. 

312 Transcript to the FDA Drug Abuse Advisory Committee, Meeting 27, "Issues Concerning NicotineConlaini.ng Cigarettes and Other Tobacco Products" (Aug. 2, 1994), at 346-353. See AR (Vol. 255 Ref. 

3445). 

313 /d. at 346-353. 

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II.A.7. 

article by Benowitz and Henningfield.314 The industry also argues that smokers actually 

compensate for changes in tar delivery rather than nicotine delivery. Furthermore, it 

denies that cigarette vent-hole blocking is a significant means of compensation. The 

industry thus argues that compensation for nicotine does not occur. 

FDA disagrees. Tobacco industry research demonstrates that smokers significantly 

compensate for nicotine. For example, research presented at a tobacco industry 

conference in 197 4 demonstrated that, "whatever the characteristics of cigarettes as 

determined by smoking machines, the smoker adjusts his pattern to deliver his own 

nicotine requirements." See Jurisdictional Analysis, 60 FR 41663. Other examples of the 

tobacco industry's understanding of compensation are documented in the Jurisdictional 

Analysis. See 60 FR 41572-41575. 

Furthermore, FDA cited research in the Jurisdictional Analysis demonstrating that 

the actual amount of nicotine delivered to the smoker does not correlate with the machinemeasured yield of the cigarette and that smokers who smoke "low-yield" cigarettes have 

been shown to obtain substantially more nicotine than the advertised yield. See 60 FR 

41659-41665. In one study, for example, the advertised yield oftested cigarettes ranged 

from 0.1 to 1.6 mg of nicotine, but the actual nicotine intake by the smokers asked to 

smoke these cigarettes ranged from 0.75 to 1.25 mg.315 Other studies have also found that 

the nicotine levels measured in smokers' blood bear either no relationship or a minimal 

314 Benowitz NL, Henningfield JE, Establishing a nicotine threshold for addiction, New England Journal 

of Medicine 1994;331: 123-125. See AR (Vol. 28 Ref. 218). 

315 Gori GB, Lynch CJ, Analytical cigarette yields as predictors of smoke bioavailablity, Regulatory 

Toxicology and Pharmacology 1985;5:314-326. See AR (Vol. 12 Ref. 142). 

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II.A.7. 

relationship to the nicotine yield of the cigarettes being smoked and that machinemeasured yields of low-tar/low-nicotine cigarettes significantly underestimate true rates of 

nicotine absorption. In most of these studies, the subjects were people who were smoking 

their usual brand of cigarettes and showed levels of nicotine not related to Federal Trade 

Commission (FTC) yields, thus refuting the suggestion that compensation is short-lived.316 

The tobacco industry misrepresents the position of Benowitz and Benningfield on 

compensation. These authors have repeatedly published research demonstrating that 

smokers compensate with current cigarettes by smoking harder or by blocking the vent 

holes.317 

In the Benowitz and Benningfield paper cited by the tobacco industry, the authors 

were discussing cigarettes-not currently on the market-with so little available nicotine 

that it would be impossible to compensate for reduced nicotine except by smoking an 

impractical number of cigarettes. The total nicotine content of these cigarettes would 

have been only about 5% of the content of currently marketed cigarettes and would have 

permitted a maximum delivery of only about 10% that of current cigarettes. The authors 

predicted that few smokers would pennanently smoke the 200 or more cigarettes needed 

to obtain the nicotine intake typically delivered by 20 conventional cigarettes. Thus, 

Benowitz and Benningfield believed that, if denied access to regular nicotine cigarettes, 

smokers would either quit or adjust over time to substantially reduced nicotine intake. 

316 Surgeon General's Report, 1988, at 158-159. See AR (Vol 129 Ref. 1592). 

317 ld. at 158-163. 

Henningfield JE, Kozlowski LT, Benowitz NL, A proposal to develop meaningful labeling for cigarettes, 

Journal of the American Medical Association 1994;272:312-314. See AR (Vol313 Ref. 4846). 

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II.A.7. 

This prediction is entirely inapplicable to currently marketed "low-yield" cigarettes 

delivering 0.1 mg of nicotine as measured by the smoking machine; a smoker need smoke 

only about 30 of these to obtain the amount of nicotine obtained with 20 "full flavor'' 

cigarettes. 318 

The tobacco industry's denial that vent blocking occurs misses important points of 

FDA's position on this issue. FDA has simply posed vent blocking as the most likely 

explanation for the well-documented fact that there is almost no difference in the nicotine 

levels observed in the bodies of smokers who smoke brands with widely varying FTC 

yields. Smoking more cigarettes is only one means by which smokers compensate. Vent 

blocking is another means at the smoker's disposal to compensate. Indeed, the studies 

relied on by the tobacco industry suggest that the frequency of vent blocking is inversely 

proportional to the yield of the cigarette. In other words, the lower the tar and nicotine 

yield of the cigarette, the more the smoker blocks the vent holes. These data support the 

position that vent blocking plays an important role in compensation. There are, in 

addition, other compensation mechanisms, such as smoking more of the cigarette than is 

smoked in testing machines, smoking more aggressively, and taking deeper inhalations.319 

The tobacco industry contends that smokers may compensate for tar rather than 

for nicotine. This contention is contradicted by a very extensive body of literature, 

documented in detail in the 1988 Surgeon General's Report,320 showing that, when the 

318 Transcript to the FDA Drug Abuse Advisory Committee, Meeting 27, "Issues Concerning NicotineContaining Cigarettes and Other Tobacco Products" (Aug. 2, 1994), at 106. See AR (Vol 255 Ref. 3445). 

319 Surgeon General's Report, 1988, at 153-158. See AR (Vol 129 Ref. 1592). 

320 Jd. at 153-169, 282-283. 

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II.A.7. 

level of nicotine in cigarettes is manipulated, smokers alter their smoke intake. Although 

the relationship is not perfect, it is similar to that which has been observed with other 

addictive drugs in numerous animal studies and some human studies. That is, when the 

dose of the drug in the cigarette is increased, the number of unit doses that are selfadministered decreases generally, although not proportionally. This results in the frequent 

observation of increased overall drug intake.321 

Conversely, when the dose is decreased, the number of unit doses that are selfadministered generally increases, although usually not proportionally. The relationship has 

been demonstrated with respect to cigarette smoking by: ( 1) administering nicotine to 

smokers via other routes, which results in decreased smoking; and (2) administering the 

nicotine blocker mecamylamine to smokers (which reduces the effects of nicotine on 

receptors in the brain), resulting in increased smoking.322 A study on compensation for 

smokeless tobacco cited by the smokeless tobacco industry showed that users increased 

their consumption when switched to a low-nicotine product.323 

321 /d. at 282-283. 

322 /d. at 165-169. 

323 Andersson G, Axell T, Curvall M, Reduction in nicotine intake and oral mucosal changes among users 

of Swedish oral moist snuff after switching to a low-nicotine product, Journal of Oral Pathology & 

Medicine 1995;24:244-250. See AR(Vol. 526 Ref. 95, vol. VII). 

The low-nicotine product had a lower pH than the higher-nicotine product Because lower pH reduces 

absorption see section II. D., below, measurements of nicotine intake cited by the industry do not 

accurately reflect compensation in this study. 

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IT. B. 

B. CONSUMERS USE CIGARETTES AND SMOKELESS TOBACCO 

TO OBTAIN THE PHARMACOLOGICAL EFFECTS OF 

NICOTINE AND TO SATISFY THEIR ADDICTION 

In section ll.A., above, the Agency concludes that the foreseeable pharmacological 

uses of cigarettes and smokeless tobacco establish that tobacco manufacturers intend their 

products to affect the structure and function of the body. The Agency may fmd additional 

evidence of such intent through evidence that consumers commonly use tobacco products 

for pharmacological effects. Where consumers use a product predominantly or nearly 

exclusively to obtain any of the effects on the structure or function of the body produced 

by a substance, such evidence would alone be sufficient to establish manufacturer intent. 

See ASH v. Harris, 655 F.2d 239-240. 

The Agency made extensive fmdings regarding consumer use of tobacco products 

in the Jurisdictional Analysis. See 60 FR 41576-41581. FDA received comments from 

the tobacco industry, public health and medical organizations and practitioners, and other 

members of the public. Upon review of the evidence in the administrative record and 

careful analysis of the comments on the Jurisdictional Analysis, the Agency concludes that 

the evidence demonstrates that consumer use of cigarettes and smokeless tobacco for the 

pharmacological effects of nicotine is predominant, in fact nearly exclusive. Moreover, the 

Agency finds that other factors associated with tobacco use-including taste and habitare significant to almost all consumers only by their association with nicotine's 

pharmacological effects on the brain. Thus, FDA fmds that actual consumer use of 

cigarettes and smokeless tobacco for the pharmacological effects of nicotine provides an 

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II.B.l. 

independent basis for the conclusion that these products are intended to affect the 

structure and function of the human body.324 

In section II.B.l., below, FDA discusses its authority to consider evidence of 

consumer use in establishing intended use. FDA presents its major findings and responds 

to significant comments in sections II.B.2. and 3., below. In section II.B.4., below, FDA 

responds to all other substantive comments. 

1. "Intended Use" May Be Established on tbe Basis of Actual 

Consumer Use 

The legislative history of the Act clearly states that consumer use can be probative 

of a product's intended use. For example, the House Report on the Medical Device 

Amendments of 1976 states that "[t]he Secretary may consider ... use of a product in 

determining whether or not it is a device." H.R. Rep. 853, 94th Cong., 2d Sess. 14 

(1976) (emphasis added), reprinted in An Analytical Legislative History of the Medical 

Device Amendments of 1976, Appendix III (Daniel F. O'Keefe, Jr. & Robert A. Spiegel, 

eds. 1976). Similarly, the legislative history of the 1938 Act states expressly that "the use 

to which the product is to be put will determine the category into which it will fall." 

S. Rep. No. 361, 74th Cong., 1st Sess. 4 (1935) (emphasis added), reprinted in 3 

Legislative History 660, 663. 

324 In this case. there is evidence not only of actual consumer use. but other evidence of manufacturer 

intent, including: (1) evidence that nicotine's addictive properties and other pharmacological effects are 

foreseeable to a reasonable tobacco manufacturer; and (2) evidence from the statements, research, and 

actions of manufacturers establishing that they intend their products to affect the structure or function of 

the bodies of tobacco users. See sections II. A., C., and D. Thus, although the evidence establishes that 

consumers use cigarettes and smokeless tobacco predominantly or nearly exclusively for the 

pharmacological effects of nicotine, this fmding is not necessary to permit reliance on the evidence of 

actual consumer use. Relied on in conjunction with the other evidence of manufacturer intent, evidence of 

actual consumer use provides substantial additional support for the Agency's conclusion. 

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II.B.l. 

Like the legislative history, FDA's regulations on adequate directions for the use 

of drugs and devices also demonstrate that actual consumer use can be a basis for 

establishing a product's intended use. 21 CFR 201.5 (drugs); 21 CFR 801.5 (devices). 

Section 201.5, which specifies the "adequate directions" that must be provided on drug 

labeling, provides examples of the "intended uses" of a drug that must be included in any 

adequate labeling. These intended uses include both: (1) "uses for which it is prescribed, 

recommended, or suggested in its oral, written, print, or graphic advertising;" and (2) 

"uses for which the drug is commonly used." 21 CFR 201.5 (emphasis added). Section 

801.5 contains parallel provisions for devices. Because adequate directions for use are 

required only for the intended uses of a product, these regulations make the "common 

use" of a product a basis for determining "intended use." 

Courts have also recognized that actual consumer use can be a persuasive basis for 

determining intent-even in the absence of other evidence that the manufacturer intends to 

affect the structure or function of the body. In ASH, the court explicitly recognized that 

actual "consumer intent" by itself could be a basis for imputing intent to the manufacturer: 

Clearly, it is well established ''that the 'intended use' of a product, 

within the meaning of the Act, is determined from its label, 

accompanying labeling, promotional claims, advertising, and any 

other relevant source." Whether evidence of consumer intent is a 

"relevant source" for these purposes depends upon whether such 

evidence is strong enough to justify an inference as to the vendors' 

intent. This requires a substantial showing .... In cases such as the 

one at hand, consumers must use the product predominantly-and 

in fact nearly exclusively-with the appropriate intent before the 

requisite statutory intent can be inferred. 

655 F.2d at 239-240 (emphasis added). Similarly, in NNFA v. Weinberger, the court held 

that evidence before the Commissioner that vitamins "were used almost exclusively for 

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44810 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

ll.B.l. 

therapeutic purposes" could be a proper basis to determine that the manufacturer intended 

a pharmacological use. 512 F.2d at 703. 

When a finding of an intent to affect the structure and function of the body is based 

exclusively on evidence of actual consumer use, the evidence must meet a high threshold. 

As quoted above, the courts in ASH and NNFA have indicated that the evidence should 

show that the actual consumer use for drug purposes is "predominant" or "nearly 

exclusive." FDA's regulations contemplate that the use be shown to be at least 

"common." 21 CFR 201.5. 

There is no requirement, however, that a product be used nearly exclusively as a 

drug before FDA may regulate it as a drug. To the contrary, a product that has both 

pharmacological uses and nonpharmacological uses can be regulated as a drug. See 

United States v. Guardian Chemical Corp., 410 F.2d 157, 162-163 (2d Cir. 1969)(a 

solvent used both to dissolve kidney stones (a drug use) and to clean instruments (a 

nondrug use) was properly regulated as a drug). Consistent with this principle, the courts 

recognize that where, as here, there is other evidence of manufacturer intent, consumer 

use for drug purposes may be relevent evidence of intended use even if that use is not 

predominant or nearly exclusive. See, e.g., United States v. An Article of Device .•. 

Tojtness Radiation Detector, 731 F.2d 1253, 1257 (7th Cir. 1984); United States v. 789 

Cases ... Latex Surgeons' Gloves, 799 F. Supp. 1275, 1285, 1294-95 (D.P.R. 1992); 

United States v. 22 ... devices . .. "The Ster-o-lizer MD-200," 714 F. Supp. at 1165; 

United States v. An Article of Device ... "Cameron Spitler Amblo-Syntonizer," 261 F. 

Supp. 243, 245 (D. Neb. 1966). 

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II.B.2. 

Consistent with these authorities, the Agency finds that actual consumer use can be 

a basis for establishing the manufacturer's intended use for the product. Where the only 

evidence of intended use is the actual consumer use of the product, the Agency may need 

to show that the use of the product for pharmacological purposes is "predominant" or 

"nearly exclusive" before establishing that a product is intended to affect the structure or 

any function of the body. At a minimum, as set forth in FDA's regulations, the Agency 

should show that the use is "common" before relying exclusively on evidence of consumer 

use to establish intended use. Where, however, actual consumer use is only one of several 

types of evidence relied upon by the Agency, more limited evidence of consumer use can 

be used to support a finding that a product is "intended to affect the structure or any 

function of the body." 

In the case of cigarettes and smokeless tobacco, as discussed below, the evidence 

establishes that the standard of "predominant" or "nearly exclusive" consumer use is met 

even though other types of evidence exist Thus, the evidence of actual consumer use of 

cigarettes and smokeless tobacco provides an independent basis for establishing these 

products' intended pharmacological uses. 

2. Consumers Use Cigarettes and Smokeless Tobacco for the 

Pharmacological Effects of Nicotine 

The evidence on consumer use of cigarettes and smokeless tobacco convincingly 

demonstrates the intended use of such products for pharmacological purposes. In the 

following sections, FDA explains this conclusion and the epidemiological and experimental 

data that confirm that consumers do use cigarettes and smokeless tobacco predominantly 

for one or more of the pharmacological effects of nicotine. 

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II.B.2. 

a. Epidemiological Evidence Shows That Consumers Use Cigarettes 

and Smokeless Tobacco for Pharmacological Effects 

Epidemiological studies establish that the vast majority of consumers use tobacco 

for at least one of three pharmacological purposes: to satisfy a nicotine addiction; to 

receive the accompanying psychoactive effects, such as relaxation and stimulation; or to 

control weight. 

To satisfy nicotine addiction. If a tobacco consumer is addicted to nicotine, then 

the key reason for use of the tobacco product is a pharmacological effect: the satisfaction 

of the addiction. 

Based upon internationally accepted definitions of addiction from the American 

Psychiatric Association and the World Health Organization (WHO), major recent studies 

show that 77% to 92% of smokers are addicted to cigarettes. In various studies, smokers 

who met the criteria for addiction included those identified by self-report (90% 

addicted),325 those who used tobacco six or more times (87% addicted),326 those who 

were daily users for at least one month (77% to 92% addicted),327 and those who reported 

any current use of cigarettes (80% addicted).328 Studies show a higher percentage of 

325 Hughes JR, Gust SW, Pechacek 1F, Prevalence of tobacco dependence and withdrawal, American 

Journal of Psychiatry 1987;144(2):205-208. See AR (Vol 81 Ref. 292). 

326 Woody GE, Cottier LB, Cacciola J, Severity of dependence: data from the DSM-IV field trials, 

Addiction 1993;88:1573-1579. See AR(Vol13 Ref. 150). 

327 Cottier L, Comparing DSM-ID-R and ICD-10 substance use disorders, Addiction 1993;88:689-696. 

See AR (Vol 13 Ref. 149). 

328 Hale KL, Hughes JR, Oliveto AH, Helzar JE, Higgins ST, Bickel WK, CottlerLB, Nicotine 

dependence in a population-based sample, in Problems of Drug Dependence, 1992, NIDA Research 

Monograph 132 (Washington DC: Government Printing Office, 1993 ). See AR (Vol 39 Ref. 60). 

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II.B.2. 

addiction among tobacco users than among users of other addictive drugs, including 

cocaine and heroin. 329 

Although there have been no population-based studies using DSM or WHO 

criteria to assess rates of addiction to smokeless tobacco, substantial evidence 

demonstrates that a high proportion of smokeless tobacco users meet individual criteria 

for addiction. See section II.A.3.c.ii., above. This evidence strongly supports the 

conclusion that a substantial proportion of such users are addicted. 330 In 1992, the 

Inspector General of the U.S. Department of Health and Human Services estimated that 

approximately 75% of young regular users of smokeless tobacco are addicted.331 

Evidence also demonstrates that many tobacco users continue to consume tobacco 

for an additional pharmacological reason related to addiction: to avoid withdrawal 

symptoms.332 As addiction specialist Jerome Jaffe has noted, "[w]ithdrawal from nicotine 

... regularly motivates continued smoking."333 

329 Anthony JC, Warner LA. Kessler RC, Comparative epidemiology of dependmce on tobacco, alcohol, 

controlled substances and inhalants: basic fmdings from the National Comorbidity Survey, Experimental 

and Clinical Psychopharmacology 1994;2:244-268. See AR (VoL 37 Ref. 4). 

330 Bmowitz NL, Pharmacology of smokeless tobacco use: nicotine addiction and nicotine-related health 

consequence, in Smokeless Tobacco or Health, Smoking and Tobacco Control Monograph 2 (Washington 

DC: Government Printing Office, 1993), at 224. See AR (VoL 93 Ref. 606). 

331 Department of Health and Human Services, Office on Smoking and Health, Spit Tobacco and Youth 

(Washington DC: Government Printing Office, 1992), at 8. See AR (VoL 7 Ref. 76). 

332 Hughes JR, Higgins ST, Hatsukami D, Effects of abstinence from tobacco: a critical review, Research 

Advances in Alcohol and Drug Problems 1990;10:3170398, at381. See AR (VoL 535 Ref. 96, vol. III.G). 

333 Jaffe JH, Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of 

Therapeutics, 8th ed. (New York: Pergamon Press, 1990), chap. 22 (522-573), at 529. See AR (VoL 535 

Ref. 96, voL III.G). 

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II.B.2. 

For stimulation. sedation. mood alteration. and cognition. Studies also reveal that 

a large proportion of consumers use tobacco for other psychoactive effects. For example, 

a recent survey of young people 10 to 22 years old found that 72.8% of daily smokers and 

53.8% of daily consumers of smokeless tobacco said they used tobacco for relaxation.334 

The 1988 Surgeon General's Report reviewed the epidemiological literature on the effects 

of smoking on mood: "The conclusion from this literature is that in the general 

population, persons perceive that smoking has functions that are relevant for mood 

regulation. Persons report that they smoke more in situations involving negative mood, 

and they perceive that smoking helps them to feel better in such situations.'m5 The 

Surgeon General's Report also noted that "some cigarette smokers believe that smoking 

helps them to think and concentrate."336 This is the belief of several prominent tobacco 

industry researchers. 337 Data demonstrating significant consumer use for the 

pharmacologically mediated effects of nicotine on mood and arousal are summarized in the 

Jurisdictional Analysis. See 60 FR 41579-41580. 

To control weight. Numerous studies show that tobacco use by many people is at 

least partially motivated by their belief that tobacco will help them control their weight. 

334 Centers for Disease Control and Prevention, Reasons for tobacco use and symptoms of nicotine 

withdrawal among adolescents and young adult tobacco users-United States, 1993, Morbidity and 

Mortality Weeldy Report 1994;43(41):745-750. See AR (Vol 43 Ref. 162). 

335 Surgeon General's Report, 1988, at 399. See AR (Vol 129 Ref. 1592). 

336 /d. at 382. 

337 Robinson J, Transcript to the FDA Drug Abuse Advisory Committee, Meeting 27, "Issues Concerning 

Nicotine-Containing Cigarettes and Other Tobacco Products" (Aug. 2, 1994 ), at 227. See AR (Vol 255 

Ref. 3445). 

Warburton DM, Nicotine: an addictive substance or a therapeutic agent, Progress in Drug Research 

1989;33:9-41, at 25. See AR (Vol 140 Ref. 1657). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44815

II.B.2. 

For example, in two surveys of young people, between one-third and one-half of smokers 

said that weight control was a reason for their smoking. 338 Additional data on the use of 

tobacco products for weight control are summarized in the Jurisdictional Analysis. See 60 

FR 41580-41581. 

b. Experimental Evidence Shows That Consumers Use Cigarettes and 

Smokeless Tobacco Products for Pharmacological Effects 

As described in section II.A.3.c.i., above, overwhelming laboratory data 

demonstrate that nicotine's pharmacological effects are central to tobacco use. Three 

fmdings from experimental studies particularly show that consumers smoke cigarettes and 

consume smokeless tobacco for the pharmacological effects of nicotine. 

Nicotine reinforces tobacco consumption. Like other addictive substances such as 

amphetamine, morphine, and cocaine, nicotine acts on a key "reward" pathway in the 

brain-known as the meso limbic system-to reinforce its own consumption. 339 As even 

the tobacco industry has noted, the "reward" generated by this pathway may explain why 

people eat food, drink water, and consume salt. The ability of nicotine to generate a 

similar "reward" for tobacco consumption reflects its pharmacological power and 

represents a clear reason why consumers use tobacco products. The data supporting 

nicotine's role in the "reward" system are discussed in section ll.A3.c.i., above. 

Nicotine controls smoking behavior. It has been convincingly demonstrated that 

smokers adapt their cigarette consumption to maintain the pharmacological effect of nicotine in 

338 Surgeon General's Report, 1988, at 438-441. See AR (VoL 129 Ref. 1592). 

339 See, e.g., Corrigall W A, Franklin KBJ, Coen KM. et al., The mesolimbic dopaminergic system is 

implicated in the reinforcing effects of nicotine, Psychopharmacology 1992;107:285-289. See AR 

(Vol. 8 Ref. 93-4). 

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II.B.2. 

the brain. Thus, smokers given cigarettes lower in nicotine change their smoking behavior to 

obtain more nicotine, and those given cigarettes higher in nicotine than their usual brand modify 

their behavior to obtain less. When given a drug to reduce the effect of nicotine in the brain, 

smokers will consume more of the same cigarettes, even though nothing else has changed. 

This is compelling evidence that niCotine plays a pivotal role in why consumers use tobacco 

products. These data are discussed in detail in section ll.A5., above. 

Nicotine in other fonns affects tobacco consumers. The ability of nicotine nasal 

spray to produce some of the classic characteristics of addiction to nicotine supports the 

position that tobacco users seek tobacco primarily for the systemic pharmacological 

effects of nicotine. In contrast to cigarette smoke, aqueous nicotine spray does not 

provide any pleasing sensory characteristics. In fact, the spray can be irritating and 

unpleasant to use, and excessive use can cause nasal ulcerations. Notwithstanding the 

unpleasantness of the nicotine delivery mechanism and the presence of painful ulcerations 

that were further aggravated by continued use of the spray, some participants in clinical 

trials submitted to FDA used the spray to maintain nicotine dependence.340 

Studies on nicotine replacement therapies also demonstrate efficacy in maintaining 

abstinence from smoking.341 The ability of nicotine to promote abstinence, even when 

delivered through the skin, without any taste or flavor, demonstrates its key role in 

maintaining tobacco consumption. 

340 FDA Drug Abuse Advisory Committee background information (Aug. 1, 1994), Joint Abuse Liability 

Review of Nicotine Nasal Spray. See AR (Vol 9 Ref. 117). 

341 See appendix 1 to Jurisdictional Analysis at 62-82. See AR (Vol. 1 Appendix 1). 

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II.B.2. 

c. The Data Do Not Support the Industry's Claim That Consumers Seek 

Nicotine for Its Sensory Effects Rather than Its Pharmacological 

Effects 

The tobacco industry responds to the overwhelming evidence that nicotine's 

phannacological actions are central reasons for tobacco consumption by arguing instead 

that nicotine's key role in tobacco products is for flavor. According to the industry, the 

nonphannacological actions of nicotine such as "flavor" are so essential to consumers that 

the nicotine level in each cigarette and unit of smokeless tobacco must be carefully 

controlled. 

This argument in no way contradicts any of the experimental and epidemiological 

evidence showing that consumers use tobacco products for the phannacological effects of 

nicotine. These studies prove nicotine's central phannacological importance by 

demonstrating, for example, that: (1) nicotine causes psychoactive effects characteristic of 

addiction even when delivered by nonoral routes, where there is no "flavor'' at all; and (2) 

the vast majority of smokers are addicted to tobacco products. 

Moreover, the industry's position that nicotine's primary role is to provide flavor is 

inconsistent with the evidence. First, the industry's position is flatly contradicted by 

numerous statements of its own scientists and executives. Several industry documents 

dismiss the role of nicotine in flavor. For example, in 1974, an American Tobacco 

Company manager concluded that Pall Mall and Lucky Strike cigarettes tasted virtually 

the same even after the addition of extraneous nicotine (referred to as "Compound W''); 

according to the manager, "increasing the level of nicotine in the smoke by the addition of 

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II.B.2. 

Compound W has little, if any, effect on taste."342 A Philip Morris presentation that 

discusses the importance of flavor in ultra-low cigarettes states flatly that "nicotine is an 

inexpensive, tasteless constituent."343 Philip Morris' comments similarly contradict the 

industry's position that nicotine has a significant role in the flavor of cigarettes. These 

comments state that Philip Morris conducted extensive investigations into the flavors in 

cigarette smoke using an "olfactometer," yet Philip Morris claims that "[n]one of that 

olfactometer work involved nicotine at all," an unlikely omission if nicotine is an important 

flavor component.344 

Tobacco industry documents also reveal that the industry draws a consistent 

distinction between nicotine's role in tobacco use and the role of flavor. A Brown & 

Williamson study emphasized the importance of nicotine delivery over all other product 

features and specifically distinguished the effects of nicotine from the taste and flavor 

characteristics of tobacco: 

In considering which product features are important in terms of 

consumer acceptance, the nicotine delivery is one of the more 

obvious candidates. Others include the taste and flavour 

characteristics of the smoke, physical features such as draw 

resistance and rate of burn, and the general uniformity of the 

product, to name but a few. The importance of nicotine hardly 

needs to be stressed, as it is so widely recognised. 345 

342 Memorandum from Irby RM (manager, new products division) to McCarthy JB (executive vice 

president, research and development), Nicotine Content of Reconstituted Tobacco (Jun. 5, 1974), at 3-4 

(emphasis added). See AR (Vol. 26 Ref. 357-3) 

343 Philip Morris Inc., First Speaker, Merit Team Remarks (Jan. 14, 1976), at 3 (emphasis added). See 

AR (Vol. 640 Ref. 2). 

344 Philip Morris Inc., Comment (Apr. 19, 1996), at 47. See AR (Vol 700 Ref. 226). 

345 BATCO, Project Wheat-Part 1: Cluster profiles of U.K. male smokers and their general smoking 

habits, Southampton, England (Jul. 10, 1975), at 3-4 (emphasis added). See AR (Vol 20 Ref. 204-J). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44819

An internal RJR document shows that the industry views nicotine's role as 

pharmacological and distinct from the smoke components that provide flavor: 

If nicotine is the sine qua non of tobacco products, and tobacco 

products are recognized as being attractive dosage forms of 

nicotine, then it is logical to design our product - and where 

possible our advertising - around nicotine delivery rather than tar 

delivery or jlavor.346 

II.B.2. 

Other industry documents further demonstrate that the industry understands that 

nicotine's role is primarily pharmacological and that any sensory role is secondary. A 

variety of industry documents shows that industry knows that "satisfaction" comes from 

inhalation of nicotine into the lungs and absorption into the bloodstream. See 

Jurisdictional Analysis, 60 FR 41773-41774. Inhalation is necessary only to provide 

systemic pharmacological effects; it would be unnecessary if nicotine's role were to 

provide sensory effects. The statements of tobacco industry scientists confirm that 

nicotine's pharmacological effects are the primary reason for tobacco use. A leading 

tobacco research director noted as early as 1972 that "[t]he primary incentive to cigarette 

smoking is the immediate salutary effect of inhaled smoke upon body function .... the 

physiological effect serves as the primary incentive; all other incentives are 

secondary."347 As recently as 1992, RJR researchers recognized that "smokers use 

cigarettes primarily as a 'tool' or 'resource' that provides them with needed psychological 

benefits (increased mental alertness; anxiety reduction, coping with stress)."348 -

346 Teague CE, Research Planning Menwrandum on the Nature of the Tobacco Business and the Crucial 

Role of Nicotine Therein (Feb. 2, 1973), at 3 (emphasis added). See AR (Vol 531 Ref. 125). 

347 Dunn WL, Philip Morris Research Center, Motives and Incentives in Cigarette Snwking (1972), at 3-4 

(emphasis added). See AR (Vol 34 Ref. 582). 

348 Robinson JH, Pritchard WS, The role of nicotine in tobacco use, Psychopharmacology 1992; 108: 397-

407 (emphasis added). See AR (Vol. 104 Ref. 945). 

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II.B.2. 

Literally dozens of such statements-made over decades by tobacco researchers 

and executives from virtually every major company-expose the industry's knowledge 

that consumers use tobacco products primarily for pharmacological effects. These 

statements are analyzed in depth in section II.C.2., below. By contrast, over this long 

period, there are virtually no tobacco company studies supporting the importance of the 

purported "sensory effects" of nicotine. 

Second, the industry offers no persuasive data that nicotine contributes 

significantly to desirable flavor. FDA has reviewed all seven studies cited by the tobacco 

industry to demonstrate a significant "sensory" role for nicotine and fmds them 

unpersuasive. 

The industry cites a single abstract, based on research partially funded by RJR, to 

justify the claim that nicotine provides ''trigeminal ('throat grab') stimulation that is 

enjoyed by smokers." The abstract describes a single study of trigeminal nerve 

manipulation in rats. 349 It is impossible to conclude from this study that nicotine 

stimulates the human trigeminal nerve in any manner significant to smokers.350 

The industry cites a single paper to show that nicotine provides aroma "that is 

enjoyed by smokers." This research is based on recordings of the olfactory nerve in frogs. 

349 Silver WL, Walker DB, NasaL trigeminal chemoreception: response to nicotine, presented at the 

Ninth Annual Meeting of the Association for Chemoreceptor Sciences, Sarasota FL (1987). See AR 

(Vol 535 Ref. 96, vol. m.M). 

350 The industry's "trigeminal nerve" theory seems to be based in part on an anatomic misunderstanding. 

The industry proposes that the sensation of "throat grab" is caused by nicotine stimulation "in the back of 

the throat (where trigeminal nerve endings are located)." In fact, sensation to the back of the throat 

(pharynx) in humans is provided by the glossopharyngeal nerve, not by the trigeminal nerve. See 

Williams PL, Warwick R, eds., Gray's Anatomy, 37th ed. (Philadelphia: WB Saunders, 1989), at 1112. 

See AR (Vol 711 Ref. 8). 

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II.B.2. 

It is impossible to conclude from this study that nicotine creates an aroma of any 

significance to smokers. 351 Indeed, another study also cited by the industry concluded that 

reducing the olfactory stimulus of cigarettes had a minor effect on smoking behavior. 352 

RJR cites one article from 1952 and three recent studies to support the contention 

that the sensory aspects of nicotine consumption are more important to users than its 

pharmacological effects. 

In a 1952 article cited by RJR for the proposition that nicotine plays an important 

role in the taste and flavor of cigarette smoke, there are no data on this subject. 353 The 

relevant statements are merely the authors' speculations. In fact, the authors speculated 

about the flavors of various types of tobacco leaves, not about the specific flavor of 

nicotine. Nor did the authors distinguish between flavor and pharmacological effects of 

nicotine; to the contrary, a portion of the article omitted by the comment states that ''the 

smoker's desires are not satiated by" a low-nicotine leaf. This observation is consistent 

with the conclusion that consumers value nicotine for its pharmacological effects. 

A more recent study cited by RJR attempted to quantify the sensory responses to 

cigarettes containing varying levels of nicotine. 354 This study did not even consider 

351 Thurauf N, Renner B, Kobal G, Responses recorded from the frog olfactory epithelium after 

stimulation with r(+)- and S(-)- nicotine, Chemical Senses 1995;20(3):337-344, at 342. See AR (Vol. 

535 Ref. 96, vol. ID.M). 

352 Baldinger B, Hasenfratz M, Battig K, Switching to ultralow nicotine cigarettes: effects of different tar 

yields and blocking of olfactory cues, Pharmacology, Biochemistry and Behavior 1995;50(2):233-239, at 

238. See AR (Vol. 535 Ref. 96, vol. Ill.A). 

353 Darkis FR., Baisden LA, Gross PM, WolfF A, Flue-cured tobacco: chemical composition of rib and 

blade tissue, Industrial and Engineering Chemistry 1952;44(2):297-301, at 300-301. See AR (Vol. 519 

Ref. 103, vol. II). 

354 Gordin HH, Perfetti TA, Mangan PP, A quantification of sensory responses related to dynamic 

cigarette performance variables, Tobacco Science 1987;31:23-27. See AR (Vo1519 Ref. 103, vol. II). 

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II.B.2. 

whether any sensory responses to nicotine are important to smokers. The authors did not 

mention the number of subjects in the study. Nor did they account for the fact that 

cigarettes with varying nicotine levels also were different in many other ways; for example, 

they had different tip drafts, tipping porosities, plug wraps, and air dilution. Much of the 

data were not published with the study. FDA notes that this study-despite serious 

flaws-still found that tobacco taste was not associated with nicotine content. 

A second recent study cited by RJR attempted to determine the smallest amount of 

nicotine change detectable to the user.

355 It did not address whether any nicotine change 

produces any important sensory effects. The authors concluded only that there is a 

detectable "perceptual response" to nicotine, which could be described as either throat 

harshness or "strength." The study did not distinguish between sensory and central 

pharmacological effects of nicotine. 

The third recent study is an RJR presentation at a conference held in 1994, after 

FDA's investigation into nicotine was under way.

356 The presentation purported to show 

that nicotine's sensory effects are important in a consumer's acceptance of tobacco 

products, but the study failed to support this claim. Indeed, a principal author of the study 

conceded to FDA in 1994 that "we were not able to separate out the importance of the 

355 Gordin HH, Perfetti TA, Hawley RW, Nicotine just noticeable difference study of full flavor low "tar" 

and ultra low "tar'' non-menthol85mm products, Tobacco Science 1988;32:62-65. See AR (Vol 519 

Ref. 103, vol. II). 

356 Pritchard WS, Robinson JH, The Sensory Role of Nicotine in Cigarette "Taste," Snwking Satisfaction 

and Desire to Smoke, presented at the International Symposium on Nicotine: The Effects of Nicotine on 

Biological Systems II, Montreal (Jul. 21-24, 1994). See AR (Vol 519 Ref. 103, vol. II). 

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II.B.3. 

sensory aspects versus the pharmacological."357 FDA notes that this study, despite serious 

flaws, still found that nicotine levels had no effect on smooth taste, harsh taste, or 

aftertaste of cigarettes. 

Thus, the industry has presented no data that show that nicotine's flavor or sensory 

effects are important to consumer acCeptance. Even if the industry had produced evidence 

to support its position, however, nicotine's pharmacological effects would still explain 

virtually all consumer use. As described in section ll.B.3., below, the sensory aspects of 

tobacco consumption are important to consumers only in how they are linked to the 

pharmacological effects of nicotine. 

Compared with the hundreds of studies conducted around the world demonstrating 

the pharmacological significance of nicotine to tobacco consumers-a conclusion that 

reflects universal scientific agreement-the evidence to support the assertion that 

nicotine's sensory role is important to consumers is unconvincing. Thus, the industry has 

provided no basis to conclude that nicotine's role in tobacco use is to provide taste, flavor, 

or any other nonpharmacological sensation. 

3. Other Factors Associated with Tobacco Use Are Secondary to 

Pharmacological Effects -

FDA has established above that consumers use tobacco products for the 

pharmacological effects of nicotine._ The tobacco industry argues that consumers use 

tobacco for a variety of nonpharmacological purposes, including for taste, out of habit and 

ritual, and for social reasons. The Agency recognizes that there are many effects of 

357 Robinson J, Transcript to the FDA Drug Abuse Advisory Committee, Meeting 27, "Issues Concerning 

Nicotine-Containing Cigarettes and Other Tobacco Products" (Aug. 2, 1994 ), at 228. See AR (Vol 255 

Ref. 3445). 

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II.B.3. 

tobacco use perceived by some consumers as nonpharmacological in nature. In surveys, 

for example, some tobacco users say they like the taste of the product; others report 

enjoying the ritual involved in its consumption. The evidence before the Agency 

demonstrates, however, that the nonpharmacological factors associated with tobacco 

consumption are secondary to the pharmacological reasons for consumer use of tobacco. 

Indeed, FDA concludes that consumers use tobacco products "nearly exclusively" for the 

pharmacological effects of nicotine. 

This conclusion is supported by comments from the Coalition on Smoking OR 

Health, representing the American Heart Association, American Lung Association, and 

American Cancer Society. The Coalition explains: 

The physicians and health professionals who comprise our 

organizations provide the health care for virtually all tobacco users 

in the United States. Based upon our long term experience as well 

as our review of the scientific literature, it is our conclusion that the 

vast majority of people who use nicotine containing cigarettes and 

smokeless tobacco products do so to satisfy their craving for the 

pharmacological effects of nicotine; that is, to satisfy their drug 

dependence or addiction. While the published scientific literature 

on the point is conclusive in our scientific opinion, there may be no 

better evidence of the reason people use these products than the 

accumulative, daily experience of the health care professionals who 

are our members.358 

One basis for FDA's fmding of nearly exclusive tobacco use for nicotine's 

pharmacological effects is that tobacco products do not exist commercially without 

nicotine. If taste, for example, were an independent reason for use of tobacco productsas claimed by the industry-<>ne would expect to find that very-low-nicotine products that 

358 Coalition on Smoking or Health, Comment (Jan. 2, 1996), at 6 (emphasis added). See AR (Vol. 533 

Ref. 102). 

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II.B.3. 

preserve tobacco taste would be popular on the market. But there are no such products. 

The tobacco industry itself knows that a tobacco product without nicotine is not 

acceptable to consumers. For example, an attorney representing RJR stated that the 

company would never eliminate nicotine from its cigarette alternative, because "without 

nicotine, you don't have a cigarette."359 A former Philip Morris researcher similarly stated 

that it was well-known within Philip Morris that nicotine delivery was more important 

than flavor in consumer acceptance of cigarettes. According to this researcher, it was 

believed within the company that while consumers might accept a cigarette that had 

adequate nicotine but marginal flavor, they were unlikely to accept a cigarette with 

relatively good flavor but "not enough"- nicotine.360 

A second basis for FDA's fmding is that the details of tobacco use can be 

distinguished from the basic motivation for tobacco use. For example, researchers have 

demonstrated that consumers will pick a favorite cigarette brand among several that 

deliver adequate nicotine.361 Habits may also explain specific patterns of cigarette 

consumption. For example, a smoker may enjoy smoking during his afternoon work 

break; another may like to smoke in the company of a particular friend. These factors 

commonly determine the details of use of many addictive substances, including opioids 

359 Memorandum of meeting between Hun PB, representing RJR Nabisco Inc., and FDA representatives 

(Oct 23, 1987). See AR(Vol34Ref. 558). 

360 Declaration of Uydess IL (Feb. 29, 1996), at 11 ~ 14. Comments concerning this declaration are 

addressed in section ll.C.6., below. See AR (Vol 638 Ref. 1). 

361 Boren JJ, Stitzer ML, Henningfield JE, Preference among research cigarettes with varying nicotine 

yields, Pharmacology, Biochemistry and Behavior 1990;36( 1 ): 191-193. See AR (Vol 535 Ref. 96, 

vol. lli.A). 

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44826 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.B.3. 

and alcohol.362 But they are separate from the underlying reason for such use, the 

pharmacological effects of the drugs. 

Third, FDA agrees with experts in the field of addiction medicine that 

nonpharmacological factors associated with tobacco use are important to consumers only 

because they have become inextiicably linked to nicotine's pharmacological effects. 

Extensive research in the field of behavioral psychology has demonstrated how animals 

and people come to associate environmental stimuli (taste, rituals, etc.) with the 

pharmacological effects of addictive drugs. In the extreme form, providing the stimulus 

alone leads to the user experiencing the pharmacological effect of the drug. This is called 

a "conditioned response." Thus, a heroin user who says he likes the feel of the needle in 

his arm has linked the sensation with the pharmacological "high" that inevitably follows. 

This heroin addict may even report a "high" after the injection of saline.363 But he or she 

still injects "nearly exclusively" for the pharmacological effects of heroin. 

Similarly, evidence in animals and humans demonstrates that nonpharmacological 

factors such as taste and habit are important to tobacco consumers only because they have 

become inextricably linked to the effects of the addictive drug. As one prominent 

addiction specialist noted, "Animal experiments support the view that the sensory and 

362 Surgeon General's Report, 1988, at 15. See AR (Vol. 129 Ref. 1592). 

363 O'Brien CP, Testa T, Ternes J, Greenstein R, Conditioning Effects of Narcotics in Humans, in 

Behavioral Tolerance: Research and TreaJment Implications, NIDA Research Monograph 18 

(Washington DC: Government Printing Office No. 017-024-00899-8, Jan. 1978), at 67-71. See AR 

(Vol. 535 Ref. 96, vol. ffi.L). 

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II.B.3. 

olfactory stimuli associated with tobacco-using behavior function as conditioned stimuli 

due to their previous association with nicotine."364 

Clinicians who treat patients dependent upon tobacco products have reached the 

same conclusion.365 For example, some smokers identify the sensation of "tracheal 

scratch" associated with inhalation as pleasurable. But, as the American Society of 

Addiction Medicine (ASAM) comments: 

The tracheal 'scratch' which arises from the inhalation of cigarette smoke is 

a sensation which has become paired with the absorption of nicotine into the 

bloodstream and the consequent effects of nicotine on the brain. People do 

not smoke for the 'scratch',· they smoke for the nicotine. The "scratch" tells 

the smoker that nicotine is on its way_to the brain and provides some 

indication of the relative dose which will shortly be coming.366 

Other evidence of "conditioned responses" comes from studies of the early stages of 

tobacco withdrawal, when providing the environmental stimuli of smoking without 

nicotine (i.e., very-low-nicotine cigarettes) alleviates some of the abstinent smokers' 

discomfort.367 This is analogous to heroin users feeling a psychological benefit from 

injecting saline when heroin is not available.368 In both cases, the benefits of the 

364 Jaffe JH, Tobacco smoking and nicotine dependence, in Nicotine Psychopharmacology (Oxford: 

Oxford University Press, 1990), 1-29, at 14. See AR (Vol 535 Ref. 96, vol lll.G). 

365 Benowitz NL, Cigarette smoking and nicotine addiction, Medical Clinics of North America 

1992;76(2):415-437. See AR (Vol535 Ref. 96, vol. Ill.A). 

366 American Society of Addiction Medicine, Comment (Dec. 29, 1995), at 5 (emphasis added). See AR 

(Vol. 528 Ref. 97). · 

367 Butschky MF, Bailey D, Benningfield JE, Pickworth WB, Smoking without nicotine delivery decreases 

withdrawal in 12-hour abstinent smokers, Pharmacology, Biochemistry and Behavior 1995;50{1):91-96. 

See AR (Vol 442 Ref. 7484). 

368 O'Brien CP, Testa T, Ternes J, Greenstein R, Conditioning Effects of Narcotics in Humans, in 

Behavioral Tolerance: Research and Treatment Implications, NIDA Research Monograph 18 

(Washington DC: Government Printing Office No. 017-024-00899-8, Jan. 1978), at 67-71. See AR 

(Vol. 535 Ref. 96, vol. III.L). 

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II.B.4. 

nonpharmacological stimuli rapidly decrease as the stimuli are no longer associated with 

the drug's effects.369 

ASAM concluded: "People who use tobacco products build up rituals around 

nicotine ingestion and experience sensations in the process of using tobacco that become 

valuable to them. However, these rituals would not exist, and the sensations would be of 

no value, but for the associated delivery of nicotine to the brain.'mo Thus, when 

someone says he or she smokes for the ''taste" or "feel" or "ritual" of cigarette 

consumption, these "reasons for use" are inextricably tied to the pharmacological effects 

of nicotine. 371 

Accordingly, FDA concludes that consumers use tobacco products 

"predominantly" and "nearly exclusively" for one or more of the pharmacological effects 

of nicotine. 

4. Responses to Additional Comments 

a. General Comments on Consumer Use 

1. The American Society of Addiction Medicine (ASAM) argues that the 

common practice of inhaling cigarette smoke demonstrates that consumers use cigarettes 

for the pharmacological effects of nicotine. According to ASAM, because of the relativel: 

369 ld. 

Butschky :MF, Bailey D, Benningfield JE, Pickworth WB, Smoking without nicotine delivery decreases 

withdrawal in 12-hour abstinent smokers. Pharmacology, Biochemistry and Behavior 1995;50(1):91-96. 

See AR (Vol. 442 Ref. 7484). 

370 American Society of Addiction Medicine. Comment (Dec. 29, 1995), at 14 (emphasis added). See AR 

(Vol. 528 Ref. 97). 

371 Surgeon General's Report. 1988, at 58-59. See AR (Vol 129 Ref. 1592). 

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II.B.4. 

low pH of cigarette smoke, nicotine absorption occurs to a significant exterit only in the 

lungs. Conversely, ASAM notes that no important sensory effects are known to result 

from cigarette smoke in the lungs. Thus, ASAM concludes that "inhalation is the key to 

nicotine absorption from cigarettes, and there is no reason other than nicotine absorption 

for the consumer to inhale the smoke."372 

ASAM further notes that tobacco advertisements historically encouraged 

consumers to inhale cigarette smoke; according to ASAM, such evidence demonstrates 

industry intent to ensure adequate nicotine delivery to smokers and thereby achieve 

substantial pharmacological effects. 

FDA agrees that inhalation demonstrates that consumers use cigarettes for 

substantial pharmacological effects. According to Gray's Anatomy, there are no taste or 

smell receptors below the level of the larynx.373 No evidence suggests that smokers enjoy 

any physical sensations associated with smoke in their lungs other than by association with 

the pharmacological effects of nicotine. Yet smokers learn to inhale-despite such 

unpleasant reactions as coughing-when the only reason to do so is nicotine absorption. 

Indeed, the industry itself has recognized that nicotine absorption is the reason 

people inhale smoke. In 1982, a leading industry researcher wrote that "[i]t is well knoWil 

that nicotine can be removed from smoke by the lung and transmitted to the brain within 

seconds of smoke inhalation. Since it is the major or sole pharmacologically active agent 

372 American Society of Addiction Medicine, Comment (Dec. 29, 1995), at 5. See AR (Vol 528 Ref. 97) 

373 Williams PL. WarwickR, eds., Gray's Anatomy, 37th ed. (Philadelphia: WB Saunders, 1989), at 

1169-1180. See AR (Vol. 711 Ref. 8). 

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II.B.4. 

in smoke, it must be presumed that this is its preferred method of absorption and thus why 

people inhale smoke."314 

2. The smokeless tobacco industry argues that FDA fails t0 distinguish among 

different smokeless tobacco products. The comment contends that FDA has based its 

conclusions entirely on evidence about moist snuff and that this evidence is inapplicable to 

chewing tobacco. 

FDA disagrees that it has ignored the distinction between moist snuff and chewing 

tobacco or that its evidence applies only to moist snuff. As described in the Jurisdictional 

Analysis, Benowitz and colleagues found that the rate and amount of nicotine absorption 

was similar for oral snuff and chewing tobacco in ten healthy volunteers. 375 See 

Jurisdictional Analysis, 60 FR 41572. The total amount of nicotine absorbed from snuff 

and chewing tobacco was estimated to be 3.6 mg and 4.5 mg, respectively.376 This study 

confirms that as much or more nicotine is absorbed from each of these products as from 

cigarettes. 

Additionally, in a study submitted by the industry, Walsh and colleagues reported 

on the use of smokeless tobacco in 1,300 U.S. college athletes. 377 Of those surveyed who 

374 Letter from Ayres CI (BATCO) to Kohnhorst EE (Brown & Williamson), transmitting partial 

summary of issues presented at Montebello Research Conference in 1982, at BW-W2-03949 (emphasis 

added). See AR (Vol34 Ref. 584-1). 

375 Benowitz NL, Porchet H, Sheiner L, et al., Nicotine absorption and cardiovascular effects with 

smokeless tobacco use: comparison with cigarettes and nicotine gum, Clinical Pharmacology and 

Therapeutics 1988;44:23-28. See AR (Vol 12 Ref. 134-1). 

376 /d. 

377 Walsh MM, Hilton JF, Ernster VL, Masouredis CM, Grady DG, Prevalence, patterns, and correlates of 

spit tobacco use in a college athlete population, Addictive Behavior 1994;19:411-427. See AR (Vol526 

Ref. 95, appendix VIII). 

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II.B.4. 

used smokeless tobacco, 39% reported using snuff only, 41% reported using both snuff 

and chewing tobacco, and 16% reported using chewing tobacco only. (Four percent failed 

to indicate the type of smokeless tobacco used.) Athletes who used both snuff and 

chewing tobacco generally reported patterns of use that were similar to those of athletes 

who used snuff only. This study supports similar patterns of use in both snuff and 

chewing tobacco users and demonstrates use of either moist snuff or chewing tobacco for 

similar pharmacological effects, such as relieving stress, satisfying strong cravings, and 

relieving the discomfort of withdrawal. 

Thus the use, effects, and nicotine absorption from chewing tobacco compare with 

moist snuff and cigarettes. See also section II.D., below. 

b. Comments on Tobacco Use To Satisfy Addiction 

1. The tobacco industry argues that FDA's claim in the Jurisdictional Analysis 

that 75% to 90% of smokers consume cigarettes to satisfy addiction is factually 

unsupported. The industry contends that FDA selectively extracted pieces of data from 

various studies to support this rate of nicotine dependence and that the studies FDA relied 

upon were conducted in sample populations of patients of substance abuse clinics who 

would have higher "scales of dependence" than the general population. 

FDA disagrees. The Agency did not selectively choose studies or selectively 

extract data from the studies on which it relied to support the reported rates of nicotine 

dependence. Rather, FDA chose from the published literature those studies that met the 

following criteria: the study used a defmition of addiction established internationally by 

major public health organizations, the study was capable of estimating the prevalence of 

nicotine addiction in a well-defined population, and the study used appropriate research 

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II.B.4. 

methods, such as random sampling of a well-defmed population, to estimate the 

prevalence of nicotine addiction. No study relied on surveying smokers at tobacco 

cessation clinics. 

The four studies identified by FDA as satisfying the stated selection criteria for 

determining the population prevalence of nicotine addiction utilize two data sets and 

smoking populations. These sample populations represent a generalizable spectrum of 

smokers. 

One of these populations (utilized in a study by Hughes et al.)318 included 

otherwise healthy, non-drug-abusing patients representative of a well-defined population. 

This was not a selectively extracted population, nor did it have an elevated prevalence of 

nicotine addiction, as argued by the tobacco industry. It consisted of over 1,000 middleaged smokers randomly sampled from a well-defined population of male heads of 

households, who were otherwise representative of men of that age. The men entered the 

study by identifying themselves as smokers. These men, on average about 51.1 years of 

age, were estimated to have a lifetime prevalence of nicotine addiction of 90%. The 

authors report that smoking habits of the men in this study were similar to those reported 

in previous studies of middle-aged men. 

The tobacco industry contests these data on the grounds that: (1) the subjects are 

representative of the heaviest 22% of U.S. smokers; and (2) the authors at the time argued 

that the DSM criteria for nicotine addiction were too expansive. The industry's first point 

is based on a statistical misinterpretation. The industry argues that since the average 

378 Hughes JR. Gust SW, Pechacek 1F, Prevalence of tobacco dependence and withdrawal, American 

Journal of Psychiatry 1987;144(2):205-208. See AR(Vol 81 Ref. 292). _ 

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II.B.4. 

cigarette consumption in the study was 28 cigarettes per day, and because 22% of 

smokers in 1991 consumed over 25 cigarettes per day, then the study applies to "at most, 

22 percent of smokers." But this reasoning confuses average and median consumption. 

The heaviest 22% of smokers, on average, consume far more than 25 or 28 cigarettes per 

day. For example, in 1985, almost half of the smokers in the group who smoked more 

than 21 cigarettes per day reported smoking 40 or more cigarettes a day.379 Thus, the 

average number of cigarettes smoked by heavy smokers is well above 28 per day. 

Accordingly, the smokers represented in the Hughes study smoke less, on average, than 

"the heaviest" smokers identified by the comment. 

The industry's second argument concerning the authors' view of the DSM criteria 

is irrelevant. Although the researchers were initially surprised at the high rates of 

dependence revealed in this study, the DSM criteria have retained credibility and are 

widely accepted by clinicians for diagnosing substance dependence. 

The second sample of data (utilized in studies by Woody et al., Cottier, and Hale 

et al.)380 is derived from a population studied during the Substance Abuse Disorders Field 

Trials for DSM-IV. This sample population came from five sites around the United States 

379 Department of Health and Human Services, Public Health Service, National Center for Chronic 

Disease Prevention and Health Promotion, Office on Smoking and Health, Reducing the Health 

Consequences of Smoking-25 Years of Progress, a Report of the Surgeon General (Atlanta: 1989), at 

295. See AR (Vol. 130 Ref. 1593). 

380 Woody GE, Cottier LB, Cacciola J, Severity of dependence: data from the DSM-IV field trials, 

Addiction 1993;88:1573-1579. See AR(Vol 13 Ref. 150). 

Cottier L, Comparing DSM-III-R and ICD-10 substance use disorders, Addiction 1993;88:689-696. See 

AR (Vol. 13 Ref. 149). 

Hale KL, Hughes JR, Oliveto AH, Helzar JE, Higgins ST, Bickel WK. Cottier LB, Nicotine dependence in 

a population-based sample, in Problems of Drug Dependence, 1992, NIDA Research Monograph 132, 

(Washington DC: Government Printing Office, 1993). See AR (Vol 39 Ref. 60). 

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Il.B.4. 

and ranged in age from 18 to 44 years. Some of the subjects were from the general 

population, and others were selected, by a random digit dialing method, from subjects 

treated for substance abuse. Three separate analyses, using different assumptions and 

methods, were perfonned on these data, and the estimates of nicotine dependence 

reported in three published articles ranged from 77% to 92%. There is no evidence that 

these rates of nicotine dependence in these sample populations are greater than those for a 

nonpredisposed population that smoked for the same period. Indeed, the population of 

non-drug-abusing middle-aged men studied by Hughes et al. had a rate of nicotine 

dependence that was consistent with, and even higher than, the rates found in the Woody 

et al., Cottier, and Hale et al. studies. 

One study of nicotine addiction rates cannot be used to establish the prevalence of 

nicotine addiction because the population examined was not representative of the 

spectrum of smokers. The sample population in this study by Breslau et al. consisted of 

394 smokers 21 to 30 years of age who were randomly selected from a well-defmed 

population in a health maintenance organization (HMO). 381 The median age was 26 years, 

and 51% of the smokers were addicted to nicotine. These studies reflect that rates of 

dependence on nicotine increase substantially with duration of exposure and with the 

smoker's age: Although 51% of these young smokers were dependent on nicotine, fully 

90% of the middle-aged smokers in the study by Hughes et al. were dependent on 

nicotine. Moreover, Breslau et al. acknowledge that the rate of dependence found in this 

sample of young smokers may not be representative of the rate among all smokers. 

381 Breslau N, Kilbey MM, Andreski MA. Nicotine dependence. major depression, and anxiety in young 

adults, Archives of General Psychiatry 1991 ;48: 1069-1074. See AR (VoL37 Ref. 17). 

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II.B.4. 

In conclusion, the studies relied on by FDA were not chosen in a preferentially 

selected manner, but on the basis of study design and methodological considerations. The 

data sets reflect populations that can be considered representative of cross sections of the 

U.S. smoking population. There is no evidence to suggest that these studies are not 

generalizable to the population of smokers. FDA believes that these studies support the 

claim that 75% to 90% of smokers consume cigarettes to satisfy nicotine addiction. 

Comments of the American Psychiatric Association agree with this assessment, stating 

that "DSM based studies ... found that 80%-90% of adult smokers are nicotine 

dependent. "382 

2. The tobacco industry argues that dependence can never be measured in a 

large population. This contention is disproved by the successful population-based studies 

just described. The industry's comments were premised on selective quotations from 

researchers, none of whom were actually agreeing with the assertion that all such studies 

are impossible or invalid. 

3. The tobacco industry criticizes the data collection methods in the 

population studies FDA relied upon to support tobacco dependence rates. The industry 

argues that self-reporting results in inaccurate conclusions and cites an article by 

Kozlowski et al. to support this contention.383 

FDA disagrees. This method of data collection is a scientifically recognized and 

accepted mode of inquiry for prevalence studies and is relied upon to determine the 

382 American Psychiatric Association, Comment (Jan. 2, 1996), at 2. See AR (Vol. 700 Ref. 1020). 

383 Kozlowski LT, Herman CP, Frecker RC, What researchers make of what cigarette smokers say: 

filtering smokers' hot air, lAncet 1980;1(8170):699-700. See AR (Vol. 535 Ref. 96, vol. m.n. 

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II.B.4. 

population prevalence of other disorders, including alcohol dependence, cocaine 

dependence, and depression. 384 Some of these are disorders for which, compared to 

tobacco use, interview methods would be less likely to reveal accurate results because of 

the criminal consequences associated with illicit drug use. Moreover, agencies that have 

expertise in tracking the prevalence of disease in this country, such as the Centers for 

Disease Control and Prevention, rely on such studies.385 The tobacco industry itself cites 

multiple surveys based on self-reporting in its comments. 

The industry also mischaracterizes the article by Kozlowski et al. The article does 

not support the industry's argument that all self-reported data in population studies are 

inaccurate. In the article, the authors suggest that self-reports of abstinence among people 

quitting smoking may be inflated. The authors do not suggest that any other information 

obtained by self-reporting is unreliable, nor do they give any reason to extrapolate their 

observations to reporting of other information about smoking behavior. Finally, despite 

their belief that some smokers may exaggerate the number and success of their attempts at 

abstinence, the authors never doubt that a large proportion of smokers try to quit. 

Accordingly, FDA concludes that the methods used in the population prevalence 

studies are accepted and reliable. 

384 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994), at 175-272. See AR (Vol. 535 Ref. 96, vol. 

ITI.B). 

385 See, e.g., Centers for Disease Control and Prevention, Reasons for tobacco use and symptoms of 

nicotine withdrawal among adolescents and young adult tobacco users-United States, 1993, Morbidity 

and Mortality Weekly Report 1994;43(41):745-750. See AR (Vol. 43 Ref. 162). 

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II.B.4. 

c. Comments on Tobacco Use for Effects on Mood and Weight 

1. The tobacco industry contends that FDA has not established that 

consumers use cigarettes or smokeless tobacco nearly exclusively either to affect mood or 

to control weight. According to the comment, the studies cited by FDA do not show that 

a high percentage of consumers use tobacco to affect mood or control weight and that 

there are an insufficient number of such studies upon which to base a conclusion. 

This comment misinterprets the standard for establishing that a product is 

"intended to affect the structure or any function of the body" through consumer use. As 

noted in section II.B. I., above, some courts have suggested that where the Agency relies 

solely on consumer use to establish intended use, consumers must use the product 

predominantly or nearly exclusively for pharmacological purposes. These cases contain no 

requirement, however, that consumers use the product in question nearly exclusively for 

each individual pharmacological effect the product produces. Thus, there is no 

requirement that constimers use nicotine nearly exclusively for each of its pharmacological 

effects. It is sufficient to establish that consumers as a group use tobacco to obtain any of 

the several effects on structure or function sought by consumers_ (for example, to satisfy 

addiction, for other psychoactive effects, and to control weight). See ASH v. Harris, 655 

F.2d at 240; NNFA v. Mathews, 551 F.2d at 334-336. 

FDA also disagrees that there are insufficient studies to support the conclusion that 

consumers use tobacco to affect mood and control weight. The many studies cited by 

FDA conclusively show that the majority of tobacco consumers rely on tobacco products 

to achieve a relaxing or calming effect See Jurisdictional Analysis, 60 FR 41579-41580. 

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II.B.4. 

For example, one survey found that over 60% of smokers aged 16 to 44 believe that 

smoking reduces nervous irritation. 386 

The use of cigarettes for weight control is similarly established in numerous 

studies. These studies show that smokers believe that smoking keeps weight down and 

that weight control is a significant motivation to continue smoking. The Surgeon 

General's 1988 Report on Nicotine Addiction reviewed a large number of studies 

demonstrating that weight control is a powerful motivator for initiation and maintenance 

of smoking in as many as one-third to one-half of young smokers.387 

d. Comments on Nonphannacological Factors Associated with 

Tobacco Use 

1. The tobacco industry quotes several addiction experts stating that there are 

social, emotional, and behavioral variables that explain patterns of tobacco use. The 

industry concludes that consumers do not use tobacco products "nearly exclusively" for 

the phannacological effects of nicotine. 

FDA disagrees. The industry confuses the details of tobacco use with the reason 

for use. While multiple factors may explain why a particular person decides to smoke a 

particular cigarette at a particular moment, data support only one reason why the vast 

majority of consumers use tobacco products day after day, year after year: to obtain the 

drug effects of nicotine. 

386 McKennell AC, Smoking motivation factors, British Journal of Social and Clinical Psychology 

1970;49(1):8-22. See AR (Vo113 Ref. 152-1). 

387 Surgeon General's Report, 1988, at 438-439. See AR (Vo1129 Ref. 1592). 

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II.B.4. 

Indeed, the scientific consensus holds that nonphannacological factors are 

important to consumers only because they are linked to the pharmacological effects of 

nicotine. Thus, Jed Rose, one of the key researchers cited by the industry to support the 

contention that consumers use tobacco for nonphannacological reasons, refers to 

nonphannacological factors as "sensory cues" that are used to meter nicotine intake. 388 

As described in section ll.B.3., above, such cues become "conditioned" as they are 

associated with the pharmacological effects of nicotine on the brain. These environmental 

factors are certainly important to tobacco consumers, as they are to users of other 

addictive drugs,389 but they are not the primary reasons for use. As a tobacco industry 

executive in a speech to the company's board of directors said: 

[T]he psychosocial motive is not enough to explain continued smoking. 

Some other motive force takes over to make smoking rewarding in its 

own right. Long after adolescent preoccupation with self-image has 

subsided, the cigarette will even preempt food in times of scarcity on 

the smoker's priority list ... We are of the conviction ... that the 

ultimate explanation for the perpetuated cigarette habit resides in the 

pharmacological effect of smoke upon the body of the smoker, the 

effect being most rewarding to the individual under stress. 390 

2. The cigarette manufacturers cite research suggesting that nicotine-free 

cigarettes have flavo291 and may help smokers to quit.392 They draw particular attention 

388 Rose JE, Behm FM, Levin ED, Role of nicotine dose and sensory cues in the regulation of smoke 

intake, Pharmacology, Biochemistry and Behavior 1993;44:891-900. See AR (Vol 8 Ref. 100). 

389 Surgeon General's Report, 1988, at 59. See AR (Vol 129 Ref. 1592). 

390 Wakeham H (Philip Morris, Inc.), Smoker Psychology Research, presented to Philip Morris board of 

directors (Nov. 26, 1969), at 237, 240. See AR (Vol. 11 Ref. 142). 

391 Levin ED, Behm PM, Rose JE, The use of flavor in cigarette substitutes, Drug and Alcohol 

Dependence 1990;26:155-160, at 159. See AR (Vol. 535 Ref. 96, III.J). 

392 Butschky MF, Bailey D, Henningfield JE, Pickworth WB, Smoking without nicotine delivery decreases 

withdrawal in 12-hour abstinent smokers, Pharmacology, Biochemistry and Behavior 1995;50(1):91-96. 

See AR (Vol 442 Ref. 7484). 

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II.B.4. 

to a recent presentation by Rose et al., in which smokers given a denicotinized cigarette 

reported the same or slightly less relief of craving than smokers given intravenous nicotine, 

and less relief than smokers given their usual brand of cigarettes.393 They also reported 

more immediate satisfaction from the denicotinized cigarette than from intravenous 

nicotine, although less than from their usual brand. The denicotinized cigarette provided 

less psychological reward than did intravenous nicotine. The smokeless tobacco 

manufacturers also suggest that no-nicotine substitutes for smokeless tobacco may have 

helped some users remain abstinent. According to the industry, this research demonstrates 

that consumers use tobacco products for reasons other than nicotine. 

FDA disagrees. The cited studies do suggest that low- or no-nicotine products can 

be used in research and in a small proportion of former users of tobacco products. Yet the 

products have been uniformly rejected by tobacco consumers, who do not view them as 

acceptable substitutes for cigarettes. When given a choice, tobacco users will not abandon 

nicotine for flavor, demonstrating the real reason they smoke. For example, Next, a 

denicotinized cigarette that was briefly marketed by Philip Morris, was removed from the 

market because, according to the company, it was not accepted by consumers. 

The cited studies replicate many others that show that the most consistent and 

strongest effects are produced by nicotine-delivering cigarettes. It is not surprising that 

nicotine injections, which, according to the studies produced significant pain and burning 

at the site of injection, do not produce all the satisfaction of smoking nor duplicate the 

393 Rose JE, Westman EC, Behm FM, Comparative effects of intravenous nicotine and de-nicotinized 

cigarette smoke, poster presented at the annual meeting of the Society for Research on Nicotine and 

Tobacco (Mar. 15-17, 1996), Washington, D.C. See AR (Vol. 711 Ref. 21). 

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II.B.4. 

taste and throat sensations of smoking. As described in section II.B.3., above, the efficacy 

of nicotine-free cigarettes in alleviating some of the symptoms of withdrawal is consistent 

with the conclusion that social and environmental factors become associated with 

obtaining the pharmacological effects of nicotine, and thus are perceived as pleasurable as 

a "conditioned response," but in and of themselves are not the reason people smoke. 

Low- or no-nicotine cigarettes may temporarily provide some relief to consumers as a 

result of the conditioned response to the sensorimotor aspects of smoking, but this 

response is subject to "rapid extinction" when nicotine is withheld. 394 This phenomenon is 

similar to the temporary fmding that heroin addicts feel pleasure from injecting themselves 

with saline. 395 

The study by Rose is entirely consistent with these findings. The study evaluated 

only the immediate effects of a denicotinized cigarette on craving reduction, satisfaction, 

and psychological reward. It did not attempt to evaluate any effects of denicotinized 

cigarettes on sustained satisfaction or relief of withdrawal symptoms. Rose himself has 

stated that smokers seek the sensory cues of smoking because ''the repetition of the 

smoking act thousands of times per year by a moderately heavy smoker leads to a strong 

conditioned association between the sensory aspects of smoking ... and the 

pharmacological effects of nicotine."396 Therefore, according to Rose, "effective 

394 /d. 

395 O'Brien CP, Testa T, Ternes J, Greenstein R, Conditioning effects of narcotics in humans, in 

Behavioral Tolerance: Research and Treatment Implications, NIDA Research Monograph 18 

(Washington DC: Government Printing Office No. 017-024-00899-8, Jan. 1978), at 67-71. See AR (Vol. 

535 Ref. 96, vol. ID.L). 

396 Rose JE, Levin ED, Inter-relationships between conditioned and primary reinforcement in the 

maintenance of cigarette smoking, British Journal of Addiction 1991;86:605-609, at 605. See AR (Vol. 

67 Ref. 58). 

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II.B.4. 

treatment of tobacco abuse needs to take into account the influence of these sensory 

cues,"397 by, for example, providing the smoker with de-nicotinized cigarettes, in addition 

to strategies to eliminate nicotine dependency. 398 He is explicit, however, that nicotine is 

the primary reinforcer of smoking behavior, and that desire for the sensory aspects of 

tobacco use is the result of conditioned reinforcement maintained by nicotine's primary 

reinforcement. 399 

3. To support the argument that consumers use tobacco products for flavor, 

the tobacco industry cites research in which smokers' satisfaction with smoking decreased 

when their upper airways were anesthetized. 

Upon review of this research, FDA finds that the studies do not support the 

contention that consumers smoke cigarettes primarily for flavor. As described above, the 

researcher who led the study, Rose, believes that nonpharmacological factors associated 

with tobacco consumption are "cues" important to smokers only by association with 

nicotine's pharmacological impact. 

Moreover, the research cited does not establish that the reason for the drop in 

smoking satisfaction upon airway anesthetization was the blockade of sensory input from 

smoke. These decreases in satisfaction might have been due simply to the unpleasant 

sensation of upper airway anesthetization, not to any blockade of sensory input from 

smoke. In this study, satisfaction with "sham smoke" also dropped with anesthesia. Sham 

smoke was so diluted as to provide few pharmacological or sensory effects. Thus, 

397 /d. 

398 /d. at 607. 

399 /d. at 605-606. 

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II.B.4. 

providing anesthesia decreased the satisfaction of consuming real cigarette smoke and 

placebo smoke.400 

The study does, however, provide data addressing the importance of the 

pharmacological aspects of smoking. Thirty minutes after smoking, the subjects who had 

received smoke delivering nicotine-regardless of whether their throats had been 

anesthetized-felt similarly satisfied. And their satisfaction was greater than that of those 

who had received "sham smoke." Thus, the study indicated that nicotine produces 

smoking satisfaction even in the absence of mouth and throat sensation. 

4. The tobacco industry cites three studies to support the argument that 

consumers use tobacco products out of "habit and ritual." 

Upon review of these studies, FDA concludes that they provide no evidence that 

"habit and ritual" are the primary motivation for use of tobacco products. As described at 

length above, "habit and ritual" are important to consumers of all addictive drugs, but only 

through their linkage to the pharmacological effects of the drug. 

First, the industry cites a study in which some smokers did not consider the first 

cigarette of the day their favorite.401 The observation relates to a detail of smoking rather 

than to underlying motivation; as described in section II.B.3., above, there are many 

reasons why an individual may desire a particular cigarette at a particular time. This is not 

evidence that "habit or ritual" is the driving biological force for maintenance of tobacco 

use. 

400 Rose JE, Tashkin DP, Ertle A. Zinser MC. Lafer R. Sensory blockade of smoking satisfaction, 

Pharmacology, Biochemistry and Behavior 1985;23:289-293, at 290 (emphasis added). See AR (VoL 42 

Ref. 124). 

401 Jarvik M, Killen JD, Varady A. Fortmann SP, The favorite cigarette of the day, Journal of Behavioral 

Medicine 1993;16:413-422. See AR (Vol. 535 Ref. 96, liLA). 

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ll.B.4. 

The industry then quotes the speculative conclusion of a study without any 

description of the research. In fact, the study's main finding was that the smell of 

cigarettes was not important for smoking behavior.402 

The industry cites another conclusion of a study without any description of the 

research. 403 One of the study's major findings was that enforced abstinence (smokers 

were not allowed to smoke for an afternoon) had different effects on subsequent smoking 

behavior than natural abstinence (smokers did not smoke while asleep at night). Basic 

biological imperatives undoubtedly affect the details of smoking behavior but certainly 

cannot explain the reason for tobacco use. 

5. The tobacco industry argues that the "social aspects" of smoking explain 

consumer use of tobacco. No studies are cited to support this conclusion. As the 

Surgeon General's Report noted in 1988, social factors influence initiation and patterns of 

use of many addictive drugs;404 the primary reason for the drug's use, however, is 

pharmacological. In this respect, nicotine is similar to heroin.405 

6. The smokeless tobacco industry argues that the evidence cited by FDA in 

support of its conclusion that consumers use tobacco products nearly exclusively for 

pharmacological effects has little to do with smokeless tobacco. Five studies were 

402 Baldinger B, Hasenfratz M. Battig K, Switching to ultralow nicotine cigarettes: effects of different tar 

yields and blocking of olfactory cues, Pharmacology, Biochemistry and Behavior 1995;50(2):233-239, at 

238. See AR (Vol. 535 Ref. 96, vol. lll.A). 

403 Jacober A, Hasenfratz M. Battig K, Cigarette smoking: habit of nicotine maintenance? Human 

Psychopharmacology 1994;9:117-123, at 117. See AR (Vol 535 Ref. 96. vol. lll.G). 

404 Surgeon General's Report, 1988, at 15. See AR (Vol129 Ref. 1592). 

405 Jaffe JH, Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of 

Therapeutics, 8th ed. (New York: Pergamon Press, 1990), chap. 22 (522-573), at 529. See AR (Vol 535 

Ref. 96, vol. lll.G). 

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II.B.4. 

submitted with the comment that are claimed to demonstrate that smokeless tobacco 

consumers use those products because they "enjoy the taste" or simply "like it," not for 

any "pharmacological effects."406 

FDA disagrees with the industry's interpretation of these studies. As discussed in 

section ll.B.3., above, when people use drugs with powerful pharmacological effects such 

as nicotine they commonly associate many environmental stimuli with the pleasurable 

experience of consuming the substance. Thus, a survey result that consumers "enjoy the 

taste" indicates only that a significant portion of consumers have linked the sensory cues 

to the pharmacological effects of nicotine. 

None of the five studies cited by the industry noted whether users who did not give 

pharmacological reasons for using smokeless tobacco had ever tried to quit. Thus, many 

of these users may not have been aware of their pharmacological addiction. As an expert 

quoted by the Inspector General of the Department of Health and Human Services 

406 Walsh MM, Hilton JF, Ernster VL, Masouredis CM, Grady DG, Prevalence, patterns, and correlates of 

spit tobacco use in a college athlete population, Addictive Behavior 1994; 19:411-427. See AR (Vol 526 

Ref. 95, vol. VIII). 

Lopez LC, Smokeless tobacco consumption by Mexican-American university students, Psychology 

Reports 1994;75:279-284. See AR (Vol 526 Ref. 95, vol. VIII). 

Glover ED, Laflin M, Flannery D, Albritton DL, Smokeless tobacco use among American college 

students, Journal of American College Health 1989;38:81-84. See AR (Vol 526 Ref. 95, vol. VII). 

Wisniewski JF, Bartolucci A.A. Comparative patterns of smokeless tobacco usage among major league 

baseball personnel, Journal of Oral Pathology and Medicine 1989;18:322. See AR (Vol 526 Ref. 95, 

vol. VIII). 

Connolly GN, Orleans GT, Kogan M, Use of smokeless tobacco in major-league baseball, New England 

Journal of Medicine 1988;318(19):1281-1285. See AR (Vol526 Ref. 95, vol. VII). 

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II.B.4. 

explained, "Many haven't tried to quit. But when we tell them the health consequences, 

and then they try to quit, they can't.'>4°7 

In studies cited by the industry, some users of smokeless tobacco stated that they 

"enjoy the taste," but a significant percentage of these users also reported that they use 

smokeless tobacco for psychological reasons. For example, in one study, a majority of 

195 users of snuff and chewing tobacco reported using tobacco for one or more 

pharmacological effects, including relieving stress, relief of "strong cravings," and 

relieving the discomfort of withdrawal.408 These statements support the conclusion that 

the majority of people who use smokeless tobacco do so for the well-established 

pharmacological effects of nicotine: stimulation, sedation, and addiction. These studies 

thus constitute additional evidence that smokeless tobacco is primarily used by consumers 

to obtain the pharmacological effects of nicotine. 

407 Department of Health and Human Services, Office on Smoking and Health, Spit Tobacco and Youth 

(Washington DC: Government Printing Office, 1992), at 8. See AR (Vol 7 Ref. 76). 

408 Walsh MM, Hilton JF, Ernster VL, Masouredis CM, Grady DG, Prevalence, patterns, and correlates of 

spit tobacco use in a college athlete population, Addictive Behavior 1994;19:411-427. See AR (Vol526 

Ref. 95, vol. VIII). 

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II.C. 

C. THE STATEMENTS, RESEARCH, AND ACTIONS OF THE 

CIGARETTE MANUFACTURERS SHOW THAT THE 

MANUFACTURERS INTEND THEIR PRODUCTS TO AFFECT 

THE STRUCTURE AND FUNCTION OF THE BODY 

In sections II.A. and ll.B., above, the Agency has concluded that cigarettes and 

smokeless tobacco are intended to affect the structure and function of the body on the 

basis of the foreseeable pharmacological effects and uses of cigarettes and smokeless 

tobacco and the widespread actual use of cigarettes and smokeless tobacco by consumers 

for pharmacological purposes. In this section, the Agency considers another category of 

persuasive evidence of intended use: the statements, research, and actions of the cigarette 

manufacturers themselves. In section II.D., below, the Agency considers the statements, 

research, and actions of the smokeless tobacco manufacturers. 

The administrative record includes extensive evidence of the cigarette 

manufacturers' statements, research, and manufacturing practices. Much of this evidence 

has only recently become available as a result of the Agency's investigation, congressional 

hearings, and other investigations and sources. This evidence is part of the relevant 

objective evidence that the Agency may consider in detennining the manufacturer's 

"intended uses" of a product. 

In the Jurisdictional Analysis, the Agency made extensive fmdings based on the 

evidence then available regarding the statements, research, and actions of the cigarette 

manufacturers. FDA received comments on these fmdings from the individual tobacco 

companies and tobacco industry trade associations, as well as from public health 

organizations and other interested groups and members of the public. After careful 

consideration of the evidence in the record and the public comments, the Agency fmds that 

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II. C. 

the evidence described in this section provides a third independent basis for concluding 

that cigarettes are in fact intended to affect the structure and function of the bodies of 

smokers. 

In section II.C.l., FDA discusses its legal authority to consider evidence of the 

manufacturers' statements, research, and actions in establishing intended use. This 

discussion shows that an intent to affect the structure or function of the body can be 

established by evidence showing that ( 1) the manufacturer "has in mind" that the product 

will be used by consumers for pharmacological purposes, or (2) the manufacturer has 

"designed" the product to provide pharmacological effects. The Agency's role in making 

these determinations is that of a fact finder. It weighs the statements, research, and 

actions of the manufacturer to determine the particular uses the manufacturer has in mind 

or designs its product to provide. 

The Agency's fact-fmding task has been made more difficult by the manufacturers' 

general refusal to cooperate with the Agency's investigation. Although some 

manufacturers did permit FDA investigators to visit their manufacturing plants in the 

spring of 1994, the manufacturers have failed to provide FDA with information and 

documents requested by FDA in July 1994 regarding nicotine in cigarettes.409 In 

particular, the manufacturers have failed to comply with FDA's request for company 

documents regarding the pharmacological effects of nicotine and the role of nicotine in 

cigarette design and manufacturing. The limited number of company documents provided 

409 See, e.g., Letter from Cbesemore RG (FDA) to Bible GC (Philip Morris Inc.) (Jul. 11, 1994). See AR 

(Vol. 54 Ref. 617). Similar letters were sent to other cigarette and smokeless tobacco manufacturers. 

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II. C. 

by the manufacturers with their comments sheds little light on the role of nicotine in 

cigarettes and does not significantly change the evidence in the record. 

The Agency's discussion of the evidence of the manufacturers' statements, 

research, and actions is divided into several parts. In section II.C.2., the Agency discusses 

the statements and research of each of the major cigarette companies and the Council for 

Tobacco Research, a trade association to which they belong. This evidence shows that the 

manufacturers have known for decades that nicotine has the characteristics of addictive 

drugs and causes other significant pharmacological effects and that consumers use 

cigarettes primarily to obtain the pharmacological effects of nicotine, including satisfaction 

of their addiction. This evidence also shows that in internal discussions, senior researchers 

for the cigarette manufacturers refer to cigarettes as drug delivery systems, calling them a 

"dispenser for a dose unit of nicotine,'>410 a vehicle for delivery of nicotine,'.4 11 and other 

similar terms. This evidence is sufficient by itself to establish that cigarettes are intended 

to affect the structure and function of the body, because it shows that the manufacturers 

"have in mind" that their products will be used specifically for pharmacological purposes. 

In sections II.C.3. and II.C.4., the Agency discusses the second basis for 

determining the manufacturers' intent through their statements, research, and actionsnamely, the evidence that manufacturers have "designed" cigarettes to provide 

pharmacologically active doses of nicotine to consumers. In section II.C.3., the Agency 

discusses the product research and development activities of the manufacturers. This 

410 Dunn WL (Philip Monis Inc.), Motives and Incentives in Cigarette Snwking (1972), at 5. See AR 

(Vol. 12 Ref. 133). 

411 Teague CE (R.J. Reynolds Tobacco Co.), Research Planning Memorandum on The Nature of the 

Tobacco Business and the Crucial Role of Nicotine Therein (Apr. 14, 1972), at 1. See AR (Vol 531 

Ref. 125). 

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II. C. 

evidence shows that the manufacturers have conducted extensive product research and 

development to establish the dose of nicotine necessary to produce pharmacological 

effects and to optimize the delivery of nicotine to consumers. 

In section II.C.4., the Agency discusses the evidence that the manufacturers do in 

fact manipulate and control nicotine deliveries in their commercial cigarettes. This 

evidence supports a finding that the manufacturers manipulate and control the delivery of 

nicotine in commercial cigarettes to provide a pharmacologically active dose of nicotine to 

consumers. Taken together, the evidence in sections II.C.3. and II.C.4. establishes yet 

another basis for finding that cigarettes are intended to affect the structure and function of 

the body. 

In section II.C.5., the Agency concludes that, when considered cumulatively, the 

evidence from the statements, research, and actions of the manufacturers is internally 

consistent and mutually corroborating, further supporting the finding that the effects of 

cigarettes on the structure and function of the body are "intended" by the manufacturers. 

Finally, in section II.C.6., the Agency responds to substantive comments concerning the 

evidence of the manufacturers' statements, research, and actions that are not addressed in 

sections II.C.2. to II.C.5.412 

412 The discussion of the statements, research, and actions of the manufacturers in this section cites 

hundreds of documents. It is the totality of the evidence from these documents that the Agency relies 

upon. No single document cited by the Agency is essential to the Agency's conclusion in section II. C. that 

the manufacturers intend their products to affect the structure and function of the body. In particular, 

although considerable evidence of the statements, research, and actions of the manufacturers was 

submitted to the Agency after the publication of the Jurisdictional Analysis on August 11, 1995, none of 

this evidence is essential to the Agency's fmding of intended use in section II. C. The new evidence is 

summarized below because it provides persuasive corroboration that the cigarette manufacturers do intend 

to affect the structure and function of the body. However, the Agency would reach the same conclusions 

regarding the intent of the manufacturers even without this additional evidence. In addition, none of the 

documents in the Agency's docket of confidential documents is essential to the Agency's determination. 

See AR (Vol. 505-518). 

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II.C.l. 

1. "Intended Use" May Be Established on the Basis of the Statements, 

Actions, and Research of the Manufacturers 

Reliance on the statements, research, and actions of manufacturers to establish 

intended use is consistent with the plain language of the statute. The statute provides that 

products "intended" to affect the structure or any function of the body are drugs or 

devices. Sections 201(g)(l)(C) and 20l(h)(3). According to a canon of statutory 

construction, words used by Congress, unless otherwise defined, will be interpreted as 

taking their ordinary meaning. See, e.g., Smith v. United States, 508 U.S. 223, 228 

(1993); Chevron v. Natural Resources Defense Council, Inc., 467 U.S. 837, 860 (1984). 

In this case, the ordinary meaning of "intend" includes "to have in mind" and "to·design" 

for a particular use. These plain meanings allow the Agency to consider the 

manufacturer's statements, research, and actions in determining intended use. 

The American Heritage Dictionary, for instance, defmes "intend" as: "I. To have 

in mind; plan. 2.a. To design for a specific purpose. b. To have in mind for a particular 

use ... .'.413 Consistent with this meaning, the Agency interprets "intended" uses to 

include those specific uses that are "in the mind" of the manufacturer or for which the 

manufacturer "designs" the product. The plain meaning of the statute thus permits the 

Agency to inquire into the statements, research, and actions of the manufacturer. What 

the manufacturer says in internal documents, the kind of research the manufacturer 

conducts, and the actions of the manufacturer in producing its product can all be evidence 

413 The American Heritage Dictionary of the English lAnguage, 2d ed. (Boston: Houghton Mifflin Co., 

1991), 668. See AR (Vol 526 Ref. 95, vol. V). Other dictionary definitions are similar. See, e.g., 

Webster's New World Dictionary of American English, 3d college ed. (New York Simon & Schuster, 

Inc., 1988), 702 ("intend 1. to have in mind as a purpose; plan 2. to mean (something) to be or be used 

(for); design .. .. ")(emphasis added). 

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II.C.l. 

of the particular uses the manufacturer has in mind or for which the manufacturer has 

designed the product. 

FDA's regulations on the meaning of "intended uses" are consistent with the 

statutory language and explicitly contemplate that FDA may examine the knowledge, 

actions, and expressions of manufacturers and other vendors. 21 CFR 201.128 and 801.4. 

These regulations state that intended uses are to be established on the basis of "objective 

intent" FDA's "objective intent" standard means that the Agency may consider objective 

evidence to determine a manufacturer's intent, notwithstanding the manufacturer's 

assertions that pharmacological effects and uses are not intended. As the courts have 

recognized, "FDA is not bound by the manufacturer's subjective claims of intent but can 

find actual therapeutic intent on the basis of objective evidence." NNFA v. Mathews, 551 

F.2d at 334 (emphasis added); accord United States v. Storage Spaces Designated Nos. 

"8" and "49," 777 F.2d 1363, 1366 n. 5 (9th Cir. 1985) ("self-serving labels cannot be 

used to mask true intent"), cert. denied, 479 U.S. 1086 (1987). 

The regulations recognize that as a fact fmder, FDA may consider a broad range of 

evidence of intended use, including evidence of the statements, research, and actions of 

the manufacturer. For example, the regulations state that ''the objective intent is 

determined by such persons' expressions ... or oral or written statements." 21 CFR 

201.128 (emphasis added). These "expressions" and "oral or written statements" can 

include relevant and probative intracompany memoranda or research. 

Indeed, the regulations provide express authority for FDA to consider evidence of 

the manufacturer's actual intent The regulations state that "objective intent ... may be 

shown by the circumstances that the article is, with the knowledge of [the manufacturer], 

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II.C.l. 

offered and used for a purpose for which it is neither labeled nor advertised." /d. 

(emphasis added). The regulations also direct FDA to consider circumstances in which 

the manufacturer "knows, or has knowledge of facts that would give him notice" that a 

product is to be used for purposes other than those expressly promoted by the 

manufacturer. I d. (emphasis added). Proving whether a manufacturer "knows" or has 

"knowledge of facts that would give him notice" of pharmacological uses of a product can 

include an inquiry into the actual understanding of the manufacturer, including 

consideration of the statements, research, and actions that may be probative of the 

manufacturer's actual knowledge. 

Moreover, the regulations provide that objective intent may be shown by the 

"circumstances surrounding the distribution of the article." Id. (emphasis added). This 

broad phrase allows the fact finder to infer the intended uses of a product based on, 

among other factors, the conduct of the manufacturer that occurs prior to distribution. 

For example, evidence that shows how distributed tobacco products are designed and 

formulated is reasonably considered a "circumstance surrounding distribution of the 

article." 

Courts have also recognized that the Agency may consider "objective evidence" to 

determine a manufacturer's intent. See NNFA v. Mathews, 551 F.2d at 334; United 

States v. Storage Spaces, 777 F.2d at 1366; Latex Surgeons' Gloves, 799 F. Supp. at 

1295 (circumstances surrounding manufacture and distribution of product demonstrated 

intended use despite manufacturer's claim to FDA that product was not a device); 

Hanson, 417 F. Supp. at 35 (statements by plaintiff distributors and importers that drug 

was needed by patients to treat cancer is relevant to intended use). 

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II.C.2. 

The Agency's role in determining intended use on the basis of the statements, 

research, and actions of the manufacturer is that of a fact fmder. The Agency's 

responsibility is to reach the best factual judgments it can from the record of the 

statements, research, and actions before it, including evidence submitted during the 

comment period. 

2. The Cigarette Manufacturers Understand That Nicotine Has 

Addictive and Other Phannacological Effects and That Smokers Use 

Cigarettes To Obtain These Effects 

As discussed below, the evidence in the record shows that the cigarette 

manufacturers have extensive knowledge of effects of nicotine on smokers. The 

manufacturers know that nicotine has the characteristics of other addictive drugs; that it 

provides other significant pharmacological effects; and that it is the primary reason that 

smokers use cigarettes. This evidence establishes that when the manufacturers offer 

cigarettes to the public, they "have in mind" that their cigarettes will be used by smokers 

to obtain the pharmacological effects of nicotine. This evidence is thus sufficient by itself 

to establish that the manufacturers intend the pharmacological uses of their products. 

a. The Statements and Research of Philip Morris 

The administrative record includes over three decades of internal statements and 

research on nicotine by Philip Morris, the nation's largest cigarette manufacturer. These 

documents indicate that senior researchers and officials at Philip Morris have long viewed 

nicotine as a "powerful pharmacological agent',..14 and "the primary reason',..15 people 

414 Charles JL (Philip Morris Inc.), Nicotine Receptor Program-University of Rochester (Mar. 18, 1980), 

in 141 Cong. Rec. H7680 (daily ed. Jul. 25, 1995). See AR (Vol 14 Ref. 175a). 

415 Philip Morris Inc., Draft Report Regarding a Proposal for a "Safer" Cigarette, Code-named Table, at 1. 

See AR(Vol 531 Ref. 122). 

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ll.C.2. 

smoke. This knowledge shows that Philip Morris understands that its product will affect 

the structure and function of the body and will be used by consumers for these drug 

effects. 

i. The Views of Senior Researchers and Officials. Philip Morris officials 

recognized the importance of the pharmacological effects of nicotine in cigarettes as early 

as 1961. That year, Helmut Wakeham, a senior Philip Morris research scientist, informed 

the company's research and development committee that "nicotine is believed essential to 

cigarette acceptability.'.416 Wakeham also explained the pharmacological effects of 

nicotine, stating that "low nicotine doses stimulate, but high doses depress functions" and 

that nicotine contributes to the "pleasurable reactions or tranquillity" produced by 

smoking.417 

By 1969, the views of the Philip Morris scientists on the pharmacological effects of 

cigarettes were communicated to the Philip Morris board of directors. During that year, 

Wakeham, who was then vice president for research and development, briefed the Philip 

Morris board of directors on why people smoke. He expressed his department's 

"conviction" that "the ultimate explanation for the perpetuated cigaret habit resides in the 

pharmacological effect of smoke upon the body of the smoker." He further stated that 

smokers' craving for cigarettes is so strong that ''the cigaret will even preempt food in 

times of scarcity": 

Farone W A, The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 6. See AR (Vol 638 Ref. 2). 

416 Wakeham H (Philip Morris Inc.), Tobacco and Health-R&D Approach (Nov. 15, 1961), at 43. See 

AR (Vol. 125 Ref. 1314). 

417 /d. at 40. 

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[T]he psychosocial motive is not enough to explain continued 

smoking. Some other motive force takes over to make smoking 

rewarding in its own right. Long after adolescent preoccupation 

with self-image has subsided, the cigaret will even preempt food in 

times of scarcity on the smoker's priority list. ... The question is 

"Why?" 

.... We are of the conviction, ... that the ultimate 

explanation for the perpetuated cigaret habit resides in the 

phannacological effect of smoke upon the body of the smoker, the 

effect being most rewarding to the individual under stress.418 

II.C.2. 

Wakeham's views on the central importance of the "pharmacological effect" of 

nicotine were shared by other senior researchers and officials at Philip Morris, as the 

following examples demonstrate: 

• In 1972, Philip Morris scientist William Dunn characterized cigarettes as a nicotine 

delivery system in the following language: 

Think of the cigarette pack as a storage container for a day's supply 

of nicotine .... 

Think of the cigarette as a dispenser for a dose unit of 

nicotine .... 

Think of a puff of smoke as the vehicle of nicotine .... 

Smoke is beyond question the most optimized vehicle of 

nicotine and the cigarette the most optimized dispenser of 

smoke.419 

• In 1974, Philip Morris' director of research, Thomas Osdene, who subsequently 

became vice president for science and technology, approved and sent to Wakeham and 

other senior Philip Morris officials a report that analogized smoking to drug use. The 

report's "working hypothesis" is that "[ d]ose-control continues even after the puff of 

smoke is drawn into the mouth." The report postulates that the consumer regulates 

418 Wakeham H (Philip Morris Inc.), Smoker Psychology Research, presented to Philip Morris board of 

directors (Nov. 26, 1969), at 237, 240. See AR (Vol 11 Ref. 142). 

419 Dunn WL (Philip Morris Inc.), Motives and Incentives in Cigarette Smoking (1972), at 5-6 (emphasis 

added). See AR (Vol. 12 Ref. 133). 

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II.C.2. 

smoke intake ''to achieve his habitual quota of the pharmacological action," and notes 

that if smokers deprived of cigarettes display an increase in aggression, it may be 

explained as "the emergence of reactions ... not unlike those to be observed upon 

withdrawal from any of a number of habituating pharmacological agents."420 

• In 1976, Philip Morris researcher A. Udow wrote a memorandum on "Why People 

Start To Smoke." The memorandum observes that once people start to smoke, one of 

the reasons they will continue to smoke is that cigarettes serve as "a narcotic, 

tranquilizer, or sedative.'.-421 

• In 1978, the authors of Philip Morris' 5-year plan for research and development stated 

that "nicotine may be the physiologically active component of smoke having the 

greatest consequence to the consumer.'.-422 

• In 1980, Philip Morris researcher Jim Charles, who subsequently became vice president 

for research and development, wrote the then vice president for research and 

development, Robert Seligman, that: 

Nicotine is a powerful pharmacological agent with multiple sites of 

action and may be the most imponant component of cigarette 

smoke. Nicotine and an understanding of its properties are 

important to the continued well being of our cigarette business 

since this alkaloid has been cited often as "the reason for 

smoking." ... Nicotine is known to have effects on the central and 

420 Philip Morris Research Center, Behavioral Research Annual Report, Part II (Nov. 1, 1974) (approved 

by Osdene TS), in 141 Cong. Rec. H7658, H7660 (daily ed. Jul. 25, 1995). See AR (Vol14 Ref. 175a). 

421 Udow A (Philip Morris Inc.), Why People Start to Smoke (Jun. 2, 1976), in 141 Cong. Rec. H7664 

(daily ed. Jul. 25, 1995) (emphasis added). See AR (VoL 14 Ref. 175a). 

422 Philip Morris Inc., Research and Development Five-Year Plan, 1979-1983 (Sep. 1978), in 141 Cong. 

Rec. H7668 (daily ed. Jul. 25, 1995) (emphasis added). See AR (Vol 14 Ref. 175a). 

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44858 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

peripheral nervous system as well as influencing memory, learning, 

pain perception, response to stress and level of arousal.423 

A statement that the Agency received from a fom1er Philip Morris research 

II.C.2. 

director, William Farone, expresses similar views. Farone was the director of applied 

research at Philip Morris from 1976-1984, during which period he supervised five 

divisions and 150 employees. According to Farone's statement: 

It is well recognized within the cigarette industry that there is one 

principal reason why people smoke-to experience the effects of 

nicotine, a known pharmacologically active constituent in 

tobacco .... 

The strongly held conviction of most industry scientists and 

product developers was that nicotine was the primary reason why 

people smoked. 424 

The administrative record contains many additional statements by Philip Morris 

researchers and officials acknowledging the significant pharmacological effects of nicotine 

and their importance to the smoker. See, e.g., 60 FR 41584-41603, 41621-41667. 

Collectively, these statements show that Philip Morris' senior scientists and officials have 

known for decades that cigarettes function as a drug delivery system, providing the 

pharmacological effects of nicotine to consumers who smoke cigarettes for the primary 

purpose of obtaining these effects. 

ii. Research into Nicotine Pharmacology. The foregoing views of Philip 

Morris' top research scientists and officials were based on extensive in-house research on 

423 Charles JL (Philip Morris Inc.), Nicotine Receptor Program-University of Rochester (Mar. 18, 1980), 

in 141 Cong. Rec. H7680 (daily ed. Jul. 25, 1995) (emphasis added). See AR (Vol 14 Ref. 175a). 

424 Farone W A. The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 1,6 (emphasis added). See AR (Vol. 638 Ref. 2). 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44859

II.C.2. 

nicotine pharmacology. The studies conducted by Philip Morris ranged from traditional 

pharmacology involving animal experiments to EEG experiments. 

Philip Morris conducted a large number of studies. In 1979 alone at least 16 

different studies on nicotine pharmacology were conducted by three different research 

groups within Philip Morris' Behavioral Research Laboratory. 425 The Animal 

Behavior Group conducted six experiments on the drug effects of nicotine in rats. 

The Neuropsychology Laboratory conducted five experiments to determine the 

pharmacological effects of nicotine on the human brain, including experiments on "[t]he 

Effects of Cigarette Smoking on the Electroencephalogram" and "[L]ong-Term Smoke 

Deprivation and the Electrical Activity of the Brain.'.-126 The Smoking Behavior Group 

conducted studies on the behavioral consequences of smoking, including studies to 

determine the consequences of smoking low-nicotine cigarettes. 

Beginning before 1980 and continuing until 1984, Philip Morris conducted 

research in search of a "nicotine analogue." This research demonstrates Philip Morris' 

knowledge that nicotine has the hallmark properties of a drug of abuse and shows the 

company's intention to preserve these properties in new products. As described by former 

Philip Morris scientist Victor DeNoble, the pwpose of the research was ''to come up with 

a molecule that would mimic nicotine's effect in the brain, and would not affect the 

peripheral nervous system and therefore not have cardiovascular liability.'o427 Thus, while 

425 Dunn WL (Philip Morris Inc.), Plans and Objectives-1979 (Dec. 6, 1978), in 141 Cong. Rec. H7668-

7670 (daily ed. Jul. 25, 1995). See AR (Vol 14 Ref. 175a). 

426 /d. at H7669-7670. 

427 Regulation of Tobacco Products (Part 2): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Cong., 2d 

Sess. 33 (Apr. 28, 1994) (testimony of Victor DeNoble) (emphasis added). See AR (Vol 708 Ref. 2). 

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II.C.2. 

the company attempted to eliminate an adverse effect of nicotine, it deliberately sought to 

retain nicotine's effects on the brain. 

To conduct this work, Philip Morris scientists had to identify and compare the 

pharmacological and behavioral effects of nicotine on the brain. The pharmacological and 

behavioral profiles of the nicotine analogues synthesized by Philip Morris chemists were 

then compared to those of nicotine.428 Since the primary goal of the nicotine analogue 

program was to develop a nicotine analogue that would retain the physiological and 

behavioral effects of nicotine on the brain, especially its reinforcing properties, the newly 

synthesized nicotine analogues were screened in animal behavioral tests designed to assess 

their reinforcing properties. (A substance has reinforcing properties if it is able to induce 

repeated, compulsive use. See section II.A.3.c.i., above.) The tests used were "exactly 

the same tests" that the National Institute on Drug Abuse (NIDA) uses ''to determine if a 

drug has an abuse potential.'>429 

One of the principal NIDA tests used by Philip Morris was a series of "selfadministration" experiments with rats. These studies determine addiction potential by 

assessing whether rats will press a lever to give themselves repeated injections of the test 

substance. There is a strong correlation between substances that are found to be self428 /d. at 5. 

See also Declaration of Victor DeNoble of Feb. 2, 1995, at 2-9. See AR (Vol31 Ref. 524-5). 

429 Regulation of Tobacco Products (Part 2): Hearings Before the Subcomminee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Cong, 2d 

Sess. 17 (Apr. 28, 1994)(testimony of Victor DeNoble). See AR (Vol 708 Ref. 2). 

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II.C.2. 

administered in rats and substances that are addictive in humans.430 Philip Morris found 

that rats would self-administer nicotine.431 According to the director of NIDA, "[t]hese 

findings from the DeNoble study indicate that nicotine has reinforcing properties, one of 

the hallmark characteristics of an addictive drug.'t432 The Philip Morris researchers also 

found that rats would develop a tolerance to nicotine, another characteristic of an 

addictive drug.433 

The senior management and top officials of Philip Morris "continually reviewed 

... and approved" this research.434 In fact, in November 1983, the president of Philip 

Morris, Shep Pollack, visited the laboratory conducting the self-administration 

experiments and watched rats inject themselves with nicotine. Pollack was informed by 

the Philip Morris researcher in charge of the study, Victor DeNoble, that Philip Morris' 

self-administration studies followed "the exact procedure that NIDA would use to 

demonstrate abuse liability," and that the studies demonstrated that nicotine is "a 

reinforcing agent."435 DeNoble further informed Pollack that although a finding of self430 Gardner EL. Brain reward mechanism, in Substance Abuse, A Comprehensive TeXlbook, 2d ed., eds. 

Lowinson JH, Ruiz P, Millman RB, et al. (Baltimore: Williams and WiJkins 1992), at 70. See AR (Vol 8 

Ref. 88). 

See also section ll.A3.c.i. 

431 Regulation of Tobacco Products (Part 2): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Con g., 2d 

Sess. 5 (Apr. 28, 1994) (testimony of Victor DeNoble). See AR (Vol 708 Ref. 2). 

432 Id. at 20 (letter from Leshner AI (NIDA) to Waxman HA (Apr. 13, 1994) (emphasis added)). 

433 /d. at 5 (testimony of Victor DeNoble). The Philip Morris researchers did not, however, fmd evidence 

of nicotine withdrawal. 

434 /d. at 5-6. 

435 Id. at 54. 

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II.C.2. 

administration does not by itself prove that nicotine is addictive, it "predicts abuse 

liability.'.436 Despite several attempts, DeNoble and his colleague Paul Mele were not 

allowed to publish the results of their self-administration studies or present their results at 

a meeting sponsored by the American Psychological Association.437 

These studies were conducted for their potential commercial applicability. The 

memorandum describing the "plans and objectives" for the Behavioral Research 

Laboratory in 1979 states expressly that "the rationale for the program rests on the 

premise that such knowledge will strengthen Philip Morris R&D capability in developing 

new and improved smoking products.'.438 

Some of Philip Morris' research attempted to assess the pharmacological effects of 

nicotine on youths. One study on the hyperkinetic child as prospective smoker observed 

that "amphetamines, which are strong stimulants, have the anomalous effect of quieting 

these children down"; the Philip Morris researchers initiated a study to determine "whether 

such children may not eventually become cigarette smokers in their teenage years as they 

discover the advantage of self-stimulation via nicotine.'.439 This study was apparently 

436 /d. 

437 /d. at 51-52, 57-94. 

438 Dunn WL, Plans and Objectives-1979 (Dec. 6, 1978), in 141 Cong. Rec. H7669. See AR (Vol 14 

Ref. 175a). 

439 Ryan FJ (Philip Morris Inc.), Relationship between smoking and personality, in Smoker 

Psychology/May 1-31, 1974 (Jun 10, 1974), in 141 Cong. Rec. H7651 (daily ed. Jul. 25, 1995) (emphasis 

added). See AR (Vol 14 Ref. 175a). 

For a further description of Philip Morris' research into hyperkinetic children, see the following 

documents reprinted in 141 Cong. Rec. H7651-7657 (daily ed. Jul. 25, 1995): 

Ryan FJ (Philip Morris Inc.}, Relationship between smoking and personality, in 

Smoker Psychology/May 1-31, 1974 (Jun 10, 1974). See AR (Vol. 14 Ref. 

175a). 

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II.C.2. 

never completed because "[o]bstacles presented by school systems and physicians ... 

have made it very difficult for us to conduct studies using school and medical records of 

minors.'.«o Another study initiated by Philip Morris involved administering "painful" 

electric shocks to college students to determine the anxiety-reducing effects of 

cigarettes.441 Although preliminary fmdings supported the hypothesis that students with a 

high anxiety factor on personality tests would puff more frequently,442 the study apparently 

had to be discontinued because "fear of shock is scaring away some of our more valuable 

Ryan FJ (Philip Morris Inc.), Hyperkinesis as a precursor of smoking, in 

Smoker Psychology/Feb.1-28,1975 (Mar. 10, 1975). See AR(Vol. 14Ref. 

175a). 

Philip Morris Research Center, Behavioral Research Annual Report (Jul. 18, 

1975)(approved by Dunn WL). See AR(Vol. 14 Ref. 175a). 

Ryan FJ (Philip Morris Inc.), Hyperactivity, in Smoker Psychology/Apr. 1-30, 

1977 (May 13, 1977). See AR (Vol. 14 Ref. 175a). 

Ryan FJ (Philip Morris Inc.), Hyperkinetic children, in Smoker 

Psychology/Feb.1-28, 1978(Mar.10, 1978). SeeAR(Vol14Ref.175a). 

440 Ryan FJ (Philip Morris Inc.), Hyperkinetic children, in Smoker Psychology/Feb. 1-28, 1978 (Mar. 10, 

1978), in 141 Cong. Rec. H7657 (daily ed. Jul. 25, 1995). See AR (Vol14 Ref. 175a). 

441 Ryan FJ (Philip Morris Inc.), Proposed Research Project: Smoldng and Anxiety (Dec. 23, 1969), in 

141 Cong. Rec. H7648 (daily ed. Jul. 25, 1995). See AR (Vol 14 Ref. 175a). 

For a further description of Philip Morris' research involving the administration of electric shocks, see the 

following documents printed in 141 Cong. Rec. H7648-7649 (daily ed. Jul. 25, 1995): 

Ryan FJ (Philip Morris Inc.), Shock I, II, III, and N, in Consumer Psychology 

(Sep.16-0ct15, 1971). SeeAR(Vol14Ref.175a). 

Ryan FJ (Philip Morris Inc.), Shock V, in Consumer Psychology (Jan. 15 - Feb. 

15, 1972). SeeAR(Vol14Ref.175a). 

Dunn WL (Philip Morris Inc.), Quarterly Report-Projects 1600 and 2302 (Oct 

5, 1972). See AR (Vol 14 Ref. 175a). 

442 Ryan FJ (Philip Morris Inc.), Shock I, II, ill, and IV, in Consumer Psychology Monthly Report 

(Sep. 16- Oct 15, 1971), in 141 Cong. Rec. H7648-7649 (daily ed. Jul. 25, 1995). See AR (Vol. 14 Ref. 

175a). 

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II.C.2. 

subjects.'>«3 In another study, Philip Morris proposed injecting nicotine into human 

subjects in order "to yield a broader picture of the role of the spike, the level, and the 

reinforcement characteristics of the substance."444 

In congressional testimony, the fonner Philip Morris president, William Campbell, 

testified that to the extent that Philip Morris controls nicotine levels in cigarettes through 

blending, this is done "for taste.'>«5 Philip Morris's research program does not support 

this statement, however. The internal research documents in the administrative record 

show that Philip Morris exhaustively investigated the phannacological properties of 

nicotine-not its gustatory properties. The intensive focus on nicotine phannacology 

reflected in the documents indicates that Philip Morris regarded nicotine's contribution to 

cigarettes as phannacological, not taste-related. Moreover, in its comments Philip Morris 

did not provide evidence of internal Philip Morris research into the taste characteristics of 

nicotine. 

443 Eichorn P A, Dunn WL (Philip Morris Inc.), Quarterly Reports-Projects 1600 and 2302 (Oct 5, 

1972), in 141 Cong. Rec. H7649 (daily ed. Jul. 25, 1995). See AR(Vol14 Ref. 175a). 

444 Dunn WL (Philip Morris Inc.), Plans and Objectives-1981 (Nov. 26, 1980), in 141 Cong. Rec. H7682 

(daily ed. Jul. 25, 1995). See AR (Vol14 Ref. 175a). 

For a further description of Philip Morris' proposed research involving nicotine injections., see: 

Dunn WL (Philip Morris Inc.), Behavioral Research Accomplishments, 1977 

(Dec. 19, 1977), in 141 Cong. Rec. H7666 (daily ed. Jul. 25, 1995). See AR 

(Vol 14 Ref. 175a). 

Dunn WL (Philip Morris Inc.), Plans and Objectives-1979 (Dec. 6, 1978), in 

141 Cong. Rec. H7669 (daily ed. Jul. 25, 1995). See AR (Vol14 Ref. 175a). 

445 Regulation ofTobacco Products (Part 1): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Cong., 2d 

Sess. 764 (Apr. 14, 1994)(testimony of William Campbell). See AR (Vol 707 Ref. 1). 

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II.C.2. 

Further examples of Philip Morris' research on nicotine pharmacology are 

presented in the Jurisdictional Analysis. See 60 FR 41590--41591, 41595-41599. Taken 

together, these studies show that Philip Morris conducted an extensive, sustained, and 

sophisticated investigation into the phannacological effects of nicotine that gave the 

company knowledge that nicotine has significant phannacological effects on smokers, 

including reinforcing effects. The research was conducted because of its commercial 

significance to Philip Morris; used techniques that are employed by government agencies 

to identify the "abuse potential" of drugs; and found that nicotine has hallmark 

characteristics of an addictive drug, including reinforcing effects and the development of 

tolerance. 

iii. Project Table. Philip Morris' recognition of the important pharmacological 

role of nicotine in cigarettes has been consistent for over three decades. New evidence 

received by the Agency during the comment period, for instance, indicates that officials 

inside Philip Morris continued to recognize the importance of nicotine's phannacological 

effects and uses in the 1990's. 

A draft Philip Morris report on "Project Table," a proposal to develop "a nicotine 

delivery device" that relies on "heating rather than burning the tobacco" to "produceD a 

cleaner, safer smoking experience," written around 1992, acknowledges that although 

"[ d]ifferent people smoke for different reasons .... the primary reason is to deliver 

nicotine into their bodies." 446 The report describes nicotine in cigarettes in explicit druglike terms: 

446 Philip Morris, Inc., Draft Report Regarding a Proposal for a "Safer" Cigarette, Code-named Table, at 

1,5 (emphasis added). See AR (Vol 531 Ref. 122). 

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Nicotine ... is a physiologically active, nitrogen containing substance. 

Similar organic chemicals include ... quinine, cocaine, atropine and 

morphine. While each of these substances can be used to affect human 

physiology, nicotine has a particularly broad range of influence.447 

II.C.2. 

Project Table provides a detailed description of the pharmacological action of 

nicotine on the brain: 

During the smoking act, nicotine is inhaled into the lungs in 

smoke, enters the bloodstream and travels to the brain in about 

eight to ten seconds. The nicotine alters the state of the smoker by 

becoming a neurotransmitter and a stimulant. Nicotine mimics the 

body's most important neurotransmitter, acetycholine (ACH), 

which controls heart rate and message sending within the brain. 

The nicotine is used to change physiological states leading to 

enhanced mental performance and relaxation. A little nicotine 

seems to stimulate, while a lot sedates a person.448 

The report also expressly places cigarettes and smokeless tobacco products in the 

same category of "nicotine delivery devices" that includes nicotine patches and inhalers, 

stating that "nicotine delivery devices range from snuff, chewing tobacco, cigars, pipes and 

conventional cigarettes to unique smoking articles, chewing gum, patches, aerosol sprays 

and inhalers.'>«9 The report thus indicates that the views of Philip Morris on the role of 

nicotine in cigarettes have been remarkably consistent. Twenty years after senior Philip 

Morris scientist William Dunn called cigarettes "a dispenser for a dose unit of 

nicotine,'.450 Philip Morris officials continue to regard nicotine as a drug and cigarettes as 

a "nicotine delivery device." The evidence of Philip Morris' statements and research on 

447 /d. at 1 (emphasis added). 

448 /d. (emphasis added). 

449 /d. at 2. 

450 Dunn WL (Philip Morris Inc.), Motives and Incentives in Cigarette Smoking (1972), at 5. See AR 

(Vol. 12 Ref. 133). 

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II.C.2. 

nicotine pharmacology persuasively documents that its cigarettes are intended to affect the 

structure or function of the body. 

b. The Statements and Research of R. J. Reynolds 

R.J. Reynolds Tobacco Company (RJR) is the nation's second largest cigarette 

manufacturer. The information in the administrative record shows that researchers and 

senior officials at RJR hold views on the pharmacological effects and uses of nicotine in 

cigarettes that are similar to those of the researchers and senior officials at Philip Morris. 

i. The Teague Memoranda. During the comment period, FDA received two 

documents written by Claude Teague in 1972 and 1973, when he was the assistant 

director of research at RJR. Teague was subsequently promoted to director of corporate 

research in 1978.451 These internal memoranda show that RJR scientists regarded nicotine 

as a "potent" and "habit-forming" drug; considered cigarettes to be "a vehicle for delivery 

of nicotine"; and conceived of the tobacco industry itself as "a specialized, highly 

ritualized and stylized segment of the pharmaceutical industry." 

Teague's 1972 memorandum, entitled "Research Planning Memorandum on the 

Nature of the Tobacco Business and the Crucial Role of Nicotine Therein," makes four 

significant points. First, the memorandum describes nicotine as a powerful and habituating 

drug. According to the memorandum, nicotine is "a potent drug with a variety of 

physiological effects.'7452 It is also "known to be a habit-forming alkaloid.''453 Nicotine's 

specific effects on the body are described as follows: 

451 American Men and Women of Science, 1995-1996, 19th ed. (New Providence: RR Bowker, 1995), 

7:62. See AR (Vol 711 Ref. 13). 

452 Teague CE, (RJ. Reynolds Tobacco Co.), Research Planning Memorandum on the Nature of the 

Tobacco Business and the Crucial Role of Nicotine Therein (Apr. 14, 1972), at 1. See AR (Vol 531 

Ref. 125). 

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44868 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

The habituated user of tobacco products is said to derive 

"satisfaction" from nicotine. Although much studied, the 

physiological actions of nicotine are still poorly understood and 

appear to be many and varied. For example, ... at different dose 

levels, nicotine appears to act as a stimulant, depressant, 

tranquilizer, psychic energizer, appetite reducer, anti-fatigue 

agent, or energizer, to name but a few of the varied and often 

contradictory effects attributed to it.'..t54 

II.C.2. 

Second, the memorandum acknowledges that nicotine is the "primary" reason for 

smoking. According to the memorandum: 

[T]he confirmed user of tobacco products is primarily seeking the 

physiological "satisfaction" derived from nicotine-and perhaps 

other active compounds. His choice of product and pattern of 

usage are primarily determined by his individual nicotine dosage . 455 requzrements . ... 

Third, the Teague memorandum describes cigarettes as drug delivery systems. 

According to the memorandum, "a tobacco product is, in essence, a vehicle for delivery 

of nicotine, designed to deliver the nicotine in a generally acceptable and attractive 

form.'..t56 The memorandum further states: 

If what we have said about the habituated smoker is true, then 

products designed for him should emphasize nicotine, nicotine 

delivery efficiency, nicotine satisfaction, and the like. What we 

should really make and sell would be the proper dosage form of 

nicotine with as many other built-in attractions and gratifications 

as possible-that is, an efficient nicotine delivery system with 

satisfactory flavor, mildness, convenience, cost, etc .... Would it 

not be better, in the long run, to identify in our minds and in the 

minds of our customers what we are really selling, i.e.~ nicotine 

satisfaction ?"51 

453 /d. (emphasis added). 

454 /d. at 1-2 (emphasis added). 

455 /d. at 1 (emphasis added). 

456 /d. 

457 /d. at 5 (emphasis added). 

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II.C.2. 

Indeed, the memorandum describes the tobacco industry itself as a "segment of the 

pharmaceutical industry":458 

In a sense, the tobacco industry may be thought of as being a 

specialized, highly ritualized and stylized segment of the 

pharmaceutical industry . ... Our Industry is then based upon 

design, manufacture and sale of attractive dosage forms of nicotine, 

and our Company's position in our Industry is determined by our 

ability to produce dosage forms of nicotine which have more 

overall value, tangible or intangible, to the consumer than those of 

our competitors. 459 

Finally, the memorandum recommends improvements in the delivery of nicotine to 

consumers. In the short term, the memorandum recommends reducing tar levels while 

maintaining nicotine levels in cigarettes: 

Our critics have lumped "tar'' and nicotine together in their 

allegations about health hazards .... An accompanying Research 

Planning Memorandum suggests an approach to reducing the 

amount of "tar" in cigarette smoke per unit of nicotine. That is 

probably the most realistic approach in today's market for 

conventional cigarette products. 460 

In the long term, the memorandum recommends a "more futuristic approach":461 

If our business is fundamentally that of supplying nicotine in 

useful dosage form, why is it really necessary that allegedly 

harmful "tar" accompany that nicotine? There should be some 

simpler, "cleaner", more efficient and direct way to provide the 

desired nicotine dosage than the present system involving 

combustion of tobacco or even chewing of tobacco .... It should 

be possible to obtain pure nicotine by synthesis or from highnicotine tobacco. It should then be possible, using modifications 

of techniques developed by the pharmaceutical and other 

458 /d. at 2. 

459 /d. (emphasis added). 

460 ld. at 6 (emphasis added). 

461 /d. 

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44870 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

industries, to deliver that nicotine to the user in efficient, effective, 

attractive dosage form, accompanied by no "tar", gas phase, or 

other allegedly harmful substances. The dosage form could 

incorporate various flavorants, enhancers, and like desirable 

additives, and would be designed to deliver the minimum effective 

amount of nicotine at the desired release-rate to supply the 

"satisfaction" desired by the user. Such a product would 

maximize the benefits derived from nicotine, minimize allegedly 

undesirable over-dosage side effects from nicotine, and eliminate 

exposure to other materials alleged to be harmful to the user. 

462 

II.C.2. 

Evidence in the record indicates that RJR acted on both of these recommendations. See 

sections ll.C.2.b.iii. and ll.C.3.b., below. 

Claude Teague's 1973 memorandum, entitled "Some Thoughts about New Brands 

of Cigarettes for the Youth Market," recommends that RJR develop "new brands tailored 

to the youth market. "

463 According to the memorandum, one of the design features that 

should be tailored to the youth market is nicotine delivery. The memorandum reaffirms 

that the "nicotine effects" and the other physical effects of smoking are "highly desirable 

to the confirmed smoker.'.-464 For the "pre-smoker" or "learner," however, the 

memorandum states that the physical effects of smoking, including the effects of nicotine, 

are "largely unknown, unneeded, or actually quite unpleasant or awkward.'.-465 

Consequently, the memorandum recommends that ''the effort here should be to affect a 

compromise to minimize the undesirable effects while retaining these which later become 

462 Id. at 7 (emphasis added). 

463 Teague CE (RJ. Reynolds Tobacco Co.), Research Planning Memorandum on Some Thoughts about 

New Brands of Cigarettes for the Youth Market (Feb. 2, 1973), at 1. See AR (Vol 531 Ref. 125). 

464 I d. at 4. 

465 ld. at 2, 4. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44871

II.C.2. 

desirable.'>466 With respect to nicotine, the memorandum recommends that "nicotine 

should be delivered at about 1.0-1.3 mg/cigarette, the minimum for confirmed smokers. 

The rate of absorption of nicotine should be kept low by holding pH down, probably 

below 6.'>467 

Teague's analysis shows that, as at Philip Morris, scientists at RJR have long 

understood that nicotine has significant pharmacological effects on the body and is the 

"primary" reason people smoke. His analysis further shows that, like Philip Morris 

scientists, RJR scientists also expressly conceived of cigarettes as a drug delivery system. 

ii. Other Statements and Research of RJR Scientists and Officials. The views 

in the Teague memoranda about the "crucial role" of the pharmacological effects of 

nicotine continued to be expressed within RJR in later years. In approximately 1977, for 

instance, RJR researchers told the RJR marketing department that "[w]ithout any 

question, the desire to smoke is based on the effect of nicotine on the body";468 that "a 

confirmed smoker attempts to get a certain desired level ofnicotine";469 and that "[t]he 

nicotine in the blood acts upon the central nervous system and produces in the average 

smoker a sensation one could describe as either stimulating or relaxing.'>470 According to 

the RJR researchers, while nicotine has a role in "mouth taste" and "mouth satisfaction," 

466 /d. at 4. 

467 /d. 

468 Senkus M (R J. Reynolds Tobacco Co.), Some Effects of Smoking (1976/1977), at 4 (emphasis added). 

See AR (Vol 700 Ref. 593 ). 

469 /d. at 5 (emphasis added). 

470 /d. at 3. 

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44872 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

that is not nicotine's primary role; rather, "the ultimate satisfaction comes from the 

nicotine which is extracted ... in the lungs.'7411 

In the late 1980's and early 1990's, moreover, RJR researchers conducted a series 

of experiments on how nicotine affects the brain. The published reports from these 

experiments revealed that 20 years after the Teague memoranda, RJR researchers 

continued to believe that: (1) nicotine has pharmacological effects on the brain; and (2) 

smokers smoke cigarettes primarily to obtain these pharmacological effects. 

In a 1989 report entitled "Effects of Smoking/Nicotine on Anxiety, Heart Rate, 

and Lateralization of EEG During a Stressful Movie," RJR used an EEG to test its 

hypothesis that "nicotine and smoking help smokers to relax and cope with stress and 

negative affect" through "activation-reducing effects on the EEG.'7472 The experiment's 

results supported RJR' s hypothesis, indicating that nicotine produced the expected 

"anxiolytic" or anxiety-reducing effects in the brain: 

The present results support the view that the electrocortical effects 

of smoking are a function of environmental stress level, cigarette 

nicotine delivery, and cortical site. They are also consistent with 

previous evidence that nicotine reduces anxiety and with our 

hypothesis that nicotine's anxiolytic properties are mediated by the 

right hemisphere. Normalfhigh-nicotine delivery cigarettes, relative 

to low-nicotine control cigarettes, produced cortical activation 

(decreased alpha power) in both hemispheres during the no-stress 

control condition ... but produced the opposite effect, decreased 

activation (increased alpha power), at the right parietal site during 

the three stressful movie scenes. 473 

471 /d. at 7-9 (emphasis added). 

472 Gilbert DG, Robinson JH, Chamberlin CL (R.J. Reynolds Tobacco Co.), et al., Effects of 

smoking/nicotine on anxiety, heart rate, and lateralization ofEEG during a stressful movie, 

Psychophysiology 1989;26(3):311-319, at 311. See AR (Vol 14 Ref. 174-2). 

473 /d. at 316 (citation omitted) (emphasis added). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44873

II.C.2. 

The 1989 study used the EEG to measure smokers' brain waves while they 

watched a film containing graphic images of industrial accidents. In a 1991 study entitled 

"Electroencephalographic Effects of Cigarette Smoking," RJR researchers measured the 

effects of smoking on brain waves under "levels of mental workload representative of 

those encountered in day-to-day living.',.¢74 They found that the pharmacological effects of 

smoking are affected by how deeply the smoker inhaled. According to the report: 

In light inhaling smokers, ... smoking was found to attenuate EEG 

activity in the delta, theta, and alpha frequency bands . . . . In deep 

inhaling smokers, smoking produced a symmetrical central midline 

increase in beta2 magnitude, an EEG effect that ... is associated 

with anxiety relief.475 

These results led the RJR researchers to propose that light inhalers and deep 

inhalers smoke to obtain different phannacological effects from nicotine and that the 

effects produced in deep-inhalers were comparable to the effects of benzodiazepines, a 

class of addictive drugs used for anxiety relief. According to the report: 

The results of the present investigation indicate that light inhaling 

... smokers may smoke primarily for purposes of mental 

activation and performance enhancement. This does not appear to 

be the case for deeper inhaling ... smokers .... An extensive 

literature suggests that increased beta2 activity may reflect the 

anxiolytic properties of the benzodiazepines independently of 

sedative effects. Thus, an important smoking motive for deep 

inhaling smokers might be anxiety reduction.476 

A year later, the RJR researchers reported the results of a study designed to isolate 

the precise effects of nicotine on the brain. In this study, some smokers were given 

474 Pritchard WS (RJ. Reynolds Tobacco Co.), Electroencephalographic effects of cigarette smoking, 

Psychopharmacology 1991;104:485-490, at 486. See AR (VoL 3 Ref. 23-2). 

475 ld. at485 (emphasis added). 

476 Id. at488 (citations omitted) (emphasis added). 

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44874 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

regular "light" cigarettes to smoke while others were given experimental cigarettes with 

virtually no nicotine. The results from the EEG showed that the regular "light" cigarette 

produced "a significant increase in beta2 magnitude," an effect associated with anxiety 

relief, and "a significant decrease in delta magnitude," an effect associated with improved 

mental alertness.477 According to the researchers, "this indicates that the beneficial 

effects of smoking on cognitive performance ... are a junction of nicotine absorbed from 

cigarette smoke upon inhalation."418 

In another report written in 1992, the RJR researchers addressed the question 

"why do people smoke?" The researchers reject the claim that people smoke to satisfy an 

addiction, but they do not reject the claim that people smoke to obtain other 

pharmacological effects from nicotine. To the contrary, as Claude Teague did 20 years 

earlier, they assert that the reason people smoke is precisely to obtain these 

pharmacological effects: 

We believe that a more reasonable hypothesis concerning why 

people smoke ... is that smokers use cigarettes primarily as a 

'tool' or 'resource' that provides them with needed psychological 

benefits (increased mental alertness, anxiety reduction, coping 

with stress).479 

In its comments, RJR asserts that nicotine is important in cigarettes because 

"nicotine plays an important role in the taste and flavor of cigarette smoke.'9480 The 

477 Robinson JH, Pritchard WS, Davis RA (R.J. Reynolds Tobacco Co.), Psychopharmacological 

effects of smoking a cigarette with typical "tar'' and carbon monoxide yields but minimal nicotine, 

Psychopharmacology 1992;108:466-472, at469. See AR(Vol. 11 Ref. 129-3). 

478 /d. at 471 (emphasis added). 

479 Robinson J, Pritchard W (R.J. Reynolds Tobacco Co.), The role of nicotine in tobacco use, 

Psychopharmacology 1992;108:397-407, at398 (emphasis added). See AR(Vol34 Ref. 589). 

480 RJ. Reynolds Tobacco Co., Comment (Jan. 2, 1996), at 50. See AR (Vol519 Ref. 103). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44875

II.C.2. 

history of RJR's research does not support the company's public position, however. If 

nicotine were important because of its role in taste, FDA would expect to fmd that RJR' s 

research would focus on nicotine's impact on taste. The administrative record, however, 

contains virtually no RJR research demonstrating or investigating nicotine's influence on 

taste.481 In contrast, RJR has extensively investigated the pharmacological impacts of 

nicotine. In total, the administrative record before FDA contains more than 20 studies 

published or funded by RJR on the effects of nicotine on the body.482 The actual number 

481 There is little scientific support for the proposition that nicotine has an important role in cigarette 

taste. The four studies cited by RJR are all discussed in section ll.B.2.c, above. Only one of the studies 

relied upon by RJR was actually conducted by RJR This limited investigation by RJR into nicotine's role 

in taste was presented after FDA's investigation had commenced. Pritchard, WS, Robinson, JH, The 

Sensory Role of Nicotine in Cigarette "Taste," Smoking Satisfaction and Desire to Smoke, presented at 

the International Symposium on Nicotine: The Effects of Nicotine on Biological Systems II (Montreal: 

Jul. 21-24, 1994). See AR (Vol 519 Ref. 103, vol. II). As discussed in section II.B.2.c., above, RJR 

researchers conceded that the study was unable to distinguish the importance of any sensory aspects of 

nicotine from its pharmacological effects. 

482 Bjercke RJ, Langone JJ, Anti-idiotypic antibody probes of neuronal nicotinic receptors, Biochem 

Biophys Res Commun 1989;162(3):1085-1092. See AR (Vol. 46 Ref. 53). 

Brazell MP, Mitchell SN, Gray J A, Effect of acute administration of nicotine on in vivo release of 

noradrenaline in the hippocampus of freely moving rats: a dose-response and antagonist study, 

Neuropharmacology 1991;30(8):823-833. See AR (Vol. 46 Ref. 58). 

Byrd GD, Chang KM, Greene JM, et al., Evidence for urinary excretion of glucuronide conjugates of 

nicotine, cotinine, and trans-3' -hydroxycotinine in smokers, Drug Metab Dispos Bioi Fate Chern 

1992;20(2):192-197. See AR (Vol. 120 Ref. 1131). 

Caldwell WS, Green JM, Byrd GD, et al., Characterization of the glucuronide conjugate of cotinine: a 

previously unidentified major metabolize of nicotine in smokers' urine, Chern Res Toxicol1992;5(2):280-

285. See AR (Vol. 46 Ref. 62). 

Caldwell WS, Greene JM, Dobson GP, et al., Intragastric nitrosation of nicotine is not a significant 

contributor to nitrosamine exposure, Ann NY Acad Sci 1993;686:213-227. See AR (Vol 128 Ref. 1388). 

Collins AC, Bhat RV, Pauly JR, et al., Modulation of nicotine receptors by chronic exposure to nicotinic 

agonists and antagonists, in The Biology of Nicotine Dependence, eds. Bock G, Marsh J (CffiA 

Foundation Symposium 152, 1990), at 68-82. See AR (Vol. 47 Ref. 71). 

deBethizy JD, Borgerding MF, Doolittle DJ, Chemical and biological studies of a cigarette that heats 

rather than burns tobacco, J Clin Pharmacol1990;30(8):755-763. See AR(Vol47 Ref. 78). 

219 
44876 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

deBethizy JD, Robinson JH, Davis RA, et al., Absorption of nicotine from a cigarette that does not burn 

tobacco, Pharmacology 1988;37(5):328-332. See AR (Vol47 Ref. 79). 

Gilbert DG, Robinson JH, Chamberlin CL, et al., Effects of smoking/nicotine on anxiety, heart rate, and 

lateralization ofEEG during a stressful movie, Psychophysiology 1989;26(3):311-319. See AR (Vol 14 

Ref. 174-2). 

Hammond DK, Bjercke R.J, Langone JJ, et al., Metabolism of nicotine by rat liver cytochromes P-450, 

Assessment utilizing monoclonal antibodies to nicotine and cotinine, Drug Metab Dispos Bioi Fate Chern 

1991;19(4):804-808. See AR(Vol. 48 Ref. 110). 

Kyerematen GA, Morgan ML, Chattopadhyay B, et al., Disposition of nicotine and eight metabolites in 

smokers and nonsmokers, Clin Pharmacol Ther 1990;48(6):641-651. See AR (Vol. 49 Ref. 146). 

Kyerematen GA, Taylor LH, deBethizy JD, et al., Pharmacokinetics of nicotine and 12 metabolites in the 

rat. Application of a new radiometric high performance liquid chromatography assay, Drug Metab Dispos 

Bioi Fate Chern 1988;16(1):125-129. See AR(Vol. 49 Ref. 145). 

Lippiello PM, Fernandes KG, The binding of L-[3H]nicotine to a single class of high afftnity sites in rat 

brain membranes, Mol Pharmacol1986;29(5):448-454. See AR (Vol. 55 Ref. 165). 

Lippiello PM, Mencherif M, Prince RJ, The role of desensitization in CNS nicotinic receptor function, in 

International Symposium on Nicotine: The Effects of Nicotine on Biological Systems 1994, S 11. See AR 

(Vol. 55 Ref. 166). 

Lippiello PM, Sears SB, Fernandes KG, Kinetics and mechanism of L-[3H]nicotine binding to putative 

high affmity receptor sites in rat brain, Mol Pharmacol1987;31( 4):392-400. See AR (Vol. 55 Ref. 162). 

Marks MJ, Grady SR. Collins AC, Downregulation of nicotinic receptor function after chronic nicotine 

infusion, J Pharmacol Exp Ther 1993;266(3):1268-1276. See AR(Vol55 Ref. 176). 

Mitchell SN, Brazell MP, Joseph MH, et al., Regionally speciftc effects of acute and chronic nicotine on 

rates of catecholamine and 5-hydroxytxyptamine synthesis in rat brain, Eur J Pharmacol 

1989;167(3):311-322. See AR (Vol 57 Ref. 200). 

Mitchell SN, Brazell MP, Scbugens MM, et al., Nicotine-induced catecholamine synthesis after lesions to 

the dorsal or ventral noradrenergic bundle, European Journal of Pharmacology 1990;179(3):383-391. 

See AR (Vol 57 Ref. 197). 

Pritchard WS, Electroencephalographic effects of cigarette smoking, Psychopharmacology 1991;104:485-

490. See AR (Vol 3 Ref. 23-2). 

Pritchard WS, Gilbert DG, Duke DW, Flexible effects of quantifted cigarette smoke delivery on EEG 

dimensional complexity, Psychopharmacology 1993; 113:95-102. See AR (Vol. 3 Ref. 23-1 ). 

Pritchard WS, Robinson JH, Guy TD, Enhancement of continuous performance task reaction time by 

smoking in non-deprived smokers, Psychopharmacology 1992; 108:437-442. See AR (Vol 67 Ref. 72). 

Robinson JH, Pritchard WS, Davis RA. Psychopharmacological effects of smoking a cigarette with typical 

"tar'' and carbon monoxide yields but minimal nicotine, Psychopharmacology 1992;108:466-472. See 

AR (Vol. 59 Ref. 236). 

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II.C.2. 

ofRJR studies may be much higher. According to an RJR spokesperson, "[w]e've not 

only done research on the pharmacological effects of nicotine but we've published it in at 

least 250 peer-reviewed journals and symposia.'>483 

RJR's sustained and sophisticated research into nicotine pharmacology 

demonstrates that RJR knows that ( 1) its product will affect consumers in a drug-like 

manner and (2) consumers will use its product to obtain these drug effects. 

iii. RJR' s Alternative Tobacco Products. Further evidence of RJR' s 

understanding of the central role of nicotine in smoking is provided by RJR' s development 

of alternative tobacco products that are designed to deliver nicotine, but not other 

constituents of cigarette smoke, to the consumer. 

RJR' s efforts to develop alternative nicotine delivery systems began more than 20 

years ago. As noted above, Claude Teague recommended in 1972 that RJR develop 

"some simpler, 'cleaner', more efficient and direct way to provide the desired nicotine 

dosage than the present system involving combustion of tobacco.'>484 In recent years, RJR 

has developed at least two alternative tobacco products. 

Smith KM, Mitchell SN, Joseph MH, Effects of chronic and subchronic nicotine on tyrosine hydroxylase 

·activity in noradrenergic and dopam.inergic neurones in the rat brain, J Neurochem 1991;57(5): 1750-

1756. See AR (Vol60 Ref. 266). 

Wonnacott S, Drasdo AL, Presynaptic actions of nicotine in the CNS, in Effects of Nicotine on Biological 

Systems, eds. Adlkofer F, Thurau K (1991), at 295-305. See AR (Vol 62 Ref. 302). 

483 Collins G, Legal attack on tobacco intensifies, New York Times, Jun. 9, 1995. See AR (Vol. 21 Ref. 

240a). 

484 Teague CE (RJ. Reynolds Tobacco Co.), Research Planning Memorandum on the Nature of the 

Tobacco Business and the Crucial Role of Nicotine Therein (Apr. 14, 1972), at 7 (emphasis added). See 

AR (Vol. 531 Ref. 125). 

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44878 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

First, in the late 1980's, RJR developed and briefly marketed Premier, a product 

that worked by heating nicotine and glycerol-coated aluminum beads contained in an 

aluminum cylinder rather than by burning tobacco. Premier resembled a conventional 

cigarette in appearance only. Inside, it contained a carbon tip, which served as the heat 

source for the aluminum cylinder. 485 RJR documents show that RJR was acutely 

interested in Premier's ability to deliver nicotine to the smoker's blood and brain. For 

instance, RJR conducted extensive plasma studies to show that smokers using Premier 

would achieve approximately the same level of nicotine in their blood as smokers using 

conventional cigarettes.486 Other smoke components, however, were reduced by about 

90%.487 Premier functioned like the alternative nicotine delivery system recommended by 

Teague. Indeed, RJR used Teague's terminology to market Premier, advertising the 

product as a "cleaner'' cigarette.488 

More recently, RJR has begun test-marketing a low-smoke product called 

Eclipse.489 Like Premier, Eclipse relies on a carbon tip as a heat source. The tip heats a 

485 Chemical and Biological Studies on New Cigarette Prototypes that Heat Instead of Burn Tobacco 

(Winston-Salem NC: RJ. Reynolds Tobacco Co., 1988), at 1-10. See AR (Vol 107 Ref. 980). 

486 /d. at vii, 457-458, 479-483, 490-492. 

deBethizy JD, Borgerding MF, Doolittle DJ, et al. (RJ. Reynolds), Chemical and Biological Studies of a 

Cigarette that Heats Rather than Burns Tobacco, J. Clin. Pharmacal., 1990;30:755-763. See AR (Vol 47 

Ref. 78). 

487 /d. at 757. 

488 Pollay RW, Carter-Whitney D, More Chronological Notes on the Promotion of Cigarettes (History of 

Advertising Archives, Aug. 1990), at 29. See AR (Vol. 215 Ref. 2891). 

489 Cabell B, Smokeless cigarette makers hope to Eclipse market, Live Report (Jun. 3, 1996). See AR 

(Vol. 711 Ref. 11 ). 

Jones C. Reynolds not blowing smoke when it comes to keeping a lid on Eclipse, The Richmond Times 

Dispatch (Jun. 10, 1996). See AR (Vol 711 Ref. 12). 

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II.C.2. 

glycerin supply in the cigarette rod, which vaporizes and extracts nicotine, but is intended 

to produce very little of the nonnal constituents of tar, as it passes through the rod to the 

smoker's mouth. The final Eclipse smoke vapor is 85% water, glycerol, and nicotine 

(versus 25% in standard cigarette smoke) and only 15% tar (versus 75% in standard 

smoke).490 Thus, Eclipse is intended to deliver nicotine at levels similar to conventional 

ultra-low-tar cigarettes, but much lower levels of tar.491 

In its comments, RJR asserts that "Premier was a cigarette" because it provided 

the smoker with "smoking taste and pleasure.'.492 Likewise, RJR asserts that "Eclipse is a 

cigarette.'.493 But the major similarity in the vapor from Premier and Eclipse and the 

smoke from a conventional cigarette is the nicotine delivery. The implication of RJR' s 

work on Premier and Eclipse is that nicotine delivery is the defining characteristic of a 

cigarette. As RJR infonned FDA officials during the launch of Premier, "without nicotine, 

you don't have a cigarette.'.494 Premier and Eclipse are thus evidence that conventional 

cigarettes are, in effect, simply nicotine delivery systems. 

iv. RJR's Legal Briefs. Before the Agency, RJR argues that nicotine is not 

addictive and that the Agency should not believe the widespread "allegations" to the 

490 Hilts P, Little smoke, but still lots of nicotine, New York Times, Nov. 27, 1994. See AR (VoL 34 

Ref. 568). 

491 Feder BJ, Ready to test new Cigarette, maker fears tough rules, New York Times, Apr. 8, 1996. See AR 

(Vol. 700 Ref. 225). 

492 RJ. Reynolds Tobacco Co., Comment (Jan. 2, 1996), at 34-35 (emphasis added). See AR (Vol. 519 

Ref. 103). 

493 RJ. Reynolds Tobacco Co., Comment (Apr. 19, 1996). See AR (VoL 700 Ref. 225). 

494 Department of Health and Human Services, Memorandum of meeting, RJR 's "Smokeless" Cigarette 

(Oct 23, 1987), at 3. See AR (VoL 34 Ref. 558-2). 

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44880 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

contrary. However, RJR has taken exactly the opposite position in court cases. There 

RJR argues that the risk of becoming addicted to cigarettes is so foreseeable to consumers 

that consumers must be held to have assumed the risk. For instance, in one case RJR 

argued that consumers should not be allowed to sue cigarette manufacturers on the 

grounds that they become addicted, because they should have foreseen this risk: 

There can be no serious suggestion that ordiriary consumers do not 

expect to find nicotine in cigarettes, or that ordinary consumers have 

not long been well aware that it may be very difficult to stop 

smoking. The common knowledge of the alleged habituating or 

"addicting" properties of cigarettes has resulted in alrrwst casual 

references to these properties in decisions from around the country 

throughout this century.495 

RJR asserts that this statement does not acknowledge addiction because RJR is 

merely stating that "allegations" concerning the addictive properties of cigarettes are well 

known. However, RJR' s position in the litigation and its position before the Agency are 

in fundamental conflict. RJR cannot consistently deny its awareness of nicotine's 

addictive properties while at the same time claiming that its consumers should be deemed 

to have an awareness of these properties. RJR's recognition of ''the common knowledge 

of the alleged habituating or 'addicting' properties of cigarettes" is thus further evidence 

of RJR' s awareness of the addictive and other pharmacological effects of cigarettes. 

In sum, the internal RJR memoranda in the administrative record, RJR's published 

research into nicotine pharmacology, RJR's development of alternative tobacco products 

that function as nicotine delivery devices, and even RJR's litigation briefs all point to the 

495 Appellees brief in reply to appellants' opposition to petition for transfer, Rogers v. R.J. Reynolds et al. 

(Sup. Ct lnd) (No. 49A02-8904 CV 164) (1990), at 7-8 (citation omitted) (emphasis added). See AR 

(Vol. 21 Ref. 229). 

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II.C.2. 

conclusion that RJR knows that its cigarettes will have pharmacological effects, that 

consumers will purchase its products to obtain these effects, and that, in essence, its 

cigarettes function as nicotine delivery devices. This is persuasive evidence that RJR 

intends its product to affect the structure and function of the body. 

c. The Statements and Research of Brown & Williamson 

The administrative record includes a large array of documents from the Brown & 

Williamson Tobacco Corporation, the third largest cigarette manufacturer in the United 

States, and its corporate parent, BAT Industries PLC, formerly British-American Tobacco 

Company (BATCO). These documents show that Brown & Williamson and BATCO 

have conducted extensive research on nicotine's pharmacological effects and that for over 

30 years senior researchers and officials at Brown & Williamson and BA TCO have 

considered nicotine to be "addictive;'.496 "an extremely biologically active compound 

capable of eliciting a range of pharmacological, biochemical and physiological 

responses'.497 and the reason "why people inhale smoke.'.498 

The documents from Brown & Williamson and BA TCO in the administrative 

record include many unpublished reports from company research, internal memoranda, 

and reports from conferences of company scientists. These documents are summarized in 

the following chronology, which illustrates that the companies have long regarded 

496 See, e.g., Yeaman A (Brown & Williamson), Implications of Battelle Hippo I and II and the Griffith 

Filter (Jul. 17, 1963), at 4. See AR (Vol 21 Ref. 221). 

497 BATCO Group R&D, Method for Nicotine and Cotinine in Blood and Urine (May 21, 1980), at 2. 

See AR (Vol. 23 Ref. 300-1). 

498 Greig CC (BATCO), Short lived Species in Smoke (Jan. 26, 1984), attached to letter from Ayres CI 

(BATCO) to Kohnhorst BE (Brown & Williamson) (Feb. 9, 1984), at 10. See AR (Vol. 34 Ref. 584). 

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II.C.2. 

themselves as "in a nicotine rather than a tobacco industry.'.499 Although the statements of 

company scientists and officials seem to become somewhat more guarded with time, the 

documents show a consistent recognition of nicotine's pharmacological effects and uses, 

including its role in causing and sustaining addiction. 

i. Statements and Research in the 1960's. In the 1 %0' s, senior officials at 

BATCO and Brown & Williamson and their senior researchers candidly discussed 

nicotine's "addictive" and "drug" effects in internal meetings. In a 1962 conference of 

BATCO researchers, for instance, Charles Ellis, the science advisor to the BA TCO board, 

acknowledged that "smoking is a habit of addiction.''500 He described the role of nicotine 

in cigarettes as follows: 

It is my conviction that nicotine is a very remarkable beneficent 

drug that both helps the body to resist external stress and also can 

as a result show a pronounced tranquil/ising effect. . . . Nicotine is 

not only a very fine drug, but the techniques of administration by 

smoking has [sic] considerable psychological advantages and a 

built-in control against excessive absorption. It is almost 

impossible to take an overdose of nicotine in the way it is only too 

easy to do with sleeping pills. 501 

Charles Ellis recommended that BA TCO conduct research "to investigate whether 

cigarette smoke produces effects on the central nervous system characteristic of 

tranquilising or stimulating drugs and, if so, to see if such activity is due solely to 

nicotine.''502 The Battelle Memorial Institute in Geneva, Switzerland, conducted this 

499 Johnson RR(BATCO), Comments on Nicotine (Jun. 30, 1963), at 10-11. See AR (Vol21 Ref. 242). 

500 Ellis C (BATCO), The s1TWking and health problem, in Smoking and Health-Policy on Research, 

Research Conference, Southampton, England (1962), at 4 (emphasis added). See AR (Vol 21 Ref. 220). 

501 /d. at 15-16 (emphasis added). 

502 /d. at 16. 

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II.C.2. 

research for BATCO, producing a series of reports in 1963 called "HIPPO l," "HIPPO 

II," "The Fate of Nicotine in the Body," and "A Tentative Hypothesis on Nicotine 

Addiction." 

These reports substantiated and explained nicotine's drug-like and addictive 

effects. "HIPPO II," for instance, suggested that "the key to the explanation of both 

phenomena of tolerance and of addiction" to nicotine could be found through "[a] 

quantitative investigation of the relations with time of nicotine-and of some possible 

brain mediators-on adreno-corticotrophic activity."503 The report further stated that "the 

so-called 'beneficial effects' of nicotine are of two kinds: 1. Enhancing effect on the 

pituitary-adrenal response to stress; 2. Regulation of body weight."504 

Similarly, "The Fate of Nicotine in the Body" found that nicotine "appears to be 

intimately connected with the phenomena of tobacco habituation (tolerance) and/or 

addiction."505 It also reported "[t]here is increasing evidence that nicotine is the key 

factor in controlling, through the central nervous system, a number of beneficial effects 

of tobacco smoke, including its action in the presence of stress situations."506 

"A Tentative Hypothesis on Nicotine Addiction" stated that ''the hypothalomopituitary stimulation of nicotine is the beneficial mechanism which makes people smoke, 

503 Haselbach C, Libert 0, Final Report on Project HIPPO II (Mar. 1963), at 4 (emphasis added). See AR 

(Vol. 64 Ref. 321). 

504 /d. at 2. 

505 Geissbuhler H, Haselbach C, The Fate of Nicotine in the Body (May 1963), at 1 (emphasis added). See 

AR (Vol. 21 Ref. 243). 

506 /d. at 1 (emphasis added). 

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44884 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

in other words, nicotine helps people to cope with stress."507 The report then suggested 

that nicotine addiction could be explained as follows: 

If nicotine intake, however, is prohibited to chronic smokers, the 

corticotropin-releasing ability of the hypothalmus is greatly 

reduced, so that these individuals are left with an unbalanced 

endocrine system. A body left in this unbalanced status craves for 

renewed drug intake in order to restore the physiological 

equilibrium This unconscious desire explains the addiction of the 

individual to nicotine.508 

The Battelle reports were distributed to the top officials at Brown & Williamson 

and other tobacco companies. Charles Ellis sent copies of the Battelle reports to the 

president of Brown & Williamson, WilliamS. Cutchins. Brown & Williamson in turn sent 

the Project Hippo reports to RJR.509 

In July 1963, Brown & Williamson's general counsel, Addison Yeaman, wrote an 

internal memorandum entitled "Implications of Battelle Hippo I and II and the Griffith 

Filter." He stated that "nicotine is addictive" and that "[w]e are, then, in the business of 

selling nicotine, an addictive drug ... "

510 

507 Haselbach C, Libert 0, A Tentative Hypothesis on Nicotine Addiction (May 30, 1963), at 1 (emphasis 

added). See AR (VoL 20 Ref. 197). 

508 ld. at 2 (emphasis added). 

509 Note to Cutchips WS (Browli & Williamson) (Jun. 19, 1963). See AR (VoL 14, Ref. 165-4). 

Letter from Ellis C (BATCO) to Yeaman AY (Brown & Williamson) (Jun. 28, 1963). See AR (VoL 14 

Ref. 165-2). 

Letter from Yeaman AY (Brown & Williamson) to Jacob EJ (R.J. Reynolds Co.) (Aug. 5, 1963). See AR 

(Vol. 14 Ref. 165-3). 

510 Yeaman AY (Brown & Williamson), Implications of Battelle Hippo I and II and the Griffith Filter 

(Jul. 17, 1963), at4(emphasis added). See AR(VoL 21 Ref. 221). 

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II.C.2. 

These views were frequently reiterated. In June of 1967, Charles Ellis stated, "we 

are in a nicotine rather than a tobacco industry."5u Several months later, at an October 

1967 meeting, BATCO researchers agreed that "[s]moking is an addictive habit 

attributable to nicotine."512 

In 1968, Sidney J. Green, who was a member of BATCO's board as well as the 

company's director of research, acknowledged that one "recognisable type" of smoking 

behavior is "addictive" smoking. He added, "it seems a good assumption that nicotine 

plays a predominant role for many smokers .... [A] good part of the tobacco industry is 

concerned with the administration of nicotine to consumers."513 

Similarly, at another BATCO research conference in 1968, the researchers agreed 

that nicotine has "pre-eminent importance" and that "the pharmacology of nicotine should 

continue to be kept under review."514 

A year later, at a 1969 meeting of BATCO researchers, BATCO scientist D. J. 

Wood stated: 

The presence of nicotine is the reason why the tobacco plant was 

singled out from all other plants for consumption in this rather 

unusual way. 

Nicotine has well documented pharmacological action. It 

is claimed to have a dual effect, acting both as a stimulant and a 

tranquilliser. It is believed to be responsible for the "satisfaction" 

511 Johnson RR (BATCO), Comments on Nicotine (Jun 30, 1963), at 10 (emphasis added). See AR (Vol. 

21 Ref. 242). 

512 Minutes ofBATCO Group R&D Conference at Montreal, Canada (Oct 24, 1967), at 2 (emphasis 

added). See AR (VoL 21 Ref. 206-4). FDA notes that the version of this document made public by 

Congress contains a handwritten edit changing "an addictive habit" to "a habit" 

513 Green SJ (BATCO), BAT Group Research (Sep. 4, 1968), at 1-2 (emphasis added). See AR(Vol15 

Ref. 192). 

514 Minutes ofBATCO Research Conference at Hilton Head, SC (Sep. 24-30, 1968), at3 (emphasis 

added). See AR (VoL 31 Ref. 525-1). 

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44886 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

of smoking, using this term in the physiological rather than the 

psychological sense.515 

II.C.2. 

And at another 1969 conference of BATCO scientists, the following conclusion 

was reached: "[t]he Conference agreed that all the evidence continues to demonstrate the 

importance of nicotine to the smoker ... . "

516 

Numerous other similar statements were made by Brown & Williamson and 

BATCO researchers and officials in the 1960's. They are described in the Jurisdictional 

Analysis. See 60 FR 41584-41586. Collectively, these statements show that even as early 

as the 1960's, Brown & Williamson and BATCO officials knew the addictive and other 

pharmacological effects of nicotine, knew that consumers smoked cigarettes for these 

effects, and viewed themselves as in the drug delivery business. 

ii. Statements and Research in the 1970's and 1980's. Throughout the 1970's 

and 1980's, Brown & Williamson and BATCO officials continued to emphasize the 

importance of nicotine in cigarettes. At a 1970 conference of BATCO researchers, for 

instance, the researchers postulated that "[n]icotine is important, and there is probably a 

minimum level necessary for consumer acceptance in any given market."511 

In 1972, S.J. Green, the BATCO board member and research director, stated that 

"[t]he tobacco smoking habit is reinforced or dependent upon the psychoSls Wood DJ (BATCO), Aspects of the R&DE Function, Notes for a talk given by Wood DJ at Chelwood, 

Sep. 1969 (Jul. 20, 1970), at 7 (emphasis added). See AR (Vol 22 Ref. 287). 

s

16 Minutes of BATCOResearch Conference at Kronberg (Jun. 2-6, 1969), at 7 (emphasis added). See 

AR (Vol. 14 Ref. 172-4). 

517 Summary and conclusions of BAT Group Research Conference at S t Adele, Quebec (Nov. 9-13, 

1970), at 1 (emphasis added). See AR(Vol 23 Ref. 294). 

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II.C.2. 

pharmacological effects mainly ofnicotine."518 Similarly, a 1972 BATCO research report 

observed: 

It has been suggested that a considerable proportion of smokers 

depend on the pharmacological action of nicotine for their 

motivation to continue smoking. 

If this view is correct, the present scale of the tobacco 

industry is largely dependent on the intensity and nature of the 

pharmacological action ofnicotine.519 

These statements demonstrate an awareness that nicotine has "reinforcing" effects, one of 

the hallmarks of an addictive substance, and that the tobacco industry is built upon these 

effects. 

At a 1974 BATCO conference, company scientists reported that BATCO research 

had found that consumers appear to smoke to fulfill their "nicotine requirements," stating 

that "the Kippa study suggests that whatever the characteristics of cigarettes as 

determined by smoking machines, the smoker adjusts his pattern to deliver his own 

nicotine requirements (about 0.8 mg per cigarette)."520 

At a 1976 BATCO conference on smoking behavior, the researchers again stated 

that nicotine has reinforcing effects on smokers, observing that nicotine is "known to be 

pharmacologically active in the brain" and is "considered to be the reinforcing factor in 

the smoking habit for at least 80% of smokers."521 

518 Green SJ (BATCO), The Association of Smoking and Disease (Jul. 26, 1972), at 1 (emphasis added). 

See AR(Vol 15 Ref. 193). 

519 Kilburn KD, Underwood JG (BATCO), Preparation and Properties of Nicotine Analogues (Nov. 9, 

1972), at 2 (citations omitted) (emphasis added). See AR (Vol 31 Ref. 524-1). 

520 Notes on BATCO Group R&D Conference at Duck Key, FL (Jan. 12-18, 1974), at 2 (emphasis added). 

See AR (Vol 25 Ref. 327). 

521 Minutes of BATCO Group R&D Conference on Smoking Behaviour at Southampton. England 

(Oct 11-12, 1976), at BW-W2-02145, BW-W2-02152-BW-W2-02153 (emphasis added). See AR (Vol. 

14 Ref. 180). 

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44888 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

At a 1977 conference, nicotine was once more the "focal point." A Brown & 

Williamson summary of the conference stated that "[i]n many cases, psychological and 

physiological changes observed in subjects ... were shown to be due to nicotine" and 

"[m]ost researchers conclude that the nicotine effect is biphasic and dosage dependent; 

small doses stimulate and large doses depress."522 

A year later, BA TCO board member and chief researcher S.J. Green explicitly 

acknowledged that nicotine is addictive. Specifically, he wrote "[t]he strong addiction to 

cigarette[ s] relTWves freedom of choice from many individuals."523 

A 1980 BATCO research report stated that "[n]icotine is an extremely 

biologically active compound capable of eliciting a range of pharmacological, 

biochemical and physiological responses in vivo."524 

A 1981 report on the pharmacology of nicotine by the Tobacco Advisory Council, 

which represents U.K. tobacco manufacturers including BATCO, stated that "nicotine is 

regarded as the lTWst pharmacologically-active compound in tobacco sl7Wke" and 

concluded that "[i]n a nutshell, our approach has been to regard nicotine as a 'drug."'525 

522 Trip report of BA TCO International Smoking Behavior Conference at Chelwood Vachery, England 

(Jan. 6, 1978), at 1-2 (emphasis added). See AR (VoL 178 Ref. 2075). 

523 Notes of Green SJ (1978) (emphasis added). See AR (Vol. 528 Ref. 97, appendix 18). 

524 BATCO Group R&D, Method for Nicotine and Cotinine in Blood and Urine (May 21, 1980), at 2 

(emphasis added). See AR (Vol. 23, Ref. 300-1 ). 

525 Cohen AJ, Roe FJC (Tobacco Advisory Council), Monograph on the Pharmacology and Toxicology of 

Nicotine (1981), at 1, 17 (emphasis added). See AR (Vol. 14 Ref 184). 

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Il.C.2. 

In 1982, a market research report for Imperial Tobacco Ltd., BATCO's Canadian 

subsidiary, referred to attitudes of adolescents "[o]nce addiction does take place," and 

states that "addicted they do indeed become." 526 The report goes on: 

Recidivism has several causes ... [including] the belief that after a 

few weeks off cigarettes, one could begin again to smoke 'just a 

few.' ... This 'just a few' business is actually a surrender to 

addiction while trying to ... pretend to oneself and to others that 

addiction is no longer present, which is nonsense.527 

At a 1983 BATCO research conference, the minutes of the proceedings state that 

"[t]he basic assumption is that nicotine ... is almost certainly the key smoke component 

for satisfaction ... "528 

In a 1984letter, C. I. Ayres of BATCO wrote to E. E. Kohnhorst, the executive 

vice president and chief operating officer of Brown & Williamson, enclosing a report 

stating that nicotine is "why people inhale smoke": 

It is well known that nicotine can be removed from smoke by the 

lung and transmitted to the brain within seconds of smoke 

inhalation. Since it is the major or sole phannacologically active 

agent in smoke, it must be presumed that this is its preferred 

method of absorption and thus why people inhale smoke.529 

In 1984, BA TCO also held two research conferences at which nicotine was 

extensively discussed. At the ft.rSt conference, BA TCO researchers held sessions on 

526 Kwechansky Marketing Research (report prepared for Imperial Tobacco Ltd.), Project Plus/Minus 

(May 7, 1982), at i, 26 (emphasis added). See AR (Vol. 108 Ref. 1571). 

527 /d. at 36-37 (emphasis added). 

528 Minutes of BATCO Research Conference at Rio de Janeiro (Aug. 22-26, 1983), at 10 (emphasis 

added). See AR (Vol 179 Ref. 2087). 

529 Greig CC, Short lived Species in Smoke (Jan. 26, 1984), attached to letter from Ayres CI (BATCO) to 

Kohnhorst EE (Brown & Williamson) (Feb. 9, 1984), at 10 (emphasis added). See AR (Vol. 34 Ref. 584). 

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44890 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

"Nicotine Dose Requirement-Background," "Nicotine Dose Estimation," "Effects of 

Nicotine-Interaction with the Brain (Pharmacology)," and "Product Modification for 

Maximal Nicotine Effects. "530 The researchers reported that " [ i intuitively it is felt that 

'satisfaction' must be related to nicotine. Many people believe it [is] a 'whole body 

response' and involves the action of nicotine in the brain."531 They also acknowledged 

"the central role of nicotine in the smoking process and our business generally."532 

At the second conference, BATCO researchers reported that "in its simplest sense 

puffing behaviour is the means of providing nicotine dose in a meteredfashion."533 

According to one BATCO researcher speaking at the conference: 

Smoking is ... a personal tool used by the smoker to refme his behaviour and 

reactions to the world at large. 

It is apparent that nicotine largely underpins these contributions through 

its role as a generator of central physiological arousal effects which express 

themselves as changes in human perfonnance and psychological well-being."534 

Other similar statements are summarized in the Jurisdictional Analysis. See 60 FR 

41584-41666. Like the statements quoted above, they show that scientists at Brown & 

530 Ayres CI (BATCO), Notes from the GR&DC [Group Research and Development Centre] Nicotine 

Conference at Southampton, England (Jul. 9-12, 1984) (slide), at BW-W2-02639. See AR (Vol. 14 Ref. 

172). 

531 Minutes ofBATCO Nicotine Conference at Southampton, England (Jun 6-8, 1984), at BW-W2-01977 

(emphasis added). See AR (Vol 22 Ref. 287-6). 

532 Ayres CI (BATCO), Notes from the GR&DC [Group Research and Development Centre] Nicotine 

Conference at Southampton, England (Jul. 9-12, 1984), at 62 (emphasis added). See AR (Vol. 14 Ref. 

172-1). 

533 Proceedings of BATCO Group R&D Smoking Behaviour-Marketing Conference, Session I (Jul. 9-12, 

1984) (slide), at BW-W2-03242 (emphasis added). See AR (Vol 21 Ref. 238). 

534 Ferris RP, The role of smoking behaviour in product development: some observations on the 

psychological aspects of smoking behaviour, in Proceedings of BA TCO Group R&D Smoking BehaviourMarketing Conference, Session III (Jul. 9-12, 1984), at 79 (emphasis added). See AR (Vol. 192 Ref. 

2172). 

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II.C.2. 

Williamson and BATCO devoted extensive attention to understanding the 

pharmacological effects and uses of nicotine, consistently regarded nicotine as being the 

primary reason consumers smoked, and viewed cigarettes as nicotine delivery devices. 

iii. Statements and Research in the 1990's. New documents received by FDA 

during the public comment period demonstrate that researchers and officials of Brown & 

Williamson and BATCO continue to hold similar views about nicotine in cigarettes in the 

1990's. The new documents are a series of memoranda relating to the potential purchase 

in 1992 by BATCO of a manufacturer of nicotine patches, Stowic Resources Ud.535 

Brown & Williamson's research department evaluated the potential purchase in a 

memorandum entitled "Transdermal Nicotine Patches." Brown & Williamson researchers 

observed that "[t]here is currently a void in the market for a product that provides tobacco 

satisfaction in a form that is acceptable and available to many segments of the market" and 

recommended that "[ w ]e should be looking for opportunities to fill the void."536 

However, Brown & Williamson researchers expressed doubts that a nicotine patch could 

provide consumers with the same pharmacological effects obtained by smoking: 

The pattern of the blood nicotine concentrations attained by 

smoking vs the patch, however, are different. With smoking, blood 

nicotine absorption is very rapid. Blood nicotine concentrations 

go through a series of peaks and troughs with successive cigarette 

smoking throughout the day .... With the patch, nicotine 

absorption is relatively slow and continuous and peak blood levels 

are not as high as with cigarette smoking. A major advantage of 

cigarette smoking over the nicotine patch system is the ability for 

535 Salter R. Transdermal Nicotine (Apr. 3, 1992); Research and Development, Response to BAT 

Industries Note on Transdermal Nicotine (28.02.92) (Mar. 27, 1992); Kausch, Research and 

Development/Quality, Transdermal Nicotine; Research and Development/Quality, Transdermal Nicotine 

Patches; McGraw M (Brown & Williamson), Nicotine Delivery Systems (Apr. 24, 1992). See AR (Vol. 

531 Ref. 124). 

536 Transdermal Nicotine Patches, at 3. See AR (Vol 531 Ref. 124). 

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44892 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

the smoker to have very flexible control over titrating his desired 

dose ofnicotine.531 

Similar views were expressed by other BAT Industries subsidiaries. BAT 

II.C.2. 

Industries' German subsidiary, for instance, stated that "[t]he rapid, peaking intake of 

nicotine which the smoker clearly wants cannot be achieved with nicotine 

application via ... plaster."538 

The German subsidiary further acknowledged that nicotine can produce 

dependency and addiction. According to the German report, which was distributed by 

BAT Industries to the then president of Brown & Williamson, R. J. Pritchard, "[t]he 

disadvantage of rapid nicotine intake similar to that achieved with a cigarette is seen in 

the danger of people possibly becoming dependent on it."539 The German subsidiary 

observed that even with nicotine gum there is a "danger of addiction," stating that "the 

smoker can organize intake to suit himself' and achieve "[a]ctive control over intake and 

the condition it produces."540 

Brown & Williamson's legal department argued against the purchase of Stowic on 

legal grounds, warning that it would suggest that Brown & Williamson is in ''the nicotine 

delivery business" and cause Brown & Williamson to "run a serious risk of facing FDA 

jurisdiction." The lawyers also argued that the purchase of Stowic would have 

"disastrous" implications for product liability litigation because " [ t ]he marketing of any 

537 /d. at 2 (emphasis added). 

538 Research and Development/Quality, Re: Trans dermal Nicotine, at 3 (emphasis added). See AR (Vol. 

531 Ref. 124). 

539 /d. at 3 (emphasis added). 

540 ld. at 2. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44893

II.C.2. 

nicotine delivery system undercuts our position on addiction."541 Ultimately, BAT 

Industries rejected the purchase of Stowic. 

iv. The Wigand Deposition. A comment from public health organizations has 

also urged FDA to consider a 1995 deposition of JeffreyS. Wigand, the vice president of 

research and development at Brown & Williamson from 1989 to 1993. According to 

Wigand's deposition, which was submitted to the Agency with the comment, and which 

has been widely publicized in the media, a number of officers of Brown & Williamson, 

including Thomas Sandefur, the company president and chief executive officer, made 

"numerous statements ... that we're in the nicotine delivery business."542 Wigand also 

testified in the deposition that Sandefur "frequently" stated the opinion and belief that 

nicotine is "addictive";543 that Brown & Williamson manipulates nicotine levels in tobacco, 

using various techniques including blending of tobacco leaves and adding ammonia 

compounds to change the pH of smoke;544 that BATCO scientists had done studies to 

identify "the boundaries of nicotine pharmacology," and that BATCO showed that 

nicotine below "0.4 milligrams does not sustain satisfaction."545 

541 McGraw M (Brown & Williamson), Nicotine Delivery Systems (Apr. 24, 1992), at 1-2 (emphasis 

added). See AR(Vol531 Ref. 124). 

542 Deposition transcript of Wigand JS (Nov. 29, 1995), at 12 (emphasis added). See AR (Vol. 700 Ref. 

224, exhibit 2). 

543 /d. at 12-13. 

544 /d. at 27-29. 

545 /d. at 27, 33. 

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44894 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

Wigand's assertions in the deposition have been disputed by Brown & Williamson, 

which contends that they are untrue. 546 His statements, however, are consistent with and 

corroborated by the views expressed by Brown & Williamson and BAT Industries officials 

since the 1%0's. Although the Agency finds Wigand's testimony to be additional relevant 

evidence of the manufacturers' intent to affect the structure and function of the body, his 

testimony is not essential to any of the Agency's determinations. 

Cumulatively, the three decades of documents from Brown & Williamson, 

BA TCO, and BAT Industries demonstrate that these companies have long understood that 

nicotine is addictive and has other significant pharmacological effects; that consumers 

smoke cigarettes to obtain the drug effects of nicotine; and that cigarettes are a drug 

delivery system, functioning as ''the means of providing nicotine in a metered fashion."547 

d. The Statements and Research of Other Cigarette 

Manufacturers 

The administrative record establishes that the other major cigarette companies, the 

American Tobacco Company, the Lorillard Tobacco Company, and the Liggett Group 

Inc., funded research studies similar to the research conducted by Philip Morris, RJR, and 

Brown & Williamson, and as a result of the research have acquired a detailed knowledge 

of the pharmacological effects of nicotine on the brain. 

For instance, American Tobacco which merged with Brown & Williamson in 1995, 

funded extensive research on nicotine pharmacology. From 1940 through 1970, American 

546 See, e.g., Freedman AM, Cigarette defector says CEO lied to Congress about view of nicotine, Wall 

Street Journal, Jan. 26, 1996. See AR (Vol 639 Ref. 2). 

547 Proceedings of BATCO Group R&D Smoking Behaviour Marketing Conference, Session I (Jul9-12, 

1984) (slide), at BW-W2-03242. See AR (Vol 24 Ref. 316). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44895

II.C.2. 

Tobacco funded 111 studies on the biological effects of cigarettes.548 According to a staff 

report of the House Subcommittee on Health and the Environment, ninety-three of these 

studies (over 80%) related to the effects of nicotine on the body.549 In one 1945 study 

funded by the company, entitled "The Role of Nicotine in the Cigarette Habit," smokers 

were given cigarettes with extremely low levels of nicotine. The study found that half of 

the subjects "definitely missed the nicotine."550 

The activities of the Council for Tobacco Research (CTR), an industry trade 

association that conducts research on behalf of the major tobacco producers in the United 

States, 551 

are further evidence of the extent of the industry's knowledge of the 

pharmacological effects of nicotine on the human brain. On behalf of the tobacco 

industry, CTR has funded numerous studies on the pharmacology of nicotine. The goal of 

these studies was to learn why nicotine makes people want to smoke: 

Most of the pharmacological studies currently being supported by The 

Council are concerned with the effects of nicotine and/or smoking on the 

central nervous system (the brain) with the object of learning more about 

why people like, want or need to smoke.552 

548 Staff Report, Evidence of Nicotine Manipulation by the American Tobacco Company, and exhibits, 

prepared by the Majority Staff Subcommittee on Health and the Environment (Dec. 20, 1994), at 3. See 

AR (Vol. 292 Ref. 4064-4066). 

549 ld. 

sso Finnegan JK, Larson PS, Haag HB (American Tobacco Co.), The role of nicotine in the cigarette habit, 

in Biologic Research on Tobacco (American Tobacco Company: 1962), at 65-66 (originally published in 

Science 1945; 1 02). See AR (Vol 14 Ref. 178-1 ). 

551 All the major cigarette manufacturers have participated in ClR. The current members include Philip 

Morris, RJ. Reynolds, Brown & Williamson, and Lorillard Tobacco Co. Although the Liggett Group is 

not currently a member of CTR, it has been so in the past See Letter from Yeaman to Ahrensfeld et al. of 

Dec. 6, 1977. See AR (Vol 478 Ref. 8069). 

552 Cotmcil for Tobacco Research, Report of the Scientific Director, 1969-1970, at 13 (emphasis added). 

See AR (Vol16 Ref. 195-4). 

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44896 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

The body of CTR research on nicotine pharmacology is extensive. For example: 

• Thirty-nine CTR studies identify the sites and mechanisms of nicotine receptors in the 

553 These C1R documents, along with the other C1R documents cited in this section, can be found in the 

administrative record, Volumes 45-64 of Docket 95N0253J: 

Abood LG, Grassi S, Noggle HD, Comparison of the binding of optically pure (-)- and ( + )-[3H] nicotine 

to rat brain membranes, Neurochem Res 1985;10(2):259-267. 

Abood LG, Lowy K, Tometsko A, et al., Electrophysiological, behavioral, and chemical evidence for a 

noncholinergic, stereospecific site for nicotine in rat brain, J Neurosci Res 1978;3(5-6):327-333. 

Abood LG, Lowy K, Tometsko A, et al., Evidence for a noncholinergic site for nicotine's action in brain: 

Psychopharmacological, electrophysiological and receptor binding studies, Arch lnt Pharmacodyn Ther 

1979;237(2):213-229. 

Abood LG, Grassi S, Tritiated Methylcarbamylcholine a new radioligand for studying brain nicotinic 

receptors, Biochem Pharmacol1990;35(23):4199-4202. 

Andersson K, Siegel R, Fuxe K, et al., Intravenous injections of nicotine induce very rapid and discrete 

reductions of hypothalamic catecholamine levels associated with increases of ACTH, vasopressin, and 

prolactin secretion, Acta Physiol Scand 1983;118(1 )35-40. 

Andersson K, Fuxe K, Eneroth P, et al., Effects of acute central and peripheral administration of nicotine 

on hypothalamic catecholamine nerve terminal systems and on the secretion of adenohypophyseal 

hormones in the male rat. Med Bio/1982;60(2):98-111. 

Andersson K, Eneroth P, Agnati LF, Nicotine-induced increases of noradrenaline turnover in discrete 

noradrenaline nerve terminal systems of the hypothalamus and the median eminence of the rat and their 

relationship to changes in the secretion of adenohypophyseal hormones, Acta Physiol Scand 1981; 

113:227-231. 

Andersson K, Fuxe K, Agnati LF, Effects of single injections of nicotine on the ascending dopamine 

pathways in the rat Evidence for increases of dopamine turnover in the mesostriatal and mesolimbic 

dopamine neurons, Acta Physiol Scand 1981;112(3):345-347. 

Andersson K, Fuxe K, Agnati LF, et al., Effects of acute central and peripheral administration of nicotine 

on ascending dopamine pathways in the male rat brain. Evidence for nicotine induced increases of 

dopamine turnover in various telencephalic dopamine nerve terminal systems, Med Bio/1981;59(3): 170-

176. 

Britto LR, Keyser KT, Lindstrom JM, et al., Immunohistochemical localization of nicotinic acetylcholine 

receptor subunits in the mesencephalon and diencephalon of the chick (Gallus gallus), J Comp Neurol 

1992;317(4):325-340. 

Chance WT, Kallman MD, Rosecrans JA, et al., A comparison of nicotine and structurally related 

compounds as discriminative stimuli, Br J Pharmacol1978;63(4):609-616. 

240 
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II.C.2. 

Davies BD, Hess W, Lin JP, et al., Evidence for a noncholinergic nicotine receptor on human phagocytic 

leukocytes, Mol Cell Biochem 1982;44(1):23-31. 

Fuxe K, Andersson K, Eneroth P, et al., Neuroendocrine actions of nicotine and of exposure to cigarette 

smoke: medical implications, Psychoneuroendocrinology 1989;14(1-2):19-41. 

Fuxe K, Andersson K, Eneroth P, et al., Neurochemical mechanisms underlying the neuroendocrine 

actions of nicotine: focus on the plasticity of central cholinergic nicotinic receptors, Prog Brain Res 

1989;79:197-207. 

Harfstrand A. Adem A. Fuxe K, et al., Distribution of nicotinic cholinergic receptors in the rat tel-and 

diencephalon: a quantitative receptor autoradiographical study using [3H]-acetylcholine, [alpha-1251] 

bungarotoxin and [3H] nicotine, Acta Physiol Scand 1988;132(1):1-14. 

Huganir RL, Delcour AH, Greengard P, et al., Phosphorylation of the nicotinic acetylcholine receptor 

regulates its rate of desensitization. Nature 1986;321:774-776. 

Lapin EP, Maker HS, Sershen H, et al., Action of nicotine on accumbens dopamine and attenuation with 

repeated administration. Eur J Pharmacol1989: 160(1):53-59. 

Lindstrom J, Schoepfer R. Conroy WG, et al., Structural and functional heterogeneity of nicotinic 

receptors, in The Biology of Nicotine Dependence, eds. Bock G, Marsh J, Ciba Foundation Symposium 

1990:23-42, 152. 

Lukas RJ, Heterogeneity of high-affinity nicotinic [3H]acetylcholine binding sites, J Pharmacal Exp Ther 

1990;253(1):51-57. 

Lukas RJ, Pharmacological distinctions between functional nicotinic acetylcholine receptors on the PC12 

rat pheochromocytoma and the TE671 human medulloblastoma, J Pharmacal Exp Ther 1989;251(1):175-

182. 

Marks MJ, Collins AC, Characterization of nicotine binding in mouse brain and comparison with the 

binding of alpha-bungarotoxin and quinuclidinyl benzilate, Mol Pharmacol1982:554-564. 

Martin BR. Aceto MD, Nicotine binding sites and their localization in the central nervous system, 

Neurosci Biobehav Rev 1981;5:473-478. 

Mitchell SN, Smith KM, Joseph MH, et al., Increases in tyrosine hydroxylase messenger RNA in the 

locus coeruleus after a single dose of nicotine are followed by time-dependent increases in enzyme activity 

and noradrenaline release, Neuroscience 1993;56(4):989-997. 

Mitchell SN, Role of the locus coeruleus in the noradrenergic response to a systemic administration of 

nicotine, Neuropharmacology 1993;32(10):937-949. 

Owman C, Fuxe K, Janson AM, et al., Chronic nicotine treatment eliminates asymmetry in striatal 

glucose utilization following unilateral transection of the mesostriatal dopamine pathway in rats, Neurosci 

Lett 1989;102(2-3):279-283. 

Pradhan SN, Bowling C, Effects of nicotine on self-stimulation in rats, J Pharmacal Exp Ther 

1971;176(1):229-243. 

Rosecrans JA. Nicotine as a discriminative stimulus: a neurobehavioral approach to studying central 

cholinergic mechanisms, J Subst Abuse 1989;1(3):287-300. 

241 
44898 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

ll.C.2. 

• Thirty-six CTR studies show that nicotine produces neurochemical and metabolic 

effects in the brain;554 

Rosecrans JA, Noncholinergic mechanisms involved in the behavioral and stimulus effects of nicotine, 

and relationships to the process of nicotine dependence, in Tobacco S11Wking and Nicotine: A 

Neurobiological Approach, eds. Martin WR, VanLoo GR., Iwamoto ET, et al., 1987:125-139. 

Schaeppi U, Nicotine treatment of selected areas of the cat brain: effects upon BEG and autonomic system, 

lnt J Neuropharmacol1968;7(3):207-220. 

Sershen H, Lajtha A, Nicotinic Binding Sites in the brain: properties, regulation, and putative endogenous 

ligands, in, Tobacco S11Wking and Nicotine: A Neurobiological Approach, eds. Martin WR, VanLoo GR., 

Iwamoto ET, et al., 1987:481-491. 

Sershen H, Reith ME, Lajtha A, et al., Noncholinergic, saturable binding of ( +1-)-[3H] nicotine to mouse 

brain, J Recept Res 1981:1-15. 

Sorenson EM, Gallagher JP, The reducing agent dithiothreitol (DTI) does not abolish the inhibitory 

nicotinic response recorded from rat dorsolateral septal neurons, Neurosci Lett 1993; 152(1-2): 137-140. 

Stitzer M, Morrison J, Domino EF, Effects of nicotine on fixed-interval behavior and their modification 

by cholinergic antagonists, J Pharmacal Exp Ther 1970;171(2):166-177. 

Sugiyama H, Hagino N, Moore G, et al., [3-H] Nicotine binding sites in developing fetal brains in rats, 

Neurosci Res1985;2(5):387-392. 

Svensson TH, Grenhoff J, Engberg G, Effect of nicotine on dynamic function of brain catecholamine 

neurons, in The Biology of Nicotine Dependence, eds. Bock G, Marsh J., CIBA Foundation Symposium 

1990; 152: 169-180. 

Toth E, Vizi ES, Lajtha A, Effect of nicotine on levels of extracellular amino acids in regions of the rat 

brain in vivo, Neuropharmacology 1993;32(8):827-832. 

Whiting PJ, Schoepfer R., Conroy WG, et al., Expression of nicotinic acetylcholine receptor subtypes in 

brain and retina. Brain Res Mol Brain Res 1991;10(1):61-70. 

Wong LA, Gallagher JP, A direct nicotinic receptor-mediated inhibition recorded intracellularly in vitro, 

Nature 1989;341(6241):439-442. 

Wong LA, Gallagher JP, Pharmacology of nicotinic receptor-mediated inhibition in rat dorsolateral septal 

neurones, J Physiol (Lond) 1991;436:325-346. 

554 Andersson K, Fuxe K, Agnati LF, et al., Effects of acute central and peripheral administration of 

nicotine on ascending dopamine pathways in the male rat brain. Evidence for nicotine induced 

increases of dopamine turnover in various telencephalic dopamine nerve terminal systems, Med Biol 

1981 ;59(3 ): 170-176. 

Andersson K, Mecamylamine pretreatment counteracts cigarette smoke induced changes in hypothalamic 

catecholamine neuron systems and in anterior pituitary function, Acta Physiol Scand 1985;125(3):445-

452. 

242 
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II.C.2. 

Andersson K., Siegel R. Fuxe K., et al., Intravenous injections of nicotine induce very rapid and discrete 

reductions of hypothalamic catecholamine levels associated with increases of ACTH , vasopressin, and 

prolactin secretion, Acta Physiol Scand 1983; 118( 1 ):35-40. 

Andersson K., Fuxe K, Eneroth P, et al., Involvement of cholinergic nicotine-like receptors as modulators 

of amine turnover in various types of hypothalamic dopamine and noradrenaline nerve terminal systems 

and of prolactin, LH, FSH and TSH secretion in the castrated male rat, Acta Physiol Scand 

1982;116(1):41-50. 

Andersson K., Fuxe K, Eneroth P, et al., Gustafsson JA, Interactions of nicotine and pentobarbitone in the 

regulation of telencephalic and hypothalamic catecholamine levels and turnover and of adenohypophyseal 

hormone secretion in the normal male rat. Naunyn Schmiedebergs Arch Pharmacol1982;321(4):287-292. 

Andersson K., Fuxe K, Eneroth P, et al., Effects of acute central and peripheral administration of nicotine 

on hypothalamic catecholamine nerve terminal systems and on the secretion of adenohypophyseal 

hormones in the male rat. M ed Biol1982;60{2):98-111. 

Andersson K., Fuxe K., Agnati LF, Effects of single injections of nicotine on the ascending dopamine 

pathways in the rat Evidence for increases of dopamine turnover in the mesostriatal and mesolimbic 

dopamine neurons, Acta Physiol Scand 1981;112(3):345-347. 

Andersson K., Eneroth P, Agnati LF, Nicotine-induced increases of noradrenaline turnover in discrete 

noradrenaline nerve terminal systems of the hypothalamus and the median eminence of the rat and their 

relationship to changes in the secretion of adenohypophyseal hormones, Acta Physiol Scand 

1981;113:227-231. 

Andersson K., Fuxe K, Eneroth P, et al., Mecamylamine induced blockade of nicotine induced inhibition 

of gonadotrophin and TSH secretion and of nicotine induced increases of catecholamine turnover in the 

rat hypothalamus, Acta Physiol Scand Suppl1980;479:27-29. 

Andersson K., Fuxe K., Eneroth P, et al., Effects of acute intermittent exposure to cigarette smoke on 

catecholamine levels and turnover in various types of hypothalamic DA and NA nerve terminal systems as 

well as on the secretion of adenohypophyseal hormones and corticosterone, Acta Physiol Scand 

1985;124(2):277-285. 

Andersson K. Eneroth P, Fuxe K. et al., Effects of chronic exposure to cigarette smoke on amine levels 

and turnover in various hypothalamic catecholamine nerve terminal systems and on the secretion of 

pituitary hormones in the male rat. Neuroendocri1Wlogy 1985;41(6):462-466. 

Bhagat B, Influence of chronic administration of nicotine on the turnover and metabolism of 

noradrenaline in the rat brain, Psychopharmacologia 1970;18(4):325-332. 

Bhagat B, Rana MW, Effect of chronic administration of nicotine on the concentrations of adrenal 

enzymes involved in the synthesis and metabolism of adrenaline, Br J Pharmacoll971;43(1):250-251. 

Bhagat B, Effects of chronic administration of nicotine on storage and synthesis of noradrenaline in rat 

brain, Br J Pharmacol1910;38(1):86-92. 

Chang PL, Bhagat B, Taylor JJ, Effect of chronic administration of nicotine on acetylcholinesterase 

activity in the hypothalamus and medulla oblongata of the rat brain, An ultrastructural study, Brain Res 

1973;54:75-84. 

243 
44900 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

Chiou CY, Long JP, Potrepka R, et al., The ability of various nicotinic agents to release acetylcholine 

from synaptic vesicles, Arch lnt Pharmacodyn Ther 1970;187(1):88-96. 

Erwin VG, Cornell K, Towell JF, Nicotine alters catecholamines and electrocortical activity in pefused 

mouse brain, Pharmacol Biochem Behav 1986;24(1):99-105. 

Essman WB, Changes in cholinergic activity and avoidance behavior by nicotine in differentially housed 

mice, lnt J Neurosci 1971;2(4):199-205. 

Fuxe K, Andersson K, Harfstrand A. et al., Increases in dopamine utilization in certain limbic dopamine 

terminal populations after a short period of intermittent exposure of male rats to cigarette smoke, J Neural 

Transm 1986;67(1-2):15-29. 

Grenhoff J, Janson AM, Svensson TH, et al., Chronic continuous nicotine treannent causes decreased 

burst firing of nigral dopamine neurons in rats partially hemitransected at the meso-diencephalic junction, 

Brain Res 1991;562(2):347-351. 

Grenhoff J, Svensson TH, Selective stimulation of limbic dopamine activity by nicotine, Acta Physiol 

Scand 1988;133(4):595-596. 

Harsing LG, Sershen H, Lajtha A. Dopamine efflux from striatum after chronic nicotine: evidence for 

autoreceptor desensitization, J Neurochem 1992;59(1):48-54. 

Knapp DE, Domino EF, Action of nicotine on the ascending reticular activating system, lnt J 

Neuropharmacology 1962;333-351. 

Lapin EP, Maker HS, Sershen H, et al., Dopamine-like action of nicotine: lack of tolerance and reverse 

tolerance, Brain Res 1987;407{2):351-363. 

Lapin EP, Maker HS, Sershen H, et al., Action of nicotine on accumbens dopamine and attenuation with 

repeated administration, Eur J Pharmaco/1989;160(1):53-59. 

Lowy K, Abood ME, Drexler M, et al., Antagonism by cholinergic drugs of behavioral effects in cats of 

an antichohnergic psychotomimetic drug and enhancement by nicotine, Neuropharmacology 

1977;16(6):399-403. 

Marty MA, Erwin VG, Cornell K, et al., Effects of nicotine on beta-endorphin, alpha MSH, and ACTH 

secretion by isolated perfused mouse brains and pituitary glands, in vitro, Pharmacol Biochem Behav 

1985;22(2):317-325. 

Mitchell SN, Smith KM, Joseph MH, et al., Increases in tyrosine hydroxylase messenger RNA in the 

locus coeruleus after a single dose of nicotine are followed by time-dependent inaeases in enzyme activity 

and noradrenaline release, Neuroscience 1993;56(4):989-997. 

Mitchell SN, Role of the locus coeruleus in the noradrenergic response to a systemic administration of 

nicotine, Neuropharmacology 1993;32(10):937-949. 

Naftchi NE, Maker H, Lapin E, et al., Acute reduction of brain substance P induced by nicotine. 

Neurochem Res 1988;13(4):305-309. 

Siegel RA. Andersson K, Fuxe K, et al., Rapid and discrete changes in hypothalamic catecholamine nerve 

terminal systems induced by audiogenic stress, and their modulation by nicotine-relationship to 

neuroendocrine function, Eur J Pharmaco/1983;91:49-56. 

244 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44901

II.C.2. 

• Fifteen CTR studies demonstrate that nicotine affects hormone secretion and 

endocrine functions involved in modulation of mood and behavior;555 

Toth E, Sershen H, Hashim A. et al., Effect of nicotine on extracellular levels of neurotransmitters 

assessed by microdialysis in various brain regions: role of glutamic acid, Neurochem Res 1992;17(3):265-

271. 

Toth E, Vizi ES, Lajtha A. Effect of nicotine on levels of extracellular amino acids in regions of the rat 

brain in vivo, Neuropharmacology 1993;32(8):827-832. 

Tung CS, Ugedo L, Grenhoff J, et al., Peripheral induction burst firing in locus coeruleus neurons by 

nicotine mediated via excitatory amino acids, Synapse 1989;4(4):313-318. 

Westfall TC, Fleming RM, Fudger MF, et al., Effect of nicotine and related substances upon amine levels 

in the brain, Ann NY Acad Sci 1967;142:83-100. 

Westfall TC, Effect of nicotine and other drugs on the release of 3H-norepinephrine and 3H-dopamine 

from rat brain slices, Neuropharmacology 1974; 13(8):693-700. 

555 Andersson K, Fuxe K, Eneroth P, et al., involvement of D 1 dopamine receptors in the nicotineinduced neuro-endocrine effects and depletion of diencephalic catecholamine stores in the male rat, 

Neuroendocrinology 1988;48(2): 188-200. 

Andersson K, Fuxe K, Eneroth P, et al., Effects of withdrawal from chronic exposure to cigarette smoke 

on hypothalamic and preoptic catecholamine, nerve terminal systems and on the secretion of pituitary 

hormones in the male, Naunyn Schmiedebergs Arch Pharmacoll989;339(4):381-396. 

Andersson K, Eneroth P, Agnati LF, Nicotine-induced increases of noradrenaline turnover in discrete 

noradrenaline nerve terminal systems of the hypothalamus and the median eminence of the rat and their 

relationship to changes in the secretion of adenohypophyseal hormones, Acta Physiol Scand 

1981;113:227-231. 

Andersson K, Fuxe K, Eneroth P, et al., Mecamylamine induced blockade of nicotine induced inhibition 

of gonadotrophin and TSH secretion and of nicotine induced inaeases of catecholamine turnover in the 

rat hypothalamus, Acta Physiol Scand Suppl1980;419:21-29. 

Andersson K, Fuxe K, Eneroth P, et al., Effects of acute intermittent exposure to cigarette smoke on 

catecholamine levels and turnover in various types of hypothalamic DA and NA nerve terminal systems as 

well as on the secretion of adenohypophyseal hormones and corticosterone, Acta Physiol Scand 

1985;124(2):277-285. 

Andersson K, Fuxe K, Eneroth P, et al., involvement of cholinergic nicotine-like receptors as modulators 

of amine turnover in various types of hypothalamic dopamine and noradrenaline nerve terminal systems 

and of prolactin, LH, FSH and TSH secretion in the castrated male rat, Acta Physiol Scand 

1982;116(1):41-50. 

Andersson K, Fuxe K, Eneroth P, et al., Effects of acute central and peripheral administration of nicotine 

on hypothalamic catecholamine nerve terminal systems and on the secretion of adenohypophyseal 

hormones in the male rat, Med Biol1982;60(2):98-111. 

245 
44902 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

• Nine CTR studies show that nicotine induces both arousal and calming effects;556 

Fuxe K, Andersson K, Eneroth P, et al., Neuroendocrine actions of nicotine and of exposure to cigarette 

smoke: medical implications, Psychoneuroendocrirwlogy 1989;14(1-2):19-41. 

Fuxe K, Andersson K, Eneroth P, et al., Neurochemical mechanisms underlying the neuroendocrine 

actions of nicotine: focus on the plasticity of central cholinergic nicotinic receptors, Prog Brain Res 

1989;79: 197-207. 

Fuxe K, Andersson K, Eneroth P, et al., Effects of Nicotine and exposure to cigarette smoke on discrete 

dopamine and noradrenaline nerve terminal systems of the telencephalon and diencephalon of the rat: 

Relationship to reward mechanisms and neuroendocrine functions and distribution of nicotinic binding 

sites in brain, in Tobacco Smoking and Nicotine: A Neurobiological Approach. eds. Martin WR, VanLoo 

G, Iwamoto ET, Davis L, 1987:225-262. 

Marty MA. Erwin VG, Cornell K, et al., Effects of nicotine on beta-endorphin, alpha MSH, and ACTH 

secretion by isolated perfused mouse brains and pituitary glands, in vitro, Pharmacal Biochem Behav 

1985;22(2):317-325. 

Rubin RP, Warner W, Nicotine-induced stimulation of steroidogenesis in adrenocortical cells of the cat 

Br J Pharmacol1975;53(3):357-362 

Siegel RA. Andersson K, Fuxe K, et al., Rapid and discrete changes in hypothalamic catecholamine nerve 

terminal systems induced by audiogenic stress, and their modulation by nicotine-relationship to 

neuroendocrine function, Eur J Pharmacol1983 ;91:49-56. 

Westfall TC, Bras ted M, Effect of 4,4' -biphenylenebis-((2-oxoethylene)-bis-(2,2- diethoxyethyl)) 

dimethylammonium dibromide (DMAE) on accumulation and nicotine-induced release of norepinephrine 

in the heart, J Pharmacol Exp Ther 1973;184:198-204. 

Westfall Tc, Bras ted M, Specificity of blockade of the nicotine-induced release of 3H-norepinephrine 

from adrenergic neurons of the guinea-pig heart by various pharmacological agents, J Pharmacol Exp 

Ther 1974; 189(3):659-664. 

ss6 Domino EF, Electroencephalographic and behavioral arousal effects of small doses of nicotine: a 

neuropsychopharmacological study. The effects of nicotine and smoking on the central nervous system, 

Ann NY Acad Sci 1967;142:216-244. 

Heimstra NW, Fallesen JJ, Kinsley SA. et al., The effects of deprivation of cigarette smoking on 

psychomotor performance, Ergonomics 1980;23(11 ):1047-1055. 

Marks MJ, Burch JB, Collins AC, Genetics of nicotine response in four inbred strains of mice, J 

Pharmacol Exp Ther 1983 ;226(1):291-302 

Nelsen JM, Goldstein L, Improvement of performance on an attention task with chronic nicotine 

treatment in rats, Psychopharmacologia 1972;26(4):347-360. 

Pradhan SN, Effects of nicotine on several schedules of behavior in rats, Arch lnt Pharmacodyn Ther 

1970; 183(1):127-138. 

Schaeppi U, Nicotine treatment of selected areas of the cat brain: effects upon EEG and autonomic 

system, lnt J Neuropharmacol1968;7(3):207-220. 

246 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44903

II.C.2. 

• Nine CTR studies use an EEG to examine the effects of nicotine on brain waves;

557 

• Nine CTR studies investigate the physiological effects of nicotine on the brain and 

their time course;

558 

Stadnicki SW, Schaeppi UH, Nicotinic changes in EEG and behavior after intravenous infusion in awake 

unrestrained cats, Arch lnt Pharmacodyn Ther 1972;197(1):72-85. 

Stadnicki SW, Schaeppi U, Nicotine infusion into the fourth ventricle of unrestrained cats: changes in 

EEG and behavior, Arch lnt Pharmacodyn Ther 1970; 183(2):277-288. 

Yamamoto Kl, Domino EF, Nicotine-induced EEG and behavioral arousal./nt J Neuropharmacol 

1965;4( 6):359-3 73. 

557 Domino EF, Electroencephalographic and behavioral arousal effects of small doses of nicotine: a 

neuropsychopharmacological srudy. The effects of nicotine and smoking on the central nervous system, 

Ann NY Acad Sci 1967;142:216-244. 

Erwin VG, Cornell K, Towell JF, Nicotine alters catecholamines and electrocortical activity in perfused 

mouse brain, Pharmacol Biochem Behav 1986;24(1):99-105. 

Kawamura H Somino EF, Differential actions of m and n cholinergic agonists on the brainstem activating 

system, lnt J Neuropharmacol 1969;8(2): 105-115. 

Marty MA, Erwin VG, Cornell K, et al., Effects of nicotine on beta-endorphin, alpha MS H, and ACTH 

secretion by isolated perfused mouse brains and pituitary glands, in vitro, Pharmacol Biochem Behav 

1985;22(2):3 17-325. 

Nelsen JM, Pelley K, Goldstein L, Chronic nicotine treatment in rats 2. Electroencephalographic 

amplitude and variability changes occurring within and between structures, Res Commun Chem Pathol 

Pharmaco/1913;5(3):694-704. 

Schaeppi U, Nicotine treatment of selected areas of the cat brain: effects upon EEG and autonomic 

system, lnt J Neuropharmaco/1968;1(3):201-220. 

Stadnicki SW, Schaeppi UH, Nicotinic changes in EEG and behavior after intravenous infusion in awake 

unrestrained cats, Arch lnt Pharmacodyn Ther 1972;197(1):72-85. 

Stadnicki SW, Schaeppi U, Nicotine infusion into the fourth ventricle ofunresttained cats: changes in 

EEG and behavior, Arch lnt Pharmacodyn Ther 1970;183(2):277-288. 

Yamamoto KI, Domino EF, Nicotine-induced EEG and behavioral arousal, lnt J Neuropharmacol 

1965;4(6):359-373. 

558 Abood LG, Grassi S, Noggle HD, Comparison of the binding of optically pure(-)- and (+)-[3H] 

nicotine to rat brain membranes, Neurochem Res 1985;10(2):259-267. 

Andersson K, Fuxe K, Eneroth P, et al., Effects of withdrawal from chronic exposure to cigarette smoke 

on hypothalamic and preoptic catecholamine, nerve terminal systems and on the seaetion of pituitary 

hormones in the male, Naunyn Schmiedebergs Arch Pharmacol1989;339(4):387-396. 

247 
44904 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.2. 

• Six CTR studies characterize the effect of nicotine on behavioral performance and 

cognitive function; 559 

• Six CTR studies research the general pharmacokinetics of nicotine; 560 

Andersson K, Fuxe K, Eneroth P, et al., Effects of acute intermittent exposure to cigarette smoke on 

catecholamine levels and turnover in various types of hypothalamic DA and NA nerve terminal systems as 

well as on the secretion of adenohypophyseal hormones and corticosterone, Acta Physiol Scand 

1985;124(2):277-285. 

Bhagat B, Influence of chronic administration of nicotine on the turnover and metabolism of 

noradrenaline in the rat brain, Psychopharmacologia 1970;18(4):325-332. 

Fuxe K, Andersson K, Harfstrand A, et al., Increases in dopamine utilization in certain limbic dopamine 

terminal populations after a short period of intermittent exposure of male rats to cigarette smoke, J Neural 

Transm 1986;67(1-2): 15-29. 

Fuxe K, Andersson K, Eneroth P, et al., Effects of Nicotine and exposure to cigarette smoke on discrete 

dopamine and noradrenaline nerve terminal systems of the telencephalon and diencephalon of the rat 

Relationship to reward mechanisms and neuroendocrine functions and distribution of nicotinic binding 

sites in brain, in Tobacco Smoking and Nicotine: A Neurobiological Approach, eds. Martin WR, Van 

Loo GR, Iwamoto ET, et al., 1987:225-262. 

Tung CS, U gedo I.., Grenhoff J, et al., Peripheral induction burst firing in locus coeruleus neurons by 

nicotine mediated via excitatory amino acids, Synapse 1989;4(4):313-318. 

Wong LA, Gallagher JP, Pharmacology of nicotinic receptor-mediated inhibition in rat dorsolateral septal 

neurones, J Physiol (wnd) 1991;436:325-346. 

Yamamoto KI, Domino EF, Nicotine-induced BEG and behavioral arousal, lnt J Neuropharmacol 

1965;4(6):359-373. 

559 Bhagat B, Wheeler N, Effect of nicotine on the swimming endurance of rats, Neuropharmacology 

1973; 12(12): 1161-1165. 

Heimstra NW, Fallesen JJ, Kinsley SA, et al., The effects of deprivation of cigarette smoking on 

psychomotor performance, Ergonomics 1980;23(11): 1047-1055. 

Marks MJ, Burch JB, Collins AC, Genetics of nicotine response in four inbred strains of mice, J 

Pharmacol Exp Ther 1983 ;226(1):291-302 

Nelsen JM, Pelley K, Goldstein I.., Chronic nicotine treatment in rats 2. Electroencephalographic 

amplittlde and variability changes occurring within and between structtlres, Res Commun Chem Pathol 

Pharmacol1973;5(3):694-704. 

Nelsen JM, Pelley K, Goldstein I.., Protection by nicotine from behavioral disruption caused by reticular 

formation stimulation in the rat, Pharmacol Biochem Behav 1975;3(5):749-754. 

Nelsen JM, Goldstein L, Improvement of performance on an attention task with chronic nicotine 

treatment in rats, Psychopharmacologia 1972;26(4):347-360. 

248 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44905

II.C.2. 

• Five CTR studies describe the development of sophisticated techniques for 

determining the presence of nicotine in body fluids; 561 

• Four CTR studies evaluate plasma profiles of nicotine; 562 

560 Becker RF, King IE, Studies on nicotine absorption during pregnancy. II. The effects of acute heavy 

doses on mother and neonates, Am J Obstet Gynecol1966;95(4):515-522. 

Haines CF Jr, Mabajan DK. Miljkovc D, et al., Radioimmunoassay of plasma nicotine in habituated and 

naive smokers, Clin Pharmacal Ther 1974;16(6):1083-1089. 

Hibberd AR., Gorrod JW, Enzymology of the metabolic pathway from nicotine to cotinine, in vitro, Eur J 

Drug Metab Pharmaco/dnet 1983;8:151-162. 

Kershbaum A, Bellet S, Cigarette, cigar, and pipe smoking. Some differences in biochemical effects, 

Geriatrics 1968;23(3):126-134. 

Monji N, Castro A, Plasma nicotine pharmacokinetics in dogs after intravenous administration: 

determination by radioimmunoassay, Res Commun Chern Pathol Pharmacol1979;23(2):267-277. 

Rama Sastry BY, Chance MB, Singh G, et al., Distribution and retention of nicotine and its major 

metabolize cotinine in the rat as a function of time, in International Symposium on Nicotine, eds. Clarke 

PBS, Quik M, Thurau K. et al., 1994:125. 

561 Castro A, Monji N, Nicotine enzyme immunoassay, Res Commun Chern Pathol Pharmacol1986; 

51(3):393-404. 

Castro A, Malkus H, Radioimmunoassays of drugs of abuse in humans: a review, Res Commun Chern 

Pathol Pharmacol1977;16(2):291-309. 

Haines CF Jr, Mabajan DK. Miljkovc D, et al., Radioimmunoassay of plasma nicotine in habituated and 

naive smokers, Clin Pharmacal Ther 1974;16(6):1083-1089. 

McNiven NL, Raisinghani KH, Patashnik S, et al., Determination of nicotine in smokers' urine by gas 

chromatography, Nature 1965;208:788-789. 

Monji N, Castro A, Plasma nicotine pharmacokinetics in dogs after intravenous administration: 

determination by radioimmunoassay, Res Commun Chern Pathol Pharmacol1979;23(2):267-277. 

562 Castro A, Monji N, Nicotine enzyme immunoassay, Res Commun Chem Pathol Pharmacol1986; 

51(3):393-404. 

Haines CF Jr, Mahajan DK. Miljkovc D, et al., Radioimmunoassay of plasma nicotine in habituated and 

naive smokers, Clin Pharmacal Ther 1974;16(6): 1083-1089. 

Monji N, Castro A, Plasma nicotine pharmacokinetics in dogs after intravenous administration: 

determination by radioimmunoassay, Res Commun Chern Pathol Pharmacol1979;23(2):267-277. 

Rama Sastry BY, Chance MB, Singh G, et al., Distribution and retention of nicotine and its major 

metabolize cotinine in the rat as a function of time, in International Symposium on Nicotine, eds. Clarke 

PBS, Quik M, Thurau K. et al., 1994:125. 

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• Four CTR studies research the factors affecting the onset and duration of nicotine's 

effects on the body; 563 

• Three CTR studies investigate the metabolic fate of nicotine;564 

• Two CTR studies specifically investigate the enzymatic systems involved in nicotine 

metabolism;565 

• Two CTR studies show that smokers metabolize nicotine faster than nonsmokers;566 

• Two CTR studies examine the factors affecting the absorption of nicotine into the 

bloodstream;567 

563 Domino EF, Electroencephalographic and behavioral arousal effects of small doses of nicotine: A 

neuropsychopharmacological study. The effects of nicotine and smoking on the central nervous system, 

Ann NY Acad Sci 1967;142:216-244. 

Hoff EC, Hockman CH, Neurophysiological aspects of the action of nicotine. The effects of nicotine and 

smoking on the central nervous system, Ann NY Acad Sci 1967; 142:121-125. 

Lapin EP, Maker HS, Sershen H, et al., Dopamine-like action of nicotine: lack of tolerance and reverse 

tolerance, Brain Res 1987;407(2):351-363. 

Stitzer M, Morrison J, Domino EF, Effects of nicotine on fixed-interval behavior and their modification 

by cholinergic antagonists, J Pharmacol Exp Ther 1970; 171(2 ): 166-177. 

564 Abood LG, Grassi S, Junig J, et al., Specillc binding and metabolism of (-)- and ( + )-[3H] nicotine in 

isolated rat hepatocytes and hepatocyte membranes, Arch lnt Pharmacodyn Ther 1985;273(1):62-73. 

Hibberd AR, Gomod JW, Nicotine delta 1 '(5)' iminium ion: a reactive intermediate in nicotine 

metabolism, Adv Exp Med Bio/1981:1121-1131. 

Vincek we, Martin BR, Aceto MD, et al., Synthesis of 4,4-ditritio-( +)-nicotine: comparative binding and 

distribution studies with natural enantiomer, J Pharm Sci 1981;70(11):1292-1293. 

565 Hibberd AR, Gorrod JW, Enzymology of the metabolic pathway from nicotine to cotinine, in vitro, Eur 

J Drug Metah Pharmacokinet 1983;8:151-162. 

Wilson KL Jr, Chang, RS, Bowman ER, et al., Nicotine-like actions of cis-metanicotine and transmetanicotine, J Pharmacol Exp Ther 1976;196(3):685-696. 

566 Hatchell PC, Collins AC, The influence of genotype and sex on behavioral sensitivity to nicotine in 

mice, Psychopharmacology (Berl) 1980;71(1):45-49. 

Jusko WJ, Role of tobacco smoking in pharmacokinetics, J Pharmacokinet Biopharm 1978;6(1):7-39. 

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• Two CTR studies examine the distribution of nicotine to the brain;568 

• Two CTR studies research the relationship of nicotine's physiological effects on the 

body to nicotine blood levels;569 and 

• One CTR study shows that there may be gender differences in the metabolism of 

nicotine. 570 

The results of the CTR-funded research show that nicotine has significant 

pharmacological effects on the body. In fact, numerous CTR studies demonstrate that 

nicotine produces pharmacological effects similar to those of other addictive substances. 

For example: 

• Thirteen CTR studies demonstrate that nicotine, like other addictive drugs, acts on 

dopaminergic receptors in the brain to release dopamine, a chemical in the brain's 

reward system that reinforces the intake of certain substances;571 

567 Haines CF Jr, Mahajan DK, Miljkovc D, et al., Radioimmunoassay of plasma nicotine in habituated 

and naive smokers, Clin Pharmacal Ther 1974;16(6):1083-1089. 

Kershbaum A, Bellet S, Cigarette, cigar, and pipe smoking. Some differences in biochemical effects, 

Geriatrics 1968;23(3):126-134. 

568 Hatchell PC, Collins AC, The influence of genotype and sex on behavioral sensitivity to nicotine in 

mice, Psychopharmacology (Berl) 1980;71(1):45-49. 

Vincek we, Martin BR. Aceto MD, et al., Synthesis of 4,4-ditritio-( +)-nicotine: comparative binding and 

distribution studies with natural enantiomer, J Pharm Sci 1981;70(11):1292-1293. 

s

69 Hatchell PC, Collins AC, The influence of genotype and sex on behavioral sensitivity to nicotine in 

mice, Psychopharmacology (Berl) 1980;71(1):45-49. 

Westfall TC, Anderson GP, Influence of nicotine on catecholamine metabolism in the rat. Arch lnt 

Pharmacodyn Ther 1967;169(2):421-428. 

570 Jusko WJ, Role of tobacco smoking in pharmacokinetics, J Pharmacokinet Biopharm 1978;6(1):7-39. 

571 Abood LG, LuX, Banerjee S, Receptor binding characteristics of a 3H-labeled azetidine analogue of 

nicotine, Biochem Pharmacol1987;36(14):2337-2341. 

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II.C.2. 

• Twelve CTR studies demonstrate that tolerance to nicotine occurs;

572 

Andersson K, Fuxe K, Eneroth P, et al., Mecamylamine induced blockade of nicotine induced inhibition 

of gonadotrophin and TSH secretion and of nicotine induced increases of catecholamine turnover in the 

rat hypothalamus, Acta Physiol Scand Suppl1980;479:27-29. 

Andersson K, Fuxe K, Eneroth P, et al., Effects of acute intermittent exposure to cigarette smoke on 

catecholamine levels and turnover in various types of hypothalamic DA and NA nerve terminal systems as 

well as on the secretion of adenohypophyseal hormones and corticosterone, Acta Physiol Scand 

1985;124(2):277-285. 

Andersson K, Fuxe K, Eneroth P, et al., Involvement of cholinergic nicotine-like receptors as modulators 

of amine turnover in various types of hypothalamic dopamine and noradrenaline nerve terminal systems 

and of prolactin, LH, FSH and TSH secretion in the castrated male rat, Acta Physiol Scand 

1982;116{1):41-50. 

Andersson K, Fuxe K, Eneroth P, et al., Interactions of nicotine and pentobarbitone in the regulation of 

telencephalic and hypothalamic catecholamine levels and turnover and of adenohypophyseal hormone 

secretion in the normal male rat, Naunyn Schmiedebergs Arch Pharmacol1982;321(4):281-292. 

Andersson K, Fuxe K, Eneroth P, et al., Effects of acute central and peripheral administration of nicotine 

on hypothalamic catecholamine nerve terminal systems and on the secretion of adenohypophyseal 

hormones in the male rat, Med Biol1982;60(2):98-lll. 

Erwin VG, Cornell K, Towell JF, Nicotine alters catecholamines and electrocortical activity in pefused 

mouse brain, Pharmacol Biochem Behav 1986;24(1):99-105. 

Fuxe K, Andersson K, Harfstrand A. et al., Increases in dopamine utilization in certain limbic dopamine 

terminal populations after a short period of intermittent exposure of male rats to cigarette smoke, J Neural 

Transm 1986;67(1-2):15-29. 

Grenhoff J, Svensson TH, Selective stimulation of limbic dopamine activity by nicotine, Acta Physiol 

Scand 1988;133(4):595-596. 

Harsing LG, Sershen H, Vizi SE, et al., N-type calcium channels are involved in the dopamine releasing 

effect of nicotine, Neurochem Res 1992; 17(7):729-734. 

Lapin EP, Maker HS, Sershen H, et al., Action of nicotine on accumbens dopamine and attenuation with 

repeated administration, Eur J Pharmacol1989;160(1):53-59. 

Lapin EP, Maker HS, Sershen H, et al., Dopamine-like action of nicotine: lack of tolerance and reverse 

tolerance, Brain Res 1987;407(2):351-363. 

Westfall TC, Effect of nicotine and other drugs on the release of 3H-norepinephrine and 3H-dopamine 

from rat brain slices, Neuropharmacology 1974;13(8):693-700. 

572 Abood LG, Lowy K, Booth H, Acute and chronic effects of nicotine in rats and evidence for a noncholinergic site of action, NIDA Res Monogr 1979:136-149. 

Abood LG, Grassi S, Costanzo M, et al., Behavioral and biochemical studies in rats after chronic 

exposure to nicotine, NIDA Res Monogr 1984;54:348-355. 

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II.C.2. 

• Three CTR studies research the neurochemical mechanisms of nicotine withdrawal; 573 

Andersson K. Fuxe K, Eneroth P, et al., Effects of withdrawal from chronic exposure to cigarette smoke 

on hypothalamic and preoptic catecholamine, nerve terminal systems. and on the secretion of pituitary 

hormones in the male, Naunyn Schmiedebergs Arch Pharmacol1989;339(4):387-396. 

Cronan T, Conradi, Bryson R, Effects of chronically administered nicotine and saline on motor activity 

in rats, Pharmacol Biochem Behav 1985;22(5):897-899. 

Domino EF, Lutz MP, Tolerance to the effects of daily nicotine on rat bar pressing behavior for water 

reinforcement, Pharmacol Biochem Behav 1973; 1(4):445-448. 

Fuxe K. Andersson K, Eneroth P, et al., Effects of Nicotine and exposure to cigarette smoke on discrete 

dopamine and noradrenaline nerve terminal-systems of the telencephalon and diencephalon of the rat 

Relationship to reward mechanisms and neuroendocrine functions and distribution of nicotinic binding 

sites in brain, in Tobacco Smoking and Nicotine: A Neurobiological Approach, eds. Martin WR, VanLoo 

GR, Iwamoto ET, et al., 1987;225-262. 

Lapin EP, Maker HS, Sershen H, et al., Dopamine-like action of nicotine: lack of tolerance and reverse 

tolerance, Brain Res 1987;407(2):351-363. 

Nelsen JM, Goldstein L, Improvement of performance on an attention task with chronic nicotine 

treatment in rats, Psychopharmacologia 1972;26(4):347-360. 

Rosecrans JA, Noncholinergic mechanisms involved in the behavioral and stimulus effects of nicotine, 

and relationships to the process of nicotine dependence, in Tobacco Smoking and Nicotine: A 

Neurobiological Approach, eds. Martin WR. VanLoo GR, Iwamoto ET, et al., 1987:125-139. 

Stitzer M, Morrison J, Domino EF, Effects of nicotine on fixed-interval behavior and their modification 

by cholinergic antagonists, J Pharmacol Exp Ther 1970;171(2):166-177. 

Wenzel DG, Azmeh N, Clark D, Studies on the acute and chronic depressor actions of nicotine in the rat, 

Arch lnt Pharmacodyn Ther 1971;193(1):23-36. 

Westfall TC, Brase DA, Studies on the mechanism of tolerance to nicotine-induced elevations of urinary 

catecholamines, Biochem Pharmacol1971;20(7):1627-1635. 

573 Andersson K., Effects of withdrawal from chronic exposure to cigarette smoke on hypothalamic and 

preoptic catechalamine nerve terminal systems and the secretion of pituitary hormones in the male, 

Naunyn Schmiedebergs Arch Pharmacol1989;339(4):387-396. 

Fuxe K., Effects of Nicotine and exposure to cigarette smoke on discrete dopamine and noradrenaline 

nerve terminal systems of the telencephalon and diencephalon of the rat relationship to reward 

mechanisms and neuroendocrine functions and distribution of nicotinic binding sites in brain, in Tobacco 

Smoking and Nicotine: A Neurobiological Approach, eds. Martin WR. VanLoo GR, Iwamoto ET, et al., 

1987:225-262. 

Rosecrans JA, Noncholinergic mechanisms involved in the behavioral and stimulus effects of nicotine, 

and relationships to the process of nicotine dependence, in Tobacco Smoking and Nicotine: A 

Neurobiological Approach, eds, Martin WR. VanLoo GR, Iwamoto ET, et al., 1987;125-139. 

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II.C.2. 

• Two CTR studies investigate the effects of nicotine withdrawal on perfonnance;574 

• Two CTR studies show that nicotine is psychoactive and produces clearly 

discriminable stimulus effects;575 and 

• Two CTR studies show that nicotine can enhance the rewarding effects of electrical 

brain stimulation. 576 

Indeed, seven CTR studies state expressly that nicotine is an addictive or 

dependence-producing drug.577 For instance, one CTR-funded study stated that "smoking 

574 Heimstra NW, Fallesen JJ, Kinsley SA, et al., The effects of deprivation of cigarette smoking on 

psychomotor performance, Ergonomics 1980;23(11 ): 104 7-1055. 

Heimstra NW, Bancroft NR. DeKock AR. Effects of smoking upon sustained performance in a 'simulated 

driving task, in the effects of nicotine and smoking on the central nervous system, Ann NY A cad Sci 

1967;142:295-307. 

515 Chance WT, Kallman MD, Rosecrans JA, et al., A comparison of nicotine and structurally related 

compounds as discrinlinative stimuli, Br J Pharmacol1978;63(4):609-616. 

Rosecrans JA, Nicotine as a discrinlinative stimulus: a neurobehavioral approach to studying central 

cholinergic mechanisms, J Subst Abuse 1989;1(3):287-300. 

576 Olds ME, Domino EF, Comparison of muscarinic and nicotinic cholinergic agonists on selfstimulation behavior, J Pharmacal Exp Ther 1969;166(2):189-204. 

Pradhan SN, Bowling C, Effects of nicotine on self-stimulation in rats, J Pharmacal Exp Ther 

1971;176(1):229-243. 

Deneau GA, lnoki R, Nicotine self-administration in monkeys, in The effects of nicotine and smoking on 

the central nervous system, Ann NY Acad Sci 1967;142:277-279. 

Other research jointly funded by the tobacco industry examines nicotine's ability to serve as a positive 

reinforcer in self-administration studies involving monkeys. See 60 FR 41642. 

577 Bosse R Gamery AJ, Glynn RJ, Age and addiction to smoking, Addict Behav 1980;5(4):341-351. 

Martin WR, VanLoo GR, Iwamoto ET, et al., Tobacco Smoking and Nicotine: A Neurobiological 

Approach (New York: Plenum Press, 1987). 

Rosecrans JA, Noncholinergic mechanisms involved in the behavioral and stimulus effects of nicotine, 

and relationships to the process of nicotine dependence, in Tobacco Smoking and Nicotine: A 

Neurobiological Approach, eds. Martin WR, VanLoo GR, Iwamoto ET, et al., 1987:125-139. 

Rosecrans JA, Nicotine as a discriminative stimulus: a neurobehavioral approach to studying central 

cholinergic mechanisms, J Subst Abuse 1989;1(3):287-300. 

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II.C.2. 

is a form of dependence no less binding than that of other addictive drugs."578 Similarly, 

another CTR-funded study observed that "compelling evidence now exists that regular 

smoking is a form of drug addiction to nicotine."579 

The Agency received no comments disputing FDA's characterization in the 

Jurisdictional Analysis of any of these CfR-funded studies. Thus, these uncontested 

studies demonstrate that the entire cigarette industry had detailed knowledge of the 

pharmacological effects of nicotine on the brain, including knowledge of research funded 

by the industry that found nicotine to be an addictive drug. 

Collectively, these CfR studies and the studies conducted by individual cigarette 

manufacturers show that the cigarette manufacturers have acted like traditional 

pharmaceutical companies. Before marketing a prescription drug, a pharmaceutical 

company studies the pharmacokinetics of the drug (how it is absorbed into the body, 

metabolized, and excreted), the pharmacodynamics of the drug (what specific effects the 

drug has on the body's chemistry and metabolism as it makes its way through the body), 

and the clinical effects of the drug (whether the drug is effective in producing the desired 

Svensson TH, Grenhoff J, Engberg G, Effect of nicotine on dynamic function of brain catecholamine 

neurons, in The Biology of Nicotine Dependence, eds. Bock G, Marsh J, CIBA Foundation Symposium 

1990;152:169-180. 

Tung CS, Ugedo L, Grenhoff J, et al., Peripheral induction burst firing in locus coeruleus neurons by 

nicotine mediated via excitatory amino acids, Synapse 1989;4(4):313-318. 

Williams JS, Crumpacker DW, Krier MJ, Stability of a factor-analytic description of smoking behavior, 

Drug Alcohol Depend 1980;5(6):467-478. 

578 Bosse R Gamery AJ, Glynn RJ, Age and addiction to smoking, Addict Behav 1980;5(4):341-351 

(emphasis added). 

579 Svensson TH, Grenhoff J, Engberg G, Effect of nicotine on dynamic function of brain catecholamine 

neurons, in The Biology of Nicotine Dependence, eds. Bock G, Marsh J, CIBA Foundation Symposium 

1990; 152: 169-180 (emphasis added). 

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II.C.2. 

therapeutic or physiological effects). The cigarette manufacturers have conducted or 

funded the same studies for nicotine. As a result, the cigarette manufacturers' 

understanding of the pharmacological effects and uses of nicotine are closely analogous 

to-if not more extensive and sophisticated than-the understanding any pharmaceutical 

company has of traditional drug products. 

e. Three Decades of Statements and Research by Cigarette 

Manufacturers Are Sufficient to Establish Intent 

As discussed in section II.C.l., above, the statements and research of a manufacturer 

are relevant evidence of the uses of a product that are "intended" by the manufacturer. This 

evidence shows that when the manufacturers offer cigarettes for sale, they "have in mind" that 

their products will be purchased for specific pharmacological uses by consumers. Hence, the 

evidence is sufficient to establish that the effects of cigarettes on the structure and function of 

the body are "intended" by the manufacturers. 

The cigarette manufacturers assert, however, that the statements and research relied 

upon by the Agency are not reliable evidence of the cigarette manufacturers' intent in this case. 

Among other things, they argue that the three decades of tobacco company statements and 

research on the addictive and other pharmacological effects of nicotine contained in the 

administrative record are irrelevant to the intended use of cigarettes and SIIDkeless tobacco 

because the statements were made and the research was conducted over a period of many 

years and are not contemporaneous with the sale of currently marketed products.580 

580 Other arguments of the manufacturers concerning the evidence that may be used to establish intended 

use are addressed in section II.B., below. 

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II.C.2. 

FDA disagrees. The extensiveness ofthe statements and research of the cigarette 

manufacturers in the administrative record, most of which have only recently become available, 

reflects a remarkably consistent pattern of the industry's views, repeated frequently over time. 

These documents and statements establish the knowledge and belief of tobacco company 

officials that cigarettes have, and are predominantly used by consumers for, phannacological 

effects. The :fuct that these statements span three decades simply demonstrates that the 

companies' knowledge and beliefs about the phannacological effects and uses of cigarettes are 

both long-standing and consistent. As described in section ll.A5., above, commercial 

cigarettes marketed today contain a level of nicotine that is sufficient to produce addiction and 

other phannacological effects. Thus, statements made 30 years ago about the phannacological 

effects of nicotine in cigarettes are equally relevant to the cigarettes being marketed today. 

Moreover, as discussed above, many of the statements and research relied upon by FDA 

are of recent origin. 

Tobacco industry comments also argue that statements of individuals employed, or 

formerly employed, by the manufacturers are not relevant to establishing the intent of any 

manufacturer because they are not formal statements of company policy. According to 

one manufacturer's comments, the only statements that are evidence of the manufacturer's 

"institutional intent" are those that have been adopted by the manufacturer "after whatever 

formalities required by the decision-making procedures of the institution have been 

followed."581 

581 RJ. Reynolds Tobacco Co., Comment (Jan. 2, 1996), at 24. See AR (Vol. 519 Ref. 103). 

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II.C.2. 

FDA disagrees that the statements of tobacco industry employees are not evidence 

of the intended use of the product. FDA is relying on the statements as evidence that the 

tobacco companies know that nicotine in tobacco has pharmacological effects and that 

consumers use tobacco to obtain those effects. Many of the statements come from 

executives at the companies. As one court observed, in a case relied upon by a tobacco 

company comment 

When a major company executive speaks, "everybody listens" in the 

corporate hierarchy, and when an executive's comments prove to 

be disadvantageous to a company's subsequent litigation posture, it 

cannot compartmentalize this executive as if he had nothing more 

to do with company policy than the janitor or watchman. 

Ezold v. Wolf, 983 F.2d 509, 546 (3d Cir. 1992) (internal citation omitted). 

Moreover, many of the statements relied upon by FDA come from individuals 

whose function within the company was to research and understand the motives for 

smoking and who regularly communicated those views to company management. A 

corporation ordinarily relies on its research department to answer scientific questions, such 

as the pharmacologic effects of its product on users and the purposes for which consumers 

use the product. The statements quoted by FDA show a highly consistent pattern of views 

within and among the research departments of the cigarette companies, demonstrating that 

the statements are not the idiosyncratic opinions of a few individuals within one company, 

but widely shared views. 

Indeed, the record shows that the cigarette manufacturers did in fact rely upon and 

regularly consult with their research scientists. In the case of Philip Morris, for instance, 

the CEO of Philip Morris, the president of Philip Morris USA, and vice presidents and 

directors from functions such as marketing met on a monthly basis with senior officials and 

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II.C.3. 

scientists from the company's research and development department to discuss Philip 

Morris' basic and applied research and othertopics.582 These regular meetings, the 

occurrence of which Philip Morris does not dispute, show that the knowledge and views 

of the Philip Morris scientists were regularly sought by and communicated to the officers 

at the head of the company. 

For these reasons, the statements and research of the cigarette manufacturers are 

sufficient evidence to establish that the manufacturers intend to affect the structure and 

function of the body. As FDA's regulations recognize, "objective intent" can be 

established by evidence that "a manufacturer knows, or has knowledge of, facts that 

would give him notice," that a product will be used for pharmacological purposes. 

21 CPR 201.128, 801.4.583 

3. The Cigarette Manufacturers Have Conducted Extensive Product 

Research and Development To Optimize the Delivery of Nicotine 

The tobacco inctustry documents in the administrative record show not only that 

the cigarette manufacturers "have in mind" that cigarettes will be used for specific 

pharmacological purposes, but also that they have "designed" cigarettes to ensure that 

smokers receive a pharmacologically active dose of nicotine. The evidence in the record 

contains two categories of evidence of the manufacturers' design: (1) the evidence of the 

582 DeclarationofUydess IL (Feb. 29, 1996), at 22-23. See AR (Vol 638 Ref. 1). 

583 The Freedom of Information Act (FOIA) and Title VII cases cited by the comments do not purport to 

set forth a standard for assessing objective intent under public health statutes like the Federal Food, Drug, 

and Cosmetic Act, and the two statutes serve different purposes than the Act They are, therefore, not 

controlling here. The FDA regulation cited by the comments is similarly inapplicable to the question of 

what evidence is relevant to establishing intended use. FDA is not contending that the statements of a 

single tobacco company employee can bind the company in such a way that the totality of the remaining 

evidence of intent can be overridden. Here, however, there is a consistent pattern of internal statements 

that, taken as a whole, are highly relevant to intent 

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II.C.3. 

manufacturers' extensive product research and development to identify the doses of 

nicotine needed to produce pharmacological effects and to optimize the delivery of 

nicotine to smokers, which is discussed below; and (2) the evidence of the manufacturers' 

control and manipulation of nicotine in marketed cigarettes, which is discussed in section 

IT.C.4., below. 

The product research and development efforts described in the administrative 

record indicate that for three decades the cigarette manufacturers have strived to develop 

ways to maintain pharmacologically active doses of nicotine despite consumer demands 

for "healthier," lower-yield products. A primary focus of the cigarette manufacturers' 

efforts has been to deliver sufficient nicotine to provide the desired pharmacological 

effects of nicotine while at the same responding to consumer health concerns by reducing 

tar deliveries. Industry documents disclose research to determine the dose of nicotine that 

must be delivered to ensure "pharmacological satisfaction,"584 

as well as estimates by 

company scientists of the range of acceptable nicotine doses to produce pharmacological 

effects. These documents show that the manufacturers are aware that consumers will not 

accept cigarettes that do not deliver a pharmacologically active dose of nicotine. 

The manufacturers' product research and development efforts have involved a 

wide variety of approaches to ensure delivery of an adequate dose of nicotine, including 

changes in tobacco blends; chemical manipulation to liberate "free" nicotine; ftlter and 

ventilation designs that selectively remove more tar than nicotine; the development of 

high-technology nicotine delivery devices that provide smokers nicotine but virtually no 

584 BATCO Group R&D Research Programme, 1984: Proposed revisions for 1985-87, Research 

Conference, Southampton, England (Sep. 1984), at 2. See AR (Vol 26 Ref. 369-1). 

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II.C.3. 

tar; genetic engineering of tobacco plants to enhance nicotine content; the search for 

nicotine "analogues" that retain nicotine's reinforcing abilities; and research into 

compounds that act synergistically to strengthen nicotine's pharmacological effects. As 

discussed in section II.C.4., below, many (but not all) of these methods are used in 

cigarettes currently marketed to the public.585 

a. Philip Morris' Product Research and Development Efforts 

Evidence on the research and development efforts of Philip Morris demonstrates 

that the company believes that cigarettes must deliver sufficient nicotine to produce 

pharmacological effects in smokers and that the company conducted extensive research to 

optimize nicotine delivery from its cigarettes. 

In a 1972 document, Philip Morris senior scientist William Dunn discussed the 

basis for the company's concerns about lowering nicotine levels below a certain minimum. 

Dunn related consumers' lack of interest in cigarettes providing less than 1 mg of nicotine 

to the fact that 1 mg of nicotine "readily" produces the desired "physiological response": 

Despite many low nicotine brand entries into the marketplace, none of 

them have captured a substantial segment of the market In fact, critics of 

the industry would do well to reflect upon the indifference of the consumer 

to the industry's efforts to sell low-delivery brands. 94% of the cigarettes 

sold in the U.S. deliver more than 1 mg of nicotine. 98.5% deliver more 

than 0.9 mg.

586 The physiological response to nicotine can readil~ be 

elicited by cigarettes delivering in the range of 1 mg ofnicotine.5 7 

585 The evidence discussed in section ILC.3. is also relevant to, and provides further support for, the 

Agency's imding that the cigarette manufacturers "have in mind" that their products will be used for 

pharmacological purposes. 

586 Dunn WL, Motives and Incentives in Cigarette Snwking (1972) (summary of erR-sponsored 

conference in St Martin), at 4. See AR (Vol. 12 Ref. 133). 

587 /d. (emphasis added). 

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44918 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.3. 

A 1978 Philip Morris document shows a similar focus on identifying the minimum amount 

of nicotine necessary to produce pharmacological effects, referred to as the threshold level 

of nicotine in the body that satisfies consumers' "nicotine need."588 The document 

discussed plans to study cigarettes in which the tar level was kept constant, but the 

nicotine level was varied. The purpose of the study was to determine how smokers react 

to levels of nicotine so close to the minimum that ''the total nicotine in the [smoker's] 

system remains at or near the nicotine need threshold."589 

This focus on producing cigarettes that provide pharmacologically active doses of 

nicotine is a prominent feature of Philip Morris' development of low-tar cigarettes. 

William Farone, the former director of applied research at Philip Morris, described the 

goals of Philip Morris' product research and development efforts in a statement submitted 

to the Agency. According to Farone, "a key objective of the cigarette industry over the 

last 20-30 years' was decreasing tar while maintaining the delivery of nicotine, and that 

tobacco company researchers therefore considered it a ''top priority" to "[m]inimiz[e] the 

exposure to the potential negative health effects of the undesirable chemical components 

in tar while maintaining an acceptable and pharmacologically active nicotine level."590 

This involved extensive product research and development Farone stated: 

Extensive, in some instances ground breaking, research by the 

tobacco industry was necessary to construct a cigarette that 

ensured an adequate delivery of nicotine as the cigarette market 

evolved from the traditional full flavored, unfiltered product of the 

588 Dunn WL, Plans and Objectives-1979 (Dec. 6, 1978), in 141 Cong. Rec. H7670 (daily ed. Jul 25, 

1995). See AR (Vo114 Ref. 175a). 

589 /d. 

59° Farone W A, The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 4 (emphasis added). See AR (Vol 638 Ref. 2). 

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1950's to the filtered, low tar cigarette demanded by many smokers 

for the last 30-40 years. The objective of industry scientists and 

product developers, simply stated, was to provide the consumer 

with the same pharmacological satisfaction derived from nicotine 

in the natural blends and flavor of the full strength cigarettes of the 

1950's as the marketplace shifted to the naturally less flavorful and 

satisfying low tar and nicotine cigarette demanded by the more 

health conscious consumer.591 

II.C.3. 

The declaration of Ian Uydess, an associate senior scientist at Philip Morris from 

1977 to 1989, confirms the company's extensive interest in nicotine delivery. According 

to Uydess, "Philip Morris wanted to know everything there was to know about 

nicotine.''592 Sophisticated equipment, such as liquid and gas chromatographs, mass 

spectrometers, infra-red spectrometers, and nuclear magnetic resonance instruments, was 

acquired by Philip Morris to research questions such as: 

( 1) How nicotine levels varied in the tobacco plant with regard to 

cultivar, stalk position, seasonal variations and 'ripeness,' (2) What 

happened to nicotine after 'curing' and during processing, (3) What 

chemical 'forms' was it in, and (4) How much of it wound up in the 

smoke when burned under different conditions (such as ... in the 

presence ... of varying amounts of other tobacco constituents, 

etc.).s93 

The evidence in the administrative record shows that to achieve the goal of 

maintaining an acceptable and pharmacologically active nicotine level, Philip Morris 

developed ways to manipulate the ratio of nicotine to tar delivered by the cigarette. This 

591 /d. at 7 (emphasis added). These statements and those by another former Philip Morris employee 

discussed below corroborate the other evidence before the Agency indicating that the tobacco industry 

conducted extensive research on nicotine levels. 

592 Declaration ofUydess IL (Feb. 29, 1996), at 14 (emphasis added). See AR (Vol638 Ref. 1). 

593 Id. at 14. 

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II.C.3. 

research was conducted in the 1970's and had as its goal "to determine what combinations 

of tar and nicotine make for optimal acceptability in a low delivery cigarette."594 

The nicotine/tar ratio in cigarettes compares the amount of nicotine delivered by a 

cigarette with the amount of tar delivered by the cigarette. In public statements, officials 

of the tobacco industry have maintained that, as tar levels have been reduced through 

techniques such as filtration and ventilation, nicotine levels have been automatically 

reduced by a corresponding amount. For instance, one industry executive testified before 

Congress in 1994, "[ w ]e do not set levels of nicotine for particular brands of cigarettes. 

Nicotine follows the tar levels .... The correlation ... is essentially perfect correlation 

between tar and nicotine and shows that there is no manipulation of nicotine."595 Thus, 

according to the cigarette manufacturers, a proportional reduction of tar and nicotine 

demonstrates that the industry has not manipulated nicotine deliveries. 

The goal of Philip Morris' research, however, was to determine whether cigarette 

acceptability could be improved by changing this "essentially perfect correlation" between 

tar and nicotine, i.e., by allowing tar to fall but maintaining a disproportionately high level 

594 Dunn WL, et al. (Philip Morris Inc.), Plans for 1972 (Sep. 8, 1971), in 141 Cong. Rec. H8128 (daily 

ed. Aug. 1, 1995). See AR (Vol 711 Ref. 6). 

There is evidence that Philip Morris' product research and development on maintaining adequate nicotine 

deliveries may have begun before the 1970's. A comment submitted to the Agency the handwritten notes 

of a Philip Morris research executive, Ronald A Tamol. According to 1965 note from Tamol, an 

objective of his research at that time was to "determine minimum nicotine . .. to keep Mrmal smoker 

'hooked .... Tamol RA (Philip Morris), Handwritten Notes (Feb. 1, 1965) (emphasis added). See AR 

(Vol 700 Ref. 593). The Agency is not relying on these notes, however, because it has not independently 

authenticated the notes. 

595 Regulation of Tobacco Products (Part 1): Hearings Before the Subcommiuee on Health and the 

Environment ofthe Committee on Energy and Commerce, U.S. House of Representatives, 103d Cong., 

2d Sess. 143, 378 (Mar. 25, 1994) (statement of Alexander Spears). See AR (Vol 707 Ref. 1). 

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II.C.3. 

of nicotine. To this end, Philip Morris researchers in 1970 began to alter cigarette designs 

to study: 

the effect of systematic variation of the nicotine/tar ratios upon 

S11Wking rate and acceptability measures. Using the Marlboro as a 

base cigarette, we will reduce the tar delivery incrementally by 

filtration and increase the nicotine delivery incrementally by 

adding a nicotine salt. All cigarettes will be smoked for several 

days by each of a panel of 150 selected volunteers.596 

The search for the optimal nicotine/tar ratio was a significant research priority at 

Philip Morris. In 1973, a 5-year research and development plan stated: "This program 

comprises a number of studies expected to provide insight leading to new cigaret designs. 

These include studies of optimum nicotine/tar ratios, [and] nicotine/menthol 

relationships. "597 

That same year, the director of research at Philip Morris, Thomas Osdene, 

distributed a five-year plan stating that "R&D management will concentrate a large part of 

the resources at its disposal" on two "major long-range" programs, one of which was 

directed at achieving: 

a dramatic reduction in cigaret tar level while maintaining the 

subjective responses equal to our present major brands . ... The 

task requires ... discovering which constituents contribute 

positively to the S11Wker's response ... and ... developing means 

of increasing the relative concentration of desirable 

constituents. 598 

596 Eichorn PA, Dunn WL (Philip Morris Inc.), Quarterly Report of Projects 1600 and 2302 (Dec. 31, 

1970), in 141 Cong. Rec. H8127-8128 (daily ed. Aug. 1, 1995) (emphasis added). See AR (Vol 711 

Ref. 6). 

597 Philip Morris USA, Research and Developme111 Five Year Plan, 1974-1978 (May 1973), in 141 Cong. 

Rec. H8130-8131 (daily ed. Aug. 1, 1995) (emphasis added). See AR (Vol. 711 Ref. 6). 

598 Osdene TS (Philip Morris Inc.), Five-Year Plan (Oct 29, 1973) attaching Dunn WL, Lowitz DA, 

Will F, R&D Strategy Outline, in 141 Cong. Rec. H8131-8132 (daily ed. Aug. 1, 1995) (emphasis added). 

See AR (Vol. 711 Ref. 6). 

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II.C.3. 

According to the Philip Morris researchers, the natural nicotine/tar ratio in tobacco 

is about 0.07.599 By 1974, the researchers found that by boosting this natural ratio to 

about 0.12 (i.e., by raising the level of nicotine in relation to the level of tar) they could 

make a low-delivery cigarette that was "comparable to the Marlboro in terms of both 

subjective acceptability and strength."600 A follow-up study in 1975 also found "evidence 

that the optimum nicotine to tar (Nff) ratio for a [low-delivery] tar cigarette is somewhat 

higher than that occurring in smoke from the natural state oftobacco."601 Thus, Philip 

Morris' research showed that for low-tar cigarettes, it was "optimal" to supply a higher 

proportion of nicotine than would occur naturally. The distribution lists accompanying 

both the 1974 study and the 1975 follow-up show these studies were distributed to senior 

officials at Philip Morris, including Helmut Wakeham, the vice president for research and 

development. 

As Philip Morris enhanced its ability to reduce tar levels, it continued to research 

the optimum nicotine levels to accompany these ever-lower tar levels. It also conducted 

research on nicotine deliveries in its competitors' low-tar brands. The Philip Morris 

researchers concluded that the nicotine-to-tar ratios in their competitors' products "go up 

as tar goes down." 602 They further stated that ''the mechanics of cigarette engineering 

599 Dunn WL, Johnston M, Ryan F, et al. (Philip Morris Inc.), Plans for 1972 (Sep. 8, 1971 ), in 141 

Cong. Rec. H8128 (daily ed. Aug. 1, 1995). See AR (Vol 711 Ref. 6). 

600 Philip Morris Research Center, Behavioral Research Annual Report (Part II), distributed by Osdene 

TS (Nov. 1, 1974), in 141 Cong. Rec. H7659 (daily ed. Jul. 25, 1995). See AR (Vol 14 Ref. 175a). 

601 Jones B, Houck W, Martin P (Philip Morris Inc.), Low Delivery Cigarettes and Increased Nicotine/Far 

Ratios, A Replication (Oct 1975), in 141 Cong. Rec. H8132 (daily ed. Aug. 1, 1995) (emphasis added). 

See AR(Vol 711 Ref. 6). 

602 Dunn WL (Philip Morris Inc.), Plans and Objectives-1979 (Dec. 6, 1978), in 141 Cong. Rec. H7670 

(daily ed. Jul. 25, 1995). See AR (Vol 14 Ref. 175a). 

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II.C.3. 

and the deliberate decisions of our competitors are such as to suggest that high 

nicotine/tar ratios be used at ultra low tar levels."603 

This extensive research on deliberately altering nicotine/tar ratios shows that 

Philip Morris did not, in fact, want to allow nicotine to "follow the tar level" but instead 

wanted to supply an optimum nicotine level that required independent manipulation of the 

nicotine delivery of cigarettes. In addition to the research on optimal nicotine/tar ratios, 

Philip Morris scientists have conducted other product development research relating to the 

delivery of nicotine. In the 1980's, Philip Morris conducted extensive research to fmd 

"nicotine analogues" that could replace nicotine in cigarettes. As described in section 

II.C.2.a.ii., above, this research was designed to find analogues that would specifically 

retain nicotine's pharmacological effects on the brain, revealing both Philip Morris' 

recognition of the pharmacological effects of nicotine and its intent to maintain these 

pharmacological effects even if compelled to cease the use of nicotine. 

Philip Morris also conducted research to determine whether a second component 

of tobacco smoke, acetaldehyde, acted synergistically with nicotine to produce reinforcing 

effects on the brain. The culmination of this research was Philip Morris' attempt to 

establish the "maximally reinforcing" ratio of acetaldehyde to nicotine in cigarette smoke. 

This research demonstrates again Philip Morris' objective of identifying pharmacologically 

active doses of nicotine and of enhancing those effects where possible. A 1982 Philip 

Morris report on research plans and objectives stated: 

Since both acetaldehyde and nicotine are reinforcing agents and 

each are contained in smoke it becomes important to determine 

ratio[s] of acetaldehyde to nicotine which produce maximal 

603 I d. at H7670 (emphasis added). 

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44924 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

reinforcing effects .... This will allow us to determine the 

optimum ratio of acetaldehyde to nicotine that maintains the most 

behavior. 604 

II.C.3. 

Philip Morris' patents further reflect and corroborate its interest in developing 

methods of enhancing nicotine deliveries. For example, among other patents related to 

nicotine, Philip Morris holds patents to permit the "release in controlled amounts and 

when desired of nicotine"605 and for "releasing nicotine into tobacco smoke."606 The 

purpose of the patented method is to "[ m]aintain[] the nicotine content at a sufficiently 

high level to provide the desired physiological activity, taste and odor which this 

material imparts.'.w7 

Collectively, the documents in the administrative record show that ensuring an 

adequate delivery of nicotine has been a dominant consideration in Philip Morris product 

research and development for nearly 30 years. As Project Table indicates, Philip Morris' 

research on the optimum way to deliver nicotine to smokers continues to this day. 

See section II.C.2.a.iii., above. 

604 DeNoble VJ (Philip Morris Inc.), Project Number 1610 (Behavioral Pharmacology) Objectives and 

Plans-1982-1983 (Jul. 20, 1982), at2 (emphasis added). See AR(Vo154 Ref. 1921). 

605 U.S. Patent No. 3,280,823, Bavley A. Air B, Robb ll EW, assigned to Philip Morris Inc., AdditiveReleasing Filter for Releasing Additives into Tobacco Smoke (Oct 25, 1966), at C2:39-40. See AR (Vol. 

26 Ref. 352). 

606 U.S. Patent No. 3,584,630, Inskeep GE, assigned to Philip Morris Inc., Tobacco Product Having Lew 

Nicotine Content Associated with a Release Agent Having Nicotine Weakly Absorbed Thereon (Jun. 15, 

1971), at C2:5-15. See AR (Vo127 Ref. 387). 

607 Jd. at C1:39-41 (emphasis added). 

U.S. Patent No. 3,280,823, Bavley A. Air B, Robb II EW, assigned to Philip Morris Inc., AdditiveReleasing Filter for Releasing Additives into Tobacco Smoke (Oct 25, 1966), at C1:43-45. See AR (Vol. 

26 Ref. 352). 

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II.C.3. 

b. RJR's Product Research and Development Efforts 

RJR has also conducted product research and development to ensure that its 

cigarettes deliver levels of nicotine to smokers that provide desired pharmacological 

effects. A presentation from RJR's researchers to its marketing department in 

approximately 1977, for example, reveals that RJR understood the importance of 

maintaining adequate nicotine deliveries as tar deliveries declined and had identified a 

range of nicotine delivery levels capable of producing pharmacological effects. According 

to this presentation, nicotine has two roles in cigarettes. First, it contributes to the "mouth 

taste" or "mouth satisfaction" derived from a cigarette.608 Second, and even more 

important, it "acts upon the central nervous system and produces in the average smoker a 

sensation one could describe as either stimulating or relaxing."609 Moreover, according to 

the presentation, "a confirmed smoker attempts to get a certain desired level of nicotine. 

About one half hour after smoking, after all the nicotine has been biologically or 

pharmacologically inactivated, the smoker experiences a need for nicotine and lights up 

another cigarette."61° For these reasons, the researchers reported that "a zero nicotine 

cigarette ... really has no potential to provide smoking satisfaction. It produces no taste 

in the mouth, but even more seriously it fails to provide the ultimate satisfaction in the 

lungs.'7611 

608 Senkus M (RJ. Reynolds Tobacco Co.), Some Effects of Smoking, (197611977), at 7-9. See 

AR (Vol. 700 Ref. 593). 

609 I d. at 3. 

610 I d. at 5. 

611 Id. at 9 (emphasis added). 

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II.C.3. 

The researchers observed that RJR's competitors "are fully aware of the 

advisability of maintaining a low tar value and also maintaining the nicotine as high as 

possible."612 They cited True, which is produced by Lorillard Tobacco Co., as an example 

of a cigarette in which tar levels had been reduced dramatically while nicotine levels had 

been left essentially unchanged, stating: 

[T]he old True had 11 mg tar [and] .6 mg nicotine-- the new True is 5 mg 

tar [and] .5 mg nicotine. So although the tar was reduced 6 mg from 11 

mg to 5 mg, nicotine was dropped only .1 mg ... . 

613 

The researchers then recommended that RJR develop cigarettes that reduced tar 

but maintained nicotine at levels sufficient to provide "(1) mouth satisfaction-<Iuality of 

nicotine" and "(2) ultimate physiological satisfaction-<Iuantity of nicotine."614 

Specifically, RJR recommended that a new brand deliver 5 mg tar and 0.5 to 0.8 mg 

nicotine, stating that "on inhalation into the lungs, 0.5 mg to 0.8 mg of nicotine would 

provide sufficient nicotine to the blood to produce the stimulation and relaxation effects 

desired by the smoker."615 As discussed in section II.C.4.a.ii., below, RJR appears to have 

implemented these recommendations. 

Similar recommendations were made by Claude Teague, Jr., RJR' s assistant 

director for research. As noted in section II.C.2.b.i., above, a 1972 memorandum written 

by RJR's assistant director for research, Charles Teague, referred to efforts at RJR to 

612 Id. at 10 (emphasis added). 

613 ld. (emphasis added). 

614 Id. at 11. 

615 /d. at 11-12 (emphasis added). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44927

II.C.3. 

"reduc[e] the amount of 'tar' in cigarette smoke per unit ofnicotine."616 In its 

comments, RJR confirms that it has conducted research on cigarettes with enhanced 

nicotine-to-tar ratios. 617 

In addition to developing low-tar cigarettes that maintain adequate nicotine 

deliveries, RJR has been particularly active in developing novel tobacco products that 

deliver nicotine but few other components of tobacco smoke. As noted in section 

II.C.2.b.i., above, Teague first recommended such a "futuristic" product in 1972, urging 

that "[t]here should be some simpler, 'cleaner', more efficient and direct way to provide 

the desired nicatine dosage than the present system involving combustion of tobacco. "

618 

RJR actually developed and marketed such an alternative tobacco product, called 

Premier, in the late 1980's. As described in section II.C.2.b.iii., above, RJR conducted 

comparative studies of the blood levels of nicotine produced by Premier and by 

conventional cigarettes to ensure that Premier delivered normal doses of nicotine to the 

user. However, because the tobacco in the product was heated rather than burned, it 

delivered the vapor recommended by Teague, with virtually no tar and other non-nicotine 

components of normal tobacco smoke. 

Currently, RJR is test-marketing a similar product, "Eclipse." As described in 

section II.C.2.b.iii., above, Eclipse, like Premier, is intended to rely primarily on heating 

616 Teague CE (RJ. Reynolds Tobacco Co.), Research Planning Menwrandum on the Nature of the 

Tobacco Business and the Crucial Role of Nicotine Therein (Apr. 14, 1972), at 6 (emphasis added). 

See AR (Vol531 Ref. 125). 

617 RJ. Reynolds Tobacco Co., Comment (Jan. 2, 1996), at 3. See AR (Vol 519 Ref. 103). 

618 Teague CE (RJ. Reynolds Tobacco Co.), Research Planning Memorandum on The Nature of the 

Tobacco Business and the Crucial Role of Nicotine Therein {Apr. 14, 1972), at 7 (emphasis added). 

See AR (Vol531-Ref. 125). 

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II.C.3. 

rather than burning tobacco and to deliver levels of nicotine similar to a conventional 

ultra-low-tar cigarette, but much reduced levels of other cigarette smoke constituents. 

RJR's extensive efforts to develop and market alternative cigarettes that deliver 

nicotine and little else show that it regards nicotine as the essential ingredient of tobacco. 

The efforts also show that RJR regards cigarettes as, in effect, devices for the delivery of 

nicotine. 

Like Philip Morris, RJR also holds various patents on ways to manipulate nicotine 

deliveries, including patents intended to "provide a cigarette which delivers a larger 

amount of nicotine in the first few puffs than in the last few puffs',()19 and intended to mask 

the harsh flavor of cigarettes with increased levels of nicotine.620 Regardless of whether 

the patents have been actually used in commercial cigarettes, they are further evidence of 

RJR' s interest in developing ways to control and manipulate nicotine deliveries. 

c. Brown & Williamson's Product Research and Development Efforts 

Like Philip Morris and RJR, Brown & Williamson and its parent BATCO have 

conducted research to identify the minimum and optimum doses of nicotine necessary to 

produce desired pharmacological effects and they have invested considerable resources to 

develop cigarettes that optimize the delivery of nicotine to smokers. In the case of Brown 

& Williamson and BATCO, these efforts have spanned over three decades and show a 

consistent focus on methods to maintain nicotine deliveries at levels sufficient to provide 

619 U.S. Patent No. 4,595,024, Greene TB, Townsend DE, Perfetti TA, assigned to RJ. Reynolds Tobacco 

Company, Segmented Cigarette, (Jun. 17, 1986), at C2:23-26. See AR (Vol 26 Ref. 370). 

620 U.S. Patent No. 4,830,028, Lawson JW, Bullings BR, Perfetti T A, assigned to RJ. Reynolds Tobacco 

Company, Salts Provided from Nicotine and Organic Acid as Cigarette Additives (May 16, 1989), at Cl. 

See AR (Vol 34 Ref. 593). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44929

II.C.3. 

pharmacological satisfaction while reducing tar deliveries. These product research and 

development efforts cover a wide variety of strategies to enhance nicotine deliveries, 

including the use of nicotine-rich tobacco blends, genetic manipulation of tobacco plants, 

chemical manipulation of tobacco blends, and novel ftlter designs. 

i. Product Research and Development in the 1960's. BATCO's product 

research and development efforts to optimize nicotine delivery in the 1960's focused on 

three areas. According to an internal Brown & Williamson memorandum written in 1965, 

one goal of BATCO research was to ''find ways of obtaining maximum nicotine for 

minimum tar."621 The approaches then under consideration for maximizing nicotine and 

minimizing tar included "alteration of blends," "addition of nicotine containing powders to 

tobacco," and "nicotine fortification of cigarette papers."622 Similarly, at a 1967 BATCO 

conference, the researchers urged that "[t]he development of low TPM, normal nicotine 

cigarettes should continue."623 

As part of its effort in the 1960's to maximize nicotine while minimizing tar, 

BA TCO investigated whether nicotine delivery could be controlled by increasing the 

proportion of "extractable nicotine" (also known as "free nicotine") in the smoke through 

increases in the alkalinity or pH of tobacco smoke. By changing the chemical 

characteristics of the smoke, this technique would increase the amount of nicotine 

621 Griffith RB (Brown & Williamson), Report to Executive Committee (Jul. 1, 1965), at 2 (emphasis 

added). See AR (Vol 27 Ref. 377). 

622 /d. 

623 Minutes ofBATCO Group R&D Conference at Montreal, Canada (Oct 25, 1967), at4 (emphasis 

added). See AR (Vol 27 Ref. 378-1). A "low TPM, cigarette refers to a cigarette low in "total particulate 

matter'' or "tar ... 

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44930 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.3. 

absorbed by the smoker without raising the level of nicotine in the cigarette. A 1966 

BATCO study confirmed that "the reaction of a smoker to the strength of the smoke from 

a cigarette could be correlated to the amount of 'extractable' nicotine in the smoke, 

rather than to the total nicotine content," further explaining that "it would appear that the 

increased smoker response is associated with nicotine reaching the brain more 

quickly.'.624 A 1967 BATCO study found that the addition of PEl (polyethyleneimine) to 

ftlters caused a significant increase in the delivery of "extractable nicotine" to the 

smoker.625 And a 1968 study reported a direct correlation between smoke pH and 

nicotine absorption in the mouth, stating that "[n]icotine retention appears to be 

dependent principally on smoke pH and nicotine content.''626 

BATCO's second objective was to develop an alternative tobacco product that 

delivered nicotine but not tar. In the 1960's, BATCO's Charles Ellis worked on Project 

ARIEL, an early Premier-like tobacco product that involved heating rather than burning 

nicotine-enriched tobacco. According to a 1967 patent, "the invention ... seeks primarily 

to furnish a smoking device which will yield nicotine in an acceptable form, both 

psychologically and physiologically, but without the necessity for taking into the system 

so much of the products of combustion as is usual when smoking a conventional 

624 BATCO, Further Work on 'Extractable' Nicotine (Sep. 30,1966), at BW-W2-11617 (emphasis added). 

See AR (Vol 62 Ref. 308). 

625 BATCO, Relation between 'Extractable Nicotine' Content of Smoke and Panel Response (Mar. 17, 

1967), at 2. See AR (Vol 176 Ref. 2045). 

626 BATCO, The Retention of Nicotine and Phenols in the Human Mouth (1968), at BW-W2-11691 

(emphasis added). See AR (Vol445 Ref. 7593). 

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II.C.3. 

cigarette."627 Although ARIEL was never commercialized, Brown & Williamson 

continues to develop and patent similar tobacco products to this day.628 Like RJR's 

development of Premier and Eclipse, Brown & Williamson and BA TCO' s development of 

these alternative tobacco products that deliver little more than nicotine shows that the 

companies regard cigarettes as, in effect, devices for the delivery of nicotine. 

Third, BA TCO launched efforts to fmd a nicotine analogue. A 1968 conference of 

BATCO researchers recommended: 

In view of its pre-eminent importance, the pharmacology of 

nicotine should continue to be kept under review and attention paid 

to the possible discovery of other substances possessing the desired 

features of brain stimulation and stress-relief without direct effects 

on the circulatory system. 629 

BATCO's interest in nicotine analogues led to a 1972 BATCO report that 

"concluded that substances closely related to nicotine in structure (nicotine analogues) 

could be important" because "[s]hould nicotine become less attractive to smokers, the 

future of the tobacco industry would become less secure."630 Thus, as with Philip Morris, 

627 U.S. Patent No. 3,356,094, Ellis CD, Dean C, Hughes IW, assigned to Battelle Memorial Institute, 

Smoking Devices (Dec. 5, 1967), at C2:66-71 (emphasis added). See AR (Vol34 Ref. 571). 

628 Philip Morris Inc., Draft Report Regarding a Proposal for a "Safer" Cigarette, Code-named Table, at 5 

(stating that "[O]ther tobacco industry patent activity by ; .. Brown & Williamson illustrates extensive 

interest in the development of a superior nicotine delivery device with or without a tobacco base"). See 

AR (Vol. 531 Ref. 122). 

Slade J, Bero LA, Hanauer P, et al., Nicotine and Addiction, the Brown & Williamson documents, 

Journal of the American Medical Association 1995;274(3):225-233, at 228. See AR (Vol528 Ref. 97). 

629 Minutes of BATCO Research Conference at Hilton Head, SC (Sep. 24-30, 1968), at 3 (emphasis 

added). See AR(Vol31 Ref. 525-1). 

630 Kilburn KD, Underwood JG (BATCO), Preparation and Properties of Nicotine Analogues (Nov. 9, 

1972), at 1. See AR(Vol. 31 Ref. 524-1). 

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44932 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.3. 

Brown & Williamson's nicotine analogue research demonstrated the company's intention 

to preserve the effects of nicotine on the brain in new tobacco products. 

Collectively, the three areas of product development research related to nicotine 

delivery in the 1960's show Brown & Williamson's long-standing focus on delivering 

pharmacologically active doses of nicotine to smokers. 

ii. Product Research and Development to Maintain Pharmacologically 

Satisfying Doses of Nicotine while Lowering Tar. Documents in the administrative record 

indicate that BATCO's efforts in the 1970's coalesced around the objective of maintaining 

nicotine deliveries in lower-tar cigarettes. The minutes of a 1975 BATCO research 

conference, for instance, observed that "[o]nce again the need for normal nicotine low tar 

cigarettes which appeal to the consumer was identified.'w31 A year later, at a 1976 

BATCO conference, the researchers predicted a "clear opportunity" for low-tar, normalnicotine cigarettes "[p]rovided we can get smokers to dissociate tar from nicotine in their 

minds in terms of a possible health hazard."632 At another 1976 conference, the 

researchers stated: 

[I] n that the 'benefits' of smoking appear to be related to nicotine, we can 

infer that the 'benefits' of smoking might disappear if cigarettes with low 

levels of nicotine became the norm ... 633 

In conjunction with their efforts to develop cigarettes that were low in tar but 

maintained nicotine delivery, Brown & Williamson and BATCO conducted product 

631 Minutes ofBATCO Group R&D Conference at Merano, Italy (Apr. 2-8, 1975), at4 (emphasis added). 

See AR (Vol27 Ref. 379-1). 

632 Minutes of BATCO Group R&D Conference on Smoking Behaviour at Southampton, England 

(Oct 11-12, 1976), at 8. See AR (Vol27 Ref. 379-2). 

633 /d. at 4. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44933

II.C.3. 

development research in the 1970's and 1980's to determine the dose of nicotine required 

to produce satisfying pharmacological effects in smokers. Project Wheat was central to 

these efforts. The multiyear project had two parts. In Part 1, the attitudes of over 1,000 

smokers were surveyed to assess their "inner need" to smoke.634 In Part 2, the smokers 

were asked to assess experimentil cigarettes with different nicotine deliveries.635 

According to BATCO: 

The purpose of the survey was to classify smokers into a number of 

categories showing distinct patterns of motivation, and different 

levels of so-called Inner Need, as a first step towards testing the 

hypothesis that a srrwker's Inner Need level is related to his 

preferred nicotine delivery. 636 

Project Wheat was thus designed to determine the optimum dose of nicotine 

delivered by cigarettes for individual smokers as a function of the strength of their "inner 

need" to smoke. BATCO researchers defmed "inner need" as the smoker's use of 

cigarettes to relieve stress, aid concentration, control appetite, and relieve craving.637 

These are the characteristic pharmacological effects of nicotine. See section II.B., above. 

They also described ''the 'inner need' dimension" as correlating "with the extent of 

inhalation, with the craving for cigarettes when these are not available, and with the 

634 Wood DJ, Wilkes EB (BATCO), Project Wheat- Part I: Cluster Profiles of U.K. Male Smokers and 

their General Smoking Habits (Jul. 10, 1975), at 1. See AR (Vol20 Ref. 204-1). 

635 Wood DJ (BATCO), Project Wheat- Part 2: U.K. Male Smokers: Their Reactions to Cigarettes of 

Different Nicotine Delivery as Influenced by Inner Need (Jan. 30, 1976). See AR (Vol 20 Ref. 204-2). 

636 Wood DJ, Wilkes EB (BATCO), Project Wheat- Part I: Cluster Profiles of U.K. Male Smokers and 

their General Smoking Habits (Jul. 10, 1975), at 1 (emphasis added). See AR(Vol20 Ref. 204-1). 

637 Wood DJ (BATCO), Project Wheat (Jan. 10, 1974). See AR (Vol 177 Ref. 2056). 

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44934 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.3. 

difficulty which consumers anticipate in giving up smoking."638 Thus, a nicotine level that 

satisfies "inner need" is one that provides desired pharmacological effects. 

According to the BATCO researchers, the hypothesis that "inner need" is related 

to nicotine delivery should be "seen as part of a general approach to the problem of 

designing cigarettes of increased consumer acceptance."639 They further explained: "In 

considering which product features are important in terms of consumer acceptance, the 

nicotine delivery is one of the more obvious candidates . ... The importance of nicotine 

hardly needs to be stressed, as it is so widely recognised.',64{) 

Project Wheat found that "[a]s predicted by the hypothesis, High Need clusters 

tend to prefer relatively high nicotine cigarettes, their optimum nicotine delivery being 

higher than that of Low Need clusters."641 Project Wheat also found that there was a 

conflict between smokers' concern for health, which led them to favor low-tar brands of 

cigarettes, and their "inner need" to smoke, which led them to seek higher nicotine levels. 

According to the project report: 

Concern for the possible health risks of smoking influences 

consumers in the direction of trying low delivery brands .... 

However there is evidence of a conflict between concern for health 

and the desire for a satisfying cigarette, from which it follows that 

low tar brands would be much more widely accepted if their 

638 Regulation of Tobacco Products (Part 3): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Cong., 

2d Sess. 438 (Jun. 21 and 23, 1994) (emphasis added). See AR (Vol 709 Ref. 3). 

639 Wood DJ, Wilkes EB (BATCO), Project Wheat- Part 1: Cluster Profiles of U.K. Male Smokers and 

their General Smoking Habits (Jul. 10, 1975), at 1. See AR (Vol 20 Ref. 204-1). 

640 Jd. at 3 (emphasis added). 

641 Wood DJ (BATCO), Project Wheat- Part 2: U.K. Male Smokers: Their Reactions to Cigarettes of 

Different Nicotine Delivery as Influenced by Inner Need (Jan. 30, 1976), at 1 (emphasis added). See AR 

(Vol. 20 Ref. 204-2). 

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nicotine deliveries could be brought within the range required by 

groups of consumer[s]. 642 

Most important, the project developed a model of the cigarette market that 

II.C.3. 

showed a "substantial potential" for cigarettes that attract smokers concerned about both 

their health and satisfying their "inner need" for nicotine. According to the project report: 

A model of the market is now proposed in which two major 

determinants of the type of cigarette which best suits a smoker's 

requirements are Inner Need and concern for health. This model 

leads to the conclusion that there is a substantial potential for a 

range of cigarettes which at present is not available. These 

cigarettes range from some with low tar and medium nicotine 

deliveries to others with medium tar and high nicotine deliveries, 

and are visualised as attracting those smokers who combine above 

average Inner Need with above average concern for health.643 

A chart in the Project Wheat report showed the magnitude of this new potential 

market. According to the chart, over 40% of smokers want a cigarette with lower tar and 

higher nicotine than currently available.644 

Project Wheat is persuasive evidence of the extensive product research and 

development by Brown & Williamson and BATCO to manipulate nicotine levels to 

provide pharmacologically active doses of nicotine. Project Wheat's "model of the 

market" showed the companies that there existed a significant market for cigarettes with 

low-tar levels but relatively enhanced nicotine levels. 

Brown & Williamson and BA TCO conducted additional research designed to 

correlate nicotine dose and pharmacological effects. For example, a 1980 BATCO Group 

642 /d. at 48. 

643 /d. at 2 (emphasis added). 

644 /d. at 50-51. 

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II.C.3. 

R&D report describes BATCO' s successful effort to develop an improved method for 

measuring nicotine and its metabolites in th~ body. The method was developed to study 

the pharmacological effects of nicotine and their relationship to nicotine dose. 

The report states that in some cases: 

the pharmacological response of smokers to nicotine is believed to be 

responsible for an individual's smoking behaviour, providing the motivation 

for and the degree of satisfaction required by the smoker. 

[W]here the causal relationship between nicotine and individual 

biochemical physiological or psychological responses are to be 

investigated, accurate information regarding nicotine dose is essential.645 

A related study was designed to provide an_animal model that would allow BATCO to 

estimate human nicotine doses and to aid in understanding the relationship between the 

dose of nicotine delivered by cigarettes and smokers' choice of particular brands.646 

A session on "Nicotine Dose Estimation" at BATCO's 1984 Smoking BehaviourMarketing Conference was intended "to review the current status of plasma/urinary 

measures ... of nicotine dose and to identify the significance for the smoker and product 

design."647 That same year, BATCO described its proposed research agenda for 1985-

1987 as including studies ''to establish the minimum dose of smoke nicotine that can 

provide pharmacological satisfaction for the smoker.',648 

645 Read GA, Anderson IGM (BATCO Group R&D), Method for Nicotine and Cotinine in Blood and 

Urine (May 21, 1980), at 2-3. See AR (Vol 59 Ref. 235). 

646 Read GA, Anderson IGM. Chapman RE (BATCO Group R&D), Nicotine Studies: A Second Report. 

Estimation of Whole Body Nicotine Dose by Urinary Nicotine and Cotinine Measurement (Mar. 3, 1981), 

at 9-10. See AR (Vol 59 Ref. 234). 

647 Proceedings of BATCO Group R&D Smoking Behaviour-Marketing Conference, Session II, Montreal, 

Canada (Jul. 9-12, 1984) (slide), at BW-W2-02641. See AR (Vol 23 Ref. 305). 

648 BATCO Group R&D Research Programme, 1984: Proposed revisions for 1985-87, Research 

Conference, Southampton, England (Sep. 1984), at 2 (emphasis added). See AR (Vol 22 Ref. 280). 

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II.C.3. 

As described below, Brown & Williamson and BA TCO pursued three different 

strategies in the late 1970's and 1980's for reducing tar deliveries in cigarettes while 

maintaining adequate nicotine deliveries. 

iii. Blending and "Y -1." One approach to reducing tar levels while 

maintaining adequate nicotine levels is through blending. As noted above in section 

II.C.3.c.i., BATCO researchers first investigated this approach 30 years ago, when they 

recommended "alteration of blends" as one way to obtain "maximum nicotine for 

minimum tar."649 By 1976, they had concluded that "there would appear to be a 

forthcoming demand for high nicotine tobaccos" in view of the interest in increasing the 

nicotine/tar ratios in low tar cigarettes.650 

By the late 1970's, Brown & Williamson had begun a decade-long effort to 

develop a high-nicotine flue-cured tobacco plant that came to be named "Y-1." As 

described in the Jurisdictional Analysis, the Agency found that the company used 

conventional and advanced genetic breeding techniques to develop a commercially viable 

plant that had almost twice the nicotine content of domestically grown varieties of flue 

cured tobacco. See 60 FR 41700-41702. Whereas typical domestic varieties of tobacco 

contain between 2.5% to 3.5% nicotine, Brown & Williamson's patent for Y-1 indicated 

that the company had succeeded in raising the nicotine level to about 6% by weight.651 

Brown & Williamson achieved this objective by cross-breeding commercial varieties of 

649 Griffith RB (BATCO), Report to Executive Committee (Jul. 1, 1965), at 2. See AR (VoL 27 Ref. 377). 

650 Minutes of BA TCO Group R&D Conference on Smoking and Behaviour at Southampton, England 

(Oct ll-12, 1976) at BW-W2-023ll (emphasis added). See AR (VoL 27 Ref. 381). 

651 U.S. Patent application, Fisher PR, Hardison HA, Bravo JE, New Variety of Tobacco Plant, assigned to 

Brown & Williamson Tobacco Corp. (1991), at 1. -See AR (VoL 68 Ref. 14). 

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II.C.3. 

tobacco with Nicotiana rustica, a wild tobacco variety that is very high in nicotine but is 

not used in commercial cigarettes because of its harshness. 

Brown & Williamson had Y -1 made into a male sterile plant, a technique that 

ensures that when the plant is grown it will not produce seeds that can be appropriated by 

others.652 Brown & Williamson grew the plant in Brazil.653 The Agency further found, -

and the company does not dispute, that Y -1 was eventually used in five different brands of 

cigarettes in 1993, and that as of mid-1994 Brown & Williamson still had 3.5 million to 4 

million pounds of additional Y-1 in storage.654 

The purpose of Y -1 was to develop_ a high-nicotine tobacco that could be used as a 

"blending tool" so that products could be designed that were lower in tar but not lower in 

nicotine.655 Although Brown & Williamson asserts that it never used Y-1 in commercial 

cigarettes to raise nicotine/tar ratios, the company does not dispute that its goal was to 

deliberately alter the traditional relationship between tar and nicotine. Indeed, Brown & 

Williamson implicitly concedes that the company used Y -1 to develop "prototypes" with 

increased nicotine/tar ratios and tested them on consumer panels.656 The development of 

Y-1 thus provides direct evidence of Brown & Williamson's intention to enhance nicotine 

deliveries. 

652 Regulation of Tobacco Products (Part 3): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 103 Cong, 2d 

Sess. 18 (Jun. 21, 1994) (testimony of David Kessler). See AR (Vol 709 Ref. 3). 

653 /d. at 142 (testimony of Thomas Sandefur, chairman and CEO, Brown & Williamson). 

654 Transcript of FDA Meeting with Brown & Williamson (Jun. 17, 1994), at 124-125. See AR (Vol 28 

Ref. 414). 

655 /d. at 85-86. 

656 Brown & Williamson Tobacco Corp., Comment (Jan. 2, 1996), at 32. See AR (Vol 529 Ref. 104). 

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II.C.3. 

iv. Chemical Manipulation. Another approach to reducing tar while 

maintaining adequate nicotine for the smoker is to alter the chemistry of tobacco smoke in 

a manner that increases the transfer of nicotine to the smoker. As discnssed above, 

BATCO did work in this area in the 1960's, which suggested that increasing the 

percentage of "extractable nicotine" delivered to the smoker resulted in "nicotine reaching 

the brain more quickly."657 

BATCO's research and development efforts continued in the 1970's and 1980's. 

In a 1976 research conference, BATCO researchers discussed how the use of a filter 

additive PEl or "alkali treatment" could "maintain nonnal nicotine reaction for the smoker 

while actually reducing the amount of nicotine per cigarette": 

A second approach ... is to aim at a lower smoke production per 

cigarette (i.e. lower tar) while maintaining "nonnal" nicotine. Work 

along these lines is already going on. A further modification of this 

approach is to maintain normal nicotine reaction for the smoker 

while actually reducing the total amount of nicotine per cigarette. 

It is believed that this can be done, e.g. by the use of P .E.I. or by 

alkali treatment of tobacco stems. 658 

Similar observations were made at other research conferences. In 1978, for instance, 

BATCO researchers stated: "With conventional cigarettes, the transfer of nicotine to the 

smoker from the tobacco has very low efficiency. Potentially, therefore, opportunities 

exist for very big savings in tobacco if this low efficiency can be greatly increased. "659 

657 BATCO, Further Work on 'Extractable' Nicotine (1966), at BW-W2-11621. See AR (Vol. 62 Ref. 

308). 

658 Morini HA (BATCO), Cigarettes with Health Reassurance (1976), at 1 (emphasis added). See AR 

(Vol. 27 Ref. 380). 

659 Notes on BATCO Group R&D Conference at Sydney, Australia (Mar. 1978), at 4 (emphasis added). 

See AR (Vol 26 Ref. 367). 

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II.C.3. 

This would not be an "opportunity" if the company did not recognize that nicotine was the 

essential active ingredient intended to be delivered. 

In 1982, BATCO researchers urged that a design objective for new products 

should be ''to enhance or maximise sensory and phannacological sensations, i.e., 'to make 

the smoke work harder' so as to achieve maximum sensation at a given delivery level."660 

And in 1984, BATCO researchers discussed a study in which "experimental cigarettes ... 

will ... be used to improve the efficient use of smoke nicotine through pH 

modification. "

661 

v. "Elasticity" Technologies. A third approach to lowering tar while 

maintaining an adequate nicotine delivery is to increase the "elasticity'' of cigarettes. 

"Elasticity" refers to the ability of a cigarette, whatever its nicotine yield as measured by a 

smoking machine, to deliver enough smoke to pennit a smoker to obtain the nicotine the 

smoker needs. The elasticity of a cigarette can be increased, for instance, by placing 

ventilation holes in the filter. These holes allow fresh air to be pulled into the smoking 

machine during inhalation, thereby diluting the smoke and reducing the measured yields. 

However, the holes can be blocked by smokers' fingers or lips, allowing the smoker to 

obtain more nicotine than the machine measured delivery. See 60 FR 41716-41718. 

Brown & Williamson and BA TCO sought to develop elasticity technologies. During a 

1983 BATCO conference, BATCO researchers observed that "[e]lasticity can be designed 

660 Minutes of BATCO Research Conference at Montebello, Canada (Aug. 30-Sep. 3, 1982}, at 3 

(emphasis added). See AR (Vol 179 Ref. 2082). 

661 BATCO, Proposed Revisions for 1985-1987 (Sep. 1984), at 1-2 (emphasis added). See AR(Vol26 

Ref. 369-1 ). 

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II.C.3. 

into a cigarette using tobacco blend and pressure drop components.'.662 A year later, at a 

1984 conference,_ BATCO researchers elaborated: 

Compensation by modifying smoking regime ... is a topic which is 

being explored ... and this includes designing products which aid 

smoker compensation. 

The marketing policy concerning this type of product is not 

clear but it is believed it will depend largely on the degree of 

elasticity in the design and how overtly this elasticity is achieved. 

The consensus is that small improvements in elasticity which are 

less obvious, visually or otherwise is likely to be an acceptable 

route.663 

Taken together, Brown & Williamson and BATCO's product research and 

development efforts exhibit a sustained focus on nicotine over the course of three decades. 

The companies recognized through their research that significant marketing opportunities 

existed for cigarettes that reduced tar deliveries but maintained nicotine deliveries at levels 

high enough to satisfy smokers' "inner need" for nicotine. They then developed a broad 

range of techniques for enhancing nicotine deliveries. These extensive efforts are 

evidence of a "design" or "plan" to manipulate and control nicotine deliveries to provide a 

pharmacologically active dose of nicotine. 

d. Other Cigarette Manufacturers' Product Research 

and Development Efforts 

i. American Tobacco Company. The American Tobacco Company 

(American Tobacco) also conducted extensive research and development on ways to 

increase and optimize nicotine deliveries. In 1969, for instance, the company 

662 BATCO, Snwking Behavior Conference: Overview(l983), atBW-W2-03292. See AR(Vol. 27 Ref. 

392). 

663 Proceedings of BA TCO Group R&D Smoking Behaviour-Marketing Conference, Session III (Jul. 9-12, 

1984), at 55 (emphasis added). See AR (Vol27 Ref. 391). 

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II.C.3. 

manufactured Lucky Strike cigarettes enriched with a nicotine salt (nicotine malate) and 

sold them in the Seattle market.664 

In 1974, the company's manager of new products, R. M. Irby, wrote to the vice 

president of manufacture and leaf, J. B. McCarthy, to summarize "our current knowledge 

regarding increasing the nicotine content of reconstituted tobacco.'.665 Irby' s 

memorandum stated that nicotine in reconstituted tobacco could be increased either by 

adding "Compound W," a code name for nicotine, to the reconstituted tobacco or by 

replacing ''the lower nicotine-containing leaf components such as Turkish ... with high 

nicotine tobacco such as Malawi sun-cured scrap (5% nicotine).'.666 

Three years later, American Tobacco researchers wrote a memorandum describing 

"suggested" ways of increasing the nicotine/tar ratio in cigarettes. The methods included 

the "addition of ammonia salts ... to tobacco, which on smoking would free the ammonia 

and thereby cause an increase in nicotine transfer to the smoke.''667 

By 1980, American Tobacco was conducting experiments on this idea by adding a 

salt (potassium carbonate) to its Tareyton blend. According to the research memorandum 

describing the experiment, "[s]ince most nicotine in tobacco is a non-volatile salt, it was 

~Letter to Waxman HA, on behalf of the American Tobacco Company(Oct 14, 1994), at3. See AR 

(Vol. 26 Ref. 355). 

665 Irby RM Jr. (American Tobacco), Nicotine Content of Reconstituted Tobacco (Jun. 5, 1974), at 1. See 

AR (Vol. 26 Ref. 357-3). 

666 Id. at 1-2. 

667 Pederson PM (American Tobacco), A Study of the Nicotine to Tar Ratio (Apr. 18, 1977), at 4. See AR 

(Vol. 26 Ref. 365). 

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II.C.3. 

thought that a greater transfer would take place if the tobacco was made basic causing 

the nicotine to volatilize when the cigarette is smoked." 668 

Other efforts by American Tobacco to increase the amount of nicotine delivered by 

its cigarettes are described in the Jurisdictional Analysis. See 60 FR 41675-41677. These 

efforts show that like Philip Morris, RJR, and Brown & Williamson, American Tobacco 

has designed and planned ways to enhance nicotine deliveries to smokers. 

ii. Lori11ard Tobacco Company. Like the other cigarette manufacturers, the 

Lorillard Tobacco Company developed knowledge about numerous ways to manipulate 

and_ control nicotine deliveries. For instance, in a 1975 presentation, Alexander Spears, 

the vice chairman and chief operating officer of Lorillard, stated that "[t]hrough [a] 

combination of ... variables, ... it is possible to manipulate the yield of nicotine from 

about .1 mg to 4 mg per cigarette."669 The variables cited by Spears as controlling 

nicotine deliveries included ''the nicotine content of the tobacco"; "[the] porosity of the 

wrapper and/or ventilation at the fJ.lter''; ''the affinity of the fllter material for nicotine, 

particularly as a function of smoke pH''; and "plant genetics."670 

In a 1981 paper on tobacco leaf blending, Spears further described "the ways in 

which higher nicotine levels can be achieved."671 Spears explained that nicotine 

668 Bodenhamer NL (American Tobacco), Leaf Services Monthly Report for June (Jun. 30, 1980) 

(emphasis added). See AR (Vol. 27 Ref. 385) 

669 Spears A W (Lorillard Tobacco Co.), Factors Affecting Smoke Delivery of Nicotine and Carbon 

Monoxide, presented at the 1975 Symposium-Nicotine and Carbon Dioxide (Nov. 17-18, 1975), in 

Symposium Proceedings-!, at 13 (emphasis added). See AR (VoL 27 Ref. 395a). 

670 /d. 

671 Spears A W, Jones ST (Lorillard Tobacco Co.), Chemical and Physical Criterias for Tobacco Leaf of 

Modem Day Cigarettes, Recent Advances in Tobacco Science, Oct 6-9, 1981;7:19-39, at 23. See AR 

(Vol. 26 Ref. 373-1). 

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II.C.3. 

concentrations of tobaccos vary widely, from 3.65% nicotine in upper-stalk Burley 

tobacco and 3.26% in upper-stalk flue-cured tobacco to 0.95% in Oriental tobacco and 

0.85% in stem-sheet or reconstituted tobacco. According to Spears, "[h]igher nicotine 

levels can be achieved by decreasing Oriental and the stem and tobacco sheet and 

increasing the Burley and upper stalk positions of both the Flue-cured and the Burley 

tobacco."672 He further observed that "current research is directed toward increasing the 

nicotine levels while maintaining or marginally reducing the 'tar' deliveries."673 

The administrative record thus reveals that the cigarette manufacturers have 

consistently focused their product research and development efforts on developing 

methods to maintain or enhance nicotine deliveries. These activities are remarkable for 

their sustained duration and for the fact that each cigarette manufacturer independently 

acquired similar capabilities to manipulate and control nicotine deliveries. This again 

demonstrates the central role of nicotine delivery in the design of cigarettes. 

e. Filter and Paper Suppliers' Product Research and 

Development Efforts 

The filter and paper suppliers for cigarette manufacturers also developed products 

to enhance nicotine deliveries, including methods for "increasing nicotine delivery without 

changing tar delivery674 and for "alter[ing] cigarette nicotine delivery independently of tar 

672 /d. at 24 (emphasis added). 

673 Id. at 31 (emphasis added). 

674 Selke W A. Making the cigarette do just what you want it to do, Journal Tobacco International, 

1983: 12 (emphasis added). See AR (Vol 102 Ref. 8%). 

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II.C.3. 

delivery."675 These efforts are not direct evidence of the manufacturers' intent, because 

the product development was conducted by suppliers, rather than the manufacturers 

themselves. Nevertheless, the suppliers' efforts corroborate the Agency's fmding that the 

cigarette manufacturers seek the capability to enhance nicotine deliveries in low-tar 

cigarettes. They show that the suppliers understood manufacturers to be interested in 

acquiring products that would enable the manufacturers to selectively remove more tar 

than nicotine from cigarette smoke. 

To develop products with enhanced nicotine deliveries, the filter and paper 

suppliers altered the filtration and ventilation systems in cigarettes. Filters are used to trap 

smoke particles before they enter the mouths of smokers. Ventilation technologies draw 

air into the cigarette through holes in the filter or through porous cigarette paper, diluting 

the smoke. The suppliers found that these systems could be manipulated to selectively 

remove more tar than nicotine, thereby increasing the nicotine/tar ratio in the smoke. 

Documents in the administrative record describe several of the methods developed 

for increasing nicotine delivery relative to tar. According to one report, "[s]imply 

changing the location of the vents in a ... filter has a measurable effect on the cigarette 

performance," with ''the nicotine content [being] ... greatest when the vents were 

positioned where the tobacco and filter were joined.'o676 The same effect could be 

achieved by perforating the cigarette paper. One report found that "[i]ncreasingly porous 

67s Lee BM (Eastman Kodak Company), Modification of Nicotine to Tar Ratio in Cigarette Smoke, 42nd 

Tobacco Chemists' Research Conference, Lexington, Kentucky (Oct 2-5, 1988), at33 (emphasis added). 

See AR (Vol 639 Ref. 2). 

676 Kiefer JE, Ventilated Filters and Their Effect on Smoke Composition, Recent Advances in Tobacco 

Science (1979), at 79. See AR (Vol 28 Ref. 465). -

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II.C.3. 

perforated papers ... selectively increase nicotine .. . .'..677 Research by a tobacco 

company confirmed the influence of paper design on tar and nicotine deliveries, fmding 

that "tar/nicotine ratios are determined primarily by paper permeability; high permeability 

produces the lowest tar/nicotine ratios.'..678 A low tar/nicotine ratio is mathematically 

equivalent to a high nicotine/tar ratio. 

Other reports have shown that cigarettes designed with increased ventilation and 

less filtration will "increas[e] nicotine delivery without changing tar delivery;'..679 and that 

the use of additives to increase the pH of the fllter will alter cigarette nicotine delivery 

independently of tar delivery, increasing the nicotine/tar ratio by up to 15%.680 

f. These Product Research and Development Efforts Were 

Undertaken for Commercial Reasons 

The cigarette manufacturers do not generally dispute that they engaged in the 

product research and development activities described above. Instead, they argue that 

their research on increasing or maintaining nicotine delivery while lowering tar was largely 

in response to "government" initiatives. In support of this claim, these comments refer to 

6

n Owens Jr. WF (Ecusta Paper and Film Group), Effect of Cigarette Paper on Smoke Yield and 

Composition, 32d Tobacco Chemists' Research Conference, Montreal, Canada (1978) (emphasis added). 

See AR (Vol 639 Ref. 2). 

678 McMurtrie A, Litringer EF, and Wu DT, Cigarette Paper Effects on Tar/Nicotine and COffar Ratios, 

35th Tobacco Chemists' Research Conference, Winston-Salem, North Carolina (1981). See AR (Vol639 

Ref. 2). 

679 Selke W A, Making the cigarette do just what you want it to do, Journal Tobacco International 

1983: 12. See AR (Vol 102 Ref. 896). 

Browne CL (Hoecbst Celanese), The Design of Cigarettes, at 72. See AR (Vol 27 Ref. 399). 

680 Lee BM (Eastman Kodak Company), Modification of Nicotine to Tar Ratio in Cigarette Smoke, 42nd 

Tobacco Chemists' Research Conference, Lexington, Kentucky (Oct 2-5, 1988), at 33. See AR (Vol 639 

Ret: 2). 

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II.C.3. 

a few sentences in a 1981 report of the U.S. Surgeon General, the recommendation of a 

scientist at NIH in 1976, and a few scattered articles from nongovernment researchers 

beginning in 1973. The comments offer no evidence from company documents to show 

that any part of the industry's extensive research on increasing nicotine delivery from lowtar cigarettes was actually motivated by the cited "initiatives." 

The evidence in the administrative record also fails to support the industry's 

claims. The large number of internal tobacco company documents available to FDA 

indicates that the companies' product research and development was conducted for 

commercial reasons. Philip Morris, for instance, stated that "the rationale" for its research 

and development efforts "rests on the premise that such knowledge will strengthen Philip 

Morris R&D capability in developing new and improved smoking products."681 

The driving force behind the efforts to enhance nicotine delivery in low-tar 

products was the industry's knowledge that people use tobacco for nicotine and that 

below a certain nicotine level, the motivation for tobacco use, and the market for tobacco 

products will disappear. RJR researchers knew in the 1970's that "a zero nicotine 

cigarette ... fails to provide the ultimate satisfaction in the lungs;" hence they 

recommended "maintaining the nicotine as high as possible" in low-tar cigarettes.682 

Similarly, a 1976 BATCO "Smoking Behaviour" conference report shows that BATCO 

was aware of the need to maintain adequate nicotine deliveries, stating that ''the 'benefits' 

of smoking appear to be related to nicotine, [and] we can infer that the 'benefits' of 

681 Dunn WL, Plans and Objectives-1979 (Dec. 6, 1978), in 141 Cong. Rec. H7669 (daily ed. Jul 25, 

1995). SeeAR(Vol. 14Ref.l75a). 

682 Senkus M (RJ. Reynolds Tobacco Co.), Some Effects of Smoking (1976/1977), at 9, 10 (emphasis 

added). See AR (Vol 700 Ref. 593). 

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44948 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.3. 

smoking might disappear if cigarettes with low levels of nicotine became the nonn."683 

Likewise, a 1972 Philip Morris presentation indicates that Philip Morris knew that 

cigarettes with inadequate levels of nicotine would not be purchased by smokers.684 

Moreover, the industry's research on selectively increasing or maintaining nicotine 

while lowering tar cannot be attributed to government initiatives because it began before 

the earliest government "initiative" cited by the comments. For example, as noted in 

section II.C.3.c.i. above, Brown & Williamson was developing "ways of obtaining 

maximum nicotine for minimum tar'' at least as early as 1965685 -well before the 1976 

NIH and the 1981 Surgeon's General documents cited by the industry. Similarly, Philip 

Morris was working on increasing nicotine levels in relation to tar as early as 1970, when 

it began experimentally altering the nicotine/tar ratio of Marlboro cigarettes by "reduc[ing] 

the tar delivery incrementally ... and increas[ing] the nicotine delivery incrementally by 

adding a nicotine salt."686 Thus, the industry was plainly developing low-tar, enhancednicotine products before any of the cited "government initiatives." 

Finally, FDA notes that to the extent that the industry accepted the 

recommendations of outside researchers who suggested the development of low-tar, highnicotine products, those recommendations were based on the researchers' conclusion that 

683 Minutes of BATCO Group R&D Conference on Smoking and Behaviour at Southampton, England 

(Oct 11-12, 1976), at4. See AR (Vol 27 Ref. 376). 

684 Dunn WL (Philip Morris Inc.), Motives and Incentives in Cigarette Snwking (1972), at 4 (emphasis 

added). See AR (Vol. 12 Ref. 133). 

685 Griffith RB (BATCO), Report to Executive Committee (Jul. 1, 1965), at 2. See AR (Vol 27 Ref. 377). 

686 Eichorn PA, Dunn WL (Philip Morris Inc.), Quarterly Report of Projects 1600 and 2302~ct. IDee. 31, 1970 (Dec. 31, 1970), in 141 Cong. Rec. H8128 (daily ed. Aug. 1, 1995). See AR (Vol. 27 Ref. 

376). 

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II.C.3. 

smokers seek adequate doses of nicotine to satisfy dependence and will compensate to 

achieve those doses when given a low-nicotine cigarette.687 The cigarette industry, in 

contrast, denies that smokers compensate for nicotine to any significant extent It is not 

credible that the industry would have accepted and acted on outsiders' recommendations 

while rejecting the fundamental premises on which the recommendations were based. 

Moreover, the Surgeon General, while suggesting that cigarettes with a lower tar-tonicotine ratio should be investigated, specifically cautioned against achieving this goal 

through strategies that reduced tar while maintaining a normal nicotine yield: 

[F) actors of "smoker compensation" must be considered in the evaluation 

of lower ''tar'' and nicotine cigarettes. Filtered, lower ''tar'' and nicotine 

cigarettes that are less vulnerable to increasing the smoke and nicotine 

deliveries are needed .... Attempting to minimize smoker compensation by 

selectively reducing ''tar'' and other smoke compounds while maintaining 

nicotine yield may carry serious disadvantages. First, maintaining nicotine 

delivery may reinfore physiologic habituation, and interfere with smoking 

cessation attempts. Second, nicotine gives rise to the tobacco-speeific 

carcinogenic N-nitrosamines ... Finally, nicotine is suspected to be a major 

smoke constituent correlated with the increased risk of cardiovascular 

disease among cigarette smokers.688 

Accordingly, the evidence establishes that the industry researched and developed 

methods to increase relative nicotine deliveries while decreasing tar deliveries for a 

commercial purpose-to ensure that cigarettes provide pharmacologically satisfying doses 

of nicotine. 

687 See, e.g., Russell MAH, et al., Comparison of effect on tobacco consumption and carbon monoxide 

absorption of changing to high and low nicotine cigarettes, British Medical Journal1973;4:512-516. See 

AR (Vol. 89 Ref. 485). 

Gori G, Low risk cigarettes: a prescription, Science 1976;94(4271):1243-1246. See AR (Vol. 535 Ref. 

96, vol. IV.D, at 1-5). 

688 Department of Health and Human Services, The Health Consequences of Smoking: The Changing 

Cigarette, A Report of the Surgeon General, 1981, at 98 (citation omitted). See AR (Vo1123 Ref. 1586). 

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44950 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

Il.C.4. 

4. The Cigarette Manufacturers Design Commercially Marketed 

Cigarettes to Provide a Pharmacologically Active Dose of Nicotine 

The evidence summarized in section II.C.3. that the manufacturers have conducted 

product research and development to establish the doses of nicotine needed to produce 

pharmacological effects and to optimize nicotine deliveries to consumers establishes that 

the manufacturers have the capacity to design cigarettes that provide pharmacologically 

active doses of nicotine. In this section, the Agency evaluates the evidence in the record 

regarding the manipulation and control of nicotine in commercial cigarettes. 689 

As discussed below, the evidence in the administrative record establishes that many 

of the product research and development efforts described in section II.C.3. are used in 

important ways in the commercial cigarettes marketed today. The available evidence 

shows that the cigarette manufacturers pay careful attention to nicotine in all phases of 

cigarette manufacture. As described in the Jurisdictional Analysis, the focus on nicotine is 

apparent at each step-from the growing and purchasing of tobacco leaves, to the 

blending of different tobacco varieties, to the design and manufacture of the finished 

cigarette. See 60 FR 41693-41733. 

The evidence in the record further demonstrates that the fmal products-the 

finished cigarettes sold to consumers-reflect the manufacturers' careful attention to 

689 The evidence in section ll.C.2., supported by the evidence in section ILC.3. that the manufacturers 

"have in mind" that these products will have and be used for pharmacological effects, is sufficient by itself 

to establish intended pharmacological use. It is thus not necessary for the Agency to establish that 

commercial cigarettes have been affumatively designed to provide a pharmacologically active dose of 

nicotine to show that the manufacturers "intend" the pharmacological effects and uses of cigarettes. For 

example, a manufacturer of a traditional full-strength cigarette may not need to take any specific design 

steps to insure that the cigarette provides a pharmacologically active dose of nicotine. Nevertheless, this 

manufacturer's understanding and expectation that the full-strength cigarette will be used by consumers 

for drug purposes would be sufficient to establish the cigarette's intended pharmacological use. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44951

II.C.4. 

nicotine. Manufacturers of commercially marketed cigarettes commonly manipulate 

nicotine deliveries to provide remarkably precise, pharmacologically active doses of 

nicotine to consumers. The principal techniques that are used to control and manipulate 

nicotine deliveries include: (1) the use of nicotine-rich tobacco blends in low-tar 

cigarettes; (2) the use of filtration and ventilation technologies that selectively remove 

more tar from smoke than nicotine; and (3) the use of chemical additives that increase the 

percentage of "free" nicotine in cigarette smoke. Control is also achieved as a result of 

extensive attention to nicotine in tobacco breeding, leaf purchasing, leaf blending, and the 

manufacture of reconstituted tobacco. 

Indeed, the evidence in the record establishes that cigarette designs in recent 

decades have been driven by the manufacturers' desire to maintain nicotine deliveries at 

pharmacologically active levels. As consumer a ware ness of the health effects of smoking 

has increased, the cigarette manufacturers have responded by adding ftlters and using 

ventilation to reduce tar deliveries. However, the manufacturers have not reduced 

nicotine deliveries proportionately. Rather, the evidence available to the Agency indicates 

that they have strived to ensure that nicotine deliveries remain at a pharmacologically 

active level.690 

a. The Manufacturers Use Nicotine-Rich Tobacco Blends 

in Low-Tar Cigarettes 

Perhaps the clearest example of deliberate manipulation and control to maintain 

nicotine deliveries at levels sufficient to provide pharmacological satisfaction occurs in the 

690 RJR's Eclipse, the new tobacco product that is being test-marketed, carries this effort to close to its 

logical conclusion-maintaining nicotine deliveries at the level of conventional ultra-low-tar cigarettes 

while allegedly reducing many of the tar components of tobacco smoke substantially below these levels. 

Eclipse is discussed further in section II.C.3.b., above (product research and development). 

295 
44952 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

manufacture of low-tar cigarettes. The evidence in the administrative record indicates that 

cigarette manufacturers commonly use nicotine-rich tobacco blends in these products. 

Approximately 80% of the cigarettes on the market today are either low-tar (6 to 15 mg 

tar) or ultra-low-tar (less than 6 mg tar).691 

i. The Use of Nicotine-Rich Tobacco Blends in the 1950's. The evidence in 

the record indicates that the use of richer nicotine blends first occurred in the 1950's, 

when filters were first added to cigarettes. Documents provided to the Agency by the 

tobacco industry show that a shift to higher nicotine blends occurred to offset the 

reductions in nicotine deliveries caused by the use of filters. According to one 1956 

document: "With the increase in production of filter tip cigarettes, ... demand has 

increased for heavier-bodied [tobacco] types that have full aroma and flavor and a 

relatively high nicotine content.'7692 

As early as 1957, the U.S. Department of Agriculture (USDA) recognized that the 

introduction of filters was causing increased demand for higher nicotine tobacco. That 

year, the director of the tobacco division of USDA's Agricultural Marketing Service, 

Stephen E. Wrather, testified before Congress that the industry had "moved up the stalk'' 

691 Federal Trade Commission, Report of"Tar," Nicotine, and Carbon Monoxide of the Smoke of 1107 

Varieties of Domestic Cigarettes (1995). See AR (Vol535 Ref. 96, vol IV.B). 

692 Jones GL, Collins WK, Measured Crop Performance Tobacco 1956, Department of Field Crops, N.C., 

State College, Raleigh N.C., Research Report No.4 (Dec. 1956), at 1 (emphasis added). See AR (Vol. 

535 Ref. 96, vol. IV.K). 

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II.C.4. 

in blending tobacco for use in filter cigarettes.693 "Moving up the stalk" is a reference to 

the higher nicotine content in the upper leaves of tobacco plants.694 

Wrather also indicated that using this higher nicotine tobacco in the blend for 

filtered cigarettes enabled manufacturers to maintain the same "strength" levels in the 

smoke that existed in unfiltered cigarettes.695 A 1957 Consumer Reports analysis of 

nicotine levels in filtered and unfiltered cigarettes placed in the record of the hearing 

showed that the average nicotine content in regular-size cigarettes with filters was higher 

than in regular-size cigarettes without filters.696 This could only have been accomplished 

through the use of higher nicotine tobacco leaves in the blend for filtered cigarettes. 

ii. The Use of Nicotine-Rich Tobacco Blends Today. During the 1960's and 

1970's, the demand of consumers for "healthier'' cigarettes led to further declines in tar 

yields. As described above in section II.C.3., this caused the cigarette manufacturers to 

develop methods to ensure that the nicotine levels in cigarettes did not drop below 

acceptable levels. 697 

693 False and Misleading Advertising (Filter-tip Cigarettes): Hearings Before the Subcommittee of the 

Committee on Government Operations, U.S. House of Representatives, 85th Cong., 1st Sess. 189 (1957) 

(testimony of Stephen E. Wrather). See AR (Vol 172, Ref. 2035). 

694 See, e.g., Brown & Williamson Tobacco Corp., Comment (Jan. 2, 1996), at 10 ("Higher stalk tobacco 

leaves do have more nicotine than lower stalk leaves on the same plant"). See AR (Vol 529 Ref. 104). 

695False and Misleading Advertising (Filter-tip Cigarettes): Hearings Before the Subcommittee of theCommittee on Government Operations, U.S. House of Representatives, 85th Cong., 1st Sess. 196 (1957) 

(testimony of Stephen E. Wrather). See AR (Vol 172, Ref. 2035). 

696 Id. at 662 (exhibit 15c). 

697 Philip Morris USA, Research and Development Five Year Plan, 1974-1978 (May 1973), in 141 Cong. 

Rec. H8130-8131 (daily ed. Aug. 1, 1995). See AR (Vol 711 Ref. 6). 

See also Low Delivery Cigarettes and Increased Nicotine/J'ar Ratios, A Replication (Oct. 1975), in 141 

Cong. Rec. H8009 (daily ed. Jul. 31, 1995). See AR (Vol. 27 Ref. 376a). 

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44954 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

The evidence in the record indicates that the low-tar cigarettes on the market 

today reflect the industry's concerns with providing an acceptable nicotine level. As 

numerous documents in the record reveal, low-tar cigarettes are specifically blended to 

increase their nicotine concentrations. For instance, the administrative record includes the 

following descriptions of the use of blending to control and manipulate nicotine: 

• William Farone, the former director of applied research at Philip Morris, stated that 

"[t]he industry employs two principal means of controlling the nicotine levels.'.698 One 

of these is "modification and control of the tobacco blend, i.e., the ratio of Burley (aircured), Bright (flue-cured), Oriental, stems, expanded tobacco products, and 

reprocessed tobacco products such as tobacco sheet made from stems and waste 

leaf."699 According to Farone: 

Product developers and blend and leaf specialists were responsible 

for manipulating and controlling the design and production of 

cigarettes in order to satisfy the consumer's need for nicotine in 

lower yield products. 

Blend changes were an especially important tool used to 

ensure desired nicotine levels. Tar is a function of tobacco weight. 

However, an all-burley cigarette will produce a higher nicotine level 

than an all-bright cigarette of the same weight. The industry knew 

that by using a higher percentage of higher nicotine tobacco in their 

low tar cigarettes they could achieve an increase of their nicotine 

levels.700 

Jones B, Houck W, Martin P (Philip Morris Inc.), Low Delivery Cigarettes and Increased Nicotine/l'ar 

Ratios, A Replication (Oct1975), in 141 Cong. Rec. H8132 (daily ed. Aug. 1, 1995). See AR (Vol 711 

Ref. 6). -

Wood OJ, Wilkes EB (BATCO), Project Wheat- Part 2: U.K. Male Smokers: Their Reactions to 

Cigarettes of Different Nicotine Delivery as Influenced by Inner Need (Jan. 30, 1976), at 2. See AR (Vol. 

20 Ref. 204-2). 

698 Farone W A, The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 5. See AR (Vol 638 Ref. 2). 

699 ld. at 5 (emphasis added). 

700 Id. at 10 (emphasis added). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44955

• Ian Uydess, the fanner Philip Morris scientist, stated that: 

Nicotine levels were routinely targeted and adjusted by Philip 

Morris in its various products at least in part, through blend 

changes .... 

When Philip Morris designed a new or modified blend, they 

used their stored tobacco inventories much like a scientist would 

use a chemical stockroom to select the ingredients needed to 

synthesize a new material. ... 

. . . Philip Morris routinely applied this knowledge of 

selective tobacco blending to achieve desired nicotine . .. levels in 

the products that it designed and marketed.101 

II.C.4. 

• Alexander Spears, the vice chairman and chief operating officer of Lorillard Tobacco 

Co., wrote that "the lowest 'tar' segment is composed of cigarettes utilizing a tobacco 

blend which is significantly higher in nicotine."102 According to Spears, the nicotine 

concentration in the lowest tar cigarettes in 1981 was 22% greater than the 

concentration in regular cigarettes (2.2% versus 1.8%).703 Spears further explains that 

"[h]igher nicotine levels can be achieved by decreasing Oriental and the stem and 

tobacco sheet and increasing the Burley and upper stalk positions of both the flue-cured 

and the Burley tobacco."704 

• Another Lorillard researcher, Vello Norman, has explained that the shift to tobacco 

blends with more nicotine-rich burley tobacco was motivated by a desire ''to impart 

701 Declaration ofUydess IL (Feb. 29, 1996), at 8, 10 (emphasis added). See AR (Vol 638 Ref. 1). 

702 Spears A W, Jones ST (Lorillard Tobacco Co.), Chemical and Physical Criteria for Tobacco Leaf of 

Modem Day Cigarettes, Recent Advances in Tobacco Science, Oct 6-9, 1981;7:19, at 22 (emphasis 

added). See AR (Vol 26 Ref. 373). 

703 Id. at 21. 

704 /d. at 24. 

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44956 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

more impact to smoke" to offset the effects of"gradually lower cigarette smoke 

yields": 

As various means were used to gradually lower cigarette smoke 

yields there has been a tendency to use more Burley in order to 

impart more impact to smoke. Thus, while total smoke yields of 

cigarettes have diminished, the relative composition of smoke has, 

in the case of many cigarettes, shifted slightly towards what is more 

characteristic of Burley. 705 

II.C.4. 

"Impact" is a term used by the tobacco industry to describe effects that are associated with 

nicotine delivery. See, e.g., Jurisdictional Analysis, 60 FR 41776-41777. 

• Similarly, a scientist at Brown & Williamson reported that "[u]ltra low tar cigarettes 

... use blends which contain about 20% more nicotine.''706 

Brown & Williamson's development of the high-nicotine Y -1 variety of tobacco, 

which is discussed above in section II.C.3.c.iii., was an attempt to use breeding and 

blending to increase nicotine concentrations in low-tar cigarettes. An example in which 

blending has been used to increase nicotine concentrations in commercial low-tar 

cigarettes is Philip Morris' Merit cigarettes. FDA has analyzed the relative nicotine 

concentrations in the regular, low-tar, and ultra-low-tar versions of Merit cigarettes. 

FDA's analysis revealed that Merit Filter 100's contained 1.46% nicotine, but that Merit 

Ultra Lights 100's contained 1.67% nicotine, and Merit Ultima lOO's (the lowest-tar 

product) contained 1.99% nicotine. See 60 FR 41723-41724. These findings, which 

705 Norman V (Lorillard Research Center), Changes in Smoke Chemistry of Modem Day Cigarettes, 

Greensboro, NC (1982), at 168. See AR (Vol 99 Ref. 813). 

706 Reynolds ML (Brown & Williamson), Symposium Summary, presented at Winston Salem. NC, at 179 

(Oct 6-9, l981)(emphasis added). See AR(Vol99 Ref. 823). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44957

II.C.4. 

show nicotine concentrations increasing as reported tar yields drop, are unchallenged by 

Philip Morris. 

A similar pattern of higher nicotine concentrations in lower tar products exists in 

other brands. For instance, in 1981, Brown & Williamson launched a new ultra-low-tar 

brand called Barclay. Tests of Barclay and fourteen other cigarettes in 1982 showed that 

the tobacco in the Barclay blend had a nicotine concentration of 2.69%-higher than any 

other brand tested. In fact, Barclay's nicotine concentration was over 90% higher than the 

regular-strength Lucky Strike cigarette tested.707 Other brands show the same pattern of 

higher nicotine concentrations in the lowest-tar cigarettes. 

These industry blending practices facilitate the use of low-tar products for 

pharmaceutical purposes. The enhanced nicotine concentrations in the lowest tar 

cigarettes result in higher nicotine deliveries than would otherwise occur, allowing 

consumers to more readily satisfy their addiction to nicotine and obtain other 

pharmacological effects of nicotine from low-tar cigarettes. 

iii. The Use of Nicotine-Rich Tobacco Blends Is Not Due to Accident or 

Taste. In the Jurisdictional Analysis, FDA summarized the evidence then available to the 

Agency regarding the use of nicotine-rich blends in low-tar cigarettes, concluding that 

"[s]ignificant evidence also demonstrates that tobacco manufacturers have used blending 

techniques to increase nicotine concentrations in low-tar cigarettes and thereby maintain 

nicotine delivery while reducing tar delivery." 60 FR 41708. The public comment period 

707 Regulation ofTobacco Products (Part 3): Hearings Before the Subcommittee on Health and the 

Environment, House Energy and Commerce Committee, U.S. House of Representatives, 103d Cong., 2d 

Sess. 173 (Jun. 23, 1994). See AR (Vol 709 Ref. 3). 

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44958 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

provided the cigarette manufacturers with an opportunity to provide an alternative 

explanation of this evidence of nicotine manipulation. As explained below, however, the 

industry does not effectively rebut the evidence that the manufacturers use nicotine-rich 

blends to enhance nicotine deliveries. The industry's failure to provide a convincing 

counter-explanation for its actions is further support for the Agency's fmding that the 

manufacturers design low-tar cigarettes with nicotine-rich blends to maintain adequate 

nicotine deliveries. 

The cigarette manufacturers make two conflicting arguments in response to the 

evidence that they manipulate tobacco blends to enhance nicotine content in low-tar 

products. First, they categorically assert that they "do not independently 'control' for or 

'manipulate' the nicotine content in any of their blends."708 

Second, they maintain that, to the extent they do control and manipulate nicotine 

content, they do so strictly for taste. Thus, they contend that (1) they "blend their 

tobaccos for flavor''709 and (2) "nicotine plays an important role in the taste and flavor of 

cigarette smoke."710 During his appearance before Congress, for instance, William 

Campbell, the president of Philip Morris, conceded that the ultra-light Merit Ultima 

cigarette uses a tobacco blend with a higher concentration of nicotine than the regular 

Merit cigarette, but insisted that "it's there for taste."711 Similarly, Thomas Sandefur, then 

708 Joint Comment of Cigarette Manufacturers (Jan. 2, 1996), Vol IV, at 66. See AR (Vol 535 Ref. 96). 

709 /d. 

710 RJ. Reynolds Tobacco Co., Comment (Jan. 2, 1996), at 50. See AR (Vol 519 Ref. 103). 

711 Regulation of Tobacco Products (Part 1): Hearings Before the Subcommittee on Health and the 

Environment, Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Cong., 2d Sess. 

764 (Apr. 14, 1994) (testimony ofW.I. Campbell). See AR (Vol 707 Ref. 1). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44959

II.C.4. 

CEO of Brown & Williamson, conceded under questioning that Brown & Williamson uses 

high-nicotine blends in low-tar products, but asserted that "[w]hat we were trying to do 

was maintain a certain amount of nicotine which gives us better taste .'.n2 

Based on the ~vidence in the record, the Agency fmds the manufacturers' 

contention that they do not control and manipulate nicotine levels in blends not to be 

credible. The high nicotine content in the blends of low-tar cigarettes is not an accident. 

It necessarily reflects the deliberate design choices of the manufacturers. Moreover, the 

manufacturers' argument that they do not control and manipulate the nicotine content of 

blends is in fundamental conflict with their assertions that they manipulate nicotine for 

taste. 

For several reasons, the Agency also does not regard the manufacturers' assertion 

that they control and manipulate nicotine only for taste to be credible. First, the 

manufacturers' assertion is contradicted by numerous internal statements of senior 

researchers and officials in the tobacco industry, made public during the Agency's 

investigation. As discussed above in section ll.C.2., many senior researchers and officials 

within the industry explicitly acknowledge that nicotine provides desired pharmacological 

effects to consumers, and refer to cigarettes as a "dispenser for a dose unit of nicotine,"713 

a "nicotine delivery device,"714 "a vehicle for delivery of nicotine,"715 "the means of 

712 Regulation ofTobacco Products (Part 3): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Congress, 

2d Sess. 227 (Jun. 23, 1994) (statement of Thomas Sandefur) (emphasis added). See AR (Vol 709 

Ref. 3). 

713 Dunn WL (Philip Morris Inc.), Motives and Incentives in Cigarette Smoking (1972), at 5. See AR 

(Vol. 12 Ref. 133). 

714 Philip Morris Inc., Draft Report Regarding a Proposal for a "Safer" Cigarette, Code-named Table, at 5. 

See AR (Vol 531 Ref. 122). 

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44960 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

providing nicotine dose in a metered fashion,"716 and a device that provides the smoker 

"very flexible control over titrating his desired dose of nicotine."717 Other senior 

executives have stated that the cigarette industry is "in the business of selling nicotine, an 

addictive drug ... "718 and that "a good part of the tobacco industry is concerned with the 

administration of nicotine to consumers."719 The industry's argument that high-nicotine 

blends are used in cigarettes only for taste cannot be reconciled with the industry's own 

internal statements that cigarettes are intended to deliver phannacological doses of 

nicotine to consumers. Indeed, one Philip Morris document quoted by the company in its 

comments calls nicotine a "tasteless" constituent of tobacco.720 

Second, the manufacturers' position on nicotine and taste cannot be reconciled 

with the industry's record of extensive research into nicotine phannacology. In contrast, 

very little of the industry's research has examined the role of nicotine in taste. In their 

comments the cigarette manufacturers cite only a handful of industry studies on this 

subject. FDA has reviewed all of these studies and fmds that they do not substantiate the 

industry's claim that nicotine's effects on taste are the reason consumers smoke. See 

715 Teague, CE (RJ. Reynolds Tobacco Co.), Research Planning Memorandum on the Nature of the 

Tobacco Business and the Crucial Role of Nicotine Therein (Apr. 14, 1972), at 1. See AR (Vol 531 

Ref. 125). 

716 Proceedings of the BATCO Group R&D-Smoking Behaviour-Marketing Conference, Session I, slides 

(Jul 9-12, 1984), atBW-W2-03242. See AR(Vol 24 Ref. 315). 

717 Transdermal Nicotine Patches, at 2. See AR (Vol 531 Ref. 124). 

718 Yeaman A (Brown & Williamson), Implications of Battelle Hippo I and II and the Griffith Filter 

(Jul. 17, 1963), at4. See AR(Vol 21 Ref. 221). 

719 GreenSJ (BATCO), BAT Group Research (Sep. 4, 1968), at2. See AR(Vol 15 Ref. 192). 

720 Philip Morris Inc., Comment(Apr. 19, 1996), at 64-65 (emphasis added), citing, "Merit Team Second 

Speaker'' (Jan. 14, 1976). See AR (Vol 700 Ref. 226). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44961

ll.C.4. 

section ll.B.2.c., above. Philip Morris's comments do state that Philip Morris conducted 

sophisticated investigations into flavor using an BEG-assisted "Qlfactometer." Yet 

according to Philip Morris, "[n]one of that 'olfactometer' work involved nicotine at 

alf'721-an omission that conflicts with the industry's assertion that nicotine has an 

important role in flavor. 

By contrast, the industry has conducted or funded hundreds of studies on nicotine 

pharmacology, focused primarily on nicotine's effects on brain function. Manufacturers 

have learned through this research that nicotine has the hallmark characteristics of an 

addictive drug, see section IT.C.3., above, and "abuse liability'';722 that nicotine changes 

patterns of human brain waves in a manner associated with anxiety relief; 723 and that 

"[n]icotine is an extremely biologically active compound capable of eliciting a range of 

pharmacological, biochemical and physiological responses."724 

The research conducted by several companies to find "nicotine analogues" to 

replace nicotine in cigarettes provides an especially clear illustration that the industry 

regarded nicotine's primary effects as pharmacological, not flavor-related. The goal of 

this research was to develop a molecule that would "mimic nicotine's effect in the 

721 /d. at47 (emphasis added) .. 

722 Regulation of Tobacco Products (Part 2): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Cong., 2d 

Sess. 33 (Apr. 28, 1994) (testimony of Victor DeNoble). See AR (Vol 708 Ref. 2). 

723 Pritchard WS (RJ. Reynolds Tobacco Co.), Electroencephalographic effects of cigarette smoking, 

Psychopharmacology 1991;104:485-490. See AR (Vol 3 Ref. 23-2). 

724 BATCO, Method for Nicotine and Cotinine in Blood and Urine (May 21, 1980), at 2. See AR (Vol 23 

Ref. 300-1 ). 

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44962 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

brain"725 and "possess[] the desired features of brain stimulation and stress-relief'726 not to 

find substitute compounds with the same flavor characteristics as nicotine. 

Third, the manufacturers' contention that they blend for taste and not for 

pharmacological effects conflicts with their assertions that they blend and design their 

products to meet consumer preferences. As discussed above in sections II.A. and II.B., 

the primary reason consumers smoke is to satisfy their addiction and obtain the other 

pharmacological effects of nicotine, such as sedation and stimulation. This fact is widely 

accepted by both the scientific community and researchers and officials within the tobacco 

industry. Cigarette manufacturers that strive to satisfy smokers' demands must necessarily 

design and blend cigarettes that produce pharmacological effects, including satisfying the 

needs of addicted smokers. This issue is further discussed in section II.C.4.f., below. 

The Agency does not find that flavor is irrelevant in the blending process. To the 

contrary, the Agency agrees that one of the objectives in tobacco blending is to provide 

flavorful cigarette smoke. In the competitive cigarette marketplace, a cigarette that 

satisfied consumers' pharmacological demands for nicotine but did not taste good would 

be unlikely to be a commercial success. RJR's experience with-Premier may, in fact, 

confmn this point. 

725 Regulation of Tobacco Products (Part 2): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 103d Cong., 2d 

Sess. 33 (Apr. 28, 1994) (testimony of Victor DeNoble). See AR (Vol 708 Ref. 2). 

726 Minutes of BATCO Research Conference at Hilton Head, SC (Sep. 24-30, 1968), at 3. See AR (Vol. 

14 Ref. 172-2). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44963

ILC.4. 

The Agency finds, however, that a cigarette that tasted good but did not satisfy 

consumers' pharmacological demands for nicotine would be even more unlikely to be a 

commercial success. As Ian Uydess, the former Philip Morris scientist, states: 

[A] cigarette having satisfactory ('high enough') nicotine levels but 

marginal flavor, stood a better chance of being 'accepted' in the 

market place than a somewhat better tasting product with zero or 

ultra-low levels of nicotine ('not enough') . 

. . . Tobacco companies like Philip Morris learned a long 

time ago that it was hard to get people to stay with a good tasting 

product if the nicotine level was too low.127 

In other words, to produce a cigarette that smokers will fmd acceptable, the cigarette 

manufacturer must use tobacco blends that provide consumers the desired 

pharmacological effects of nicotine. 

For these reasons, FDA concludes that cigarette manufacturers use nicotine-rich 

blends in low-tar cigarettes to ensure that these cigarettes deliver pharmacologically active 

doses of nicotine. 

b. The Manufacturers Use Filtration and Ventilation Technologies 

That Selectively Remove More Tar than Nicotine and That Allow 

Smokers To Inhale More Nicotine than the Measured Levels 

The evidence before the Agency also supports a fmding that cigarette 

manufacturers use cigarette filters and ventilation to manipulate nicotine deliveries. 

Especially in low-tar products, the available evidence indicates that cigarette 

manufacturers and their filter suppliers have engineered ftltration and ventilation systems 

to bring about greater reductions in tar than in nicotine, thereby increasing the nicotine/tar 

ratio. According to William Farone of Philip Morris, "modification of the construction of 

727 Declaration ofUydess IL (Feb. 29, 1996), at 11, 13 (emphasis added). See AR (VoL 638 Ref. 1). 

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44964 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II. CA. 

the cigarette such as filter type, the type of filter material used, the number and placement 

of ventilation holes, [and] the density, composition and porosity of the cigarette paper'' is 

the second principal means of controlling nicotine used by the industry. 728 

The effect of filtration and ventilation on nicotine deliveries is recognized in the 

technical tobacco literature. According to an article by a researcher at Lorillard Tobacco 

Co.: 

[V]entilated filters caused a significant drop in the amount of 

nicotine retained on the fllter . 

. . . [S ]rrwke from ventilated cigarettes is relatively 

enriched in nicotine.129 

Similarly, scientists at Eastman Kodak Co., a manufacturer of cigarette fllters, have 

observed that "[a]s ventilation is increased, the nicotine content ... increases 

markedly.'mo 

Indeed, some filter manufacturers have openly promoted the ability of their fllters 

to increase nicotine/tar ratios. For instance, Filtrona Ltd.'s Filtrona Ratio filter was 

promoted as "a new option available to cigarette designers which allows management of 

the yield ratios of important smoke components relative to tar, [including] ... nicotine."731 

728 Farone W A, The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 5. See AR (VoL 638 Ref. 2). 

729 Norman V, Ihrig AM, Shoffner RA (Lorillard Tobacco Co.), The effect of tip dilution on the filtration 

efficiency of upstream and downstream segments of cigarette ftlters, Beitrage zur Tabakforschung 

International, Jut 1984; 12( 4 ): 178-185, at 184 (emphasis added). See AR (Vol. 103 Ref. 923 ). 

730 Kiefer JE (Eastman Kodak Co.), Ventilated ftlters and their effect on smoke composition, Recent 

Advances in Tobacco Science (1979), at 78. See AR(Vo128 Ref. 465). 

731 Papers, filters, and tipping, Tobacco Reporter, Apr. 1985;112(4):32. See AR (Vo1351 Ref. 5624). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44965

II.C.4. 

When applied to commercial brands, this filter increased nicotine deliveries by over 25%, 

while leaving tar deliveries virtually unchanged. 732 

In their comments on the Jurisdictional Analysis, the cigarette w..anufacturers 

acknowledge that filtration and ventilation in low-tar cigarettes produce enhanced 

nicotine/tar ratios, but they argue that this is strictly an unavoidable physical 

phenomenon-not a design feature. The administrative record does not support their 

position. 

Contrary to the cigarette manufacturers' contention, the filter manufacturers 

describe the role of filters and ventilation as not simply removing tar and nicotine 

according to immutable proportions determined by the laws of physics. Filters are highly 

engineered products that are "designed exclusively to yield the maximum satisfaction 

from a carefully chosen tobacco blend. "

733 The object of filters and ventilation is to 

"control the yield of the many constituents that the smoker receives" and to "act[] more 

as a smoke modifier than as an absolute ttlter which removes all particles of a known 

As described above in section ll.C.3.e., the administrative record indicates that 

fllter manufacturers have developed numerous strategies for independently changing tar 

and nicotine deliveries. When the cigarette manufacturer selects a filter and ventilation 

design, therefore, the cigarette manufacturer's choices necessarily affect the relative 

732 Id. 

733 Philips JA (Filtrona International Ltd), Filters for cigarettes: an integral part of the cigarette, Tobacco 

Repcner (Oct 1981), at 34 (emphasis added). See AR (VoL 351 Ref. 5624). 

734 ld. at 34 (emphasis added). 

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44966 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

nicotine and tar deliveries. A decision to place the ventilation holes close to the tobacco 

rod will increase relative nicotine deliveries, 735 as will a decision to increase the porosity of 

the cigarette paper.736 The use of increasingly porous perforated cigarette paper will 

"selectively increase nicotine."737 A decision to rely on relatively more ventilation and 

relatively less filtration is another ''toolD" that "increas[es] nicotine delivery without 

changing tar delivery."738 Likewise, when manufacturers decide to increase the pH of the 

filter through use of an additive, this increases cigarette nicotine delivery "independently" 

of tar delivery. 739 Thus, contrary to the position of the cigarette manufacturers, there are 

many technical choices that manufacturers make in filtration and ventilation design that 

determine the extent to which the cigarette filter and ventilation will increase nicotine 

deliveries relative to tar deliveries. 

The statement of William Farone corroborates the evidence showing that 

deliberate design decisions have caused the selective filtration and ventilation observed in 

73s Kiefer JE (Eastman Kodak Co.), Ventilated filters and their effect on smoke composition, Recent 

Advances in Tobacco Science (1979), at 79. See AR (Vo128 Ref. 465). 

736 McMurtrie A. Litringer EF, Wu DT (Brown & Williamson), Cigarette Paper Effects on Tar/Nicotine 

and COffar Ratios, 35th Tobacco Chemists' Research Conference, Winston-Salem, North Carolina 

(Oct 6-9, 1981). See AR (Vo1.639 Ref. 2). 

737 Owens WF Jr. (Ecusta Paper and Film Group), Effect of Cigarette Paper on Smoke Yield Composition, 

32d Tobacco Chemists' Research Conference, Montreal, Canada (1978) (emphasis added). See AR (Vol. 

639 Ref. l 0). 

738 Selke W A, Making the cigarette do just what you want it to do, Journal Tobacco International 

1983: 12. See AR (Vol 102 Ref. 896). 

739 Lee BM (Eastman Kodak Co.), Modification of Nicotine to Tar Ratio in Cigarette Smoke, 42d Tobacco 

Chemists' Research Conference, Lexington, Kentucky (Oct 2-5, 1988), at 33. See AR (Vol 639 Ref. 2). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44967

low-tar cigarettes. According to Farone, "[t]he cigarette industry ... altered the 

cigarette filter in order to increase nicotine delivery."140 Specifically, he states: 

Filter design and ventilation allowed the design and manufacture 

of cigarettes that removed a higher percentage of tar than 

nicotine. Selective filtration was accomplished by altering the 

technical specifications for a filter, e.g. by selecting different filter 

tow combinations, varying the denier per filament, and deciding 

whether or not to use additives in the filter .... [A]ppropriate 

filters were identified to attain a predetermined nicotine/tar 

ratio.741 

The example of the regular-length Benson & Hedges filtered cigarettes that 

Congressman Henry A. Waxman described on the floor of the U.S. House of 

II.C.4. 

Representatives in July 1995 also contradicts the position of the cigarette industry.742 The 

cigarette industry maintains that high nicotine/tar ratios are unavoidable in ultra-low-tar 

cigarettes because the high levels of filtration and ventilation in these cigarettes inevitably 

remove more tar than nicotine. The Benson & Hedges example, however, shows that (1) 

ultra-low-tar and nicotine levels can be achieved without increasing the ratio of nicotine to 

tar and (2) the high nicotine/tar ratios typically observed in cigarettes with ultra-low tar 

levels are therefore the result of deliberate design choices of manufacturers. 

The Benson & Hedges cigarette was marketed as an ultra-low-tar cigarette from 

1978 to 1985, with tar levels consistently below or near 1 milligra.m.743 In three of those 

740 Farone W A, The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 11 (emphasis added). See AR (VoL 638 Ref. 2). 

741 /d. (emphasis added). 

742 Remarks of Waxman HA, 141 Cong. Rec. H8009-8010 (daily ed. JuL 31, 1995). See AR (VoL 27 

Ref. 376a). 

743 /d. 

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II.C.4. 

years (1978, 1984, and 1985), the nicotine levels were also proportionately low, 

producing a normal nicotine/tar ratio.744 Thus, in these years, the filtration and ventilation 

technologies used by the manufacturer to reduce tar deliveries did not selectively increase 

nicotine deliveries. In contrast, from 1979 to 1983, the nicotine levels were elevated 

relative to the tar levels, producing a high nicotine/tar ratio.745 These changes in the 

nicotine/tar ratio were not due to chance.746 These facts thus establish that the 

manufacturer, in this case Philip Morris, had the technical ability to achieve ultra-low-tar 

levels without causing nicotine levels to be relatively enhanced. 

The evidence also indicates that cigarette manufacturers also use "elasticity" 

technologies, principally ventilation techniques that can be readily blocked, to allow 

smokers to increase their nicotine intakes above the levels measured on smoking machines. 

One example is Brown & Williamson's Barclay cigarette. This cigarette was first 

introduced as an ultra-low-tar cigarette in 1981. As noted above in section IT.C.4.a.ii., 

tests in 1982 showed that the tobacco in the Barclay blend had a higher nicotine 

concentration than any other cigarette brand tested. Barclay also had more total nicotine 

in the tobacco rod than any other cigarette tested. For instance, Barclay had over 60% 

more total nicotine in the cigarette rod (12.80 mg per cigarette) than regular-strength 

Lucky Strike (7.92 mg per cigarette). Yet despite its high nicotine levels, Barclay had the 

second lowest nicotine yields of any cigarette tested, as measured by the FTC smoking 

machine method. Thus, even though, as noted, Barclay had over 60% more nicotine in 

744 /d. 

74S /d. 

746 /d. 

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II.C.4. 

the cigarette rod than the regular-strength Lucky Strike, its nicotine yield on the FfC 

smoking machine (0.15 mg per cigarette) was 90% lower than the yield of the Lucky 

Strike (1.46 mg per cigarette). 

Barclay was able to combine the highest total nicotine content with the secondlowest measured nicotine yield by relying on a "channel-ventilated" filter system. An 

investigation commenced by FfC in 1981 found that air flow through these channels is 

compromised during actual smoking and that, as a result, Barclay actually delivered 

considerably more nicotine and tar to the smoker than is obtained using the FTC's testing 

method. In 1983, the FfC successfully sued to enjoin Brown & Williamson from using 

nicotine, tar, and carbon monoxide results obtained from the FTC's smoking machines in 

Barclay advertising. See 60 FR 41718. 

While Barclay is a striking example of a fllter that delivers more nicotine to its 

smokers than to a smoking machine, the use of ventilation systems that can be blocked by 

smokers is common. As FDA reported in the Jurisdictional Analysis, the evidence in the 

record indicates that 32% to 69% of smokers of low-tar cigarettes block ventilation holes. 

See 60 FR 41717. 

In sum, the evidence in the record supports a fmding that the increase in nicotine 

deliveries relative to tar deliveries produced by selective flltration and ventilation result 

from the deliberate design choices of the manufacturers. The manufacturers do not 

persuasively refute this fmding. Accordingly, the Agency fmds that the manufacturers use 

filtration and ventilation technologies that are designed to selectively remove more tar than 

nicotine. 

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II.C.4. 

c. The Manufacturers Use Chemical Additives to Increase the Delivery 

of "Free" Nicotine 

The evidence in the record also supports a finding that the cigarette manufacturers 

control and manipulate nicotine deliveries through chemical manipulation. One way they 

do this is through the use of ammonia technologies that increase the delivery of "free" 

nicotine to smokers by raising the alkalinity or pH of tobacco smoke. "Free" nicotine is 

also sometimes referred to as "volatile," "extractable," or "non-ionized" nicotine. The use 

of ammonia compounds to increase pH is an outgrowth of the industry's product 

development research to improve the efficient use of smoke nicotine through pH 

modification. See section II.C.3., above. 

The use of ammonia compounds is common in the cigarette industry. Ammonia 

compounds have been regularly identified in the list of cigarette ingredients submitted by 

the industry to the Department of Health and Human Services. 747 Indeed, the comments 

of the cigarette manufacturers concede that several ammonia-related compounds are used 

in the manufacture of cigarettes.748 

An article in the Wall Street Journal describes the extent of the industry's reliance 

on ammonia technology. 749 According to the article, which is based on two major Brown 

& Williamson internal reports, Brown & Williamson adds ammonia compounds to "almost 

all" of its nonmenthol brands; Brown & Williamson views ammonia technology as ''the 

747 Joint Comment of Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol. IV, at 84. See AR (Vol 535 

Ref. 96). 

748 /d. 

749 Freedman AM, Impact booster tobacco fmn shows how ammonia spurs delivery of nicotine, Wall 

Street Journal (Oct 18, 1995). See AR (Vol. 639 Ref. 2). 

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II.C.4. 

soul of Marlboro" and ''the key factor" that "makes Marlboro a Marlboro"; and Brown & 

Williamson found that ammonia technology was also used by RJR, Lorillard, and 

American Tobacco Co.750 In congressional testimony, Thomas Sandefur, the CEO of 

Brown & Williamson, confirmed the widespread use of ammonia within the cigarette 

industry. 751 

It is well established that the addition of ammonia compounds to tobacco increases 

pH. This increase transforms nicotine that is "bound" in nicotine salts to "free" 

nicotine. 752 This effect is described in Brown & Williamson's 1991 "Handbook for Leaf 

Blenders and Product Developers," which states that "[a]mmonia, when added to a 

tobacco blend, reacts with the indigenous nicotine salts and liberates free nicotine."753 

Changing the chemical form of nicotine from a bound nicotine salt to free nicotine 

has several significant consequences, according to the evidence in the administrative 

record. First, it increases the quantity of nicotine that is transferred from the cigarette to 

750 ld. 

751 Regulation ofTobacco Products (Part 3): Hearings Before the Subcommittee on Health arul the 

Environment of the Committee on Energy arui Commerce, U.S. House of Representatives, 1 03d Cong., 

2d Sess. 224-225 (Jun. 23, 1994) (statement of Thomas Sandefur). See AR (Vol 709 Ref. 3). 

752 See, e.g., Armitage AK, Turner OM, Absorption of nicotine in cigarette and cigar smoke through the 

oral mucosa, Nature, Jun. 27, 1970;226:1231-1232. See AR(Vol45 Ref. 25). 

Surgeon General's Report, 1988, at 29. See AR (Vol 129 Ref. 1592). 

753 Regulation of Tobacco Products (Part 3): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy arui Commerce, U.S. House of Representatives, 103d Cong., 

2d Sess. 21 (Jun. 21, 1994) (statement of David Kessler) (emphasis added). See AR(Vol 709 Ref. 3). 

Brown & Williamson has acknowledged in its comment that the Handbook is a Brown & Williamson 

document Brown & Williamson Tobacco Corp., Comment (Jan. 2, 1996), at 37. See AR (Vol 529 

Ref. 104). 

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44972 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

the smoke. According to William Farone, the former director of applied research at Philip 

Morris: 

The use of ammonia chemistry was important to the industry in 

maintaining adequate nicotine delivery to satisfy smokers. The 

industry was able to deliver more of the available nicotine in the 

blend to the smoker by using ammonia compounds . ... In the 

complex world of tobacco smoke chemistry, by increasing the pH 

of the aerosol in the mainstream smoke, more of the aerosol would 

be in the vapor phase and less in the liquid (or condensed) phase. 

By increasing the ratio of vapor phase to liquid phase, one 

increases the total nicotine delivery since the condensed phase is 

less likely to survive the filter and the trip to the lungs.154 

Similarly, documents from the American Tobacco Company state: 

There has been an interest in increasing the amount of nicotine that 

is transferred from the tobacco to the mainstream smoke while 

leaving the "tar'' level unchanged. Since most of the nicotine in 

tobacco is a non-volatile salt, it was thought that a greater transfer 

would take place if the tobacco was made basic causing the 

nicotine to volatilize when the cigarette is smoked. 755 

The second effect of increasing the free nicotine is to increase the amount of 

nicotine absorption that takes place in the mouth. It is well-established that free nicotine is 

significantly more absorbable than bound nicotine.756 As early as 1968, researchers at 

BATCO, Brown & Williamson's parent, reported that there is a direct correlation between 

smoke pH and nicotine absorption in the mouth, stating that "[n]icotine retention appears 

754 Farone W A, The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 13 (emphasis added). See AR (Vol638 Ref. 2). 

755 Bodenhamer NL (American Tobacco), Leaf Services Monthly Report for June (Jun. 30, 1980) 

(emphasis added). See AR (Vol 27 Ref. 385). 

756 See, e.g., Armitage AK. Turner OM, Absoxption of nicotine in cigarette and cigar smoke through the 

oral mucosa, Nature, Jun. 27, 1970;226:1231-1232. See AR(Vol. 45 Ref. 25). 

Surgeon General's Report, 1988, at 29. See AR (VoL 129 Ref. 1592). 

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to be dependent principally on smoke pH and nicotine content."757 Similarly, RJR 

researchers have reported that: 

[B]y raising pH ... from 6.0 to 6.5 [in a low-tar cigarette] you 

raise the level of nicotine that is transferred to the taste buds and 

body fluids in the mouth to the same level as with the higher tar 

cigarette. And hence, even though the tar level has been dropped 

from 25 mg to 10 mg, by raising the pH from 6.0 to 6.5, you 

increase the nicotine transfer in the mouth . ... 758 

II.C.4. 

This effect of increased nicotine absorption in the mouth appears to be related to 

what some cigarette manufacturers describe as smoke "impact." For example, Brown & 

Williamson's Handbook for Leaf Blenders states that by adding ammonia: 

the ratio of extractable nicotine to bound nicotine in the smoke may 

be altered in favor of extractable nicotine. As we know, extractable 

nicotine contributes to impact in cigarette smoke and this is how 

ammonia can act as an impact booster.759 

RJR describes this effect as "mouth satisfaction," which it distinguishes from "the 

ultimate satisfaction" which "comes from the nicotine which is extracted ... in the 

lungs."760 

The third effect of increasing free nicotine appears to be to increase the rate of 

transfer of nicotine to the brain. This effect is discussed in a BA TCO research paper 

757 BATCO, The Retention of Nicotine and Phenols in the Human Mouth (1968), at BW-W2-11691. See 

AR (Vol. 445 Ref; 7593). 

758 Senkus M (RJ. Reynolds Tobacco Co.), Some Effects of Smoking (1976/1977), at 7 (emphasis added). 

See AR (Vol 700 Ref. 593). 

759 Regulation of Tobacco Products (Pan 3): Hearings Before the Subcommiuee on Health and the 

Environment of the Commiuee on Energy and Commerce, U.S. House of Representatives, 1 03d Cong., 

2d Sess. 21 (Jun. 21, 1994) (statement of David Kessler). See AR (Vol 709 Ref. 3). 

760 Senkus M (RJ. Reynolds Tobacco Co.), Some Effects of Smoking (1976/1977), at 7, 9. See AR (Vol. 

700 Ref. 593). 

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44974 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II. CA. 

entitled "Further Work on Extractable Nicotine." 761 According to this report, when 

smoke is inhaled into the lungs, there is virtually complete retention of the nicotine, 

regardless of whether the nicotine is in its free or bound form. However, the report 

hypothesizes that the speed of absorption is different when free or extractable nicotine is 

increased and that "with a higher 'extractable' nicotine, nicotine reaches the brain more 

quickly."762 RJR researchers have also recognized that pH adjustments affect the speed of 

nicotine absorption, recommending that in designing cigarettes for new smokers "[t]he 

rate of absorption of nicotine should be kept low by holding pH down, probably 

below 6."763 

FDA notes that the use of chemical manipulation to boost free nicotine levels may 

raise the amount of nicotine delivered to the smoker without a corresponding increase in 

nicotine yield, as measured by the FfC smoking machine. Thus, the actual nicotine 

delivery to the smoker from some brands may be higher than the FTC yield because of the 

addition of ammonia or similar compounds to increase free nicotine. 

Based on this evidence, the Agency fmds that cigarette manufacturers manipulate 

and control nicotine deliveries through the use of ammonia compounds. These 

compounds transform bound nicotine to free nicotine. According to the industry's own 

documents, this transformation facilitates consumer use of cigarettes for pharmacological 

761 BATCO, Further Work on 'Extractable' Nicotine (1966), at BW-W2-11615 (emphasis added). See 

AR (Vol. 62 Ref. 308). 

762 /d. at 7 (emphasis added). 

763 Teague CE (RJ. Reynolds Tobacco Co.), Research Planning Memorandum on Some Thoughts About 

New Brands ofCigarenesfor the Youth Market (Feb. 2, 1973), at4 (emphasis added). See AR(VoL 531 

Ref. 125). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44975

II. CA. 

purposes by: ( 1) increasing the amount of nicotine that is transferred from the tobacco to 

the smoke; (2) increasing the absorption of nicotine in the mouth; and (3) possibly 

increasing the speed of nicotine transfer to the brain. 

d. Nicotine Deliveries Have Increased in Recent Years by Design, 

Especially in Low-Tar Cigarettes 

The use of the methods described above, especially the use of nicotine-rich 

tobacco blends and selective flltration and ventilation, have increased nicotine deliveries to 

consumers. In the Jurisdictional Analysis, FDA found that nicotine deliveries as measured 

by the FfC smoking machine have been increasing since 1982, with the greatest increases 

occurring in the ultra-low-tar category. See 60 FR. 41727-41730. These increases have 

been occurring without parallel increases in tar deliveries, thus indicating an industry-wide 

trend of designing cigarettes with enhanced nicotine deliveries. 

The nicotine/tar ratios in low-tar cigarettes reflect these changes. The Agency's 

statistical analysis shows that, according to 1994 Federal Trade Commission data, the 

lowest-tar products had a markedly higher ratio of nicotine to tar than that found in 

higher-tar products. None of the 153 products with 14 or more milligrams of tar (the 

high-tar segment of the market) had a nicotine/tar ratio greater than 1 to 12. By contrast, 

88 of the 93 products with 6 or fewer milligrams of tar (the ultra-low-tar segment) had a 

nicotine/tar ratio greater than 1 to 12. See 60 FR. 41724. The industry did not challenge 

these figures in their comments. 

The increase in nicotine/tar ratios has occurred primarily in the last two decades. 

In comparison with the 1994 results, only 2 of the 142 marketed cigarettes included in the 

FTC's report for 1972 had a nicotine/tar ratio greater than 1 to 12. Thus, the evidence 

319 
44976 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

from the reported nicotine and tar deliveries supports the conclusion that as the market for 

lower tar cigarettes grew over the last 25 years, manufacturers deliberately altered what 

had been the traditional ratio of nicotine to tar, increasing nicotine levels in relation to tar 

levels.764 

This increase in the nicotine/tar ratios is persuasive evidence that the 

manufacturers design cigarettes to increase their relative nicotine deliveries. Without 

manufacturer intervention, nicotine levels tend to follow tar levels, because methods that 

reduce tar deliveries tend to reduce nicotine deliveries as well. As one industry executive 

testified before Congress, "[n]icotine levels follow the tar level. .. The correlation ... is 

essentially perfect correlation between tar and nicotine."765 The increase in nicotine 

deliveries relative to tar deliveries indicates that the manufacturers have taken affrrmative 

steps to enhance nicotine deliveries. 

The manufacturers dispute this finding. Although they first asserted that nicotine 

deliveries fall proportionately with tar deliveries, they now assert that the increase in 

nicotine/tar ratios is due to the unavoidable effects of flltration and ventilation-not any 

intentional actions of the manufacturers. The record does not support the industry's 

assertion, however. First, as discussed in section ll.C.4.a.ii., above, the cigarette 

764 Federal Trade Commission, Report of the "Tar" and Nicotine Content of 142 Varieties of Cigarettes 

{Jul. 1972). See AR (Vol. 314 Ref. 4856). On a percentage basis, only 1.4% of the 1972 products had a 

nicotine/tar ratio greater than 1 to 12. In 1994, that figure grew to 26.3% overall, and rose to 95% for the 

93 products in the lowest tar category. ld.; Federal Trade Commission, Tar, Nicotine, and Carbon 

Monoxide of the Smoke of933 Varieties of Domestic Cigarettes (1994). See AR (Vol 29 Ref. 485). 

765 Regulation of Tobacco Products (Part 1): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 103d Cong., 

2d Sess. 143, 378 (Mar. 25, 1994) (statement of Alexander Spears). See AR (Vol 707 Ref. 1). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44977

II.C.4. 

manufacturers deliberately use tobacco blends with the highest nicotine concentrations in 

the lowest tar cigarettes. 

Second, the record contradicts the industry's contention that they do not control 

the extent to which filtration and ventilation selectively reduce tar more than nicotine. 

Indeed, the record indicates that the manufacturers affirmatively use filtration and 

ventilation to enhance nicotine/tar ratios. See section II.C.4.b., above. 

Moreover, as the Agency reported in the Jurisdictional Analysis, increases in 

nicotine deliveries relative to tar deliveries have occurred in all categories of cigarettes. 

Although the increases in nicotine delivery are largest among the ultra-low-tar cigarettes, 

relative nicotine deliveries have also been increasing in low-tar and high-tar cigarettes. 

See 60 FR 41727-41731. The manufacturers' theory regarding the unavoidable effects of 

ftltration and ventilation in ultra-low-tar cigarettes cannot explain these other increases in 

relative nicotine deliveries. 

The evidence in the record provides specific examples where manufacturers appear 

to have designed cigarettes to achieve enhanced nicotine deliveries. As discussed in 

section IT.C.3.b., above, for example, RJR researchers in the mid-1970's recommended 

"maintaining the nicotine as high as possible" in low-tar cigarettes.766 Researchers 

specifically recommended that RJR develop a new brand that would deliver 5 mg tar and 

0.5 to 0.8 mg nicotine, stating that "on inhalation into the lungs, 0.5 to 0.8 mg of nicotine 

766 Senkus M (RJ. Reynolds Tobacco Co.), Some Effects of Smoking (1976/1977), at 10 (emphasis added). 

See AR (Vol. 700 Ref. 593). 

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44978 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

would provide sufficient nicotine to the blood to produce the stimulation and relaxation 

effects desired by the smoker."161 

In the late 1970's and 1980's, RJR began to market ultra-low-t2.r cigarettes that 

met these specifications. For instance, RJR fli'St introduced an ultra-light version of its 

Winston brand in 1981. That year, the Winston Ultra Lights lOO's had a tar delivery of 5 

mg and a nicotine delivery of 0.5 mg-exactly the deliveries recommended by its 

researchers as providing the sufficient nicotine to provide the pharmacological effects 

sought by consumers. 768 As recently as 1994, both the king-size Winston Ultra Lights 

(hard pack) and the Winston Ultra Lights lOO's (hard pack) continued to have these 

recommended deliveries of 5 mg tar and 0.5 mg. nicotine, as did king-size Camel Ultra 

Lights and several other RJR ultra-low-tar brands.769 

Another example of deliberate design to achieve relatively enhanced nicotine 

deliveries appears to be the Merit Ultra Lights by Philip Morris. Philip Morris researchers 

conducted extensive research in the 1970's to determine "what combinations of tar and 

nicotine make for optimal acceptibility in a low delivery cigarette."770 This research 

concluded that a higher nicotine/tar ratio (at least 0.09), compared to the natural ratio of 

767 /d. at 11-12 (emphasis added). 

768 Federal Trade Commission, "Tar," Nicotine and Carbon Monoxide of the Smoke of200 Varieties of 

Cigarettes (1981). See AR (Vol535 Ref. 96, vol. ill.D). 

769 Federal Trade Commission, Tar, Nicotine, and Carbon Monoxide of the Smoke of 933 Varieties of 

Domestic Cigarettes (1994). See AR(Vol29 Ref. 485). 

770 Dunn WL, Johnston M, Ryan F (Philip Morris Inc.), Plans for 1972 (Sep. 8, 1971), in 141 Cong. Rec. 

H8128 (daily ed. Aug. 1, 1995). See AR (Vol 711 Ref. 6). 

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II. CA. 

0.07, was optimal.771 Similarly, shortly thereafter, Philip Morris introduced the king-size 

Merit Ultra Lights with an elevated nicotine/tar ratio of approximately 0.10.772 The kingsize Merit Ultra Lights (hard pack) continued to have an elevated nicotine/tar ratio of 0.10 

as recently in 1994.773 According to William Farone, the former director of applied 

research at Philip Morris, the Merit Ultra Lights is an example of "a blend change 

incorporating the greater use of higher nicotine tobacco ... [to] produce a low tar 

cigarette with the desired pharmacologically active level ofnicotine."714 

These brands do not appear to be isolated examples. The evidence in the record 

indicates that the design of cigarettes to achieve specific nicotine deliveries is a common 

practice within the cigarette industry. According to Farone, cigarettes are designed to 

"attain a predetermined nicotine/tar ratio."715 Likewise, Ian Uydess, the former Philip 

Morris scientist, states that "[n]icotine levels were routinely targeted and adjusted by 

Philip Morris."116 

771 Jones B, Houck W, Martin P (Philip Morris Inc.), Low Delivery Cigarettes and Increased Nicotineffar 

Ratios, A Replication (Oct 1975), in 141 Cong. Rec. H8132 (daily ed. Aug. 1, 1995) (emphasis added). 

See AR(Vol 711 Ref. 6). 

772 Federal Trade Commission, "Tar," Nicotine, and Carbon Monoxide of the Smoke of200 Varieties of 

Cigarettes (1981), See AR (Vol 535 Ref. 96, vol. ill.D). 

773 Federal Trade Commission, Tar, Nicotine, and Carbon Monoxide of the Smoke of933 Varieties of 

Domestic Cigarettes (1994). See AR (Vol 29 Ref. 485). 

774 Farone W A, The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 10 (emphasis added). See AR (Vol 638 Ref. 2). 

775 /d. at 11 (emphasis added). 

776 Declaration of Uydess n.. (Feb. 29, 1996), at 8 (emphasis added). See AR (Vol 638 Ref. 1 ). 

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44980 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

e. The Manufacturers Precisely Control Nicotine Deliveries 

A principal feature of all marketed cigarettes is the precise control over nicotine 

delivery achieved by the manufacturers. Annual variations in the nicotine content of raw 

tobacco leaves originating in the same geographical area can be as high as 100%.777 

Nevertheless, the nicotine deliveries in commercial cigarettes are consistent to a tenth of 

1%. See 60 FR 41694. This is a high degree of control even for a conventional 

pharmaceutical company. It does not occur by chance, and the industry does not pretend 

that it does. The precise control ensures that smokers receive a consistent nicotine dosage 

within a brand from cigarette to cigarette, pack to pack, and year to year. 

The evidence in the record supports a finding that the manufacturers' precise 

control over nicotine levels reflects the central role of nicotine in cigarette manufacturing. 

According to the statement of William Farone of Philip Morris, the cigarette industry even 

developed "complex computer models to help determine nicotine and tar deliveries."778 

These models "allowed blend ingredients, filter and paper components, and numerous 

other variables to be considered simultaneously" and "enabled product developers to 

identify which components were required to produce specific nicotine and tar 

deliveries."779 

The administrative record demonstrates that the industry pays careful attention to 

nicotine throughout the manufacturing process. In particular, as described below, nicotine 

777 Joint Comment of Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol. IV, at32. See AR (Vol535 

Ref. 96). 

778 Farone W A, The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 13. See AR (Vol 638 Ref. 2). 

779 /d. at 13-14. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44981

II.C.4. 

plays an essential role in tobacco growing, leaf purchasing, leaf blending, and the 

manufacture of reconstituted tobacco. This control provides smokers seeking the 

pharmacological effects of nictine with a remarkably consistent dose of nicotine from 

cigarette to cigarette. 

i. Tobacco Growing. Cigarette manufacturers' ability to control nicotine 

delivery begins with tobacco growing. Although cigarette manufacturers do not directly 

control what tobacco farmers grow, they have successfully influenced the characteristics 

of tobacco crops, including their nicotine content. 

As discussed in the Jurisdictional Analysis, cigarette manufacturers were influential 

in establishing the Minimum Standards Program (MSP) administered by the USDA. This 

program began in the 1960's in response to the emergence of so-called "discount" 

varieties of tobacco that had low nicotine contents. The MSP eliminated the discount 

varieties and helped control the variation in the nicotine content of the tobacco crop by 

setting minimum and maximum permissible levels of nicotine. See 60 FR 41697-41698. 

Moreover, tobacco leaf experts have reported that the nicotine level in certain 

varieties of tobacco rose in response to the needs of cigarette manufacturers. For 

instance, an expert with a U.S.leaf company observed in 1983 that "[o]nce the 

manufacturer has expressed a preference for a certain style of leaf, cultural practices can 

be implemented on the farm to try to fulfill his requirements."780 According to this expert, 

780 Glass JM, Production and leaf chemistry of burley tobacco in Latin America, in Recent Advances in 

Tobacco Science, 37th Tobacco Chemists' Research Conference (1983), at 81. See AR (Vol528 Ref. 97, 

appendix 19). 

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44982 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

"a noticeable change has occurred in leaf chemistry" of burley tobacco imported into the 

United States-"especially the increase in nicotine levels."181 

ii. Leaf Purchasing. The industry's direct control over nicotine delivery starts 

with its leaf purchasing decisions. As described in the Jurisdictional Analysis, see 60 FR 

41703-41706, and as the industry comments themselves confrrm, important leaf 

characteristics in purchasing include "stalk position," "impact," and "smoke quality." 

These characteristics correlate closely with the nicotine content in the tobacco leaves. 

The industry acknowledges that, as a general rule, the relative position of a 

tobacco leaf on the stalk of the plant will determine the nicotine content in that leaf. 782 

The nicotine level usually goes up from the bottom to the top of the stalk. According to 

Brown & Williamson's comment, "[h]igher stalk tobacco leaves do have rrwre nicotine 

than lower stalk leaves on the same plant."183 

The Agency has found that stalk position plays a key role in the leaf purchasing 

practices of cigarette manufacturers. The industry does not dispute the significance of 

stalk position. For example, Brown & Williamson does not dispute the Agency's finding 

that stalk position is the "first thing" Brown & Williamson looks for during leaf 

purchasing. See 60 FR 41705. Similarly, RJR concedes that stalk position is one of the 

three primary "quality determinants" used by RJR in leaf purchasing. 784 Because of the 

781 /d. at 77 (emphasis added). 

782 RJ. Reynolds Tobacco Co., Comment (Jan. 2, 1996), at 44. See AR (Vol 519 Ref. 103 ). 

Brown & Williamson Tobacco Corp., Comment (Jan. 2, 1996), at 10. See AR (Vo1529 Ref. 104). 

783 Brown & Williamson Tobacco Corp., Comment (Jan. 2, 1996), at 10 (emphasis added). See AR 

(Vol. 529 Ref. 104). 

784 RJ. Reynolds Tobacco Co., Comment (Jan. 2, 1996), at44. See AR(Vo1519 Ref. 103). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44983

II. CA. 

relationship between stalk position and nicotine content, when manufacturers select 

tobacco leaves based on stalk position, they are in effect controlling the nicotine content 

of the leaves they purchase. 

It is also undisputed that "impact" is associated with the nicotine level in a tobacco 

leaf and that "impact" plays a role in leaf purchasing. RJR, for instance, admits that 

"impact is ... an element of any smoking of tobacco, including smoking of samples 

purchased during the auction season;" and that "nicotine is reported to be a factor" 

in "impact."785 

Cigarette manufacturers deny that nicotine plays a role in leaf selection. In their 

words, "nicotine content is not a principal criterion in the purchase of leaf."786 The 

Agency does not find this assertion to be credible. Finished cigarettes have highly 

consistent nicotine deliveries. This control could not be achieved without taking into 

account nicotine content in the purchase of tobacco leaves. If nicotine content was not a 

critical purchasing factor, manufacturers would have no assurance that they were 

purchasing leaves that could be blended together to provide consistent nicotine deliveries 

in the fmished cigarettes. 

iii. Leaf Blending. Leaf blending is one of the primary means the industry uses 

to control nicotine levels in cigarettes. This is acknowledged by the industry, which states 

in its joint comment that "[t]obacco is blended for consistency and uniformity .... "787 At 

785 /d. at 43-44. 

786 Joint Comment of Cigarette Manufac11.1rers, Comment (Jan. 2, 1996), Vol. IV, at 58. See AR (Vol 535 

Ref. 96). 

787 /d. at 66. 

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44984 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

a minimum, therefore, the industry has conceded one of the Agency's points in its 

Jurisdictional Analysis: blending to ensure "consistency and uniformity" enables the 

industry to overcome naturally occurring variations in nicotine associated with genetics 

and soil and climatic conditions. See 60 FR 41706. 

The joint industry comment provides a graphic representation of the naturally 

occurring variations in nicotine levels in raw tobacco. The industry's submission shows 

the rising but substantially fluctuating nicotine levels in flue-cured tobacco from the early 

1950's through the early 1990's.788 Through blending, tobacco manufacturers are able to 

overcome these variations and produce a remarkably consistent product with uniform 

nicotine levels. 

The central role of blending in ensuring consistent nicotine yields is acknowledged 

in the industry comments. As Brown & Williamson observes, ''the manufacturing 

challenge is to maintain constancy of product composition not only from day to day, but 

month to month and year to year despite variation in the raw material."789 

iv. Reconstituted Tobacco. The tobacco industry also pays careful attention 

to nicotine during the manufacture of reconstituted tobacco, which makes up about 15% 

to 25% of the tobacco in cigarettes.790 The process of manufacturing reconstituted 

tobacco is described in detail in the Jurisdictional Analysis. See 60 FR 41719-41721. The 

careful management of nicotine in this process allows the manufacturers to control 

precisely the level of nicotine in reconstituted tobacco. 

788 ld. at Vol. IV, Fig. 1. 

789 Brown & Williamson Tobacco Corp., Comment (Jan. 2, 1996), at 17. See AR (Vol 529 Ref. 104). 

790 Joint Comment of Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol. IV, at 72. See AR(Vol 535 

Ref. 96). 

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II.C.4. 

The statement of William Farone, the fonner Philip Morris director of applied 

research, describes how "the industry has used reconstituted tobacco products to assist in 

controlling the nicotine delivery in cigarettes."791 According to Farone: 

By controlling the ingredients that go into making reconstituted 

tobacco, the industry controls the chemical and physical properties 

of the fmished sheet, including its nicotine content . ... The 

reconstituted tobacco blend destined for a low tar cigarette can be 

made with a higher concentration of (high-nicotine] burley tobacco 

scraps than the blend of reconstituted tobacco designated for a full 

flavor brand. 792 

Farone also describes how cigarette manufacturers monitor nicotine levels in 

reconstituted tobacco, stating that "[q]uality control checks involving the use of a gas or 

liquid chromatography to ascertain the exact nicotine amounts are routinely employed 

during the process."793 In its comments, Philip Morris confmns that it regularly measures 

nicotine levels in reconstituted tobacco. According to Philip Morris' comments: 

Representative periodic sampling is done with respect to all tobacco materials that 

go into the cigarette manufacturing process-natural leaf tobacco, expanded 

tobacco, as well as blended and reconstituted leaf. Such periodic sampling 

includes measurements of ... alkaloids or nicotine.194 

791 Farone W A. The ManipulaJion and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 12. See AR (Vol 638 Ref. 2). 

792 /d. 

793 /d. 

794 Philip Morris Inc., Comment (Apr. 19, 1996), at 56 (emphasis added). See AR (Vol 700 Ref. 226). 

The Agency also received a declaration relating to reconstituted tobacco from Jerome Rivers, a former 

supervisor in Philip Morris' Blended Leaf Plant, Declaration of Rivers J (Mar. 7, 1996). See AR (Vol. 

640 Ref. 3), as well as two affidavits from current Philip Morris employees denying some of Rivers' 

assertions (Philip Morris Inc., Comment (Apr. 19, 1996), Appendix 3. See AR (Vol. 700 Ref. 226)), and 

supplemental comments relating to Rivers' declaration submitted by Philip Morris after the close of the 

comment period. Philip Morris Inc., Supplemental Comments (May 30, 1996). See AR (Vol. 700 Ref. 

1331). After considering Rivers' declaration. the two affidavits, and Philip Morris' original and 

supplemental comments, the Agency has determined that it will not rely on the Rivers declaration or 

the two affidavits. 

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44986 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

There is also evidence that reconstituted tobacco is used by cigarette 

manufacturers as a vehicle for the addition of ammonia compounds. An article in the Wall 

Street Journal reports that Philip Monis, Brown & Williamson, and R.J. Reynolds add 

ammonia to their reconstituted tobacco.795 According to the article, internal Brown & 

Williamson documents describe the "nicotine pick-up potential" of ammonia in 

reconstituted tobacco. The tobacco company documents described in the article state that 

ammonia added to reconstituted tobacco can scavenge nicotine from the tobacco in the 

rest of the cigarette, significantly increasing the level of "free nicotine" in the cigarette. 

One of the documents, a Brown & Williamson competitive analysis of Marlboro, states 

that ammonia-treated reconstituted tobacco is ''the soul of Marlboro."796 

As a result of the industry's focus on nicotine in the areas described above, as well 

as in other areas described in the Jurisdictional Analysis, cigarette manufacturers provide 

smokers seeking the pharmacological effects of nicotine with a remarkably consistent dose 

of nicotine from cigarette to cigarette. 

f. Satisfying Consumer Preferences Requires Controlling and 

Manipulating Nicotine Deliveries to Satisfy Addiction and 

Provide Other Pharmacological Effects 

The cigarette industry maintains that it does not control and manipulate nicotine 

deliveries because its sole objective is to design cigarettes that meet consumer preferences. 

Brown & Williamson, for example, asserts that 

[I]ts intent is to design, manufacture and market its cigarettes to 

meet the preferences of adult smokers over competing brands, not 

to create and maintain addiction .... Consumer demand determines 

795 Freedman AM, Tobacco fllDl shows bow ammonia spurs delivery of nicotine, Wall Street Journal (Oct 

18, 1995). See AR (Vol. 639 Ref. 2). 

796 ld. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44987

the content of the tobacco blends used in marketed B&W 

cigarettes. 797 

II.C.4. 

Similarly, RJR asserts that it "designs, manufactures, and markets a broad range of 

cigarette products in response to the ... demands of adult smokers" and "not ... to 

provide smokers with pharmacologically active 'doses' of nicotine."798 

The Agency agrees that cigarette manufacturers, like other manufacturers of 

consumer products, design their products to meet consumer demand. The Agency 

disagrees, however, that this establishes that cigarette manufacturers do not control and 

manipulate nicotine levels for pharmacological purposes. The unstated premise of the 

manufacturers' argument is that the consumer demands they seek to satisfy do not include 

a desire for the pharmacological effects of nicotine. This is simply not credible. To the 

contrary, the Agency finds that what the cigarette manufacturers describe as satisfying 

consumer preferences is, in reality, providing consumers with cigarettes that sustain 

consumers' addiction and offer other desired pharmacological effects of nicotine. 

It is beyond reasonable dispute that consumers of cigarettes smoke for the 

pharmacological effects of nicotine, including satisfaction of their addiction. As discussed 

in sections ll.A and II.B., above, this fact is widely accepted in the scientific community. 

As discussed in section ll.C.2. and 3., above, this fact is also accepted by the cigarette 

manufacturers' own scientists. The implication of this fact for cigarette design is clear: to 

compete in the marketplace, cigarette manufacturers must produce cigarettes that sustain 

797 Brown & Williamson Tobacco Corp., Comment (Jan. 2, 1996), at 3, 12 (emphasis added). See AR 

(Vol. 529 Ref. 104). 

798 RJ. Reynolds Tobacco Co., Comment (Ian. 2, 1996), at 3-4. See AR (Vol 519 Ref. 103). 

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44988 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

smokers' addiction and provide the other pharmacological effects of nicotine sought by 

smokers. Any cigarette manufacturer that failed to provide these pharmacological effects 

would soon fmd itself out of business, because addicted smokers and other smokers 

seeking the pharmacological effects of nicotine would switch to other brands. 

Brown & Williamson provides an example of how meeting consumer preferences 

compels cigarette manufacturers to control and manipulate nicotine. As noted above, 

Brown & Williamson's comments assert that Brown & Williamson designs its cigarettes to 

meet "consumer demands." As discussed above in section IT.C.2.c., however, the 

documents in the record from Brown & Williamson and its parent, BATCO, also 

acknowledge that "a considerable proportion of smokers depend on the pharmacological 

action of nicotine for their motivation to continue smoking"799 and that "nicotine plays a 

predominant role for many smokers."800 Indeed, as recently as 1992, company 

researchers stated that what "the smoker clearly wanti' is "[t]he rapid, peaking intake of 

nicotine."801 Both Brown & Williamson's assertion that it designs cigarettes to meet 

"consumer demands" and its acknowledgment that smokers seek ''the pharmacological 

action of nicotine" leads to an obvious conclusion: Brown & Williamson's efforts to meet 

consumer preferences necessarily require the company to design cigarettes that provide 

consumers with the pharmacological effects of nicotine. 

799 Kilburn KD, Underwood JG (BATCO), Preparation and Properties of Nicotine Analogues (Nov. 9, 

1972), at 2 (emphasis added). See AR (Vol 31 Ref. 524-1). 

800 Green SJ (BATCO), BAT Group Research (Sep. 4, 1968), at 2 (emphasis added). See AR (Vol 15 

Ref. 192). 

801 Transdermal Nicotine, Research and Development/Quality, at 3 (emphasis added). See AR (Vol 531 

Ref. 125). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44989

II.C.4. 

Documents in the administrative record confmn that in designing cigarettes to 

meet "consumer demands," the cigarette manufacturers carefully take into account 

consumers' pharmacological need for nicotine. One example is Project Wheat As 

discussed above in section II.C.3.c.ii., BATCO conducted Project Wheat in the mid1970's to determine smokers' "Inner Need" for nicotine.802 BATCO undertook ihis 

research for the express purpose of improving its ability to meet consumer demands. As 

the BATCO researchers stated, Project Wheat was "seen as a part of a general approach 

to the problem of designing cigarettes of increased consumer acceptance" because "[i]n 

considering which product features are important in terms of consumer acceptance, the 

nicotine delivery is one of the more obvious candidates. " 803 

Project Wheat found that no cigarettes then on the market provided the "low tar 

and medium nicotine deliveries" sought by smokers who had an average "Inner Need" for 

nicotine, but "an above average concern for health."804 According to a "model of the 

market" developed in Project Wheat, over 40% of smokers wanted cigarettes with a 

higher ratio of nicotine to tar than was then available.805 Shortly thereafter, ultra-low-tar 

cigarettes made with nicotine-rich tobacco blends were introduced into the market, 

including a Brown & Williamson cigarette called Barclay. See section II.C.4.a.ii., above. 

802 Wood DJ, Wilkes EB (BATCO), Project Wheat- Part 1: Cluster Profiles of U.K. Male Smokers and 

Their General Smoking Habits (Jul. 10, 1975), at 1. See AR (Vol 20 Ref. 204-1). 

803 /d. at 1, 3 (emphasis added). 

804 Wood DJ (BATCO), Project Wheat- Part 2: U.K. Male Smokers: Their Reactions to Cigarettes 

of Different Nicotine Delivery as Influenced by Inner Need (Jan. 30, 1976), at 2. See AR (Vol 20 

Ref. 204-2). 

805 BATCO Group R&D Conference on Smoking Behaviour at Southampton, England (Oct 11-12, 1976), 

at BW-W2-02308. See AR (Vol 178 Ref. 2074 ). 

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44990 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.4. 

The process of "consumer preference testing," which is described in the comments 

of the cigarette manufacturers, is one of the ways the manufacturers refine nicotine 

deliveries. In its comments, Brown & Williamson explains that it asks consumers to rate 

prototype cigarettes to determine if its tobacco blends produce "satisfaction," "strength," 

and other desirable attributes to eonsumers. According to Brown & Williamson, 

"satisfaction," as used in consumer preference testing, "reflects the consumer's total 

reaction to the total smoking experience delivered by the cigarettes."806 If consumer 

testing shows that a Brown & Williamson cigarette produces insufficient satisfaction, 

Brown & Williamson says its product developers will "adjust product recipes and designs 

to improve or maintain product preference."807 

In reality, however, Brown & Williamson knows that nicotine's pharmacological 

effects play the primary role in cOnsumer "satisfaction." For instance, in 1983, BATCO 

researchers reported their "basic assumption" that "nicotine, ... is alrrwst certainly the 

key srrwke component for satisfaction."808 Likewise, in a 1984 conference, the BATCO 

researchers reported that "'satisfaction' must be related to nicotine. Many people believe 

it [is] a 'whole body response' and involves the action of nicotine in the brain.'7809 Thus, 

Brown & Williamson understands that reports of inadequate satisfaction in consumer 

preference testing can signal a need to enhance nicotine deliveries. 

806 Brown & Williamson Tobacco Corp., Comment (Jan. 2, 1996), at 8. See AR (Vol 529 Ref. 104). 

807 Id. at 9. 

808 Minutes of BATCO Research Conference at Rio de Janeiro (Aug. 22-26, 1983), at 10 (emphasis 

added). See AR (Vol 22 Ref. 287-5). 

809 BATCO, Conference Outline (Jun. 6-8, 1984), at BW-W2-01977 (citation omitted) (emphasis added). 

See AR (Vol 22 Ref. 287-6). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44991

II. CA. 

The statements of William Farone, the fonner Philip Morris director of applied 

research, and Ian Uydess, the former Philip Morris scientist, make precisely this point. 

They confirm that product developers for the cigarette manufacturers do in fact adjust 

nicotine levels during consumer testing. According to Farone: 

This concept of nicotine delivery being essential to consumer 

satisfaction was common knowledge within Philip Morris and the 

rest of the industry. When consumer testing indicated that a 

product was lacking in "impact" or some similar descriptor that 

could be associated with nicotine, experienced market researchers 

and product developers would compensate by increasing nicotine 

levels . ... 810 

Similarly, Ian Uydess states: 

In the case of nicotine, specific levels of nicotine would be targeted 

in the test products (test 'articles') in a range that extended from 

'ultra-low' (or even zero) nicotine deliveries, to deliveries equal 

to, or slightly above that found in some of their own (or a 

competitor's) 'full-flavor' or 'full-bodied' products. This was done 

to examine how the smoker would react to various nicotine levels 

as a predictor of how well these products might do in the market 

with specific regard to: "not enough nicotine", "an acceptable level 

of nicotine", or ''too much nicotine."811 

Thus, the Agency concludes that the manufacturers' explanation for their actions 

does not withstand scrutiny. Overwhelming evidence establishes that smokers seek the 

phannacological effects of nicotine from cigarettes. See section II.A and II.B., above. 

Overwhelming evidence also establishes that the manufacturers know that. See section 

ll.C.2., above. Manufacturers that design their products to meet consumer demands that 

81 ° Farone W A, The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 8 (emphasis added). See AR (Vol 638 Ref. 2). 

811 Declaration of Uydess IL (Feb. 29, 1996), at 11. See AR (Vol 638 Ref. 1 ). 

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44992 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.5. 

they know are pharmacological in nature are necessarily engaged in designing products to 

provide pharmacological effects. 

In sum, the evidence discussed in this section discloses that the manufacturers use 

several methods to control and manipulate nicotine deliveries in commercial cigarettes. 

These design features include: (1) the use of various tobacco blends with varying nicotine 

levels; (2) fllter ventilation and related technologies that selectively remove more tar than 

nicotine and allow smokers to obtain more nicotine than the measured FfC yields; and (3) 

the use of ammonia technologies that increase the delivery of "free" nicotine. In addition, 

the evidence shows that the manufacturers control nicotine levels in virtually all aspects of 

cigarette manufacture, thereby ensuring that smokers receive a consistent nicotine delivery 

in each cigarette. Combined with the evidence regarding product research and 

development in section II.C.3., this evidence shows that the manufacturers "design" 

cigarettes to provide a consistent, pharmacologically active dose of nicotine to smokers, 

thereby establishing that cigarettes are "intended" to affect the structure and function of 

the body. 

5. Conclusion 

The Agency's role in determining intended use through the statements, research, 

and actions of the manufacturer is to be a fact fmder. In this case, after careful 

consideration of the evidence and the comments, the Agency fmds that the evidence of 

cigarette manufacturers' statements, research, and actions demonstrates that cigarettes are 

intended to cause significant pharmacological effects in smokers. The Agency makes this 

fmding for three principal reasons. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44993

II.C.5. 

First, as described in section ll.C.2., above, the evidence shows that the cigarette 

manufacturers are aware of and have exhaustively studied the pharmacological effects and 

uses of nicotine. In the case of Philip Morris, RJR, and Brown & Williamson, the 

manufacturers conducted extensive in-house research on the pharmacological effects and 

uses of nicotine. Their researchers and officials repeatedly expressed the view that 

nicotine causes pharmacological effects, that consumers smoke cigarettes to obtain these 

effects, and that cigarettes are delivery devices for nicotine. The evidence further shows 

that the cigarette manufacturers as a group funded extensive research into nicotine 

pharmacology through the Council for Tobacco Research. This _evidence establishes that 

the manufacturers "have in mind" that cigarettes will be used for the particular purpose of 

delivering the pharmacological effects of nicotine to smokers. 

Second, the evidence in sections ll.C.3. and ll.C.4. shows that the cigarette 

manufacturers "design" cigarettes to have pharmacological effects. This evidence reveals 

that the manufacturers have conducted extensive product research and development to 

identify pharmacologically active doses of nicotine and to optimize the delivery of nicotine 

to smokers and that company researchers repeatedly recommended the development of 

cigarettes that maintain adequate nicotine deliveries. 

This evidence also shows that the cigarette manufacturers carefully control and 

manipulate the nicotine delivery of their commercially marketed cigarettes to provide 

smokers with a pharmacologically active dose of nicotine. Among other practices, the 

manufacturers use high-nicotine blends that increase nicotine deliveries in their lowest-tar 

products; rely on filtration and ventilation technologies that selectively remove more tar 

than nicotine; add ammonia compounds that increase the delivery of "free" nicotine; and 

337 
44994 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.5. 

carefully control the nicotine level in all cigarettes. Through the use of these practices, the 

cigarette manufacturers are able to deliver sufficient nicotine to satisfy consumers. An 

inevitable consequence of these practices is to keep consumers smoking by sustaining their 

addiction. 

Third, the manufacturers have been unable to provide a convincing explanation 

that refutes either the evidence showing that they have in mind the pharmacological effects 

and uses of cigarettes or the evidence showing that they have designed cigarettes to 

provide these effects. This failure is significant because the manufacturers alone have 

access to the company documents and other information that would provide a complete 

explanation of their knowledge and design practices. The absence of a credible counterexplanation by the persons best situated to explain the evidence before the Agency adds 

additional support for the Agency's fmdings. 

Under the legal standards described in section II.C.l., above, the evidence that the 

manufacturers (1) "have in mind" that cigarettes will be used for pharmacological 

purposes and (2) "design" cigarettes to deliver a pharmacologically active dose of nicotine 

each provides an independent basis for establishing intended use. Taken together, the_ two 

categories of evidence are consistent with each other and mutually reinforcing. Taken as a 

whole, therefore, the evidence from the statements, research, and actions of the 

manufacturers amply supports the finding that the effects of cigarettes on the structure and 

function of the body are "intended" by the cigarette manufacturers. 

338 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44995

II.C.6. 

6. Response to Comments 

a. Comments on Statements and Research on Nicotine's Drug Effects 

i Comments on Specific Philip Morris Statements and Research Projects. In 

July 1995, a large number of Philip Morris internal documents reflecting over a decade of 

its research on smoking motivation were published in the Congressional Record. A 

smaller number of documents from Philip Morris became available as a result of a lawsuit 

brought against Philip Morris by a smoker.812 In its Jurisdictional Analysis, FDA 

reproduced statements from those documents as evidence that company officials believed 

that consumers use cigarettes to obtain the pharmacological effects of nicotine. 

A comment submitted by Philip Morris argues that the documents do not provide 

such evidence because FDA allegedly mischaracterized or took out of context some of the 

quotes from the documents. Philip Morris argues that: (1) other statements in the 

documents show that Philip Morris researchers were actually uncertain why people smoke; 

(2) in addition to studies on the pharmacological motivations for smoking, Philip Morris 

conducted studies on other motives for smoking, demonstrating that Philip Morris did not 

believe that pharmacological motives for smoking were primary; (3) FDA omitted 

passages from the documents that would have cast them in a different light; and (4) some 

of the statements cited by FDA were actually only hypotheses of Philip Morris 

researchers, or the hypotheses of outside researchers, which were not ultimately supported 

by the results of their studies. 

812 Cipollone v. liggett Group Inc., No. 83-2864 (D.N.J. dismissed Nov. 3, 1992). 

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44996 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

FDA has reviewed all of the publicly available documents written by Philip Morris 

officials. The Agency has concluded that, both individually and as a whole, they 

demonstrate that Philip Morris conducted extensive, sophisticated research on the 

pharmacological effects of nicotine in cigarettes and the pharmacological motives for 

smoking, and that officials responsible for research and development at all levels of the 

company expressed consistent beliefs throughout the period covered by the documents 

that the pharmacological effects of nicotine were the prima.Iy reason people smoke. The 

documents also demonstrate that these beliefs, and the data supporting them, were held by 

and communicated to company executives,including the board of directors. Below, FDA 

addresses each of Philip Morris' arguments, with examples from individual documents 

claimed by Philip Morris to have been mischaracterized. In every case, the documents 

speak for themselves. 

1. Philip Morris argues that it conducted studies on other motives for 

smoking, demonstrating that Philip Morris did not believe that phannacological motives 

for smoking were primary. Philip Morris cites a single document from 1970 for this 

premise. 

FDA has reviewed the studies on smoking motivation referred to in the publicly 

available Philip Morris documents. The relative importance Philip Morris placed on 

pharmacological motives for smoking compared to other motives is clear from these 

studies. The vast majority of the company's studies were conducted to assess the 

pharmacological effects of, and motives for, smoking. A small minority of the studies 

were intended to assess other reasons for smoking. Indeed, the research documents show 

that Philip Morris' focus on the pharmacological effects of nicotine increased over time. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44997

II.C.6. 

By the early 1980's, when the large collection of documents made public by Congress end, 

Philip Morris' research on smoking motivation was overwhelmingly dominated by 

research on the pharmacological effects of nicotine. A 1980 report, for instance, describes 

fifteen major studies-eleven of which examined various aspects of nicotine's 

pharmacological effects on smokers and on dose-regulating behavior by smokers.813 The 

nicotine-related studies included: 

( 1) Studies on the effects of cigarettes and nicotine on electrical and chemical activity 

in the human brain. The objectives of this program are described as follows: 

It is our belief that the reinforcing properties of cigarette 

smoking are directly relatable to the effects that smoking 

has on electrical and chemical events within the central 

nervous system. Therefore, the goals of the 

electrophysiology program are to: (I) Determine how 

cigarette smoking affects the electrical activity of the brain, 

and Cm Identify, as far as possible, the neural elements 

which mediate cigarette smoking's reinforcing actions.814 

(2) Studies on rats demonstrating that nicotine is "reinforcing" (causes animals to 

"self-administ[er]" nicotine, i.e., seek repeated doses), tests positive in drug 

discrimination tests which can predict whether a substance has mood-altering 

effects in humans, and acts centrally in the brain. The objectives of this program 

include "(I) To develop a better understanding of the behavioral pharmacological 

actions of nicotine, particularly the action which reinforces smoking behavior."815 

813 Dunn WL (Philip Monis Inc.), Plans and Objectives-1981 (Nov. 26, 1980), in 141 Cong. Rec. 

H7681-7683 (daily ed. Jul. 25, 1995). See AR(Vol14 Ref. 175a). 

814 !d. at H7681. 

815 !d. at H7682. 

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44998 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

(3) Studies on the level of nicotine in saliva over time, and on the correlation of 

salivary nicotine levels to blood nicotine levels, to answer the question, "Does a 

low systemic level of nicotine trigger the smoking response?"816 

Philip Morris provides no additional or later documents that would suggest that 

these studies are not representative. Thus, the extensive and sustained investigation into 

nicotine pharmacology reflected in Philip Morris' documents demonstrates that its 

researchers believed that the pharmacological effects of nicotine were the primary reason 

for smoking. Moreover, as detailed in section ll.C.2.a.iii., above, a 1992 Philip Morris 

document shows that the views expressed by Philip Morris officials in the 1970's and 

1980's are still held by Philip Morris employees.817 

Moreover, even if Philip Morris had significantly researched other motives for 

smoking, this could not render Philip Morris' research into the pharmacological motives 

for smoking irrelevant. Neither FDA nor the courts have suggested that a product with 

pharmacological uses must not have any other uses if it is to be regulated as a drug or 

device. When it has been established that a manufacturer intends that its product be used 

for a pharmacological purpose, FDA's jurisdiction is not defeated by a showing that the 

816 ld. at H7682. 

See also Dunn WL (Philip Morris Inc.), Plans and Objectives-1979 (Dec. 6, 1978) ("All of the effort of 

the Behavioral Research Laboratory is aimed at achieving this objective: To understand the psychological 

reward the smoker gets from smoking, to understand the psychophysiology underlying this reward, and to 

relate this reward to the constituents in smoke"), in 141 Cong. Rec. H7668-7670 (daily ed. Jul. 25, 1995). 

See AR (Vo114 Ref. 175a). 

Dunn WL (Philip Morris Inc.), Plans and Objectives-1980 (Jan. 7, 1980), in 141 Cong. Rec. H7670-

7672 (daily ed. Jul. 25, 1995). See AR (Vo114 Ref. 175a). 

817 Philip Morris Inc., Draft Report Regarding a Proposal for a "Safer" Cigarette, Code-named Table. See 

AR (Vol. 531 Ref. 122). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 44999

II.C.6. 

manufacturer also intends the product to be used for other, nonpharmacological purposes. 

See, e.g., United States v. Guardian Chemical Corp., 410 F.2d 157, 162-163 (2d Cir. 

1969) (solvent intended both to dissolve kidney stones and to clean medical instruments 

was properly regulated as a "drug"). Thus, if there is evidence that nicotine-containing 

tobacco products are intended to produce significant drug effects in consumers, the fact 

that manufacturers may also intend them to provide "flavor" or other nonpharmacological 

effects would not defeat a fmding that such products are "drugs" within the meaning 

of the Act. 

2. Philip Morris also contends that in reproducing certain quotes from Philip 

Morris documents, FDA omitted portions of the documents that would have shown that 

the author did not believe that people smoke to obtain the pharmacological effects of 

nicotine. Philip Morris cites four examples. FDA has reviewed each of the documents in 

question and has concluded that each of the statements quoted in the Jurisdictional 

Analysis has been fairly presented and has not been taken out of context. 

First, FDA reproduced in the Jurisdictional Analysis a number of quotes from 

memoranda, presentations, and letters by William Dunn, a senior scientist at Philip Morris, 

who was responsible for a large number of research projects on smoking motivation. The 

quotes demonstrated that Dunn believed people smoke to obtain the pharmacological 

effects of nicotine. See 60 FR 41591, 41596-41599, 41682, 41756, 41761. Philip Morris 

claims that several quotes were taken out of context, and that the full context 

demonstrates that Dunn did not believe the pharmacological effects of nicotine are the 

primary reason people smoke, and in fact did not know why people smoke. Philip Morris 

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45000 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

also contends that the quotes attributed to Dunn were in fact the views of other scientists 

that Dunn was simply describing. 

The collected writings of William Dunn could not be clearer. As is fully 

demonstrated in the Jurisdictional Analysis, he made repeated statements throughout his 

career reflecting a consistent belief that people smoke primarily to obtain the 

psychophannacological effects of nicotine. As recently as 1994, when Dunn was visited 

by FDA investigators, he told them that people smoke for the nicotine.818 At a conference 

in 1972, Dunn explained his "conviction" that consumers smoke for the phannacological 

effects of nicotine. This quote also refutes Philip Morris' claim _that Dunn was merely 

describing the views of other scientists: 

Let me explain my conviction. 

The cigarette should he conceived not as a product but as a 

package. The product is nicotine. The cigarette is but one of many 

package layers .... The smoker must strip off all these package 

layers to get to that which he seeks . ... Think of the cigarette pack 

as a storage container for a day's supply of nicotine .... Think of 

the cigarette as a dispenser for a dose unit of nicotine .... Think of 

a puff of smoke as the vehicle of nicotine: 

1) A convenient 35 cc mouthful contains approximately 

the right amount of nicotine 

2) The smoker has wide latitude in further calibration: 

puff volume, puff interval, depth and duration of 

inhalation . . . 

3) Highly absorbable: 97% nicotine retention 

4) Rapid transfer: nicotine delivered to blood stream in 

1 to 3 minutes .... 

Smoke is beyond question the most optimized vehicle of nicotine.819 

818 See notes summarizing May 10, 1994 meeting between FDA and Dunn WL. See AR (Vol 21 

Ref. 231). 

819 Dunn WL (Philip Morris Inc.), Motives and Incentives in Cigarette Smoking (1972), at 5-6 (emphasis 

added). See AR (Vol 12 Ref. 133). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45001

II.C.6. 

Dunn further explained how he and other Philip Morris officials could both express 

uncertainty about "why people smoke" and believe that they smoke for the 

phannacological effects of nicotine: "If we accept the premise that nicotine is what the 

smoker seeks, we've still not answered the question 'Why do people smoke'? We've 

merely reformulated it to read 'Why does the smoker take nicotine into his system?"'820 

Thus, it was Dunn's "conviction" that people smoke to obtain a systemic dose of 

nicotine. What remained to be determined was precisely why the pharmacological effects 

of nicotine were reinforcing to smokers and what biochemical mechanisms were triggered 

by nicotine in the central nervous system. In fact, the records of Philip Morris research 

between the 1960's and the 1980's demonstrate that Philip Morris spent those decades 

conducting exhaustive research to determine the physiological and psychoactive effects of 

nicotine inhalation that cause smokers to repeatedly seek nicotine, and to ascertain the 

"dose-regulating" mechanisms through which smokers obtain an adequate amount of 

nicotine to achieve those effects.821 See Jurisdictional Analysis, 60 FR 41599. 

Accordingly, FDA concludes that it has appropriately represented the words of 

William Dunn. 

The second document is a 1969 speech to the board of directors of Philip Morris 

by Helmut Wakeham, vice president for research and development. The speech begins 

with the statement that scientists cannot yet give a definitive explanation of why people 

smoke "backed up by fact." The speech nevertheless attempts to answer the question by 

820 ld. at 6-7. 

821 See documents printed in 141 Cong. Rec. H7646-7683 (daily ed. Jul. 25, 1995), and 141 Cong. Rec. 

H8127-8135 (daily ed. Aug. 1, 1995). See AR (Vol. 14 Ref. 175a and VoL 711 Ref. 6). 

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II.C.6. 

marshaling three types of available evidence: what smokers say about why they smoke, 

what differences in personality characterize smokers and nonsmokers, and what the 

"immediate effects of smoke inhalation upon ... human body function" are.822 In the 

latter category, the speech provides a long list of nicotine's effects on human body 

function, including "arousal center in brain stem excited."823 Following this discussion of 

the evidence, the speech concludes with the quote cited by FDA in the Jurisdictional 

Analysis: "We are of the conviction, in view of the foregoing, that the ultimate 

explanation for the perpetuated cigaret habit resides in the pharmacological effect of 

smoke upon the body of the smoker, the effect being most rewarding to the individual 

under stress."824 

This document speaks for itself. It is beyond question that the quoted statement 

reflects the "conviction" of the author of the speech that people continue to smoke to 

obtain the pharmacological effects of nicotine, and that this conviction existed as a result 

of the available data. 

The third document cited by Philip Morris provides equally weak support for the 

claim that Philip Morris researchers were uncertain whether people smoke to obtain 

nicotine. From an internal Philip Morris document entitled "Why People Start to Smoke," 

FDA printed a quote from the end of the document describing the results of a "special 

822 Wakeham H (Philip Morris Inc.}, Smoker Psychology Research (Nov. 26, 1969), at 9. See AR 

(Vol. 11 Ref. 142). 

823 ld. at 10. 

824 ld. at 11. 

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study done for Philip Morris" on "the motivation that leads to a continuation of 

smoking":825 

[T]he circumstances in which smoking occurs may be generalized 

as follows: 

1. 

2. 

3. 

As a narcotic, tranquilizer, or sedative. Smokers 

regularly cigarettes at times of stress. 

At the beginning or ending of a basic activity .... 

Automatic smoking behavior.826 

II.C.6. 

Philip Morris points to a statement, from the portion of the document on why 

people start smoking, that "[t]here are surprisingly few hard facts on the question ofthe 

initiation of smoking, ,,s

27 claiming that this somehow shows that the author is unsure of 

why people continue to smoke. As the document itself demonstrates, the author· describes 

no uncertainty on the question of why people continue to smoke. 

The fourth document cited by Philip Morris is the first of several Philip Morris 

reports on research conducted by the company to test its hypothesis that smoking is used 

in times of stress as an "anxiety reducer."828 The proposed study involved administering 

shocks to college students and determining whether stress caused the students to smoke 

more. According to Philip Morris, the research proposal expresses uncertainty about 

whether smoking mitigates stress, and therefore cannot support FDA's conclusion that 

Philip Morris officials believed that nicotine's pharmacological effects motivate smoking 

behavior. 

825 Udow A (Philip Morris Inc.), Why People Start to Smoke (Jun. 2, 1976), in 141 Cong. Rec. H7663-

H7664 (daily ed. Jul. 25, 1995) (emphasis added). See AR (Vol 14 Ref. 175a). 

826 /d. at H7664. 

827 /d. at H7663 (emphasis added). 

828 Ryan FJ (Philip Morris Inc.), Proposed Research Project: Smoking and Anxiety (Dec. 23, 1969), in 

141 Cong. Rec. H7648 (daily ed. Jul. 25, 1995). See AR (Vol 14 Ref. 175a). 

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II.C.6. 

FDA disagrees that this document can be used to demonstrate that Philip Morris is 

uncertain about the relationship of smoking and stress. Because the document in question 

merely proposes the research to test the hypothesis that smoking reduces anxiety, it does 

not attempt to answer the question posed. What Philip Morris fails to point out is that this 

research, once begun, showed a "very high" correlation between personality factors, 

"particularly the Anxiety factor," and puff rate and that the researchers were "very much 

encouraged by the trend of these findings."829 In fact, this study design appears to have 

been abandoned in favor of other designs only because ''fear of shock is scaring away 

some of our more valuable subjects."830 Subsequent research reports show that Philip 

Morris researchers continued to obtain results showing a correlation between anxiety and 

both puffmg and nicotine intake,831 and subsequent statements by Philip Morris 

researchers continue to show that they believed that one of the primary motives for 

smoking is to relieve stress.832 

829 Dunn WL (Philip Morris Inc.), Consumer Psychology (Sep.16-0ct. 15,1971) (discussing projects 

entifled, "Shock I, II, III, IV''), in 141 Cong. Rec. H7648-7649 (daily ed. Jul 25, 1995). See AR (Vol 14 

Ref. 175a). 

830 Dunn WL (Philip Morris Inc.), Quarterly Report-Projects 1600 and 2302 (Oct. 5, 1972) in 141 Cong. 

Rec. H7649 (daily ed. Jul25, 1995). See AR (Vol14 Ref. 175a). 

831 Dunn WL (Philip Morris Inc.), 1600 Objectives for 1973 (Nov. 14, 1972) (subjects show differential 

heart rate when threatened with shock on days when they are allowed to smoke compared to days when 

they are not), in 141 Cong. Rec. H8130 (daily ed. Aug. 1, 1995) See AR (Vol 711 Ref. 6). 

Philip Morris Research Center, Behavioral Research Annual Report (Jul 18, 1975), in 141 Cong. Rec. 

H7652, H7654 (daily ed. Jul. 25, 1995). See AR (Vol 21 Ref. 240a-2). 

832 Udow A (Philip Morris Inc.), Why People Start to Smoke (Jun. 2, 1976) (''the circumstances in which 

smoking occurs may be generalized as follows: 1. As a narcotic, tranquilizer, or sedative. Smokers 

regularly use cigarettes at times of stress .... "),in 141 Cong. Rec. H7664 (daily ed. Jul. 25, 1995). 

See-AR(Vol14Ref.175a). 

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II.C.6. 

Not only do the documents discussed immediately above contradict Philip Morris' 

assertion that its employees do not know why people smoke, but the available Philip 

Morris documents contain overwhelming support for the finding that Philip Morris 

officials believe that the major reason people smoke is to obtain the pharmacological 

effects of nicotine. Expressions of this belief are repeated frequently and consistently over 

the period of years reflected in these documents. See, e.g., Jurisdictional Analysis, 60 FR. 

41595-41599,41608,41613-41615,41650-41652. 

3. Philip Morris contends that in reproducing William Dunn's statement of his 

"conviction" that cigarettes are the "most optimized vehicle" for delivering nicotine, see 

comment 2, above, FDA omitted a subsequent paragraph in which the scientist attempted 

to defuse concern about his "drug-like conceptualization of the cigarette": 

Lest anyone be made unduly apprehensive about this drug-like 

conceptualization of the cigarette, let me hasten to point out that 

there are many other vehicles of sought-after agents which dispense 

in dose units: wine is the vehicle and dispenser of alcohol, tea and 

coffee are the vehicles and dispensers of caffeine, matches dispense 

dose units of heat, and money is the storage container, vehicle and 

dose-dispenser of many things. 833 

Philip Morris claims that this paragraph demonstrates that the earlier part of the quote 

cannot be used as evidence that Philip Morris intends cigarettes as nicotine delivery 

systems. 

FDA disagrees. The paragraph quoted by Philip Morris illustrates that tobacco 

company officials were aware of the potential consequences of admitting that cigarettes 

are "drug-like." Moreover, the paragraph does not in any way undercut the fundamental 

833 Dunn WL (Philip Morris Inc.), Motives and Incentives in Cigarette Smoking (1972), at 6. See AR 

(Vol. 12 Ref. 133). 

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II.C.6. 

point made by Dunn: that cigarettes are nicotine delivery systems. The fact that other 

items can also be conceptualized as delivery systems for various things cannot alter what it 

was that Dunn believed was the essential ingredient delivered by cigarettes: doses of 

nicotine. He did not conceptualize cigarettes as delivery systems for flavor, or taste, or 

something to occupy one's hands. Rather, he conceptualized cigarettes as delivery 

systems for "a dose unit of nicotine," which is "delivered to [the] blood stream in 1 to 3 

minutes."834 

4. Philip Morris also contends that in reproducing certain quotes from Philip 

Morris documents, FDA omitted portions of the documents that were inconsistent with 

the quoted portion. 

First, Philip Morris contends that FDA omitted a significant passage from a quote 

on a proposed Philip Morris study on smoking and hyperactivity. The full quote with the 

omitted passages follows: 

Some children are so active (or "hyperkinetic") that they are unable to sit 

quietly in school and concentrate on what is being taught. In recent years it 

has been found that amphetamines, which are strong stimulants, have the 

anomalous effect of quieting these children down and enabling them to 

concentrate in the face of distractions which otherwise would have 

disrupted their attention. Many children are therefore regularly 

administered amphetamines throughout grade school years. The wisdom 

of such prescription is open to question and some published reports have 

suggested that caffeine, in the form of coffee or tea for breakfast would 

produce the same end result. We wonder whether such children may not 

eventually become cigarette smokers in their teenage years as they discover 

the advantage of self-stimulation via nicotine. We have already 

collaborated with a local school system in identifying some such children 

presently in the third grade; we are reviewing the available literature on the 

topic; and we may propose a prospective study of this relationship. It 

would be good to show that smoking is an advantage to at least one 

834 /d. at 5-6. 

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subgroup ofthe population. Needless to say, we will not propose giving 

cigarettes to children. 835 

II.C.6. 

The full quote demonstrates that Philip Morris researchers regarded nicotine as a stimulant 

and proposed to study whether hyperactive youths use cigarettes, not for flavor or taste, 

but to self-medicate an attentional disorder. It is completely consistent with FDA's 

finding that Philip Morris officials believe that nicotine in cigarettes has pharmacological 

effects and that consumers use cigarettes to obtain those effects. 

Philip Morris claims that the researchers were equating nicotine and caffeine. It is 

clear from this and later references to this study that Philip Morris was interested in 

whether nicotine is used to self-medicate hyperactivity by smokers who as children were 

"known to have their hyperactive or impulsive behaviors reduced by drugs (e.g., 

Ritalin)."836 If the researchers equated nicotine and caffeine, they regarded both 

substances as stimulant drugs that could be used to treat hyperactivity through their 

pharmacological effects. It is unlikely that they did equate them, however, since the same 

researchers had 2 years earlier demonstrated that nicotine produces a much more 

pronounced stimulant effect than caffeine.837 

Philip Morris also claims that this document proposed a study on hyperkinetic 

adults, rather than children. Nothing in the available documents supports this claim. The 

documents mention only a study of hyperkinetic "children," whom Philip Morris 

835 Dunn WL (Philip Morris Inc.), Smoker Psychology/May 1-31, 1974 (Jun. 10, 1974), in 141 Cong. Rec. 

H7651 (daily ed. Jul. 25, 1995). See AR (VoL 14 Ref. 175a). 

836 Dunn WL (Philip Morris Inc.), Smoker Psychology/April1-30, 1977 (May 13, 1977), in 141 Cong. 

Rec. H7657 (daily ed. JuL 25, 1995). See AR (VoL 14 Ref. 175a). 

837 Memorandum from Schori TR to Dunn WL, Smoking and Caffeine: A Comparison of Physiological 

Arousal Effects (May 17, 1992), at 1-2. See AR (Vol. 15 Ref. 189-7). 

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II.C.6. 

researchers propose to identify and follow to establish whether they become smokers in 

their "teenage years." 

Second, Philip Morris contends that the context of a statement made by Helmut 

Wakeham that "nicotine is believed essential to cigarette acceptability'' refers to its role in 

taste and flavor.838 The full text of this document contradicts Philip Morris' argument. As 

explained in the Jurisdictional Analysis, 60 FR 41595, earlier in Wakeham's presentation, 

he described the pharmacological effects of nicotine on smokers: 

(a) Low nicotine doses stimulate, but high doses depress functions. 

(b) Continued usage develops tolerance .... 

In contrast to those effects, it is also recognised that smoking 

produces pleasurable reactions or tranquility, and that this is due at least in 

part to nicotine, and not entirely to the physical manipulations involved in 

smoking. 839 

Three pages later, under the heading "Controlled Nicotine in Filler and Smoker," 

Wakeham says: 

Even though nicotine is believed essential to cigarette acceptability, 

a reduction in level may be desirable for medical reasons. 

Problems: 

1. How much nicotine reduction will be acceptable to the 

smoker? 

2. What taste difference will be tolerated?840 

The document, on its face, demonstrates two things: (1) Wakeham believed that 

nicotine produced pharmacological effects in smokers; and (2) the problem of determining 

838 Wakeham H (Philip Morris Inc.), Tobacco and Health-R&D Approach (Nov. 15, 1961), at 43. See 

AR (Vol. 125 Ref. 1314). 

839 /d. at 40. 

840 /d. at 43. 

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II.C.6. 

the level of nicotine reduction that would be "acceptable to the smoker" is separate from 

the problem of determining what taste difference would be tolerated. Had Wakeham 

believed that nicotine is essential only for taste, only the second question would have been 

relevent. Instead, he recognized that a reduction in nicotine would not be acceptable to 

smokers for the additional reasons he had already spelled out that nicotine produces 

mood-altering reactions that smokers seek. The plain language of the document thus fails 

to substantiate Philip Morris' claim that Wakeham believed that nicotine is essential only 

for taste. As in many other tobacco company documents, nicotine's role in taste, if it is 

mentioned at all, is seen as secondary to its pharmacological role. See Jurisdictional 

Analysis, 60 FR 41772-41778. 

5. Philip Morris argues that some ofthe statements cited by FDA were only 

Philip Morris researchers' "premises" and "working hypotheses" or even the hypotheses of 

outside researchers. According to Philip Morris, these statements are not "facts" or 

conclusions based on data and are therefore irrelevant to intended use. 

FDA disagrees that these consistent statements of Philip Morris researchers that 

people smoke to obtain the pharmacological effects of nicotine are irrelevant to Philip 

Morris' intent in manufacturing and marketing cigarettes. In establishing the intended use 

of Philip Morris' tobacco products, the premises, hypotheses, and beliefs of the scientists 

whose job within the company is to understand the motives for smoking, and who 

regularly communicate those views to company executives, are highly relevant. Philip 

Morris and other tobacco companies contend that cigarettes are labeled for "pleasure," not 

pharmacological effects, and that nicotine is present in cigarettes only for flavor. On this 

basis, the company argues that cigarettes are not intended as drugs or devices. Nowhere, 

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II.C.6. 

however, in the publicly available Philip Morris documents, or in the documents produced 

by Philip Morris in this proceeding, do their scientists put forward a premise or hypothesis 

that people smoke primarily for nicotine's flavor and/or any other nonpharmacological 

motive-much less communicate such a view to company executives. The evidence in the 

administrative record demonstrates, instead, that during the entire period covered by those 

documents, Philip Morris scientists were communicating to their superiors their scientific 

opinion that nicotine's phannacological effects are the primary motivator of smoking 

behavior. 

6. Philip Morris also argues that its researchers' "hypotheses" were not 

ultimately supported by the results of their research. 

FDA disagrees that the documents show that the major premises of Philip Morris 

scientists concerning the role of nicotine in tobacco use were disproven. These premises 

center on the scientists' often stated belief that cigarette smoking is reinforced by the 

phannacological effects of nicotine on the brain. In fact, this premise continued to be 

repeated and even strengthened over the period of research reflected in the documents. 

For example, the major premise of a 197 4 research report is that ''the smoking habit is 

maintained by the reinforcing effects of the pharmacologically active components of 

smoke. A corollary to this premise is that the smoker will regulate his smoke intake so as 

to achieve his habitual quota of the phannacological action."841 

Philip Morris attempts to use this research report in support of its claim that Philip 

Morris scientists failed to fmd support for their beliefs that people smoke to obtain the 

841 Philip Morris Research Center, Behavioral Research Annual Report, Part II (Nov. 1, 1974) (approved 

by Osdene TS), in 141 Cong. Rec. H7658, H7660 (daily ed. Jul. 25, 1995). See AR (Vol 14 Ref. 175a). 

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II.C.6. 

pharmacological effects of nicotine. According to Philip Morris, this report refuted the 

compensation theory.842 Philip Morris' claim that its researchers refuted their major 

premises fails on two grounds. First, the document shows that Philip Morris researchers 

considered the compensation theory to be at most a "corollary" of their major premise that 

smoking is maintained by the reinforcing effects of nicotine. Philip Morris makes no 

attempt to show that the major premise was dis proven. Nor could it. Philip Morris 

conducted one of the earliest definitive studies on nicotine's reinforcing effects in the early 

1980's, well before similar research had been published by outside scientists. As William 

Dunn told T.S. Osdene, Philip Morris' director of research, the company's research made 

"it quite clear that nicotine can function as a positive reinforcer for rats."843 As described 

in section ll.A.3.c.i., above, the ability of a substance to function as a "positive reinforcer'' 

in animals is one of the most telling pieces of evidence that the substance will be addictive 

in humans. 

Second, both the 1974 and subsequent research reports (through and including the 

last available report in 1980) show that Philip Morris continued to believe in, and test, the 

compensation theory, using ever more sophisticated and precise methods. Philip Morris 

relies on a statement from the 1974 report in which the researchers note that previous 

attempts to show compensation by analyzing the number and amount of cigarettes smoked 

had shown positive trends but not convincing evidence that the smoker regulates intake of 

842 ''Compensation," as described in section II. A. 7.i., above, describes the behavior of smokers who are 

given cigarettes with more or less nicotine than their usual brands. Data, including tobacco industry data, 

show that smokers "compensate" by altering their smoking behavior (e.g., by smoking more cigarettes or 

smoking each cigarette more intensely) to obtain their customary nicotine intake. 

843 Dunn WL (Philip Morris Inc.}, Plans and Objectives-1981 (Nov. 26, 1980), in 141 Cong. Rec. H7681-

7682 (daily ed. Jul. 25, 1995). See AR (Vol14 Ref. 175a). 

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II.C.6. 

nicotine. Philip Morris omits subsequent statements demonstrating that the researchers 

have not "refuted" the compensation theory, but have merely decided to take a new 

approach to establishing compensation. Following the statement quoted by Philip Morris, 

the researchers state that they "question whether the indices of intake which have been 

investigated to date are, in fact, the appropriate indices to be measuring."844 Instead, they 

believe that new evidence suggests that compensation may be accomplished through the 

inhalation patterns of smokers: 

[O]bservations [concerning differences in how smoke is inhaled from 

smoker to smoker] have made us aware of a heretofore unnoticed 

mechanism that has the potential of affording the smoker a wide latitude of 

control over the amount of smoke he brings into contact with the 

absorption sites.845 

The researchers go on to describe a new series of experiments designed ''to systematically 

observe the inhalation patterns of smokers" and thereby determine whether compensation 

for nicotine is occurring.846 The researchers also developed, three years later, a new 

theoretical model to explain their inability up to that point to demonstrate compensation. 

Under this theory, some smoking is triggered by "deficits or surfeits of nicotine (or some 

unknown smoke components)" and some by external stimuli: 

The adoption of this point of view by members of the staff will lead us to 

recognize that apparent failures of [the] nicotine compensation model may 

not in fact be failures at all and that nicotine compensation is a real 

phenomenon which is masked by the fact that smokirs smoke many 

cigarettes out of habit rather than need.847 

844 Philip Morris Research Center, Behavioral Research Annual Report, Part II (Nov. 1, 1994), in 141 

Cong. Rec. H7658, 7660 (daily ed. Jul. 25, 1995). See AR (Vol 14 Ref. 175a). 

845 /d. 

846 /d. 

847 Dunn WL (Philip Morris Inc.), Behavioral Research Accomplishments-1977 (Dec. 19, 1977), in 141 

Cong. Rec. H7666-7667 (daily ed. Jul. 25, 1995) (emphasis added). See AR (Vo114 Ref. 175a). 

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II.C.6. 

The Philip Morris research reports demonstrate that Philip Morris continued to attempt to 

measure inhalation patterns throughout the-period covered by the reports, and that the 

researchers continued to believe, and sometimes showed, that smokers compensate for 

nicotine.848 

Finally, Philip Morris cites a small number of minor studies in the Philip Morris 

research documents in which the researchers did not find discernible effects due to 

smoking; it claims that these show that Philip Morris failed to find support for the belief 

that nicotine's pharmacological effects motivate smoking. The apparent failure of a small 

fraction of its studies to demonstrate particular pharmacological effects from nicotine 

cannot obscure what is evident from a fair reading of the publicly available research 

reports: the company's research on nicotine demonstrated that nicotine had many 

significant pharmacological effects on smokers. The record also shows that, through the 

period covered by the reports, Philip Morris' emphasis on the pharmacological 

motivations for smoking increased and its research on the pharmacological effects of 

nicotine grew in size and sophistication. By the end of that period, Philip Morris had 

successfully established that nicotine is a positive reinforcer in rats, that it produces 

psychoactive effects like other drugs of abuse, that it produces tolerance, and that it acts 

848 See, e.g., Letter from Dunn WL to Schachter S (Sep. 8, 1975) (Philip Morris expects inhalation 

patterns "to be dose-regulating mechanisms of remarkable precision and sensitivity"), in 141 Cong. Rec. 

H7662 (daily ed. Jul. 25, 1995). See AR (Vol 14 Ref. 175a). 

Dunn WL (Philip Morris Inc.), Behavioral Research Accomplishments-1977 (Dec. 19, 1977) ("We have 

... [s]hown that we can distinguish between [nicotine] regulator and nomegulator smokers and that after 

being deprived, the regulators do indeed try to make up for lost intake"), in 141 Cong. Rec. H7666 (daily · 

ed. Jul. 25, 1995). See AR (Vol 14 Ref. 175a). 

Dunn WL (Philip Morris Inc.), Plans and Objectives-1981 (Nov. 26, 1980), in 141 Cong. Rec. H7681, 

H7683 (daily ed. Jul. 25, 1995). See AR (Vol l4_Ref. 175a). 

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II.C.6. 

centrally in the brain. These are the standard animal tests performed by pharmaceutical 

companies and public health organizations to establish that a substance is addictive. At 

this time, Philip Morris was also engaged in a broad-based study of the effects of smoking 

and nicotine on human brain wave patterns to "identify as far as possible the neural 

elements which mediate cigarette smoking's reinforcing actions."849 The record thus 

contradicts Philip Morris' claim that its research failed to bear out the premise that people 

smoke to obtain nicotine. 

7. Philip Morris argues that FDA has mischaracterized statements of Philip 

Morris officials in several company documents related to the addictive effects of nicotine 

and cigarettes. FDA has reviewed the statements and concluded that it has not 

mischaracterized the statements that it relied on. 

First, in the Jurisdictional Analysis, 60 FR 41607-41608, FDA cited a Philip 

Morris study on a smoking cessation campaign in Greenfield, Iowa, in 1969 as evidence 

that Philip Morris researchers recognized that smoking cessation produces a withdrawal 

syndrome. Philip Morris claims that its study did not conclude that nicotine is "addictive" 

and that the study showed only that former smokers experienced ''transient ... common 

behavioral mannerisms such as eating more, tapping their fingers, twiddling their thumbs, 

biting their lips, chewing on matches, or feeling ill-tempered.'.sso Philip Morris also argues 

that this study was published more than 20 years ago and therefore is not "new" evidence. 

849 /d. at H7681. 

850 Philip Morris Inc., Comment (Jan. 2, 1996), at 17. See AR (Vol 519 Ref. 1 05). 

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II.C.6. 

FDA believes that the Philip Morris study on the Iowa "cold turkey" campaign 

provides solid evidence that Philip Morris knows that abstinence from smoking produces a 

significant, long-term withdrawal syndrome. As discussed in section ILA.3., above, 

withdrawal is recognized as one of the characteristic features of drug dependence. 

Contrary to the comment's claim that the study revealed only mild and ''transient" 

symptoms, the study author, a Philip Morris researcher, summarizes the symptoms of 

those who quit smoking this way: 

Even after eight months quitters were apt to report having neurotic 

symptoms, such as feeling depressed, being restless and tense, being 

ill-tempered, having loss of energy, being apt to doze off, etc. They 

were further troubled by constipation and weight gains which 

averaged about Sibs. per quitter.851 

The researcher later reports on the worsening of health symptoms among the 

quitters, observing that their "list of complaints is long and impressive."852 The author 

encapsulates the quitters' experience as follows: 

This is not the happy picture painted by the Cancer Society's antismoking commercial which shows an exuberant couple leaping in 

the air and kicking their heels with joy because they've kicked the 

habit. A more appropriate commercial would show a restless, 

nervous, constipated husband bickering viciously with his bitchy 

wife who is nagging him about his slothful behavior and growing 

waistline. 853 

Accordingly, this study provides evidence that Philip Morris knows that smokers suffer 

significant, long-term withdrawal symptoms, a characteristic feature of addictive 

851 Ryan FJ (Philip Morris Inc.), Bird-1: A Study of the Quit-Smoking Campaign in Greenfield, Iowa, in 

Conjunction with Movie, Cold Turkey (Mar. 1971), at 1. (emphasis added). See AR (VoL 390 Ref. 6394). 

852 Id. at31. 

853 !d. at33 (emphasis added). 

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II.C.6. 

substances. There is no support for Philip Morris' contention that the withdrawal 

symptoms reported in this study are not comparable to withdrawal symptoms from other 

drugs that produce physical dependence. The withdrawal symptoms reported by Philip 

Morris include many of the same changes in mood, behavior, and physical functioning 

identified as evidence of a withdrawal syndrome for all drugs that produce physical 

dependence. They are the same symptoms that have been recognized by the Surgeon 

General and other public health organizations as evidence that nicotine produces a 

withdrawal syndrome and physical dependence.854 

Finally, Philip Morris' claim that this study was published 20 years ago is 

misleading. The material quoted in the Jurisdictional Analysis and here comes principally 

from an internal Philip Morris study report that was not published.sss Another version of 

the study was published, in which the quoted material was omitted.856 

Philip Morris also argues that FDA "deliberately mischaracterize[d]" another Philip 

Morris document in which Philip Morris acknowledges both nicotine dependence and a 

withdrawal syndrome from cigarette deprivation. FDA notes that Philip Morris challenges 

only the use of the statement to show that Philip Morris acknowledges withdrawal; Philip 

· Morris makes no claim that this statement does not acknowledge nicotine dependence. 

854 Surgeon General's Report, 1988, at 198-221. See AR (Vol129 Ref. 1592). 

American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994 ), at 244. See AR (Vol 5 Ref. 46-1 ). 

855 Ryan FJ (Philip Morris Inc.), Bird-1: A Study of the Quit-Smoking Campaign in Greenfield, Iowa, in 

Conjunction with Movie, Cold Turkey (Mar. 1971). See AR(Vol21 Ref. 207). 

856 Ryan FJ (Philip Morris Inc.), Cold turkey in Greenfield, Iowa: a follow-up study, in Smoking 

Behavior: Motives and Incentives, ed. Dunn WL (Washington DC: VH Winston & Sons, 1973). See 

AR (Vol. 8 Ref. 105). 

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II.C.6. 

The document is a report from W. L. Dunn toT. S. Osdene, vice president for 

research and development, entitled, "Plans and Objectives-1980." In describing the 

company's "Experimental Psychology Program," the report states that the first objective 

of the program is to "gain better understanding of the role of nicotine in smoking." The 

report describes one of its approaches to this objective as follows: 

Identification of two smoking population subgroups, one of which has 

greater nicotine needs than the other. We have described these people in 

the past as compensators and noncompensators, and attempted to define 

them by their consumption changes when nicotine deliveries were 

moderately shifted. However, we've had no great success in the 

identification to date. Now we may have two extra tools to use: 

Commercial PM cigarettes of ultra low tar and nicotine, and salivary 

nicotine concentrations. Others, principally at Columbia University, have 

suggested that shifts to ultra low nicotine cigarettes produce the same type 

of psychological stress behaviors as quitting. We therefore propose a shift 

study in which smokers are shifted to an ultra low brand, and the key 

dependent variable becomes the presence or absence of the withdrawal 

syndrome. Those who show evidence of nicotine dependence and those 

who do not can then be used to test our hypotheses on the relationship of 

salivary concentration to smoking behavior. 857 

Philip Morris claims that this statement contains no acknowledgment of a cigarette 

withdrawal syndrome, because the Philip Morris researchers: (1) found no support for 

their hypothesis that people compensate for changes in nicotine yield; (2) were merely 

testing hypotheses proposed by outside researchers; and (3) were referring to 

psychological stress behaviors, not physiological symptoms when they spoke of 

withdrawal. 

The full text of this statement fails to support Philip Morris' strained construction. 

The obvious purpose of the statement is to explain that the researchers intended to try a 

857 Dunn WL (Philip Morris Inc.), Plans aru:l Objectives-1980 (Jan. 7, 1980), in 141 Cong. Rec. H7670, 

H7672 (daily ed. Jul. 25, 1995) (emphasis added). See AR (Vol. 14 Ref. 175a). 

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II.C.6. 

new approach to identifying "compensators" and "noncompensators," relying on evidence 

of withdrawal/dependence. The researchers are clear that withdrawal is an established 

syndrome they will use to identify compensators and noncompensators, not the reverse. 

The only outside hypothesis mentioned in the statement is the notion that switching to 

ultra-low nicotine cigarettes can be used to induce the same stress behaviors as quitting. 

The more fundamental notion that quitting produces a withdrawal syndrome is not an 

outsider's hypothesis but a clearly accepted premise of the entire approach. Nothing in 

the statement suggests that the researchers intend to test an "hypothesis" that quitting 

produces withdrawal; they intend to use this accepted fact to search for compensators and 

noncompensators. Finally, there is no evidence in the document to support Philip Morris' 

assertion that the Philip Morris researchers were referring to psychological stress 

behaviors, not physiological symptoms. 

Philip Morris also contends that FDA inappropriately characterized a Philip Morris 

memo, which FDA briefly cited in a footnote to the Jurisdictional Analysis, as indicating 

that people smoke to avoid "withdrawal." According to Philip Morris, the memo merely 

placed cigarettes in the same category as alcohol, tea, coffee, chewing gum, overeating, 

and sex. 

Philip Morris' characterization focuses on the introduction of the memo, while 

ignoring its central purpose. The actual purpose of the memo is to propose to study the 

question of why people continue to smoke despite "compelling pressures upon the smoker 

to discontinue the behavior'' and to "document the penalties imposed by discontinuation of 

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II.C.6. 

cigarette smoking."858 The memo offers the following rationale for documenting the 

"penalties" of discontinuation: 

The literature on the subject cites body weight gains up to twenty pounds. 

Constipation has been cited as another sequelae (Ejrup, 1965), as well as 

blisters in the mouth. Chessick(1964) has warned against the 

"neurovegetative disequilibrium" that can result and Masoni (1963) 

contends that some may not be able to stabilize emotionally. There is 

anecdotal and lay observation of lowered efficiency and heightened 

irritability upon withdrawal. We know, too, that in periods of nonvoluntary deprivation, as in concentration camps of World War II, the 

incentive value of the cigarette exceeds that of essential foodstuff.859 

The actual text of the memo thus demonstrates clearly that Philip Morris has knowledge of 

significant withdrawal symptoms associated with smoking deprivation. The memo 

displays no skepticism about the existence of the cited withdrawal symptoms. 

8. Philip Morris argues that reports of animal research conducted in its 

laboratories by Philip Morris researchers Victor DeNoble and Paul Mele do not conclude 

that nicotine is addictive. 

The reports in question showed that Philip Morris had established that nicotine 

functions as a "positive reinforcer'' in rats (causes them to seek repeated doses), and has 

other psychoactive effects characteristic of addictive substances. See Jurisdictional 

Analysis, 60 FR 41754-41758. These reports also showed that Philip Morris conducted 

research to fmd nicotine analogues (substitutes) that would have equal or greater 

reinforcing and psychoactive effects as nicotine. I d. These central nervous system effects 

were characterized by Philip Morris as "desirable properties" of nicotine that could be 

858 Dunn WL (Philip Morris Inc.), Stating the Risk Study Problem (Jul. 29, 1969), at 3. See AR (Vol 15 

Ref. 189-6). 

859 /d. 

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II.C.6. 

"enhanced" as a result of nicotine analogue research.860 Finally, these research reports 

showed that Philip Morris conducted research to find an "optimum" combination of 

nicotine and acetaldehyde (another component of smoke) that had "maximal reinforcing 

effects. "

861 

FDA disagrees that it inappropriately relied on these studies. FDA did not cite 

these documents for the proposition that Philip Morris acknowledged that nicotine is 

addictive. FDA cited them, appropriately, as evidence that Philip Morris: (1) had 

conducted research demonstrating that nicotine is a positive reinforcer, one of the 

characteristic features of addictive substances; and (2) understood that the 

pharmacological effects of nicotine were essential to the market for tobacco products and 

intended to offer products that affect the central nervous system. See Jurisdictional 

Analysis, 60 FR 41750-41762. 

9. Philip Morris states that, during his tenure at Philip Morris, Victor 

DeNoble repeatedly advised his colleagues that the fact that a substance has positive 

reinforcement effects does not mean that the substance is "addictive." 

FDA agrees that animal self-administration does not alone demonstrate 

conclusively that a substance will be addictive in humans. As DeNoble stated in his 

testimony before Congress, however, "[t]he self-administration study is a classical 

hallmark to indicate that a solution or drug substance has ... the potential to be a drug of 

860 Charles JL (Philip Morris Inc.), Nicotine Receptor Program-Vniversity of Rochester (Mar. 18, 1980). 

See AR (Vol 32 Ref. 532). 

861 DeNoble VJ (Philip Morris Inc.), Project Number 1610 (Behavior Pharmacology) Objectives and 

Plans 1982-1983 (Jul. 20, 1982), at 2. See AR (Vol345 Ref. 5443). 

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II.C.6. 

abuse in humans."862 As described earlier, a drug's abuse liability refers to its potential to 

cause drug dependence/addiction. 

As described in section ll.A3.c., above, a complete screen for abuse liability also 

includes studies that demonstrate that the drug's reinforcing effects are caused by its 

actions in the central nervous system, that the drug has psychoactive effects, that the drug 

produces withdrawal and/or tolerance. Philip Morris research also demonstrated that 

nicotine has each of these properties.863 These results distinguish nicotine from such 

nonaddictive substances as saccharin, which are not psychoactive. 

As described in section ll.C.2.a.ii., above, corporate executives were informed that 

Philip Morris' own research predicted that nicotine would be a drug of abuse in humans. 

A reasonable manufacturer with this information should have foreseen that nicotine was 

likely to be addictive in humans. 

l 0. Tobacco industry comments challenge the reliability of a report submitted 

by William A Farone, director of applied research at Philip Morris from 1976 to 1984, 

entitled ''The Manipulation and Control of Nicotine and Tar in the Design and 

862 Regulation of Tobacco Products (Part 2): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce. U.S. House of Representatives. 103d Cong. 

2d Sess. 18 (Apr. 28, 1994) (testimony of Victor J. DeNoble). See AR (Vol 708 Ref. 2). 

863 See, e.g., Dunn WL (Philip Morris Inc.), Plans and Objectives-1980 (Jan. 7, 1980), in 141 Cong. Rec. 

H7668, H7669 (daily ed. Jul. 25, 1995). See AR (Vol 14 Ref. 175a). 

DeNoble VJ (Philip Morris, Inc.) Nicotine Program-Behavioral Research lAboratory (Apr. 24, 1980), 

at 2. See AR (Vol 345 Ref. 5446). 

Ryan FJ (Philip Morris Inc.), Bird-]: A Study of the Quit-Smoking Campaign in Greenfield, Iowa, in 

Conjunction with Movie, Cold Turkey (Mar. 1971). See AR (Vol 21 Ref. 207). 

DeNoble VJ, Mele PC (Philip Morris Inc.), Development of behavioral tolerance following chronic 

nicotine administration (unpublished manuscript). See AR (Vol 346 Ref. 5464). 

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II.C.6. 

Manufacture of Cigarettes: A Scientific Perspective." In this report, Farone describes the 

beliefs of Philip Morris, and, in some cases the tobacco industry, concerning: the essential 

role of nicotine in tobacco use; research conducted by the industry on nicotine's 

pharmacological effects; and techniques used by the industry to reduce tar while 

maintaining an adequate level of nicotine. Farone bases his report on personal knowledge, 

as well as company documents and published literature. The tobacco industry argues 

generally that the information in Farone's report should not be relied upon because: (1) 

many of his statements about Philip Morris or the industry are not supported by 

documentary evidence; and (2) Farone left Philip Morris in 1984 and therefore does not 

have personal know ledge of the current operations of the company. 

Other comments argue that Farone's report provides additional factual support for 

the conclusion that Philip Morris scientists and executives understand and intend that the 

primary role of nicotine in Philip Morris' products is to provide nicotine's pharmacological 

effects to consumers. These comments also argue that Victor DeNoble, former research 

scientist for Philip Morris, has publicly confirmed the accuracy of many of the statements 

made by Farone. Finally, these comments argue that the reliability of the information 

provided by Farone, is enhanced by its consistency with the sworn testimony of the former 

vice president for research and development for Brown & Williamson. 

FDA disagrees with the tobacco industry comments that Farone's report is not 

reliable evidence relevant to establishing the intended use of cigarettes. Farone was a 

high-ranking manager within Philip Morris, whose responsibilities gave him first-hand 

knowledge of the information presented in the report. As director of applied research, 

Farone supervised five research divisions with a total of 150 employees, mostly 

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II.C.6. 

professionals. He reported directly to the vice president for research and development and 

regularly met with other senior management officials, including the CEO and president of 

Philip Morris, to discuss Philip Morris activities related to basic and applied research, 

product and process development, manufacturing, and results of test marketing of new 

products.864 He was thus in a position to have personal knowledge of the views and 

activities of Philip Morris concerning the topics discussed in his report. Thus, the fact that 

he does not cite documentary evidence to support each statement in the report is irrelevant 

to the weight to which the report is entitled.865 

The fact that Farone left Philip Morris in 1984 also provides no basis to consider 

his report irrelevant. As discussed above in section ll.C.2.e., the extensive collection of 

tobacco company statements relied on by the agency reflects a consistent pattern of 

tobacco industry views spanning three decades. These statements provide evidence of the 

long-standing knowledge and beliefs of tobacco company officials that cigarettes are 

primarily used by consumers for the pharmacological effects of nicotine. Farone's 

statements about the knowledge, beliefs, and actions of the tobacco industry are entirely 

consistent with the body of industry statements relied on by the agency, adding to their 

credibility. Moreover, Farone's statements are consistent with the recent Philip Morris 

864 Declaration ofUydess n.. (Feb. 29, 1996), at 23-24. See AR (Vol 638 Ref. 1). 

865 FDA notes that Philip Morris has submitted two affidavits from current employees which purport to 

provide, based on the personal knowledge of the affiants, information about the measurement of nicotine 

levels in reconstituted tobacco. Neither of these affidavits cites any documentary support. Thus, Philip 

Morris appears to believe that FDA is entitled to rely on information based on personal knowledge. Philip 

Morris Inc., Comment (Apr. 19, 1996), at appendix 3. See AR (Vol. 700 Ref. 226). 

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II.C.6. 

document concerning Project Table,866 demonstrating that the company's views have not 

changed since Farone left the company. 

11. Tobacco industry comments also challenge specific statements made in 

Farone's report. FDA addresses those comments that challenge statements cited by the 

Agency. 

The tobacco industry contests Farone's statement that it is widely believed within 

the tobacco industry that nicotine is the primary reason people smoke. The industry 

argues that the documents cited by Farone do not support this statement, and that industry 

evidence shows that consumers do not smoke cigarettes "nearly exclusively" or "solely" 

for the phannacological effects of nicotine.867 

FDA disagrees with these comments. As described above and in sections 

II.C.6.a.ii. and iii., below, there is ample support, including the documents cited by 

Farone, for the conclusion that tobacco industry officials believe that people use tobacco 

primarily to obtain the pharmacological effects of nicotine. Moreover, as discussed above, 

Farone's position and responsibilities within Philip Morris were such that the statements 

based on his personal knowledge may be considered reliable evidence. Finally, Farone's 

statement is corroborated by the existence of dozens of similar statements by Philip Morris 

officials in other documents cited in section II.C.2.a.i., above, and in the Jurisdictional 

Analysis. See 60 FR 41584-41620. 

866 Philip Morris, Inc., Draft Report Regarding a Proposal for a "Safer'' Cigarette, Code-named Table. 

See AR (VoL 531 Ref. 122). 

867 Philip Morris Inc., Comment (Apr. 19, 1996), at 57. See AR (Vol. 700 Ref. 226). 

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II.C.6. 

The tobacco industry comments present no contradictory statements or other 

evidence to demonstrate that tobacco industry officials do not believe that nicotine is the 

primary reason people smoke. Instead, the industry argues that there is evidence that, in 

fact, consumers do not smoke cigarettes "solely" or "nearly exclusively" for the 

pharmacological effects of nicotine. These comments misconstrue the nature of the 

evidence required to establish intended use. The statements of Farone and others are 

properly used by FDA to show that Philip Morris knows that consumers use cigarettes for 

the pharmacological effects of nicotine. This knowledge is relevant to establishing the 

company's intent to affect the structure and function of the body. See 21 CFR 201.128 

and 801.4. In establishing intended use through a manufacturer's actual knowledge, it is 

not necessary for the Agency to show knowledge that consumers use tobacco nearly 

exclusively for its pharmacological effects. Cf Action on Srrwking and Health v. Harris, 

655 F.2d 236, 240 (D.C. Cir. 1980) (FDA must establish nearly exclusive consumer use 

for pharmacological effects only where there is no other evidence of manufacturer's 

intent). 

Moreover, as described in section II.B., above, the scientific evidence 

demonstrates that the pharmacological effects of nicotine are the primary motivation for 

tobacco use, and that other aspects of tobacco use, such as flavor, are secondary. Indeed, 

the data show that tobacco users enjoy the flavor of tobacco products because they have 

come to associate its flavor with obtaining the pharmacological effects of nicotine. Thus, 

contrary to Philip Morris' comment, even though not necessary to establish "intended 

use," the evidence shows that consumers do use tobacco products nearly exclusively for 

the pharmacological effects of nicotine. 

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II.C.6. 

ii Comments on Specific RJR Statements and Research Projects. Like Philip 

Morris, RJR argues that FDA misused statements and research reports by RJR officials 

that the Agency relied upon as evidence that RJR officials believe that consumers use 

cigarettes to obtain the pharmacological effects of nicotine. FDA has reviewed the 

statements and research reports in context and concluded that, with one minor exception, 

the Agency correctly relied upon them. 

I. RJR argues that the 1972 memorandum by Claude Teague, assistant 

director for research at RJR,868 cited by FDA, does not provide evidence of the intended 

use of cigarettes because Teague was only presenting a "hypothesis" to stimulate 

discussion, and because the document does not reflect institutional intent. RJR focuses 

heavily on the fact that one of the quoted paragraphs and a few other phrases in the 

document begin with "if' or otherwise suggest uncertainty. 

At the time the Jurisdictional Analysis was published, two paragraphs from the 

memorandum that had been published in the New York Times. The complete nine-page 

memorandum was subsequently submitted to the Agency in a comment and is discussed 

above in section ll.C.2.b.i. The full document demonstrates that RJR' s assistant vice 

president for research asserted as fact, not hypothesis, that nicotine's pharmacological 

effects are the primary reason people smoke and that cigarettes are nicotine delivery 

systems. Before the paragraph that begins "If nicotine is the sine qua non of tobacco 

products," Teague says: 

868 Teague CE (RJ. Reynolds Tobacco Co.), Research Planning Memorandum on the Nature of the 

Tobacco Business and the Crucial Role of Nicotine Therein (Apr. 14, 1972), at 1-2. See AR (Vol53l 

Ref. 125). 

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Nicotine is known to be a habit-forming alkaloid, hence the 

confirmed user of tobacco products is primarily seeking the 

physiological "satisfaction" derived from nicotine-and perhaps 

other compounds .... Thus a tobacco product is, in essence, a 

vehicle for delivery of nicotine, designed to deliver the nicotine in a 

generally acceptable and attractive form. Our industry is then based 

upon design, manufacture and sale of attractive dosage forms of 

nicotine .... 869 

The actual text of the document thus flatly contradicts RJR' s claim that Teague was 

II.C.6. 

making "suppositions" about nicotine that were "very tentative."870 He was, instead, 

stating as established fact that people smoke for the pharmacological effects of nicotine. 

The later statement, "If nicotine is the sine qua non of tobacco," is thus not an 

"hypothesis" but a rhetorical device to encapsulate the author's previously expressed 

position. 

2. In the Jurisdictional Analysis, FDA relied upon the statements of RJR 

researchers in published papers that many of the most important effects of smoking cited 

by smokers as the reasons they smoke are the pharmacological effects of nicotine. RJR 

argues that none of the papers asserts that the pharmacological effects of nicotine are the 

most important reason for smoking, and that the papers also refer to the role of 

nonpharmacological effects in smoking behavior. RJR also contends that these papers do 

not show that consumers use tobacco nearly exclusively for its pharmacological effects. 

FDA disagrees. A fair reading of these studies indicates that the authors view 

nicotine as playing a far more significant role in smoking motivation than other, 

nonpharmacological motives. 

869 ld. at 1. 

870 RJ. Reynolds Tobacco Co., Comment (Jan 2, 1996), at 30. See AR (Vol 519 Ref. 103). 

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II.C.6. 

For example, a paper published in 1991 refers to the fact that some smokers report 

that they smoke to increase their mental alertness, while others smoke to calm their 

moods; the paper attempts to prove that both sets of motives can be attributed to the 

effects of nicotine on different hemispheres of the brain.871 The study demonstrated that 

smoking produced EEG effects in different hemispheres of the brain, depending on the 

depth of inhalation, leading the researchers to conclude that "light inhaling ... smokers 

may smoke primarily for purposes of mental activation and performance enhancement" 

while "an important motive for deep inhaling smokers might be anxiety reduction."872 

Nonpharmacological motives for smoking are not mentioned at all. In studies where they 

are mentioned, RJR researchers never claim that nonpharmacological motives are more 

important to the smoker than nicotine. 

RJR' s contention that its published studies do not demonstrate "nearly exclusive 

consumer use" of cigarettes for pharmacological effects does not diminish their relevance 

to establishing intended use. These studies were designed by RJR to examine the effects 

of smoking on the human brain and on behavior, not to quantify consumer use. These 

studies are properly used by FDA to show that RJR knows that consumers use cigarettes 

for the pharmacological effects of nicotine. A manufacturer's actual knowledge is relevant 

to establishing the intended use of these products to affect the structure and function of 

the body. See 21 CFR 201.128 and 801.4. Moreover, when the evidence of tobacco 

manufacturer's statements, research, and actions demonstrates that their products are 

871 Pritchard WS (RJ. Reynolds Tobacco Co.), Electroencephalographic effects of cigarette smoking, 

Psychopharmacology 1991;104:485-490. See AR(VoL 3 Ref. 23-2). 

872 /d. at 488. 

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ll.C.6. 

actually intended to affect the structure or function of the body, it is not necessary for the 

Agency to show that consumers use tobacco nearly exclusively for its phannacological 

effects. Some courts have suggested such a showing could be required, but only where 

there is no other evidence of the intended use and FDA is relying exclusively on actual 

consumer use. Action on SITWking and Health v. Harris, 655 F.2d 236, 240 (D.C. Cir. 

1980). The "nearly exclusive" consumer use standard is inapplicable in the context of 

direct evidence of manufacturers intent. See sections ILB.l., above, and II.E.l., below. 

3. In the Jurisdictional Analysis, 60 FR 41601, FDA stated that attorneys for 

RJR had, in a court filing, described the following pharmacological "benefits" of smoking: 

"satisfaction; stress reduction; relaxation; stimulation; aided concentration; increased 

memory retention; alleviation of boredom and fatigue; avoidance of loss of vigilance in 

repetitive and sustained tasks."873 RJR argues that FDA's use of this litigation response 

was misleading because: (1) the listed benefits were only those reported by smokers or 

the literature, and were not subscribed to by RJR; (2) FDA omitted from the quote 

benefits that were not pharmacological; and (3) the listed benefits were not characterized 

by RJR as "pharmacological" or "significant," and are likely due to other aspects of 

smoking, including the sensory aspects. RJR also states that even if some of the benefits 

quoted by FDA "are in some sense pharmacological," the litigation response is not 

evidence of intended use. 

873 Reply to Interrogatories, Gilboy v. American Tobacco Co. et al., No. 314002 (La. Dist Ct). See AR 

(VoL 15 Ref. 194-1). FDA notes that Lorillard bas not contested FDA's reliance on a similar court filing 

by Lorillard in Covert v. Lorillard et al., No. 88-1018-B (M.D.La). See AR (VoL 15 Ref. 194-2). 

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II.C.6. 

FDA disagrees that its use ofthe company's statements in litigation was misleading 

or that the statements fail to provide evidence of intended use. The statement filed in 

court by RJR was used as evidence that RJR, speaking as a corporation, knows that 

consumers use tobacco for its pharmacological effects. The knowledge of a manufacturer 

that its product is used for pharmacological effects provides objective evidence of intent to 

affect the structure and function of the body. The fact that RJR was repeating benefits 

reported by consumers does not in any way undercut FDA's reliance on the quote: RJR's 

awareness of how consumers use its product is highly relevant. The fact that the original 

quote included two nonpharmacological "benefits" of smoking similarly fails to diminish 

the relevance of the quote. When it has been established that a manufacturer intends that 

its product be used for a pharmacological purpose, FDA's jurisdiction is not defeated 

by a showing that the manufacturer also intends the product to be used for other, 

nonpharmacological purposes. Guardian Chemical Corp., 410 F.2d at 162-163. 

Finally, while RJR did not explicitly characterize the benefits as pharmacological in 

this particular filing, RJR scientists have published reports demonstrating that the company 

knows that these "benefits" of tobacco are due to the pharmacological effects of nicotine. 

In one paper, for example, RJR scientists reported on a study whose purpose was to 

isolate the psychopharmacological effects of nicotine from the effects of other aspects of 

the cigarette: 

Anxiety relief and improved mental alertness are two of the benefits 

of smoking commonly reported by smokers as their reason for 

smoking .... [The study results] indicate that the beneficial effects 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45031

of smoking on cognitive performance ... are a function of nicotine 

absorbed from cigarette smoke upon inhalation. 874 

II.C.6. 

Thus, RJR scientists characterize the very effects that the corporation listed in the pleading 

as nicotine's phannacological effects. 

4. RJR challenges FDA's use in the Jurisdictional Analysis of the statement of 

its former CEO, F. Ross Johnson, in response to a question from a reporter about whether 

tobacco is addictive: "Of course it's addictive. That's why you smoke the stuff."875 RJR 

argues that this statement is not evidence of intent because, as Johnson "explained" in a 

subsequent letter to the reporter, he used the term "addictive" not in the "technical" sense, 

but as an expression of the "common experience that some people find it hard to·quit 

smoking, and so continue to smoke."876 RJR also argues that Johnson's statement should 

not be attributed to RJR because, at the time he made it, he was no longer employed by 

RJR, and ''there is no indication that Johnson's comment reflected anything he learned or 

observed" at RJR.877 

The arguments put forward by RJR for discounting the statement of its former 

CEO are not persuasive. It is doubtful that the former CEO of a tobacco company would 

874 Robinson JH, Pritchard WS, Davis RA (RJ. Reynolds Tobacco Co.), Psychopharmacological effects of 

smoking a cigarette with typical "tar" and carbon monoxide yields but mjnimal nicotine, 

Psychopharmacology 1992;108:466-472, at471 (emphasis added.). See AR(Volll Ref. 129-3). 

See also Pritchard WS (RJ. Reynolds Tobacco Co.), Electroencephalographic effects of cigarette smoking, 

Psychopharmacology 1991;104:485-490 (presenting evidence that both mental alertness and anxiety 

reduction are a function of nicotine's effects on different parts of the brain). See AR (Vol 3 Ref. 23-1 ). 

875 Shapiro E, Big spender fmds new place to spend, Wall Street Journal (Oct 6, 1994). See AR (Vol 21 

Ref. 230). 

876 RJ. Reynolds Tobacco Co., Comment (Jan. 2, 1996), at 21. See AR (Vol519 Ref. 103). 

877 /d. 

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45032 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

state that tobacco is "addictive" without foreseeing that he would be understood to mean 

the term in its ''technical" sense. The further suggestion that the statement did not reflect 

Johnson's knowledge while at RJR is similarly unconvincing. 

5. RJR argues that FDA incorrectly stated that a particular research article878 

found that tobacco users report "craving." FDA has reviewed the article in question and 

agrees with the comment that it does not clearly fmd that smokers report craving. 

iii. Comments on Specific Brown & Williamson Statements and Research 

Projects. In the Jurisdictional Analysis, FDA cited over 75 Brown & Williamson and 

BATCO documents to demonstrate the cigarette manufacturer's knowledge that cigarettes 

produce significant pharmacological effects, including causing and sustaining addiction, 

and are used by smokers for these effects. FDA also cited a substantial number of 

documents from Brown & Williamson's affiliate, Imperial Tobacco, and from American 

Tobacco, a company with which Brown & Williamson recently merged. Although Brown 

& Williamson makes a general assertion that the Agency has mischaracterized these 

documents, the company makes no attempt to refute FDA's specific characterizations of 

the vast majority of the Brown & Williamson documents cited by FDA. The Agency 

believes that these documents speak for themselves and fully support its conclusion that 

. Brown & Williamson intends cigarettes to affect the structure and function of the body. 

With respect to the few Brown & Williamson documents regarding nicotine 

pharmacology that the company does specifically address, FDA has reviewed the 

company's comments and concludes that the company's statements and research were 

878 Robinson JH, Pritchard W, The role of nicotine in tobacco use, Psychopharmacology 1992;108:395-

405. See AR (Vol. 14 Ref. 175). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45033

II.C.6. 

properly characterized in the Jurisdictional Analysis. These comments and FDA's 

responses are presented below. 

1. FDA relied on a large number of statements from researchers and high-ranking 

officials of Brown & Williamson and BATCO acknowledging that nicotine is addictive. 

Brown & Williamson makes a general argument that none of the statements by BATCO 

employees about addiction is attributable to Brown & Williamson, because their employees 

were merely reciting language from government and other external sources. The company 

provides only one example to support this contention. FDA quoted from a speech by Charles 

Ellis, the science advisor to BATCO' s Board of Directors, in which he tokl an audience of 

tobacco industry officials: "smoking is a habit of addiction .... '..s79 According to the 

comment, Ellis' "tenninology mirrored virtually identical phrases used by the Royal College of 

Physicians three nxmths earlier ... [and] does not support any conclusion about his own 

views.'..sso Brown & Williamson also makes a baftling argument that the Surgeon General two 

years later determined that smoking was a "habit" rather than an "addiction" and that the 

Surgeon General's determination "clearly trumps the earlier imprecise language quoted by 

FDA" 

FDA has reviewed the full text of Ellis' speech and finds no support for Brown & 

Williamson's contention that Ellis was merely reciting the views of the Royal College; in the 

quoted passage, Ellis is clearly stating his own views. FDA is similarly unable to conclude that 

the 1964 determination of the U.S. Surgeon General transformed Ellis' assertion two years 

879 Ellis C (BATCO), The smoking and health problem, in Snwking and Health-Policy on Research, Research 

Conference, Southampton. England(1962), at4. See AR(VoL 21 Ref 220). 

880 Brown & Williamson Tobacco Corp., Comment (Jan. 2, 1996), at 27. See AR (Vol 529 Ref. 104). 

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45034 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

earlier that "smoking is a habit of addiction" into the statement that it is simply a habit. 

Because Brown & Williamson provides no evidence that other statements of its officials 

concerning the addictive properties of nicotine were not their own views, and the documents 

themselves do not support such a conclusion, FDA finds no basis to disregard those 

statements. 

2. Brown & Williamson also challenges FDA's reliance on a report entitled, "A 

Tentative Hypothesis on Nicotine Addiction," arguing that it was not written by tobacco 

company researchers, reports no data, and is ''nothing more than specu1ation.'.s81 

The report in question was sent to BATCO by the Battelle scientists who were doing 

contract work for BATCO on nicotine phannacology, among other things, and contains their 

hypothesis of the mechanism by which smokers become addicted to nicotine. While the 

document hypothesizes as to the mechanism of addiction, it treats the existence of nicotine 

addiction as a fact, not hypothesis. For example, after hypothesizing that when smokers are 

deprived of nicotine, their endocrine systems become unbalanced, the report says: "[a] body 

left in this unbalanced status craves for renewed drug intake in order to restore the 

physiological equilibrium. This unconscious desire explains the addiction of the individual 

to nicotine."882 

A copy of the report was sent by Charles Ellis to Addison Yeaman, the general 

counsel of Brown & Williamson. Accordingly, this document provides evidence that 

881 /d. at 29. 

882 Haselbach C, Libert 0, A Tentative Hypothesis on Nicotine Addiction (May 30, 1963), at 2. See AR 

(Vol. 20 Ref. 197-1). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45035

II.C.6. 

company executives had knowledge that nicotine is addictive.883 Indeed, shortly 

thereafter, Yeaman wrote a memo in which he accepted the view that nicotine is addictive, 

and concluded, "[ w]e are, then, in the business of selling nicotine, an addictive drug.'.s84 

3. A comment from Brown & Williamson argues that FDA has distorted its 

nicotine research by not recognizing that the research failed to confirm the hypotheses of 

its researchers. In support of this argument, Brown & Williamson offers only one 

example. According to the comment, the results of "Project HIPPO" failed to support its 

hypotheses. 

The example put forward by Brown & Williamson does not establish that FDA 

distorted Brown & Williamson nicotine research. First, Brown & Williamson fails in its 

attempt to show misuse of the research project. Second, FDA relied on dozens of Brown 

& Williamson documents reflecting over thirty years of research, the vast majority of 

which Brown & Williamson does not challenge. 

Project HIPPO consisted of a series of studies commissioned in the early 1960's by 

BATCO to investigate the role of nicotine in why people smoke, and specifically to 

compare the effects of nicotine with those of tranquilizers, which were perceived as 

marketplace competition for tobacco: 

The aim of the whole research "HIPPO" was to understand some of 

the activities of nicotine-those activities that could explain why 

883 Letter from Ellis C to Yeaman A (Brown & Williamson) (Jun. 28, 1963). See AR (Vol 14 

Ref. 165-2). 

884 Yeaman A (Brown & Williamson), Implications of Battelle Hippo I and II and the Griffith Filter 

(Jul. 17, 1963), at4. See AR (Vol21 Ref. 221). Brown & Williamson protests FDA's use of this 

document, claiming that it was stolen from Brown & Williamson and is privileged FDA does not believe 

that this document can be considered confidential, having been published in newspapers and other media 

throughout the United States and made available to the public without limitation by the University of 

California 

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cigarette smokers are so fond of their habit. It was also our 

purpose to compare these effects of the new drugs called 

''tranquillizers" which might supersede tobacco habits in the near 

future.885 

II.C.6. 

Contrary to the position taken by Brown & Williamson, Project HIPPO's authors reported 

that they were successful in demonstrating that nicotine was superior to tranquilizers in 

certain ways: 

Our investigation definitely shows that both kinds of drugs 

act quite differently, and that nicotine may be considered ... as 

more "beneficial"--{)r less noxious-than the new tranquillizers, 

from some very important points of view. 

The so-called "beneficial" effects of nicotine are of two kinds: 

1. Enhancing effect on the pituitary-adrenal response to stress; 

2. Regulation of body weight." 886 

Although the researchers did not show that nicotine acted through certain hypothesized 

biochemical mechanisms, the documents demonstrate that this was not the central purpose 

of the research. Thus, Project HIPPO successfully demonstrated to BA TCO that nicotine 

has two significant pharmacological effects on tobacco users: it acts like tranquilizers in 

helping them respond to stress, and it regulates body weight. 

4. A comment from a public health organization pointed out a number of 

additional statements in BATCO and Brown & Williamson internal documents 

acknowledging the importance of nicotine's pharmacological effects to use of tobacco 

products.887 For example, the comment provided a copy of a handwritten note by S. J. 

Green, the long-time director of research and a board member at BATCO, in which Green 

885 Haselbach CH, Libert 0, Final Report on Project HIPPO II (Mar. 1963), at 1. See AR (Vol 64 

Ref. 321). 

886 Id. at 2 (emphasis added). 

887 American Society of Addiction Medicine, Comment (Dec. 29, 1995), at 3. See AR (Vol 528 Ref. 97). 

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II.C.6. 

says that "[t]he strong addiction to cigarette[s] removes freedom of choice from many 

individuals."888 The comment also provided a copy of a 1978 BATCO document that 

forecast developments in technology that could be used to produce current cigarette 

products. The author defined "a finished smoking material" as having the following 

purposes: "[t]o generate smoke, taste, and pharmacological effect.'.s89 

FDA agrees that many of the statements to which the comment draws attention 

provide additional support for the determination that Brown & Williamson knows that 

tobacco produces pharmacological effects on consumers, including addiction, and that 

consumers smoke cigarettes to sustain addiction and for other pharmacological effects. 

iv. Other Comments. 

1. Tobacco industry comments argue that the evidence compiled by FDA of a 

massive industry research enterprise on nicotine pharmacology is irrelevant to the intended 

use of the industry's products. The comments contend that the industry conducted this 

research to understand and improve its products, to compare the pharmacology of new 

cigarettes with that of other cigarettes, to be prepared for government restrictions on 

tobacco products, and to respond to consumer preferences. The comments also argue 

that the kind of research conducted by the industry was also being done by outside 

researchers and reported in the public domain. Thus, according to the comments, such 

research need not be related to the interests of manufacturers. For these reasons, 

888 Notes of Green SJ (1978). See AR (Vol. 528 Ref. 97, appendix 18). 

889 Kilburn KD (BATCO), A Technological Forecast of the Future ofTobacco Processing (Oct 16, 

1978), at 60. See AR (VoL 258 Ref. 3524). 

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II.C.6. 

according to the comments, the industry's research is not evidence of intent to affect the 

structure and function of the body. 

FDA disagrees that the industry's extensive and sophisticated research into 

nicotine's pharmacological effects is irrelevant to the intended use of the products. This 

research establishes that the industry has actual knowledge that nicotine has powerful 

pharmacological effects and that consumers use tobacco to obtain those effects. 

"Objective intent" to affect the structure or function of the body may be established by a 

manufacturer's "knowledge of facts that would give him notice that a device introduced 

into interstate commerce by him is to be used for conditions, purposes, or uses other than 

the ones for which he offers it." 21 CFR 201.128 and 801.4. 

The argument that other researchers conducted and published nicotine research 

similar to that conducted by the tobacco industry fails to provide an adequate basis to 

disregard the industry's research as evidence of intent. Although there may undoubtedly 

be other motives for this kind of research, the industry's own documents establishes that 

their motive is directly related to providing an adequate dose of nicotine the 

pharmacologically active ingredient in tobacco. 

In its comments, Brown & Williamson even aclmowledges that some ofBATCO's 

most significant nicotine research was conducted, not because of outside pressure, but 

because Charles Ellis, senior scientific advisor to BATCO, believed that an alternative 

cigarette that provided only a nicotine aerosol could satisfy smokers and because he 

wanted to identify the "beneficial properties of nicotine."890 Indeed, as described in the 

890 Brown & Williamson Tobacco Corp., Comment (Jan. 2, 1996), at 23. See AR (Vol 529 Ref. 104). 

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II.C.6. 

Jurisdictional Analysis, Ellis believed that the research was critical "to elucidate the effects 

of nicotine as a beneficent alkaloid drug"891 and because "we are in a nicotine rather than a 

tobacco industry."892 See also Jurisdictional Analysis, 60 FR 41621-41640. Industry 

documents further show that the research was not merely exploratory, but was intended to 

be used in product development. 893 

None of the additional motives claimed by the industry for its nicotine research are 

inconsistent with FDA's fmding that the research was conducted because the industry 

believes people use tobacco to obtain the pharmacological effects of nicotine, and wanted 

to gather infonnation about nicotine how to ensure that tobacco products provide an 

adequate dose of nicotine. Each of the motives listed by the industry logically coexist with 

the industry's belief that consumers use tobacco for its pharmacological effects. Indeed, 

most of the proffered explanations themselves strongly suggest that the industry believes 

that the phannacological effects of nicotine are central to the success of its products. For 

example, the most obvious explanation for a company's decision to compare the nicotine 

pharmacokinetics of a new cigarette with that of existing cigarettes is that the company 

believes that the pharmacological effects of nicotine are important to the success of the 

new product. 

891 Ellis C (BATCO), The smoking and health problem in Smoking and Health-Policy on Research, 

Research Conference, Southampton, England (1962), at 16. See AR (VoL 21 Ref. 232). 

892 Johnson RR (BATCO), Comments on Nicotine (Jun. 30, 1963), at 10-11. See AR (VoL 21 Ref. 242). 

893 Dunn WL (Philip Morris lnc.), Plans and Objectives-1979(Dec. 6, 1978), in 141 Cong. Rec. H7668-

7669 (daily ed. Jul. 25, 1995) (nicotine pharmacology research would be used to "strengthen Philip Morris 

R&D capability in developing new and improved smoking products"). See AR (VoL 14 Ref. 175a). 

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II.C.6. 

Similarly, the claim that the research on nicotine pharmacology was conducted to 

be prepared for government restrictions is consistent with the industry's belief that it must 

understand and preserve the pharmacological effects of nicotine to ensure the continued 

success of tobacco. This explanation for the industry's nicotine research was presented 

by the companies as the rationale for their nicotine analogue research. Internal documents 

show that the companies wanted to develop substitutes for nicotine that would mimic 

nicotine's pharmacological effects on the central nervous systems of smokers should 

restrictions prevent their continued use of nicotine.894 

The industry's claim that it conducted research on maintaining and increasing 

nicotine deliveries from low-tar cigarettes because government officials "published 

concerns that smokers switching to lower 'tar' delivery cigarettes might change their 

smoking patterns if nicotine levels were too low"895 similarly suggests that the industry 

believes that smokers smoke to obtain an adequate dose of nicotine. As discussed in 

section II.C.3.f., above, the small number of recommendations that low-tar, high-nicotine 

cigarettes be investigated were premised on the view that smokers use cigarettes to satisfy 

their dependence on nicotine and will compensate when given low nicotine cigarettes by 

smoking more intensely or more cigarettes to obtain an adequate dose of nicotine. It is 

not credible that the cigarette industry would develop cigarettes whose avowed pwpose is 

to avoid smoker compensation, unless they share the view that smokers use cigarettes to 

obtain an adequate dose of nicotine. 

894 See, e.g., Kilburn KD, Underwood JG (BATCO), Preparation and Properties of Nicotine Analogues 

(Nov. 9, 1972), at 1-2. See AR (Vol 31 Ref. 524-1). 

895 Brown & William.son Tobacco Corp., Comment (Jan. 2, 1996), at 30. See AR (Vol 529 Ref. 104). 

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II.C.6. 

Finally, the claim that the research was conducted to respond to consumer 

preferences strongly suggests that the tobacco companies understand that consumers 

prefer products that deliver the pharmacological effects of nicotine. Where, as here, the 

tobacco industry is marketing a product to which most of its consumers are addicted, 

satisfying consumer preferences requires the company to understand the consumer's need 

for nicotine in order to supply a sufficient dose of nicotine. If, on the other hand, 

consumer preferences were limited to taste and flavor, research on nicotine pharmacology 

would be irrelevant to satisfying those preferences. 

Even if the record supported the industry's claim that its research was initiated for 

some purpose other than its belief that people use tobacco for nicotine's pharmacological 

effects (which it does not), this would not alter the fact that the research results 

demonstrated to the industry that consumers use tobacco primarily for nicotine's 

pharmacological effects. 

2. Tobacco company comments argue that the tobacco industry's nicotine 

research does not establish that adults smoke solely or "nearly exclusively" to obtain 

nicotine. One company, while acknowledging that its parent "explored the effects of 

nicotine and the role it played in smoking," contends that its research "generally bas 

concluded that the presence and effects of nicotine do not alone account for smoking 

enjoyment'..s96 

First, the industry's contention that its research shows that nicotine does not 

"alone" account for tobacco use is not in any way inconsistent with FDA's conclusion that 

896 /d. at 22-23. 

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II.C.6. 

the industry's research demonstrates that nicotine plays a central role in tobacco use. 

Indeed, throughout its comments, the tobacco industry implicitly acknowledges that its 

research demonstrates that nicotine does play a critical role in tobacco use. 

Second, this research is persuasive evidence that the manufacturers intend 

cigarettes and smokeless tobacco products to affect the structure or function of the body 

of tobacco users. As described elsewhere in this notice, FDA's regulations provide that 

whether a product is "intended to affect the structure or any function of the body" may be 

established by, among other things, evidence that the vendor has knowledge that its 

product is being used for a pharmacological purpose, even though the product is not 

promoted for that purpose. 21 CFR 201.128 and 801.4. These regulations do not require 

the manufacturer to have knowledge that consumers use the product solely or nearly 

exclusively for a pharmacological purpose. 

The industry's own research establishes that it has actual knowledge that 

consumers use tobacco products primarily for their pharmacological effects. This is 

persuasive and sufficient evidence that the manufacturers intend to affect the structure or 

function of the body. Furthermore, the tobacco industry's nicotine research, together with 

the other evidence in the record on consumer use, demonstrates that consumers use 

tobacco overwhelmingly for nicotine's pharmacological effects. 

3. In the Jurisdictional Analysis, FDA reviewed the industry research and 

statements demonstrating that tobacco companies are aware of the high percentage of 

smokers who have made unsuccessful attempts to quit. This evidence demonstrates that a 

large proportion of tobacco users display one of the characteristic features of addiction: 

continued use despite attempts to quit. See Jurisdictional Analysis, 60 FR 41667-41673. 

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II.C.6. 

One tobacco company argued that it had never determined that smokers cannot quit and 

that its research was not directed at control of smokers' ability to quit. Another tobacco 

company cited evidence that it knows many smokers would like to quit smoking, but that 

this is irrelevant to whether they are actually unable to quit. This company contends that 

the fact that many people do quit shows that tobacco is not addictive. 

Both companies' comments rely on a false assumption about the relationship of the 

ability to quit and addiction. As described above in section II.A.3., "addiction" is not a 

condition that can be demonstrated only if no user is ever able to quit. Substantial 

percentages of users of such addictive substances as heroin and cocaine are eventually able 

to quit without formal treatment.897 In fact, more than half of people seeking treatment 

for alcohol or drug abuse who also smoke cigarettes report that quitting smoking would 

be harder than giving up their other drug of abuse.898 

The characteristic feature of all addictive substances is that it is very difficult (not 

impossible) to quit and that addicted users often fail despite serious attempts to do so. See 

section II.A.3., above. Tobacco company data bear this out. For example, a BATCO 

researcher presented data at a major BA TCO conference showing that, although 40% of 

Canadian smokers have tried to quit, fewer than 4% were able to quit permanently within 

897 Kleber HD, Conney D, Don't you believe that nicotine isn't addictive, New York Times, Apr. 4, 1994. 

See AR (Vol 196 Ref. 2497). 

898 Kozlowski LT, Wilkinson A, Skinner W, et al., Comparing tobacco cigarette dependence with other 

drug dependencies, Journal of the American Medical Association 1989;261(6):898-901. See AR (Vol. 41 

Ref. 92). 

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II.C.6. 

the past year.899 Similarly, a Philip Morris researcher reported that of smokers who made 

an attempt to quit in Greenfield, Iowa, only 28% were still abstaining after 7 months.900 

The argument that tobacco companies do not have knowledge of the low success 

rates experienced by tobacco users who attempt to quit defies credibility. Not only is this 

a matter of common knowledge, but the Council for Tobacco Research (of which every 

major tobacco company is or has been a member) sponsored a book on tobacco research 

in which the authors review, among many topics, a wealth of data on the difficulty of 

quitting.901 Indeed, the very company that argued that its knowledge was limited to the 

fact that some smokers want to quit has argued in court that consumers should be held to 

the knowledge that it is very difficult to quit.902 

4. One comment provided additional tobacco industry-funded research on 

nicotine pharmacology that had not been included in the Jurisdictional Analysis. FDA has 

confmned that the following studies submitted with the comment are additional tobacco 

industry-funded studies on nicotine pharmacology and the relationship of nicotine to 

tobacco use: 

(1) Knapp PH, Bliss CM, Wells H, "Addictive aspects in heavy cigarette 

smoking," American Journal of Psychiatry 1963;119:966-972 (supported by the 

Tobacco Industry Research Committee); 

899 Proceedings of the BA TCO Group R&D Smoking Behaviour-Marketing Conference, Session ill 

(Jul. 9-12, 1984), atBW-W2-02790. See AR(Vol25 Ref. 337-1). 

900 Ryan FJ (Philip Morris Inc.), Cold Turkey in Greenfield Iowa: a follow-up study in Smoking 

Behavior: Motives and Incentives, ed Dunn WL (Washington DC: VH Winston & Sons, 1973), at 233 

(table 1). See AR (Vol 8 Ref. 105). 

901 Larson PS, Silvette H, Tobacco-Experimental and Clinical Studies: A Comprehensive Account of the 

World literature (1968), Supplement I at 300-302. See AR (Vol 50 Ref. 151). 

902 Appellees brief in reply to appellants' opposition to petition for transfer, Rogers v. R.J. Reynolds et al., 

No. 49A02-8904 CV 164(Sup. Ct Ind 1990), at 7-8. See AR(Vol21 Ref. 229). 

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II.C.6. 

(2) Ague C, "Nicotine content of cigarettes and the smoking habit: their relevance 

to subjective ratings of preferences in smokers," Psychopharmacologia 

1972;24:326-330 (supported by the Tobacco Research Council); 

(3) Beckett AH, Triggs EJ, "Enzyme induction in man caused by smoking," 

Nature 1%7;216:587 (supported by the Tobacco Research Council); and 

( 4) Bowman ER, Turnbull LB, McKennis H, "Metabolism of Nicotine in the 

Human and Excretion of Pyridine Compounds by Smokers," Journal of 

Pharmacology and Experimental Therapeutics 1959; 127:92-95 (supported by the 

Tobacco Industry Research Committee and the American Tobacco Company).903 

The study by Knapp, Bliss, and Wells, which was funded by the Tobacco Industry 

Research Committee, the predecessor to the Council for Tobacco Research, concluded 

that nicotine produces addiction in some tobacco users. 

b. Comments on Product Research and Development To Optimize and 

Manipulate Nicotine Delivery 

i. Comments on Specific Philip Morris Product Research and Development 

Projects. 

1. A comment from Philip Morris argues that FDA has mischaracterized its 

nicotine analogue research. The comment concedes that Philip Morris conducted research 

in which the company developed a "behavioral, peripheral and central nervous system 

profile of nicotine" and compared nicotine analogues to this profile.904 The comment 

asserts, however, that the company's research on nicotine analogues is not evidence of 

intended use because outside researchers were also investigating nicotine analogues, Philip 

903 American Society of Addiction Medicine, Comment (Dec. 29, 1995), at appendix 9. See AR (VoL 528 

Ref. 97). 

904 Philip Morris Inc., Comment(Jan. 2, 1996), at 25. See AR (VoL 519 Ref. 105). 

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II.C.6. 

Morris provided analogues to outside researchers, and the research did not result in 

development of a commercial product.905 

Philip Morris appears to be arguing that if outside researchers were also interested 

in nicotine analogues for unspecified reasons, then Philip Morris' own intent in conducting 

this research is irrelevant. FDA disagrees. Philip Morris' purpose in conducting nicotine 

analogue research provides evidence of the company's know ledge that nicotine's 

psychoactive and reinforcing effects are central to the market for tobacco. The purposes 

of outside researchers do not diminish or alter Philip Morris' motives in any way. 

Philip Morris' internal documents and the statements of former Philip Morris 

employees reveal that the purpose of its nicotine analogue research was to find chemicals 

that mimic nicotine's effects on the central nervous system, but not its adverse effects on 

the cardiovascular system, that could be substituted for nicotine in cigarettes to produce a 

safer cigarette.906 Specifically, Philip Morris sought to identify, through sophisticated 

laboratory studies in rats, whether nicotine produces discriminative stimulus effects (which 

predict whether a substance has mood-altering effects in humans) and reinforcing effects 

90s Additional comments alleging that FDA misrepresented the results of Philip Morris' studies on 

nicotine's reinforcing properties and invalidly equated reinforcement with addiction are addressed in 

section ll.C.6.a.i., above. 

906 See, e.g., Regulation of Tobacco Products (Part 2): Hearings Before the Subcommittee on Health and 

the Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 103d 

Cong., 2d Sess. (Apr. 28, 1994), at 5, 35 (restimony of Victor DeNoble) See AR (VoL 708 Ref. 2). 

See also, Charles JL (Philip Morris Inc.), Nicotine Receptor Program-University of Rochester (Mar. 18, 

1980) ("The original charge of the nicotine program was (1) to ascertain if the central and peripheral 

effects could be 'separated' and (2) to design a nicotine analogue which would have CNS activity 

equivalent to nicotine with little or no peripheral effect"). See AR (Vol32 Ref. 532). 

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II.C.6. 

(which predict whether a substance will induce repeated compulsive use in humans), and 

then fmd analogues that could produce the same effects, for use in future cigarettes. 907 

Philip Morris' nicotine analogue research thus demonstrates that Philip Morris 

knows that nicotine's psychoactive and reinforcing effects are critical to the success of 

existing tobacco products. 

2. In the Jurisdictional Analysis, FDA presented evidence that Philip Morris 

conducted research on acetaldehyde, another component of cigarette smoke that was 

hypothesized to contribute to tobacco's reinforcing effects. According to Philip Morris 

research reports, the objective of this research was to fmd the "maximally reinforcing" 

combination of nicotine and acetaldehyde.908 Philip Morris argues that its research to find 

the maximally reinforcing combination of acetaldehyde and nicotine is not relevant to the 

intended use of cigarettes because the mean level of acetaldehyde in cigarettes is declining 

and is commonly found in proportions far from those found to be maximally reinforcing. 

Philip Morris also argues that its research does not establish that acetaldehyde is addictive. 

Regardless of whether Philip Morris has increased the acetaldehyde levels in its 

cigarettes, its research on acetaldehyde is further evidence of the company's understanding 

of the reinforcing properties of cigarettes and the steps it has taken to exploit those 

properties. In fact, there is some evidence that acetaldehyde levels in Philip Morris 

products have increased since 1982, the year that Philip Morris conducted its 

907 DeNoble VJ, Carron L (Philip Morris Inc.), Progress in Behavior Pharmacology Laboratory (Mar. 27, 

1981), at 1-32. See AR (Vol. 32 Ref. 541). There is no evidence that Philip Morris tested these 

analogues to ensure that they produced the same "taste" as nicotine. 

908 DeNoble VJ (Philip Morris Inc.), Project Number 1610 (Behavior Pharmacology) Objectives and 

Plans 1982-1983 (Jul. 20, 1982), at 2 See AR (Vol345 Ref. 5443). 

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II.C.6. 

reinforcement research. According to a report in the Wall Street Journal, a competing 

tobacco company that analyzed Marlboro King Size cigarettes found that acetaldehyde 

levels in that brand had increased 40% between 1982 and 1991.909 

Although a determination that acetaldehyde is a positive reinforcer is not 

equivalent to a finding that it is addictive, it is one of the most critical pieces of evidence 

that a substance is addictive. For a complete description of the role of reinforcement in 

addiction, see section II.A.3.c., above. Philip Morris' research into acetaldehyde's use as 

a multiplier of the reinforcing effects of nicotine provides evidence of Philip Morris' intent 

to deliver a reinforcing drug. 

3. Philip Morris disputes William Farone's statement that designing cigarettes 

with reduced tar but an acceptable level of nicotine was a key objective of the tobacco 

industry. Philip Morris makes a series of arguments that purport to explain why the tar 

and nicotine levels in marketed cigarettes have not been reduced proportionately. The 

company argues that the "physics" of the ftlter technologies used to reduce tar and 

nicotine do not reduce these two constituents to the same degree, resulting in a slight 

increase in the nicotine-to-tar ratio, and that the Merit Ultra Lights brand of cigarettes is 

not an example of manipulation of nicotine-to-tar ratios. 910 

Neither of these arguments challenges Farone's statement that the tobacco industry 

conducted extensive product development research on how to reduce tar while 

maintaining a level of nicotine that provides the consumer with the same "pharmacological 

909 Freedman AM, Fine tuning Marlboro, Wall Street Journal, (Oct 18, 1995). See AR (Vol 533 

Ref. 102). 

910 Philip Morris Inc., Comment (Apr. 19, 1996), at 61-62. See AR (Vol 700 Ref. 226). 

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II.C.6. 

satisfaction" as full strength cigarettes.911 Philip Morris' arguments with respect to the 

methods used to control nicotine-to-tar ratios are addressed in sections II.C.4., above, and 

section ll.C.6.c.ii., below. 

Tobacco industry comments also state that Farone fails to acknowledge that, 

beginning in the 1970's, outside scientists recommended that research be conducted on the 

development of a high nicotine/low tar cigarette. This argument has already been 

addressed above in section II.C.3.f. In this context, FDA notes that Farone is reporting on 

the tobacco industry's internal reasons for conducting the research, and these reasons are 

relevant to establishing the companies' intent to affect the structure or function ofthe 

body. 

4. Philip Morris challenges the reliability of statements made in a declaration 

submitted to FDA by Ian L. Uydess, a research scientist who worked for Philip Morris 

from 1977 to 1981, and from 1982 to 1989. Uydess' declaration is based on his own 

participation in research and development projects at Philip Morris; his personal 

observations of activities in other parts of the company; his attendance at meetings and 

discussions held among the scientists, engineers and management at Philip Morris; and his 

close association with other scientists and senior management at Philip Morris.912 Philip 

Morris argues that the information provided by Uydess is unreliable because: (1) he left 

Philip Morris seven years ago; (2) he did not work on the development of commercial 

cigarettes; and (3) his declaration reports, in part, on information relayed to him informally 

911 Farone W A, The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 7. See AR (Vol 638 Ref. 2). 

912 Declaration of Uydess IL (Feb. 29, 1996), at S. See AR (Vol 638 Ref. 1). 

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II.C.6. 

by colleagues. In contrast, other comments argue that the reliability of Uydess' statement 

is shown by its consistency with the statement of other former tobacco company officials. 

FDA disagrees that Uydess' declaration is unreliable or irrelevant to establishing 

the knowledge and actions of Philip Morris. His position and tenure at the company gave 

him personal knowledge of the views of Philip Morris officials on the role of nicotine in 

cigarettes, and of the company's research and actions in developing new products. 

Moreover, like Farone, Uydess' statements about the knowledge, views, and actions of 

Philip Morris are consistent with a large body of Philip Monis documents and statements, 

covering over three decades. Uydess' statements are also consistent with the recent Philip 

Morris document concerning Project Table, demonstrating that the company's views have 

not changed since Uydess left the company. The information he provided is thus 

corroborated by evidence already gathered by FDA. 

5. Philip Morris also challenges particular statements made by Uydess in his 

declaration. FDA addresses those comments that challenge statements relied on by the 

Agency. 

Philip Morris argues that Uydess' statement that Philip Morris conducted 

exhaustive research on nicotine chemistry in tobacco leaf and tobacco smoke is true but 

irrelevant because: (1) any manufacturer in the business of selling an agricultural product 

develops expertise in the product; (2) tobacco chemistry is widely studied outside Philip 

Morris; and (3) the company's research was not used to increase artificially the nicotine 

yield of its commercial cigarettes. 

FDA disagrees that extensive research by a tobacco manufacturer into the amount 

of nicotine in tobacco leaf and tobacco smoke-using highly sophisticated equipment 

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II.C.6. 

developed, in part, by the company-is irrelevant to the manufacturer's intent in selling 

cigarettes. Philip Morris' arguments suggest that Uydess' statement relates to the 

company's research on tobacco chemistry in general, rather than to any specific 

component in tobacco. Uydess says, however, that Philip Morris' exhaustive research 

related specifically to nicotine and that Philip Morris "wanted to know everything there 

was to know about nicotine."913 The intensity of Philip Morris' focus on nicotine provides 

evidence that the company knows that nicotine is central to the success of its products. 

Philip Morris' public position is that if nicotine is important, it is important, like 

flavorants, only for its sensory appeal. The company, however, offers no evidence or 

argument that its exhaustive research on nicotine pharmacology is matched by its research 

on any other flavor or sensory aspects of nicotine. Moreover, as described in section 

II.C.2.a., above, Philip Morris' public position is contradicted by the views of its scientists, 

who have repeatedly stated that the primary reason for smoking is nicotine's 

pharmacological effects. FDA concludes that the extent of Philip Morris' research on 

nicotine is relevant to establishing its intent to affect the structure or function of the body. 

ii. Comments on Specific RJR Pro<luct Research and Development Projects. 

1. RJR contends that Premier and Eclipse are not "alternative cigarettes" but 

conventional cigarettes, and that they were created to address public criticisms of 

cigarettes. RJR also disputes FDA's fmdings that Premier contained very little tobacco 

and that the nicotine in blood studies conducted on Premier show that RJR intended 

Premier to deliver nicotine to the smoker's blood and brain. 

913 /d. at 14 .. 

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II.C.6. 

RJR' s arguments concerning Premier and Eclipse are not persuasive. RJR now 

claims that Premier was a conventional cigarettes because it was a "roll of tobacco 

wrapped in paper''; "contained sugars, humectants, flavorings, tobacco paper, and a ftlter''; 

was ''taxed as a cigarette"; and was "marketed for smoking taste and pleasure."914 In fact, 

Premier resembled a conventional cigarette in outward appearance only. It contained a 

carbon tip that served as the heat source. A nicotine source had been combined with 

glycerol and adsorbed within alpha-alumina spheres contained within an aluminum cylinder 

positioned directly behind the carbon heat source. RJR informed FDA that at least 70% of 

the nicotine delivered by Premier was provided from spray-dried tobacco. The remaining 

nicotine was provided from the cut tobacco leaf surrounding this cylinder and the tobacco 

extract-treated paper filter positioned in front of the cellulose acetate fllter.915 Although 

there was a small amount of tobacco in Premier, it was not burned; the only component of 

Premier that was burned was the carbon heat source and some paper, to "simulateD the 

ash of other cigarettes."916 

The critical aspect of Premier is the fact that the major constituents of its smoke 

differed from those in the smoke of conventional cigarettes in almost every way except 

nicotine content.917 In other words, virtually the only constituent of tobacco smoke that 

RJR designed Premier to preserve was nicotine. 

914 RJ. Reynolds Tobacco Co., Comment (Jan. 2, 1996), 35. See AR (Vol 519 Ref. 103). 

9

u Letter with enclosures from Hutt PB, outside counsel for RJR, to Budicb KM, FDA (Jan. 26, 1988). 

See AR (Vol34 Ref. 556). 

916 RJ. Reynolds Tobacco Co., Chemical and Biological Studies on New Cigarette Prototypes That Heat 

Instead of Burn Tobacco (Winston-Salem NC. 1988), at 4. See AR (Vol107 Ref. 980). 

917 ld. at 134-136. 

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II.C.6. 

FDA does not contest that Premier was developed to address criticisms of 

cigarettes; undoubtedly, Premier was an attempt to make a safer cigarette. However, 

making a safer cigarette would not require the company to maintain a near-nonnal nicotine 

delivery, or to ensure that the nicotine was actually delivered to the smoker's blood in the 

same quantity as from conventional cigarettes, unless the company believed that ensuring 

near-normal nicotine blood levels was an essential feature of a profitable cigarette. RJR's 

argument that its pharmacokinetic comparisons of the nicotine levels delivered by Premier 

and a conventional cigarette were intended simply as comparisons of the two products, 

apparently without any further purpose, is unpersuasive. According to RJR' s publication 

summarizing the studies conducted on Premier, RJR did not conduct similar 

pharmacokinetic studies on the delivery of any other smoke constituent to the smoker's 

blood.918 This fact demonstrates that RJR believes that nicotine is the defming ingredient 

of cigarettes and that delivery of an adequate level of nicotine to the smoker's blood is 

central to the success of its products. 

The RJR nicotine blood level study is also directly at odds with the company's 

public position that nicotine's role is limited to providing taste or flavor. The amount of 

nicotine delivered into a smoker's bloodstream is irrelevant to nicotine's ability to function 

as a flavoring agent. Nicotine absorption into the bloodstream is relevant only if the 

company believes that nicotine delivers pharmacological effects to the smoker and that 

these effects are important to the use of the product. RJR' s reliance on a Surgeon General 

recommendation that cigarettes with low tar-to-nicotine ratios be evaluated for their 

918 /d. at 457-557. 

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II.C.6. 

pharmacological properties and effects on compensation919 merely underscores RJR' s 

understanding that the nicotine in cigarettes delivers pharmacological effects and that 

consumers use cigarettes for these effects. 

RJR's last argument, that its study was necessary because an FDA representative 

later asked whether nicotine was delivered by Premier in amounts comparable to 

conventional cigarettes, is similarly unavailing. As RJR acknowledges in its comment, the 

study had already been conducted at the time FDA asked the question. Moreover, FDA 

asked this question because FDA saw the delivery of nicotine to the blood of smokers as 

relevant to whether Premier should be regulated as a drug or device. 

2. RJR also argues that FDA has misused an RJR book on tobacco flavors in the 

Jurisdictional Analysis. FDA noted that the book, which contains over one thousand 

flavorants for tobacco, does not list nicotine as a flavorant.920 RJR contends that the book 

describes only flavors that could be added to tobacco, and nicotine is not listed because RJR 

does not add nicotine. 

FDA does not find RJR's argument persuasive. Even if the book were limited to 

flavors that "could be added" to tobacco (a limitation that is not stated in the book itself), the 

claim that RJR does not use it as an additive would not logically exclude it from the category of 

substances that "could" be added. The book does not purport to list only those substances 

that are actually added by RJR to its tobacco products. 

919 Department of Health and Human Services, The Health Consequences of Smoking: The Changing 

Cigarette, A Repon of the Surgeon General, 1981, at 58. See AR (VoL 123 Ref. 1586). 

920 Leffmgwell JC, Yound HJ (RJ. Reynolds Tobacco Co.), Tobacco Flavoring for Smoking Products 

(Winston-Salem NC: RJ. Reynolds Tobacco Co., 1972). See AR (VoL 34 Ref. 591). 

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II.C.6. 

Moreover, RJR's c1aim that it does not add nicotine raises an inconsistency. If it is the 

company's position that nicotine is benignly used (and controlled) in tobacco solely for its 

effects on flavor, and is an extremely important flavorant in tobacco, why have a policy-as 

RJR c1aims921-of not adding it when appropriate? The book does list many other naturally 

occurring components oftobacco and tobacco smoke as flavorants, apparently contemplating 

their addition to tobacco. That RJR policy in itself therefore seems at odds with the c1aim that 

nicotine is used for flavor. 

3. RJR also maintains that IDA's reliance on an RJR patent was misplaced. In 

the Jurisdictional Analysis, IDA cited an RJR patent for a process that increases the nicotine 

content of a cigarette but masks the resulting harsh taste of the cigarette.922 IDA used the 

patent to show that the tobacco industry wanted to increase nicotine in some cigarettes despite 

its harsh flavor. RJR dismisses the significance of this patent, arguing that IDA has ignored 

''basic principles of flavor" and that people like harsh flavors. RJR also argues that the patent 

is irrelevant because the process it described for increasing nicotine and masking the resuhing 

flavor was not used in commercial cigarettes. 

RJR' s argument is contradicted by its own patent and by the statements of a flavor 

specialist employed by the company. Both acknowledge that nicotine's harsh flavor can be 

unpleasant to the smoker and must be masked by the addition of sugars or other chemicals. 

The patent itseJf demonstrates that the company, as the assignee of the patent, knows that 

increasing nicotine past a certain point in low-tar cigarettes produces a harshness that leads to 

921 RJ. Reynolds Tobacco Co., Comment (Jan. 2, 1996), at 50. See AR (VoL 519 Ref. 103). 

922 U.S. Patent No. 4,830,028. Lawson JW, Bullings BR. Perfetti TA. RJ. Reynolds Tobacco Company, 

Salts Provided from Nicotine and Organic Acid as Cigarette Additives (May 16, 1989), at Cl. See AR 

(Vol. 34 Ref. 593). 

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II.C.6. 

rejection by consumers. Rather than simply keep nicotine below that point, as a company 

would do if nicotine were present solely for flavor, the patent describes a process for increasing 

nicotine and simuhaneously masking its harshness. The claim that the processes in the patent 

were not used does not in any way undercut FDA's conclusion that the patent demonstrates 

RJR's know1edge that nicotine's effects on taste are sometimes negatively related to product 

acceptance, and RJR' s desire to increase nicotine content even beyond the point where nicotine 

has a demonstrably negative effect on taste. 

Moreover, an RJR flavor specialist has written that although nicotine is necessary for 

"satisfaction," its flavor in some tobacco blends is "a 'harshness' which can be choking and 

unpleasant," requiring that steps be taken to mask nicotine's flavor.923 

Thus, it is clear that RJR officials recognize that nicotine's flavor is sometimes a 

liability that must be masked to permit nicotine to fulfill its pharmacological functions. 

4. RJR comments that a document that refers to "physiological satisfaction," 

which FDA cited as an RJR Marketing Report, is in fact an Imperial Tobacco Co. 

document.924 

FDA agrees that this document is an Imperial Tobacco Co. document rather than 

an RJR document. The document is one of dozens of tobacco industry documents in 

which the term "satisfaction" is used to describe a pharmacological effect. It is therefore 

relevant to establishing the industry's understanding and use of that term. 

923 Leffmgwell JC (RJ. Reynolds Tobacco Co.), Nitrogen components of leaf and their relationship to 

smoking quality and aroma, presented at the 30th Tobacco Chemists' Research Conference, at 9. See AR 

(Vol. 28 Ref. 450). 

924 Imperial Tobacco Ltd, Matinee Marketing Strategy (1971) ("A cigarette that delivers physiological 

satisfaction, yet is low in tar and nicotine, must surely be a major objective"), quoted in Memorandum to 

File from Joyal C (Dec. 27, 1992), at ll. See AR (VoL 27 Ref. 384). 

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iii Comments on Specific Brown & Williamson Product Research and 

Development Projects. 

II.C.6. 

1. A comment from Brown & Williamson argues that FDA has distorted its 

nicotine research by not recognizing that the research was not commercialized. According 

to the comment, Project ARIEL was never commercialized. 

ARIEL was an alternative cigarette, developed by Charles Ellis, and referred to by 

BATCO researchers as a "device[] for the controlled administration of nicotine." 925 

ARIEL eliminated almost every ingredient of conventional cigarettes other than nicotine. 

Its purpose was to provide ''the same benefits, pleasure and satisfaction without the 

disadvantages" of a conventional cigarette.926 The relevance of this product to intent is 

that it demonstrates that BATCO regarded nicotine as the essential ingredient in, and the 

source of the pleasure and satisfaction from, cigarettes. ARIEL's development 

demonstrates Brown & Williamson's knowledge of and belief in nicotine's central role in 

cigarettes, regardless of its ultimate failure to be accepted by consumers, or Brown & 

Williamson's decision not to market it. 

2. As described above, a BATCO study entitled "Project Wheat" was 

conducted to determine the level of nicotine preferred by smokers and correlate it with the 

extent to which the smoker relies on cigarettes to meet "inner needs."927 A smoker's inner 

need level was defined by the extent to which the smoker used nicotine to relieve stress, 

925 Minutes of BATCO Research Conference at Hilton Head Island, SC (Sep. 24-30, 1968), at 3. See AR 

(Vol 31 Ref. 525). 

926 U.S. Patent No. 3,258,015. Ellis CD, Dean C, Schachner H, et al., Battelle Memorial Institute, 

Smoking Device (Jun. 28, 1966). See AR (Vol 34 Ref. 569). 

927 Wood OJ, Wilkes EB (BATCO), Project Wheat- Part 1: Cluster Profiles of U.K. Male Smokers and 

their General Smoking Habits (Jul. 10, 1975), at 1. See AR (VoL 20 Ref. 204-1). 

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II.C.6. 

aid concentration, avoid weight gain, or reduce craving. BATCO hypothesized that ''the 

inner need dimension was probably defining a requirement for nicotine."928 FDA pointed 

out that inner need therefore correlated with the extent to which a smoker used cigarettes 

for pharmacological effects. Project Wheat was intended to allow BATCO to market 

cigarettes with different nicotine levels designed to satisfy identified groups of consumers. 

Brown & Williamson argues that FDA had no basis for concluding that a smoker's inner 

need was defined by the extent to which the smoker used cigarettes for the drug effects of 

nicotine, that Project Wheat failed to fmd any significant correlation between inner need 

levels and preferred nicotine delivery, that the term "inner need" came from an outside 

researcher, not BATCO, and that FDA falsely suggested that Project Wheat identified an 

allegedly "addictive" dose of nicotine. 

Brown & Williamson's attempts to discredit FDA's characterization of Project 

Wheat are not persuasive. FDA relied on the study as evidence that Brown & Williamson 

had conducted research on the dose of nicotine required by consumers with the purpose of 

designing cigarettes to satisfy their nicotine requirements. Brown & Williamson 

acknowledges that Project Wheat was designed to determine whether smokers who 

smoked to satisfy an ''Inner Need" had preferred nicotine delivery levels, and that this 

information was to be used to design cigarettes to meet their needs.929 These facts alone 

demonstrate that it was the tobacco company's intention to produce cigarettes with 

satisfying doses of nicotine. (Nowhere did FDA state that the study was intended to 

establish "addictive" doses of nicotine.) 

928 /d. at 5. 

929 Brown & Williamson Tobacco Corp., Comment(Jan. 2, 1996), at43-44. See AR (Vol 529 Ref. 104). 

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II.C.6. 

Moreover, both Project Wheat and other Brown & Williamson research 

demonstrate that the company knew that "Inner Need" level corresponded to the smoker's 

use of cigarettes for pharmacological effects. Project Wheat researchers concluded that 

future studies to design cigarettes with acceptable nicotine levels should classify smokers 

along a single dimension of inner need that might correspond to "pharmacological 

addiction": 

[l]t would be preferable to position respondents along the single ~ension 

of Inner Need .... the suggestion is very much in line with that made by 

Russell ... who ... concluded that it might prove more useful to classify 

smokers according to their position on a single dimension of 

pharmacological addiction rather than in terms of their profiles on the six 

types of smoking.930 

Brown & Williamson's assertion that stress relief, aided concentration, and weight control 

are not among the principal pharmacological effects of nicotine is not credible. In fact, as 

early as 1962, Project HIPPO concluded that nicotine's most significant pharmacological 

benefits were its ability to relieve stress and to control weight gain.931 

Contrary to Brown & Williamson's argument, Project Wheat found a correlation 

between inner need level and preferred nicotine delivery.932 Thus, the Project Wheat 

researchers concluded that inner need correlated with preferred nicotine delivery and 

agreed with Russell that inner need is related to pharmacological addiction. 

930 Wood DJ (BATCO), Project Wheat- Pan 2: U.K. Male Snwkers: Their Reactions to Cigarettes of 

Different Nicotine Delivery as Influenced by Inner Need (Jan. 30, 1976), at 49 (citation omitted) 

(emphasis added). See AR (VoL 20 Ref. 204-2). 

931 Haselbach CH, Libert 0, Final Report on Project HIPPO II (Mar. 1963), at 2. See AR (VoL 14 

Ref. 163-1). 

932 Wood DJ (BATCO), Project Wheat- Pan 2: U.K. Male Snwkers: Their Reactions to Cigarettes of 

Different Nicotine Delivery as Influenced by Inner Need (Jan. 30, 1976), at 47-48 ("High Need clusters 

tend to prefer relatively high nicotine cigarettes, and ... their optimum nicotine delivery is certainly 

higher than is that of the Low Need clusters.") See AR (VoL 20 Ref. 204-2). 

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45060 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

3. A comment from Brown & Williamson claims that the company has never 

marketed a product that used "elasticity" to enable smokers to compensate for lowered 

nicotine yields. The company concedes that internal documents show that "BATCO 

explored the possibility of using its knowledge of compensation in the development of low 

'tar' products" but claims that these were only theoretical discussions.933 

FDA relied, in part, on the industry's product development research on increasing 

nicotine as evidence that the industry understands that tobacco satisfaction is a function of 

the pharmacological effects of nicotine and of the industry's attempts, successful or not, to 

ensure that tobacco users receive sufficient nicotine to achieve those effects. FDA did not 

rely on this research as evidence that the researched products were marketed. 

In fact, however, there is good reason to believe that Brown & Williamson, as well 

as other tobacco companies, have incorporated "elasticity" into their marketed products. 

For example, Brown & Williamson's Barclay cigarettes were promoted as ultra-low 

cigarettes, with advertised deliveries of I mg tar and .02 mg nicotine, as measured by the 

FTC method. Federal Trade Commission v. Brown & Williamson, 778 F.2d 35, 37 (D.C. 

Cir. 1985). Philip Morris and RJR complained to the FTC that Barclay's channelventilated ftlter system allowed the cigarette to produce low tar and nicotine yields when 

measured by the FTC (smoking machine) method, but to actually deliver far more tar and 

nicotine to the smoker. According to the complaint, the FTC smoking machine is able to 

"smoke" the cigarette without obstructing Barclay's unique ventilation system, but "when 

the cigarette is smoked between human lips its air ventilation system is inevitably 

933 Brown& Williamson Tobacco Corp., Comment (Jan. 2, 1996). at42. See AR(VoL 529 Ref. 104). 

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II.C.6. 

obstructed and the cigarette delivers disproportionately more tar and nicotine than other 

comparably rated cigarettes." /d. at 37. 

The FTC brought an enforcement proceeding to enjoin Brown & Williamson from 

using the FfC tar and nicotine figures in Barclay advertisements. Federal Trade 

Commission v. Brown & Williamson, 580 F. Supp. 981 (D.D.C. 1983), affd in part, 

rev'd in part, 778 F.2d 35 (D.C. Cir. 1985). The district court found, and the Court of 

Appeals agreed, that use of the FfC tar and nicotine figures for Barclay was false and 

misleading, because-primarily as a result of its channel-ventilated filter system-Barclay 

delivers significantly more tar and nicotine to the smoker than indicated by the FTC yields. 

580 F. Supp. at 989; 778 F.2d at 41-42. Thus, Barclay represents a clear example ofthe 

use of fllter technology to provide elasticity, i.e., to enable the smoker to extract more 

nicotine from the smoke than the advertised yield. 

Brown & Williamson argues that Barclay is not an example of a product designed 

to provide elasticity, and that there is no evidence to support FDA's claim that the 

channel-ventilated filter boosts nicotine delivery. FDA disagrees. The district court 

opinion in Federal Trade Commission v. Brown & Williamson demonstrates that Barclay 

cigarettes deliver substantially more nicotine than their advertised yields and that this 

increase in nicotine delivery over the machine-tested yield is due to compromising the 

channel-ventilated fllter during human smoking. The district court cited a study submitted 

by Brown & Williamson, which found that "smokers who smoked Barclay received 

approximately 1-1/2 to 2 times as much nicotine into their systems as smokers of the other 

cigarettes [with comparable FTC ratings] tested." 580 F. Supp. at 988. The court also 

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II.C.6. 

found that the increase in nicotine and tar deliveries was due to compromising the 

ventilation system under actual smoking conditions. 580 F. Supp. at 989. 

The conclusion that Barclay was designed to provide elasticity is also supported by 

evidence that Barclay was reported to contain significantly more nicotine than comparable 

cigarettes. As described above in section II.C.4., an independent study conducted in 1982 

showed that Barclay had both the highest nicotine concentration and the most total 

nicotine in the rod of all the cigarette brands tested, including regular strength (high 

tar/high nicotine) cigarettes.934 Compared to the other cigarettes with comparable FfC 

nicotine ratings (~0.2 mg nicotine, as published in 1981 FfC Report) that were tested, 

Barclay contained a tobacco blend with a 50% to 95% higher nicotine concentration, and 

20% to 85% more total nicotine. Thus, while Barclay had among the lowest FfC yields, 

it delivered a significantly higher level of nicotine during human smoking because (1) it 

contained more nicotine than any comparable cigarette, and (2) the nature of the filter 

permitted smokers to defeat the ventilation system and obtain substantially more nicotine 

than the advertised yield (1-112 to 2 times the nicotine of comparable cigarettes, according 

to Brown & Williamson's own study). 

iv. Other Comments. 

1. Comments from the tobacco industry argue that the tobacco company 

studies cited by FDA do not support the fmding that smokers compensate. One comment 

argues that Brown & Williamson and BATCO researchers did not acknowledge that 

934 Regulation of Tobacco Products (Pan 3): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 103d Cong., 2d 

Sess. 173 (Jun. 23, 1994) (data from Neal Benowitz). See AR (Vol 709 Ref. 3). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45063

II.C.6. 

smokers compensate to obtain a dose of nicotine that satisfies a physiological need. This 

comment does concede, however, that it is "hardly news" that "the phenomenon of 

compensation was internally 'recognized' or 'acknowledged' by tobacco 

manufacturers."935 This comment also argues that reductions in tar and nicotine yields 

have resulted in reductions of the amount of nicotine obtained by smokers. On the other 

hand, a comment from a public health organization provided additional examples of 

industry statements and research on compensation. 936 

FDA has reviewed the studies relied on in this section of the Jurisdictional Analysis 

and concludes that they provide a wealth of evidence that the tobacco industry 

understands that smokers compensate to obtain a desired dose of nicotine. The contention 

that these studies fail to demonstrate compensation cannot be supported. For example, 

BATCO researchers stated in 1984 that "it is accepted that nicotine is both the driving 

force and the signal (as impact) for compensation in human smoking behavior.''937 

A large number of additional industry studies cited by FDA found that 

compensation occurred to one degree or another. See Jurisdictional Analysis, 60 FR 

41659-41666. Throughout these studies and conference reports, tobacco company 

officials consistently recognize that compensation behaviors occur to adjust nicotine dose. 

The public health organization comment provided several additional examples of tobacco 

industry acknowledgment that compensation occurs because smokers are attempting to 

935 Brown & Williamson Tobacco Corp., Comment (Jan. 2, 1996), at 40. See AR (VoL 529 Ref. 104). 

936 American Society of Addiction Medicine, Comment (Dec. 29, 1995), Table 6. See AR (Vol. 528 Ref. 

97). 

937 Minutes of BATCO Group R&D Smoking Behaviour-Marketing Conference, Session ID (Jul 9-12, 

1984), at 56. See AR (Vol 25 Ref. 325-1). 

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45064 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

maintain their customary nicotine dose. For example, a 1981 monograph on nicotine 

published by the Tobacco Advisory Council (an industry organization of ~hich BATCO 

was a member) reviewed the evidence on compensation and concluded that while 

regulation of nicotine intake is not consistently seen in every study: 

Human subjects appear to modify their smoking behaviour to 

maintain the total dosage of nicotine when they smoke cigarettes of 

varying nicotine content. ... Studies of nicotine antagonists 

indicate that smokers seek an effective brain level of nicotine when 

modifying their smoking behaviour.938 

Accordingly, the industry's research amply supports FDA's conclusion that the 

tobacco industry knows that smokers use cigarettes to "compensate" -to obtain desired 

doses of nicotine. 

2. One comment from a tobacco manufacturer argues that "much" of the 

nicotine-related research did not result in alterations to marketed products, and a comment 

from another cigarette manufacturer argues that its product development research did not 

result in the addition of "extraneous nicotine." 

The claim that some of the industry's research did not result in changes to 

commercial-marketed products does not alter the relevance of the industry's research to 

establishing manufacturers' awareness of the pharmacological effects of nicotine. As 

noted above, the knowledge produced by the research is evidence of intended use. 

Moreover, there is a great deal of evidence that the knowledge was acted upon. Even the 

industry comments do not claim that none of the research was acted upon. For example, 

the brands of cigarettes advertised as lowest in tar and nicotine have the highest 

938 Cohen AJ, Roe JC (Tobacco Advisory Council), Monograph on the 'Pharmacology and Toxicology of 

Nicotine' (1981), at 38 (citation omitted). See AR (VoL 34 Ref. 583). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45065

II.C.6. 

concentrations of nicotine on the market, reflecting industry to ensure that nicotine levels 

in low-yield products do not fall below minimum levels that consumers will accept. See 

section II.C.4.a., above. 

Finally, the argument that none of the product development research resulted in 

the addition of "extraneous nicotine" to commercial cigarettes is irrelevant to establishing 

intended use. Whether or not this statement is true, the research, in and of itself, 

establishes the knowledge of tobacco manufacturers that nicotine delivery is essential to 

the success of their products. In addition, the evidence shows that nicotine has actually 

been manipulated in commercial cigarettes, demonstrating that tobacco manufacturers 

have not merely researched but have taken affirmative steps to ensure the delivery of an 

adequate dose of nicotine. See Jurisdictional Analysis, 60 FR 41693-41733. It is the fact 

that the industry has manipulated nicotine delivery, rather than the manner in which it is 

accomplished, that is relevant to establishing the intended use of these products. 

c. Comments on Nicotine Manipulation and Control 

i. Comments on the Use of High-Nicotine Blends in Low-Yield Cigarettes. 

1. The cigarette manufacturers contend that the use of high-nicotine blends in 

low-tar cigarettes does not affect the nicotine delivery of these cigarettes. According to 

the manufacturers, the increase in nicotine from the use of high-yield blends is more than 

offset by other design features, such as a reduction in the total mass of tobacco in the 

cigarette and increased filtration and ventilation. 

The Agency disagrees. It is beyond reasonable dispute that the use of highnicotine blends does affect nicotine deliveries. Indeed, the joint comment of the 

manufacturers acknowledge this point. The comment concedes that "nicotine content of 

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45066 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

the leaf' is one ofthe "factors that determine the nicotine yield in the cigarette smoke."939 

Of the four factors that the comment lists as determining nicotine yield, two of the factors 

-"the blend itself' and "the percentage of processed tobaccos" 940-relate directly to the 

concentration of nicotine in the cigarette rod. Similarly, Alexander Spears, the vice 

chairman and chief operating officer of Lorillard, has acknowledged that among other 

factors, "the nicotine yield of a cigarette is determined by the nicotine content of the 

tobacco. "

941 

Although it may be true that other design features of low-tar cigarettes reduce 

nicotine deliveries, the use of high-nicotine blends is designed to offset those reductions. 

Thus, high-nicotine blends result in higher nicotine deliveries than would be provided by a 

low-tar cigarette that did not use such blends. 

Moreover, the nicotine yields measured on an FfC smoking machine do not 

accurately predict the amount of nicotine that will be inhaled and absorbed by smokers 

because smokers of low-yield products frequently compensate for the low nicotine 

deliveries by inhaling more deeply or puffmg more frequently. See Jurisdictional Analysis, 

60 FR 41573-41574. The use of higher nicotine blends in low-yield cigarettes increases 

the total amount of nicotine that is available to be extracted by smokers. 

939 Joint Comment of Cigarette Manufacturers, Comment, (Jan. 2, 1996), Vol. N, at 69 (emphasis added). 

See AR (Vol 535 Ref. 96). 

940 /d. at 70. 

941 Spears A W (Lorillard Tobacco Co.), Factors Affecting Snwke Delivery of Nicotine and Carbon 

Monoxide, presented at the 1975 Symposium-Nicotine and Carbon Dioxide (Nov. 17-18, 1975), in 

Symposium Proceedings-/, 12-18, at 13 (emphasis added). See AR(Vol 27 Ref. 395a). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45067

ILC.6. 

2. Brown & Williamson's comments concede that it used Y-1, a high-nicotine 

tobacco, in marketed cigarettes. The comments assert, however, that Y -1 "was never 

used by B& W for the purpose of altering the ratio of nicotine to tar in the smoke of any 

commercialized brands."942 What is beyond dispute, however, is the original purpose of 

the creation of Y-1. As described in section II.C.3.c.iii., Brown & Williamson developed 

Y -1 as a "blending tool" so that it could maintain nicotine levels while tar levels dropped. 

Y -1 is thus a central example of product research and development to enhance nicotine 

deliveries. 

ii Comments on Nicotine Deliveries and Nicotine-to-Tar Ratios. 

1. The cigarette industry asserts in its comments that the reduction in the 

nicotine delivery of cigarettes over the last 40 years demonstrates that the industry has not 

sought to control or manipulate nicotine. According to the industry, nicotine deliveries 

have dropped by 60% over the last 40 years. The industry maintains that the fact that 

cigarette manufacturers have reduced nicotine deliveries shows that the manufacturers do 

not control or manipulate nicotine deliveries to provide a pharmacologically active 

dose of nicotine. 

The Agency agrees that nicotine deliveries as measured by smoking machines have 

declined over the last 40 years. This comparison is misleading, however. The recent 

trends show that nicotine deliveries have stopped declining and are, in fact, increasing -

especially in low-tar cigarettes. From 1982 to 1991, the nicotine deliveries in the lowesttar category of cigarettes increased approximately 15%. See Jurisdictional Analysis, 60 

942 Brown & Williamson Tobacco Cotp., Comment (Jan. 2, 1996), at 32. See AR (Vol 529 Ref. 104). 

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45068 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

FR 41731. Although the industry maintains that "[n]icotine levels follow the tar level" in 

"essentially perfect correlation"943 and that this correlation shows that the industry does 

not manipulate nicotine,944 nicotine deliveries did not follow tar deliveries during this 

period. Rather, while nicotine deliveries were increasing from 1982 to 1991, tar deliveries 

declined or remained essentially flat.945 

The recent trend of increasing nicotine deliveries in low-tar cigarettes supports the 

Agency's finding that the cigarette manufacturers have controlled and manipulated 

nicotine to maintain a pharmacologically active dose. The trend is evidence that as tar 

deliveries dropped to low and ultra-low levels in the late 1970's and the 1980's, the 

manufacturers took steps to maintain a pharmacologically active nicotine dose by 

enhancing nicotine deliveries. 

The overall trend in nicotine deliveries is also fully consistent with-and indeed 

corroborates-the Agency's position. Forty years ago, cigarettes delivered over 2.5 mg 

of nicotine per cigarette.946 According to tobacco industry documents, however, nicotine 

deliveries as low as 0.5 to 0.8 mg per cigarette "provide sufficient nicotine to the blood to 

produce the stimulation and relaxation effects desired by the smoker."947 Thus, nicotine 

943 Regulation of Tobacco Products (Part 1), Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 103d Cong., 

2d Sess. 378 (Mar. 25, 1994) (statement of Alexander Spears). See AR (Vol 707 Ref. 1). 

944 /d. 

945 From 1982 to 1991, nicotine deliveries increased in ultra-low-tar, low-tar, and high-tar cigarettes. 

Tar deliveries, however, decreased in the high-tar and low-tar categories and increased only marginally 

(approximately 3%) in the ultra-low-tar category. See Jurisdictional Analysis, 60 FR 41728-41731. 

946 Joint Comment of the Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol. ill, ''Sales Weighted 

Average 'Tar' and Smoke Nicotine"Graph. See AR (Vol 535 Ref. 96). 

947 Senkus M (R J. Reynolds Tobacco Co.), Some Effects of Smoking (1976/1977), at 12 (emphasis 

added). See AR (Vol 700 Ref. 593). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45069

II.C.6. 

deliveries could be reduced significantly from 1956levels without intelfering with the 

ability of cigarettes to satisfy smokers' addiction and to provide other desired 

pharmacological effects of nicotine. 

Once nicotine deliveries neared the minimum thresholds identified by the cigarette 

manufacturers, however, the manufacturers reversed course and began to enhance nicotine 

deliveries. As the tobacco industry documents in the record indicate, the industry feared 

that at these low levels, cigarettes might not deliver sufficient nicotine to smokers. See 

section ll.C.3., above. Consequently, the cigarette manufacturers began to take measures 

to raise nicotine deliveries, such as using nicotine-rich tobacco blends in ultra-low tar 

cigarettes. See section ll.C.4., above. The trend of increasing nicotine deliveries since 

1982 reflects these actions. 

Moreover, the Agency disagrees with the manufacturers that efforts to enhance 

nicotine deliveries will necessarily be reflected in the nicotine deliveries measured by 

smoking machines. To the contrary, the evidence in the record indicates that some of the 

methods used by the cigarette manufacturers to enhance nicotine deliveries are not 

reflected in the measured nicotine deliveries. The use of "elasticity" technologies, such as 

ventilation systems that can be blocked by smokers, is one example. As described in 

section II.C.4.b, these technologies are designed to allow smokers to inhale more nicotine 

than would be measured by a smoking machine. Similarly, the use of ammonia 

technologies to liberate "free" nicotine, which is described in section II.C.4.c., has effects 

BATCO and Philip Morris researchers reached similar conclusions. According to one BA TCO research 

study, a smoker's "nicotine requirement" is "about 0.8 mg per cigarette." Notes on the BATCO Group 

R&D Conference at Duck Key, FL (Jan. 12-18, 1974), at 2. See AR (Vol. 25 Ref. 327). Likewise, Philip 

Morris researchers recognized that "[t]he physiological response to nicotine can readily be elicited by 

cigarettes delivering in the range of 1 mg of nicotine." Dunn WL (Philip Morris Inc.), Motives and 

Incentives in Cigarette Smoking (1972), at 4. See AR (Vo112 Ref. 133). 

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II.C.6. 

on nicotine absorption that are not reflected in the nicotine levels measured by a smoking 

machine. 

2. The cigarette industry criticizes various aspects of FDA's methodology in 

calculating nicotine deliveries. The industry's comments assert that these alleged 

methodological problems make FDA's findings of increased nicotine deliveries unreliable. 

The Agency disagrees with these comments. The industry itself acknowledges in 

its comments that nicotine deliveries have increased among the lowest-tar cigarettes.948 

This acknowledgment renders most of the industry's specific methodological objections 

irrelevant because it confirms the Agency's finding that nicotine deliveries have increased 

in the ultra-low-delivery category. 

Moreover, the specific methodological comments of the cigarette industry are not 

well founded, as discussed below. 

First, the cigarette industry is mistaken when it argues that FDA chose to use 1982 

as its reference year to distort the trends in nicotine deliveries. FDA did not calculate 

these deliveries. Rather, these figures were calculated by the Federal Trade Commission 

(FTC), which annually reports tar and nicotine data for cigarettes. The FTC began its 

analysis in 1982 because this was the first year in which computer-readable data was 

available in the FTC files. 

Second, the cigarette industry is mistaken when it suggests that the FTC did not 

follow the approach recommended by the Surgeon General for calculating sales-weighted 

tar and nicotine deliveries. In fact, the FTC followed this approach. 

948 Joint Comment of Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol. III, at 206. See AR 

(Vol. 535 Ref. 96). 

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II.C.6. 

Third, FDA disagrees that brand shifting accounts for the increase in nicotine 

deliveries observed in the data. Brand shifting is unlikely to significantly affect reported 

average deliveries because brand shifts can occur in both directions (and so tend to cancel 

each other out) and because no single variety of cigarettes has a sufficient proportion of 

the sales to affect category averages. 

Moreover, the data are inconsistent with the industry's brand-shifting theory. The 

data show that tar deliveries have either declined slightly (high- and low-tar categories) or 

increased slightly (ultra-low-tar category), while nicotine deliveries have increased 

significantly in these categories. If brand shifting was in fact causing the rise in nicotine 

deliveries in the three categories, tar deliveries should have risen similarly, which they did 

not. Most significantly, brand shifting cannot explain the increase in nicotine deliveries 

that was observed when all brands (from all three categories) were averaged together. 

Fourth, FDA disagrees that normal analytical variation explains the observed 

increases in nicotine deliveries. The statistical chance that analytical variation could 

explain the results is vanishingly small. To begin with, the laboratory equipment used to 

measure nicotine and tar yields produces generally consistent results. The equipment has 

20 ports, four of which are dedicated to measuring the tar and nicotine content of 

"monitor cigarettes" to guard against any "drifting" of the equipment. 

Moreover, the trends reported by FDA from the FTC data reflect the results of 

literally tens of thousands of individual measurements of cigarettes. The reported tar and 

nicotine yield for any specific cigarette variety in a given year is the average of the test 

results of 100 individual cigarettes. The average tar and nicotine yields for all cigarette 

varieties in a given yield category, such as low-yield cigarettes, is the average of the 

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II.C.6. 

reported tar and nicotine yields for each cigarette variety in the category. Any analytical 

variation in the testing of individual cigarettes will have at most a very small effect on the 

averages reported from so large a sample size. 

Fifth, the questions raised by the industry regarding the origin of the salesweighted data are groundless. The data for 1984, 1985, and 1986 came from the FfC. 

Although the FfC may not have issued a report on tar and nicotine deliveries for each of 

those years, the FfC informed the Agency that it did nonetheless collect tar and nicotine 

data for these years. The 1991 and 1992 data do use information from slightly fewer 

brands than the brands listed in the FTC's published reports for those years; however, the 

explanation is that the FfC did not have tar, nicotine, and sales data for every single brand 

listed in the published reports. Only those brands for which data were missing were 

eliminated by the FTC in calculating the sales-weighted averages. The sales data used by 

the FfC to calculate the sales-weighted averages came from the tobacco manufacturers. 

Finally, contrary to the industry's assertion, FDA did put the data and analysis it 

relied upon in the administrative record.949 

Thus, contrary to the comments of the industry, FDA fmds that a reasonable 

methodology was used to calculate nicotine deliveries. 

3. Philip Morris asserts that it has few cigarettes with an enhanced nicotine/tar 

ratio of 0.1 0, compared to the naturally occurring ratio of 0.07. The company argues that 

this is evidence that it does not design its cigarettes to enhance nicotine deliveries. Philip 

Morris further asserts that two Philip Morris brands with nicotine/tar ratios of 

949 See Letter from Schultz WB (FDA), to Merrill R (Covington & Burling) (Dec. 27, 1995). See AR 

(Vol. 711 Ref. 7). 

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II.C.6. 

approximately 0.10 analyzed by Rep. Henry A. Waxman and cited by FDA (Merit Ultima 

and regular Benson & Hedges filtered cigarettes) do not reflect intentional nicotine 

manipulation. 

The Agency disagrees that cigarettes with an elevated nicotine/tar ratio of 0.10 are 

uncommon. In 1995, for instance, over 90 varieties of cigarettes had a nicotine/tar ratio 

of 0.10 or higher.950 Particularly among ultra-low-tar cigarettes, there are many examples 

of cigarettes with relatively enhanced nicotine deliveries and nicotine/tar ratios. Over 40% 

of cigarettes with tar deliveries of 5 mg or less have an enhanced nicotine/tar ratio of 0.10 

or greater.951 One example is the Merit Ultima, which is manufactured by Philip Morris 

and has a nicotine/tar ratio of 0.10.952 Other examples are RJR's Winston Ultra Lights 

1 00' s and king-size Camel Ultra Lights, which have tar deliveries of 0.5 mg and nicotine 

deliveries of 0.5 mg, resulting in a nicotine/tar ratio of 0.10.953 The deliveries of nicotine 

and tar in the Winston Ultra Lights IOO's and the king-size Camel Ultra Lights are exactly 

the deliveries that RJR researchers recommended to produce "a low tar value" while 

"maintaining the nicotine as high as possible."954 The existence of low-tar cigarettes with 

relatively elevated nicotine deliveries is compelling evidence that cigarette manufacturers 

design these cigarettes to provide enhanced nicotine deliveries. 

950 Federal Trade Commission, Report of "Tar, " Nicotine, and Carbon Monoxide of the Smoke of 1107 

Varieties of Domestic Cigarettes (1995). See AR (Vol. 535 Ref. 96, vol IV. B). 

951 1d. 

952 !d. 

953 !d. 

954 Senkus M (RJ. Reynolds Tobacco Co.), Some Effects of Smoking (1976/1977), at 10. See AR (Vol. 

700 Ref. 593). 

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II.C.6. 

Moreover, even if no ultra-low-tar cigarettes had a nicotine/tar ratio of precisely 

0.10, this would prove very little. As discussed in section II.C.3.a., Philip Morris' product 

development efforts concluded that "the optimum nicotine to tar ... ratio for a [lowdelivery] cigarette is somewhat higher than that occurring in smoke from the natural state 

of tobacco."955 This research did not conclude that the "somewhat higher'' ratio had to be 

a ratio of 0.10 (which is more than 40% higher than the "natural ratio" of 0.07) or greater. 

Consistent with Philip Morris' product development recommendations, most of the 

lowest-yield cigarettes do in fact have "somewhat higher'' nicotine/tar ratios of 0.08 or 

greater. See Jurisdictional Analysis, 60 FR 41724. 

The Agency rejects Philip Morris' claim that the enhanced nicotine/tar ratio of 0.10 

in Merit Ultima can be explained by "the physics of low-yield filtration and ventilation."956 

FDA's own analysis has shown that the Merit Ultima uses a blend richer in nicotine than 

the blends used in either the Merit Filter IOO's or the Merit Ultra Lights. See 

Jurisdictional Analysis, 60 FR 41723-41724. This deliberately chosen nicotine-rich blend 

contributes to the elevated nicotine/tar ratio in the Merit Ultima-apart from any effects of 

filtration or ventilation. See section II.C.4.a.ii. Moreover, to the extent that flltration and 

ventilation contribute to the elevated nicotine/tar ratio, this effect is the result of deliberate 

design decisions. See section II.C.4.b. 

The Agency is also not persuaded that the enhanced nicotine/tar ratios in the 

regular Benson & Hedges filtered cigarettes can be dismissed as "minuscule variations" in 

955 Jones B, Houck W, Martin P (Philip Morris Inc.), Low Delivery Cigarettes and Increased Nicotine/Tar 

Ratios, A Replication (Oct 1975), in 141 Cong. Rec. H8132 (daily ed. Aug. 1, 1995) (emphasis added). 

See AR (Vol 711 Ref. 6). 

956 Philip Morris Inc., Comment (Jan. 2, 1996), at43. See AR (Vol 519 Ref. 105). 

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II.C.6. 

tar and nicotine deliveries. A statistical analysis of the cigarettes prepared for and released 

by Rep. Waxman concluded that the possibility that the cigarette's enhanced nicotine/tar 

ratio could be explained by random fluctuations in tar and nicotine levels was virtually 

zero.957 

iii. Comments on Chemical Manipulation. 

1. Comments from the tobacco industry acknowledge that cigarette 

manufacturers add ammonia compounds to tobacco. However, the comments argue that 

the addition of ammonia does not have pharmacological significance because virtually all 

nicotine in cigarette smoke is absorbed into the bloodstream regardless of the pH of the 

smoke; because substantial amounts of ammonia would be required to raise smoke pH 

from 6.0 to 7.5 or 8.0; and because ammonia compounds do not increase the efficiency of 

the transfer of nicotine from the tobacco to the smoke. 

The Agency disagrees with these comments. They conflict with the evidence from 

the cigarette industry documents in the record, as well as with basic scientific principles. 

The evidence in the record demonstrates that the cigarette manufacturers add 

ammonia compounds to cigarettes to produce several pharmacological effects. As 

described in the industry documents, the pharmacologically significant effects of adding 

ammonia compounds to tobacco are (1) to increase the transfer of nicotine from the 

cigarette to the smoke; (2) to increase the rate of nicotine absorption in the mouth; and (3) 

possibly to increase the speed of nicotine absorption in the lungs. See section ll.C.4.c. 

957 Statement of Waxman HA, 141 Cong. Rec. H8009 (daily ed. Jul. 31, 1995). See AR (Vol 27 

Ref. 376a). 

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II.C.6. 

Each of these three effects of adding ammonia compounds is significant even if the 

industry were correct that the lungs absorb virtually all of the nicotine that is inhaled.958 

The first effect-increasing the transfer of nicotine from the cigarette to the smoke-is 

significant because it increases the quantity of nicotine delivered to the lungs. Most of the 

nicotine in a cigarette never enters the mouth of a smoker. Rather, it is trapped in the 

fllter; lost to the atmosphere; or destroyed or decomposed by the heat of the cigarette. 959 

According to the statement of Dr. Farone, the former Philip Morris Director of Applied 

Research, however, the effect of adding ammonia compounds is ''to deliver more of the 

available nicotine in the blend to the smoker."960 Documents from the American Tobacco 

Company make a similar point, asserting that the use of alkaline compounds will 

"increas[ e] the amount of nicotine that is transferred from the tobacco to the mainstream 

smoke."961 

The second effect is likewise significant regardless of the efficiency of nicotine 

absorption in the lungs. This effect is to increase the amount of nicotine that the smoker 

958 In fact. it is not clear that the lungs absorb virtually all the nicotine that is inhaled. According to one 

researcher, "(d]epending on inhalation patterns, retention times, and related factors, smokers may retain 

anywhere from 30% or less up to 90% or more of the total nicotine generated and delivered via the 

inhaled smoke." Huber GL, Physical, chemical, and biological properties of tobacco, cigarette smoke, and 

other tobacco products, Seminars in Respiratory Medicine 1989;10:297-332, at 304. See AR (Vo1333 

Ref. 5045). 

959 Armitage AK., Dollery cr, George CF, et al., Absorption and metabolism of nicotine from cigarettes, 

British Medical Journal, 1975:313-316, at 315 ("[N]o more than 25% of the total nicotine content of the 

cigarette is likely to appear in the mainstream smoke. Most of the nicotine is lost into the surrounding air 

and sidestream smoke or is retained in the butt''). See AR (Vo1131 Ref. 1462). 

960 Farone W A, The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 13. See AR (Vol 638 Ref. 2). 

961 Bodenhamer NL (American Tobacco), Leaf Services Monthly Report for June (Jun. 30, 1980). See AR 

(Vol. 27 Ref. 385). 

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II.C.6. 

absorbs through the mouth-not the lungs. Adding ammonia compounds raises the pH of 

the tobacco smoke. See section II.C.4.c. According to RJR researchers, by raising pH in 

a low-tar cigarette from just 6.0 to 6.5, "you increase the nicotine transfer in the 

mouth. "

962 

The third effect is a possible increase in the speed of nicotine absorption in the 

lungs. The increase in pH caused by the addition of ammonia compounds increases the 

proportion of "free" or "extractable" nicotine in the smoke. See section II.C.4.c. 

According to documents from BATCO, Brown & Williamson's parent company 

hypothesized that "with a higher 'extractable' nicotine, nicotine reaches the brain more 

quickly."963 The BATCO researchers further postulate that "in human smoking a 

difference in the time of nicotine absorption of tenths of a second may be important."964 

In light of this evidence from former cigarette industry employees and the 

industry's own documents, the industry's assertion that adding ammonia compounds has 

no pharmacological significance is not credible. 

The tobacco industry comment also asserts that significant quantities of ammonia 

compounds are needed to raise the pH of smoke from 6.0 to 7.5 or 8.0. However, no 

scientific support is provided for this assertion. Moreover, even if the assertion were 

correct, it would be largely irrelevant Significantly smaller increases in smoke pH are 

likely to have the pharmacological effects described above. As noted above, for instance, 

962 Senkus M (RJ. Reynolds Tobacco Co.), Some Effects of Smoking (197611977), at 7 (emphasis added). 

See AR (Vol 700 Ref. 593). 

963 BATCO, Further Work on 'Extractable' Nicotine, Southampton. England (1966), at 7. See AR (Vol. 

62 Ref. 308). 

964 /d. at 9. 

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II.C.6. 

documents from RJR conclude that simply increasing the pH of smoke from 6.0 to 6.5 is 

sufficient to increase the absorption of nicotine in the mouth. 965 

The Agency further disagrees with the tobacco industry comment that the pH of 

cigarette tobacco has no bearing on the efficiency of nicotine transfer from the tobacco to 

the smoke. It is a basic scientific principle that compounds in free or unbound forms are 

vaporized more readily than compounds bound together in salts.966 Studies of cocaine, for 

instance, show that when cocaine is bound as a salt (as in cocaine hydrochloride), much of 

the cocaine is degraded during pyrolysis; in contrast, when the cocaine is converted to 

"free" form, the transfer of the cocaine to the smoke is much greater.967 The tobacco 

industry comment provides no evidence to refute these basic scientific principles or to 

rebut the evidence in the record showing that the conversion of nicotine from its bound 

form to its free form increases the transfer of nicotine to smoke.968 

965 Senkus M (R J. Reynolds Tobacco Co.), Some Effects of Smoking (1976/1977), at 7 (emphasis added). 

See AR (Vol 700 Ref. 593). 

966 Morrison RT, Boyd RN, Organic Chemistry, 2d ed., 1966, in Barnett G, Chiang CN eds., 

Pharmacokinetics and Pharmacodynamics of Psychoactive Drugs, A Research Monograph, Biomedical 

Publications, 2d edition, 1985, at 26. See AR (Vol 711 Ref. 19). 

967 Cook CE, Jeffcoat AR, Perez-Reyes M, Pharmacokinetic smdies of cocaine and phencyclidine in man, 

in Barnett G, Chiang CN eds., Pharmacokinetics and Pharmacodynamics of Psychoactive Drugs, A 

Research Monograph, Biomedical Publications, 2d edition, 1985, at 64-65. See AR (Vol 711 Ref. 16). 

968 After the close of the comment period, FDA received a series of RJR documents from the 1970's 

regarding the effect of pH adjustments on nicotine delivery. These documents had been made public in a 

lawsuit involving RJR Although not necessary to FDA's analysis, these documents provide further 

confrrmation that cigarette manufacturers raise the pH of cigarette smoke to increase the amount of ''free 

nicotine" that is delivered to the smoker, and that this increase in "free nicotine" has a pharmacological 

effect One of these documents describes RJR's fmding that the pH level of Marlboro and Kool cigarettes 

had risen significantly, with corresponding increases in ''free" nicotine deliveries, and in sales. Teague CE 

(RJR), Implications and Activities Arising from Co" elation of Smoke pH with Nicotine Impact, Other 

Smoke Qualities, and Cigarette Sales, at 1-3. See AR (Vol 711 Ref. 47). The document states: 

In essence, a cigarette is a system for delivery of nicotine to the smoker in 

attractive, useful form. At "normal" smoke pH, at or below about 6.0, 

essentially all of the smoke nicotine is chemically combined with acidic 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45079

substances hence is non-volatile and relatively slowly absorbed by the smoker. 

As the smoke pH increases above about 6.0, an increasing proportion of the 

total smoke nicotine occurs in "free" form, which is volatile, rapidly absorbed 

by the smoker, and believed to be instantly perceived as nicotine "kick." 

/d. at 2 (emphasis added). The document continues: 

As a result of its higher smoke pH, the current Marlboro, despite a two-thirds 

reduction in smoke "tar" and nicotine over the years, calculates to have 

essentially the same amount of "free" nicotine in its smoke as did the 

WINSTON. Over the same period, with some reduction in smoke pH and about 

two-thirds reductions in smoke "tar" and nicotine, the calculated amount of 

"free" nicotine in WINSTON smoke bas decreased by about two-thirds. Thus, 

currently the calculated amount of "free" nicotine in Marlboro smoke is 

almost three times the amount in WINSTON smoke. 

II.C.6. 

/d. (emphasis added; underscoring in original). This document goes on to describe methods of increasing 

smoke pH: 

/d. at4. 

Methods which may be used to increase smoke pH and/or nicotine "kick" 

include: (1) increasing the amount of (strong) burley in the blend, (2) reduction 

of casing sugar used on the burley and/or blend, (3) use of alkaline additives, 

usually ammonia compounds, to the blend, (4) addition of nicotine to the blend, 

(5) removal of acids from the blend, (6) special filter systems to remove acids 

from or add alkaline materials to the smoke, and (7) use of high air dilution 

filter systems. Methods 1-3, in combination, represent the Philip Morris 

approach, and are under active investigation. 

A document entitled "Outline for Smoke pH Presentation" presents further data on the increase 

in pH in Marlboro cigarettes and Kool cigarettes. Finding that, as compared to RJR's Winston brand, 

Marlboro cigarettes had several characteristics, including alkaline stem additives and ammonia-puffed 

leaf, "all combining to raise smoke pH," the presentation states: 

We must conclude that the difference between Marlboro and Winston must be 

deliberate .... What we are seeing and measuring fits what we know about 

Philip Morris and Brown and Williamson product philosophies. They appear 

to design products primarily to deliver optimum nicotine impact and 

satisfaction--aiming also at a relatively bland smoke, letting flavor fall where it 

will. 

Another document in the series is a memorandum to RJR' s Director of Marketing and Planning 

recommending the development of a new "youth-appeal" brand with more tar and nicotine. Colby FG, 

Cigarette Concept to Assure RJR a Larger Segment of the Youth Market (Dec. 4, 1973). See AR (Vol. 

711 Ref. 47). According to the memorandum, "any desired additional nicotine 'kick' could be easily 

obtained through pH regulation." 

When these documents were made public, RJR officials responded that the documents are not 

important and that subsequent studies on Marlboro showed that pH levels between 1973 and 1988 

declined, while sales remained steady or increased. Weinstein H, Documents tie nicotine levels, cigarette 

sales, Los Angeles Times, A1 (May 23, 1996). See AR (Vol 711 Ref. 18). 

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II.C.6. 

2. Comments from the tobacco industry argue that ammonia compounds are 

added to tobacco to enhance the flavor characteristics of cigarette smoke and bind the 

tobacco together, but not for their effect on nicotine. The Agency disagrees with this 

comment. The record contains numerous internal documents that indicate that the effect 

of adding ammonia compounds is to change the delivery or absorption of nicotine. For 

instance, the Brown & Williamson's 1991leafblending manual states that "la]mmonia, 

when added to a tobacco blend, reacts with the indigenous nicotine salts and liberates 

free nicotine."969 Similarly, William Farone, the former director of applied research at 

Philip Morris, states that "[t]he use of ammonia chemistry was important to the industry 

in maintaining adequate nicotine delivery to satisfy smokers."970 The industry's assertion 

that the use of ammonia is simply for taste and binding cannot be reconciled with this 

evidence. Even if ammonia does have a flavor component, this fact does not negate the 

evidence in the record regarding ammonia's effect on nicotine. 

The tobacco industry cites the addition of ammonia compounds to foods as 

evidence of ammonia's role in flavor. The use of ammonia compounds in foods, however, 

is not dispositive evidence of the use of ammonia compounds in tobacco, because the 

ammonia compounds in cigarettes are burned and inhaled rather than ingested. Moreover, 

one of the recognized uses for ammonia compounds in foods is "pH control," 21 CFR 

969Regulation of Tobacco Products (Part 3): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Cong., 

2d Sess., 21 (Jun. 21, 1994) (statement of David Kessler) (emphasis added). See AR (Vol 709 Ref. 3). 

97° Farone W A. The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 13 (emphasis added). See AR (Vol 638 Ref. 2). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45081

184.1133-184.1143, which is the same use of ammonia compounds described in the 

internal tobacco company documents. 

3. Comments from the tobacco industry argue that FDA has taken a 

II.C.6. 

contradictory position in the Jurisdictional Analysis by finding both that cigarette 

manufacturers add ammonia compounds to increase the pH of tobacco and that cigarette 

manufacturers add acids to reduce the harshness of smoke. 

FDA's positions are not inconsistent. The Jurisdictional Analysis found, based on 

the evidence then available, that when manufacturers use tobaccos that produce naturally 

high pH levels in smoke or that have naturally high nicotine contents, the manufacturers 

sometimes face the problem that the cigarette smoke contains too much nicotine and is too 

harsh. In these situations, the record indicates that manufacturers have developed ways to 

reduce harshness, including lowering pH. See Jurisdictional Analysis, 60 FR 41711-

41713. In other situations, manufacturers face the opposite problem of cigarette smoke 

that may not deliver enough nicotine. In these latter situations, the record indicates that 

manufacturers will enhance nicotine deliveries, including adding ammonia compounds to 

raise the pH of the tobacco and the smoke, which increases the delivery of free nicotine to 

the smoker. See section IT.C.4.c. 

4. Brown & Williamson makes two comments regarding chemical 

manipulation. First, Brown & Williamson asserts that its internal documents show its 

knowledge that pH level does not affect nicotine delivery. Second, Brown & Williamson 

asserts that its internal documents show that the addition of ammonia compounds is simply 

a booster of smoke "impact." 

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II.C.6. 

The Agency disagrees with Brown & Williamson's characterization of its 

documents. Contrary to Brown & Williamson's comment, the administrative record 

shows that researchers working for Brown & Williamson and Brown & Williamson's 

parent, BATco·, have consistently understood that pH levels affect nicotine delivery. As 

early as 1968, BATCO researchers wrote that "[n]icotine retention appears to be 

dependent principally on smoke pH and nicotine content."971 See sections II.C.3.c.i., 

II.C.3.c.iv., II.C.4.c. 

In fact, one of the documents cited by Brown & Williamson contradicts its 

assertion. In a passage not quoted by Brown & Williamson, the document refers to the 

"pH dependent effect of nicotine," further underscoring the company's understanding of 

the relationship between pH and nicotine.972 

The Agency does agree with Brown & Williamson that the 1991 blenders 

handbook links the addition of ammonia compounds to the "impact" of smoke. However, 

the document makes it clear that "impact" is simply a surrogate term for nicotine delivery, 

stating that the ammonia compounds increase ''the ratio of extractable nicotine to bound 

nicotine in the smoke"; that "extractable nicotine contributes to the impact in cigarette 

smoke"; and that "this is how ammonia can act as an impact booster." 973 

971 BATCO, The Retention of Nicotine and Phenols in the Mouth (1968), at BW-W2-11691 (emphasis 

added). See AR (Vol 445 Ref. 7593). 

972 Ayres CI (BATCO), Notes from the GR&DC Nicotine Conference, in Proceedings of the Smoking 

Behaviour-Marketing Conference, Session lli (Jul. 9-12, 1984), at BW-W2-02642 (emphasis added). See 

AR (Vol. 14 Ref. 172). 

973 Regulation ofTobacco Products (Part 3): Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 103d Cong., 

2d Sess. 21 (Jun. 21, 1994) (statement of David Kessler). See AR(Vol 709 Ref. 3). 

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II.C.6. 

iv. Comments on Flavorings and Casings. 

1. The cigarette manufacturers dispute that flavorings and casings are 

sometimes used to mask the unpleasant sensory characteristics of nicotine in cigarettes. 

The tobacco industry claims that flavorings and casings are used solely to affect the flavor 

and aroma of the cigarette. 

The Agency agrees that flavorings and casings influence flavor. Nevertheless, the 

record shows that these ingredients have another use-that of masking the flavor of harsh 

high-nicotine tobaccos. In the Jurisdictional Analysis, the Agency cited several pieces of 

evidence showing that flavorings and casings are used to mask nicotine. See 60 FR 

41711-41714. For instance, a "flavorist" for RJR wrote that "in air-cured tobaccos 

(cigar, burley, Maryland), the pH of smoke is generally alkaline and the flavor effect of 

nicotine is a 'harshness' which can be choking and unpleasant." 974 In these tobaccos, 

according to the flavorist, "the effect of nicotine is greatly modified, and the harshness is 

dramatically reduced .... by addition of sugars ... to 'mellow' the smoke."975 None of 

this evidence is rebutted by the cigarette manufacturers. 

In addition, the statement of William Farone, the former director of applied 

research at Philip Morris, confirms that flavorings are used to mask the harshness of 

nicotine. According to Farone's statement: 

The tobacco industry found that in the manipulation of the nicotine/tar ratio, the 

methods used to increase the nicotine to tar ratio sometimes resulted in a 

cigarette that was too harsh. With a standard nicotine/tar ratio in a traditional 

cigarette no flavor smoothing compounds are generally needed to produce a 

974 Leffmgwell JC, Nitrogen components of leaf and their relationship to smoking quality and aroma, 

Recent Advances in Tobacco Science, vol. 2, at 9. See AR (Vol 28 Ref. 450). 

975 /d. 

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45084 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

palatable cigarette. The higher tar levels in traditional cigarettes mask the 

harshness of nicotine and the associated compounds produced in higher nicotine to 

tar ratios. A low tar cigarette with a higher nicotine/tar ratio than a traditional 

cigarette could be very harsh due to the lack of sufficient specific tar components 

to mask the nicotine and related basic compounds. To overcome the harshness 

due to the increased burley in the blend, the industry used flavor "srrwothers. "976 

Thus, the evidence in the record supports the finding in the Jurisdictional Analysis 

that the cigarette industry sometimes uses flavorings to mask the harshness of nicotine in 

cigarettes with nicotine-rich tobacco blends. 

2. The cigarette manufacturers cite the use of menthol in cigarettes as 

evidence that they do not use flavorings to mask the effects of nicotine. According to the 

industry, menthol is not used to mask the effects of high-nicotine tobaccos because 

menthol cigarettes generally have nicotine yields that are lower than or equal to regular 

cigarettes. 

The Agency rejects this argument. The evidence before the Agency indicates that 

flavorings like cocoa, sugars, and licorice, which produce acids in smoke, are used to 

mask the bitterness or harshness of nicotine. See Jurisdictional Analysis 60 FR 41711-

41714. The evidence does not indicate that menthol is used to mask harshness of tobacco. 

Consequently, the data presented by the industry on menthol is irrelevant to whether other 

fla vorants are used to mask nicotine. 

v. Comments on the Consistency of Nicotine Deliveries. 

1. The cigarette manufacturers argue that the ability to produce cigarettes 

with uniform and consistent levels of nicotine is not evidence of any "intended use." They 

976 Farone W A, The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 14-15 (emphasis added). See AR (VoL 638 

Ref. 2). 

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II.C.6. 

assert that blending to achieve consistency is a common practice among manufacturers 

that make consumer goods from agricultural products. 

However, the remarkable degree of consistency in nicotine deliveries achieved by 

the manufacturers is especially relevant to the issue of the manipulation and control of 

nicotine. As discussed in section II.C.4.e.iii., above, the manufacturers' precise control 

over nicotine deliveries refutes the manufacturers' assertion that ''the companies do not 

independently 'control' for or 'manipulate' the nicotine content in any of their blends."977 

Moreover, the manufacturers' precise control over nicotine deliveries is consistent withand corroborates-the Agency's finding that manufacturers intend that cigarettes will be 

used for pharmacological purposes. As discussed in the Jurisdictional Analysis, an FDA 

laboratory study showed that nicotine delivery varies so little from lot to lot of cigarettes 

that it equals or exceeds the degree of control exercised by pharmaceutical companies 

over the active ingredients in prescription drugs.978 The manufacturers' precise control 

over nicotine deliveries enable the industry to ensure that consumers can use cigarettes to 

satisfy addiction or to obtain other pharmacological effects. 

vi. Comments on Breeding. 

The comments of the cigarette industry claim that the cigarette manufacturers do 

not manipulate nicotine through plant breeding or agronomic practices. While the 

comments make several valid points on tangential issues, they do not affect the basic 

conclusions made in the Jurisdictional Analysis. 

977 Joint Comment of Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol. V, at 66. See AR (Vol. 535 

Ref. 96). 

978 FDA, Center for Drug Evaluation and Research, Division of Drug Analysis, Memorandum on Analysis 

of Packages of Cigarettes (Apr. 4, 1994). See AR(Vol. 29 Ref. 487). 

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45086 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

1. Regarding FDA's contention that American-grown tobaccos have had 

increasingly high levels of nicotine since the mid 1950's, the comments fault FDA for 

singling out the years 1955 and 1980 for comparison. 

The Agency reported in the Jurisdictional Analysis the change in nicotine content 

between 1955 and 1980 because those were the years analyzed in the paper by DeJong 

cited by the Agency.979 The Agency agrees that the more recent data from the North 

Carolina Official Variety Trials, as submitted by the comments, show that nicotine content 

of leaves from that area has leveled off since 1980, and that the last 17 years appear to 

show a decrease in nicotine leve1s.980 The Agency does not agree, however, that it should 

have compared nicotine levels in the 1950's to nicotine levels in 1989, as suggested by the 

cigarette manufacturers. Unusually low nicotine levels were recorded in 1989 when 

compared with the five years preceding and succeeding it. 

Other articles and infonnation support the Agency's contention that the nicotine 

content of domestic tobacco increased from the 1950's to 1980. For example, one study 

cited by a comment concluded that nicotine levels "changed dramatically'' from the mid1950's to the early 1980's and ascribed the increase to changes in production practices.981 

979 DeJong DW, The role of American tobacco leaf chemistry in low-yield cigarettes: an agricultural 

viewpoint Tabak Journal International, May 1985;376-383. See AR (Vol 27 Ref. 401). 

980 Joint Comment of Cigarette Manufactnrers, Comment (Jan. 2, 1996), Vol IV, at 18. See AR (Vol 535 

Ref. 96). 

981 Bowman DT, Wernsman EA, Corbin TC, et al., Contribution of genetic and production technology to 

long-term yield and quality gains in flue-cured tobacco, Tobacco Science 1984;28:30-35, at 34-35. See 

AR (Vol. 535 Ref. 96, vol. IV. A). 

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II.C.6. 

In addition, Earl Wemsman of North Carolina State University told the Agency that 

nicotine levels have increased over the past 30 years. 982 

The Agency, however, does not agree with the industry's claim, that "FDA's 

reliance on the DeJong data., together with the Agency's total failure to acknowledge 

contrary data. from equally or more authoritative sources, reflects a general strategy of 

selective and biased citation from the scientific literature."983 In fact, both sets of data. 

reflect rising nicotine levels in tobacco from the mid 1950's through 1980. 

2. The cigarette industry comments assert that the manufacturers have 

rejected high-nicotine tobacco crops produced during drought years. According to the 

industry, this rejection of high-nicotine crops shows that the manufacturers do not seek to 

manipulate nicotine through breeding high-nicotine tobaccos. 

The Agency does not agree that any reliable inference can be drawn from the 

rejection of tobacco crops in drought years. This evidence establishes only that nicotine 

content can on occasion rise too high for the manufacturers' use. The Agency has never 

maintained that nicotine levels could not reach excessive levels. To the contrary, as 

discussed in the Jurisdictional Analysis, the Agency recognizes that too much nicotine in a 

cigarette can make the cigarette too harsh, requiring the use of flavors and casings to mask 

the harshness. See 60 FR 41712-41713. 

3. The cigarette industry comments raise a number of issues regarding FDA's 

discussion of the Minimum Standards Programs (MSP's). The comment claims that 

982 Memorandum of Mar. 22, 1994, teleconference, from Murray M, to Wemsman E (Mar. 23, 1994). 

See AR (VoL 256 Ref. 3459). 

983 Joint Comment of Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol. IV, at 9. See AR (Vol 535 

Ref. 96). 

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45088 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

"FDA has mischaracterized the nature, purpose and effect of the ... MSP's by claiming 

that the MSP's were designed to ensure that nicotine levels did not fall below a specified 

level," and that by "minimizing the role of the USDA, tobacco breeders, and State 

Extension-Research Services, FDA mischaracterizes the tobacco industry's participation in 

these programs as 'controlling."'984 The comment argued that the cigarette manufacturers 

do not control the MSP's, that the MSP's are not designed to maintain nicotine above a 

specified level, and that the MSP's prevent the introduction of high-nicotine varieties into 

cultivation. 

The Agency does not find compelling any of the arguments raised by the comment 

that were intended to dispute the two most significant fmdings of the Agency regarding 

MSP's: that they are used to ensure that nicotine levels do not fall below a specified level, 

and that the cigarette manufacturers are active participants in the program. 

The comment points out that there are a variety of purposes of the MSP' s, and 

argues that therefore it is incorrect for FDA to claim that their purpose is "to ensure that 

nicotine levels in marketed tobacco do not fall below specified levels."985 FDA agrees that 

the MSP's have purposes in addition to controlling nicotine levels. However, the fact 

remains that the MSP' s help ensure that nicotine levels in marketed tobacco do not fall 

below the level in acceptable tobacco varieties. DeJong made this point clear when he 

wrote that ''the first minimum standards programme was initiated in 1964 .... Discount or 

low-nicotine cultivars had previously been declared outside the price support system."986 

984 Id. at 18-19 (emphasis added). 

985 /d. at 21-22. 

986 DeJong DW, The role of American tobacco leaf chemistry in low-yield cigarettes: an agricultural 

viewpoint, TahakJournallnternational, May 1985:382 (emphasis added). See AR(Vo127 Ref. 401). 

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II.C.6. 

FDA's point, which is not disputed by the comment, is that the discount and MSP 

programs discourage the planting of varieties that accumulate unusually low levels of 

nicotine. 

FDA believes that it appropriately characterized the industry's role in the MSP's. 

The agency noted that the MSP's are administered by the USDA. See Jurisdictional 

Analysis, 60 FR 41697. In stating that the manufacturers exert control over the MSP's, 

the Agency did not imply that they exert sole control over all aspects of the programs. 

The manufacturers do, however, each have a vote on the MSP committees that set up the 

rules and administer the programs. They also represent by far the largest economic bloc 

on those committees. 

4. The cigarette industry asserts that the cigarette manufacturers do not 

control the agronomic practices used by tobacco farmers for the purpose of increasing the 

nicotine content of tobacco. The comment maintains that all of the agronomic practices 

cited by the Agency as raising nicotine levels provide significant advantages to the farmer 

completely independent of any nicotine-enhancing properties. The comment also notes 

that some agronomic practices, such as irrigation, decrease nicotine content, and that 

recommendations regarding other practices, such as decreasing the use of nitrogen from 

the very high levels that were used for a few years, also result in decreased nicotine levels. 

The Agency generally agrees with the comment on these points. The Agency 

never stated, and did not mean to imply, that cigarette manufacturers exert direct control 

over tobacco farmers or breeders. The Agency also agrees that farmers do not use 

nicotine-elevating agricultural practices exclusively for the purpose of elevating nicotine 

levels. The Agency is aware that farmers choose the agricultural practices they use for a 

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45090 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

variety of purposes. Nevertheless, DeJong noted that "[h]eavy application of nitrogen 

fertilization, early topping and tight chemical sucker control all acted in concert to push 

alkaloid levels upward."987 

In any case, the Agency's fundamental point regarding tobacco breeding and 

fanning is that tobacco leaves sold in the U.S. contain adequate levels of nicotine to enable 

the manufacturers to maintain nicotine delivery in their products at the levels they choose. 

When, in the early and mid-1950's, fanners grew a preponderance oflow-nicotine 

tobaccos, programs were set up to ensure that fanners would no longer grow such 

tobaccos. Since that time, manufacturers have had no difficulty purchasing tobaccos that 

provide the levels of nicotine that they need for their products. And in at least one welldocumented case, Brown & Williamson doubled the nicotine content of one variety of 

flue-covered tobacco as a "blending tool" for use in low-tar cigarettes. This "Y-1" 

tobacco was designed to enable the company to maintain nicotine levels while lowering 

the tar content of cigarettes. See section II.C.3.c.iii., above. 

vii. Comments on Leaf Purchasing. 

1. The cigarette manufacturers assert that over time there has been no 

increase in the nicotine content of the tobacco they purchase. The manufacturers argue 

this is evidence that they do not use nicotine content as a principal factor in leaf selection. 

The Agency disagrees with the manufacturers' factual assertion regarding trends in 

nicotine content. The evidence in the record indicates that the nicotine content has 

increased in the tobacco purchased by cigarette manufacturers. As pointed out in the 

987 /d. 

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II.C.6. 

Jurisdictional Analysis, the nicotine content in American tobaccos of all types has 

increased since the 1950's. 60 FR 41696-41697. Moreover, a 1978 article submitted by 

the Tobacco Institute and entitled "Genetic Manipulation for Tailoring the Tobacco Plant 

To Meet the Requirements of the Grower, Manufacturer, and Consumer'' states that "[i]n 

the United States the demand for lower stalk flue-cured tobacco has decreased."988 This 

confmns the existence of a trend first described by USDA officials in congressional 

testimony in the late 1950's. See section II.C.4.a.i., above. At that time USDA indicated 

that the tobacco industry had "moved up the stalk'' in blending tobaccos by using the 

higher nicotine leaves in the upper part of the tobacco plant. 989 

2. The cigarette manufacturers also assert that they have rejected highnicotine tobaccos. Again, they claim that this is evidence that they do not use nicotine 

content as a principal factor in leaf selection. 

The Agency disagrees with the manufacturers' argument. As noted above in 

section II.C.6.c.vi., the Agency recognizes that too much nicotine in a cigarette can make 

the cigarette too harsh. 

3. In its comments, Brown & Williamson disputes that it regularly adjusts the 

stalk position of its leaf purchases during the buying season based upon the results of 

nicotine analyses. The company's response, however, conflicts with the information 

988 Chaplin JF, Genetic manipulation for tailoring the tobacco plant to meet the requirements of the 

grower, manufacturer, and consumer, Bulletin D'/nformation Coresta 1978;17-32, at 21 (emphasis 

added). See AR (Vol 535 Ref. 96). 

989 Hearings on False and Misleading Advertising (filter-tip cigarettes), Subcommittee on Government 

Operations, U.S. House of Representatives, 85th Cong. 1st Sess. 189 (Jul. 1957). See AR (Vol 172 Ref. 

2035). 

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45092 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

provided to FDA by company employees during FDA's May 1994 visit to Brown & 

Williamson. See Jurisdictional Analysis, 60 FR 41705. Moreover, Brown & Williamson 

provides no affidavits or other documentary evidence to support its comment. 

viii. Comments on Reconstituted Tobacco. 

1. The cigarette manufacturers assert that they do not use reconstituted 

tobacco to manipulate or control nicotine levels. As evidence of this point, they argue that 

nicotine levels in reconstituted tobacco are lower than those in most tobacco blends. 

The Agency disagrees with the argument. Evidence in the record shows that 

reconstituted tobacco is used by cigarette manufacturers as a site for the addition of 

ammonia compounds. According to an article in the Wall Street Journal, an internal 

Brown & Williamson handbook describes the "nicotine pick-up potential" of ammonia in 

reconstituted tobacco.990 The article also states that ammonia added to reconstituted 

tobacco can scavenge nicotine from the tobacco in the rest of the cigarette, significantly 

increasing the level of "free nicotine" in the cigarette. 

2. The cigarette manufacturers assert that they do not closely monitor and 

control the level of nicotine in reconstituted tobacco. 

The Agency disagrees with this assertion. The record shows that finished 

~igarettes contain precisely controlled and consistent nicotine levels. See Jurisdictional 

Analysis, 60 FR 41732. Because reconstituted tobacco is a significant ingredient in 

fmished cigarettes, the precise control over nicotine in the fmished cigarettes could not be 

99° Freedman AM, Tobacco fum shows how ammonia spurs delivery of nicotine, Wall Street Journal 

(Oct 18, 1995), Al. See AR (Vol 639 Ref. 2). 

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II.C.6. 

achieved unless the manufacturer also precisely controlled the nicotine level in 

reconstituted tobacco. Without such precise control, the wide variations in the nicotine 

levels of the tobacco stems and other raw ingredients of reconstituted tobacco would 

produce significant variations in the nicotine content of reconstituted tobacco and the 

fmished cigarettes. 

ix. Other Comments. 

1. The Agency found in the Jurisdictional Analysis, based on the evidence 

then available, that cigarette manufacturers sometimes increase the degree to which the 

''tipping paper," which is wrapped around the filter, is extended over the tobacco rod. See 

60 FR 41721. One study cited by the Agency reported that this increased "overwrap" 

reduced the nicotine deliveries reported by the FfC testing method (because the test 

protocol requires stopping the test when the cigarette is smoked to within 3 millimeters of 

the tipping paper), while allowing smokers to increase their nicotine intake above the 

reported levels (by smoking the tobacco under the overwrap).991 

The manufacturers raise a number of questions about the data on which FDA 

relied and seek to depict FDA's discussion of the overwrap width as speculative. In most 

cases, however, the information that would answer the questions raised by the 

manufacturers is within their control, but is nevertheless not provided. 

991 Grunberg NE, Morse DE, Maycock VA. et al., Changes in overwrap and butt length of American filter 

cigarettes, NY State Journal of Medicine Jul. 1985;310-312. See AR (Vol 29 Ref. 478). 

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II.C.6. 

For example, the manufacturers argue that smokers do not smoke the overwrap 

because it is unpalatable, but they do not provide evidence to support this assertion 

despite the fact that the extensive consumer testing conducted by the manufacturers 

undoubtedly provides the infonnation necessary to resolve whether the overwrap is 

smoked and whether it is palatable. The manufacturers also argue that the increase in 

overwrap width found in many cigarettes would not increase the amount of nicotine 

available to smokers if the bum rate of the cigarette were simultaneously increased. The 

burn rate of cigarettes is information known to the cigarette manufacturers but not to 

FDA. Yet the manufacturers fail to provide information on burn rate that would permit 

resolution of the issue they raise. 

Moreover, although the manufacturers deny that the overwrap has been widened 

to increase availability of nicotine, they offer no alternative explanation for the increase 

found in the study relied on by FDA. In light of the ease with which the manufacturers 

could have provided the information necessary to show that the overwrap is not used to 

provide elasticity, and their failure to provide it, FDA concludes that the evidence 

supports the finding made in the Jurisdictional Analysis. Nevertheless, only additional 

information can help determine whether an increase in the tipping paper reduces the 

accuracy of the FfC measurement. 

2. The cigarette manufacturers assert that the fact that they may hold patents 

permitting them to carefully manipulate and control nicotine does not prove that they 

actually do so. They also argue that patents are submitted by individual employees and 

that, as such, they are not evidence of the company's intentions. 

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II.C.6. 

FDA cited the multitude of patents held by tobacco manufacturers on methods of 

manipulating nicotine delivery as additional evidence that the manufacturers have engaged 

in extensive research to develop methods to optimize nicotine delivery. The fact that the 

manufacturers have invested considerable resources in developing means of manipulating 

and controlling nicotine deliveries, including developing and acquiring patents, 

demonstrates that the manufacturers seek to be able to manipulate and control nicotine 

deliveries and have in fact "designed" and "planned" methods of doing so. This evidence 

is relevant to establishing the manufacturers' intentions. In light of the large number of 

patents held by the industry with the common goal of manipulating nicotine delivery, the 

argument that all of these patents were obtained by individual employees working without 

the direction of the manufacturers is not credible. 

3. In the Jurisdictional Analysis, the Agency found that the failure of the 

cigarette manufacturers to remove nicotine from cigarettes was evidence that the 

manufacturers intend their products to provide the pharmacological effects of nicotine. 

See 60 FR 41779-41787. In their comments, however, the cigarette manufacturers assert 

that they do not have the capacity to manufacture an acceptable denicotinized cigarette 

and, even if they did, this would not establish that the manufacturers intend to affect the 

structure or function of the body. 

In the Agency's view, the failure of denicotinized cigarettes in the marketplace is 

further evidence of the essential role of nicotine in cigarettes. The fact that efforts to 

introduce denicotinized cigarettes have failed demonstrates that consumers smoke 

cigarettes primarily to obtain the pharmacological effects of nicotine. Moreover, evidence 

that a manufacturer has, but does not use, technology that could remove a 

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45096 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.C.6. 

pharmacologically active ingredient from its product is relevant evidence that the 

manufacturer intends that the product will have pharmacological effects upon consumers. 

The manufacturers' assertion that denicotinized cigarettes have failed because of 

inadequacies in the denicotinizing technologies is not supported by the evidence in the 

record. To the contrary, the record contains abundant evidence that the reason a 

denicotinized cigarette will not succeed is because it fails to provide the pharmacological 

effects sought by consumers. For instance, an RJR document asserts that "a zero nicotine 

cigarette ... really has no potential to provide smoking satisfaction. It produces no taste 

in the mouth, but even more seriously it fails to provide the ultimate satisfaction in the 

lungs."992 

4. The cigarette manufacturers argue that the evidence in the administrative 

record does not establish that they add "extraneous" nicotine to cigarettes. According to 

the manufacturers, the failure of the Agency to demonstrate that they add extraneous 

nicotine means that the Agency has not demonstrated that the manufacturers manipulate 

and control nicotine. 

The Agency disagrees. The administrative record contains abundant evidence that 

tobacco manufacturers can manipulate and control nicotine deliveries without adding 

extraneous nicotine. The record before the Agency demonstrates that the manufacturers 

have developed and used many techniques to manipulate and control nicotine, and few of 

them involve the addition of extraneous nicotine. These techniques are discussed in detail 

in section II.C.4., above and include using nicotine-rich blends in low-yield cigarettes, 

992 Senkus M (RJ. Reynolds Tobacco Co.), Some Effects of Smoking (1976/1977), at 9 (emphasis added). 

See AR(Vol 700Ref. 593). 

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II.C.6. 

using filtration and ventilation techniques that selectively remove more tar than nicotine, 

and chemical manipulation to increase free nicotine deliveries. All of these techniques 

manipulate and control nicotine deliveries; all of them facilitate consumer use of cigarettes 

for pharmacological purposes; and none of the techniques require the addition of 

extraneous nicotine. 

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45098 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II. D. 

D. THE STATEMENTS, RESEARCH, AND ACTIONS OF THE 

SMOKELESS TOBACCO MANUFACTURERS SHOW THAT THE 

MANUFACTURERS INTEND THEIR PRODUCTS TO AFFECT THE 

STRUCTURE AND FUNCTION OF THE BODY 

In sections II.A. and II.B., above, the Agency concluded that smokeless tobacco is 

"intended" to affect the structure and function of the body on the basis of the foreseeable 

pharmacological effects and uses of smokeless tobacco and its widespread actual use by 

consumers for pharmacological purposes. In this section, the Agency considers a third 

category of evidence of intended use: the statements, research, and actions of the smokeless 

tobacco manufacturers. 

The administrative record includes considerable evidence of the smokeless tobacco 

manufacturers' statements, research, and manufacturing practices. Much of this evidence has 

only recently become available as the result of the Agency's investigation, congressional 

hearings, and other investigations and sources. As discussed in section II.C.l., above, this 

evidence of the statements, research, and actions of the manufacturers is part of the relevant 

objective evidence that the Agency may rely upon in determining a product's "intended uses." 

The Agency's role in making these determinations is that of a fact fmder. The Agency's factfmding task has been made more difficult by the manufacturers' general refusal to cooperate 

with the Agency's investigation. In particular, the manufacturers failed to provide FDA with 

information and documents requested by the Agency in July 1994 regarding the role of 

nicotine in smokeless tobacco.993 This lack of cooperation has made the Agency's 

investigation more difficult The limited number of company documents provided by the 

993 See, e.g., Letter from Chesemore RG (FDA) to Gierer V (U.S. Tobacco Company) Jul. 19, 1994. See AR 

(Vol. 54 Ref. 619). 

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II.D. 

manufacturers with their comments sheds little light on the role of nicotine in smokeless 

tobacco and does not significantly change the evidence in the record. 

The Agency made extensive findings based on the evidence then before it regarding 

the statements, research, and actions of the smokeless tobacco manufacturers in the 

Jurisdictional Analysis. The Agency received comments on these fmdings from the tobacco 

industry, public health organizations and other groups and members of the public. 

After careful consideration of the evidence in the record and the public comments, the 

Agency finds that the evidence provides an independent basis for concluding that smokeless 

tobacco is in fact intended to affect the structure and function of the bodies of smokeless 

tobacco users. 

As described in this section, the evidence from internal company documents and other 

sources shows that smokeless tobacco manufacturers: (1) know that nicotine has 

pharmacological effects and uses, including causing and sustaining addiction; and (2) 

manipulate and control the delivery of nicotine from smokeless tobacco in a manner that 

promotes tolerance and addiction in consumers. Indeed, in the case of the nation's largest 

smokeless tobacco manufacturer, the statements of senior officials and the company's 

marketing strategies reveal that the company relies on an explicit "graduation process," under 

which users of smokeless tobacco are encouraged to progress from "starter'' products that 

deliver low levels of nicotine to products that deliver higher and more addictive levels of 

nicotine. The cumulative evidence shows that the manufacturers design smokeless tobacco 

with an intent to affect the structure and function of the body.994 

994 The discussion of the statements, research, and actions of the manufacturers in this section cites many 

documents. It is the totality of the evidence from these documents that the Agency relies upon. No single 

document cited by the Agency is essential to the Agency's conclusion that the manufacturers intend their 

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45100 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.D.l. 

1. The Smokeless Tobacco Manufacturers Understand That Nicotine Has 

Addictive and Other Pharmacological Effects and That Consumers Use 

Smokeless Tobacco To Obtain these Effects 

Extensive evidence in the administrative record, including statements and research of 

smokeless tobacco manufacturers, demonstrates that the manufacturers know that nicotine 

causes significant pharmacological effects, including addiction. These statements and 

research also demonstrate that the manufacturers understand that consumers use smokeless 

tobacco to obtain the pharmacological effects of nicotine. 

For example, Brown & Williamson Tobacco Corporation, which is also a smokeless 

tobacco manufacturer, " 995 understands that nicotine is addictive; that nicotine has other 

significant pharmacological effects; and that consumers use tobacco products to obtain 

nicotine. See section ILC.2.c., above. Researchers for Brown & Williamson's parent 

corporation, BATCO, have long regarded "buccal administration of nicotine" through 

products such as chewing tobacco and wet snuff as alternatives to the delivery of nicotine 

through cigarettes.996 According to these researchers, these types of tobacco usagesmoking, chewing, and snuffmg-allow nicotine to go directly into the blood and to the 

brain; they stated that "[t]he common factor in all the types of tobacco usage ... is nicotine, 

products to affect the structure and function of the body. In particular, none of the documents in the Agency's 

docket of confidential documents is essential to the Agency's determination. See AR (Vols. 505-518). 

995 Valero G, Moist poised to overtake leaf; smokeless tobacco, U.S. Distribution Journal, Dec. 15, 1995; 

222(12):12. See AR (Vol. 711 Ref. 22). 

996 Minutes of B.A.T. Group Research Conference at St. Adele, Quebec (Nov. 9-13, 1970), at 3. See AR 

(Vol. 44 Ref. 15-2). 

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II.D.l. 

either absorbed through the lungs or the lining of the nose or mouth. Taken in these ways 

nicotine will quickly enter a direct route, in the blood, to the brain."997 

Indeed, as recently as 1992, Brown & Williamson stated that "[t]he fact that people 

use snuff and chewing tobacco indicates that administration routes other than the inhalation 

route can deliver tobacco satisfaction."998 BA TCO scientists use "satisfaction" as a 

euphemism for the pharmacological effects of nicotine, stating "[i]ntuitively it is felt that 

'satisfaction' must be related to nicotine. Many people believe it [is] a 'whole body 

response' and involves the action of nicotine in the brain."999 See section ll.E.2., below. 

Similarly, a senior vice president for marketing for United States Tobacco Company 

(UST), the nation's largest smokeless tobacco manufacturer,1000 wrote in a memo on new 

product development that "virtually all tobacco usage is based upon nicotine, 'the kick, ' 

satisfaction."1001 The executive further stated: 

Nicotine gives the consumer satisfaction. Some would describe it as a 

pleasant feeling. Others would describe it as a kick. ... Others would 

describe it as a relaxing feeling. 1002 

997 BATCO Group R&D Conference on Smoking Behaviour at Southampton, England (Oct 11-12, 1976), at 

BW-W2-02145 (emphasis added). See AR (Vol 14 Ref. 180-2). 

998 Transdermal Nicotine Patches, at 3. See AR (Vol 531 Ref. 124). 

999 BATCO Nicotine Conference at Southampton, England (Jun. 6-8, 1984) at BW-W2-01977 (emphasis 

added). See AR (Vol22 Ref. 287-7). 

1000 UST has 82% of the market for moist snuff products sold in the United States in 1994. It also has nearly 

40% of the market for all smokeless tobacco sold in the United States. See Valero G, Moist poised to 

overtake leaf; smokeless tobacco, U.S. Distribution Journal, Dec. 15, 1995; 222(12): 12. See AR (Vol. 711 

Ref. 22). 

1001 Deposition of Erik Lindqvist, transcript of jury trial proceedings at 1662 in Marsee v. U.S. Tobacco, Civil 

Action No. 84-2777R (W.D. Ok 1986) (emphasis added). See AR (Vol 22 Ref. 292). 

1002 ld. 

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45102 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.D.l. 

Another UST document compares the nicotine delivery of one of its products, Skoal 

Bandits, with the nicotine delivery of cigarettes. This document states: 

The nicotine contents are more or less equivalent to that of a good 

quality cigarette of average strength. The nicotine is absorbed, 

giv[ing] satisfaction to the smoker. 1003 

Like the major cigarette manufacturers, UST has funded its own studies on nicotine 

pharmacology, including studies on the absorption of nicotine from snuff and chewing 

tobacco, the effects of smokeless tobacco on performance and psychophysiological response, 

and detection of nicotine in blood.1004 Other UST studies were designed to compare routes 

of nicotine administration in snuff and cigarette smoking1005 and to describe the 

pharmacokinetics of nicotine and its major metabolites in experienced and inexperienced snuff 

1003 Potential Questions and Answers, submitted in Marsee v. U.S. Tobacco, Civil Action No. 84-2777R 

(W.D. Ok 1986), at 1. See AR (Vol30 Ref. 509). 

1004 Kyerematen, GA, Dvorchik, BH, Vesell, ES, Influence of different forms of tobacco intake on nicotine 

elimination in man, Pharmacology 1983;26:205-209. See AR (Volll9 Ref. 1102). 

Landers DM, Crews DJ, Boutcher SH, et al., The effects of smokeless tobacco on performance and 

psychophysiological response, Medicine and Science in Sports & Exercise 1992;24(8):895-903, as cited in 

Health Effects of Smnkeless Tobacco: Hearings Before the Subcommittee on Health and the Environment of 

the Committee on Energy and Commerce, U.S. House of Representatives, 103d Cong., 2d Sess. 144 (Nov. 29, 

1994). See AR (Vol 710 Ref. 4). 

Allen JK, Stem JR, Harris], Analysis of Nicotine in Blood by HPLC with Electrochemical Detection, 

(Abstract), submitted for presentation at the lOth International Symposium on Column Liquid 

Chromatography, San Francisco, CA (May 18-23, 1986), as cited in Health Effects of Smokeless Tobacco: 

Hearings Before the Subcommittee on Health and the Environment of the Committee on Energy and 

Commerce, U.S. House of Representatives, 103d Cong., 2d Sess. 144 (Nov. 29, 1994). See AR (Vol 710 

Ref. 4). 

Baldini FD, Skinner JS, Landers DM, et al., Effects of varying doses of smokeless tobacco at rest and during 

brief, high-intensity exercise, Military Medicine 1992;157:51-55, as cited in Health Effects of Smokeless 

Tobacco: Hearings Before the Subcommittee on Health and the Environment of the Committee on Energy 

and Commerce, U.S. House of Representatives, 103d Cong., 2d Sess. 144 (Nov. 29, 1994). See AR (Vol 710 

Ref. 4). 

1005 U.S. Tobacco Company, Results of Comparison of Routes of Nicotine Administration. Plaintiffs exhibit 

3.28 from Marsee v. U.S. Tobacco, Civil Action No. 84-2777R (W.O. Ok 1986). See AR (Vol24 Ref. 318). 

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II.D.l. 

takers.1006 The study comparing routes of nicotine administration, for instance, found that 

smokeless tobacco can actually deliver more nicotine than cigarettes to new tobacco users, 

stating that "for naive tobacco users, bioavailability of nicotine is greater after snuff dipping 

than after cigarette smoking .... "

1007 

UST is also a founding member of the Council for Tobacco Research (CTR). 1008 As 

discussed in section II.C.2.d., above, CTR has funded many studies on behalf of its members 

evaluating the pharmacological effects of nicotine on the body. At least one of these studies 

stated that nicotine in tobacco can cause "drug addiction."1009 As a member of the Council 

for Tobacco Research, UST thus had direct knowledge of the pharmacological effects and 

the consumer uses of nicotine. 

1006 U.S. Tobacco Company, Pharmacokinetics of Nicotine and Its Major Metabolites in Naive and Habiruated 

Snuff Takers. Plaintiffs exhibit3.27 from Marsee v. U.S. Tobacco, Civil Action No. 84-2777R (W.D. Ok. 

1986). See AR (Vol 24 Ref. 317). 

1007 U.S. Tobacco Company, Results of Comparison of Routes of Nicotine Administration. Plaintiffs exhibit 

3.28 from Marsee v. U.S. Tobacco, Civil Action No. 84-2777R (W.D. Ok. 1986). See AR (Vol 24 Ref. 318). 

1008 UST has been intimately connected with CTR since its inception. The minutes of the initial meeting in 

March 1954 of the Tobacco Industry Research Council, the predecessor of the Council for Tobacco Research, 

indicate that UST's president was the first vice chairman of the Council TIRC, Report on Meeting (Mar.15, 

1954). See AR(Vol 301 Ref. 4393). Subsequently, UST's president served as adirectorofCTRfrom 1976 

to 1984. Organization and Function of CTR (summaries of CTR meetings, 1976-1984). See AR (Vol 342 

Ref. 5382). Prior to 1988, UST manufactured cigarettes and was a class A member of CTR. Since 1988, 

UST has been a class B member of CTR. Health Effects of Smokeless Tobacco: Hearing Before the 

Subcommittee on Health and the Environment of the Committee on Energy and Commerce, U.S. House of 

Representatives, 103d Cong., 2d S~. 137 (Nov. 29, 1994). See AR (Vol 710 Ref. 4). 

1009 See, e.g., Svennson TH, Grenhoff J, Engberg G, Effect of nicotine on dynamic function of brain 

catecholamine neurons, in The Biology of Nicotine Dependence, eds. Bock G, Marsh J, CIBA Foundation 

Symposium, 1990;152:169-180. See AR (Vol 61 Ref. 273). 

Tung CS, Ugedo L, Grenhoff J, et al., Peripheral induction burst fuing in locus coerulus neurons by nicotine 

mediated via excitatory amino acids, Synapse 1989;4(4):313-318. See AR (Vol 61 Ref. 278). 

Rosecrans JA, Nicotine as a discriminative stimulus: a neurobehavioral approach to studying central 

cholinergic mechanisms, J Subst Abuse 1989;1(3):287-300. See AR (Vol 59 Ref. 239). 

447 
45104 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.D.l. 

Nicotine's pharmacological effects are also understood by Procordia A.B., the parent 

of Pinkerton Tobacco Company, the nation's third largest smokeless tobacco 

manufacturer.1010 Through corporate subsidiaries, Procordia has extensively investigated the 

pharmacological effects of nicotine, including funding numerous studies on nicotine's effects 

on the brain.1011 

1010 Valero G, Moist poised to ovena.ke leaf, smokeless tobacco, U.S. Distribution Journal, Dec. 15, 1995; 

222(12):12. See AR(Vol. 711 Ref. 22). 

1011 Procordia owns two foreign smokeless tobacco manufacturers, Svenska Tobaks AB and Swedish Tobacco 

Co. Through Svenska Tobaks and Swedish Tobacco, Procordia funded the following studies on nicotine 

pharmacology: 

Adem A, Jossan SS, d' Argy R, et al., Distribution of nicotinic receptors in human thalamus as visualized by 

3H-nicotine and 3H-acetylcholine receptor autoradiography, J Neural Transm 1988;73(1):77-83. See AR 

(Vol. 45 Ref. 10}. 

Adem A. Nordberg A, Jossan SS, et al., Quantitative autoradiography of nicotinic receptors in large 

cryosections ofhuman brain hemispheres, Neurosci Lett 1989;101(3):247-252. See AR (Vol. 45 Ref. 9). 

Andersson. K, Eneroth P, Agnati L, Nicotine-induced increases of noradrenaline turnover in discrete 

noradrenaline nerve terminal systems of the hypothalamus and the median eminence of the rat and their 

relationship to changes in the secretion of adenohypophyseal hormones, Acta Physiol Scand 1981; 113:227-

231. See AR (Vol. 273 Ref. 3784). 

Andersson K, Fuxe K., Agnati LF, et al., Effects of acute central and peripheral administration of nicotine on 

ascending dopamine pathways in the male rat brain. Evidence for nicotine induced increases of dopamine 

turnover in various telencephalic dopamine nerve terminal systems, Med Bio/1981;59(3):170-176. See AR 

(Vol. 45 Ref. 11). 

Andersson K, Fuxe K, Eneroth P, et al., Interactions of nicotine and pentobarbitone in the regulation of 

telencephalic and hypothalamic catecholamine levels and turnover and of adenohypophyseal hormone 

secretion in the normal male rat. Naunyn Schmiedebergs Arch Pharmaco/1982;321:287-292. See AR (Vol. 

423 Ref. 7141). 

Andersson K, Hockey GRJ, Effects of cigarette smoking on incidental memory, Psychopharmacology 

1977;52:223-226. See AR (Vol 125 Ref. 1300). 

Biber A, Scherer G, Hoepfner I, et al., Determination of nicotine and cotinine in human serum and urine: an 

interlaboratory study, Toxicol Lett 1987;35(1):45-52. See AR (Vo1140 Ref. 1649). 

Copeland JR, Adem A, Jacob P, et al., A comparison of the binding of nicotine and nornicotine stereoisomers 

to nicotinic binding sites in rat brain cortex, Naunyn Schmiedebergs Arch Pharmaco/1991;343(2):123-127. 

See AR (Vo1152 Ref. 1887). 

Falkebom Y, Larsson C, Nordberg A, Chronic nicotine exposure in rat a behavioral and biochemical study of 

tolerance, Drug Alcohol Depend 1981;8:51-60. See AR (Vo114l Ref. 1679). 

448 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45105

ll.D.l. 

Fuxe K. Andersson K , Eneroth P, et al., Neurochemical mechanisms underlying the neuroendocrine actions 

of nicotine: focus on the plasticity of central cholinergic nicotinic receptors, Prog Brain Res 1989;79: 197-

207. See AR (Vol47 Ref. 95). 

Fuxe K. Everitt BJ, Hokfelt T, On the action of nicotine and cotinine on central 5-hydrcxytryptamine 

neurons, Pharmacal Biochem Behav 1979;10(5):671-677. See AR (Vol 152 Ref. 1869). 

Fuxe K, von Euler G, Finnman UB, et al., Reduction of [3 H]nicotine binding in hypothalamic and cortical 

membranes by dopamine 01 receptors, Acta Physiol Scand 1989;136(2):295-296. See AR (Vol. 127 Ref. 

1351). 

Fuxe K. Agnati LF, Jansson A. et al., Regulation of endocrine function by the nicotinic cholinergic receptor, 

CIBA Foundation Symposium 1990;152:113-130. See AR (Vol131 Ref. 1450). 

Grenhoff J, Aston Jones G, Svensson TH, Nicotinic effects on the firing pattern of midbrain dopamine 

neurons, Acta Physiol Scand 1986;128(3)351-358. See AR (VoL 143 Ref. 1771). 

Larsson C. Nordberg A, Comparative analysis of nicotine-like receptor-ligand interactions in rodent brain 

homogenate, J Neurochem 1985;45:24-31. See AR(Vol141 Ref. 1684). 

Larsson C, Lundberg PA, Halen A, et al., In vitro binding of 3H-acetylcholine to nicotinic receptors in rodent 

and human brain, J Neural Transm 1987;69:3-18. See AR (Vol. 137 Ref. 1586). 

Larsson C, Nilsson L, Halen A. et al., Subchronic treatment of rats with nicotine: effects on tolerance and on 

[3 H]acetylcholine and [3 H]nicotine binding in the brain, Drug Alcohol Depend 1986;17:37-45. See AR 

(Vol. 141 Ref. 1677). 

Nisell M, Nomikos GG, Svensson TH, Systemic nicotine-induced dopamine release in the rat nucleus 

accumbens is regulated by nicotinic receptors in the ventral tegmental area, Synapse 1994;16:36-44. See AR 

(Vol. 276 Ref. 3870). 

Nordberg A. Romanelli L, Sundwall A. et al., Effect of acute and subchronic nicotine treatment on cortical 

acetylcholine release and on nicotinic receptors in rats and guinea-pigs, British Journal of Pharmacology 

1989;98(1):71-78. See AR(Vol. 131 Ref. 1454). 

Nordberg A. Wahlstrom G, Amelo U, et al., Effect of long-term nicotine treatment on [3-H]nicotine binding 

sites in the rats brain, Drug Alcohol Depend 1985;16:9-17. See AR (Vol 141 Ref. 1678). 

Nordberg A. Bergh C. Effect of nicotine on passive avoidance behaviour and motoric activity in mice, Acta 

Pharmacal Toxicol Copenh 1985;56(4):337-341. See AR (Vol 274 Ref. 3820). 

Nordberg A. Sundwall A. Pharmacodynamic effects of nicotine and acetylcholine biosynthesis, in mouse 

brain, Acta Pharmacal Toxicol Copenh 1983;52(5):341-347. See AR (Vol 133 Ref. 1503). 

Nordberg A. Larsson C, Studies of muscarinic and nicotinic binding sites in brain, Acta Physiol Scand Suppl 

1980;479:19-23. See AR (Vol 137 Ref. 1590). 

Pilotti A. Enzell CR, McKennis H Jr, et al., Studies on the identification of tobacco alkaloids, their 

mammalian metabolites and related compounds by gas chromatography- -Mass Spectrometry, Beitrage zur 

Tabakforschung 1976;8(6):339-349. See AR (Vol 96 Ref. 704). 

449 
45106 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.D.l. 

Furthermore, numerous studies of the pharmacological effects and chemistry of 

nicotine and the sites and mechanisms of nicotine receptors in the brain have been funded by 

the Smokeless Tobacco Research Council.1012 The Smokeless Tobacco Research Council 

Schievelbein H, Absorption of Nicotine Under Various Conditions (an introductory review), presented at the 

Nicotine Workshop (Nov. 1974), Beitrage zur Tabakforschung 1976;8(5):196-202. See AR (Vol. 60 Ref. 

254). 

Schmiterlow CG, Hansson E, Andersson G, et al., Distribution of Nicotine in the Central Nervous System, 

Annals of the New York Academy of Sciences 1967; 142:2-14. See AR (Vol. 152 Ref. 1859). 

Schmiterlow CG, Hansson E, Tissue distribution of C 14-nicotine, in Von Euler US (ed.), Tobacco Alkaloids 

and Related Compounds 1965:75-86, ed. Von Euler US. See AR (Vol. 60 Ref. 256). 

Siegel RA, Andersson K, Fuxe K, et al., Rapid and discrete changes in hypothalamic catecholamine nerve 

terminal systems induced by audiogenic stress, and their modulation by nicotine-relationship to 

neuroendocrine function, Eur J Pharmacol1983;91:49-56. See AR (Vol. 60 Ref. 262). 

Svensson TH, Engberg G, Effect of nicotine on single cell activity in the noradrenergic nucleus locus 

coerulus, Acta Physiol Scand Supp/1980;479:31-34. See AR (Vol. 422 Ref. 7124). 

Szuts T, Olsson S, Lindquist NG, et al., Long-term fate of [14C]nicotine in the mouse: retention in the 

bronchi, melanin-containing tissues and urinary bladder wall, Toxicology 1978;10(3):207-220. See AR (Vol. 

131 Ref. 1458). 

1012 Anand R, and Lindstrom J, Chromosomal localization of seven neuronal nicotinic acetylcholine receptor 

subunit genes in humans, in Report of the Council for Tobacco Research- USA, Inc. 1992, at 101. See AR 

(Vol. 465 Ref. 7874). 

Bencherif M, Lukas RJ, Cytochalasin modulation of nicotinic cholinergic receptor expression and muscarinic 

receptor function in human TE671/RD cells: a possible functional role of the cytoskeleton, Journal of 

Neurochemistry 1993;61(3):852-864. See AR(Vol. 141 Ref. 1683). 

Britto LRG, Keyser KT, Lindstrom JM, et al., Immunohistochemical localization of nicotinic acetylcholine 

receptor subunits in the mesenchephalon and diencephalon of the chick (Gallus Gallus), The Journal of 

Comparative Neurology 1992;317:325-340. See AR (VoL 131 Ref .1453). 

Cbolerton S, McCracken NW, Idle JR, Sources of inter-individual variability in nicotine pharmacokinetics, in 

Nicotine and Related Alkaloids: Absorption, Distribution, Metabolism, and Excretion, eds. Gorrod JW, and 

Wahren J (1993), at 219-253. See AR (Vo147 Ref. 70). 

Gerzanich V, Anand R, Lindstrom J, Homomers of a8 and a.7 subunits of nicotinic receptors exhibit similar 

channel but contrasting binding site properties, Molecular Pharmacology 1994;45(2):212-220. See AR 

(Vol. 276 Ref. 3861). 

Hsu YN, Amin J, Weiss D, et al., Chronic nicotine exposure decreases the activation of a.4~2 but not a.3~2 

neuronal nicotinic receptors expressed in xenopus oocytes, in International Symposium on Nicotine: The 

450 
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II.D.l. 

Effects of Nicotine on Biological Systems /I, eds. Clarke PBS et al. (Montreal: Jul. 21-24, 1994). See AR 

(Vol. 135 Ref. 1529). 

Keyser KT, Britto LRG, Schoepfer R. et al., Three subtypes of a-bungarotoxin - sensitive nicotinic 

acetylcholine receptors are expressed in chick retina, Journal of Neuroscience, Feb. 1993;13(2):442-454. 

See AR (Vol 126 Ref. 1343). 

Marks R. Lindstrom J, Schroder H, Cellular and subcellular visualization of the ~2- subunit of the nicotinic 

acetylcholine receptor in the mouse cerebral cortex, in International Symposium on Nicotine: The Effects of 

Nicotine on Biological Systems II, eds. Clarke, PBS, et al., at session 1, 4 (Montreal: Jul. 21-24, 1994). 

See AR (Vol 104 Ref. 952). 

McFarland BJ, Seidler FJ, Slotkin T A, Inhibition of DNA synthesis in neonatal rat brain regions caused by 

acute nicotine administration, Developmental Brain Research 1991;58:223-229. See AR (Vol 414 

Ref. 6940). 

McLane DE, Wu X, Schoepfer R. et al., Identification of sequence segments forming the a-bungarotoxin 

binding sites on two nicotinic acetylcholine receptor a subunits from the avian brain, in Report of the 

Councilfor Tobacco Research- USA, /nc./991. See AR(Vol 19 Ref. 195-22). 

McLane DE, Wu X, Lindstrom JM, et al., Epitope mapping of polyclonal and monoclonal antibodies against 

two a-bungarotoxin-binding a subunits from neuronal nicotinic receptors, in Report of the Council for 

Tobacco Research- USA, Inc. 1992. See AR (Vol 19 Ref. 195-23). 

Navarro HA, Seidler FJ, Schwartz RD, et al., Prenatal exposure to nicotine impairs nervous system 

development at a dose which does not affect viability or growth, Brain Research Bulletin 1989;23: 187-192. 

See AR (Vol. 137 Ref. 1585). 

Nelson S, Shelton GD, Lei S, et al., Epitope mapping of monoclonal antibodies to torpedo acetylcholine 

receptor "(subunits, which specifically recognize the E subunit of mammalian muscle acetylcholine receptor, 

inReportofthe Council for Tobacco Research- USA, lnc./992. See AR(Vol 19 Ref. 195-23). 

Seeman JI, Secor HV, Armstrong DW, et al., Enantiomeric resolution and chiral recognition of racemic 

nicotine and nicotine analogues by ~-cyclodextrin complexation. S tructure-enantiomeric resolution 

relationships in host-guest interactions, Analytical Chemistry 1988;60:2120-2127. See AR (Vol 275 

Ref. 3836). 

Slotkin T A, Cbo H, Whitmore WL, Effects of prenatal nicotine exposure on neuronal development selective 

actions on central and peripheral catecbolaminergic pathways, Brain Research Bulletin 1987;18(5):601-611. 

See AR (Vol 137 Ref. 1573). 

Slotkin T A, Navarro liA, McCook EC, et al., Fetal nicotine exposure produces postnatal up-regulation of 

adenylate cyclase activity in peripheral tissues, life Sciences 1990;47:1561-1567. See AR (Vol 276 

Ref. 3865). 

Slotkin T A, Lappi SE, Tayyeb Ml, et al., Chronic prenatal nicotine exposure sensitizes rat brain to acute 

postnatal nicotine challenge as assessed with ornithine decarboxylase, life Sciences 1991;49(9):665-670. 

See AR (Vol 137 Ref. 1580). 

Slotkin T A, Developmental effects of nicotine, in International Symposium on Nicotine: The Effects of 

Nicotine on Biological Systems II, eds. Clarke PBS, et al., at session 4, S15 (Montreal: Jul. 21-24, 1994). 

See AR (Vol. 60 Ref. 264). 

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45108 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.D.2. 

was formed by the major smokeless tobacco manufacturers to fund scientific studies on 

behalf of the manufacturers. One such study recognized that nicotine is "the major 

pharmacologically active component of tobacco."1013 

2. The Smokeless Tobacco Manufacturers Manipulate Nicotine Deliveries 

from Smokeless Tobacco in a Manner That Promotes Tolerance and 

Addiction in Users 

The evidence in the record also demonstrates that smokeless tobacco manufacturers 

manipulate the nicotine delivery of their products to produce graduated deliveries of nicotine 

that promote tolerance and addiction. Specifically, the evidence shows that the nicotine 

deliveries of smokeless tobacco are manipulated so that products intended for new users 

deliver low amounts of nicotine, while products intended for experienced users deliver far 

higher amounts of nicotine. This manipulation of nicotine delivery is accomplished primarily 

S lotkin T A, Lappi SE, Seidler FJ ., Impact of fetal nicotine exposure on development of rat brain regions: 

critical sensitive periods or effects of withdrawal?, Brain Research Bulletin 1993;31:319-328. See AR (Vol. 

137 Ref. 1571). 

Wahlsten JL, Lindstrom JM, Conti-Tronconi BM, Amino acid residues within the sequence region cx55-74 of 

torpedo nicotinic acetylcholine receptor interacting with antibodies to the main immunogenic region and with 

snake a-neurotoxins, in Report of the Council for Tobacco Research- USA, Inc. 1993, at 166-167. See AR 

(Vol. 465 Ref. 7873). 

Wahlsten JL, Lindstrom JM, Ostlie N, et al., Myasthenia gravis: effect on antibody binding of conservative 

substitutions of amino acid residues forming the main immunogenic region of the nicotinic acetylcholine 

receptor, in Report of the Council for Tobacco Research- USA, Inc. 1993, at 166. See AR (Vol. 465 Ref. 

7873). 

Yu CI, Morgan DG, Wecker L, Northern blot analysis demonstrates the presence of three different transcripts 

of neuronal nicotinic acetylcholine receptor <X4 gene in rat brain, in International Symposium on Nicotine: 

The Effects of Nicotine on Biological Systems II, eds. Clarke PBS, et al., at session 2, P1 0 (Montreal: 

Jul. 21-24, 1994). See AR(Vol104Ref. 952). 

1013 Cholerton S, McCracken NW, Idle JR. Sources of inter-individual variability in nicotine 

pharmacokinetics, in Nicotine and Related Alkaloids: Absorption, Distribution, Metabolism, and Excretion, 

eds. Gorrod JW, WahrenJ (1993):219-253, at 219 (emphasis added). See AR (Vol47 Ref. 70). 

452 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45109

II.D.2. 

through the use of chemicals that alter the pH (acidity or alkalinity) of the tobacco. The 

effect is to promote tolerance and addiction in users. 

The evidence of nicotine manipulation in smokeless tobacco in a manner that 

promotes tolerance in addiction in users is extensive. First, evidence shows that products 

intended for new users deliver less nicotine than products intended for experienced users. 

These graduated nicotine deliveries lead to increased tolerance and addiction because they 

allow new users to avoid adverse reactions to nicotine by beginning with low-nicotine 

products, while allowing experienced users to obtain sufficient nicotine to sustain their 

addiction by progressing to high-nicotine products. 

Second, governmental data on smokeless tobacco use confirms that the graduated 

nicotine deliveries promote tolerance and addiction. These data show that since the advent of 

smokeless tobacco products with graduated nicotine deliveries, the number of children and 

adolescents who use and are addicted to smokeless tobacco has risen substantially. 

Third, evidence from internal company documents and marketing campaigns of the 

nation's largest smokeless tobacco manufacturer, UST, shows the conscious manipulation of 

nicotine deliveries. UST deliberately relies on an explicit "graduation process" that 

introduces new users to low-nicotine delivery products while providing experienced users 

with higher-nicotine delivery products. 

In combination with the evidence that the manufacturers understand the 

pharmacological effects and uses of nicotine, this evidence of nicotine manipulation to 

promote pharmacological effects in users demonstrates that the effects of nicotine in 

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45110 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.D.2. 

smokeless tobacco on the structure and function of the body are "intended" by the 

manufacturers. 

a. Evidence of Graduated Nicotine Deliveries 

Absorption of a drug through the buccal mucosa in the mouth into the bloodstream 

can be increased or decreased by adjusting the pH of the drug. Phannaceutical companies 

regularly alter pH by adding alkaline or acidic additives to drugs to increase or decrease their 

absorption into the bloodstream. Raising the pH converts many drugs from an ionized fonn 

into a non-ionized or"free" fonn that more readily crosses biological membranes.1014 

Nicotine absorption is affected in this manner by pH levels. Increasing the pH of 

nicotine converts ionized nicotine into non-ionized nicotine, rendering it significantly more 

absorbable in the mouth.1015 For this reason, the manufacturer of nicotine gum adds sodium 

carbonate to increase pH and enhance the absorption of nicotine.1016 Tobacco industrysupported researchers have acknowledged that nicotine absorption in the mouth increases as 

a function of pH and that "the pharmacological response is clearly dependent on the amount 

of nicotine in the mouth as free base."1017 Indeed, the senior vice president for marketing at 

1014 Benet LZ, Steiner LB, Pharmacokinetics: The dynamics of drug absorption, distribution, and elimination 

in Goodman and Gilman's The Pharmacological Basis of Therapeutics (1990), 3-32, at 4-5. See AR (Vol. 

711 Ref. 14). 

1015 Surgeon General's Report, 1988, at 29. See AR (Vol 129 Ref. 1592). 

1016 Henningfield JE, Radzius A, Cooper TM, et al., Drinking coffee and carbonated beverages blocks 

absorption of nicotine from nicotine polacrilex gum, Journal of the American Medical Association, 

1990;264:1560-1564. See AR (VoL 29 Ref. 491-2). 

1017 Armitage AK. Turner DM, Absorption of nicotine in cigarette and cigar smoke through the oral mucosa, 

Nature, 1970;226:1231-1232, at 1232. See AR(VoL 143 Ref. 1810). 

Cholerton S, McCracken NW, Idle JR. Sources of inter-individual variability in nicotine pharmacokinetics, in 

Nicotine and Related Alkaloids: Absorption, Distribution, Metabolism, and Excretion, eds. Garrod JW, 

Wahren J (1993), at 220-221 ("Absorption of nicotine from chewing tobacco and nicotine gum is facilitated 

by buffering of the preparations to an alkaline pH (approx. 8.5)"). See AR (VoL 47 Ref. 70). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45111

II.D.2. 

UST conceded that it was his understanding that .. if the pH of the snuff product is raised, ... 

the rate of absorption of the nicotine would be increased in the user's mouth."1018 

The data collected and analyzed by fDA1019 and others1020 demonstrate that moist 

snuff products marketed as "starter" products have relatively low pH levels, while products 

for established users have significantly higher pH levels, resulting in a pattern of graduated 

delivery of free nicotine. UST' s principal line of starter products is its "Skoal Bandits" line. 

The pH levels for Skoal Bandits are low, ranging from 5.2 to 5.6 for Skoal Bandits Classic to 

6.8 to 7.1 for Skoal Bandits Mint; the free nicotine provided by Skoal Bandits is also low, 

ranging from 0.2% to 0.4% for Skoal Bandits Classic to only 6.4% to 9.9% for Skoal 

Bandits Mint. See Jurisdictional Analysis, 60 FR 41737. Likewise, another UST starter 

product, "Happy Days," has a pH of 6.0 and provides only 0.9% free nicotine. In contrast, 

UST' s principal product for established users, Copenhagen, has a pH of 7. 7 to 8.1. Because 

pH is measured on a logarithmic scale, the alkalinity of Copenhagen is approximately two 

1018 The exchange from the Marsee trial transcript on this point was: 

Q: And correspondingly, if the pH of the snuff product is raised. then, the rate of 

absorption of the nicotine from the snuff product would be increased in the user's 

mouth? 

A: Although I am not an expert on this, that is to the best of my understanding 

correct 

Deposition of Erik Lindqvist. Marsee v. U.S. Tobacco, Civil Action No. 84-2777R (W.R. Ok 1986). 

Transcript of jury trial proceedings, at 1668. See AR (Vol. 29 Ref. 489-2).The relationship between ionized 

nicotine and nicotine in its free fon;n is thus similar to the relationship between cocaine and "free-base" or 

"crack" cocaine. Increasing the pH of cocaine, through the addition of alkaline additives such as sodium 

bicarbonate and ammonia. converts cocaine salt into free-base or crack cocaine, thereby significantly 

increasing the rate at which the cocaine is absorbed into the bloodstream. Siegel RK., Part ill cocaine free 

base use, Journal of Psychoactive Drugs 1982;14:311-318, 352-359. See AR (Vol. 711 Ref. 23). 

1019 The table on the next page presents the results of the studies performed by the two FDA laboratories in St 

Louis, Missouri, and Cincinnati, Ohio. 

mo Djordjevic MV, Hoffmann D, Glynn T, et al., US commercial brands of moist snuff, 1994, Assessment of 

nicotine, moisture, and pH, Tobacco Control, 1995;4:62-66. See AR (Vol. 528 Ref. 97, appendix 9). 

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45112 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.D.2. 

TOTAL NICOTINE 

I!H %Free Nicotine* Conten!{ml!!mt}** 

MANUF ACTURERI 

PRODUCT NAME St.Louis Cine. St.Louis Cine. St. Louis Cine. 

U.S. Tobacco Co. 

Skoal Key 8.22 61.3 12.4 

Copenhagen Snuff 8.14 7.71 56.5 32.7 13.2 13.8 

Skoal L.C. Class 8.04 7.92 51.1 44.5 12.7 13.8 

Skoal L.C. Wint 7.50 7.57 23.1 26.0 12.7 13.9 

Skoal L.C. Mint 7.35 7.52 17.6 24.0 13.2 13.7 

Skoal L.C. Spear. 7.20 7.50 14.0 23.3 12.5 13.8 

Skoal Or.F.C. Wint 7.41 19.7 13.6 

Skoal L.C. Strai. 7.47 7.41 22.0 19.5 12.1 13.8 

Skoal L.C. Cherry 7.15 7.38 12.3 18.5 12.5 13.6 

Skoal Band Mint 6.83 7.06 6.4 9.9 6.7 8.8 

Skoal Band. Wint 6.56 6.72 3.3 4.8 7.8 8.2 

Happy Days L.C. Mint- 6.00 0.9 13.9 

Skoal Band Strai. 5.48 0.3 10.8 

Skoal Band. Class. 5.61 5.23 0.39 0.2 10.4 9.9 

Helme Tobacco Co.*** 

Redwood Full Flavor 7.52 24.0 12.6 

Silver Cr. L.C. 7.22 13.7 6.0 

Cooper Wint L.C. 6.99 8.5 5.7 

Gold River L.C. 5.77 0.6 6.4 

ConwoodCo. 

KodiakWint 8.20 8.22 59.9 61.0 11.4 11.7 

Kodiak Choice Wint 7.98 47.7 11.4 

Kodiak Straight 7.39 7.82 19.0 38.4 10.6 10.4 

Hawken Wint 5.56 5.58 0.35 0.4 4.4 0.4 

Pinkerton Tobacco Co. 

Redman F. C. Ex. Wint 7.58 12.3 

Renegade Wint 6.81 7.17 5.8 13.2 11.8 

L.C. = long cut 

* Calculated using the Henderson-Hasselbach Equation for acid base equilibrium. This calculation strictly 

is dependent on the pH determination. Any error in the pH determination will affect the percent free nicotine 

calculation. 

** Measured on wet basis 

***Now Swisher International, Inc. 

456 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45113

11.0.2. 

orders of magnitude higher than the alkalinity of Skoal Bandits Classic and Happy Days (as 

measured in hydrogen ion concentrations). The level of free nicotine provided by 

Copenhagen is 33% to 57%, also far higher than the levels provided by Skoal Bandits or 

Happy Days.1021 

The same pattern of graduated nicotine deliveries is found in the smokeless tobacco 

products of other manufacturers. Conwood' s principal line of moist snuff starter products, 

"Hawken," has a pH of 5.6 and provides 0.4% free nicotine, whereas Conwood's product 

marketed for established users, "Kodiak-Wintergreen," has a pH of 8.2 and provides about 

60% free nicotine.1022 Similarly, the principal starter product of Swisher International, Inc. 

(formerly Helme Tobacco Co.), "Gold River L.C.," has a pH of 5.8 and provides 0.6% free 

nicotine, whereas its product marketed for established users, "Redwood Full Flavor," has a 

pH of 7.5 and provides 24% free nicotine.1023 

These graduated nicotine deliveries directly promote tolerance and addiction. New 

users of smokeless tobacco have not developed a tolerance to nicotine. As a result, as a UST 

study documented, too much nicotine causes adverse reactions such as nausea and vomiting 

in new users, 1024 discouraging future experimentation with smokeless tobacco. Once 

tolerance to nicotine is developed, however, increasing doses of nicotine are required to 

1021 See Table of .. Total Nicotine" above. 

1022 ld. 

1023 ld. 

1024 U.S. Tobacco Company, Pharmacokinetics of Nicotine and Its Major Metabolites in Naive and 

Habituated Snuff Takers, Plaintiff's exhibit 3.27 from Marsee v. U.S. Tobacco, Civil Action No. 84-2777R 

(W.O. Ok 1986), at 9. See AR (VoL 24 Ref. 317). 

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45114 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

11.0.2. 

produce the desired pharmacological effects.1025 Thus, if nicotine levels were kept unif~mnly 

low to accommodate new users, the experienced user would not obtain the higher level of 

nicotine delivery needed to satisfy the user's addiction and to provide other desired 

pharmacological effects. 

Graduating nicotine deliveries avoid these consequences and lead to increased 

tolerance and addiction. The low levels of nicotine delivery in starter brands, such as Skoal 

Bandits, allow the new user to develop a tolerance to nicotine1026 without nausea and other 

adverse reactions. Once this tolerance is developed, the high levels of nicotine delivery in 

brands such as Copenhagen provide the experienced user with the desired increase in nicotine 

dose. Nicotine addiction is the final result. 

There are several techniques the smokeless manufacturers use to achieve control over 

pH levels in smokeless tobacco. According to one report, pH adjustment is "done through 

fermentation, by adding alkaline buffering agents such as sodium carbonate and ammonium 

carlxmate, or by altering the moisture content."1027 The Swedish Tobacco Company, which 

like Pinkerton Tobacco Company is owned by Procordia AB, has admitted that "[i]n order to 

release the nicotine from the tobacco, the snuff is made slightly alkaline-sodium carbonate 

is added ... . " 1028 The Smokeless Tobacco Council has also reported that two alkaline 

102s Surgeon General's Report, 1988, at 44-45. See AR (VoL 129 Ref. 1592). 

1026 Connolly GN, Orleans Cf, Blum A, Snuffmg tobacco out of sport, American Journal of Public Health 

Mar. 1992;82(3):352. See AR (VoL 94 Ref. 629). 

1027 Connolly GN, Marketing of Nicotine Addiction By One Oral Snuff Manufacturer, Tobacco Control 

1995;4:73-79, at 74. See AR (Vol. 528 Ref. 97, appendix 9). 

1028 Swedish Tobacco Company, Smokeless Tobacco from Gothenburg, 1994, appendix B, quoted in 

statement of Gregory N. Connolly in Health Effects of Smokeless Tobacco: Hearings Before the 

Subcommittee on Health and the Environment of the Committee on Energy and Commerce, U.S. House of 

Representatives, 103d Cong., 2d Sess. 53 (Nov. 29, 1994) (emphasis added). See AR (VoL 710 Ref. 4). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45115

II.D.2. 

buffering agents, sodium carbonate and ammonium carbonate, are used in smokeless 

tobacco sold in the U.S. 1029 

Despite this evidence, the smokeless tobacco industry argues that the pattern of pH 

values in smokeless tobacco is not the result of intentional nicotine manipulation. The 

Agency disagrees. The pH values in the upper ranges seen in marketed smokeless tobacco 

for established users do not occur naturally in the tobacco used for the production of 

smokeless tobacco. Jack Benningfield, chief, clinical pharmacology branch of the Addiction 

Research Center at the National Institute on Drug Abuse, testified before Congress: 

Naturally occurring tobacco ... does not occur, at least in these kinds 

of tobaccos, at the high pH levels that we observed. Nonnal 

fennentation processes typically result in acidification, as anyone has 

found when they saw their wine turn into vinegar. But here we see 

very high [alkaline] pH levels in some of the products.1030 

Moreover, other product features reflect a consistent attempt to market products that 

deliver smaller amounts of nicotine to new users and products that deliver larger amounts to 

established users. For example, UST's Skoal Bandits and Pinkerton's starter product, 

Renegades, are packaged in teabag-like pouches, which both contain a much smaller amount 

of snuff (about 0.5g) than the usual standard size "pinch" of snuff (about 1.5g). The pouch 

system also delays the release of nicotine from the snuff.1031 Thus, FDA data show that, 

1029 Letter to Waxman HA and Bliley, Jr. TJ (U. S. House of Representatives) from Pape SM (Patton, Boggs 

& Blow) (May 3, 1994), with enclosure Ingredients Added to Tobacco in the Manufacture ofSnwkeless 

Tobacco Products as of Apri/4, 1994. See AR (Vol 192 Ref. 2173). 

1030 Health Effects of Snwkeless Tobacco: Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 103d Cong., 2d 

Sess. 98 (Nov. 29, 1994) (statement of Jack Henningfield). See AR (Vol 710 Ref. 4). 

1031 Memorandum from Ciolino L, Moist Snuff Nicotine Release Studies (Sep. 28, 1994), at 1. See AR (Vol. 

30 Ref. 500-2). 

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45116 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

ll.D.2. 

under typical use conditions, a standard size "pinch" of Copenhagen releases 12 times as 

much nicotine in the first 2 minutes as a pouch of Bandits. 1032 

The evidence thus demonstrates that smokeless tobacco manufacturers intentionally 

manipulate the pH levels of smokeless tobacco, thereby controlling and adjusting the level of 

nicotine delivered to consumers. Products intended for new users have uniformly lower 

levels of pH and nicotine delivery than products intended for experienced users. The effect is 

to promote nicotine tolerance and addiction in users of smokeless tobacco. 

b. Evidence that Teenage Users Graduate from Smokeless Tobacco with 

Low Nicotine Deliveries to Products with High Nicotine Deliveries 

Data on teenage use of smokeless tobacco shows that the manufacturers' graduated 

nicotine deliveries have increased addiction to smokeless tobacco among young people. 

These data show that: (I) children and adolescents begin smokeless tobacco use with low 

nicotine delivery starter products and then switch to products with higher nicotine deliveries; 

and (2) the number of children and adolescents addicted to smokeless tobacco has risen 

substantially since the introduction of smokeless tobacco products with graduated nicotine 

deliveries. 

Before the introduction of starter brands with low levels of nicotine in the early 

1970's, virtually no teenagers and young adults used smokeless tobacco. According to the 

Centers for Disease Control and Prevention (CDC), "[i]n 1970, the use of smokeless tobacco 

1032 Id. at 2. See AR (Vol30 Ref. 500-2). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45117

II.D.2. 

was a behavior primarily restricted to older men."1033 In that year, only 2.2% of young males 

used smokeless tobacco, compared with 12.7% of males age 65 or older. 1034 

In the 1970's, however, smokeless tobacco manufacturers began t0 market lownicotine "starter'' products.1035 These products have proven extremely successful in 

atttacting young new users. Use by adolescent males aged 18 to 19 has increased 

approximately 1,500% between 1971 and 1991.1036 Overall, use of smokeless tobacco almost 

tripled between 1970 and 1991.1037 As discussed in section II.B.2., above, it has been 

estimated that approximately 75% of the regular young users of smokeless tobacco are 

addicted to nicotine. 

Although the majority of the industry's advertising dollars are spent on promoting 

low- and medium-nicotine brands,1038 these brands serve mainly as a stepping stone to the 

high-nicotine delivery products. Most of the increased sales of smokeless tobacco are sales 

of high-nicotine delivery brands, like Copenhagen.1039 

1033 Health Effects of Smokeless Tobacco: Hearings Before the Subcommittee on Health and the 

Environment of the Committee on Energy and Commerce, U.S. House of Representatives, 103d Cong., 2d 

Sess. 34 (Nov. 29, 1994) (statement of Michael P. Eriksen). See AR (VoL 710 Ref. 4). 

1034 /d. 

1035 Connolly GN, In the search for a perfect starter product: manipulation of nicotine in oral snuff brands 

(1994) (unpublished), at 3-4. See AR (VoL 30 Ref. 511). 

1036 Centers for Disease Control and Prevention, Office of Smoking and Health, unpublished data from 1970 

and 1991 National Household Interview Surveys (rate of snuff use among 18-19 year-old males was 0.5% in 

1970 and 7.6% in 1991). See AR (VoL 31 Ref. 521-1). 

1037 /d. 

1038 Connolly GN, In the search for a perfect starter product: manipulation of nicotine in oral snuff brands 

(1994) (unpublished), at 5. See AR (VoL 30 Ref. 511). 

1039 /d. at 6. 

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45118 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.D.2. 

A study by CDC confirms the role of low-nicotine delivery brands as starter products. 

The study analyzes data from CDC's 1993 Teenage Attitudes and Practices Survey (TAPS) 

and from a follow-up study to the 1989 TAPS!040 The authors found that the percentage of 

beginning teenage snuff users who bought Skoal Bandits (low nicotine delivery) and Skoal 

(medium nicotine delivery) was higher than the percentage of experienced teenage snuff users 

who bought these products. 1041 Similarly, the proportion of teenage snuff users who chose 

Copenhagen (high nicotine delivery) was about three times higher among those who used 

snuff for 4 years or more than among those who used snuff for 1 year or less!042 Use of 

Copenhagen was also higher among those who used smokeless tobacco more frequently and 

with increased intensity. 1043 The study also included an analysis that found that of those who 

used Skoal Bandits or Skoal at the beginning ofthe study, nearly a third had switched to 

Copenhagen 4 years later.1044 However, among those who used Copenhagen at the beginning 

of the study, 83% were still using it 4 years later. Thus, teenage moist snuff users were 

significantly more likely to graduate to a higher nicotine delivery product than to switch 

down to a lower nicotine delivery product. 1045 

The CDC report concluded that these fmdings "support the hypothesis that snuff 

users in earlier stages of tobacco use and nicotine addiction, use brands with low levels of 

1040 Tomar S, Giovino G, Eriksen M, Smokeless tobacco brand preference and switching among U.S. 

adolescents and young adults, Tobacco Control1995;4:61-12. See AR (Vol. 528 Ref. 97, appendix 9). 

1041 /d. at 69. 

1042 ld. at 71. 

1043 /d. 

1044 [d. 

104S /d. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45119

II.D.2. 

free nicotine, and then 'graduate' to brands with high levels."1046 The report further stated 

that "[t]his pattern of brand preference probably reflects a progression of nicotine addiction 

and the need to increase nicotine intake to maintain the same physiological and psychological 

effects (chronic tolerance)."1047 

More frequent smokeless tobacco use, and use of products with higher amounts of 

free nicotine, result in greater difficulty in quitting, which is one of the characteristic features 

of addiction. See section II.A.3.b., above. CDC has found that 74% of young people who 

use smokeless tobacco daily report that "it's really hard to quit," compared with only 11% of 

those who use smokeless tobacco infrequently.1048 When CDC evaluated the data by brand, 

it found that, of young people who used smokeless tobacco only infrequently, 22% of 

infrequent Copenhagen users reported that it was very difficult to quit, compared with only 

7% of infrequent Skoal or Skoal Bandits users. 1049 

Thus, empirical evidence indicates that the manufacturers' manipulation of nicotine 

deliveries has led to increased tolerance and addiction to nicotine among young smokeless 

tobacco users. Combined with the evidence of the manufacturers' understanding of the 

pharmacological effects of nicotine, and the laboratory evidence of graduated nicotine 

deliveries, this evidence shows that (1) the manufacturers manipulate nicotine in a manner 

that encourages new users to become tolerant and addicted to nicotine; and (2) there has 

1046 Id. at 72. 

1047 ld. at 71. 

1048 Health Effects of Smnkeless Tobacco: Hearings Before the Subcommittee on Health and the Environment 

of the Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Cong., 2d Sess. 40 

(Nov. 29, 1994) (statement of Michael P. Eriksen). See AR (Vol. 710 Ref. 4). 

1049 ld. 

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45120 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.D.2. 

been a significant increase in smokeless tobacco use and nicotine tolerance and addiction 

among young smokeless tobacco users since the manufacturers began manipulating nicotine 

deliveries. This evidence provides a sufficient basis for the Agency's conclusion that the 

manufacturers intend to affect the structure and function of the body. 

c. Documentary Evidence of UST's Deliberate "Graduation Process" 

Although further evidence is unnecessary to establish that smokeless tobacco is 

intended to affect the structure and function of the body, evidence from the major moist snuff 

producer, UST, provides striking confirmation of an intentional plan to cause tolerance and 

addiction in users of smokeless tobacco. This evidence shows that UST intentionally 

manufactures products that deliver low, medium, and high amounts of nicotine; markets the 

lower nicotine delivery products to new users; and encourages established users to select 

higher nicotine delivery products. UST documents explicitly describe the company's strategy 

as a "graduation process," which the company exploits through marketing and advertising 

techniques. 

UST's development of products offering graduated nicotine deliveries began in the 

late 1960's or early 1970's. The company initiated the "Lotus Project." A 1972 

memorandum describing the project states that the "aim" was "[t]o make it easier for a new 

user to use tobacco in the mouth"; that the "target group" was "[n]ew users ... age group 

15-35"; and that the "product" should provide "[n]icotine satisfaction" that was "[m]ild" and 

"[i]nstant but not shocking."1050 In another document discussing the Lotus Project, the 

president of UST s foreign subsidiary, United Scandia International, wrote to the president of 

UST to describe the graduated nicotine deliveries that should be offered: 

1050 The Lotus Project, from Marsee v. U.S. Tobacco, trial exhibit 159. See AR (Vol 30 Ref. 505-3). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45121

There should be three products of three different tastes and strengths 

of nicotine. 

a. High nicotine, strong tobacco flavor ... 

b. Medium strength of nicotine ... 

c. ww nicotine, sweet product. 1051 

II.D.2. 

Shortly after these Lotus Project documents were written, UST began aggressively to 

market low-nicotine starter products to new users. An advertisement for "Happy Days," one 

of the first low-nicotine products, targeted the product "for You Guys Just Starting Out."1052 

In addition, UST's low-nicotine delivery products were marketed as starter products through 

free sampling on college campuses and at sports events.1053 

A brochure for Skoal Bandits contained instructions on how to use the products, a 

marketing approach tailored to the new user.1054 In contrast, advertisements for UST's highnicotine delivery product, Copenhagen, do not contain instructions or suggestions that they 

be tried by new users. Rather, Copenhagen's advertisements emphasize "satisfaction," an 

implied drug claim. See section II.E.2., below. They also seem to encourage graduation, 

using the slogan "Sooner or Later, It's Copenhagen."1055 

tost Inttacompany correspondence from Watson WW, president, United Scandia Internationals, to Bantle LA, 

president, U.S. Tobacco Company (JUD. 2, 1972) at 2, from Marsee v. U.S. Tobacco, trial exhibit 158 

(emphasis added). See AR (Vol 30 Ref. 505-2). 

tOSl Connolly GN, In search for a perfect starter product: manipulation of nicotine in oral snuff brands 

(1994) (unpublished). See AR (Vol30 Ref. 511). 

10s

3 U.S. Tobacco Company, College Representative Manual, Introduction (Jul. 31, 1985). See AR (VoL 30 

Ref. 512). 

Health Effects of Smokeless Tobacco: Hearings Before the Subcommittee on Health and the Environment of 

the Committee on Energy and Commerce, U.S. House of Representatives, 103d Cong., 2d Sess. 108 (Nov. 29, 

1994). See AR (VoL 710 Ref. 4). 

1054 Connolly GN. In search for a perfect starter product: manipulation of nicotine in oral snuff brands 

(1994) (unpublished), at 5. See AR(Vol. 30 Ref. 511). 

lOSS /d. 

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45122 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.D.2. 

In its comment, UST denies that it ever used a graduation strategy. However, 

documents presented to a congressional subcommittee in 1994, and other evidence, indicate 

that by the 1980's senior USTofficials were explicitly describing their marketing approach as 

a "graduation process." For example: 

• An executive vice-president of UST stated in a 1986 interview published in a UST 

newsletter: 

for each market there is a set of criteria which have been established, 

and must be met. Skoal Bandits is the introductory product, and then 

we look towards establishing a normal graduation process. 1056 

• Similarly, Ken Carlsen, a division manager in UST's sales department from 1979 to 1986, 

stated in an interview in the Wall Street Journal: 

They talked about graduation all the time-in sales meetings, memos 

and manuals for the college program. It was a mantra. 1057 

There are numerous other statements in the record from UST officials that refer expressly to 

UST's "graduation process."1058 Indeed, two UST documents illustrate the company's 

1056 Interview of Jack Africk, executive vice president of U.S. Tobacco Company and president of the 

international division, Up to Snuff, 1986, at 2 (emphasis added). See AR (Vol 196 Ref. 2496). 

1057 Freedman AM, Juiced up: how a tobacco giant doctors snuff brands to boost their "kick," Wall Street 

Journal, Oct 26, 1994 (emphasis added). See AR (Vol 20 Ref. 201). 

1058 See UST statements on nicotine manipulation, use of starter brands and graduation strategy, as cited in 

statement of Gregory N. Connolly in Health Effects of Smokeless Tobacco: Hearings Before the 

Subcommittee on Health and the Environment of the Committee on Energy and Commerce, U.S. House of 

Representatives, 103d Cong., 2d Sess. 58-64 (Nov. 29, 1994). See AR (Vol. 710 Ref. 4). These statements 

include the following: 

"For people who haven't tasted (snufi) you'd of conrse begin them on a product 

that had a little tobacco taste, but wouldn't tum them off .... The graduation is to 

a more tobacco-y product ..• to a stronger product(s)." Source: Barry Nova, 

former president, U.S. Tobacco Company, WaU Street Journal, Oct 26, 1994 

(emphasis added). 

"Product Graduation Process . ... The Smokeless Consumer Marketing 

Representative must be aware of the importance of developing new users on a 

continuing basis and the importance of developing basis and the graduation 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45123

11.0.2. 

strategy graphically. The first, a chart depicting a "graduation process," displays a hierarchy 

of UST products. 1059 Arrows labeled "graduation process" represent the progression 

envisioned in this process, from the starter products, Skoal Bandits, at the bottom, past Skoal 

Long Cuts, which delivers an intermediate level of nicotine, to Copenhagen at the top of the 

chart. 

The second document, another chart, depicts the graduation process as a bullseye. 1060 

"Prospective new users" is printed just outside the outermost ring of the chart, "Bandits" is 

printed in the outer ring, "Long Cut" and "Skoal'' are printed in successive inner rings, and 

"Cope" is printed in the bullseye. The rings of the chart thus progress from the lowest 

nicotine delivery products on the outside to the highest nicotine delivery products in the 

center of the bullseye. Marketing strategies for each circle are listed outside the bullseye and 

further demonstrate the company's intention to sell low-nicotine delivery products to new 

sampling brands and competitive brands." Source: U.S. Tobacco Company 

Document no. 2215172, Marsee Court Transcript at 114, vol. 4, read into the 

record by Mr. Braly (emphasis added). 

"Sampling Skoal Bandits often and intensively in and around the retail account 

.... create[s] new customers and feed[s] the graduation process." Source: U.S. 

Tobacco Company Document no. 2101576, Marsee Court Transcript at 115, vol. 4, 

read into the record by Mr. Braly (emphasis added). 

Skoal Bandits "will continue to fuel the new user base to assure graduation to our 

priority moist brands." Source: U.S. Tobacco Company Document no. 2077832, 

Marsee Court Transcript at 112, vol. 4, read into the record by Mr. Braly 

(emphasis added). 

"This brand (Happy Days) has been clearly positioned as a starter product." 

Source: U.S.Tobacco Document no. 2143461, Marsee Court Transcript at 114, vol. 

4, read into the record by Mr. Braly (emphasis added). 

1059 Health Effects of Smokeless Tobacco: Hearings Before the Subcommittee on Health and the Environment 

of the Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Cong., 2d Sess. 62 

(Nov. 29, 1994). See AR(Vol 710Ref. 4). 

1060 /d. at 101. 

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45124 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.D.2. 

users and high-nicotine delivery products to established users. For example, "mass" free 

sampling is planned for Bandits, "quality 1 on 1" sampling for Skoal Long Cut, and no 

sampling for Copenhagen. Similarly, while "mass" advertising is planned for Bandits, only 

''focused" advertising to "[r]einforce image among current users" is planned for Copenhagen. 

And while public relations efforts for Bandits and Long Cut are to be "[e]ducational," public 

relations efforts for Skoal and Copenhagen are to "[e]mphasize tradition and heritage."1061 

The UST documents show further that the company's manipulation of nicotine was 

deliberate. A senior vice president for marketing at UST, for example, has conceded that one 

UST product under development in the early 1980's was intended to deliver less nicotine by 

design by lowering pH.1062 

These UST documents provide persuasive confirmation that UST produces smokeless 

tobacco brands with a range of nicotine deliveries in order to allow users to progress from 

low-nicotine delivery products to high-nicotine delivery products. Low-nicotine delivery 

products, which avoid overdosing new users who have not yet developed a tolerance to 

nicotine, are deliberately marketed to "you guys just starting out." Once these new users 

develop a tolerance to nicotine, UST provides them with high-nicotine delivery products that 

1061 U.S. Tobacco Company, Expanding User Base (undated). This document was disclosed during discovery 

in Marsee v. U.S. Tobacco. See AR (Vol 30 Ref. 518) 

1062 The exchange from the Marsee trial transcript on this point was: 

Q: So this Red Seal menthol product was intended to deliver less nicotine by 

design by lowering the pH; is that correct? 

A: That is correcL 

Deposition of Erik Lindqvist, transcript of jury trial proceedings at 1668 Marsee v. U.S. Tobacco, Civil 

Action No. 84-2777R (W.D. Ok. 1986) (emphasis added). See AR (VoL 22 Ref. 292). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45125

II.D.3. 

satisfy their addiction to nicotine. This is strong evidence that smokeless tobacco is intended 

to affect the structure and function of the body. 

3. Conclusion 

After careful consideration of the evidence in the administrative record and the 

comments on the Jurisdictional Analysis, the Agency finds that smokeless tobacco 

manufacturers intend that their products cause significant pharmacological effects in 

smokeless tobacco users. The Agency bases this finding primarily on two grounds. 

First, the evidence shows that smokeless tobacco manufacturers understand that 

nicotine, one of the principal ingredients in smokeless tobacco, has pharmacological effects 

and uses, including causing and sustaining addiction. 

Second, the evidence shows that the major smokeless tobacco manufacturers carefully 

manipulate the delivery of this pharmacologically active and addictive drug in a manner that 

promotes tolerance and addiction. Specifically, they manufacture low-nicotine delivery 

products for new users, who have not yet developed a tolerance to nicotine, and highnicotine delivery products for experienced users, who need higher nicotine doses to sustain 

their addiction. In the case of UST, the company's internal documents explicitly 

acknowledge this "graduation process." The effect of this nicotine manipulation has been to 

increase addiction to smokeless tobacco among young people. 

Based on the cumulative evidence, the Agency fmds that smokeless tobacco 

manufacturers intend to market smokeless tobacco that produces tolerance and addiction in 

smokeless tobacco users. The Agency therefore concludes that smokeless tobacco is 

intended to affect the structure and function of the body within the meaning of the Federal 

Food, Drug, and Cosmetic Act. 

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45126 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

11.0.4. 

4. Response to Comments 

a. Comments on pH Manipulation 

Comments submitted by the smokeless tobacco industry challenge the Agency's 

assertion that manufacturers produce graduated nicotine deliveries in their products primarily 

by manipulating the pH of the tobacco. The comments claim that the Agency presented no 

evidence of pH manipulation, that pH is not a determinant of nicotine absorption, that other 

factors determine nicotine absorption, and that FDA's data shows that smokeless tobacco has 

a low capacity to alter salivary pH, negating the possibility that the tobacco pH is relevant to 

absorption. None of these comments, however, present a persuasive rebuttal to the Agency's 

analysis. 

1. The smokeless tobacco industry comments contend that the data presented by 

the Agency demonstrate that pH levels vary widely within products and little across product 

lines, making implausible the claim that companies manipulate and control pH as a way of 

controlling nicotine delivery from smokeless tobacco. Specifically, regarding the FDA 

laboratory data, one comment questions FDA's assertion that smokeless tobacco 

manufacturers control the delivery of nicotine, as measured by free nicotine calculations 

based on smokeless tobacco pH, when those values can vary up to 300% for the same 

product. 

The Agency disagrees with this comment. Review of the data presented by four 

laboratories (two FDA laboratories, the laboratory of the National Institute for Drug Abuse 

(NIDA), and the laboratory of the American Health Foundation) shows that despite some 

variation within product brands, there is a remarkably consistent pattern of pH manipulation 

across product lines. For example, all of the laboratories found that for UST products, 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45127

II.D.4. 

Copenhagen has the highest average pH, the Long Cut brands have intermediate pH's, and 

most flavors of Skoal Bandits have the lowest average pH's. The FDA laboratories and the 

American Health Foundation laboratory found that Con wood's starter product (Hawken) had 

pH levels less than 6, while its product for experienced users (Kodiak Wintergreen) had pH 

levels greater than 8. FDA also examined various products of Swisher International and 

found the same pattern of pH and nicotine dose graduation. 

FDA agrees that there is some variation within products, in part due to storage 

conditions and storage duration. The fact that there is variation within products may also 

reflect the natural variation one would expect in an organic product that is marketed in a 

biologically active state. For example, processes occur during the shelf life of the product 

that could alter pH over time.1063 Nonetheless, the evidence demonstrates that there is a 

consistent pattern in which products marketed as "starter products" are substantially lower in 

pH than are products marketed to experienced users. 

There is no basis in the administrative record to conclude that these patterns of pH 

graduation could occur naturally or would be induced by the manufacturer for any reason 

other than to alter nicotine delivery. The high pH levels observed in the moist snuff products 

with high nicotine deliveries does not occur naturally.1064 

2. Smokeless tobacco industry comments state that FDA relies upon laboratory 

(in vitro) pH data, which the comments claim are not relevant to consumer (in vivo) 

1063 Djordjevic MV, Hoffman D, Glynn T, et al., US commercial brands of moist snuff, 1994, assessment of 

nicotine, moisture, and pH, Tobacco Control1995;4:62-66, at 63-64. See AR (Vol 528 Ref. 97, appendix 9). 

1064 Health Effects of Smokeless Tobacco: Hearings Before the Subcommittee on Health and the Environment 

of the Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Cong., 2d Sess. 98 

(Nov. 29, 1994) (testimony of Jack Benningfield). See AR (Vol 710 Ref. 4). 

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45128 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.D.4. 

absorption of nicotine from smokeless tobacco. Specifically, these comments state that the 

Agency failed to present any data demonstrating a connection between smokeless tobacco 

pH, measured in vitro, and the actual rate and extent of nicotine absorbed in smokeless 

tobacco users. 

FDA disagrees that in vitro data on smokeless tobacco pH are irrelevant to nicotine 

absorption in humans. Basic scientific principles, experience with nicotine gum and patches, 

and FDA laboratory data, demonstrate that the effect of increasing pH is to increase the 

amount of free nicotine available for absorption. 

As described in section ll.D.2.a., above, it is well established that the absorption of 

drugs into the bloodstream can be increased by adjusting pH levels, and that increasing the 

pH of nicotine converts nicotine salts into free nicotine, rendering it significantly more 

absorbable. Researchers funded by the tobacco industry have confirmed this point, stating 

that nicotine absorption in the mouth increases as a function of pH and that ''the 

pharmacological response is clearly dependent on the amount of nicotine in the mouth as 

free base."1065 

The nicotine polacrilex gum (Nicorette ), which is approved for treatment of nicotine 

addiction by providing relief from withdrawal symptoms, provides further evidence of the 

relationship between pH and nicotine absorption. The gum is formulated to provide a pH of 

approximately 8, and the nicotine in the gum is well-absorbed at this pH. Versions of the 

nicotine gum that had lower pH levels, however, provided insufficient nicotine absorption.1066 

1065 Armitage AK, Turner DM, Absorption of nicotine in cigarette and cigar smoke through the oral mucosa, 

Nature 1970;226:1231-1232. See AR(Vol 143 Ref. 1810). 

1066 Henningfield JE, Radzius A, Cooper TM, et al., Drinking coffee and carbonated beverages blocks 

absorption of nicotine from nicotine polacrilex gum, Journal of the American Medical Association 1990; 

264:1560-1564. See AR(Vol 29 Ref. 491-2). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45129

II.D.4. 

One of the principal effects of pH adjustment is to alter the rate of drug delivery to 

the target receptors in the body. The rate of drug delivery is well known to affect a wide 

range of pharmacological effects for numerous drug products. For example, a slow rate of 

absorption is the critical reason that nicotine patches do not produce mood-altering 

effects.1067 These effects occur only when nicotine is absorbed quickly into the body. 

FDA conducted tests to assess the speed of nicotine transfer across the membranes 

using smokeless tobacco with different pH levels. The results showed that, consistent with 

scientific theory, pH levels affected nicotine transfer: nicotine from the high-pH product was 

transferred across membranes more quickly than was nicotine from the low-pH product. In 

fact, in the first 2 minutes, the amount of nicotine released from a typical size pinch of 

Copenhagen, a product with a high pH, was 12 times higher than the amount of nicotine 

released from a Skoal Bandit pouch, a product with a low pH.1068 

For these reasons, FDA fmds that there is an adequate scientific basis to conclude that 

in vitro pH values predict changes in nicotine delivery. 

3. One smokeless tobacco industry comment presents a study performed by 

Andersson, 1069 which it claims refutes FDA's reliance on in vitro pH data. The comment 

states that the Andersson study demonstrated higher levels of nicotine in users of lower pH 

chewing tobacco than in users of higher pH moist snuff. According to the comment, 

1067 Benowitz NL, Pharmacodynamics of nicotine: implications for rational treatment of nicotine addiction, 

British Journal of Addiction 1991;86:495-499, at 496. See AR (Vol 71 Ref. 52). 

1068 See Ciolino L, Moist Snuff Nicotine Release Studies (Sep. 28, 1994), at 2. See AR (Vol 30 Ref. 500-2). 

1069 Andersson G, Bjomberg G, Curvall M, Oral mucosal changes and nicotine disposition in users of 

Swedish smokeless tobacco products: a comparative study, J Oral Pathol Med 1994:161-167. See AR (Vol. 

526 Ref. 95, vol. VII). 

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45130 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

11.0.4. 

Andersson's data demonstrate that the smokeless tobacco product with the highest pH (8.5 

to 8.6) had the poorest buccal absorption of nicotine. The comment argues that these data 

support the contention that smokeless tobacco pH is irrelevant to nicotine absorption in the 

smokeless tobacco user. 

FDA disagrees with this comment In fact, the Andersson study found that the degree 

of nicotine extraction was "significantly higher'' among users of loose moist snuff than among 

users of moist snuff in pouches.1070 This fmding is consistent with FDA's analysis, because 

the loose moist snuff had a higher pH than the moist snuff in pouches.1071 

Moreover, the comment mischaracterizes the Andersson findings in other ways as 

well. First, the study did not compare absorption characteristics on a gram-for-gram basis 

across products differing in pH. For example, the smokeless tobacco product with the 

highest absorption, a type of chewing tobacco, had over twice as much nicotine in it as any of 

the moist snuff products used in this study and subjects in the study used varying amounts of 

smokeless tobacco. Thus, nicotine absorption in the study could have been affected by the 

uncontrolled variation in the amount of nicotine consumed, confounding the effects of pH on 

nicotine absorption. 

Second, the study measured nicotine blood levels at only one time point, which is 

inadequate to determine nicotine absorption (rate or extent). Third, the authors did not claim 

that the study demonstrated anything about the effects of pH on absorption. 

1070 Id. at 164. 

1071 ld. 

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II.D.4. 

Thus, the Andersson study provides no support for the argument that in vitro data are 

inadequate to describe the amount of nicotine available for absorption. 

4. The comments from the smokeless tobacco industry state that a variety of 

biological and behavioral factors are stronger determinants of nicotine absorption than the pH 

of the product. The comments cite such factors as the length of time the smokeless tobacco 

is left in the mouth, the extent to which the smokeless tobacco is "worked" by the user, the 

rate and volume of expectorate, and the frequency and amount of swallowing, as well as 

salivary pH. 

FDA agrees that other factors can influence nicotine absorption besides pH levels. 

Moreover, some of these additional factors are within the control of the manufacturer, 

including the use of pouches for some products; additives, such as humectants; the cut of the 

tobacco; and the use of various binding agents. Nonetheless, the role of these other factors 

appears to be less significant. The UST report entitled "Pharmacokinetics of Nicotine and its 

Major Metabolites in Naive and Habituated Snuff Takers," for instance, concluded, that after 

using identical portions of snuff there "appears to be no differences" in plasma nicotine levels 

between inexperienced and experienced smokeless tobacco users.1072 One would expect 

many of the factors cited by the comment, including rate and volume of expectorating, and 

frequency and amount of swallowing, to differ between inexperienced and experienced users, 

but these differences apparently did not affect amount of nicotine absorption in the two 

groups. 

1072 U.S. Tobacco, Pharmacokinetics of Nicotine and its Major Metabolites in Naive and Habituated Snuff 

Takers, UST document from Marsee, plaintiffs exhibit 3.27 at 13. See AR (VoL 344 Ref. 5436). 

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II.D.4. 

Similarly, the final results from a preliminary study cited by the smokeless tobacco 

industry concluded that "buccal nicotine absorption was not affected by saliva discharge 

rate."1073 These results are similar to those of a companion study by Nemeth-Coslett et al., 

which studied the effect of the chewing rate on nicotine absorption from nicotine gum.1074 In 

another study by these researchers, pH was varied, producing a strong effect on nicotine 

absorption from nicotine gum. In this companion study, there was minimal absorption under 

acidic conditions and significant absorption under alkaline conditions.1075 Taken together, 

these studies show that the effects of pH on nicotine absorption are more significant than the 

effects of oral manipulation. 

Moreover, behavioral factors should have a minor impact when comparing the effect 

of a series of smokeless tobacco on a given user, because the habits of the user should be 

relatively constant. Therefore, for any individual smokeless tobacco user, a product line with 

graduated pH levels will produce graduated nicotine deliveries. 

In conclusion, although the Agency agrees that biological and behavioral factors can 

influence absorption of nicotine, the Agency fmds that product pH has an established and 

significant role in controlling the absorption of nicotine. 

5. A smokeless tobacco industry comment emphasizes the role of saliva and 

states that the pH levels of smokeless tobacco do not influence nicotine absorption. The 

1073 Cohen C, Radzius A. Simmons E, et al., Time course of buccal nicotine absorption (NIDA unpublished 

report. 1994) (emphasis added). See AR (Vol 711 Ref. 15). 

1074 Nemeth-Coslett R, Benowitz NL, Robinson N, et al., Nicotine gum: chew rate, subjective effects and 

plasma nicotine, Pharmacology, Biochemistry,&: Behavior 1988;29:747-751. See AR (Vol 711 Ref. 10). 

1075 Henningfield JE, Radzius A. Cooper TM, et al., Drinking coffee and carbonated beverages blocks 

absorption of nicotine from nicotine polacrilex gum, Journal of the American Medical Association 1990; 

264:1560-1564. See AR (Vo129 Ref. 491-2). 

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II.D.4. 

comment argues that FDA data show that the buffering capacity of saliva is greater than that 

of smokeless tobacco. Thus, according to the comment, when the smokeless tobacco and 

saliva mix in the mouth, the resultant pH of the mixture is determined by the saliva and not 

the tobacco. 

FDA disagrees with this comment. FDA assessed the buffering capacity of saliva in a 

report entitled "Relative Buffering Capacity of Saliva and Moist Snuff."1076 This study tested 

1-ml, 25-ml, 5-ml, and 10-ml volumes of saliva.1077 For each brand of smokeless tobacco 

tested, the product pH was measured and a l.Sg quantity of tobacco, representing a typical 

pinch, was selected. The effect of saliva volume on the resultant pH of saliva/moist snuff 

mixtures was then evaluated. Contrary to the comments of the smokeless tobacco 

manufacturers, the results of this study indicate that the saliva pH was altered by addition of 

the smokeless tobacco at all saliva volumes tested, demonstrating that product pH will 

influence the amount of free nicotine available for absorption. 

FDA's Artificial Saliva Study, which is cited by the comment, does not conflict with 

these results. As clearly stated in the FDA memorandum summarizing the study, the 

Artificial Saliva Study was designed to measure and compare the rate of nicotine release from 

smokeless tobacco. The study did not measure smokeless tobacco effects on the pH of the 

artificial saliva.1078 

1076 Memorandum from Ciolino L, Relative Buffering Capacity of Saliva and Moist Snuff. (Sep. 28, 1994). 

See AR (Vol 29 Ref. 499). 

1077 /d. at 2. 

1078 Memorandum from Ciolino L, Moist Snuff Nicotine Release Studies (Sep. 28, 1994), at table IV.B. 

See AR (Vol 30 Ref. 500-2). 

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II.D.4. 

Moreover, there are several reasons why the Artificial Saliva Study cannot be used to 

answer the question of whether saliva pH or product pH dominates in the absorption process 

for nicotine from smokeless tobacco. First, the experiments in the Artificial Saliva Study 

were conducted for all of the products using only 0.5g of smokeless tobacco. This amount 

(0.5g) was used because this is the net tobacco weight in the Skoal Bandits pouch and 

because the purpose of this study was to make a controlled comparison among products. As 

stated in the FDA memo, however, 1.5g of tobacco more closely represents a typical "pinch" 

for Copenhagen, as well as for Skoal Long Cut Wintergreen and Skoal Original Fine Cut 

Wintergreen.1079 Thus, the amount of product used in the experiments is three times lower 

than in typical use conditions for the latter three products, and certainly no conclusion can be 

drawn from this study as to whether salivary pH or product pH would dominate under typical 

use conditions. 

Second, the experiments in the Artificial Saliva Study were conducted using 10 ml of 

saliva. Although there is about 10 ml of saliva in the human mouth, the volume of saliva that 

contacts the plug of moist snuff when it is initially placed in the mouth and used as directed is 

much less than 10 ml. When used as directed by the manufacturers, moist snuff is intended to 

stay in one place in the mouth, limiting mixing with saliva. Its use does not require the active 

oral manipulation and accompanying salivary saturation of chewing tobacco products. A 

pinch or a pouch of moist snuff is a self-contained dosing unit that is wedged between the 

gum and cheek in such a manner that it would be relatively protected from rapid saturation 

by saliva. 

1079 ld. at 1. 

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11.0.4. 

Indeed, the industry's own instructions to users are to lodge the product between the 

cheek and gum to minimize such mixing or float. In direct marketing and advertising 

campaigns, new users are specifically instructed on how to use moist snuff products to 

minimize mixing with saliva. For example, in a UST advertisement entitled "Walt Garrison 

answers your questions about smokeless tobacco," the advertising copy states: "Just take a 

small pinch between your thumb and forefinger, put it between your cheek and gum, and 

leave it there. The tobacco will slowly release its great flavor to give you real tobacco 

satisfaction."1080 In another UST advertisement, the instructions are consistent: "How do I 

use Skoal Bandits? Simply take a pouch and place it between your upper lip and gum. Leave 

it there, but DON'T CHEW IT. The pouch works like a teabag, holding the tobacco in, but 

letting the flavour out."1081 These instructions to consumers minimize salivary mixing and 

oral dissolution of the products. The less saliva contacts the product, the more the product 

pH controls absorption. 

Third, the product pH's of the particular tins of smokeless tobacco used in the 

Artificial Saliva Study were not determined. Without knowing the product pH levels, the 

relative effects of saliva and product on the net solution pH after addition of the product 

cannot be evaluated. When discussing FDA's Artificial Saliva Study, the comment 

misrepresented pH levels that were measured as part of the Reproducibility Study portion of 

this work as the product pH levels. The measurements in the Reproducibility Study were 

made on different lots of smokeless tobacco than were used in the Artificial Saliva Study. 

1080 Ernster VL, Advertising and promotion of smokeless tobacco products, Monographs/National Cancer 

Institute 1989:87-94, at 90. See AR (Vol65 Ref. 853). 

1081 Advertisement: .. Introducing Skoal Bandits, The new way to enjoy tobacco." See AR (Vol 241 

Ref. 3260). 

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ll.D.4. 

The smokeless tobacco manufacturers themselves argue that there is lot-to-lot variability for 

product pH. Accordingly, the products' pH from the Reproducibility Study were not 

necessarily the same as the pH of the products tested in the Artificial Saliva Study. 

In conclusion, the comment mischaracterized the Agency's laboratory data and drew 

erroneous conclusions from the data presented. In fact, FDA's analyses shows that the pH of 

smokeless tobacco affects the pH levels of the saliva in contact with the smokeless tobacco, 

thereby controlling the level of nicotine absorption. 

6. One smokeless tobacco industry comment states that solids, such as tobacco, 

cannot have a pH value. 

Solid materials must mix with a liquid before the product's pH is measured. When 

using the terms "tobacco pH" or "product pH," the Agency and other laboratories that have 

conducted studies on smokeless tobacco pH are referring to the measured pH when the 

smokeless tobacco product is allowed to contact an aqueous environment such as water or 

saliva, as the product does when it is placed in the tobacco user's mouth. The studies on 

smokeless tobacco pH are designed to determine whether various brands of smokeless 

tobacco are designed, formulated, processed, or otherwise manipulated to control the pH of 

the product after contact with the aqueous environment in the user's mouth. 

7. Smokeless tobacco industry comments cite two reports written by Jeffrey R 

Idle criticizing smokeless tobacco pH studies and reports and FDA laboratory data. The 

comments also claim that Idle's analysis was sent to the Centers for Disease Control and 

Prevention (CDC) by the UST and was shared with "interested parties." The comments 

assume that CDC shared this analysis with FDA and question why the analysis is not in the 

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II.D.4. 

administrative record. Idle's analysis was not placed in the administrative record when the 

Jurisdictional Analysis was issued because the Agency was not aware of the document. 

The Agency has reviewed the memorandum of Jeffrey Idle to UST entitled "FDA 

Proposed Rule: FDA Memoranda," dated December 13, 1995, and relevant portions of 

Idle's memorandum to UST dated February 9, 1995.1082 For several reasons, some of which 

are described below, FDA concludes that Idle and the cornrnenters either misunderstood or 

mischaracterized FDA's results and analyses. Moreover, Idle's review selects certain data 

favorable to his position, while ignoring data contrary to his position. 

a. Idle's analysis asserts that FDA's reliance on the laboratory data showing 

graduated nicotine deliveries is not valid because the analytic methods used by the 

laboratories were not standardized. 

FDA acknowledges that the four laboratories involved conducted independent 

analyses, using slightly different methods, to compare the nicotine deliveries of various 

brands of smokeless tobacco. Nonetheless, all four laboratories found a remarkably similar 

trend of graduated nicotine delivery across product lines. Contrary to Idle's comment, the 

fact that different laboratories, using different methods, reach the same conclusion 

increases-rather than diminishes-the reliability of the conclusion. 

b. Idle's analysis asserts that the fact that a range of pH levels and free nicotine 

deliveries were observed for individual brands in the laboratory data shows that the 

manufacturers do not control pH or free nicotine. According to Idle's analysis, if pH levels 

1082 Memorandum from Idle JR to U.S. Tobacco Company (Dec. 13, 1995). See AR (Vol 529 Ref. 98, 

appendix 6). 

Statement of Jeffrey R Idle (Feb. 9, 1995). See AR (Vol. 526 Ref. 95, vol. VI). 

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II.D.4. 

and free nicotine delivery were controlled, the pH levels and free nicotine deliveries would 

never vary within a brand. 

FDA disagrees with this comment There are many explanations for the range of pH 

and free nicotine values observed within individual brands, including product fermentation 

during storage, natural variation in nicotine content and pH levels in tobacco leaves, and 

normal variation in laboratory analysis. Despite these variations, the data reveal a clear 

pattern of graduated pH levels and free nicotine delivery. It would have been surprising if no 

variations were measured by the laboratories. 

c. Idle's analysis states that the majority of nicotine in all tobacco products is 

trapped inside the leaf particles and that acidic (low pH) conditions, not alkali (high pH) 

conditions, are necessary to leach nicotine out of smokeless tobacco. These assertions, 

however, are contradicted by the evidence in the administrative record. As discussed above, 

studies by FDA and other researchers, including researchers funded by the smokeless tobacco 

manufacturers, provide direct evidence that the release and absorption of nicotine increases as 

pH levels increase. 

d. Idle's analysis states that the Skoal Long Cuts and Copenhagen are 

indistinguishable in terms of their nicotine content, rates of nicotine release, and pH levels. 

This assertion, however, is contradicted by the data measured in FDA laboratories. While the 

total nicotine content in Skoal Long Cuts and Copenhagen are similar, the products' pH and 

delivery of free nicotine differ substantially. For instance, FDA's data shows that Skoal Long 

Cut Cherry has a pH of 7.15 to 7.38 and a free nicotine delivery of 12.3% to 18.5%. These 

levels are substantially lower than Copenhagen, which has a pH of 7. 71 to 8.14 and a free 

nicotine delivery of 32.7% to 56.5%. See section II.D.2.a., above. 

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II.D.4. 

8. One comment states that there is no evidence in the administrative record that 

smokeless tobacco manufacturers add compounds for the purpose of affecting nicotine 

absorption into the bloodstream. 

The Agency disagrees with this comment As discussed in section II.D.2.a., above, 

there is substantial evidence in the record that the manufacturers add buffering agents to raise 

the pH levels in smokeless tobacco, which has the effect of increasing nicotine absorption. 

9. In the Jurisdictional Analysis, FDA reported that smokeless tobacco delivers 

nicotine at its most rapid rate within 5 minutes after placing the product in the mouth.1083 

Blood levels then continue to rise while the smokeless tobacco product is kept in the 

mouth.1084 One smokeless tobacco industry comment contends that this FDA finding is false 

and misleading. According to the comment, the Agency relied on in vitro data that do not 

purport to simulate bioavailability in users. In addition, the comment states that the Agency 

did not cite any evidentiary support for its statement that the bolus dose results in peak 

pharmacological concentrations in users, maintained by slow continued release of nicotine 

from the product. 

The Agency disagrees that its statement concerning the bolus dose of nicotine 

delivered by smokeless tobacco is false or misleading. The administrative record contains in 

vitro data demonstrating that when smokeless tobacco was placed in simulated saliva, a 

significant amount of nicotine was released from the products within the first 5 seconds.1085 

1083 Benowitz N, Porchet H, Sheiner L, et al., Nicotine absorption and cardiovascular effects with smokeless 

tobacco use: comparison with cigarettes and nicotine gum, Clinical Pharmacology and Therapeutics 

1988;44:23-28, at 25. See AR (Vol 12 Ref. 134). 

1084 Id. at 24, fig. 1. 

1085 Memorandum from Ciolino L, Moist Snuff Nicotine Release Studies (Sep. 28, 1994), at table IV. A See 

AR (Vol. 30 Ref. 500-2). 

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45140 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

ll.D.4. 

This study provides strong evidence that a significant amount of nicotine is available for 

absorption within the first 5 seconds of use. 

Additionally, the administrative record includes an in vivo pharmacokinetic study 

consistent with these in vitro results. This study concluded that rate of nicotine absorption 

peaks about 5 minutes after placing oral snuff and chewing tobacco in the mouth. 1086 

Thus, the Agency provided both in vivo and in vitro data independently 

demonstrating that peak pharmacologic concentrations of nicotine are delivered within 5 

minutes of placing smokeless tobacco in the mouth. The comment provided no evidence to 

rebut this conclusion. 

b. Comments on the Graduation Process 

I. Two smokeless tobacco industry comments contend that persuasive evidence 

of a graduation process would have come from a survey of smokeless tobacco users showing 

that switching is unidirectional (i.e., that when a user switches, he always switches from a 

pouch to a loose tobacco product and from a lower to a higher pH product), but that FDA 

failed to present such evidence. The comments claim that consumer demographic data 

demonstrate that there is "significant brand loyalty" and that many smokeless tobacco users 

stay with the brand they first choose. Furthermore, the comments claim that any switching 

that does occur does not indicate any patterns, and that social and other factors cause 

smokeless tobacco users to choose their own brands. 

1086 Benowitz N, Porchet H, Sheiner L, et al., Nicotine absorption and cardiovascular effects with smokeless 

tobacco use: comparison with cigarettes and nicotine gum, Clinical Pharmacology and Therapeutics 

1988;44:23-28, at 26. See AR (VoL 12 Ref. 134). 

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11.0.4. 

Contrary to the comments, the evidence in the record does in fact demonstrate a clear 

pattern of switching from brands of smokeless tobacco that deliver low levels of nicotine to 

brands that deliver higher levels of nicotine. As discussed in section II.D.2., above, an 

analysis of data from CDC's 1993 Teenage Attitudes and Practices Survey (TAPS) and a 

follow-up study from the 1989 TAPS shows that most brand switching involves switching 

from products with low nicotine delivery to products with higher nicotine delivery. 

The comments do not provide data or any other documentation to the Agency to 

support the claim that there is no pattern to brand switching. Without any such evidence to 

support its claim, the smokeless tobacco industry has not provided an adequate basis to rebut 

the Agency's fmdings. 

2. UST denies that it uses a graduation strategy in the manufacture and 

marketing of its products. Specifically, the UST comment states: 

As best as U.S. Tobacco can now determine, the term "graduation 

process" as used in the early 1980s (1) did not relate to increasing 

levels of nicotine and pH; (2) did not drive the company's marketing 

strategies; and (3) is contradicted by consumer behavior in the 

marketplace. 1087 

The Agency does not fmd UST's position to be credible. Contrary to UST's 

assertions, its products do deliver graduated levels of nicotine, see section ll.D.2.a., above; 

UST's marketing strategies do target low-nicotine products for new users and high-nicotine 

products for experienced users, see section II.D.2.c., above; and consumers do shift from 

low-nicotine products to high-nicotine products. See section ll.D.2.b., above. Moreover, 

senior UST officials, including the president of UST, and other UST documents do use the 

1087 U.S. Tobacco Company, Comment (Jan. 2, 1996), at32. See AR (Vol529 Ref. 98). 

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II.D.4. 

phrase "graduation process" to describe USTs marketing approach. See section 

II.D.2.c., above. 

3. UST alleges that FDA's reliance on various UST documents and statements 

made by UST executives is ill-founded. UST claims that, among other things, the Agency 

took statements out of context; the statements were not representative of UST s position; 

and the Agency improperly relied on statements, documents, and offers of proof from the 

plaintiff's attorneys in a product liability suit. 

The Agency believes that all of the documents and statements speak for themselves 

and fully support the position taken in the Jurisdictional Analysis. A summary of those 

comments and the Agency's response follows: 

a. In the Jurisdictional Analysis, the Agency referred to several statements made 

by a UST senior vice-president for marketing which demonstrate that UST understands the 

relationship between the pH of its products and nicotine delivery. UST states that the 

Agency mischaracterized the comments and failed to mention that the marketing executive 

disclaimed his expertise with respect to pH and nicotine in a prior exchange within the cited 

deposition. 

While the Agency did not mention the prior exchange in the Jurisdictional Analysis, 

this omission does not affect the meaning of the relevant passages. As the record shows, this 

senior vice-president for marketing acknowledged his understanding that as the pH of the 

smokeless tobacco product is lowered, the rate of nicotine absorption by the user is also 

lowered: 

Q. Mr. Lindqvist, is it your understanding that as the pH of the product is 

lowered, that the rate of absorption of nicotine by the user is also lowered? 

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11.0.4. 

A. That would be my understanding, yes. 1088 

The record also shows that this senior vice president participated in discussions with other 

senior level executives within the company about product development and specifically made 

suggestions for pH levels for those products that reflect his knowledge of the relationship of 

pH to the nicotine strength of the product. For instance, in discussing the specifications for a 

"premium project," he recommended that UST set "pH at the level of Copenhagen or 

higher."1089 These statements demonstrate knowledge of the relationship of pH and 

nicotine delivery. 

b. In the Jurisdictional Analysis and in section ll.D.2.c., above, the Agency cites 

several UST documents that referred to the "Lotus Project." These documents disclosed the 

company's intent to produce products with varying amounts of nicotine and to develop a low 

nicotine product especially for new users. UST states that some of the comments referred to 

were just "one individual's preliminary thoughts"1090 about a low-nicotine product. Further, 

UST states that the Lotus Project documents refer to a Swedish marketing campaign by a 

foreign smokeless tobacco manufacturer, not a project planned for the United States or any 

other market by U.S. Tobacco. 

The UST documents in question speak for themselves. The "one individual's 

preliminary thoughts" were those of the president of UST' s smokeless tobacco foreign 

1088 Deposition of Erik Lindqvist, Marsee v. U.S. Tobacco, Civil Action No. 84-2777R (W.D. Ok. 1986) 

Transcript of jury trial proceedings at 1668. See AR (Vol 29 Ref. 489-2). 

1089 U.S. Tobacco Company memo from Erik Lindqvist (Sep. 22, 1981) (emphasis added). This document 

was discussed in the trial transcript in Marsee v. U.S. Tobacco at 1668-1669. See AR (Vol 29 Ref. 489-2). 

1090 Joint Comments of the Smokeless Tobacco Manufacturers (Jan. 2, 1996), at 24. See AR (Vol 526 

Ref. 95). 

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II.D.4. 

subsidiary and were made to the president of UST in a memorandum written on UST 

letterhead and labeled "Intra-Company Correspondence."1091 Contrary to UST's comment, 

the president of UST expressly stated that the Swedish smokeless tobacco company and UST 

were "cooperat[ing] on this project" and that "he wanted a Lotus product for the U.S. 

market."1092 Suggestions for product development made by corporate executives carry 

significant weight and cannot be dismissed as one individual's preliminary thoughts. See 

Ezold v. Wolf, 983 F.2d 509,546 (3d. Cir. 1992). Furthermore, UST acknowledges that 

"[s]uch a portion pack product, intended to appeal to cigarette smokers, was ultimately 

marketed in the U.S. under the brand name Skoal Bandits."1093 

c. In the Jurisdictional Analysis and in section ll.D.l. above, the Agency cited as 

a UST document that posed "Potential Questions and Answers" about UST's introduction of 

Skoal Bandits in a foreign market.1094 One question the company assumes consumers will 

ask is, "How much nicotine does it contain? Is it absorbed?"1095 The company replies that 

the product contains about as much nicotine as an average cigarette and that "[t]he nicotine is 

absorbed, giv[ing] satisfaction to the smoker."1096 The Agency stated that the document 

1091 Intra-company correspondence from Watson WW (president, Scandia Internationals) to Bantle LA 

(president, U.S. Tobacco Company) (Jun. 2, 1972), from Marsee v. U.S. Tobacco, trial exhibit 158. See AR 

(Vol. 30 Ref. 505-2). 

1092 Minutes from meeting in Greenwich at Bantle LA's office (Jul. 18, 1972), at 1, from Marsee v. U.S. 

Tobacco, trial exhibit 159. See AR (Vo130 Ref. 505-3). 

1093 Joint Comments of the Smokeless Tobacco Manufacturers (Jan. 2, 1996), at 24. See AR (Vol 526 

Ref. 95). 

1094 Potential Questions and Answers, submitted in Marsee v. U.S. Tobacco, at 1. See AR (Vol 30 Ref. 509). 

109S Jd. 

1096 ]d. 

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ILD.4. 

demonstrates the manufacturer's intent to provide nicotine for absorption and thereby 

provide "satisfaction" to the smokeless tobacco user. UST argues that there is no suggestion 

by FDA that any of the statements contained in the document were ever communicated to the 

public, within or outside of the United States, and therefore that this document is irrelevant to 

establishing intended use. 

FDA disagrees. This document is relevant to establishing the intent of the 

manufacturer, whether or not the information within the document was ultimately 

communicated to the public. The evidence relevant to establishing intended use is discussed 

in greater detail in sections TI.C.l. and II.C.2.e., above, and II.E., below. As described 

therein, the manufacturer's intent may be demonstrated by company documents, regardless of 

whether the documents are disclosed to the public. In this case, the questions and answers on 

nicotine content and absorption demonstrate USTs knowledge of nicotine's effects on users 

of smokeless tobacco and the company's awareness of users' desire for satisfying doses of 

nicotine. 

d. UST states that FDA relies on documents from a product liability lawsuit 

(Marsee v. UST), as well as sections of the trial transcript, and contends that these are 

distortions and mischaracterizations from plaintiff's attorneys. The comments also state that 

FDA relied on unsubstantiated statements made by the plaintiff's attorney in that case as part 

of an offer of proof. 

In several instances, the Agency cited portions of a trial transcript that recorded the 

questioning of a senior UST official. The statements relied on by FDA were made by the 

UST official for a deposition or as part of the trial proceedings under penalty of perjury. The 

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Agency does not have any reason to believe that the testimony was fraudulent, nor has the 

comment suggested that it was. 

The Agency agrees that some of the quotes cited in the Jurisdictional Analysis and in 

this document were entered into the trial record of Marsee as an offer of proof. None of 

these quotes, however, are essential to FDA's analysis. Moreover, the Agency does not have 

any reason to believe that the attorneys mischaracterized the statements made in the 

documents, nor has the comment offered any such reason. The comment has thus provided 

no persuasive basis on which to reject this evidence. 

e. UST argues that the Agency misinterprets the use of the terms "strength" and 

"nicotine satisfaction," as used in UST internal company documents. The company states 

that there is no evidence to support FDA's contention that "strength" refers to the delivery of 

nicotine. The comment further states that "satisfaction" is highly subjective and means 

something different to different people and that "nicotine satisfaction," as used in the 

smokeless tobacco company documents, refers to ''taste." 

The evidence shows that "strength," as used in various UST company documents, 

refers to nicotine delivery. Express statements made by UST officials refer to "strength" of 

nicotine and differentiate both "strength" and "satisfaction" from "taste" of the product.1097 

As described in section II.D.2.c., above, for instance, one UST document specifically urged 

UST to develop products with ''three different ... strengths of nicotine."1098 Another UST 

1097 The Lotus Project, attached to minutes from a meeting in Greenwich at Bantle LA's office (Jul 18, 

1972), from Marsee v. U.S. Tobacco, trial exhibit 159. See AR (VoL 30 Ref. 505-3). 

1098 Intra-company correspondence from Watson WW (president. Scandia Internationals) to Bantle LA 

(president. U.S. Tobacco Company) {Jun. 2, 1972), at 2, from Marsee v. U.S. Tobacco, trial exhibit 158. 

See AR (VoL 30 Ref. 505-2). 

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II.D.4. 

document states: "Our sales and marketing groups have asked for a W.B. type chew with less 

strength saying the present product contains too much nicotine for the type chewer to whom 

they would like to direct the sale of such a product."1099 

Another UST document explicitly links nicotine with satisfaction, stating that 

"virtually all tobacco usage is based upon nicotine, 'the kick', satisfaction."1100 

Based on these statements and other statements in the record, the evidence in the 

record supports the Agency characterization of strength and satisfaction. 

4. UST argues that there is nothing in the record to support FDA's assertion that 

its advertisements encourage established users to graduate to higher nicotine delivery 

products. 

The Agency disagrees with this comment. UST' s advertisements specifically promote 

graduation to higher-nicotine products. Low-nicotine products are marketed for new users, 

sometimes referred to as "You Guys Just Starting Out." In contrast, advertisements for highnicotine products use slogans like "Sooner or Later It's Copenhagen" that promote 

graduation to the higher nicotine product. See section ll.D.2.c., above. 

Moreover, as discussed in section ll.D.2.c, above, a UST chart depicts the graduation 

process as a bullseye and shows how UST's marketing strategies encourage graduation. 

1099 Health Effects of Smokeless Tobacco: Hearings Before the Subcommittee on Health and the Environment 

of the Committee on Energy and Commerce, U.S. House of Representatives, 1 03d Cong. 2d Sess. 61 

(Nov. 29, 1994) (emphasis added). See AR (VoL 710 Ref. 4). 

1100 Deposition of Erik Lindqvist, Marsee v. U.S. Tobacco, transcript of jury trial proceedings, at 1662 

(emphasis added). See AR (VoL 29 Ref. 489-2). 

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II.D.4. 

c. Other Comments 

I. One comment argues that FDA intends to assert jurisdiction over the entire 

moist snuff industry by relying exclusively on information about one company, UST, without 

any infonnation in the record about other companies. 

FDA disagrees with this comment. In section II.A., above, FDA has concluded that 

the phannacological effects and uses of smokeless tobacco would be foreseeable to any 

reasonable manufacturer of smokeless tobacco. On the basis of these foreseeable 

consequences, FDA has found that smokeless tobacco manufacturers intend to affect the 

structure and function of the body. This basis for establishing jurisdiction applies equally to 

all the smokeless tobacco manufacturers. 

In section ll.B., above, FDA has established that the intended use of smokeless 

tobacco is to affect the structure and function of the body based on the actual consumer use 

of smokeless tobacco. This finding applies equally to all the smokeless tobacco 

manufacturers. 

In this section, FDA has found that the smokeless tobacco manufacturers intend to 

affect the structure and function of the body based on the statements, research, and actions of 

the manufacturers. Contrary to the comment, the record contains substantial evidence of the 

statements, research, and actions of smokeless tobacci> manufacturers other than UST. 

First, the evidence shows that the major smokeless tobacco manufacturers have 

knowledge of the pharmacological effects of nicotine, one of the major constituents of 

smokeless tobacco. Some of the smokeless tobacco manufacturers, like UST and Brown & 

Williamson, have conducted their own extensive research into nicotine phannacology. All 

the major smokeless tobacco companies have acquired knowledge of nicotine phannacology 

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II.D.4. 

through their participation in the research of the Smokeless Tobacco Research Council. See 

section II.D.l., above. 

Second, the evidence also shows that smokeless tobacco manufacturers manipulate 

the delivery of nicotine to consumers. In addition to testing the nicotine deliveries of UST 

products, FDA also tested the nicotine deliveries of smokeless tobacco manufactured by 

Conwood Co. and Swisher International. This testing showed that like UST, these 

companies also graduate their nicotine deliveries in a manner that promotes tolerance and 

addiction. Another company, Pinkerton Tobacco Co., also controls nicotine deliveries 

through the use of pouches for its starter products. See section II.D.2.a., above. 

This evidence of (1) knowledge of nicotine's pharmacological effects and uses and 

(2) manipulation of nicotine deliveries in a manner that encourages tolerance and addiction 

thus applies to the major smokeless tobacco manufacturers. The evidence is sufficient to 

establish that these manufacturers intend their products to affect the structure and function of 

the body.llOI 

2. One comment states that FDA fails to distinguish between different smokeless 

tobacco products, namely moist snuff and chewing tobacco. The comment states that FDA is 

required to establish independently that each product is intended to affect the structure and 

function of the body. The comment also claims that FDA does not have any information 

about categories of smokeless tobacco other than moist snuff. 

FDA believes that there is no basis in the record for treating chewing tobacco 

differently than moist snuff. Studies demonstrate that both snuff and chewing tobacco 

1101 FDA's authority to assenjurisdiction over a class of similar products, such as smokeless tobacco, rather 

than assen jurisdiction company by company is funher discussed in section IT.F., below. 

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products rapidly deliver equal or even greater amounts of nicotine to the bloodstream than 

the amounts delivered by cigarettes. 1102 These studies also show that both snuff and chewing 

tobacco produce similar peak blood levels of nicotine. Moreover, as described in sections 

II.A and II.B., above, the evidence shows that all smokeless tobacco-including both moist 

snuff and chewing tobacco-is addictive and is used by consumers for phannacological 

effects. Because the pharmacological effects of moist snuff and chewing tobacco are 

essentially the same, the two products should be treated the same. 

In addition, moist snuff and chewing tobacco are generally manufactured by the same 

companies. The manufacturers do not argue that a "Chinese wall" exists at these companies 

that separates their moist snuff operations from their chewing tobacco operations. Therefore, 

having established that these manufacturers intend that their moist snuff products affect the 

structure and function of the body, FDA may properly presume that these manufacturers have 

the same intent when manufacturing another product (in this case, chewing tobacco) that 

causes the same pharmacological effects. 

1102 Department of Health and Human Services, Office on Smoking and Health, Report of the Advisory 

Committee to the Surgeon General, The Health Consequences of Using Smokeless Tobacco (Washington DC: 

DHHS, 1986), at 143-167. See AR(Vol128 Ref. 1591). 

Benowitz N, Porchet H, Sheiner L, et al Nicotine absorption and cardiovascular effects with smokeless 

tobacco use: comparison with cigarettes and nicotine gum, Clinical Pharmacology and Therapeutics 

1988;44:23-28. See AR {Vol12 Ref. 134). 

There is also evidence that tobacco manufacturers deliberately use high-nicotine tobaccos in chewing tobacco. 

A document submitted to the record by the tobacco industry states that chewing tobaccos utilize dark, aircured tobacco types that are "cultivated in a manner conducive to heavy body and high nicotine content" 

Tobacco, in Encyclopedia of Chemical Technology, eds., Kirk RE, Othmer DF {New York The Interscience 

Encyclopedia Inc.), 14:244. See AR {Vol. 535 Ref. 96, vol. IV. B). 

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II.E. 

E. THE "INTENDED USE" OF A PRODUCT IS NOT DETERMINED 

ONLY ON THE BASIS OF PROMOTIONAL CLAIMS 

Sections ll.A.-0., above, described the evidence before the Agency establishing 

that cigarettes and smokeless tobacco are intended to affect the structure or function of 

the body, and briefly discussed FDA's legal authority to consider evidence of foreseeable 

phannacological effects and uses, actual consumer use, and the statements, research, and 

actions of manufacturers. In this section, FDA responds to comments on the legal basis 

for considering these groups of evidence. 

Several comments agreed with the analysis of the intended use of cigarettes and 

smokeless tobacco set forth in the Jurisdictional Analysis. The tobacco industry, ·however, 

submitted several comments in opposition to the Agency's analysis of the intended use of 

cigarettes and smokeless tobacco, including the joint comments submitted by the cigarette 

manufacturers and the joint comment submitted by the smokeless tobacco manufacturers. 

The Agency received additional comments that made arguments similar to those of the 

tobacco industry. 

The principal contention of the tobacco industry is that whether a product is 

''intended" to affect the structure or any function of the body may be determined "only" on 

the basis of the claims made by the manufacturer to the consumer in connection with the 

sale and distribution of the product According to the tobacco industry, because they do 

not overtly promote the phannacological use of cigarettes and smokeless tobacco, their 

products are not "intended" to affect the structure or function of the body under the Act 

and FDA is therefore powerless to regulate them. 

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The tobacco industry's argument cannot be correct. Their contention is contrary 

to the plain language of the Act, FDA's regulations, judicial precedent, and the Agency's 

long-standing interpretation of the Act. If adopted, this interpretation would allow any 

drug manufacturer or importer to avoid FDA jurisdiction simply by not making certain 

types of claims-even for products with powerful pharmacological effects. 

As discussed more fully below, the Agency finds that the arguments made by the 

tobacco industry are unpersuasive and that the determination of whether a product is 

"intended" to affect the structure or function of the body may be based not only on the 

promotional claims of the manufacturer, but also on other objective evidence of intended 

use. This other objective evidence of intent may include evidence of the foreseeable 

pharmacological effects and uses of the product, evidence of how consumers actually use 

the product, and evidence of the manufacturers' statements, research, and actions that 

reveal the product's intended uses. 

Moreover, the Agency disagrees with the premise of the manufacturers' 

argument-namely, that consideration of promotional claims shows that cigarettes and 

smokeless tobacco are not drugs or devices under the Act As discussed in section ll.E.2., 

below, the Agency agrees with the comments that argue that the manufacturers' 

advertisements do in fact support the Agency's conclusion that cigarettes and smokeless 

tobacco have intended pharmacological uses. 

1. The "Intended Use" of a Product May Be Established on the Basis of 

All Relevant Objective Evidence of Intent 

As noted in section ll.A 1., above, in determining whether an article is "intended" 

to affect the structure or function of the body, ''the FDA is not bound by the 

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II.E.l. 

manufacturer's subjective claims of intent," but rather can find actual intent "on the basis 

of objective evidence." National Nutritional Foods Ass'n (NNFA) v. Mathews, 551 F.2d 

325, 334 (2d Cir. 1977). That is, the Agency determines a product's intended use 

objectively by evaluating all of the relevant evidence in the record from the perspective of 

a reasonable fact finder. See 21 CFR 201.128, 801.4. In determining intended use, the 

Agency may "examine a wide range of evidence." United States v. Two Plastic Drums . .. 

Black Currant Oil, 761 F. Supp. 70, 72 (C.D. Ill. 1991), affd, 984 F.2d 814 (7th Cir. 

1993). 

Although promotional claims are relevant objective evidence of intent, the statute, 

the Agency's regulations, and judicial and administrative precedent do not restrict FDA to 

consideration of only the manufacturer's promotional claims.1103 The Act has not beenand should not be-interpreted in a manner that would permit manufacturers of products 

that contain known drug ingredients and have known pharmacological uses to circumvent 

FDA regulation by deliberately avoiding overt drug claims. When a product contains a 

known drug ingredient like nicotine, the Agency may properly look beyond the 

manufacturer's promotional claims to other objective evidence of the intended uses of the 

product. This ability to look beyond and behind promotional claims that deliberately deny, 

1103 The Agency agrees that the claims made by the manufacturer in advertising and promotional 

materials can be relevant evidence of the manufacturer's intent Indeed, in many cases, no further 

evidence of intended use is needed. In the case of a typical approved drug, the manufacturer will 

forthrightly promote the pharmacological uses to which the drug should be put. the drug will in fact 

produce the promoted pharmacological effects, and consumers will use the drug for its promoted purposes. 

Promotional claims may be implied as well as express. For example, the Act provides that, in 

determining whether labeling or advertising is misleading, the Agency must consider the representations 

"suggested" as well as "made" in the labeling or advertising. Section 201(n), 21 U.S.C. 321(n). 

Similarly, courts have found an intent to affect the structure or function of the body based on commercial 

names that "suggest" drug uses. See, e.g., United States v. Storage Spaces Designated Nos. "8" and 

"49," 777 F.2d 1363, 1366 (9th Cir. 1985), cert. denied, 479 U.S. 1086 (1987). 

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II.E.1. 

or are silent about, the actual intended uses of a product is critical to FDA's capacity to 

protect the public health under the Act. 

a. The Plain Meaning of the Statute Authorizes FDA To Consider 

All Evidence of Intent 

"When interpreting a statute, [the courts] look ftrst and foremost to its text." 

United States v. Alvarez-Sanchez, 114 S. Ct. 1599, 1603 (1994). The pertinent provision 

from the statutory definition of "drug," section 20l(gX1)(C) of the Act, 21 U.S.C. 321 

(g)(l)(C), states: "The term 'drug' means ... articles (other than food) intended to affect 

the structure or any function of the body of man or other animals" (emphasis added). The 

corresponding device defmition, section 201(h)(3), states: 

The term "device" ... means an instrument, apparatus, implement, 

machine, contrivance, implant, in vitro reagent, or other similar 

related article, including any component, part, or accessory, which 

is ... intended to affect the structure or any function of the body of 

man or other animals. 

21 U.S.C. 321(h)(3) (emphasis added). 

These defmitions do not dictate that the "intended" effects or uses of an article be 

established in any particular manner or by any specific type of evidence. Similarly, they do 

not preclude the use of any type of evidence to make the pertinent showing. The statutory 

language is plain on its face and permits FDA to consider any relevant evidence in 

determining what uses are "iritended." 

The broad statutory language cannot be reconciled with the narrow view that 

"only" claims made to the consumer in connection with the sale of a product are relevant 

in determining the "intended" uses of a product. If Congress had meant to so limit the 

evidence that could be used to determine intended uses, it would have used a phrase such 

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II.E.l. 

as "promoted to," "labeled to," "advertised to," or "represented to" in lieu of "intended 

to" in the defmitional sections. Indeed, Congress explicitly refers to representations, 

labeling, and advertising in other sections of the Act. See section 20l(n) of the Act, 21 

U.S.C. 32l(n) (whether a drug or device is misbranded depends, among other factors, on 

the manufacturer's "representations" made in "labeling or advertising"); section 502(a), 21 

U.S.C. 352(a) (a drug or device is misbranded if, among other bases, its "labeling" is false 

or misleading); section 502(n), 21 U.S.C. 352(n) (a drug is misbranded, among other 

bases, unless its "advertisements and other descriptive printed matter'' contain certain true 

statements). That Congress did not expressly restrict the Agency to promotional claims 

means that evidence of intended use need not be limited to promotional claims. As the 

Supreme Court recently observed, "it is generally presumed that Congress acts 

intentionally and purposely when it includes particular language in one section of a statute 

but omits it in another." Keene Corp. v. United States, 508 U.S. 200, 208 (1993). 1104 

The tobacco industry's position also conflicts with the canon of statutory 

construction that words used by Congress, unless otherwise defmed, will be interpreted as 

taking their ordinary meaning. See, e.g., Smith v. United States, 113 S. Ct. 2050, 2054 

(1993); Chevron v. Natural Resources Defense Council, Inc., 467 U.S. 837, 860 (1984). 

Contrary to the manufacturers' view, the ordinary and widely accepted meanings of 

"intend" are significantly broader than those of "promote." 

1104 Similarly, the legislative history of the Act cited by the tobacco industry fails to support the tobacco 

industry's position. Nowhere in that history are any authoritative statements that intended use may be 

established only by promotional claims. SeeS. Rep. No. 361, 74th Cong., 1st Sess. 4 (1935) reprinted in 

3 Legislative History 660; S. Rep. No. 493, 73d Cong., 2d Sess. (1934) reprinted in 2 Legislative History 

720; H. Rep. No. 853, 94th Cong., 2d Sess. (1976) reprinted in An Analytical Legislative History of the 

Medical Device Amendments of 1976, appendix III. Section II.E.3.a. provides additional discussion of 

the legislative history. 

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As discussed in section ll.C.l., above, one ordinary meaning of "intend" is to have 

in mind or design for a particular purpose. Consistent with this meaning, the Agency 

interprets "intended uses" to include those uses that are "in the mind" of or planned by the 

manufacturer or for which the manufacturer designs the product. The evidence that is 

relevant to establish the uses that the manufacturer "has in mind" or for which the 

manufacturer has designed the product is plainly substantially broader than evidence of 

only promotional claims. It may include, for instance, evidence of the internal statements, 

research, and actions of the manufacturer's senior scientists and officials. 

As discussed in section IT. A 1., above, "intend" in its ordinary legal usage also 

encompasses readily foreseeable consequences. As the Supreme Court recognized nearly 

a century ago, "[t]he law presumes that every man intends the legitimate consequences of 

his own acts." Agnew v. United States, 165 U.S. 36, 53 (1897). Consistent with this 

meaning, "intended uses" include the foreseeable pharmacological effects and uses of the 

product The evidence that is relevant to establish these effects and uses is substantially 

broader than evidence of promotional claims. It may include, for instance, evidence of a 

product's widely known pharmacological effects and uses.1105 

1105 Additional demonstration that the intended use of a product may be determined based on evidence 

other than the express claims of the manufacturer is provided by the Dietary Supplement Health and 

Education Act (OSHEA), Pub. L. No. 103-417, 108 Stat 4325. Before the passage of the OSHEA, dietary 

ingredients and dietary supplements that did not have taste, aroma, or nutritive value (and thus were not 

foods, see Nutrilab, Inc. v. Schweiker, 713 F.2d 335, 337 (7th Cir. 1983)) could be classified as "drugs" if, 

among other things, the manufacturer made claims that the product would affect the structure or any 

function of the body. In the OSHEA, Congress created an exception to section 201(g)(l)(C). Under this 

exception, a dietary supplement or dietary ingredient "for which a truthful and not misleading statement is 

made ... is not a drug under clause (C) solely because the label or the labeling contains such a 

statement" 21 U.S.C. 321(g)(1}(C} (emphasis added). The fact that Congress expressly provided that an 

intent to affect the structure and function of the body cannot be established "solely" on the basis of 

promotional claims plainly implies that other evidence beyond promotional claims can be relevant 

evidence of intent 

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The tobacco industry's view that the "intended use" of a product may be 

determined "only" by examining promotional claims thus cannot be squared with the plain 

language of the statute. Congress did not provide that FDA may regulate only products 

"promoted" to affect the structure or function of the body. Rather, Congress provided 

that FDA may regulate products "intended" to affect the structure or function of the body. 

A wide range of evidence can be probative of a manufacturer's intent. 

b. FDA's Regulations Authorize FDA To Consider All Evidence of Intent 

Consistent with the plain language of the statute, FDA's regulations defming 

"intended use" for drugs and devices, 21 CFR 201.128 (drugs) and 21 CFR 801.4 

(devices), clearly contemplate that FDA may consider a range of evidence that extends 

well beyond the claims made by manufacturers in connection with the sale and distribution 

of their products. Even if the statute were not plain on its face, the Agency has broad 

discretion to interpret the Act in a reasonable manner consistent with its public health 

purposes. United States v. An Article of Drug ... Bacto-Unidisk, 394 U.S. 784,798 

(1969). 

These regulations, which have been in effect for four decades, defme the "intended 

uses" of drugs and devices that must be included in the product's labeling. Although they 

do not specifically defme the statutory terms "drug" or "device," the Agency routinely 

uses the regulations to interpret the statutory intent requirement. See section ll.A.l., 

Indeed, in United States v. Ten Cartons, More or Less, of an Article ... Ener-B Vitamin B-12, 72 F.3d 

285, 287 (2d Cir. 1995), the Second Circuit Court of Appeals stated that this language clearly implies that 

a dietary supplement can be a drug under this section for reasons other than the claims made for it, such 

as its method of intake. Thus, the court found that Boer~ B, which was a vitamin B-12 supplement 

designed to be applied to the inside of the nose and absorbed into the bloodstream through the nasal 

mucous membranes, was a drug. /d. 

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above. Indeed, the comments of the tobacco industry assert that these regulations have 

"authoritatively ... defined" intended use under the Act. 1106 

The regulation that describes the intended use of drugs provides: 

The words "intended use" or words of similar import . .. refer to 

the objective intent of the persons legally responsible for the 

labeling of drugs. The intent is detennined by such persons' 

expressions or may be shown by the circumstances surrounding the 

distribution of the article. This objective intent may, for example, 

be shown by labeling claims, advertising matter, or oral or written 

statements by such persons or their representatives. It may be 

shown by the circumstances that the article is, with the knowledge 

of such persons or their representatives, offered and used for a 

purpose for which it is neither labeled nor advertised. The 

intended uses of an article may change after it has been introduced 

into interstate commerce by its manufacturer. If, for example, a 

packer, distributor, or seller intends an article for different uses than 

those intended by the person from whom he received the drug, such 

packer, distributor, or seller is required to supply adequate labeling 

in accordance with the new intended uses. But if a manufacturer 

knows, or has knowledge of facts that would give him notice, that a 

drug introduced into interstate commerce by him is to be used for 

conditions, purposes, or uses other than the ones for which he 

offers it, he is required to provide adequate labeling for such a drug 

which accords with such other uses to which the article is to be put. 

21 CFR 201.128 (emphasis added). Section 801.4, which defmes "intended use" for 

devices, is essentially the same except for the use of the word "device" in lieu of "drug" 

and the reference to regulations governing devices. 

The italicized language shows that the "intended uses" of a product may be 

detennined not only by "labeling claims" and "advertising matter," but also by other 

"expressions" and "oral or written statements" made by persons legally responsible for the 

1106 Joint Comment of the Cigarette Manufacturers, Comment (Jan. 2, 1996), vol II. at 6; see AR (Vol 

535 Ref. 96); accord Joint Comment of the Smokeless Tobacco Manufacturers, Comment (Jan. 2, 1996) at 

102 ("[t]he regulation desaibing FDA's understanding of 'intended use' is consistent with the 

congressional purpose behind the drug defmition"). See AR (Vol 526 Ref. 95). 

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labeling of drugs (without limitation on the persons to whom the statements are made); 

"the circumstances surrounding the distribution of the article"; ''the circumstances that the 

article is with the knowledge of such persons ... offered and used for a purpose for which 

it is neither labeled nor advertised"; and evidence that "a manufacturer knows or has 

knowledge of facts that would give him notice" that a drug "is to be used" for purposes 

other than those for which the manufacturer offered the product. 

Thus, the plain language of the regulations provides that the intended use of a 

product can be determined on the basis of evidence other than the promotional claims 

made by the manufacturer. If the Agency had meant to restrict its consideration to 

promotional claims exclusively, as the tobacco industry suggests, it would have written a 

narrow regulation expressly so providing-not the broadly written regulation it actually 

wrote and administers. 

In effect, the tobacco industry unreasonably urges the Agency to ignore the 

express language of the regulation and refuse to consider any evidence of intended use 

other than promotional claims. The Agency disagrees with this interpretation. FDA 

interprets the regulation to allow the Agency to consider any relevant evidence of intent, 

including, as discussed in sections II.A., II.B., II. C., and II.D., above, the foreseeable and 

actual effects and uses of the product and the internal statements, research, and actions of 

the manufacturer. The Agency has for years consistently interpreted the regulation in this 

manner. The Agency's interpretation of its own regulations is reasonable and is entitled to 

"controlling weight unless it is plainly erroneous or inconsistent with the regulation." 

Thomas Jefferson Univ. v. Shalala, 114 S. Ct. 2381, 2386 (1994). 

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c. Judicial Decisions Authorize FDA To Consider All Evidence of Intent 

The tobacco industry contends that the courts have repeatedly held that the 

"intended use" of a product must be based on promotional claims and that the Act does 

not pennit FDA to exercise jurisdiction over a product as a drug or a device unless the 

manufacturer or vendor makes overt claims for the product in connection with its sale. 

Clearly, courts have found that the vendor's claims are a relevant source of 

evidence establishing the intended use of a product, and FDA fully agrees with these 

holdings. The Agency does not, however, agree with the tobacco industry's view that the 

cited precedents can reasonably be read to limit the Agency to consider only such overt 

claims when detennining the intended use of a product In most of the cases cited by the 

tobacco industry, the relevance of other types of evidence was not at issue because the 

manufacturers' promotional claims were found to be sufficient to establish the intended 

use of the products. Thus, FDA did not need to rely on other evidence to prove the 

intended use of the article, and the courts were not called upon to decide the relevance of 

other evidence. See, e.g., Bradley v. United States, 264 F. 79 (5th Cir. 1920); United 

States v. Nutrition Service, Inc., 227 F. Supp. 375, 381, 383, 386 (W.D. Pa. 1964), a.ffd, 

347 F.2d 233 (3d Cir. 1965); United States v. An Article . .. "Sudden Change," 409 F.2d 

734, 737 (2d Cir. 1969); Estee Lauder, Inc. v. FDA, 727 F. Supp. 1, 2-3 (D.D.C. 1989). 

Generically, the cases relied upon by the tobacco industry represent instances in 

which manufacturers made drug claims for products without known drug ingredients and 

without known phannacological uses-not cases where manufacturers attempted to 

market a product with a known drug ingredient or use without complying with the Act. 

Bradley, for instance, involved phannaceutical claims that were made for mineral water. 

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In this situation, claims do have an essentially dispositive role. Pharmaceutical claims will 

bring the product within FDA's jurisdiction, whereas relabeling the product to eliminate 

these claims may, in some circumstances, remove the product from FDA's jurisdiction. 

The situation is fundamentally different, however, where the product contains a 

known drug ingredient like nicotine and has known pharmacological uses such as 

addiction maintenance, sedation, and stimulation. In these cases, "[s]elf serving labels 

cannot be used to mask true intent." Storage Spaces Designated Nos. "8" and "49," 777 

F.2d. at 1366 n.5. As the Second Circuit has observed, "a fact fmder should be free to 

pierce ... a manufacturer's ... misleading 'nutritional' labels to fmd actual therapeutic 

intent on the basis of objective evidence." NNFA v. FDA, 504 F.2d 761, 789 (2d Cir. 

1974), cert denied, 420 U.S. 946 (1975); accord NNFA v. Mathews, 551 F.2d at 334 

("FDA is not bound by the manufacturer's subjective claims of intent but can fmd actual 

therapeutic intent on the basis of objective evidence."). 

Contrary to the tobacco industry's assertions, numerous courts have unequivocally 

stated that FDA could consider evidence from "any relevant source" to establish the 

"intended" use of a product. The courts have enunciated a principle that defmes broadly 

the scope of the evidence that is to be used to establish intended use. That is, the intended 

use is based on "labeling, promotional material, advertising and any other relevant 

source." United States v. An Article . .. "Sudden Change," 409 F.2d at 739 (emphasis 

added); accord NNFA v. Mathews, 551 F.2d at 334; Action on Smoking and Health v. 

Harris (ASH), 655 F.2d 236, 239 (D.C. Cir. 1980); Storage Spaces Designated Nos. "8" 

and "49," 777 F.2d at 1366; Hanson v. United States, 417 F. Supp. 30, 35 (D. Minn.), 

aff'd, 540 F.2d 947 (8th Cir. 1976); see also United States v. 250 Jars of U.S. Fancy Pure 

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II.E.1. 

Honey, 218 F. Supp. 208, 211 (E.D. Mich. 1963) (in determining intended use, a "court is 

not limited to the labels on such article or to the labeling which accompanies it, but may 

look at all relevant sources"), affd, 344 F.2d 288 (6th Cir. 1965).u07 

The scope of"any relevant source" is extremely broad. As one court recently 

held, to determine intent under this standard, the Agency may "examine a wide range of 

evidence, including the vendor's stated intent, actual use of the product, consumer use of 

the product, and product marketing." Two Plastic Drums, 761 F. Supp. at 72. Without 

any implication that these are the exclusive types of evidence, courts have construed the 

Act to find the types of evidence discussed below, in addition to express claims, to be 

"other relevant sources" of a product's intended use. 

i. Pharmacological or Physical Effects. 

In United States v. Undetermined Quantities . .. "Pets Smellfree," 22 F.3d 235 

(lOth Cir. 1994), the court relied heavily on expert testimony about the physiological 

effects of a pharmacologically active ingredient, chlortetracycline (CTC), to establish that 

an animal food additive, "Smellfree," was in fact a drug. Specifically, the court cited 

"affidavits demonstrating that the use of CTC will reduce the normal levels of bacteria in 

the animal's intestine and that this can affect the way the animal's body functions" to 

"establishO that Smell Free is intended to affect a bodily function of animals." I d. at 240. 

1107 Courts have adopted a parallel approach in determining intent under similar provisions of the Act 

For example, in the context of determining whether a product is "intended for export" for purposes of 

section 801(eXl), 21 U.S. C. 801(eX1), "a court must examine the manufacturer's subjective intent as well 

as any other evidence relating to that issue." United States v. Various Articles of Drug, Bulk Antibiotics, 

etc., Civ. No. M-95-912, slip op. at 9 (D. Md Jun. 6, 1996). 

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II.E.1. 

ii Consumer Use. 

In ASH, a case involving a previous FDA decision not to regulate cigarettes as 

drugs, the court explicitly recognized that consumer use could establish the "intended use" 

of a product, stating that"[ w]hether evidence of consumer intent is a 'relevant source' ... 

depends upon whether such evidence is strong enough to justify an inference as to the 

vendor's intent." 655 F.2d at 239-240; see also NNFA v. Weinberger, 512 F.2d 688, 703 

(2d Cir. 1975) (evidence before the Agency that vitamins "were used almost exclusively 

for therapeutic purposes" could be a proper basis to measure intent on an objective basis); 

NNFA v. Mathews, 551 F.2d 325 (2d Cir. 1977);1108 United States v. 789 Cases ... Latex 

Surgeons' Gloves, 799 F. Supp. 1275, 1294-1295 (D.P.R. 1992) (intended use determined 

by all the facts, including "actual use"); Two Plastic Drums, 761 F. Supp. at 72 ("a court 

should examine a wide range of evidence, including ... actual use of the product .... "); 

United States v. Kasz Enterprises, Inc., 855 F. Supp. at 539 ("Objective intent can be 

demonstrated by, among other things ... evidence that the vendor is aware that his 

product is being offered or used by others for a purpose for which it is neither labeled nor 

advertised") (emphasis added). 

Several other courts have concluded that relevant "consumer use" can be defmed 

in terms of the uses that doctors and other medical practitioners make of medical devices. 

See United States v. An Article of Device ... Toftness Radiation Detector, 731 F.2d 

1108 The manufacturers attempt to diminish the force of the NNF A cases by characterizing the courts' 

acceptance of evidence of actual consumer use as "dictum." This argument trivializes the reality that two 

different panels (consisting of six different jurists) over the course of three years reviewed and-without 

expressing any reservations regarding its legal soundness-accepted the proposition that consumer use 

was relevant to determine the intended use of a product The courts' only reservation related to the lack of 

record evidentiary support regarding the extent of consumer use. NNFA v. Weinberger, 512 F.2d at 703; 

NNF A v. Mathews, 557 F.2d at 335. 

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II.E.1. 

1253, 1257 (7th Cir. 1984) (chiropractic instrument was a device under the Act, relying in 

part_on testimony of manufacturers' witnesses showing how they used the article to treat 

patients); United States v. 22 ... "The Ster-o-Lizer MD-200," 714 F.Supp. at 1165 

(actual use of a sterilizer by surgeons was evidence of intended use); United States v. An 

Article of Device. 0. Labeled in Part: "Cameron Spitler Amblo-Syntonizer," 261 F. 

Supp. 243, 245 (D. Neb. 1966) (physician use of a product for treatment of eye ailments 

caused the product to be a device even in the absence of express claims by the physician or 

by the manufacturer in the labeling). 

iii. Other Evidence. 

Contrary to the contention that the phrase "intended to affect" must be read 

narrowly to refer only to promotional representations used in connection with the sale of 

the product, courts have considered a wide variety of other relevant evidence. In 

American Health Products Co. v. Hayes, for example, in addition to considering product 

effect and other evidence, the court found that a "starch blocking" product (known as 

"Starchblocker") was a drug, based in part on evidence of how the product was 

formulated. 574 F. Supp. 1498, 1508 (S.D. N.Y. 1983) (citing evidence that the products 

were "manufacture[ d] . 0 • by a process which concentrates the antinutrient to the 

exclusion of components which contribute food value"). In Tojtness Radiation Detector, 

in addition to considering medical use and other evidence, the court cited as evidence of 

intended use the fmancial arrangements (such as tuition and leases) through which 

chiropractors were trained in use of the product. 731 F.2d at 1257 n.2. In NNFA v. 

Mathews, the court noted that both the toxicity of the product, 557 F.2d at 335, and FDA 

experience, id. at 335 n.8, may be considered in determining the intended use of a product. 

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II.E.l. 

With regard to the latter evidence, the court stated that FDA's "general awareness of the 

'numerous and widespread' therapeutic usages" can be relied upon if part of the record. 

Id. at 335 n.8; see also Latex Surgeons' Gloves, 799 F. Supp. at 1295 (circumstances 

surrounding storage and handling of products, as well as identity of customers, are 

relevant to intended use). 

The tobacco industry contends that the court in United States v. Articles of Drug 

for Veterinary Use, 50 F.3d 497 (8th Cir. 1995), held that documentary materials must be 

promotional in nature before they can be considered as evidence of intended use. The 

comments, however, seriously mischaracterize the facts and holding of that case. The case 

involved products made from colostrum (a component of breast milk) that FDA argued 

were subject to regulation as drugs by virtue of the pharmacological claims made by the 

manufacturer, not because of the product's ingredients or actual pharmacological effects. 

This is simply another case in which promotional claims alone were sufficient to bring 

under FDA's drug jurisdiction a product without established pharmacological effects or 

uses. This case has no relevance in determining what kind of evidence can be used to 

establish the intended use of a product containing a known drug ingredient with widely 

known pharmacological effects and uses. 

Similarly, the tobacco industry mischaracterizes United States v . ... "Instant Alberty 

Food.., 83 F. Supp. 882 (D.D.C. 1949), and United States v. Pro-Ag, Inc., 796 F. Supp. 1219 

(D. Minn. 1991), aff'd, 968 F. 2d 681 (8th Cir. 1992). These cases involved ''nutritional" 

products that lacked any established pharmacological effects and were pro rooted for treating 

disease or affecting the structure or function of the body. Because the sole basis for 

establishing intended use was prorootional claims made to consumers, the courts held that the 

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II.E.l. 

promotional material must ordinarily have been distributed and relied on by consumers 

purchasing the products. These cases are not relevant where the government is relying on 

evidence establishing the intended uses of products with known pharmacological effects and 

uses, including evidence of the actual knowledge of manufacturers who are marketing the 

products for those effects and uses. 1109 

Thus, as a review of the judicial precedent reveals, promotional claims are a 

sufficient basis for an intended use fmding, but not a necessary or exclusive basis. Not 

only has no court ever held that a promotional claim must always be present, but 

numerous courts have held that a product's intended use may be determined based on 

evidence from "any relevant source." 

d. The Agency's Administrative Precedent Supports the Agency's 

Consideration of More Than Promotional Claims 

In administrative actions, the Agency has determined intended use on the basis of 

evidence other than promotional claims by the manufacturer. This administrative 

precedent is entitled to deference. See Wichita and Affiliated Tribes v. Hodel, 788 F.2d 

765,778 (D.C. Cir. 1986) ("a high level of deference [is] afforded an agency on review 

when the issue turns on the interpretation of the agency's own prior proclamations"). 

1109 Indeed, the court in Alberty Food recognized that. even if the manufa.<:turel" had loo.g since stopped 

distributing the literature, the government could still establish intmt if it could show that the manufa.<:turel" 

actually intended the products to be used for the treatment of disease: 

it is oo.ly to the extent that the abmdonment of such disseminatioo. m-ate£ an 

inference that the shipper did not intmd, 'When it shipped the drugs in interstate 

commerce, that they be used for the treatment of the diseases named oo. the booklets, 

that the abandonment can be said to be an effective defense. The government might 

introdllce evidence to show that, notwithstanding such abandonment, it l4W stiU the 

intention of the shipper that the drugs be used for the treatment of the diseases 

mentioo.ed in the booklets. 

83 F. Supp. at 887 (emphasis added). 

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II.E.l. 

Several of these precedents were described in the Jurisdictional Analysis. See 60 

FR 41527-41531. Beginning in the 1980's, for instance, FDA took enforcement actions 

against "caine" products that were used as imitation cocaine. These imitation cocaine 

products contained bulk anesthetic powders, such as lidocaine or ephedrine, and were 

often sold as "incense." To determine the products' intended drug use, the Agency relied 

upon laboratory analyses of the products, the outlets in which the products were sold 

(e.g., "head shops"), and "street" information that the products provide a "cheap high."u 10 

See Jurisdictional Analysis, 60 FR 41528. Similarly, in the early 1980's, FDA started to 

regulate as unapproved drugs U.S. imports of Catha edulis, or "khat," even though the 

Agency did not have any information about or claims by vendors.uu Khat is a shrub 

whose leaves act as a stimulant narcotic that affects the central nervous system when 

chewed or used as tea. The Agency relied on evidence of khat's actual effects and widely 

known uses to determine that it was intended for use as a drug. 

The Agency has also taken the position that including a known drug ingredient in a 

product and listing this ingredient on the label of the product can be sufficient to make the 

product a drug. Thus, the Agency has formally taken the position that any skin cream that 

contains a pharmacologically active level of hormones and lists the presence of hormones 

1110 See memorandum from chief, prescription drug compliance branch (Aug. 4, 1982), reprinted inRx 

Drug Study Bulletin #258; OH. FDC 64350, Case No.C-3-84-686 (S.D. Ohio 1984); FDA Administrative 

File for Mid-America Drug Co:, regulatory letter 84-DT-12 and response; FDA Administrative File for 

Sam's Imports, Dearborn. Ml, regulatory letter 85-DT-3 and response; FDA Administrative File for 

NALPAC, Ltd., Oakpark. Ml, regulatory letter 85-DT-5 and response; FDA Administrative File for 

Tower Enterprises, Ida, MI, regulatory letter 85-DT-2 and response. In 1994, the government prosecuted 

Edwin and Thomas Dews in Michigan for selling a product called "Milky Trails," labeled as a room 

deodorizer but in fact containing lidocaine. Case No. 94 CR 20040-BC (B.D. Mich.). See AR (Vol. 4 Ref. 

3~2). 

1111 FDA Import Alert 66-23 (Mar. 26, 1982, revised Apr. 2, 1986, and Feb. 9, 1993). See AR (Vol 4 

Ref: 30-1). 

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II.E.l. 

on the label is a drug. See 58 FR 47611, 47612 (Sep. 9, 1993); Drug Study Bulletin No. 

67 (Mar. 28, 1994); see also 54 FR 40618, 40619 (Oct. 2, 1989). Similarly, FDA 

considers dentifrice products containing fluoride to be drugs, irrespective of whether any 

claims are made, because fluoride is widely accepted as an anticavity agent by the dental 

products industry and consumers and because fluoride affects the structure of the tooth. 

See 59 FR 6084, 6088 (Feb. 9, 1994); see also 50 FR 39854 (Sep. 30, 1985). 

As these examples and the additional examples described in the Jurisdictional 

Analysis indicate, the Agency regularly looks beyond a manufacturer's express 

promotional claims to the likely pharmacological use and effect of a product in 

determining whether a product is intended to affect the structure or function of the body. 

e. Policy Considerations Also Weigh Strongly in Favor of the Agency's 

Interpretation 

Finally, policy considerations also conflict with the tobacco industry's position and 

weigh strongly in favor of the Agency's interpretation. The purpose of the Federal Food, 

Drug, and Cosmetic Act is to "safeguard the public health" and protect "consumer 

welfare." H. Rep. No. 2139, 75th Cong., 3d Sess. 1-2 (1938), reprinted in 6 Legislative 

History 360. The Supreme Court has recognized that ''the Food, Drug and Cosmetic Act 

is to be given a liberal construction consistent with the Act's overriding purpose to protect 

the public health." United States v. An Article of Drug . .. Bacto-Unidisk, 394 U.S. 784, 

798 (1969). As the Court stated: 

The purposes of [the Act] thus touch ... the lives and health of 

people which, in the circumstances of modem industrialism, are 

largely beyond self-protection. Regard for these purposes should 

infuse construction of [the Act] if it is to be treated as a working 

instrument of government and not merely as a collection of English 

words. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45169

II.E.l. 

United States v. Dotterweich, 320 U.S. 277, 280 (1943). 

The tobacco industry's theory would frustrate these public health purposes. If 

promotional claims alone determined the "intended use" of a product, a manufacturer 

could market a potent tranquilizer solely for its "pleasurable" effect or an amphetamine for 

its "energizing" effect and avoid the Act's reach. The same manufacturer could coat the 

tranquilizer or amphetamine with sugar, advertise it for its "taste and flavor," and again 

escape FDA regulation. It is not hard to imagine a manufacturer of a generic version of 

Prozac, an antidepressant drug currently approved by FDA and available only by 

prescription, who would seek to avoid FDA regulation by advertising its product as 

intended solely for the "pleasure" of its consumers. If these products could so easily 

escape FDA regulation, the public health would be endangered. 

These examples are not purely hypothetical. As discussed above, manufacturers of 

imitation cocaine or "caine" products, which contain anesthetic drugs such as lidocaine, 

have attempted to avoid FDA regulation by selling their products as "incense." Although 

FDA has successfully asserted jurisdiction over these products in the past, the Agency 

could be precluded from doing so under the manufacturers' legal theory. 

New evidence received during the comment period provides another example of 

the possible results if the Agency accepted the manufacturers' legal theory. In 1992, the 

British American Tobacco Company (BATCO), the parent company of Brown & 

Williamson Tobacco Corporation, considered purchasing a manufacturer of nicotine 

patches, Stowic Resources Ltd., because "[t]here is currently a void in the market for a 

product that provides tobacco satisfaction in a form that is acceptable and available to 

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II.E.l. 

many segments of the market."1112 The purchase was ultimately rejected after BATCO 

and Brown & Williamson researchers found that nicotine patches did not provide the 

consumer with "[t]he rapid, peaking intake of nicotine which the smoker clearly 

wants."1113 Under the manufacturers' theory, however, it would nonetheless be legally 

permissible for BATCO and Brown & Williamson to sell high-potency nicotine patches or 

any other product whose sole purpose was to deliver pharmacologically active doses of 

nicotine without FDA regulation so long as the manufacturers claimed to market the 

products exclusively for ''tobacco satisfaction." 

For sound policy reasons, the Agency must be able to look beyond a 

manufacturer's promotional claims when determining whether to regulate a product that 

contains a known drug or that has known pharmacological uses. Where manufacturers 

avoid promoting the pharmaceutical uses of products that contain drug ingredients or 

where manufacturers deliberately make ambiguous claims or otherwise seek to obscure the 

true nature of their products, FDA must be free to consider other objective evidence to 

establish the true intended use of the product. As discussed in sections ll.A.l., II.B.l., 

and Il.C.l., above, this other objective evidence may include the product's foreseeable 

pharmacological effects and uses, actual consumer use, and the statements, research, 

and actions of manufacturers. 

1112 Brown & Williamson, Transdermal Nicotine Patches (1992), at 3. See AR (Vol 531 Ref. 124). 

1113 Kausch, Research and Development/Quality, Transdermal Nicotine (1992). See AR (Vol 531 

Ref. 124). 

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2. Consideration of Tobacco Manufacturers' Promotional Claims 

Supports the Agency's Position 

II.E.2. 

The Agency also disagrees with the premise of the tobacCo industry's positionnamely, that consideration of their promotional claims will demonstrate that cigarettes and 

smokeless tobacco products are not intended to affect the structure or function of the 

body. In fact, consideration of the claims made in tobacco advertising lends support to the 

Agency's determination that cigarettes and smokeless tobacco are "intended" to affect the 

structure and functidn of the body. 

Several comments on the Jurisdictional Analysis urge FDA to consider the 

promotional claims of the tobacco manufacturers in determining whether the 

manufacturers intend to affect the structure or function of the body. The comments of the 

American Society of Addiction Medicine, for example, assert that consideration of 

promotional claims provides further support for the finding that tobacco manufacturers 

intend to affect the structure and function of the body. Conversely, the tobacco industry 

comments maintain that consideration of these claims will show that the manufacturers do 

not intend to affect the structure or function of the body. 

The Agency agrees that promotional claims can be relevant evidence of intended 

use. See section II.E.l., above. As the tobacco industry comments recognize, these 

claims can be of two types, implied or express.

1114 Express claims for a product overtly 

promote the product's effects on the structure or function ofthe body. Implied claims 

1114 Joint Comments of the Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol ll, at 91. See AR 

(Vol. 535 Ref. 96) ("the determining factor is claims-implied or expressed-made in marketing the 

product") (emphasis added). See also section 201(n) of the Act (21 U.S.C. 321(n)) (in determining 

whether labeling or advertising is misleading the Agency must consider both the representations "made" 

and the representations "suggested" by the manufacturer). 

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II.E.2. 

suggest, but do not explicitly recommend, pharmacological use. The courts have 

recognized that implied drug claims can make a product a drug even in the presence of 

express disclaimers warning against drug use. For instance, in a case involving an 

imitation cocaine product sold as incense and advertised as not for drug use, the Ninth 

Circuit held: 

The fact that the items were called "incense" and advertised as "Not 

for drug use" cannot be controlling on the issue of whether they are 

drugs. Where, as here, the items are otherwise promoted and 

advertised in ways that suggest they are cocaine substitutes, [the 

vendor's] intent in distributing the products is clear. Self-serving 

labels cannot be allowed to mask the vendor's true intent as 

indicated by the overall circumstances. 

United States v. Storage Spaces Designated Nos. "8" and "49," 777 F.2d 1363, 1366 

n.5 (9th Cir. 1985) (emphasis added), cert. denied, 419 U.S. 1086 (1987). 

As suggested in the comments, the Agency has examined the promotional claims 

of the tobacco manufacturers. Although recent tobacco product advertisements do not 

make express drug claims, the implied pharmacological claims in some tobacco 

advertisements provide additional support for the Agency's fmding of intended 

pharmacological use. In particular, as described below, advertisements that promise that 

tobacco products will provide "satisfaction" suggest to the consumer that use of tobacco 

products will provide desired pharmacological benefits, including satisfying addiction. 

The use of "satisfaction" claims in tobacco product advertising is common. Since 

the 1970's, most major tobacco manufacturers have used advertising campaigns that 

promote "satisfaction." For instance, the R.I. Reynolds Tobacco Company (RJR) has 

used a promise of "satisfaction" to advertise many cigarette brands, including Camel 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45173

II.E.2. 

Lights, Salem, Real, More, and Now. 1115 A 1990 advertisement for Now brand cigarettes, 

for example, asks "Can a cigarette have just 2 mgs of tar and still be satisfying to smoke? 

... NOW can."1116 Likewise, "satisfaction" claims have been used by Brown & 

Williamson, Lorillard, and Liggett & Myers.1117 In one typical, recent advertisement, 

Lorillard promoted its True brand with the slogan "The Lowest with True Satisfaction ... 

True Delivers."1118 Some of these advertisements distinguish "satisfaction" from taste. 

For example, a Brown & Williamson advertisement for Barclay states: 

If your ultra light is ultra boring, why do you still smoke it? 

Because you probably think that's the sacrifice you have to make. 

Well, not any longer. We've just made ultra lights you don't have 

to make any sacrifices for. At least not on taste. And not on 

satisfaction. 1119 

Smokeless tobacco manufacturers also rely on "satisfaction" claims in advertising. 

The nation's largest smokeless tobacco manufacturer, United States Tobacco Company 

(UST), has used satisfaction promises to advertise several brands, including Copenhagen, 

1115 See Tobacco Advertisements, in American Society of Addiction Medicine, Comment (Dec. 29, 1995), 

appendix 6, at 89-90,92, 94-96, 98. See AR (VoL 528 Ref. 97). 

1116 /d. at 98. 

1117 Jd. at 82-86, 88, 91, 97, 99. 

1118 Id. at 99 (emphasis added). 

1119 Id. at 97 (emphasis added). 

In addition to differentiating between taste and satisfaction in the quoted passage, this advertisement also 

uses the term "satisfying" in a subsequent passage to describe the flavor of Barclay, stating that"[ w ]e gave 

Barclay a new blend of tobaccos for a smoother, more satisfying flavor." /d. This dual usage of 

satisfaction occurs in other advertisements. For instance, in an advertisement for Camel Lights, RJR uses 

satisfaction both as an independent attribute of its product (promising "All the flavor and satisfaction 

that's been missing in your low tar cigarette") and as an adjective to describe the product's taste 

(promising "a rich, rewarding, truly satisfying taste"). ld., at 95 (emphasis added). 

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45174 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.E.2. 

Skoal, and Happy Days.1120 In fact, the slogan "It Satisfies" is the signature of UST' s 

Copenhagen brand and appears on the lid of each package. 1121 

The tobacco industry argues that "satisfaction" is not an implied drug claim. In its 

view, "satisfaction" is not a euphemism for the consumer's pharmacological response to 

nicotine. Rather, as one cigarette manufacturer commented, "'[s]atisfaction' .... reflects 

the consumer's total reaction to the total smoking experience delivered by the 

cigarettes."1122 

The Agency agrees that the term "satisfaction" reflects the consumer's reaction to 

the experience of smoking a cigarette or using smokeless tobacco. Indeed, it is precisely 

for this reason that the Agency fmds that the use of the term to promote cigarette and 

smokeless tobacco is an implied drug claim. 

The meaning of a promise of "satisfaction" depends upon the needs or 

expectations of the consumer. A "satisfying" meal means something quite different from a 

"satisfying" movie, which in tum means something different from a "satisfying" driving 

experience. A product that is satisfying to consumers is one that fulfills the needs or 

expectations of the consumer. Thus, a "satisfying" meal must meet the consumer's desires 

for taste and nutrition, while a "satisfying" driving experience must meet the consumer's 

desires for power, maneuverability, and comfort. 

1120 ld. at 93, 100-101. 

1121 Id. at 100. 

1122 Brown & Williamson Tobacco Corp., Comment (Jan. 2. 1996), at 8. See AR (Vol 529 Ref. 104). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45175

II.E.2. 

In the case of cigarettes and smokeless tobacco, a "satisfying" product must meet 

the consumer's motivations for using the product. As discussed in sections ILA. and 

II.B., above, these motivations are primarily pharmacological. Most users of tobacco 

products are addicted to nicotine. They use cigarettes and smokeless tobacco to satisfy 

their addiction and to obtain other pharmacological effects, such as anxiety reduction or 

stimulation. To these users, a manufacturer's promise of "satisfaction" implies that the 

product will fulfill their craving for the pharmacological effects of nicotine-satisfying 

their addiction and providing the sought-after mood-altering effects of nicotine. 

The tobacco industry's internal documents themselves show that consumer 

"satisfaction" is intimately connected to nicotine's pharmacological effects and that the 

tobacco manufacturers know this. The internal company documents that have recently 

become publicly available show that for the past three decades, tobacco industry officials 

have consistently expressed the view that nicotine's pharmacological effects are essential 

to consumer satisfaction. 

Officials at Brown & Williamson and its parent company, the British American 

Tobacco Company (BATCO), for instance,_have consistently linked nicotine delivery to 

consumer satisfaction. Thus, BATCO scientists have stated: 

• "Nicotine has well documented pharmacological action .... It is believed to be 

responsible for the 'satisfaction' of smoking, using this term in the physiologicalrather than the psychological sense.''1123 

• "The basic assumption is that nicotine ... is almost certainly the key smoke 

component for satisfaction . ... "1124 

1123 Wood DJ, BATCO Group Research and Development, Aspects of the R&D£ Function, notes for a talk 

given at Chelwood, Sep. 1969 (Jul. 20, 1970), at 7 (emphasis added). See AR (Vol 22 Ref. 287). 

1124 BATCO Group R&D Research Conference, Rio de Janeiro, Brazil (Aug. 22-26, 1983), at 10 

(emphasis added). See AR(Vol179 Ref. 2087). -

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45176 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.E.2. 

• "[N]icotine . .. probably provides the basis of smoking satisfaction. 1125 

• [I]n its simplest sense puffing behavior is the means of providing nicotine dose in 

a metered fashion. "1126 

• "Intuitively it is felt that 'satisfaction' must be related to nicotine. Many people 

believe it [is] a 'whole body response' and involves the action-of nicotine in the 

brain."1127 

Other industry officials have expressed the same view. For example: 

• Senior RJR scientists have written that "the confirmed user of tobacco products is 

primarily seeking the physiological 'satisfaction' derived from nicotine"11 '2B and 

that "the ultimate satisfaction comes from the nicotine which is extracted ... in 

the lungs."1129 

1125 BATCO, Proceedings of the SmoKing Behaviour Marketing Conference, Session I slides (Jul. 9-12, 

1984) (emphasis added). See AR (Vol. 21 Ref. 238). 

1126 /d. 

1127 BATCO, Nicotine Conference Outline (Jun. 6-8, 1984) at BW-W2-01977 (emphasis added). See AR 

(Vol. 22 Ref. 290). 

The record contains numerous other similar BATCO and Brown & Williamson statements. For example, 

as part of their evaluation of whether BA TCO should purchase a manufacturer of nicotine patches, Brown 

& Williamson researchers in 1992 stated that "[t]he fact that people use snuff and chewing tobacco 

indicates that administration routes [of nicotine] other than inhalation can deliver tobacco satisfaction." 

Transdermal Nicotine Patches, at 3 (emphasis added). See AR (Vol. 531 Ref. 124). 

Similarly, as part of Project Wheat. BATCO researchers reported that ''there is evidence of a conflict 

between concern for health and the desire for a satisfying cigarette, from which it follows that low tar 

brands would be much 17U)re widely accepted if their nicotine deliveries could be brought within the range 

required by groups of consumer[s]." Wood DJ (BATCO), Project Wheat-- Part 2: U.K. Male SI7U)kers: 

Their Reactions to Cigarettes of Different Nicotine Deliveries as Influenced by Inner Need (Jan. 30, 

1976), at 48 (emphasis added). See AR (VoL 20 Ref. 204-2). 

1128 Teague CE, RJ. Reynolds, Research Planning Mei7U)randum on the Nature of the Tobacco Business 

and the Crucial Role of Nicotine Therein (Apr. 14, 1972), at 1 (emphasis added). See AR (VoL 531 

Ref. 125). 

Teague also wrote that ''what we are really selling [is] nicotine satisfaction." /d. at 5 (emphasis added). 

1129 Senkus M (RJ. Reynolds Tobacco Co.), Some effects of smoking (1976/1977), at 9 (emphasis added). 

See AR (VoL 700 Ref. 593). 

Senkus also wrote that .. a zero nicotine cigarette ... really has no potential to provide si7U)king 

satisfaction. It produces no taste in the mouth, but even more seriously it fails to provide the ultimate 

satisfaction in the lungs." ld. at 9 (emphasis added). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45177

II.E.2. 

• William Farone, the fanner Philip Morris director of applied research, has written 

that "[t]he objective of industry scientists and product developers, simply stated, 

was to provide the consumer with the ... pharmacological satisfaction derived 

from nicotine . ... "1130 

• The senior vice president for marketing at UST has written that "[v]irtually all 

tobacco usage is based upon nicotine, 'the kick', satisfaction."1131 

Indeed, tobacco manufacturers have even conducted opinion surveys that show 

that tobacco users understand that their "satisfaction" is based on nicotine. For instance, 

an affiliate of Brown & Williamson reported that "[m]ost respondents, with a bias toward 

men, realised that nicotine was the attribute in cigarettes causing addiction. It was also 

usually seen as the component providing satisfaction."1132 

These statements show that, when consumers use cigarettes and smokeless 

tobacco, their degree of "satisfaction" is closely related to the phannacological effects of 

nicotine delivered by the product. The statements also show that tobacco manufacturers 

have long been aware of the central role of nicotine in consumer satisfaction. In effect, the 

1130 Farone W A. The Manipulation and Control of Nicotine and Tar in the Design and Manufacture of 

Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 7 (emphasis added). See AR (Vol638 Ref. 2). 

1131 Testimony of Erik Lindqvist, Marsee v. U.S. Tobacco, Civil Action No. 84-2777R (W.D. Ok. Jun 5, 

1986) transcript of jury trial proceeding~. at 1662 (emphasis added). See AR (Vol 22 Ref. 292). In 

another document describing Skoal Bandits, UST states: 

The nicotine contents are more or less equivalent to that of a good quality 

cigarette. The nicotine is absorbed, giv[ing] satisfaction to the smoker. 

Potential Questions and Answers, submitted in Marsee v. U.S. Tobacco, Civil Action No. 84-2777R 

(W.D. Ok. 1986) (emphasis added). See AR (VoL 30 Ref. 509). 

1132 Attitudes Towards Smoking and Health, attached to letter from Johnston AH (market research 

manager, Carreras Rothmans Ltd.) to Bentley HE (Imperial Tobacco Ltd.) (Jul. 26, 1979), at 12 (emphasis 

added). See AR (Vol. 21 Ref. 218). 

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45178 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

statements establish that the manufacturers use "satisfaction" as a code-word for the 

pharmacological effects of nicotine. 

II.E.3. 

The Agency has reviewed the manufacturers' promotional claims and finds that 

they are consistent with-and in fact provide further support for-the Agency's 

conclusion that cigarettes and smokeless tobacco are "intended" to affect the structure and 

function of the body. When manufacturers of an addictive and psychoactive product use 

words like "satisfaction" in their advertisements, the word takes on special connotations to 

the consumer. The advertisements make an implicit pharmacological appeal and hence 

become further _evidence that the products are intended to affect the structure and function 

of the body. 

3. Response to Additional Comments on Legal Theory 

The discussion in sections ll.A-E.2., above, has responded to many of the major 

comments regarding the Agency's legal analysis of intended use. In this section, the 

Agency responds to additional comments of the manufacturers and others on this issue. 

a. General Comments 

1. The tobacco industry contends that the legislative history of the Federal 

Food, Drug, and Cosmetic Act conflicts with the Agency's interpretation of the Act and 

shows that Congress determined that only promotional claims can be considered in 

determining whether a product is "intended to affect the structure or any function of the 

body." 

The Agency has carefully reviewed the legislative history of the Act and concludes 

that it fails to support the tobacco industry's position. Indeed, what little legislative 

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II.E.3. 

history there is confirms the Agency's interpretation that evidence of intent should not be 

restricted to promotional claims. 

Congress most directly addressed the issue during consideration of the 1976 

Medical Device Amendments. In the House Report, the Committee on Energy and 

Commerce specifically considered whether a manufacturer could avoid having its product 

regulated as a medical device intended for human use by labeling and promoting the device 

as intended for animal use only. Contrary to the tobacco industry's position, the House 

Report concluded that FDA would not be bound by the manufacturer's promotional 

claims: 

This is not to say, however, that a manufacturer of a device that is 

banned by the Secretary [for human use] can escape the ban by 

labeling the device for veterinary use. The Secretary may consider 

the ultimate destination of a product in determining whether or not 

it is for human use, just as he may consider actual use of a product 

in determining whether or not it is a device. 

Medical Device Amendments of 1976, H.R. Rep. No. 94-853, 94th Cong., 2d Sess. 14 

(emphasis added), reprinted in An Analytical Legislative History of the Medical Device 

Amendments of 1976, appendix ill. Congress' reasoning confmns the plain meaning of 

the statutory definitions of "drug" and "device." It shows that Congress plainly intended 

FDA to be able to look behind a manufacturer's promotional claims and to determine 

intent based on the actions of the manufacturer and the actual uses of the product. 

The tobacco industry relies primarily on a passage from the 1935 Senate Report, 

which states that ''the manufacturer of the article, through his representations in 

connection with its sale, can determine the use to which the article is to be put." S. Rep. 

No. 361, 74th Cong., 1st Sess. 4 (1935), reprinted in 3 Legislative History 60,663. 

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II.E.3. 

However, the first sentence of the paragraph from which the tobacco industry quotes 

states that "[t]he use to which the product is to be put will detennine the category into 

which it will fall." I d. This quotation is consistent with the Agency's interpretation that 

consumer use can establish "intended use" independent of the manufacturer's claims. 

Furthennore, the passage quoted by the tobacco industry is taken out of context, 

however. Congress was not addressing the issue of how to detennine whether a product 

is intended to affect the structure or function of the body under the Act's drug definition, 

section 201(g)(l)(C). Rather, the issue being discussed was the circumstances under 

which the Agency must regulate a product both as a food and as a drug intended for use in 

the diagnosis or treatment of disease under section 20l(g)(l)(B) of the Act. (By 

defmition, a "food" cannot be regulated as a drug under section 201(g)(l)(C) of the Act.) 

In this context, the Senate Committee stated that a manufacturer could "escape" 

regulation of a product as a food by "representing the article fairly and unequivocally as a 

drug product." /d. 

The Senate Committee did not say that promoting the article exclusively as a food 

could remove the article from the drug defmition of section 201(g)(l)(B), however. To 

the contrary, the Committee stated that "[i]f it is to be used only as a food it will come 

within the defmition of food and none other." ld. (emphasis added). Thus, this legislative 

history shows that a manufacturer's representations cannot force the Agency to regulate a 

product containing a drug as a food; rather, regulation as a food is compelled only if the 

sole use of the product is as a food. Accordingly, the legislative history on which the 

comments rely supports only the limited argument that a manufacturer's representations 

can ensure that a product is regulated as a drug. The passage does not support-and 

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II.E.3. 

indeed contradicts-the position that a manufacturer's representations can prevent 

regulation of a product as a drug. 

The cigarette industry also cites the following language from the same Senate 

Committee report to support the view that a manufacturer's claims are the only relevant 

consideration in detennining the intended use of a product: 

While soaps sold only for ordinary toilet or household use are 

specifically exempted from the defmition of cosmetic and will not 

be subject to the defmition of drug, soaps for which claims 

concerning disease are made or which are sold as pharmacopoeial 

articles will come within the defmition of drug and will thus be 

subject to regulation. 

/d. at 3-4, reprinted in 3 Legislative History 662-663. This language, however, merely 

states the unarguable and long-settled principle that a drug claim can bring any article 

(regardless of the article's composition or effects) within the Agency's jurisdiction. See, 

e.g., United States v. An Article . .. "Sudden Change," 409 F.2d 734, 739 (2d Cir. 1969). 

This is not the issue before the Agency in this case. 

The passages of the legislative history quoted by the tobacco industry, "when read 

fairly and in light of their true context, ... cannot be said to demonstrate a [true] 

Congressional desire." Jewell Ridge Coal Corp. v. United Mine Workers, 325 U.S. 161, 

168-169 (1945). The most that can reasonably be said in support of the tobacco 

industry's view is that the legislative history is sparse and ambiguous-a circumstance that 

calls for deference to the Agency's interpretation of the plain language of the statute. As 

the Supreme Court recently held, "[ w]hen we find ... that the legislative history is 

ambiguous and unenlightening on the matters with respect to which the regulations deal, 

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II.E.3. 

we customarily defer to the expertise of the agency." Rust v. Sullivan, 500 U.S. 173, 

186 0991). 

2. The cigarette manufacturers contend that reading a foreseeability standard 

into "intended use" is unworkable because it would convert "every foreseeable off-label 

use" of a drug or a device into an "intended use" attributable to the manufacturer. In 

support of this contention, the cigarette industry points to what has become known as 

FDA's "practice of medicine" policy, under which the Agency recognizes that physicians 

may, if their medical judgment so dictates, prescribe (but not promote) an approved drug 

for an unapproved use without violating the Act. See 37 FR 16503 (Aug. 15, 1972). 

The Agency disagrees with this comment. Fundamental differences distinguish offlabel uses of approved drugs from cigarettes and smokeless tobacco. First, before a drug 

can have an off-label use, the drug must first have been regulated by FDA for an approved 

use. Unlike off-label uses of approved drugs, cigarettes and smokeless tobacco have not 

previously been regulated by FDA for approved uses. 

Second, FDA's practice-of-medicine policy is based on FDA's long-standing 

policy of not interfering with the practice of medicine. Most off-label uses of prescription 

drugs are prescribed by a physician. FDA has made a policy judgment that, because of the 

involvement of a doctor, FDA will not generally interfere with these off-label uses. The 

policy considerations that underlie the practice-of-medicine policy are entirely missing in 

the case of cigarettes and smokeless tobacco. 

In any event, under the practice-of-medicine policy, "[w]here the unapproved use 

of an approved new drug becomes widespread or endangers the public health, 'FDA will 

investigate and' take whatever action is warranted to protect the public." See 37 FR 

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II.E.3. 

16504 (Aug. 15, 1972) (emphasis added). Thus, this policy recognizes that the Agency 

may assert jurisdiction over unapproved uses of drugs when they become "widespread" or 

endanger the public health-even in the absence of promotional claims by the 

manufacturer. This closely parallels the Agency's interpretation that it may assert 

jurisdiction over products when it becomes foreseeable that they will have drug effects 

upon, and be used for drug purposes by, a significant proportion of consumers. 

3. The smokeless tobacco industry asserts that FDA's reliance on consumer 

use to confer drug or device status on an article is, in effect, an attempt to defme drugs 

and devices in the same way that the Act defmes foods. Under the Act, the term "food" 

means "articles used for food or drink for man or other animals." Section 201(t), 21 

U.S.C. 321(t). The smokeless tobacco industry argues that if"drug" or "device" status 

can be inferred whenever a product is used in a certain way, then the statutory intent 

requirement becomes mere surplusage. 

The Agency disagrees. To determine that a product is a drug or device, FDA is 

required to show that the "intended use" by a manufacturer for a product is as a drug or 

device. This statutory intent requirement can be satisfied based on "use" alone only where 

the use is sufficiently widespread. Evidence of "use" can also provide a relevant source of 

information in combination with other types of evidence. See ASH, 655 F.2d at 239-240. 

4. The tobacco industry characterizes evidence from the statements, research, 

and actions of manufacturers as "classic examples of subjective intent, i.e., motives that 

are not publicly expressed," and states that the regulations allow the Agency to prove the 

"intended use" of a product based only on evidence of "objective intent." Thus, the 

tobacco industry argues that the Agency must disregard the extensive evidence in the 

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II.E.3. 

administrative record indicating that the manufacturers actually intend that cigarettes and 

smokeless tobacco have, and will be used for, pharmacological effects. 

FDA concludes that evidence of the statements, research, and actions of tobacco 

manufacturers is relevant to detennine the "intended use" of a product. The tobacco 

industry's position that evidence bearing on their actual intentions is not relevant conflicts 

with the plain language of the Act. The tobacco industry's position also conflicts with the 

regulations defining "intended uses." 1133 

Moreover, acceptance of the tobacco industry's argument that FDA must 

disregard evidence of the manufacturers' statements, research, and actions would frustrate 

the public health purposes of the Act. FDA does not test products before they are 

marketed, nor does the Agency have the right to examine the manufacturer's testing data 

before a new product is marketed unless the manufacturer submits an application for 

approval of the drug or device prior to marketing. Consequently, neither FDA nor the 

consumer is ordinarily in a position to know whether a new product that the manufacturer 

claims is not a drug or device in fact has pharmacological effects on consumers. In 

contrast, the manufacturer, through its research and product development activities, 

knows the effects of the product on consumers and knows how the manufacturer's 

fonnulation and design choices are likely to influence the uses to which the product will be 

put. To interpret "intended use" to exclude evidence of what the manufacturer has 

1133 The phrase "subjective intent" is ambiguous. To the extent that "subjective intent" is understood to 

refer to the actual intent of the manufacturer, the Agency may consider objective evidence of this 

"subjective" or actual intent in determining the manufacturers' intent Alternatively, to the extent that 

"subjective intent" is understood to refer to the intent the manufacturer claims to have, see, e.g., NNF A v. 

Mathews, 557 F.2d at 334; see also Latex Surgeons' Gloves, 799 F. Supp. at 1295, "the FDA is not bound 

by the manufacturer's subjective claims of intent but can fmd actual therapeutic intent on the basis of 

objective evidence." Mathews, 557 F.2d at 334. 

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II.E.3. 

designed its product to do, and anticipates its product will be used for, would thus permit, 

and even encourage, unscrupulous manufacturers to conceal their knowledge of the 

products' significant pharmacological effects so as to avoid application of the Act This 

would directly undercut the public health purposes of the Act. 

Accordingly, FDA concludes that objective evidence of tobacco manufacturers' 

actual intent from their statements, research, and actions is relevant to establishing the 

intended use of cigarettes and smokeless tobacco. 1134 

b. Comments on Administrative Precedents 

The tobacco industry and an individual commented on the administrative 

precedents. The comments make two main arguments. First, the comments argue that 

FDA did not rely solely on known pharmacological effects or consumer use to establish 

the intended use of the products discussed in the examples. Second, the comments argue 

that the examples cited did not represent authoritative interpretations of the law. The 

comments address each of the examples in some detail. 

FDA's response is set forth below. In brief, the cited examples are valid 

precedents in which FDA found intended drug or device use based on factors other than 

express claims (i.e., known effects or consumer use). Moreover, contrary to the tobacco 

1134 Even if the Agency accepted the tobacco industry's argument that manufacturers' statements, 

research, and actions cannot be considered to prove the manufacturers' intent. it does not follow that such 

evidence is not also relevant for other purposes. For example, much of this evidence corroborates the 

scientific evidence showing that tobacco products have significant pharmacological effects and are used 

by consumers to obtain these effects. The Agency may properly use the evidence of the statements, 

research, and actions to establish these facts. Furthermore, the Agency may properly use the evidence 

from the statements, research, and actions of the manufacturers to rebut assertions by the manufacturers 

that they do not intend to make products that have-and are used for pharmacological effects. 

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ILE.3. 

industry's assertions, the examples support the position that nicotine in tobacco products 

is a drug. 

1. The tobacco industry asserts that FDA's administrative precedents are not 

analogous to tobacco products because the precedents in fact relied on implied 

promotional claims in establishing intended use. For instance, the comments assert that 

the mere listing of the word "honnone" on a skin cream was viewed by FDA as an implied 

drug claim and argue that "the Agency asserted that any statement in the labeling of these 

products that honnones are present is an implied drug claim ... Thus, the detennining 

factor is claims-implied or express-made in marketing the product."1135 

These comments on the basis for FDA's fmding of intended use are incorrect. 

First, in most of the administrative precedents, no implied claims were involved. For 

instance, there were no express or implied claims involved in the Agency's assertion of 

jurisdiction over "khat." Similarly, in most of the imitation cocaine precedents, the 

manufacturers were deliberately trying to avoid FDA jurisdiction by advertising their 

products for nondrug uses.1136 The novelty condom precedents discussed in the 

Jurisdictional Analysis, in which the condoms were labeled as novelty and not functional 

condoms, also did not involve any promotional claims. See 60 FR 41530 (Aug. 11, 1995). 

1135 Joint Comment of Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol. II, at 91 (emphasis in 

original). See AR (Vol 535 Ref. 96). 

1136 The Agency recognizes that in one imitation cocaine case, United States v. Storage Spaces 

Designated Nos. "8": and "49," 777 F.2d 1363 (9th Cir. 1985), the reviewing court did f"md some 

evidence of promotional claims. Even in that case, however, "the items were called 'incense' and 

advertised as 'Not for drug use,"' and the court stated that "[s]elf-serving labels cannot be allowed to 

mask the vendor's true intent as indicated by the overall circumstances." /d. at 1366 n.5. In most of 

FDA's actions against imitation cocaine, the manufacturers' promotional materials were generally 

designed to disguise the actual intended use. 

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II.E.3. 

It is true that the listing of hormones on the label of skin creams can be considered 

an implied drug claim. However, this implied claim argument does not distinguish 

cigarettes and smokeless tobacco from the administrative precedents. If the mere listing of 

the drug ingredient "hormone" on a skin cream constitutes an implied drug claim, then 

similar implied drug claims are regularly made for tobacco products. Many cigarette 

advertisements list nicotine deliveries. 1137 Nicotine is a widely recognized drug with 

significant pharmacological effects. It is the active ingredient in several products regulated 

as drugs by FDA. Therefore, if the listing of hormones in skin creams can be considered 

an implied drug claim, the listing of nicotine in cigarette advertisements can also be 

considered an implied drug claim. 

Moreover, in the case of hormone-containing skin creams, FDA independently 

relied upon the foreseeable drug effects of the creams as a basis for establishing intent. 

FDA took the position that the inclusion of pharmacologically active levels of hormones in 

the skin creams was a sufficient basis for regulating the products as drugs. See 58 FR 

47611, 47613 (Sep. 9, 1993). 

2. The tobacco industry also alleges that, in some of the examples, intended 

drug use had previously been established because the product contained an active drug 

ingredient For instance, the tobacco industry argues that the imitation cocaine cases 

involved bulk prescription drug ingredients (e.g., lidocaine and ephedrine) that were 

diverted for use in the imitation cocaine products. The comments' point seems to be that 

once intended drug use is established for one use of a drug, FDA can establish the same 

1137 American Society of Addiction Medicine, Comment (Dec. 29, 1995), appendix 6. See AR (Vol 528 

Ref. 97). 

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II.E.3. 

drug intent with respect to manufacturers of other products containing the drug as an 

ingredient. 

The Agency agrees that the presence of a known drug ingredient can be substantial 

evidence of an intent to affect the structure and function of the body. However, the 

Agency disagrees that this point distinguishes any of the administrative precedents from 

tobacco products. To the contrary, cigarettes and smokeless tobacco contain a known 

drug, nicotine, that has addictive and other significant pharmacological effects. It is the 

active drug ingredient in several products regulated as drugs by FDA, including nicotine 

patches, nicotine gum, and nicotine nasal sprays. The comments' position leads to the 

conclusion that products containing nicotine, including cigarettes and smokeless tobacco, 

are also drugs. 

3. The tobacco industry argues that the administrative precedents are not 

authoritative interpretations of the law. Instead, the comments assert, the examples 

consist of unchallenged assertions, preliminary pronouncements in certain rulemaking 

proceedings, and judicial default and consent decrees, rather than specific actions and 

litigated cases. One comment minimizes some of the examples by stating that preliminary 

views and opinions are not binding on FDA itself. Another comment asserts that the 

"Agency position" in the case of one example, vaginal products, was really that of an 

independent advisory committee, and, in any case, the Agency itself later rejected the 

position. Still another comment contends that the Agency cited a relatively small number 

of examples, implicitly suggesting that this limited the precedential value of the collection 

of examples. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45189

II.E.3. 

The Agency disagrees with the premise that only examples supported by binding 

regulation or judicial precedent would be valid evidence of Agency interpretation. FDA 

cited the examples to illustrate that the Agency has over the years consistently taken the 

position that express drug or device claims are not required for a finding of intended 

phannacological use or effect. These examples constitute highly relevant evidence of the 

Agency's past interpretations of its governing statute. 

Further, FDA's statements in Federal Register preambles and proposed 

regulations-although not binding-are official statements of Agency position. See 21 

CFR 10.85(d)(l) and (e) (texts of proposed and final regulations, and related preambles, 

are valid FDA interpretations). Although the Agency did not concur fully with its 

advisory committee in the vaginal products example, the position expressed in the example 

was that of the Agency. See 59 FR 5226, 5227 (Feb. 3, 1994). These and other official 

Agency interpretive statements deserve strong consideration. Notifications to 

manufacturers also represent official Agency positions. See 21 CFR 10.85(dX1); see also 

Kickapoo Oil Co. v. Murphy Oil Corp., 779 F.2d 61,66 (Temp. Em. Ct. App. 1985) 

("Notice of Probable Violation" constitutes agency interpretation). 

The examples document the Agency's consistent historical position that intended 

use is not limited to express claims. See Udall v. Tallman, 380 U.S. 1, 17-18 (1965) 

(consistent past agency practice can be evidence of agency interpretation). The examples 

cover a number of years and represent a variety of circumstances. They cover both 

individual products and categories of products. They include drugs and devices. The 

intended users ranged from physicians and researchers to ordinary consumers to those 

seeking a cocaine substitute. They include intended use based on both product effect and 

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II.E.3. 

consumer use. The Agency's application of the intended use concept is not a new 

regulatory construct. Rather, as these examples illustrate, the Agency has applied the 

concept in a variety of contexts, both formal and informal. Whether any of these examples 

represent "binding" interpretation is irrelevant given the limited purpose for which they are 

cited. As the court in Kickapoo Oil found, enforcement actions, notices of potential 

violations, statements in various briefs, and similar documents all constitute persuasive 

evidence of an agency's past interpretation of its governing statute. 

4. One comment attempts to distinguish tobacco products from khat by 

arguing that FDA relied on product effect and consumer use to regulate khat only because 

there were no express claims, whereas tobacco products have express claims (e.g., for 

smoking taste and pleasure). The Agency disagrees. Even if the khat had been labeled as 

a decorative plant or a culinary herb, for example, such express claims would not have 

been binding and FDA would have taken the same action. (In fact, as the comment 

acknowledges, FDA suspected that the khat might have been falsely declared as a 

permitted Egyptian vegetable.) 

The same comment also argues that FDA was merely aiding a sister agency, the 

Drug Enforcement Agency (DEA), in controlling a product that DEA considered to be a 

drug of abuse. The comment notes that it is not necessary to establish intended use for a 

DEA-controlled substance. In fact, for a decade after FDA first issued the khat Import 

Alert, DEA did not have jurisdiction over the product. Even after the active ingredient 

was listed as a controlled substance, FDA retained separate jurisdiction to detain the 

product. Obviously, any FDA detention action-before or after khat was scheduled as a 

controlled substance-had to be accomplished under FDA's authority. 

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ILE.3. 

The comment further argues that the example is not relevant because the 

evidentiary standard for import detention is low (i.e., that the product only has to "appear" 

to be violative under section 801(a) of the Act, 21 U.S.C. 381). A differing evidentiary 

standard does not render the evidence relied upon by the Agency in determining khat's 

intended use irrelevant to establishing intended use. In determining whether an imported 

product "appears" to be a drug or device, the Agency uses the same kinds of evidence as it 

does in determining whether a domestic product "is" a drug or device. While the 

Agency's evidentiary burden under section 801(a) may be lower than it is when the 

Agency finally determines that a product is a drug or device under the Act, the types of 

evidence that are relevant do not differ. 

Still another comment asserts that, because khat is intended to be used as a tea, it 

is a food and not a drug. The Agency agrees that the Federal Food, Drug, and Cosmetic 

Act excludes a food from the definition of "drug" under section 201(g)(l)(C). However, 

khat is not a food because it is not used primarily for taste, aroma, or nutritive value. 

Nutrilab, Inc., 713 F.2d at 337. Instead, its foreseeable use was to obtain stimulant 

narcotic effects. Moreover, the Agency notes that khat is not used exclusively as tea, but 

is also chewed and smoked like tobacco. 

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II. F. 

F. RESPONSE TO ADDITIONAL COMMENTS 

In this section, the Agency responds to additional comments regarding the 

evidence that cigarettes and smokeless tobacco are "intended to affect the structure or any 

function of the body" and the Agency's use of that evidence. 

1. Some comments assert that FDA may not rely on evidence relating to 

particular manufacturers to find intended use for all manufacturers of a particular product, 

but must instead detennine intended use on a product-by-product basis by producing 

evidence specific to each individual manufacturer and even to each individual brand of 

tobacco products. The Agency disagrees with these comments. In appropriate 

circumstances, FDA can detennine that a type of product is subject to its jurisdiction 

without focusing on the individual manufacturer or brand. 

As discussed in other parts of section II., the evidence of intended use applies to all 

cigarettes and smokeless tobacco products on the market. This evidence establishes that 

cigarettes and smokeless tobacco are highly addictive, cause other psychoactive effects 

(such as relaxation and stimulation), and affect weight regulation and that these effects are 

widely accepted in the scientific community. Based on this evidence, it is foreseeable to 

any reasonable manufacturer that cigarettes and smokeless tobacco will have and be used 

for these addictive, psychoactive, and other pharmacological effects. The evidence also 

shows that actual consumer use of these products for their pharmacological effects is 

predominant and, in fact, nearly exclusive. Given the foreseeable pharmacological effects 

and uses of cigarettes and smokeless tobacco and the actual consumer use of cigarettes 

and smokeless tobacco for pharmacological effects, the Agency concludes that all of these 

products are "intended to affect the structure or any function of the body." 

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II.F. 

In addition, the Agency has collected evidence of the tobacco industry's 

statements, actions, and research demonstrating the industry's widespread awareness of 

the addictive and other pharmacological effects of cigarettes and smokeless tobacco, the 

industry's widespread knowledge that consumers use its products for these effects, and 

the industry's widespread manipulation of nicotine levels in its products to ensure that 

adequate amounts of nicotine are delivered to consumers. This evidence is further 

objective evidence that these products are "intended to affect the structure or any function 

of the body." 

In the case of cigarettes, the evidence shows that the major manufacturers engaged 

in extensive research into nicotine pharmacology either as individual companies or through 

the industry-funded Council for Tobacco Research. Moreover, the evidence shows that 

the major cigarette manufacturers manipulate the nicotine level in cigarettes through 

techniques such as blending, the use of ammonia technologies, and the design of cigarette 

fllters and ventilation. In the case of smokeless tobacco, the evidence shows that the 

major manufacturers of smokeless tobacco have also sponsored research into nicotine 

pharmacology either as individual companies or through the industry-funded Smokeless 

Tobacco Research Council. In addition, the evidence shows widespread nicotine 

manipulation by major smokeless tobacco manufacturers through pH adjustments or the 

use of teabag-like pouches that reduce nicotine delivery in their starter products. 

Although the Agency often chooses to take enforcement actions against particular 

manufacturers of a specific product rather than to assert regulatory authority over all 

manufacturers of the product as a group, the Agency may choose a different regulatory 

approach when circumstances warrant. The Agency has concluded that such a different 

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45194 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II. F. 

approach is appropriate here. In concluding that these products are drug delivery devices 

within the meaning of the Act, the Agency is relying not on product labeling or express 

representations in promotional materials, 1138 but on other relevant objective evidence of 

intended use-dispositive evidence concerning the foreseeable pharmacological effects 

and uses of these products, actual consumer use of these products, and evidence of 

industry-wide actions, practices, and knowledge. Further, the public health concerns that 

the Final Rule seeks to address-the appeal and availability of tobacco products to young 

people~ be addressed effectively and efficiently only through the regulation of all 

cigarettes and smokeless tobacco as a group. 

There is ample precedent to support FDA regulation of essentially identical 

products as a group, rather than setting criteria or restrictions on a product-by-product or 

manufacturer-by-manufacturer basis. For example, in administering the Act's device 

provisions, the Agency traditionally classifies at one time all products that are sufficiently 

similar that they can be considered the same type of device for purposes of applying the 

Act's regulatory controls. See 21 CFR 860.3(i) (definition of"generic type of device"). 

In making these device classification decisions, the Agency relies on the cumulative 

evidence from several manufacturers. Further, reclassification of one product of a 

particular type results in the reclassification of the entire group. See Proposed Rule: 

Medical Devices Classification Procedures, 42 FR 46028 (Sep. 13, 1977); see also Ftnal 

Rule: Medical Devices Classification Procedures, 43 FR 32988 (Jul. 28, 1978). Thus, 

FDA applies the same regulatory requirements to all devices within an identified device 

1138 As discussed in section II.E.2., above, however, the implied claims in tobacco manufacturers' 

promotional materials provide further support for the Agency's conclusion. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45195

II. F. 

type. This approach is necessary to provide similar regulatory treatment for essentially 

identical products of different manufacturers and distributors. See 42 FR 46031; 43 FR 

32989. Proceeding otherwise would require FDA to classify individually each 

manufacturer's device and to undertake the classification process whenever a new 

manufacturer marketed a product within an existing category of devices. Because 

cigarettes and smokeless tobacco affect the structure and function of the body and are 

devices under the Act, it is consistent with the Agency's approach to device classification 

to determine the intended use of all cigarettes and smokeless tobacco. 

Similarly, the Agency limits the use of certain potentially dangerous ingredients in 

drug products by establishing uniform standards rather than manufacturer-specific 

restrictions. See, e.g., 21 CFR 310.506 (1974 action restricting use of vinyl chloride); 21 

CFR 310.507 (1977 action restricting use of trichloroethane in aerosol products); 21 

CFR 310.508 (1975 action restricting use of halogenated salicylanilides); 21 CFR 310.513 

(1976 action restricting use of chloroform in drug products). 

Regulating the products of some cigarette and smokeless tobacco manufacturers 

while allowing others to be marketed without the restrictions that FDA has determined are 

necessary would frustrate important public health goals. For example, the goal of 

reducing tobacco use among young people would be severely compromised if one tobacco 

company could continue advertising in the manner limited by the regulations. Similarly, it 

would be anomalous to prohibit some manufacturers, but not others, from filling vending 

machines with cigarettes in facilities accessible to persons under the age of 18. 

Furthermore, if FDA proceeded against some but not all manufacturers, the result would 

be inequitable because some companies would be subject to FDA regulation while their 

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45196 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II. F. 

competitors remain unregulated. The Supreme Court has recognized that proceeding 

against similar products one at a time can result in "great inequities .... [because] 

competitors selling drugs in the same category would go scot-free until the tedious and 

laborious procedures of litigation reached them." Weinberger v. Hynson, Westcott and 

Dunning, Inc., 412 U.S. 609, 626 (1973). 

One comment cites a statement in Action on Smoking and Health v. Harris (ASH), 

655 F.2d 236, 242 n.IO (D.C. Cir. 1980), that "[t]he very structure of the Act. .. calls for 

case-by-case analysis," and argues that the statement supports its argument that the 

Agency must make jurisdictional determinations on a product-by-product or brand-bybrand basis. This statement in ASH, however, was made in the context of a discussion of 

the Agency's freedom to revise its interpretation of its jurisdiction without constraint by 

long-standing interpretations. In ASH, the court found that FDA's decision to deny a 

citizen's petition requesting that the Agency exercise jurisdiction over cigarettes was not 

arbitrary, capricious, or contrary to law. /d. at 241, 243. The court made clear, however, 

that the Agency decision reviewed in the ASH case would not prevent FDA from revising 

its interpretation if new evidence became known. /d. at 242 n.IO. New evidence would 

present a new "case" to the Agency that would appropriately be analyzed on its own 

merits.1139 The statement in ASH therefore does not stand for the proposition that the 

Agency must niake jurisdictional determinations on a manufacturer- or brand-specific 

basis. 

1139 See section IV., below, for a detailed discussion of why new evidence justifies the Agency's change in 

position on the application for the Act to tobacco products. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45197

II.F. 

Moreover, although it is true that the Agency often conducts product-by-product 

analyses of its jurisdiction under the Act, it is by no means clear that a "product" is 

equivalent to a "brand" or a "manufacturer" in this instance, given that different brands of 

cigarettes, snuff, and chewing tobacco are, respectively, virtually identical in content, size, 

shape, and packaging and are marketed in a closely similar manner. 

Here, the Agency has elected to assert regulatory authority over cigarettes and 

smokeless tobacco by issuing regulations, rather than by undertaking enforcement actions 

against particular brands or manufacturers, and litigating, on a case-by-case basis, the 

status of each product. This approach is authorized by the Act. See section 70l(a) of the 

Act, 21 U.S.C. 371(a) (providing "[a]uthority to promulgate regulations for the efficient 

enforcement of [the] Act"); see also Hynson, 412 U.S. at 624-625 (noting that, although 

regulatory agencies "usually proceed[] on a case-by-case basis, giving each [party] subject 

to regulation separate hearings .... [t]here is not always a constitutional reason why that 

must be done"). The Agency concludes that the approach it has adopted here has 

provided the manufacturers with ample opportunity to raise the numerous issues and 

concerns they share, as reflected in the voluminous consolidated comments submitted by 

both the cigarette and smokeless tobacco industries, as well as to raise evidentiary and 

other issues specific to individual manufacturers. The Agency further concludes that this 

approach is the one that most effectively serves the public health concerns the fmal rule 

seeks to address. 

In support of the argument that the Agency is required to have evidence specific to 

each manufacturer, the comments cite cases that involved instances in which the evidence 

of intended use consisted only of labeling and promotional materials containing express 

541 
45198 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.F. 

claims. These cases support the principle that a connection must exist between a 

manufacturer's product and the representations in labeling and promotional materials for 

such evidence to support a finding that the product is "intended" to be a drug or a device, 

for example, evidence that consumers rely on these representations. See, e.g., United 

States v. Articles of Drug for Veterinary Use, 50 F.3d 497, 500-501 (8th Cir. 1995); 

United States v. Pro-Ag, Inc., 196 F. Supp. 1219, 1226-1229 (D. Minn. 1991); Estee 

Lauder, Inc. v. FDA, 727 F. Supp. 1, 2-3 (D.D.C. 1989). Estee Lauder, for instance, 

involved traditional skin cream ingredients that by themselves were "cosmetics" but not 

"drugs" within the meaning of the Act. 727 F. Supp. at 3. The only evidence that made 

the products "drugs" was the manufacturer's anti-aging claims in the labeling. I d. In such 

a case, there would not be a basis to attribute Estee Lauder's drug claims to another 

manufacturer's skin cream whose labeling contained no drug claims. Evidence regarding 

drug claims in the labeling of a specific product is generally appropriately limited to the 

manufacturer that created or adopted the labeling and the product that accompanies 

the labeling. 

These cases do not, however, support the argument that the Agency is required to 

have manufacturer-specific evidence when evidence other than labeling and promotional 

materials is used to determine intended use.1140 As a result, the cases are not controlling 

here because the evidence of the intended use of tobacco products is not based on express 

1140 One comment also cites Hanson v. United States, 417 F. Supp. 30 (D. Minn. 1976), aff'd per curium, 

540 F.2d 947 (8th Cir. 1976). In Hanson, the court explained that "the 'intended use' of a product ... is 

determined from its label, accompanying labeling, promotional claims, advertising, and any other 

relevant source." /d. at 35 (emphasis added). The comment omitted the italicized language. Not only 

does the case not support the proposition for which it is cited, but the question of whether "intended use" 

determinations must be made on a product-by-product basis was not before the coun. 

542 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45199

claims in labeling and promotional materials but on evidence that applies to all 

manufacturers of cigarettes and smokeless tobacco. 

II. F. 

In the case of tobacco products, the evidence of intended use is far broader than 

labeling for specific products. The evidence regarding the foreseeable pharmacological 

effects and uses of cigarettes and smokeless tobacco and the actual consumer use of 

cigarettes and smokeless tobacco for pharmacological effects described in sections ll.A. 

and ll.B., above, applies equally to all ofthe manufacturers and is sufficient to establish 

that each individual product is "intended to affect the structure or any function of the 

body," regardless of the identity of the manufacturer. The evidence concerning the 

statements, actions, research, and knowledge of the manufacturers also supports such a 

determination. As discussed in sections II. C. and II.D., above, this evidence shows that 

tobacco manufacturers conducted similar research into nicotine pharmacology; engaged in 

similar product research and development; use similar methods to manipulate and control 

nicotine deliveries in commercial products; and jointly belong to associations that have 

conducted further research into nicotine pharmacology. The evidence thus shows both a 

widespread understanding within the industry of the pharmacological effects and uses of 

cigarettes and smokeless tobacco and widespread design of these products to provide 

pharmacologically active doses of nicotine. 

For all of these reasons, it is reasonable and consistent with the public health 

protection goals of the Act generally and of the tobacco regulations specifically to 

attribute evidence from all relevant sources-the foreseeability of the pharmacological 

effects of nicotine for which consumers use cigarettes and smokeless tobacco, the actual 

consumer use of these products for these effects, the industry's widespread knowledge of 

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45200 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II.F. 

nicotine's pharmacological effects and uses, and the industry's widespread manipulation 

and control of nicotine-to all manufacturers of cigarettes and smokeless tobacco. 1141 

2. Tobacco industry comments argue that some of the statements, research, 

and actions attributed to particular manufacturers are not relevant to intended use because 

they are not contemporaneous with the sale of currently marketed products. The Agency 

disagrees with these comments. One industry comment cites cases involving products 

1141 The Agency has also determined that processed loose cigarette tobacco, which is used by smokers who 

roll their own cigarettes, is subject to FDA jurisdiction. One comment contends that the use of "roll-yourown" cigarette tobacco is ''fundamentally different from other tobacco products." Consolidated comment 

of the "Roll-Your-Own" cigarette tobacco manufacturers (Brown & Williamson Tobacco Corp., Robert 

Burton Associates, Consolidated Cigar Corporation, Douwe Egberts Van Nelle Inc., House of Windsor, 

Inc., Lane Limited, and Republic Tobacco, L.P.) (Jan. 2, 1996), at 11. See AR (Vol. 702 Ref. 1578). The 

Agency disagrees. Processed loose cigarette tobacco is a cigarette that has not yet been assembled Rollyour-own cigarettes contain tobacco and are smoked. Like the tobacco used in manufactured cigarettes, 

loose tobacco contains pharmacologically active doses of nicotine. And, like the tobacco incorporated into 

commercially manufactured cigarettes, loose tobacco is not simply raw leaves as they are picked from 

plants in the field Rather, this tobacco has been cured and treated with many chemicals, and had its 

moisture content controlled Consumers obtain separately the components of a cigarette (e.g., processed 

loose tobacco and special cigarette papers) and then use those components to assemble their own 

cigarettes. While these homemade products are more crudely manufactured than those produced by 

cigarette companies, they have the same effect-the smoke from these products is inhaled, and the 

products deliver nicotine, a drug, for inhalation by the lungs and absorption into the brain. Loose tobacco 

thus has foreseeable and actual pharmacological effects and uses parallel to manufactured cigarettes, and 

therefore is "intended to affect the structure or any function of the body" within the meaning of the Act 

Further, one of the manufacturers of "roll your own" cigarette tobacco, Brown & Williamson, is also a 

manufacturer of cigarettes (as well as a manufacturer of smokeless tobacco). Evidence concerning Brown 

& Williamson's statements, research, and actions, particularly its knowledge that consumers use tobacco 

products for pharmacological purposes, is discussed in section II. C., above. Because a "roll your own" 

cigarette is fundamentally the same product as a commercially manufactured cigarette, the evidence 

discussed in section II. C., above, is also relevant to the manufacturers' intent in producing and selling 

"roll your own" cigarette tobacco, and is further evidence that processed loose tobacco is subject to FDA 

jurisdiction. 

In addition to the factual and legal arguments supporting the Agency's assertion of jurisdiction over 

processed loose cigarette tobacco, public health concerns also support including processed loose cigarette 

tobacco in this proceeding. A ''roll-your-own" cigarette poses the same risks as a commercially 

manufacturered cigarette. The Agency's regulations include restrictions on the access of persons younger 

than 18 years of age to these products. As discussed in section III.E. of the Final Rule, the public health 

goals of the Agency's regulations would be thwarted if the regulations were limited to manufactured 

cigarettes and smokeless tobacco. To exclude processed loose tobacco would provide a simple and obvious 

way to avoid the restrictions in the regulation. If such an exception existed, cigarettes could be packaged 

and sold in such a way as to be considered "roll-your-own" products, and young persons would have 

access to addictive tobacco products, thereby undermining the purpose of the Final Rule. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45201

II. F. 

whose labeling expressly promoted the products as having therapeutic value in treating 

certain diseases or as affecting the structure or function of the body. See United States v. 

Pro-Ag, Inc., 796 F. Supp. 1219 (D. Minn. 1991), aff'd, 968 F.2d 681 (8th Cir. 1992); 

United States v. Neptone, No. C-83-0864 EFL, CCH <][ 38,240 (N.D. Cal. Oct. 25, 1983); 

United States v. Various Quantities ... "Instant Alberty Food," 83 F. Supp. 882 (D.D.C. 

1949). In these cases, however, promotional claims made to consumers were the sole 

basis for establishing intended use. As a result, the courts found that labeling and other 

promotional material must ordinarily accompany the product and be relied on by 

consumers purchasing the products. These cases are not controlling, however, where the 

product has widely recognized pharmacological effects and uses and the government is 

relying on evidence from other sources-such as evidence of the known and foreseeable 

pharmacological effects and uses and actual consumer use of the product, and the 

statements, research, and actions of the manufacturers that demonstrate their intention to 

facilitate the product's pharmacological effects. 

Unlike labeling, which is usually evidence of a manufacturer's current express 

claims for a product,1142 the internal documents remain relevant because they evidence an 

actual intent to affect the structure or function of the body that has not been refuted by 

more current actions. Indeed, the court in Alberty Food, a case cited by the comments, 

recognized that the mere fact that a manufacturer or shipper stops producing and 

1142 In certain circumstances, such as where consumers continue to rely on previous claims or where 

discontinued labeling shows a "continuity of purpose" to sell a product as a drug, old labeling can 

establish intended use. See, e.g., United States v. Nutrition Service, Inc., 227 F. Supp. 375, 386-387 

(W.D. Pa. 1964); United States v. 789 Cases ... LAtex Surgeons' Gloves, 799 F. Supp. 1275, 1285 

(D.P.R 1992), aff'd, 347 F.2d 233 (3d Cir. 1965). 

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45202 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II. F. 

distributing literature that renders a drug misbranded is not an unconditional defense to a 

charge that the manufacturer or shipper intended to misbrand drugs subject to an 

enforcement action: 

[i]t is only to the extent that the abandonment of such dissemination 

creates an inference that the shipper did not intend, when it shipped 

the drugs in interstate commerce, that they be used for the 

treatment of the diseases named on the booklets, that the 

abandonment can be said to be an effective defense. The 

government might introduce evidence to show that, 

notwithstanding such abandonment, it was still the intention 

of the shipper that the drugs be used for the treatment 

of the diseases . .. 

83 F. Supp. at 887 (emphasis added). 

The court's analysis is pertinent here. The record establishes that the 

manufacturers have not "abandoned" the design, manufacturing, and marketing practices 

discussed in the internal documents. To the contrary, the products continue to be 

marketed and sold in virtually the same manner and form as they were when those 

documents were produced. See section II.C.2.e., above. Thus, the record here supports 

the Agency's conclusion that the internal documents remain a relevant source of evidence 

of intended use. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45203

II. G. 

G. CONSIDERED CUMULATIVELY, THE EVIDENCE 

OVERWHELMINGLY DEMONSTRATES THAT CIGARETTES 

AND SMOKELESS TOBACCO ARE INTENDED TO AFFECT 

THE STRUCTURE AND FUNCTION OF THE BODY 

As discussed in sections IT.A.-F., the evidence in the record provides several 

independent bases for the Agency's detennination that cigarettes and smokeless tobacco 

are intended to affect the structure and function of the body. Independently, the evidence 

in each of these distinct categories of evidence is a sufficient basis for the Agency's 

conclusion that the manufacturers of cigarettes and smokeless tobacco "intend" their 

products to affect the structure and function of the body. 

In reaching a fmal determination of the intended use of cigarettes and smokeless 

tobacco, it is also appropriate for the Agency to consider the objective evidence of 

intended use as a whole. Considered together, the evidence in each of the different 

categories of evidence before the Agency-the evidence of the foreseeable 

pharmacological effects and uses of cigarettes and smokeless tobacco; the evidence of the 

actual consumer use of cigarettes and smokeless tobacco for pharmacological purposes; 

and the evidence of the manufacturers' intent as revealed through the manufacturers' 

statements, research, and actions are highly consistent and support the same conclusion: 

cigarettes and smokeless tobacco are intended to affect the structure and function of the 

body. When viewed from the perspective of what a reasonable manufacturer would 

foresee, how consumers actually use the products, or what is revealed in internal company 

documents, the evidence in the record demonstrates that cigarettes and smokeless tobacco 

have intended pharmacological effects and uses. This convergence of independent 

categories of evidence is highly probative. Taken as a whole, therefore, the evidence in 

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45204 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

II. G. 

the record convincingly establishes that cigarettes and smokeless tobacco are "intended" 

to affect the structure and function of the body within the meaning of the Act. 

548 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45205

III. 

llL CIGARETTES AND SMOKELESS TOBACCO ARE COMBINATION 

PRODUCTS CONSISTING OF "DRUG" AND "DEVICE" COMPONENTS 

As discussed in sections I. and IT., above, the Agency has determined that ( 1) 

cigarettes and smokeless tobacco "affect the structure or any function of the body," and 

(2) these effects on the structure and function of the body are "intended" by the 

manufacturers. These two determinations establish that cigarettes and smokeless tobacco 

are subject to FDA jurisdiction under the Federal Food, Drug, and Cosmetic Act (the 

Act). This section explains the basis for the Agency's conclusion that cigarettes and 

smokeless tobacco are "combination products" consisting of a "drug," nicotine, and 

"device" components that deliver nicotine to the body. 

Under the Act, a product that is intended to affect the structure or function of the 

body can be a "drug" under section 201(g)(l)(C) or a "device" under section 20l(h)(3). 

The principal difference between a "drug" and a "device" is that a device is "an 

instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other 

similar or related article" that "does not achieve its primary intended purposes through 

chemical action within or on the body ... and ... is not dependent upon being 

metabolized for the achievement of its primary intended purposes." Section 20l(h)(3). 

Since the enactment of the Safe Medical Devices Act of 1990, certain products that are 

intended to affect the structure or function of the body can also be regulated as a 

"combination product," consisting of a drug and a device. Section 503(g)(l), 21 U.S.C. 

353(g)(l). A combination product is a product composed of two regulated components, 

such as a drug and a device, that "are physically, chemically, or otherwise combined or 

mixed and produced as a single entity." 21 CFR 3.2(e)(l). Examples of combination 

549 
45206 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

III. 

products include drug delivery systems such as nebulizers, transderrnal patches, and 

prefllled syringes, 1143 as well as prefllled intravenous infusion pumps. 

In the Jurisdictional Analysis, the Agency set forth its current view that cigarettes 

and smokeless tobacco products are combination products under the Act. The Agency 

explained that "FDA considers device-like products, such as instruments, implements, 

machines, contrivances, implants, or other similar or related articles ... , whose primary 

purpose is delivery of a drug, and that are distributed with a drug product, to be drug 

delivery systems." 60 FR 41521. The Agency concluded, based on the evidence then 

available to it, that: 

Cigarettes and smokeless tobacco function in a similar manner in that they 

contain a drug, nicotine; are used to deliver that drug to the site at which 

the drug will be absorbed into the body, the mouth or lungs; and after the 

drug has been delivered, the delivery system, the cigarette butt or 

smokeless tobacco material, depleted of nicotine, remains and must be 

disposed of. Only the nicotine delivered by these products achieves its 

primary intended purpose by chemical action in or on the body. 

60 FR 41521-41522. With respect to cigarettes, the Agency further explained that: 

The primary purpose of parts of the cigarette ... is to effectuate the 

delivery of a carefully controlled amount of nicotine to a site in the human 

body where it can be absorbed. The drug, nicotine, is generally contained 

within the treated rolled tobacco. The delivery system, the nicotinecontaining cigarette, must be lit to have its intended effect on the structure 

or function of the body, and, once lit and used, is discarded. When lit, the 

cigarette produces nicotine-containing smoke, which is inhaled by the 

consumer and when absorbed into the lungs, yields on average 

approximately 1.0 mg of nicotine. 

60 FR 41522. With respect to smokeless tobacco, the Agency further explained that: 

Smokeless tobacco products function like infusion devices or transderrnal 

patches that deliver continuous amounts of nicotine to the cheek tissue for 

1143 Intercenter Agreement between the Center for Drug Evaluation and Research and the Center for 

Devices and Radiological Health (Ocl 31, 1991), at 6. See AR (Vol 30 Ref. 289). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45207

absorption into the bloodstream. The device element of smokeless 

products is the tobacco, which contains the nicotine but is not intended to 

be consumed. Instead, in normal use, most of the tobacco in the product is 

not absorbed by the user and is removed from the mouth after absorption 

of the nicotine through the cheek tissue. 

The primary purpose of the tobacco is to provide a palpable vehicle 

that allows nicotine to be extracted from the tobacco by the user's saliva so 

that it may be absorbed into the body. 

60 FR 41522-41523. 

After carefully considering the evidence in the administrative record and the 

III. A. 

comments received, the Agency reaffirms these findings and concludes that cigarettes and 

smokeless tobacco are combination products that contain a "drug" and a "device." 

A. NICOTINE IN CIGARETTES AND SMOKELESS TOBACCO 

ISADRUG 

For the reasons set forth in sections I. and IT., above, the Agency concludes that 

the nicotine in cigarettes and smokeless tobacco is a "drug" under section 201(g)(l)(C). 

The nicotine in these products "affect[s] the structure or any function of the body" by 

sustaining addiction, by producing other important pharmacological effects on the central 

nervous system, including tranquilizing and stimulant effects, and by controlling weight. 

See section I., above. These effects of the nicotine in cigarettes and smokeless tobacco 

are "intended" by the manufacturers. See section IT., above. Therefore, the nicotine in 

cigarettes and smokeless tobacco meets the statutory defmition of a "drug" under section 

201 (g)(l )(C). 

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45208 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

III. B. 

B. CIGARETTES AND SMOKELESS TOBACCO CONTAIN 

DELIVERY DEVICES AND ARE COMBINATION PRODUCTS 

UNDER THE ACT 

Cigarettes and smokeless tobacco are not simply packaged nicotine. As discussed 

below, the rest of the cigarette or smokeless tobacco product includes a delivery device 

that delivers a controlled amount of nicotine to the body. This combination of the drug 

nicotine and a delivery device makes these products "combination products." 

Under the Act, a device is: 

an instrument, apparatus, implement, machine, contrivance, implant, in 

vitro reagent, or other similar or related article, including any component, 

part, or accessory, which is ... intended to affect the structure or any 

function of the body of man ... and which does not achieve its primary · 

intended purposes through chemical action within or on the body of man 

... and which is not dependent upon being metabolized for the 

achievement of its primary intended purposes. 

Section 20l(h)(3). This definition was intended to bring within the reach of the statute 

articles that are intended to affect the structure or function of the body, but are physically 

distinguishable from drugs, which in general are substances in liquid, powder, or other 

drug dosage fonn that are ingested, injected, rubbed, or otherwise absorbed into the body. 

The definition establishes a four-part test for a device. First, the article must be "an 

instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other 

similar or related article." Second, the article must be "intended to affect the structure or 

any function of the body." Third, the article must not "achieve its primary intended 

purposes through chemical action within or on the body of man." And fourth, the article 

must not be "dependent upon being metabolized for the achievement of its primary 

intended purposes." Both cigarettes and smokeless tobacco contain a delivery device that 

meets these four criteria. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45209

III.B.l. 

1. Cigarettes Are Combination Products 

By weight, the drug nicotine is only a small part of a cigarette.u44 First, the 

cigarette also has components that together constitute an "instrument, implement, ... 

contrivance or similar or related article" under the Act. As a cigarette manufacturer has 

acknowledged, cigarettes are "a highly engineered product."1145 They have components 

that have been carefully designed to deliver controlled, pharmacologically active doses of 

nicotine to the smoker, including the tobacco blend, the ftlter, and the ventilation system. 

See section II.C.4., above. Collectively, the drug delivery components of cigarettes are an 

instrument, implement, contrivance, or similar article that is designed to release a nicotinecontaining aerosol, i.e., the tobacco smoke, that, upon combustion outside the body, is 

inhaled by the smoker and serves as the vehicle for nicotine delivery. 

Second, consistent with section 20l(h)(3) of the Act, the device components of 

cigarettes are "intended to affect the structure or any function of the body." Cigarettes are 

"intended" to deliver nicotine to the body. See Section II, above. The nicotine delivered 

by the device components of cigarettes "affect[s] the structure or any function of the 

body." See Section I, above. The device components of cigarettes are thus designed to 

achieve the specific purpose of affecting the structure and function of the body by 

delivering a controlled amount of nicotine to the body. 

1144 Regulation of Tobacco Products (Part 3): Hearings before the Subcommittee on Health and the 

Environment, House Energy and Commerce Committee, U.S. House of Representatives, 1 03d Cong., 

2d Sess. 173 (Jun. 23, 1994). See AR (Vol. 709 Ref. 3). 

1145 Response of RJ. Reynolds Tobacco Company, Appendix D, FDA Docket No. 94P-0069 (Nov. 2, 

1994), at 78. See AR (Vol. 447 Ref. 7640). 

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45210 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

III.B.l. 

Third, as required by the statutory defmition, the device components do not 

achieve their delivery purpose through "chemical action within or on the body." Although 

the nicotine delivered by cigarettes achieves its primary intended purpose through a series 

of chemical actions inside the body, the device components do not rely on chemical 

actions within or on the body to achieve their drug delivery pwpose. Rather, the device 

components of cigarettes achieve their primary purpose by delivering nicotine to the body 

in an aerosol fonn. This nicotine-containing aerosol is produced by combustion outside 

the body-not by chemical actions within or on the body. 

Fourth, as required by the statutory definition, the device components in cigarettes 

are not "dependent upon being metabolized" to achieve their primary intended purpose. 

Metabolism is ''the conversion of one chemical species to another."1146 To be 

metabolized, most substances must first be ingested or absorbed into the body, where 

metabolism occurs after the substance reaches the gastrointestinal tract (the liver) or the 

systemic circulation.1147 In the case of cigarettes, the nicotine delivered by a cigarette is 

inhaled and delivered to the bloodstream where it can achieve its intended purpose, before 

any metabolism takes place. Thus, the device components achieve their primary intended 

purpose without being metabolized. 

Cigarettes are similar to other articles that are routinely regarded as combination 

products containing both a drug and a drug delivery instrument, apparatus, machine, 

contrivance, or similar or related article under the Act. In 1991, the Agency's Center for 

1146 Rowland M, Thomas TN, Clinical Pharmacokinetics: Concepts and Applications (Baltimore: 

Williams & Wilkins, 1995, 3d ed.), at 15. See AR (Vol 711 Ref. 49). 

1147 See ld. at14. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45211

III.B.l. 

Drug Evaluation and Research and the Agency's Center for Devices and Radiological 

Health reached an intercenter agreement delineating the types of products that would be 

considered to have drug and device components. Under this agreement, an article "with 

[the] primary purpose of delivering or aiding in the delivery of a drug and distributed 

containing a drug (i.e., 'pre-filled delivery system')" is regarded as a combination product 

with drug and device components.1148 The intercenter agreement speciflcally lists 

nebulizers, transdermal patches, and pre-filled syringes as examples of"pre-fllled delivery 

systems."1149 Prefllled intravenous infusion pumps, which are used to deliver drugs to 

patients intravenously, are another example. Cigarettes are comparable to these articles. 

Nebulizers and metered dose inhalers are products filled with a drug used by persons with 

asthma to relieve constricted airways. Like nebulizers and metered dose inhalers, 

cigarettes contain an instrument, implement, contrivance, or similar or related article for 

converting a drug into an aerosolized form for inhalation. Cigarettes are also similar to 

prefilled intravenous infusion pumps, in that drug delivery components of both deliver the 

drug to the body for absorption, after which the device components are discarded or 

destroyed. 

The internal tobacco company documents themselves recognize that cigarettes 

should be regarded as nicotine delivery devices. For example, as early as 1972, a senior 

Philip Morris researcher characterized the cigarette as "a dispenser for a dose unit of 

nicotine" and stated that "[s]moke is beyond question the most optimized vehicle of 

1148 lntercenter Agreement between the Center for Drug Evaluation arul Research arul the Center for 

Devices and Radiological Health (Oct 31, 1991), at 6. See AR (Vol. 30 Ref. 289). 

1149 ld. 

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45212 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

III.B.l. 

nicotine and the cigarette the most optimized dispenser of smoke."1150 Twenty years later, 

a Philip Morris official continued to describe cigarettes as "nicotine delivery devices," 

placing "conventional cigarettes" in the same category as nicotine "chewing gums, 

patches, aerosol sprays and inhalers."1151 

Researchers at other cigarette manufacturers have expressed similar views. In 

1962, a senior BATCO scientist described the advantages of nicotine delivery through 

cigarettes, stating that ''the techniques of administration by smoking ha[ ve] considerable 

psychological advantages and a built-in control against excessive absorption."1152 Decades 

later, BATCO researchers continued to characterize cigarettes in device-like terms, 

describing cigarettes as ''the means of providing nicotine doses in a metered fashion" 1153 

and as a delivery mechanism that allows "the smoker to have very flexible control over 

titrating his desired dose of nicotine."1154 Similarly, in the words of one senior RJR 

scientist, "a tobacco product is, in essence, a vehicle for delivery of nicotine, designed to 

deliver the nicotine in a generally acceptable and attractive form." 1155 

1150 Dunn WL (Philip Morris Inc.), Motives and Incentives in Cigarette Smoking (1972), at 5-6 (emphasis 

added). See AR (Vo112 Ref. 133). 

IISI Philip Morris Inc., Draft Report Regarding a Proposal for a "Safer" Cigarette, Code-named Table, at 2 

(emphasis added). See AR(Vo1531 Ref. 122). 

llSl Ellis C (BA TCO), The smoking and health problem, in Smoking and Health-Policy on Research, 

Research Conference, Southampton, England (1962), at 4. See AR (Vol. 21 Ref. 220). 

1153 Proceedings of the BATCO Group R&D Smoking Behaviour-Marketing Conference, Session I, slides 

(Jul. 9-12, 1984), at BW-W2-03242 (emphasis added). See AR (Vo124 Ref. 315). 

1154 Transdermal Nicotine Patches, at 3. See (AR Vol. 531 Ref. 124). 

uss Teague CE (RJ. Reynolds Tobacco Co.), Research Planning Memorandum on the Nature of the 

Tobacco Business and the Crucial Role of Nicotine Therein (Apr. 14, 1972), at 2 (emphasis added). See 

AR (Vol. 531 Ref. 125). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45213

III.B.2. 

The history of the manufacturers' product research and development further 

demonstrates that cigarettes are designed to deliver nicotine to the smoker. As described 

in section II.C.3., above, the manufacturers have engaged in extensive product research 

and development for over three decades to optimize the delivery of nicotine from 

cigarettes. This product research and development has even included the development of 

novel tobacco products, such as Premier by RJR, that are designed to deliver nicotine to 

the smoker "by heating, rather than burning, tobacco."1156 See section ll.C.3., above. 

For these reasons, the Agency has determined that cigarettes are most 

appropriately considered a prefilled delivery system under the intercenter agreement. 

They are a combination product under the Act consisting of the drug nicotine and a device 

for delivering nicotine to the smoker. 1157 

2. Smokeless Tobacco Is a Combination Product 

The Agency has also determined that smokeless tobacco is a combination product. 

First, as required by the statutory definition, smokeless tobacco is an "instrument, ... 

implement, contrivance, ... or similar or related article" for delivering nicotine to the 

consumer. The principal device component in these products is the processed tobacco, 

the purpose of which is to deliver the nicotine to the cheek and gum tissue for absorption 

1156 Chemical andBiological Studies on New Cigarette Prototypes that Heat Instead of Bum Tobacco 

(Winston-Salem NC: RJ. Reynolds Tobacco Co., 1988), at 3. See AR (Vol 107 Ref. 980). 

1157 As discussed in Section II.F., above, the Agency has also determined that processed loose cigarette 

tobacco, which is used by smokers who roll their own cigarettes, is subject to FDA jurisdiction. Processed 

loose tobacco has a drug and a device component As noted in Section II.F., consumers obtain separately 

the components of a cigarette (e.g., processed loose tobacco and special cigarette papers) and then use 

those components to assemble their own cigarettes. While these homemade products are more crudely 

manufactured than those produced by cigarette companies, they perform the same device function of 

delivering a nicotine-containing aerosol to the body for inhalation by the lungs. 

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III.B.2. 

into the body. The processed tobacco provides the nicotine to the consumer's body in a 

fonn that is palatable and absorbable, thereby allowing the nicotine to diffuse from the 

tobacco to the buccal mucosa. Some products also have a device component consisting of 

a porous pouch that holds the processed tobacco in position in the mouth, controlling the 

absorption of nicotine into the buccal mucosa. 

Smokeless tobacco is placed in the mouth, where it fonns a matrix from which 

nicotine is solubilized and then diffused across the buccal mucous membranes into the 

bloodstream. Thus, the tobacco matrix is the vehicle for rapidly and efficiently delivering 

nicotine to the smokeless tobacco user through buccal absorption. Smokeless tobacco is 

thus similar to other combination products that contain instruments, apparatuses, 

contrivances, or similar or related articles intended to deliver drugs. For example, 

smokeless tobacco resembles transdennal nicotine patches. Transdennal nicotine patches 

are considered combination products under an intercenter agreement.1158 Similar to 

transdennal nicotine patches, smokeless tobacco contains an instrument, implement, or 

similar or related article that brings the nicotine into close contact with body tissue, where 

it can diffuse through the body's membranes into the bloodstream. Smokeless tobacco is 

also comparable to prefilled intravenous infusion pumps, in that the drug delivery 

components of both products deliver a drug to the body and are discarded after drug 

delivery is complete. This feature distinguishes the delivery device components of 

smokeless tobacco from drugs. A drug is typically ingested or absorbed in the body; in the 

case of smokeless tobacco, most of the tobacco in the product is not ingested or absorbed 

1158 lntercenter Agreement between the Center for Drug Evaluation and Research and the Center for 

Devices and Radiological Health (Oct 31, 1991), at 6. See AR (Vol. 30 Ref. 289). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45215

III.B.2. 

by the user and is removed from the mouth. Several aspects of the smokeless tobacco 

may be engineered by the manufacturer to control the rate and extent of absorption of 

nicotine, the drug to be delivered. For example, the cut of the tobacco may be altered to 

affect the rate of diffusion of the nicotine through the buccal mucosa. 

Second, consistent with section 201(h)(3) of the Act, the device components of 

smokeless tobacco are "intended to affect the structure or any function of the body." 

Smokeless tobacco are "intended" to deliver nicotine to the body. See Section II., above. 

The nicotine delivered by the device components of smokeless tobacco "affect[s] the 

structure or any function of the body." See Section 1., above. The device components of 

smokeless tobacco are thus designed to achieve the specific purpose of affecting the 

structure and function of the body by delivering a controlled amount of nicotine to the 

body. 

Third, as required by the statutory definition, the device components of smokeless 

tobacco do not "achieve [their] primary intended purposes through chemical action within 

or on the body." The nicotine in smokeless tobacco achieves its primary purposes 

through chemical actions in the body. The device components, however, achieve their 

drug delivery function simply by bringing nicotine into contact with the buccal mucosa. 

To achieve the drug delivery purpose, the tobacco blend (and pouch, if any) must be 

placed in the mouth and the nicotine must diffuse away from the tobacco. These are 

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III.C. 

physical processes, not chemical ones, 1159 that are analogous to the physical processes 

through which transdennal nicotine patches deliver nicotine to the body. 

Fourth, as required by the statutory definition, the device components in smokeless 

tobacco are not "dependent upon being metabolized." After buccal absorption of nicotine 

is complete, the remaining tobacco material (and pouch, if any) is expectorated whole. 

The critical absorption of nicotine does not require the metabolism of any part of the 

tobacco matrix. 

For these reasons, the Agency has determined that smokeless tobacco is a 

combination product under the Act consisting of the drug nicotine and device components 

for delivering nicotine to the user. 

C. RESPONSE TO COMMENTS 

1. Several tobacco industry comments assert that drug delivery systems containing 

drugs are simply drugs, not combination products. These comments maintain that the 

Agency's position removes any distinction between the terms "drug" and "device" and 

could result in drugs in tablet or capsule forms being viewed as a combination product 

consisting of a drug and a drug delivery device. 

Since passage of the Safe Medical Devices Act of 1990, however, the Agency 

could consider some capsules or tablets as combination products under section 503(g). 

For example, capsules utilizing osmotic pumps to deliver a drug could be regarded as a 

1159 See Webster's Collegiate Dictionary (Springfield, MA: G&C Merriam, 1977 ed.), at318; 

Remington's Pharnuzceutical Sciences (Easton, PA: Mack Publishing, 1980, 16th ed. ), at 1388. See AR 

(Vol. 711 Ref. 50). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45217

III. C. 

combination of a "drug" and a "device." The capsules, emptied of the drug, are not 

absorbed into the body, but are excreted. The delivery mechanism of these capsules is 

similar to that of a prefilled syringe. Yet there are basic differences between drug delivery 

systems like cigarettes and smokeless tobacco, on the one hand, and most drugs in tablet 

or capsule form, on the other. As discussed in section lll.B., above, cigarettes and 

smokeless tobacco have major physical components that deliver nicotine to the consumer 

but are not absorbed or metabolized within the body. This is not the case with most 

tablets and capsules, which are absorbed completely along with the drug they deliver and 

act ''through chemical action within or on the body." These basic differences mean that 

the Agency's decision to consider cigarettes and smokeless tobacco as combination 

products is reasonable and will not require the Agency to change its treatment of most 

products that have been adequately regulated as drugs, and begin to regulate them as 

combination products. The Supreme Court has recognized that the Agency has the 

discretion to apply the Act's statutory terms to products that reasonably meet those 

definitions. The fact that a strained extension of the Agency's analysis could lead to an 

illogical result will not preclude its use when the use itself is reasonable. United States v. 

Sullivan, 332 U.S. 689, 694 (1948). 

2. Tobacco industry comments also argue that cigarettes and smokeless tobacco 

cannot have device components, because if the Agency is right that nicotine is a drug, the 

primary intended purpose of a cigarette or a smokeless tobacco product taken as a whole 

is dependent upon the chemical action of nicotine within the body. According to the 

comments, if the primary mode of action of a cigarette or a smokeless tobacco product 

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45218 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

taken as a whole involves the chemical action of nicotine, the cigarette or smokeless 

tobacco product cannot meet the statutory defmition of a device. 

III. C. 

FDA disagrees with these comments. These comments confuse the defmition of a 

device with the defmition of a combination product. While it is true that under the statute, 

a device or device component cannot achieve its primary purpose by chemical action 

within or on the body, a combination product consisting of a drug and a device very well 

may. Indeed, Congress enacted section 503(g) of the Act specifically to recognize and 

address products, for example, that have a device component whose primary intended 

purpose is to deliver a drug by means other than chemical action or metabolizing action 

within or on the body, and a drug component that achieves its primary intended purpose 

through chemical action and/or by being metabolized. The statute recognizes that a single 

product can contain components with interdependent, yet distinct, purposes. Under the 

interpretation urged by the comments, there could never be a combination product 

composed of a drug and a device where the primary mode of action of the product is by 

chemical action. That interpretation is entirely at odds with the statutory language and 

purpose of section 503(g), as well as with FDA's long-standing practice of regulating as 

combination products many products containing a drug and a device. 

562 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45219

IV. FDA'S ASSERTION OF JURISDICTION OVER CIGARETTES AND 

SMOKELESS TOBACCO AT THIS TIME IS JUSTIFIED 

IV. 

The Food and Drug Administration (FDA) has always exercised jurisdiction under 

the Federal Food, Drug, and Cosmetic Act (the Act) over tobacco products when there 

was evidence that these products were "intended" to treat or prevent disease or to affect 

the structure or function of the body. As discussed in section ll.E., above, the Agency 

may consider relevant evidence from any source in determining whether a product is 

intended as a drug or device. On previous occasions when the Agency has been asked to 

consider whether tobacco products were within its jurisdiction, however, there was 

insufficient evidence to conclude that tobacco products were intended to affect the 

structure or function of the body, except where the manufacturer expressly promoted a 

tobacco product for use in treating disease or affecting the structure or function of 

the body. 

Since the last occasion on which FDA considered whether to assert jurisdiction 

over tobacco products without claims, the state of the evidence has changed dramatically. 

A wealth of new evidence has become available demonstrating that: (1) the ability of 

nicotine in cigarettes and smokeless tobacco to produce addiction and other significant 

pharmacological effects is widely known and therefore foreseeable to a reasonable tobacco 

manufacturer, (2) consumers use cigarettes and smokeless tobacco predominantly to 

obtain the pharmacological effects of nicotine; and (3) previously undisclosed statements, 

research, and actions of tobacco manufacturers demonstrate that they intend their 

products to be used as nicotine delivery devices. As described in section ll., above, FDA 

has determined that this evidence establishes that cigarettes and smokeless tobacco are 

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45220 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

IV. 

"intended to affect the structure or any function of the body" within the meaning of the 

Act's "drug" and "device" defmitions. FDA has therefore revised its position and 

concluded that all currently marketed cigarettes and smokeless tobacco are in fact 

"intended to affect the structure or any function of the body" and therefore are within its 

jurisdiction. 

Information developed since 1980 also demonstrates that for most people tobacco 

use and nicotine addiction begin in childhood and adolescence. The data now suggest that 

if children and adolescents can be prevented from initiating tobacco use, they are unlikely 

to begin tobacco use later in life, thereby preventing the onset of tobacco-related disease 

and premature death. Before the importance of youth-centered interventions was 

identified, most of the regulatory approaches available under the Federal Food, Drug, and 

Cosmetic Act to address tobacco-related disease and death, such as removal of the 

products from the market, were not believed to be feasible. The new information that 

nicotine addiction is a pediatric disease provides an additional basis to conclude that 

restricting the sale, distribution, and use of cigarettes and smokeless tobacco to people 

under the age of eighteen is an effective tool to reduce the adverse health consequences of 

tobacco use. Thus, asserting jurisdiction over cigarettes and smokeless tobacco now 

presents an opportunity to use the Agency's resources efficiently for substantial public 

health gains. 

Several comments maintain that the Agency is not permitted to change its earlier 

interpretation of the Act. However, it is a well-established principle of administrative law 

that an Agency may revise its interpretation or application of a statute if it supplies a 

reasoned explanation for its changed interpretation or position. See Action on Smoking 

564 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45221

IV. 

and Health v. Harris (ASH), 655 F.2d 236,242, n.lO (D.C. Cir. 1980) (recognizing that 

FDA is permitted to modify its earlier position on tobacco products and that the new 

position would be accorded deference by the courts); see also Motor Vehicle Mfrs. Ass'n 

v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29, 57 (1983); Chevron, U.S.A., Inc. v. 

Natural Resources Defense Council, Inc., 467 U.S. 837, 862 (1984); Rust v. Sullivan, 

500 U.S. 173, 186-187 (1991); Smiley v. Citibank, N.A., 116 5. Ct. 1730 (1996). Indeed, 

an agency is expected to reevaluate the wisdom of its interpretations and make changes in 

those interpretations when warranted by current knowledge and circumstances. Rust, 500 

U.S. at 186-187. In Rust, the Court explained as follows: 

This Court has rejected the argument that an agency's 

interpretation is not entitled to deference because it represents a 

sharp break with prior interpretations of the statute in question. In 

Chevron, we held that a revised interpretation deserves deference 

because an initial agency interpretation is not instantly carved in 

stone and the agency, to engage in informed rule making, must 

consider varying interpretations and the wisdom of its policy on a 

continuing basis. An agency is not required to establish rules of 

conduct to last forever, but rather must be given ample latitude to 

adapt its rules and policies to the demands of changing 

circumstances. 

I d. (citations and internal quotation marks omitted); see also American Trucldng Ass'ns 

v. Atchison, Topeka, and Santa Fe Ry. Co., 387 U.S. 397 (1967) (an agency, "faced with 

new developments or in light of reconsideration of the relevant facts and its mandate, may 

alter its past interpretation and overturn past administrative rulings and practice"). The 

new evidence presented in the Jurisdictional Analysis and in section IT., above, provides a 

reasoned basis for FDA's change in position on the applicability of the Act to cigarettes 

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45222 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

IV.A 

and smokeless tobacco without claims. In this section, FDA describes its earlier decisions 

on whether to regulate particular tobacco products and reviews the new evidence that 

now supports the Agency's assertion of jurisdiction over cigarettes and smokeless 

tobacco. 

A. FDA HAS ALWAYS EXERCISED AUTHORITY TO REGULATE 

TOBACCO PRODUCTS WHEN THE EVIDENCE ESTABLISHED 

THAT THEY FELL WITHIN THE DRUG OR DEVICE 

DEFINITIONS 

FDA's assertion of jurisdiction over tobacco products is not new. For more than 

80 years FDA has taken the position that it has jurisdiction over tobacco products that fall 

within the Act's definitions of regulated products. As early as 1914, the Agency-claimed 

jurisdiction to regulate tobacco products labeled or used for "medicinal purposes."1160 

In the succeeding decades, FDA brought and won enforcement actions against cigarettes 

that were intended to treat or prevent disease or to affect the structure and function of the 

body. See, e.g., United States v. 354 Bulk Cartons ... Trim Reducing-Aid Cigarettes, 

178 F. Supp. 847,851 (D.N.J. 1959) (cigarettes claimed to reduce weight were intended 

to affect the structure or function of the body); United States v. 46 Cartons, More or Less, 

Containing Cigarettes, 113 F. Supp. 336, 338-339 (D.N.J. 1953) (cigarettes claimed to 

1160 The predecessor to FDA issued the following statement about its jurisdiction over tobacco: "Tobacco 

and its preparations, when labeled in such a manner as to indicate their use for the cure, mitigation, or 

prevention of disease, are drugs within the meaning of the act. and, as such, are subject to the provisions 

thereof .... On the other hand, tobacco and its preparations which are not so labeled and are used for 

smoking or chewing or as snuff and not for medicinal purposes are not subject to the provisions of the 

act" U.S. Department of Agriculture Service and Regulatory Announcements, No. 13 (1914), cited in 

Joint Comment of the Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol I, at 5 (emphasis added). 

See administrative record (AR) (Vol. 535 Ref. 96). Thus, to escape regulation under this interpretation of 

the Agency's authority, a tobacco product must not be labeled as a drug and must not be used as a drug. 

At the time this statement was issued, a drug was deimed only as an article intended for the cure, 

mitigation, or prevention of disease, hence the limitation to use for "medicinal purposes." The definition 

was expanded in 1938 to include "articles intended to affect the structure or any function of the body." 

566 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45223

IV.B.l. 

prevent respiratory diseases were intended to treat or prevent disease). For many years, 

the existing evidence about the intended use of tobacco products was insufficient to 

conclude that tobacco manufacturers intended tobacco products as drugs or devices 

except when disease or structure-function claims were expressly made for the products. It 

is nevertheless indisputable that the Agency has consistently claimed jurisdiction over 

tobacco products when it has determined that they are intended to affect the structure or 

function of the body or to treat or prevent disease. What has changed is the nature of the 

evidence before the Agency on the question of whether cigarettes and smokeless tobacco 

are "intended to affect the structure or any function of the body." 

B. A CHANGE IN THE EVIDENCE BEFORE THE AGENCY NOW 

ESTABLISHES "INTENT" TO AFFECT THE STRUCTURE AND 

FUNCTION OF THE BODY 

1. Previous Agency Position and the Evidence on Which It Was Based 

The Agency last considered whether to regulate tobacco products without disease 

or structure-function claims in connection with citizen petitions submitted in the late 

1970's by Action on Smoking and Health (ASH) and others. The petitions sought to have 

FDA regulate all cigarettes as drugs or devices. 

At the time that FDA responded to ASH's citizen petitions, the only evidence 

before the Agency was that presented by the petitioners: studies showing that nicotine 

produces some pharmacological effects in animals and humans and some very early 

evidence concerning the addictive properties of nicotine. The proposition that nicotine in 

cigarettes was addictive was not yet widely accepted in the scientific community, and the 

petition provided insufficient evidence to demonstrate addiction. Indeed, at the time the 

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45224 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

IV.B.l. 

petitions were submitted, no major public health organizations had concluded that nicotine 

is addictive. Because it was not yet recognized that nicotine is addictive, no data were 

available quantifying the proportion of smokers who were addicted and thus using 

cigarettes to satisfy their addiction. 

The petitioners also presented no evidence that the tobacco companies knew of the 

pharmacological properties of nicotine, or that consumers used cigarettes for their 

pharmacological effects, or that the companies manipulated the levels of nicotine in 

cigarettes to satisfy smokers' need for nicotine. The petitions thus rested on evidence that 

nicotine has some pharmacological effects and the largely unsubstantiated assertion that 

many consumers used cigarettes for a drug purpose. 

FDA concluded that although intended use could be established by evidence other 

than promotional claims, the evidence in the petitions was insufficient to fmd that the 

manufacturers of cigarettes "intended" these products to prevent, mitigate, or treat disease 

or to affect the structure or function of the body. For example, in response to the petition 

urging FDA to regulate filtered cigarettes as devices because they were intended to 

mitigate disease, the Agency said: 

ASH asserts that objective evidence other than manufacturers' claims can 

be material to a determination of intended use under the statutory 

defmition, and that National Nutritional Foods Ass'n v. Food and Drug 

Administration, 504 F.2d 761 (2d Cir. 1974), cert. denied, 420 U.S. 946 

(1975), is authority for this interpretation (Petition No.2, p. 21). We 

agree. However, the court there held that the vendor's intent is the crucial 

element in the statutory definition and that objective evidence sufficient to 

pierce the manufacturer's subjective claims must be presented (504 F.2d at 

789). 

. .. [National Nutritional Foods Ass'n v. Weinberger, 512 F.2d 

688 (2d Cir. 1975) and National Nutritional Foods Ass'n v. Mathews, 557 

F.2d 325 (2d Cir. 1977)] support FDA's position that it is the intent of the 

manufacturers or vendors that objective evidence must establish and that 

568 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45225

evidence of consumer use can be one element of objective evidence to be 

weighed in determining if the intended purpose of a product subjects it to 

regulation under the Act ASH has not established that consumers use 

attached cigarette filters for the prevention, mitigation, or treatment of 

disease to the extent necessary to allow FDA to impute the requisite 

intended uses to manufacturers or vendors.1161 

IV.B.l. 

ASH appealed the Agency's decision not to regulate cigarettes as drugs. In ASH, 

the Court of Appeals deferred to FDA's determination and concluded that the evidence on 

"intended use" was not sufficient to overrule the Agency's interpretation. ASH v. Harris, 

655 F.2d 236 (D.C. Cir. 1980). The ASH court recognized both that FDA was permitted 

to modify its interpretation and that the Agency's new position would be accorded 

deference by the courts. Id. at 237, 242, n.IO. The court expressly left open the· 

possibility that at some point in the future FDA might appropriately determine that 

cigarettes did fall within the Agency's jurisdiction: "Nothing in this opinion should suggest 

that the Administration is irrevocably bound by any long-standing interpretation and 

representations thereof to the legislative branch. An administrative agency is clearly free 

to revise its interpretations." /d. at 242, n.lO. 

The ASH decision, moreover, by no means supports the proposition that the 

industry comments urge, namely, that evidence of intended use must be limited to 

manufacturers' drug claims. The ASH court held that a fmding that tobacco products 

were intended to affect the structure or function of the body could be based on substantial 

consumer use evidence alone or in combination with other evidence of vendor intent. /d. 

at 239-240. Nor was it the Agency's position at the time of the ASH case that the 

1161 Letter from Goyan JE to Banzhaf, ill JF and Georgiades PN (Nov. 25, 1980), at 8-9. See AR (Vol 28 

Ref. 238). 

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45226 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

IV.B.2. 

intended use of cigarettes could be established only through a manufacturer's overt drug 

claims. As noted above, FDA's 1980 response to ASH on its petition urging FDA to 

regulate filtered cigarettes as devices expressly stated that objective evidence other than 

claims is relevant to establishing intended use. In addition, the brief flied by the Agency 

before the Court of Appeals repeatedly stated the Agency's formal legal position that the 

intended use of cigarettes could be established through manufacturer's representations or 

other objective evidence of intent.1162 As stated in that brief, the petition denial was based 

on "two fmdings": 

(1) that there was no evidence in the record that manufacturers or 

vendors of cigarettes represent that cigarettes are intended to affect 

the structure or any function of the body; and (2) that there was no 

evidence in the record of any other sort that manufacturers or 

vendors of cigarettes intend that cigarettes affect the structure or 

any function of the body (Denial Letter at 4 ). 1163 

Thus, even at the time of the Agency's last decision on its jurisdiction over 

cigarettes, the Agency recognized that intended use could be established on the basis of 

objective evidence of intent other than manufacturers' claims. FDA concluded at that time 

that such other evidence had not been presented to the Agency. 

2. New Evidence Supporting the Agency's Change in Position 

In the years since FDA's decision on the ASH petitions, dramatic new evidence 

has become available on the issue of tP.e intended use of cigarettes and smokeless tobacco. 

FDA has therefore reevaluated the issue of its jurisdiction over tobacco products and finds 

1162 Brief for Appellees at 9 n. 7, 27-28,30, Action on Snwking and Health v. Ha"is, No. 79-1397, 

reported at 655 F.2d 236 (D.C. Cir. 1980). See AR (Vol 504 Ref. 8918). 

1163 Jd. at 30 (emphasis in original). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45227

IV.B.2. 

that the evidence now supports a detennination that cigarettes and smokeless tobacco are 

intended to affect the structure and function of the body, regardless of whether drug 

claims are made for the products. FDA bases this detennination on three important 

categories of evidence that have emerged since FDA last declined to exercise jurisdiction 

over tobacco products without claims: (1) the development of a scientific consensus, on 

the basis of overwhelming scientific evidence, that nicotine in cigarettes and smokeless 

tobacco is highly addictive and produces significant effects on the structure and function 

of the body, making it foreseeable to a reasonable tobacco manufacturer that its products 

will have phannacological effects and be used for those effects by a substantial proportion 

of consumers; (2) scientific data establishing that the vast majority of consumers who use 

cigarettes and smokeless tobacco are addicted to them and use these products nearly 

exclusively to obtain the pharmacological effects of nicotine; and (3) newly disclosed 

evidence showing that tobacco companies have in mind that their products will be used by 

consumers for pharmacological purposes and have designed their products to affect the 

structure and function of the body. As described in section ll., above, FDA believes that 

each category of evidence provides an independent basis on which to conclude that 

cigarettes and smokeless tobacco are intended to affect the structure and function of the 

body. 

In the Jurisdictional Analysis and in section ll., above, FDA describes at length the 

body of evidence now before it The vast majority of that evidence-including evidence 

that predates FDA's denial of the ASH petitions but was not made public by the tobacco 

industry-was not available to FDA in 1980. Since 1980, the quality, quantity, and scope 

of the evidence regarding the intended use of cigarettes and smokeless tobacco have 

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45228 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

IV.B.2. 

increased and sharpened dramatically. As described below, the evidence on the addictive 

nature of nicotine and on manufacturers' research on, manipulation of, and control over 

nicotine levels has grown exponentially. 

a. Since 1980, a Scientific Consensus Has Emerged That Nicotine 

Is Addictive and Has Other Significant Pharmacological Effects 

and Uses 

As described in section II.A., above, evidence that the pharmacological effects and 

uses of cigarettes and smokeless tobacco are foreseeable in a significant proportion of 

consumers is a sufficient basis on which to fmd that cigarettes and smokeless tobacco are 

intended to affect the structure and function of the body. Since 1980, the last time that 

FDA considered whether cigarettes were intended to affect the structure or function of the 

body, evidence of nicotine's addictiveness and other significant pharmacological effects 

and uses has become widely known and thus foreseeable by the manufacturers. 

Before 1980, no major public health organization had determined that nicotine was 

an addictive drug. Between 1980 and 1994, however, every leading scientific deliberative 

panel and organization with expertise in addiction concluded that nicotine is addictive or 

dependence-producing. These organizations include the American Psychiatric 

Association, in its Diagnostic and Statistical Manual of Mental Disorders, Third Edition 

(DSM-ID); the World Health Organization; the American Medical Association; the 

American Psychological Association; the American Society of Addiction Medicine; the 

Royal Society of Canada; and the Medical Research Council in the United Kingdom. In 

1986, the U.S. Surgeon General issued a report concluding for the first time that 

smokeless tobacco is addictive. And in 1988, the Surgeon General issued a landmark 

report concluding that nicotine in cigarettes is addictive. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45229

IV.B.2. 

These organizations relied on data from animal and human studies demonstrating 

nicotine's ability to produce addiction. Defmitive studies had not been conducted before 

1980. During the 1980's and 1990's, however, there was an explosion of new studies on 

nicotine designed to detennine whether nicotine is addictive. Thus, new studies, not 

available when the ASH petitions were decided, now conclusively demonstrate that 

nicotine has the characteristics of an addictive drug. 1164 The new data support the 

following fmdings, among others: 

• Nicotine is self-administered by animals, demonstrating that it is a "positive reinforcer'' 

(i.e., it causes repeated, compulsive use of the drug), one of the hallmark 

characteristics of addictive drugs; 1165 

1164 See section II.A.3., above, for a complete description of these studies and their significance in 

assessing nicotine's addictiveness. 

1165 Goldberg SR, Spealman RD, Goldberg DM. Persistent behavior at high rates maintained by intravenous 

self-administratioo of nicotine, Science 1981;214:573-575. See AR(Vol. 5 Ret: 35-2). 

Goldberg SR, Spealman RD, Maintenance and suppression of behavior by intravenous nicotine injectioos in 

squirrel monkeys, Federation Proceedings 1982;41(2):216-220. See AR (Vol 39 Ret: 52). 

Spealman RD, Goldberg SR, Maintenance of scheduled-controlled behavior by intravenous injectioos of 

nicotine in squirrel monkeys, Journal of Pharmacology and Experimental Therapeutics 1982;223(2):402-408. 

See AR (Vol 42 Ret: 146). 

Risner ME, Goldberg SR, A comparisoo of nicotine and cocaine self-administratioo in the dog: fixed-ratio and 

progressive-ratio schedules of intravenous drug infusioo, Journal of Pharmacology and Experimental 

Therapeutics 1983;224(2):319-326. See AR(Vol 42 Ret: 119). 

Cox BM, Goldstein A. Nelsoo WT, Nicotine self-administratioo in rats, British Journal of Pharmacology 

1984;83:49-55. See AR (Vol 8 Ret: 93-1). 

Slifer BL, Balster RL, Intravenous self-administratioo of nicotine: with and without schedule-induction, 

Pharmacology, Biochemistry and Behavior 1985;22:61-69. See AR (Vol 8 Ret: 93-3). 

Corrigall W A. Coen KM. Nicotine maintains robust self-administration in rats on a limited-access 

schedule, Psychopharmacology 1989;99:473-478. See AR (Vol 347 Ref. 5495). 

573 
45230 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

IV.B.2. 

• Consistent with the animal self-administration data, nicotine serves as a positive 

reinforcer in humans; 1166 

• Nicotine is psychoactive, serving as a discriminative stimulus in animals1167 and 

producing subjective effects in humans; 1168 

1166 Henningfield JE, Miyasoto K, Jasinski DR, Cigarette smokers self-adm.inistex intravenous nicotine, 

Pharmacology, Biochemistry and Behavior 1983;19:887-890. See AR (Vol. 39 Ref 71). 

Surgeon General's Report, 1988, at 192. See AR (Vol. 129 Ref. 1592). 

1167 S tolerman IP, Discriminative stimulus effects of nicotine in rats trained under different schedules of 

reinforcement, Psychopharmacology 1989;97:131-138. See AR(Vol. 8 Ref. 90-6). 

Craft RM, Howard JL, Cue properties of oral and transdennal nicotine in the rat, Psychopharmacology 

1988;96:281-284. See AR (Vol. 74Ref 115). 

Stolerman IP, Garcha HS, Pratt JA, et al., Role of training dooe in discrimination of nicotine and related 

compounds by rats, Psychopharmocology 1984;84:413-419. See AR(Vol 8 Ref 90-5). 

Garcha HS, Goldberg SR, Reavill C, et al., Behavioural effects of the optical isomers of nicotine and nornicotine, 

and cotinine, in rats, British Journal of Pharmacology 1986;88:298. See AR (Vol. 38 Ref 44). 

Takada K, Swedberg MDB, Goldberg SR, et al., Discriminative stimulus effects of intravenous l-nicotine and 

nicotine analogs or metabolites in squirrel monkeys, Psychopharmacology 1989;99:208-212 See AR (Vol. 43 

Ref 153). 

1168 Benningfield JE, Miyasato K, Jasinski DR, Abuse liability and pharmacodynamic characteristics of 

intravenous and inhaled nicotine, Journal of Pharmacology and Experimental Therapeutics 1985;234: 1-

12. See AR (Vol 39 Ref. 69). 

Pomerleau CS, Pomerleau OF, Euphoriant effects of nicotine in smokers, Psychopharmacology 

1992;108:460-465. See AR (Vol 87 Ref. 426). 

Perkins KA, Grobe JE, Epstein LH, et al., Effects of nicotine on subjective arousal may be dependent on 

baseline subjective state, Journal of Substance Abuse 1992;4: 131-141. See AR (Vol 348 Ref. 5516). 

Perkins KA, Grobe JE, Epstein LH, et al., Chronic and acute tolerance to subjective effects of nicotine, 

Pharmacology, Biochemistry and Behavior 1993;45:375-381. See AR (Vol 271 Ref. 3728). 

Sutherland G, Russell MA, Stapleton J, et al., Nasal nicotine spray: a rapid nicotine delivery system, 

Psychopharmacology 1992;108:512-518. See AR (Vol 91 Ref. 526). 

574 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45231

IV.B.2. 

• Nicotine reliably produces a withdrawal syndrome; 1169 

• Nicotine, like other addictive drugs (e.g., cocaine, amphetamine, and morphine), 

produces its addictive effects by actions increasing dopamine concentrations within the 

meso limbic system of the brain.1170 

In addition to the core studies demonstrating nicotine's addictiveness, other widely 

publicized information relevant to the fmding that nicotine in cigarettes and smokeless 

tobacco has significant pharmacological effects has become available since 1980. This 

new information includes, for example: 

• Studies showing that nicotine produces EEG effects on the brain that are reproducible 

and are known to be associated with changes in mood and alertness; 1171 

1169 American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 

(Washington DC: American Psychiatric Association, 1994), at 244-245. See AR (VoL 37 Ref. 8). 

WestRJ, Jarvis MJ, Russell MAH, et al., Effect of nicotine replacement on the cigarette withdrawal 

syndrome, British Journal of Addiction 1984;79(2):215-219. See AR (VoL 8 Ref. 102-1). 

Hughes JR, Hatsukami D, Signs and symptoms of tobacco withdrawal, Archives of General Psychiatry 

1986;43:289-294. See AR (VoL 8 Ref. 102-2). 

Hughes JR, Higgins ST, Hatsukami D, Effects of abstinence from tobacco: a critical review, Research 

Advances in Alcohol and Drug Problems 1990;10:317-398, at 381-382. See AR (Vol 535 Ref. 96. III.G). 

1170 Oarlce PBS, Mesolimbic dopamine activation-the key to nicotine reinforcement? CIBA Foundation 

Symposium 1990;152:153-168. See AR (VoL 3 Ref. 19-2). 

Di Chiara G, Imperato A, Drugs abused by humans preferentially increase synaptic dopamine 

concentrations in the mesolimbic system of freely moving rats, Proceedings of the National Academy of 

Sciences of the United States of America 1988;85:5274-5278. See AR (Vol 75 Ref. 128). 

Corrigan W A, Franklin K.BJ, Coen KM, et al., The mesolimbic dopaminergic system is implicated in the 

reinforcing effects of nicotine, Psychopharmacology 1992;107:285-289. See AR (VoL 8 Ref. 93-4). 

1171 Norton R. Brown K, Howard R. Smoking, nicotine dose and the lateralisation of electrocortical 

activity, Psychopharmacology 1992;108:473-479. See AR(VoL 3 Ref. 22). 

Pritchard WS, Gilbert 00, Duke DW, Flexible effects of quantified cigarette-smoke delivery on BEG 

dimensional complexity, Psychopharmacology 1993;113:95-102. See AR (VoL 3 Ref. 23-1). 

575 
45232 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

IV.B.2. 

• Data that have led expert bodies to conclude that marketed cigarettes and smokeless 

tobacco deliver pharmacologically active (addicting) doses of nicotine; 1172 

• Studies showing that nicotine exposure causes an increase in the number of nicotinic 

receptors in the central nervous system, a phenomenon associated with development of 

tolerance to the effects of nicotine; 1173 and 

• Studies done in the 1980's and 1990's showing that nicotine replacement therapies are 

effective in assisting smoking cessation, which provide additional evidence that 

nicotine is the ingredient in cigarettes that causes addiction. 1174 

Pritchard WS, Electroencephalographic effects of cigarette smoking, Psychopharmacology 1991;104:485-

490. See AR (VoL 3 Ref. 23-2). 

Golding JF, Effects of cigarette smoking on resting EEG, visual evoked potentials and photic driving, 

Pharmacology, Biochemistry and Behavior 1988;29:23-32. See AR (VoL 3 Ref. 23-3). 

1172 Department of Health and Human Services, Public Health Service, The Health Consequences of Using 

Smokeless Tobacco: A Report of the Advisory Committee to the Surgeon General, 1986, NIH Publication 

No. 86-2874 (Bethesda MD: DHHS, PHS, 1986). See AR (VoL 128 Ref. 1591). 

Surgeon General's Report, 1988, at 13-17. See AR(VoL 129 Ref. 1592). 

Transcript to the FDA Drug Abuse Advisory Committee, Meeting 27, "Issues Concerning NicotineContaining Cigarettes and Other Tobacco Products," Aug. 2, 1994, at 336-342. See AR (Vol. 255 Ref. 

3445). 

1173 Marks MJ, Burch JB, Collins AC, Effects of chronic nicotine infusion on tolerance development and 

nicotine receptors, Journal of Pharmacology and Experimental Therapeutics 1983;226:817-825. See AR 

(VoL 41 Ref. 103). 

Surgeon General's Report, 1988, at 53-54. See AR (VoL 129 Ref. 1592). 

Department of Health and Human Services, Centers for Disease Control and Prevention, Preventing 

Tobacco Use Among Young People: A Report of the Surgeon General (Atlanta: USDHHS, 1994), at32-

33. See AR (VoL 133 Ref. 1596). 

Benwell MEM, Balfour DJK, Anderson JM, Evidence that tobacco smoking increases the density of 

(-)-eH]nicotine binding sites in human brain, Journal of Neurochemistry 1988;50:1243-1247. See AR 

(Vol. 136 Ref. 1570). 

1174 See, e.g., Fiore MC, Smith SS, Jorenby DE, et al., The effectiveness of the nicotine patch for smoking 

cessation: a meta analysis, Journal of the American Medical Association 1994;271:1940-1947. See AR 

(Vol. 6 Ref. 64-1). 

576 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45233

IV.B.2. 

On the basis of the voluminous new data on nicotine that have become available 

since 1980 and the virtually universal consensus that has emerged from these data that 

nicotine is highly addictive and produces other significant pharmacological effects, FDA 

has concluded that nicotine's addictive and other pharmacological effects and uses are so 

widely recognized that they must be considered foreseeable to a reasonable tobacco 

manufacturer. The conclusion that nicotine's effects are so widely known and foreseeable 

would have been impossible when FDA last considered whether to regulate cigarettes 

because neither the definitive data nor the scientific consensus existed. 

b. Since 1980, Evidence Has Become Available That Consumers Use 

Tobacco Predominantly for Its Pharmacological Effects 

As described in section II.B., above, evidence that consumers use a product 

predominantly or nearly exclusively for its pharmacological effects permits the Agency to 

conclude that the product is intended to affect the structure or function of the body; The 

Agency recognizes that for many years there was general awareness of the difficulty 

smokers experienced in trying to stop smoking. Since 1980, however, scientific evidence 

has shown that the vast majority of smokers and users of smokeless tobacco use cigarettes 

and smokeless tobacco to satisfy addiction or for other pharmacological effects. The 

evidence that has emerged since the last time that FDA considered whether to regulate 

cigarettes includes, for example: 

• Evidence that 77% to 92% of smokers and as many as 75% of young regular 

smokeless tobacco users are addicted; 1175 

See appendix 1 to Jurisdictional Analysis, at 62-83. See AR (Vol. 1 Appendix 1). 

1175 Hughes JR. Gust SW, Pechacek 1F, Prevalence of tobacco dependence and withdrawal, American 

Journal of Psychiatry 1987; 144(2):205-208. See AR (Vol. 66 Ref. 4). 

577 
45234 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

IV.B.2. 

• Evidence that a higher percentage of people who use cigarettes become addicted than 

people who use other addictive drugs, including cocaine and heroin; 1176 

• Evidence that, of young people aged 10 to 22 years, 72.8% of daily smokers and 

53.8% of daily users of smokeless tobacco use tobacco to "relax" themselves; 1177 and 

• Data demonstrating that many smokers believe that smoking helps them control their 

weight and that continued smoking is related to concerns about weight gain.1178 

This new evidence, together with some existing evidence that smokers use cigarettes to 

control their moods, is sufficient to demonstrate that cigarette smokers and smokeless 

tobacco users consume tobacco predominantly to satisfy addiction, alter moods, and 

control weight. FDA would have been unable to reach this conclusion in 1980. At that 

time there was no evidence on the proportion of smokers and smokeless tobacco users 

who were addicted to tobacco (indeed, there was no agreement that nicotine was 

Woody GE, Cottier LB, Cacciola J, Severity of dependence: data from the DSM-IV field trials, Addiction 

1993;88:1573-1579. See AR(Vol13 Ref. 150). 

Cottier L, Comparing DSM-ill-R and ICD-10 substance use disorders, Addiction, 1993;88:689-696. See 

AR (Vol. 13 Ref. 149). 

Hale KL. Hughes JR. Oliveto AH, et al., Nicotine dependence in a population-based sample, in Problems 

of Drug Dependence, 1992, NIDA Research Monograph 132 (Washington DC: Government Printing 

Office, 1993). See AR (Vol39 Ref. 60). 

Department of Health and Human Services, Office on Smoking and Health, Spit Tobacco and Youth 

(Washington DC: Government Printing Office, 1992), at 8. See AR (Vol 7 Ref. 76). 

1176 Anthony JC, Warner LA, Kessler RC, Comparative epidemiology of dependence on tobacco, alcohol, 

controlled substances and inhalants: basic fmdings from the National Comorbidity Survey, Experimental 

and Clinical Psychopharmacology 1994;2:244-268. See AR (Vol535 Ref. 96, vol. III.A). 

1177 Centers for Disease Control and Prevention. Reasons for tobacco use and symptoms of nicotine 

withdrawal among adolescent and young adult tobacco users-United States, 1993, Morbidity and 

Mortality Weekly Report 1994;43(41):745-750, at 747. See AR (Vol43 Ref. 162). 

1178 Surgeon General's Report, 1988, at 438-441. See AR (Vol 129 Ref. 1592). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45235

IV.B.2. 

addictive), and evidence on the use of tobacco for other pharmacological effects was 

insufficient to conclude that cigarettes and smokeless tobacco are consumed 

predominantly for their pharmacological effects. 

c. Since 1980, Evidence Has Become Available Demonstrating That 

Tobacco Manufacturers Actually Intend Their Products To Affect 

the Structure and Function of the Body 

As described in section TI.C., above, FDA may also fmd that cigarettes and 

smokeless tobacco are "intended to affect the structure or any function of the body" on 

the basis of objective evidence that the manufacturers of these products actually intend 

them to affect the structure or function of the body. Such objective evidence includes 

company-funded research and internal statements showing that the manufacturers know or 

have knowledge of facts that would give them notice that consumers are using cigarettes 

and smokeless tobacco to obtain nicotine's pharmacological effects. Relevant objective 

evidence of intent also includes evidence that manufacturers have taken actions to ensure 

that consumers obtain pharmacologically active doses of nicotine from marketed tobacco 

products. 

As discussed in section TI., above, FDA, congressional, and other investigations 

into tobacco products over the last two years have uncovered a wealth of documents from 

a wide range of tobacco companies, the vast majority of which had not been made public 

by the tobacco industry. Although in some cases these documents date back to the early 

1960's, they have not been available to the public or to FDA until recently. As described 

in greater detail in section IT., above, the newly discovered documents reveal the following 

facts, among others, none of which were known when FDA last considered its jurisdiction 

over cigarettes: 

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45236 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

IV.B.2. 

• Statements from tobacco company researchers and executives show that the 

tobacco industry knows that nicotine is a drug, that consumers use tobacco 

primarily for the phannacological effects of nicotine, and that nicotine is addictive; 

• The tobacco industry has conducted extensive and sophisticated research to 

understand precisely how nicotine affects the structure and function of the body; 

• The tobacco industry has conducted product development research on how to 

manipulate nicotine delivery from cigarettes to ensure that cigarettes deliver 

pharmacologically active doses of nicotine; 

• The tobacco industry has manipulated the delivery of nicotine from marketed 

cigarettes to maintain and enhance the delivery of nicotine from low-yield 

cigarettes through the use of higher nicotine tobaccos, chemicals added to tobacco, 

and selective filtration and ventilation; 

• The smokeless tobacco industry has manipulated the delivery of nicotine from 

smokeless tobacco to create product lines with graduating nicotine deliveries, and 

at least one company has used a "graduation strategy" designed to encourage new 

users to begin with the lowest nicotine products and then graduate to the higher 

nicotine products. 

These facts, among others, demonstrate that the tobacco industry knows that 

consumers use their products to obtain nicotine's phannacological effects and that they 

have taken specific actions to facilitate that use. FDA has concluded on the basis of this 

new evidence that tobacco manufacturers actually intend cigarettes and smokeless tobacco 

to affect the structure or function of the body. 

580 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45237

IV.B.2. 

Almost none of the evidence of tobacco industry knowledge and actions was 

available to the Agency when it last declined to exercise jurisdiction over cigarettes 

without claims. One comment argues that FDA's earlier decision not to regulate tobacco 

products without claims is directly attributable to the tobacco industry's withholding of 

material documents. Indeed, Joseph Califano, who was Secretary of the Department of 

Health, Education, and Welfare at the time that FDA last declined to regulate cigarettes, 

has testified under oath before Congress that he would have "moved to regulate" had he 

known what FDA now knows about the internal tobacco company documents. 1179 He 

further testified that he had consulted with both President Jimmy Carter and then Surgeon 

General Julius Richmond and both agreed that, had this evidence been available, they too 

would have moved to regulate.118° FDA agrees with several comments that argue that not 

allowing FDA to change its position on the basis of this new evidence would reward the 

tobacco industry for its long-successful efforts to conceal its knowledge and actions 

related to nicotine. 

FDA's decision to change its previous position that cigarettes and smokeless 

tobacco are not intended to affect the structure or function of the body is thus based on an 

overwhelming body of new evidence that has become available since FDA last considered 

this issue. The new evidence persuades the Agency to conclude that its previous position 

is no longer consistent with. the relevant facts and should be changed. FDA's lengthy 

description of the new evidence in the Jurisdictional Analysis and in this document 

1179 Regulation ofTobacco Products (Part 2): Hearings Before the Subcommittee on Health and the 

Environment, Committee on Energy and Commerce, U.S. House of Representatives, 103d Cong., 2d 

Sess.166 (May 17, 1994). See AR(Vol. 708 Ref. 2). 

1180 /d. 

581 
45238 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

IV.C. 

provides a reasoned explanation for its change in position. The Agency's new position is 

therefore entitled to deference. American Trucking, 387 U.S. at 416. 

C. NEW EVIDENCE THAT NICOTINE ADDICTION IS A 

PEDIATRIC DISEASE PERMITS EFFECTIVE REGULATORY 

INTERVENTION 

In addition to the new evidence establishing that cigarettes and smokeless tobacco 

are "intended to affect the structure or any function of the body," new information 

developed since 1980 on young people's use of tobacco products shows that FDA's 

regulatory resources can be used effectively to reduce tobacco-related disease and death. 

Recent data establish that most of the people who suffer the adverse health consequences 

of using cigarettes and smokeless tobacco begin tobacco use in childhood and 

adolescence. Moreover, new data suggest that anyone who does not begin tobacco use in 

childhood or adolescence is unlikely ever to begin. This information provides a unique 

public health opportunity to substantially reduce the more than 400,000 deaths from 

tobacco use each year in the United States. If children and adolescents can be successfully 

prevented from initiating tobacco use and becoming addicted to cigarettes and smokeless 

tobacco, they are unlikely to begin tobacco use later in life, thereby preventing the onset of 

tobacco-related disease and premature death. 

Major recent reports have emphasized the effectiveness of legislative and 

regulatory interventions that focus on restricting children's access to tobacco products and 

on reducing the appeal of tobacco products to youth.1181 Before the importance of youthcentered interventions was identified, the regulatory approaches available under the Act to 

1181 Department of Health and Human Services, Office on Smoking and Health, Preventing Tobacco Use 

Among Young People: A Report of the Surgeon General (Washington, DC: Government Printing Office, 

1994) (hereinafter cited as Surgeon General's Report, 1994). See AR (Vol. 133 Ref. 1596). 

5&2 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45239

IV.C.l. 

address tobacco-related disease and death, such as removal of the products from the 

market, were not believed to be feasible. It is now apparent, however, that FDA's 

authority to restrict the sale, distribution, and use of cigarettes and smokeless tobacco to 

people under the age of eighteen is an effective tool to reduce the adverse health 

consequences of tobacco use. Thus, asserting jurisdiction over cigarettes and smokeless 

tobacco now presents an opportunity to use the Agency's resources effectively for 

substantial public health gains. 

1. New Information Shows that Cigarette and Smokeless Tobacco Use 

Begins Almost Exclusively in Childhood and Adolescence 

Although it has long been known that some people begin tobacco use before 

adulthood, definitive analyses of data published in the 1990's have revealed that the vast 

majority of tobacco users begin their use while children or adolescents. Moreover, new 

evidence shows that children and adolescents are beginning to smoke at younger ages than 

ever before. The new analyses show that the average age when people first try smoking a 

cigarette is 14.5 years of age, 1182 82% of adults who have ever smoked had their first 

cigarette before age 18, and more than half of them had already become regular smokers 

by that age.1183 Recent analyses also show that the mean average age when people 

become daily smokers is 17.7 years of age.1184 These data have critical implications for 

public health interventions. As stated by the Surgeon General in 1994, "[n]early all first 

1182 /d. at67. 

1183 /d. at 65. 

1184 /d. at67. 

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45240 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

use of tobacco occurs before high school graduation; this finding suggests that if 

adolesce.nts can be kept tobacco-free, most will never start using tobacco."1185 

IV.C.l. 

Not only does tobacco use begin predominantly among children and adolescents, 

but recent evidence shows that more and more children and adolescents are using tobacco. 

Approximately three million American youths currently smoke and an additional one 

million adolescent males use smokeless tobacco. 1186 Despite a decline in smoking rates in 

most segments of the American adult population, the rates among children and adolescents 

have recently begun to rise.1187 Tobacco use has been increasing among eighth and tenth 

graders in each of the last four years. In December 1995, 19% of eighth graders and 29% 

of tenth graders reported having smoked in the last 30 days, an increase of one-third since 

1991.1188 Tobacco use has also been increasing among high school seniors in each of the 

last three years. In December 1995, 33.5% of high school seniors reported having 

smoked in the last 30 days, an increase of one-fifth since 1992.1189 

1185 ld. at 5. 

1186 /d. 

1187 Centers for Disease Control and Prevention. Cigarette smoking among adults-United States, 1991, 

Mortality and Morbidity Weekly Report, 1993;42(12):230-233. See AR(Vol2 Ref. 17-1). 

Johnston LD, O'Malley PM, BachmanJG, National Survey Results on Drug Use from the Monitoring the 

Future Study /975-1993, Vol. 1: Secondary School Students, NIH Pub. No. 94-3809 (Rockville, MD: 

National Institute on Drug Abuse. 1994), at 9, 19. See AR (Vol2 Ref. 17-1). 

University of Michigan. News and Information Service, Smoking rates climb among American teenagers, 

who fmd smoking increasingly acceptable and seriously underestimate the risks (Jul. 20, 1995), at table 1. 

See AR (Vol3 Ref. 10-2). 

1188 Price J, Teen smoking, marijuana use increase sharply, study shows, Washington Times (Dec. 16, 

1995), atA2. See AR(Vol 711 Ref. 5). 

1189 /d. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45241

IV.C.l. 

There has been a similar increase in smokeless tobacco use by young people. Over 

the past 25 years, the market for smokeless tobacco has shifted dramatically from adults to 

young people. See Jurisdictional Analysis, 60 FR. 41748. For example, use of moist snuff 

among males aged 18-19 increased from 0.5% in 1970 to 7.5% in 1991.119° Current use 

of smokeless tobacco by children and adolescents is high and begins early. School-based 

surveys in 1991 estimated that 19.2% of ninth- to twelfth-grade boys use smokeless 

tobacco.1191 Among high school seniors who had ever tried smokeless tobacco, 73% did 

so by the ninth grade.1192 

This increase in tobacco use by young people has severe public health 

consequences. Although they believe that they will not become addicted to tobacco, 

recent data establish that children and adolescents become addicted to nicotine in the same 

manner as adults. Among smokers aged 12-17, 70% already regret their decision to 

smoke and 66% say they want to quit.1193 Those who are able to quit experience 

withdrawal symptoms and relapse rates similar to those reported in adults.1194 As stated in 

a study of youthful smoking sponsored by the Canadian affiliate of Brown & Williamson: 

1190 Centers for Disease Control and Prevention, Office of Smoking and Health, unpublished data. 

Informal communication between Office of Smoking and Health and Ann Witt. FDA. 

1191 Kann L, Warren W, Collins JL, Results from the national school-based 1991 youth risk behavior 

survey and progress toward achieving related youth objectives for the nation, Public Health Reports, 

1993;108(Supp.l):47-54. See AR (Vol4 Ref. 24). 

1192 Surgeon General's Report. 1994, at 101. See AR (Vol133 Ref. 1596). 

1193 The George H. Gallup International Institute, Teenage Attitudes and Behavior Concerning TobaccoReport of the Findings (Sep. 1992), at 54. See AR (Vo136 Ref. 381). 

1194 Centers for Disease Control and Prevention, Reasons for tobacco use and symptoms of nicotine 

withdrawal among adolescent and young adult tobacco users-United States, 1993, Morbidity and 

Mortality Weekly, 1994;43(41):745-750. See AR (Vol. 2 Ref. 14-1). See AR (Vol 2 Ref. 14-1). 

585 
45242 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

The desire to quit seems to come earlier now than before, even prior to the 

end of high school. In fact, it often seems to take hold as soon as the 

recent starter admits to himself that he is hooked on smoking. However, 

the desire to quit, and actually carrying it out, are two quite different 

things, as the would-be quitter soon learns.1195 

IV.C.l. 

A child or adolescent whose cigarette use continues into adulthood increases his or 

her risk of dying from cancer, cardiovascular disease, or lung disease. 1196 Indeed, 

approximately one out of every three young people who become regular smokers will die 

prematurely as a result.1197 Moreover, the younger one begins to smoke, the more likely 

one is to become a heavy smoker and suffer from smoking-related diseases.1198 

Smokeless tobacco use can cause oral cancer and the risk increases with increased 

exposure to smokeless tobacco use.1199 One study of 117 high school students who were 

Surgeon General's Report, 1994, at 78. See AR (Voll33 Ref. 1596). 

1195 Kwechansky Marketing Research for Imperial Tobacco, Ltd., Project Plus/Minus (May 7, 1982), in 

Study Highlights. See AR (Vol21 Ref. 214). 

1196 McGinnis JM, Foege WH, Actual causes of death in the United States, Journal of the American 

Medical Association, 1993;270(18):2207-2212. See AR (Vol 277 Ref. 3906). 

1197 Memorandum from Eriksen MP (CDC) to Lorraine C (FDA) (Aug. 7, 1995); CDC Fact Sheet based 

on Pierce JP, Fiore, MC, Novotny, TE, et al., Trends in cigarette smoking in the United States: projections 

to the year 2000, Journal of the American Medical Association 1989;261:61-65 and Peto R. Lopez AD, 

Boreham J, et al., Mortality from Smoking in Developed Countries, 1950-2000: Indirect Estimates from 

National Vital Statistics (Oxford: Oxford University Press, 1994); Centers for Disease Control and 

Prevention, Office on Smoking and Health, unpublished data from the 1986 National Mortality 

FollowbackSurvey. See AR(Vol 711 Ref. 20). 

1198 Taioli E, Wyder EL, Effect of the age at which smoking begins on frequency of smoking in adulthood, 

New England Journal of Medicine, 1991;325(13):968-969. See AR (Vol. 101 Ref. 876). 

Escobedo LG, Marcus SE, Holtzman D, Sports participation, age of smoking initiation, and the risk 

of smoking among U.S. high school students, Journal of the American Medical Association, 

1993;269(11):1391-1395. See AR (Vol 75 Ref. 149). 

1199 Department of Health and Human Services, The Health Consequences of Using Smokeless Tobacco: 

A Report of the Advisory Committee to the Surgeon General (1986) (Washington DC: DHHS), at 44. See 

AR (Vol. 128 Ref. 1591). 

586 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45243

IV.C.2. 

smokeless tobacco users revealed that nearly 50% had oral leukoplakia, a precancerous 

lesion that cannot be scraped off. 1200 Five percent of oralleukoplakias become malignant 

in 5 years.

1201 Tobacco use, which overwhelmingly begins in childhood, is ultimately 

responsible for over 400,000 deaths each year in the United States.1202 

2. New Infonnation Shows that Effective Restrictions on Access and 

Advertising to Children and Adolescents Can Decrease Tobacco Use 

by Children 

Despite laws in every State making it illegal for minors to purchase tobacco, 

America's children have easy access to tobacco products and are subjected to pervasive 

advertising images that portray tobacco use in terms that are highly attractive to them. As 

described in the Proposed Rule, 60 FR 41321-41338 (Aug. 11, 1995) and in sections IV 

and VI.D.6 of the fmal rule, recent studies have shown that regulatory programs that are 

effective in restricting access to tobacco products by those under 18, and that restrict 

advertising of these products can substantially reduce illegal tobacco use by children and 

adolescents. 

State laws prohibiting the purchase of tobacco by minors are rarely enforced1203 

and a significant percentage of underage smokers are able to obtain cigarettes through 

1200 Greer RO, Poulson TC, Oral tissue alterations associated with the use of smokeless tobacco by teenagers, Oral Surgery, Oral Medicine, Oral Pathology, 1983;56(3):275-284. See AR (Vol. 5 Ref. 95). 

Surgeon General's Report, 1994, at39. See AR (Vol133 Ref. 1596). 

1201 Surgeon General's Report, 1994, at 39. See AR (Vol 133 Ref. 1596). 

1202 Centers for Disease Control and Prevention, Cigarette smoking-attributable mortality and years of 

potential life lost--United States, 1990, Morbidity arul Mortality Weekly Report, 1993;42(33):645-649. 

See AR (Vol. 4 Ref 43). 

1203 Department of Health and Human Services, Office of the Inspector General, Youth Access to Tobacco 

(Washington DC: DHHS, Publication No. OEI-02-91-00880, Dec. 1992), at 5-8. See AR (Vol. 14 Ref. 

19-1). 

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IV.C.2. 

vending machines and over-the-counter sales.1204 Studies show that most children and 

adolescents who use tobacco products purchase their own cigarettes and smokeless 

tobacco. The 1994 Surgeon General's Report, Preventing Tobacco Use Among Young 

People, examined 13 studies of over-the-counter sales and determined that approximately 

67 percent of minors are able to purchase tobacco illegally. Moreover, successful 

cigarette purchases by children and adolescents from vending machines averaged 88%. 1205 

In addition to over-the-counter and vending machine purchases, many children and 

adolescents receive cigarettes and smokeless tobacco through free samples distributed by 

tobacco manufacturers at shopping malls, zoos, baseball games, rock concerts, and 

through the mail.1206 Even elementary school children receive free samples.1207 

Distributing free samples of "starter'' brands to young people has been a cornerstone of 

the successful campaign to boost moist snuff sales by the largest smokeless tobacco 

Kusserow RP, Department of Health and Human Services, Office of the Inspector General, Youth Access 

to Tobacco (Washington DC: DHHS, Publication No. OEI-02-90-02310, May 1990), at3-5. See AR 

(Vol. 4 Ref. 19-2). 

1204 Battelle for Centers for Disease Control and Prevention, Office of Smoking and Health, Design of 

Inspection Surveys for Vendor Compliance with Restrictions on Tobacco Sales to Minors (Apr. 1994), at 

14, 18. See AR (Vol49 Ref. 529). 

1205 Surgeon General's Report, 1994, at 249. See AR (Vol. 133 Ref. 1596). 

1206 Davis RM, Jason LA, The distribution of free cigarette samples to minors, American Journal of 

Preventive Medicine, 1988;4(1):21-26. See AR(Vol 7 Ref. 70-1). 

Department of Health and Human Services, Reducing the Health Consequences of Smoking: 25 Years of 

Progress, A Report of the Surgeon General (Washington DC: DHHS, 1989), at 597. See AR (Vol. 130 

Ref. 1593). 

1207 Davis RM, Jason LA, The distribution of free cigarette samples to minors, American Journal of 

Preventive Medicine, 1988;4(1):21-26. See AR(Vol. 7 Ref. 70-1). 

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IV.C.2. 

manufacturer.1208 See also section II.D., above. The distribution of free samples to 

minors occurs despite the industry's voluntary code against distributing tobacco products 

to minors. 

Recent studies have shown that effective youth access restrictions can reduce 

tobacco use by young people. In one community, for example, a comprehensive and 

intense community intervention involving retailer licensing, regular compliance checks, 

and penalties for merchant violations significantly reduced illegal sales from 70% to less 

than 5% two years later. Further, rates of experimentation and regular smoking dropped 

by more than 50% among seventh- and eighth-graders.1209 Both the Surgeon General of 

the United States and the Institute of Medicine have recently concluded that effective, 

enforced restrictions on minor's access to tobacco products are important tools to reduce 

use of tobacco by children and adolescents. 1210 

Pervasive advertising of tobacco products using imagery that is attractive to young 

people also influences children and adolescents to use tobacco products. Many studies 

have shown that young people are aware of, respond favorably to, and are influenced by 

cigarette advertising.1211 Even very young children are aware of cigarette advertisements. 

1208 National Cancer Institute, Strategies to Control Tobacco Use in the United States: A Blueprint for 

Public Health Action in 1990's {Washington DC: NIH Publication No. 92-3316, Oct. 1991), at 236. See 

AR (Vol 7 Ref. 72). 

1209 Jason LA. Ji PY, Aries MD, Active enforcement of cigarette control laws in the prevention of cigarette 

sales to minors, Journal of the American Medical Association, 1991 ;266(22 ):3159-3161. See AR (Vol. 6, 

Ref. 8). 

1210 Surgeon General's Report, 1994, at 254, 275. See AR (VoL 133 Ref. 1596). 

Institute of Medicine, Growing Up Tobacco Free: Preventing Nicotine Addiction in Children and Youths 

(Washington DC: National Academy Press, 1994), at 199. See AR (VoL 6 Ref. 11). 

1211 Institute of Medicine, Growing Up Tobacco Free: Preventing Nicotine Addiction in Children and 

Youths (Washington DC: National Academy Press, 1994), at 123-124. See AR (Vol. 12 Ref. 149-1). 

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IV.C.2. 

One study found that 30% of 3-year-olds and 91% of 6-year-olds could identify Joe Camel 

as a symbol for smoking.1212 Another study found that Joe Camel was more familiar to 

young children than Ronald McDonald, despite the fact that Ronald McDonald appears in 

television commercials, while cigarette commercials do not appear on the airwaves. 1213 

Moreover, recent studies show that campaigns that use imagery that is appealing 

to children and adolescents are successful in attracting young people to those brands. 

Before the Joe Camel cartoon character was introduced in 1986, Camel cigarettes had less 

than 3% of the youth market. By 1989, Camel's share ofthe youth market had risen to 

8.1% and, by 1992, 13-16% of smokers under 18 were smoking Camel. During this same 

period, however, there was no significant increase in adult purchases of Camel 

cigarettes.1214 These and other studies discussed in the Proposed Rule, 60 FR 41329-

Surgeon General's Report, 1994, at 188-192. 

Tye JB, Warner K, Glantz SA, Tobacco advertising and consumption: evidence of a causal relationship, 

Journal of Public Health Policy, 1987;8:492-508. See AR (Vol 48 Ref. 520). 

Pierce JP, Evans N, Farkas AJ, Tobacco Use in California, An Evaluation of the Tobacco Control 

Program, 1989-1993, A Repon to the California Depanment of Health Services (San Diego: University of 

California, 1994), at 85. See AR (Vol 7 Ref. 93). 

1212 Fischer PM, MP Schwartz, Richards JW, Brand logo recognition by children aged 3 to 6 years, 

Mickey Mouse and Old Joe the Camel, Journal of the American Medical Association, 1991;266(22):3145-

3148. See AR (Vol 2 Ref. 24-2). 

1213 Mizerski R, The Relationship Between Cartoon Trade Character Recognition and Product Category 

Attitude in Young Children, presented at Marketing & Public Policy Conference (May 13-14, 1994). See 

AR(Vol. 13 Ref.169). 

1214 Surgeon General's Report, 1994, at 70. See AR (Vol 133 Ref. 1596). 

U.S. Public Health Service and U.S. Depanment of Education, Teenage Attitudes and Practices Survey 

(1989), cited in Centers for Disease Control and Prevention, Changes in the cigarette brand preferences of 

adolescent smokers-United States, 1989-1993, Morbidity and Monality Weekly Report, 1994;43(32):577-

581. See AR (Vol. 13 Ref. 172). 

The George H. Gallup International Institute, Teenage Attitudes and Behavior Concerning TobaccoReport of the Findings (Sep. 1992), at 64. See AR (Vol 36 Ref. 381). 

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IV.C.3. 

41333, and in section VI.D. of the Final Rule provide compelling evidence that 

promotional campaigns can be extremely effective in attracting young people to tobacco 

products. Both the Surgeon General of the United States and the Institute of Medicine 

have concluded that unrestricted advertising of cigarettes and smokeless tobacco 

promotes consumption of tobacco by young people. 1215 Recent studies also show that 

government restrictions on tobacco promotion can reduce both tobacco consumption in 

the population as a whole, and initiation of tobacco use by young people.1216 

3. New Information Indicates that Regulatory Interventions Can Reduce 

Tobacco-Related Dlness If They Focus on Preventing Children from 

Becoming Addicted 

Tobacco products have historically been legal and widely available in this country. 

It was only after millions of people became legally addicted to the nicotine in cigarettes 

and smokeless tobacco that health experts became fully aware of the extraordinary health 

risks involved in the consumption of these products. Consequently, tobacco use has 

Centers for Disease Control and Prevention, Changes in the cigarette brand preference of adolescent 

smokers, U.S. 1989-1993, Morbidity and Mortality Weekly Report, 1994;43(32):577-581. See AR (Vol 2 

Ref. 25-1). 

tm Surgeon General's Report, 1994, at 10, 159-195. See AR (Vol 133 Ref. 1596). 

Institute of Medicine, Growing Up Tobacco Free: Preventing Nicotine Addiction in Children and Youths 

(Washington DC: National Academy Press, 1994), at 131. See AR (VoL 7 Ref. 96). 

l216 Toxic Substances Board, Wellington, New Zealand, Health or Tobacco-an End to Tobacco 

Advertising and Promotion (May 1989). See AR (Vol 14 Ref. 178). 

Smee C, Effect of Tobacco Advertising on Tobacco Consumption-A Discussion Document Reviewing the 

Evidence , 1-50 (London: Department of Health, Economics, and Operational Research Division, 1992) 

(draft). See AR (Vol 14 Ref. 181). 

Laugeson M, Meads C, Tobacco advertising restrictions, price, income and tobacco consumption in 

OECD countries, 1960-1986, British Journal of Addiction 1991 ;86: 1343-1354. See AR (Vol 15 

Ref. 185). 

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IV.C.3. 

become not only one of the most serious public health problems facing the United States 

today but one of the most difficult to solve. 

Because of the grave health consequences of the use of tobacco products, it has 

been argued that FDA should exercise its jurisdiction to remove them from the market. 

As described in the Proposed Rule, 60 FR 41348-41349, and in section I.B of the fmal 

rule, however, a ban is not a feasible approach to a product to which 35 to 45 million 

Americans are addicted. Abrupt removal of these products from the market could cause 

widespread adverse reactions and, in any event, is unlikely to keep cigarettes and 

smokeless tobacco out of the hands of addicted users. Black markets are likely to develop 

to supply addicted users with these products, and these black market products could be 

even more dangerous than those currently on the market. Thus, removal of cigarettes and 

smokeless tobacco from the market would not be an effective use of FDA's regulatory 

resources. Before it was understood that nicotine addiction is a pediatric disease, 

moreover, there was an insufficient basis to conclude that other regulatory approaches 

available to FDA would constitute effective uses of the Agency's resources. 

To effectively address the death and disease caused by tobacco products, addiction 

to cigarettes and smokeless tobacco must be eliminated or substantially reduced. The new 

evidence that nicotine addiction begins almost exclusively in childhood and adolescence 

demonstrates that this can be achieved by preventing children and adolescents from 

starting to use tobacco. Because the new evidence suggests that anyone who does not 

begin tobacco use in childhood or adolescence is unlikely ever to begin/ 217 effective 

1217 Surgeon General's Report, 1994, at 5, 58, 65-67. See AR (Vol 133 Ref. 1596). 

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IV.D. 

regulatory strategies to prevent children from initiating tobacco use and becoming 

addicted to nicotine, including restrictions on access and advertising, are likely to result in 

a significant reduction in tobacco-related illness and death. The infonnation that has 

developed since 1980 that nicotine addiction is a pediatric disease thus provides a rationale 

for regulating tobacco in a manner that is likely to produce significant public health gains. 

D. RESPONSE TO COMMENTS 

Most of the comments that the Agency received generally recognized that an 

agency may change its position under appropriate circumstances. The comments differed 

widely, however, on whether such circumstances are present in this proceeding. 

1. Some tobacco industry comments assert that relevant circumstances are 

unchanged since 1980-the date of the ASH decision and the last time the Agency 

evaluated this issue-and that therefore the Agency cannot offer a reasoned explanation 

for its change in position. Other comments differ sharply and contend that the available 

data have grown substantially. One comment stated that FDA has "obtained and 

considered substantial, new relevant data never previously considered, analyzed, or known 

by the FDA, never previously presented to or considered by Congress, and apparently, 

intentionally withheld by the tobacco industry from the FDA, Congress, and the American 

public."1218 The Agency agrees that the evidence available to FDA today is far greater 

than the data available in 1980. 

Of the comments contending that there has been no change in the legally relevant 

facts since 1980, one comment asserts that, because it has been widely reported for 

1218 Coalition on Smoking or Health, Comment (Jan. 2. 1996), at 6. See AR (VoL 533 Ref. 102). 

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IV.D. 

centuries that nicotine has "drug effects," there cannot be any new information on 

nicotine's drug effects that would warrant a change in the Agency's jurisdiction. This 

contention is unpersuasive. Although the Agency recognizes that nicotine has long been 

known to have some "drug effects," as set forth in this section and in section II. above, 

both the scientific understanding of nicotine's effects and the nature of the effects that are 

known to occur have changed dramatically since the last time that FDA considered its 

jurisdiction over tobacco products. The fact that nicotine is now universally recognized as 

highly addictive, but was generally unrecognized as such before 1980, adequately 

demonstrates the change in evidence on the nature of nicotine's drug effects. In addition, 

there has been a dramatic change in the evidence of consumers' use of tobacco products 

primarily for their pharmacological effects and on the tobacco industry's knowledge of 

nicotine's pharmacological effects and deliberate manipulation of nicotine levels. The new 

evidence on these issues fully warrants a change in position. 

Tobacco industry comments further assert that tobacco industry research or 

studies comparable to such research were available in published scientific literature before 

1980. The Agency notes that none of the evidence of tobacco industry research on 

nicotine was presented to the Agency in support of the ASH petitions. The fact that a few 

pieces of this evidence existed in 1980 but were never collected in one place or brought to 

the Agency's attention, moreover, is clearly not equivalent to the overwhelming 

accumulation of newer evidence before the Agency today, especially when coupled with 

the recent virtual consensus reached by the scientific community regarding the addictive 

nature of nicotine. 

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IV.D. 

Similarly, some comments assert that, because ASH alleged in 1977 that nicotine 

was addictive and that many consumers used cigarettes to satisfy addiction, there has been 

no change to justify a new policy. ASH's allegations, however, did not constitute 

evidence. FDA must make its decisions on the basis of well-founded scientific facts. 

Today there is a well-founded consensus that nicotine is addictive in a huge proportion of 

its consumers. Neither the consensus nor the data to support it existed when FDA 

responded to the ASH petitions. 

2. Comments both in favor of and opposed to the Agency's changed position 

discuss the current applicability of Federal Trade Commission v. liggett & Myers 

Tobacco Co., 108 F. Supp. 573 (S.D.N.Y. 1952), affd mem., 203 F.2d 955 (2d Cir. 

1953). One comment explained that the liggett & Myers decision underscores the 

dramatic change in the quality and quantity of the evidence over the decades. The Agency 

agrees with that comment. The liggett & Myers court, whose decision predated the 1964 

Surgeon General's Report, found that the "soothing" properties of cigarettes were 

insufficient to establish that cigarettes were intended to affect the structure or function of 

the body. Id. at 576-577 ("[M]any things soothe the troubled mind of modem man and I 

do not feel that this is the type of effect which the statute contemplates."). No evidence 

was presented to the court to show that any "soothing" effects of cigarettes were due to 

nicotine or were even pharmacological in nature. FDA's current initiative is not based on 

unspecified "soothing" properties of cigarettes, but on the significant phannacological 

effects of the drug nicotine, including its addictive effects, consumer use of tobacco for 

these effects, and on the tobacco industry's knowledge of nicotine's effects and its 

deliberate manipulation of nicotine delivery. 

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IV.D. 

3. One public interest group comment asserts that there need not be any 

change in the underlying evidence for FDA to revise its application of the Act; 

disagreement with the prior policy alone is sufficient. The Agency agrees that the case law 

supports this proposition. See, e.g., Rust, 500 U.S. at 187; Chevron, 467 U.S. at 865. 

The Agency's change in position is fully justified, however, by the overwhelming new 

evidence that has become available to FDA since 1980. The Agency also notes that a 

change in the case law can justify a change in position and that new case law on "intended 

use" since 1980 provide further support for the Agency's determination that cigarettes and 

smokeless tobacco are intended to affect the structure and function of the body. 

4. One comment argues that public attention on the health consequences of 

tobacco has changed its focus over the decades from tar content to nicotine addiction. 

That is, until the mid-1980's, public perception of the dangers of cigarette smoking was on 

tar and the components of tar rather than on the addictiveness of nicotine. The Agency 

fmds that this historical point further supports the Agency's changed position regarding its 

jurisdiction over tobacco products without claims. 

5. One comment states that new disclosures since the issuance of the 

Jurisdictional Analysis provide further support for FDA's assertion of jurisdiction. The 

Agency agrees that the evidence demonstrating that manufacturers of tobacco products 

intend to affect the structure and function of the body has continued to accumulate. 

In sum, after review of all of the comments, the Agency fmds that a change in 

FDA's position on jurisdiction over cigarettes and smokeless tobacco is warranted by the 

new evidence. 

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V.A. 

V. CONGRESS HAS NOT PRECLUDED OR PREEMPTED FDA FROM 

REGULATING CIGARETTFS AND SMOKELFSS TOBACCO 

The comments of the tobacco industry and others assert that Congress has 

precluded or preempted the Agency from regulating cigarettes and smokeless tobacco. As 

described in this section, the Agency disagrees. Contrary to the position of the tobacco 

industry, Congress has neither expressly nor impliedly preempted or precluded FDA from 

regulating tobacco products. The language of the Federal Food, Drug, and Cosmetic Act 

(the Act) does not preclude FDA jurisdiction. Indeed, the history of FDA's regulation of 

tobacco shows that Congress understood that FDA could regulate tobacco products when 

an intent to affect the structure or function of the body is established. Moreover; FDA's 

assertion of jurisdiction is fully consistent with the narrowly crafted preemption provisions 

in the Federal Cigarette Labeling and Advertising Act and the Comprehensive Smokeless 

Tobacco Health Education Act and with the existence of other statutes that address 

tobacco products. 

A. THE PLAIN LANGUAGE OF THE FEDERAL FOOD, DRUG, AND 

COSMETIC ACT DOFS NOT PRECLUDE FDA JURISDICTION 

OVER TOBACCO PRODUCTS 

"[T]he first place where we must look to see if Congress has spoken to the issue 

. with which we are concerned and whether congressional intent in that regard is clear is the 

face of the statute." Kofa v. INS, 60 F.3d 1084, 1088 (4th Cir. 1995); see also Time 

Warner Cable v. Doyle, 66 F.3d 867, 875 (7th Cir. 1995), cert. denied, 116 S. Ct. 974 

( 1996). In the instant case, the express language of the Act does not exclude tobacco 

products from FDA's jurisdiction. The key language that defmes drugs and devices as 

products "intended to affect the structure or any function of the body" nowhere excludes 

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V.A. 

tobacco products. Because Congress has not excluded tobacco products from the drug 

and device definitions under the Act, it cannot be said to be clear that Congress intended 

to preclude FDA from regulating cigarettes and smokeless tobacco. See Central Bank of 

Denver v. First Interstate Bank of Denver, 114 S. Ct. 1439, 1448 (1994) (Congress 

knows how to enact legislation expressly). 

Congress is able to exclude and has excluded specific products, including tobacco 

products, from a statute's reach when it wishes to do so. For example, Congress has 

expressly excluded other products from FDA's jurisdiction under the Act. See, e.g., 21 

U.S.C. 321(i) (excluding "soap" from definition of "cosmetic"); 21 U.S.C. 392 (excluding 

meat products to the extent that they are covered by the Meat Products Inspection Act); 

21 U.S.C. 321(s) (excluding pesticides from the definition of food additive under certain 

circumstances). Moreover, Congress has expressly excluded tobacco products from the 

reach of other regulatory statutes. See 15 U.S.C. 2052(a)(1)(B) (excluding ''tobacco and 

tobacco products" from the definition of "consumer products" in the Consumer Product 

Safety Act); 15 U.S.C. 1261(f)(2) (excluding ''tobacco and tobacco products" from the 

definition of"hazardous substance" in the Federal Hazardous Substances Act); 15 U.S.C. 

2602(2XB)(iii) (excluding ''tobacco or any tobacco product" from the defmition of 

"chemical substance" in the Toxic Substances Control Act); 21 U.S.C. 802(6) (excluding 

"tobacco" from the defmition of "controlled substance" in the Controlled Substances Act); 

15 U.S.C. 1459(a)(l) (excluding "tobacco or tobacco product" from the defmition of 

"consumer commodity'' in the Fair Packaging and Labeling Act). Indeed, tobacco is 

excluded from the defmition of "dietary supplement" under the Act, but no similar 

exclusion appears in the defmition of "drug" or "device." See 21 U.S.C. 321(g), (h), (ft). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45255

V.B. 

Accordingly, the absence of an express exclusion from the Act for tobacco demonstrates 

that Congress has chosen not to exclude from FDA's jurisdiction tobacco products that 

fall within the Act's detmitions of "drug" or "device." Because Congress chose not to 

exclude tobacco products from the reach of the Act, the Agency need not read an 

exemption into the Act administratively. 

B. THE LEGISLATIVE HISTORY OF THE FEDERAL FOOD, DRUG, 

AND COSMETIC ACT DEMONSTRATES THAT FDA'S 

JURISDICTION OVER TOBACCO PRODUCTS IS NOT 

PREEMWTEDORPRECLUDED 

Several comments from the tobacco industry and others assert that FDA lacks 

jurisdiction over cigarettes and smokeless tobacco without therapeutic claims because 

FDA communicated its prior position to Congress and Congress "acquiesced" in that 

interpretation by failing to enact legislation expressly authorizing FDA to regulate tobacco 

without therapeutic claims. These comments cite to unenacted legislation that, if passed, 

would have explicitly granted jurisdiction over tobacco products to FDA, and they 

contend that Congress' failure to enact these bills demonstrates that Congress concluded 

that FDA should not have jurisdiction over cigarettes. These comments variously rely on 

Flood v. Kuhn, 407 U.S. 258 (1972), Zemel v. Rusk, 381 U.S. 1, 11 (1965), United States 

v. Rutherford, 442 U.S. 544 (1979), NI.RB v. Bell Aerospace Co., 416 U.S. 267, 274-275 

(1974), United States v. uslie Salt Co., 350 U.S. 383, 396-397 (1956), and Ruhe v. 

Bergland, 683 F.2d 102, 104 (4th Cir. 1982). 

FDA disagrees with these comments on three independent grounds. Congress' 

failure to enact legislation explicitly granting FDA authority over tobacco products does 

not preclude FDA's assertion of jurisdiction over tobacco products because: ( 1) Congress 

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V.B. 

has long known that FDA asserts jurisdiction over tobacco products that are intended to 

affect the structure or function of the body and has taken no action to alter this 

interpretation of FDA's jurisdiction; (2) even if Congress has acquiesced in an 

interpretation that FDA lacks jurisdiction, the Supreme Court has made clear that 

congressional acquiescence in an Agency's interpretation cannot be used to prevent the 

Agency from changing that interpretation; and (3) the Supreme Court has rejected the 

argument that Congress' failure to adopt legislation or amendments to a statute can be 

used to interpret a law adopted by a prior Congress. 

First, the Agency does not agree that Congress has ratified or otherwise 

acquiesced in an interpretation of the Act that precludes FDA regulation of cigarettes and 

smokeless tobacco that are intended to affect the structure or function of the body. As 

discussed in section IV., above, FDA has long exercised legal authority to regulate 

tobacco products when the evidence established that the products had intended uses that 

fell within the Act's defmition of a "drug." See, e.g., U.S. Department of Agriculture 

Service and Regulatory Announcements, No. 13 ( 1914 );1219 United States v. 354 Bulk 

Cartons ... Trim Reducing-Aid Cigarettes, 178 F. Supp. 847, 851 (D.N.J. 1959) 

(cigarettes claimed to reduce weight were drugs because they were intended to affect the 

structure or function of the body); United States v. 46 Cartons, More or Less, Containing 

Cigarettes, 113 F. Supp. 336, 338-339 (D.N.J. 1953) (cigarettes claimed to prevent 

respiratory diseases were drugs because they were intended to treat or prevent disease). 

Indeed, as the comments point out, FDA has repeatedly told Congress that a tobacco 

1219 The USDA citation appears in the Joint Comment of the Cigarette Manufacrurers., Comment (Jan. 2, 

1996), Vol I. at5. See AR(Vol535Ref. 96). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45257

V.B. 

product that falls within the definition of a drug or device because it was promoted to treat 

disease or to affect the structure or function of the body would be within the Agency's 

jurisdiction. See, e.g., Hearings Before the Consumer Subcomm. of the Senate Comm. on 

Commerce on S. 1454, 92d Cong., 2d Sess. 239 (1972) (FDA Commissioner Charles C. 

Edwards testified that "cigarettes and other tobacco products would be drugs subject to 

the Federal Food, Drug, and Cosmetic Act if medical claims are made for the product ... 

[or] if recommended for use in controlling appetite ... "). 

Second, even if the Agency had consistently interpreted the Act to preclude FDA 

regulation of tobacco products even when they were intended to affect the structure or 

function of the body, the legislative history cited by the tobacco industry would not 

preclude FDA from changing its interpretation. Acquiescence in an agency interpretation 

can be used only to confrrm that an agency is acting within its authority, not to prevent an 

agency from changing its interpretation. Motor Vehicle Mfrs. Ass'n v. State Farm Mut. 

Auto. Ins. Co., 463 U.S. 29, 45 (1983) ("While an agency's interpretation of a statute may 

be confrrmed or ratified by subsequent congressional failure to change that interpretation 

... even an unequivocal congressional ratification ... of [a prior regulatory standard] 

would not connote approval or disapproval of an agency's later decision to rescind the 

regulation") (internal citations omitted); Massachusetts v. Secretary of Health and Human 

Services, 899 F.2d 53, 61 (1st Cir. 1990) (''the ratification of one agency policy by 

Congress does not preclude a change in that policy"), vacated on other grounds, 500 U.S. 

949 (1991). 

Finally, it is well established that "subsequent legislative history" cannot be relied 

upon to interpret previous legislation. The principal evidence cited by the comments that 

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V.B. 

Congress intended to preclude FDA jurisdiction over tobacco is unenacted legislation that, 

if passed, would have explicitly granted jurisdiction over tobacco products to FDA. The 

comments contend that Congress' failure to enact these bills demonstrates that Congress 

intended to exclude tobacco products from FDA's jurisdiction over drugs and devices. 

FDA disagrees. Congress can implement policy in only one way: passage of a bill 

by the House and the Senate that is either signed by the President or approved by an 

overridden veto. INS v. Chadha, 462 U.S. 919, 954-955 (1983); Central Bank, 114 S. 

Ct. at 1453. Congress has not enacted any legislation, signed by the President or 

approved by an overridden veto, that excludes cigarettes and smokeless tobacco from the 

drug and device definitions. The comments' argument is inconsistent with Chadha 

because it would allow Congress to change the law (by inaction) without any role for the 

President.1220 

The gravamen of the comments' argument is that Congress' failure to modify the 

"drug" and "device" definitions after their original passage can be used to discern 

congressional intent as to the scope of those definitions. This argument has been rejected 

by the courts. Courts have repeatedly rejected claims that the failure of Congress to adopt 

legislation or amendments to a statute can be used to interpret a law adopted by a prior 

Congress. As the Supreme Court has explained: 

We have stated .... that failed legislative proposals are a particularly 

dangerous ground on which to rest an interpretation of a prior statute. 

Congressional inaction lacks persuasive significance because several 

equally tenable inferences may be drawn from such inaction, including the 

1220 In addition, under Supreme Court authority, Congress's explicit grant of jurisdiction to an agency 

does not necessarily indicate that the agency previously lacked jurisdiction. United States v. New York 

Tel. Co., 434 U.S. 159, 177 n.25 (1977). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45259

inference that the existing legislation already incorporated the 

offered change. 

V.B. 

Central Bank, 114 S. Ct. at 1453 (citations and internal quotation marks omitted); see 

also Brecht v. Abrahamson, 113 S. Ct. 1710, 1719 (1993) ("[a]s a general matter, we are 

reluctant to draw inferences from Congress' failure to act") (citations and internal 

quotation marks omitted); United States v. Wise, 370 U.S. 405, 411 (1962). 

Moreover, as discussed in some comments, bills have been proposed, but not 

enacted, that would explicitly exclude tobacco products from the reach of the Act. See, 

e.g., S. 1295, 104th Cong., 1st Sess. (1995); H.R. 2265, 104th Cong., 1st Sess. (1995); 

H.R. 2283, 104th Cong., 1st Sess. (1995). Under the comments' theory, as discussed 

above, the fact that such legislation was proposed but not enacted would mean that 

Congress intends FDA to have jurisdiction over tobacco products. Therefore, because 

bills have been proposed but not enacted on both sides of the issue, Congress would have 

implicitly both granted jurisdiction to FDA and excluded jurisdiction from FDA. That 

result would, of course, be absurd. 

Other legislative history relied on by the comments also fails to establish that FDA 

lacks jurisdiction over tobacco products that are intended to affect the structure or 

function of the body. In asserting that FDA does not have jurisdiction over tobacco 

products, some comments rely heavily on statements and actions in Congresses that 

followed the enactment of the 1938 Federal Food, Drug, and Cosmetic Act (e.g., 

statements by members that FDA lacks jurisdiction over tobacco products). Several 

comments also cite to remarks regarding FDA's lack of jurisdiction made by individual 

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V.B. 

members of Congress who were antismoking advocates. The comments assert that these 

statements are akin to admissions. 

These statements are unpersuasive as evidence of Congress' intent in enacting the 

"drug" and "device" definitions in sections 201(g)(l)(C) and 201(h)(3) of the Act, 21 

U.S.C. 321 (g)(l)(c) and 321(h)(3). The courts have made clear that infonnal statements 

by subsequent Congresses cannot negate the broad reach of the language from the 1938 

Act granting FDA authority to regulate articles "intended to affect the structure or any 

function of the body." See Waterman Steamship Corp. v. United States, 381 U.S. 252, 

269 ( 1965) (''the views of a subsequent Congress fonn a hazardous basis for inferring the 

intent of an earlier one") (citations and internal quotation marks omitted); Pennsylvania 

Med. Soc'y v. Snider, 29 F.3d 886, 898 (3d Cir. 1994) ("Post-enactment legislative 

history is not a reliable source for guidance. Even when a subsequent House Committee 

has actually commented upon an earlier statute, the interpretation carries little weight with 

the courts") (citations and internal quotation marks omitted); Central Bank, 114 S. Ct. at 

1452 (''the interpretation given by one Congress (or a committee or Member thereof) to 

an earlier statute is of little assistance in discerning the meaning of that statute") (citations 

and internal quotation marks omitted); Heintz v. Jenkins, 115 S. Ct. 1489, 1492 (1995) 

{where Congressman made statement after the statute became law, the statement "is not a 

statement upon which other legislators might have relied in voting for or against the Act, 

but it simply represents the views of one infonned person on an issue about which others 

may (or may not) have thought differently"). 

Furthennore, as other comments argue, neither the Agency nor the congressional 

committees and members involved were aware, at the time when the statements and 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45261

v.c. 

actions were made, of the new evidence, summarized in section II., above, showing that: 

(1) nicotine is highly addictive; (2) the vast majority of consumers use tobacco products to 

satisfy their addiction and for other pharmacological effects; and (3) the tobacco industry 

has long known that consumers use tobacco products for the pharmacological effects of 

nicotine and have facilitated these effects through manipulation of nicotine delivery. These 

comments contend that reliance on congressional statements or actions made before this 

evidence was known would reward the tobacco industry for concealing evidence about the 

nature of its products. Other comments assert that the legislative history cited by the 

tobacco industry is not dispositive in this instance because only now has FDA amassed 

sufficient evidence to demonstrate that nicotine in tobacco products is intended to act 

as a drug. 

FDA agrees. Evidence that has come to light in the last few years demonstrates 

that cigarettes and smokeless tobacco are intended to affect the structure and function of 

the body. Earlier Congresses did not have access to this evidence of intended use. Thus, 

statements and actions by members of previous Congresses have no bearing on whether 

the current evidence shows that cigarettes and smokeless tobacco are within FDA's 

jurisdiction because they are "intended to affect the structure or any function of the body." 

C. OTHER STATUTES DO NOT PRECLUDE OR PREEMPT FDA'S 

JURISDICTION OVER TOBACCO PRODUCTS 

Several comments assert that the Federal Cigarette Labeling and Advertising Act 

(the Cigarette Act), 15 U.S.C. 1331-1341, and the Comprehensive Smokeless Tobacco 

Health Education Act (the Smokeless Act), 15 U.S.C. 4401-4408, which concern health 

warnings on packaging of cigarettes and packaging and advertising of smokeless tobacco 

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45262 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

v.c. 

respectively, explicitly preempt FDA action concerning the labeling or advertising of 

tobacco products. Other comments assert that the existence of several statutes relating to 

tobacco products-including the Cigarette Act and the Smokeless Act, as well as section 

1926 of the Public Health Service Act-demonstrates Congress' intent to establish a 

"comprehensive" tobacco regulation program that somehow implicitly precludes or 

preempts FDA's regulation of cigarettes under the Act. 

The Agency disagrees. None of the statutes cited either expressly or impliedly 

preempts FDA regulation of tobacco products generally, nor do the statutes cited conflict 

with the fmal rule. These comments have misread the Cigarette Act and the Smokeless 

Act. Both of these statutes contain specific provisions addressing the extent to which 

FDA and other Federal agencies are preempted from regulating cigarettes and smokeless 

tobacco. These provisions are narrowly written and do not preempt FDA from asserting 

jurisdiction when an intent to affect the structure or function of the body can be 

established. The Cigarette Act, for instance, contains two preemption provisions relating 

to cigarettes. The first provision is narrowly tailored in scope, applying only to 

"statement[s] relating to smoking and health ... on any cigarette package." 15 U.S.C. 

i334(a). That provision is not triggered by the content of the final rule because the 

Agency is not requiring any statements regarding smoking and health on the cigarette 

package. 

The Cigarette Act's second preemption provision, which applies to the advertising 

and promotion of cigarettes, is expressly directed at State law: "No requirement or 

prohibition based on smoking and health shall be imposed under State law with respect to 

the advertising or promotion of any cigarettes the packages of which are labeled in 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45263

V.C. 

conformity with the provisions of this Act." 15 U.S.C. 1334(b). If Congress had intended 

to preempt other Federal initiatives by this provision, it would have done so by, for 

example, adding the words "or Federal" between "State" and "law" in section 1334(b). In 

fact, Congress did just the opposite. The legislative history of the Cigarette Act 

establishes that Congress considered and rejected preemption of Federal regulation in the 

advertising preemption provision. Conf. Rep. 897, 9lst Cong., 2d Sess. 2 (1970), 

reprinted in 1970 U.S.C.C.A.N. 2652, 2677. ("The House bill contained a blanket 

preemption (applicable to all Federal departments and agencies as well as State and local 

governments) with respect to requiring statements relating to smoking and health in 

advertisements of cigarettes .... The Senate preemption applied only to States and their 

political divisions .... With minor technical amendments the conference version is the 

same as the Senate amendment."). 

Because Congress specifically addressed the question of Federal preemption in the 

Cigarette Act, the Agency must follow Congress' determination. General preemption 

jurisprudence (although applicable to preemption of State law, and not controlling in 

situations involving preemption of Federal law) also counsels against reading the express 

preemption provision in the Cigarette Act to extend beyond its terms. See Cippollone v. 

liggett Group, Inc., 505 U.S. 504,517 (1992) ("the pre-emptive scope of the 1965 Act 

and the 1969 Act is governed entirely by the express language in§ 5 of each Act"); see 

also Medtronic,lnc. v. Lohr, 64 U.S.L.W. 4625 (U.S. Jun. 26, 1996)(rejecting broad 

interpretation of preemption provision).1221 Accordingly, the Agency declines to read a 

1221 See Preamble to the Final Rule. Section X., for a more detailed discussion of preemption principles. 

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blanket preemption of FDA jurisdiction over cigarettes into the Cigarette Act when 

Congress expressly drafted a narrow preemption provision. 

v.c. 

The preemptive reach of the Smokeless Act is also circumscribed to particular 

areas. See 15 U.S.C. 4406(a). The preemption provision in that act applies only to 

"statement[ s] relating to use of smokeless tobacco and health" on packages and 

advertisements other than outdoor billboard advertisements. I d. This narrow provision 

cannot be read to preempt FDA jurisdiction, which authorizes regulation in a variety of 

areas unrelated to the specific statements covered by the preemption provision. As 

described in the preamble to the fmal rule, FDA is exercising its jurisdiction without 

imposing requirements that conflict with this provision. 

Nor does the existence of other statutes that regulate tobacco impliedly preempt 

FDA's regulation of tobacco under its authority to regulate drugs and devices. "It is, of 

course, a cardinal principle of statutory construction that repeals by implication are not 

favored." United States v. United Continental Tuna Corp., 425 U.S. 164, 168 (1976). 

Moreover, the doctrine of implied preemption has been applied only in the context of 

congressional preemption of State laws. See, e.g., Time Warner Cable, 66 F.3d at 874; 

see also Duvall v. Bristol-Myers-Squibb Co., 65 F.3d 392,396 (4th Cir. 1995) (''the 

doctrine of preemption is based on the Supremacy Clause of the United States 

Constitution," which is used to invalidate State laws that conflict with Federal legislation), 

petition for cert.filed, 64 U.S.L.W. 3439 (US Dec. 22, 1995) (No. 95-1010). Because 

the matter here does not involve Federal preemption of State law, the doctrine has 

no applicability. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45265

v.c. 

In the absence of an express preemption provision, one Federal statute precludes 

giving effect to another Federal statute only where there is an irreconcilable conflict 

between the two laws. Connecticut Nat'l Bank v. Germain, 503 U.S. 249, 253 (1992) 

("so long as there is no 'positive repugnancy' between two laws, a court must give effect 

to both") (citation omitted); Morton v. Mancari, 417 U.S. 535, 551 (1974) ("The courts 

are not at liberty to pick and choose among congressional enactments, and when two 

statutes are capable of co-existence, it is the duty of the courts, absent a clearly expressed 

congressional intention to the contrary, to regard each as effective"). As described in 

detail in the preamble to the final rule, FDA regulation of tobacco products under the 

authority of the Act does not conflict with other statutes in the current regulatory scheme 

for tobacco products, and is clearly capable of coexisting with those statutes. 

The fact that FDA's jurisdiction over tobacco products may overlap with the 

jurisdiction of other Federal agencies is not sufficient to invalidate that jurisdiction. FDA 

has overlapping jurisdiction with other agencies for several products. For example, while 

FDA regulates pesticides with respect to their content in food, see 21 U.S.C. 342 

(adulteration), 21 U.S.C. 343 (misbranding), 21 U.S.C. 1401 (pesticide residue 

monitoring), the Environmental Protection Agency (EPA) regulates the registration, use, 

and labeling of pesticides with respect to their effect on the environment under the Federal 

Insecticide, Fungicide, and Rodenticide Act, 7 U.S.C. 136 et seq., and the U.S. 

Department of Agriculture is charged with monitoring pesticide research and development 

to improve methods of pest control, 7 U.S.C. 5881. In addition, both FDA and the U.S. 

Department of Agriculture regulate meat and poultry products, including animal drug 

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V.D. 

residues found within those products. Finally, FDA and the Federal Trade Commission 

share responsibilities for the regulation of the advertising of drugs and devices. 

Other Federal agencies have overlapping and complementary jurisdiction that 

arises from their differing missions and expertise. See, e.g., Rueth v. U.S. EPA, 13 F.3d 

227, 228 (7th Cir. 1993) (EPA and Army Corps of Engineers have concurrent jurisdiction 

under the Clean Water Act); Public Utility Dist. No. 1 v. Bonneville Power Admin., 947 

F.2d 386, 395 (9th Cir. 1991) (the Federal Energy Regulatory Commission has concurrent 

jurisdiction with other Federal agencies, as well as States, over hydroelectric projects), 

cert. denied, 503 U.S. 1004 (1992); United Packinghouse, Food and Allied Workers lnt'l 

Union, AFL-CIO v. NLRB, 416 F.2d 1126, 1133-1134 n.11 (D.C. Cir.) (National Labor 

Relations Board and the Equal Employment Opportunity Commission have concurrent 

jurisdiction over racial discrimination claims), cert. denied, 396 U.S. 903 (1969). 

Accordingly, the mere fact that other agencies regulate tobacco for certain purposes does 

not mean that FDA lacks jurisdiction. 

D. RESPONSE TO COMMENTS 

Most of the comments received on this issue have been addressed in the preceding 

discussion. The remaining comments are addressed below. 

1. Many of the comments regarding congressional intent rely primarily on 

attenuated inferences. For example, several comments assert that, because Congress 

exempted tobacco from the reach of other statutes, such an exemption should be found by 

implication in the Act Similarly, another comment asserts that, because tobacco, drugs, 

and devices are each exempted under the Toxic Substances Control Act, Congress clearly 

believed that tobacco products were not drugs or devices. FDA disagrees. If the 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45267

V.D. 

reasoning reflected in these comments were adopted, Congress would be legislating by 

inference. Moreover, as discussed previously in this section, earlier Congresses did not 

have access to the new evidence on the intended use of tobacco products. This change in 

the evidence makes it especially inappropriate to construe such specific and limited past 

congressional actions so expansively. 

2. One comment argues that under Flood v. Kuhn, 407 U.S. 258 (1972), FDA 

is precluded from asserting jurisdiction over cigarettes and smokeless tobacco because the 

tobacco industry has relied on previous Agency statements that it lacked jurisdiction over 

tobacco products without claims. 

FDA disagrees that the decision in Flood precludes FDA's assertion of jurisdiction 

over tobacco products that are intended to affect the structure or function of the body. 

Flood is inapplicable to tobacco products on at least two grounds. First, the Flood court, 

noting that baseball is "an exception and an anomoly," held that the antitrust laws could 

not be applied to baseball to invalidate baseball's "reserve system" for players without new 

legislation, based in part on baseball's "unique place in our American heritage." 407 U.S. 

at 266, 282. Cigarettes and smokeless tobacco occupy a very different place in American 

life. Tobacco products, unlike baseball, are responsible for the deaths of over 400,000 

Americans each year. The Supreme Court has refused to extend the principle upheld in 

Flood beyond baseball even to other professional sports. See, e.g., Haywood v. National 

Basketball Association, 401 U.S. 1204 (1971); Radovich v. National Football League, 

352 U.S. 445 (1957); United States v. International Boxing Club, 348 U.S. 236 (1955). 

It is inconceivable that the principle extends to bar the application of public health statutes 

to products previously unregulated by those statutes. 

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45268 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

V.D. 

Second, the court in Flood was concerned about the retroactive application of its 

decision to an industry that had relied on its exemption from the antitrust laws. There is 

no evidence that the tobacco industry has relied to its detriment on any belief that tobacco 

products without claims are not subject to FDA jurisdiction. In Flood, there was ample 

evidence of such reliance; the baseball industry had set up an elaborate contracting system, 

in place since 1887, that would plainly violate the antitrust laws, in reliance on Supreme 

Court holdings that baseball was exempt from those laws. The plaintiff in the case sought 

to have that system invalidated retroactively. The tobacco industry has pointed to no 

evidence of reliance in the form of actions it has taken that plainly violate the Federal 

Food, Drug, and Cosmetic Act and that the Agency is seeking to remedy retroactively. 

The industry is simply interested in maintaining its ability to sell its products free of FDA 

regulation. Moreover, even had the industry relied on the absence of comprehensive FDA 

regulation, such reliance would have been inappropriate given the tobacco industry's 

failure to disclose information relevant to the intended use of cigarettes and smokeless 

tobacco. 

In fact, internal tobacco company documents show that the tobacco industry has 

not acted in reliance on the belief that tobacco products without c1aims are always outside 

FDA's jurisdiction. These documents disclose that members of the industry were aware 

that evidence other than claims could be used to declare jurisdiction over tobacco 

products and took steps to avoid the disclosure of such evidence. For example, a Brown 

& Williamson memorandum submitted to the record in this proceeding reveals that a 

company lawyer recommended to the president and chief executive officer of Brown & 

Williamson that the company not become involved in the sale of nicotine patches, stating: 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45269

V.D. 

"If we did anything which suggested we were simply in the nicotine delivery business, we 

would run a serious risk of facing FDA jurisdiction."1222 There was no suggestion in any 

of the submitted documents that any claims would be placed on cigarettes as a result of 

the company's sale of nicotine patches. Nevertheless, the company recognized that FDA 

jurisdiction might follow solely based on evidence suggesting company knowledge that 

cigarettes are related to other nicotine delivery systems. The company ultimately chose 

not to become involved in the sale of nicotine patches. For these reasons, Flood v. Kuhn 

is inapplicable. 

1222 McGraw M, Nicotine Delivery Systems (Apr. 24, 1992), at 1. See AR (Vol 531 Ref. 124). 

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45270 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI. FDA EMPLOYED PROCEDURES THAT PROVIDED AN 

OPPORTUNITY FOR FULL PUBLIC PARTICIPATION AND 

EXCEEDED ALL LEGAL REQIDREMENTS 

VI. 

The Agency went to great lengths to involve the public in the process by which the 

Agency made its final jurisdictional detennination. On February 25, 1994, FDA 

Commissioner David Kessler wrote to Scott Ballin, chainnan of the Coalition on Smoking 

OR Health, regarding the possibility of FDA regulation of cigarettes in response to certain 

petitions that had been flled with the Agency. The Commissioner explained: 

[T]he agency has examined the current data and information 

on the effects of nicotine in cigarettes .... Evidence brought 

to our attention is accumulating that suggests that cigarette 

manufacturers may intend that their products contain 

nicotine to satisfy an addiction on the part of some of their 

customers .... This evidence ... suggests that cigarette 

vendors intend the obvious -- that many people buy 

cigarettes to satisfy their nicotine addiction. Should the 

agency make this finding based on an appropriate record or 

be able to prove these facts in court, it would have a legal 

basis on which to regulate these products .... 1223 

The letter was made publicly available and covered by the press.

1224 

1223 Letter from Kessler DA (FDA) to Ballin SD (Coalition on Smoking OR Health) (Feb. 25, 1994). See 

AR (Vol. 35 Ref. 365). 

1224 Neergaard L (Associated Press) FDA considers calling nicotine a drug, banning cigarettes (Feb. 26, 

1994). See AR (Vol 711 Ref. 30). 

Associated Press, FDA considers classification of nicotine as drug, Chicago Tribune (Feb. 26, 1994). See 

AR (Vol. 711 Ref. 31). 

Chen E, Government agency claims power to ban nearly all cigarettes; FDA fears nicotine used for 

addiction, The Houston Chronicle (Feb. 26, 1994). See AR (Vol 711 Ref. 32). 

ChenE, In shift, FDA says it could classify nicotine as a drug, Los Angeles Times (Feb. 26, 1994). See 

AR (Vol. 711 Ref. 33). 

Hilts PJ, U.S. Agency suggests regulating cigarettes as an addictive drug, New York Times (Feb. 25, 

1994). See AR (Vol 711 Ref. 34). 

Tribune News Services, The Salt lAke Tribune (Feb. 26, 1994). See AR (Vol 711 Ref. 35). 

614 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45271

VI. 

In the months that followed, Commissioner Kessler testified twice before Congress 

regarding the accumulating evidence relating to the intended use of cigarettes.1225 That 

testimony was extensive and detailed. 

In July and August of that year, FDA Associate Commissioner for Regulatory 

Affairs Ronald G. Chesemore wrote to all of the major cigarette and smokeless tobacco 

companies requesting all documents relating to "all research on nicotine ... , including 

their pharmacological effects, and all documents relevant to nicotine" in their products.1226 

On August 1, 1994, FDA held a Drug Abuse Advisory Committee meeting that was fully 

open to the public on the subject of the abuse potential of nicotine. 

On August 11, 1995, FDA provided the public with an extensive Federal Register 

document analyzing the Agency's authority to assert jurisdiction over cigarettes and 

smokeless tobacco based on the evidence before the Agency at that time. See 

Jurisdictional Analysis, 60 FR 41453-41787. This document, which accompanied the 

Agency's announcement of its proposal to regulate the sale and distribution of cigarettes 

and smokeless tobacco, see 60 FR 41314-41375, provided the public with a full view of 

FDA claims authority to regulate nicotine; agency cites manipulation of cigarette 'drug,' St. Louis Post 

Dispatch (Feb. 26, 1994). See AR(Vol 711 Ref. 36). 

Schwartz J, In policy shift, FDA is ready to consider regulating tobacco, The Washington Post (Feb. 26, 

1994). See AR (Vol 711 Ref. 37). 

122' Statement by David Kessler; M.D., Commissioner of Food and Drugs, on Nicotine-Containing 

Cigarettes, before the Subcommittee on Health and the Environment. Committee on Energy and 

Commerce, U.S. House of Representatives (Mar. 25, 1994). See AR (Voll Appendix 7). 

Statement by David Kessler, M.D., Commissioner of Food and Drugs, on the Control and Manipulation of 

Nicotine in Cigarettes, before the Subcommittee on Health and the Environment. Committee on Energy 

and Commerce, U.S. House of Representatives (Jun. 21, 1994). See AR (Vol. 1 Appendix 8). 

1226 See, e.g., Letter from Cbesemore RG (FDA) to Bible GC (Philip Morris Inc.) (Jul. 11, 1994) See AR 

(Vol. 1 Appendix 3) 

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45272 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI. 

the Agency's legal analysis. In addition, the Jurisdictional Analysis was supported by over 

600 footnotes, each of which identified for the public the evidence on which the Agency 

relied to support its findings. The Agency also placed on the record 313 pages of 

appendices related to the Jurisdictional Analysis. 

On August 16, 1995, the Agency put on public display some 20,000 pages of 

materials that it cited in the Jurisdictional Analysis and the proposed rule. With the 

exception of three documents, discussed below, the Agency made available to the public 

all of the materials on which it relied to support the Jurisdictional Analysis and the 

Proposed Rule. On September 29, 1995, the Agency supplemented the administrative 

record by putting on public display approximately 13,000 documents comprising some 

190,000 pages of factual and analytical materials the Agency considered in the course of 

issuing the Jurisdictional Analysis and the Proposed Rule. Although it was under no legal 

obligation to do so, the Agency made these additional materials available because of the 

importance of the jurisdictional issue and the Proposed Rule. 

The administrative record also includes the comments received from the public, as 

discussed in more detail below. The Agency received over 700,000 comments, some 

directed to the Jurisdictional Analysis, some directed to the Proposed Rule, and many with 

overlapping discussions. Though many comments consisted of form letters, the Agency 

received over 95,000 distinct or unique sets of comments. The cigarette manufacturers 

jointly submitted 2,000 pages of comments and 45,000 pages of exhibits. The smokeless 

tobacco manufacturers jointly submitted 474 pages of comments and 3,372 pages of 

exhibits. The initial comment period remained open for 144 days. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45273

VI. 

The Agency also made one other significant addition to the public record relating 

to its jurisdictional determination. On March 20, 1996, the Agency published a notice in 

the Federal Register providing an additional30 day comment period limited to specific 

documents the Agency added to the docket in support of its Jurisdictional Analysis. See 

61 FR 11419. These materials consisted of declarations and a report from three former 

tobacco industry employees. 

In addition, as discussed further below, the Agency has added to the final record of 

the jurisdictional determination a comparatively small number of documents that expand 

upon or confirm information made available in the Jurisdictional Analysis or the Proposed 

Rule, or that address alleged deficiencies in the Agency's initial record. 

Despite the Agency's efforts to involve the public in this jurisdictional 

determination, FDA received several comments regarding the procedures the Agency 

followed in publishing the Jurisdictional Analysis. Some of these comments complained 

that the Agency designated certain documents in the administrative record supporting the 

Jurisdictional Analysis as "confidential," and that the shielding of these documents denied 

the public a meaningful opportunity to comment on the Agency's analysis. One of these 

comments also contended that FDA refused to disclose nonconfidential information on 

which the Agency relied in the Jurisdictional Analysis. Some comments claimed that FDA 

failed to set forth a balanced view of the issues raised in the Jurisdictional Analysis. 

Instead, they argued, FDA concealed certain issues in order to deny the public the 

opportunity to comment on the Agency's analysis. At least one interested person also 

maintained that the comment period was so short as to be arbitrary and capricious. 

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45274 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI. A 

Finally, one comment objected to the Agency's use of certain affidavits and reports from 

former tobacco industry scientists without first providing the public an opportunity to 

cross-examine these individuals. However, other than this one comment on a narrow 

category of evidence in the administrative record, the Agency received no comments 

concerning, and no objection to, the Agency's decision to use a notice-and-comment type 

format to reach a final jurisdictional determination.1227 

As the discussion that follows demonstrates, the procedures the Agency employed 

in reaching its fmal jurisdictional determination exceeded the requirements of the AP A, the 

case law construing the AP A, and the Agency's own procedural requirements either for a 

jurisdictional determination or for a conventional informal rulemaking. 

A. ADEQUACY OF THE RECORD 

Several tobacco industry comments complained about the adequacy of the record 

in support of the Jurisdictional Analysis. They contended that the Agency violated the 

APA, 5 U.S.C. 553(b) and (c), and the Due Process Clause of the Fifth Amendment to the 

Constitution, 1228 by failing to disclose all of the information the Agency "considered or 

1227 Because of the unique importance of the jurisdictional issue, the Agency published the Jurisdictional 

Analysis in the Federal Register and invited comments on it The Agency, however, was not required by 

the Administrative Procedure Act (AP A) to invite public comment on the issue of the Agency's 

jurisdiction. Likewise, the Act neither requires that the Agency commence a rulemak:ing proceeding, nor 

conduct a formal evidentiary hearing, before it makes a jurisdictional determination. Nevertheless, 

because of the great importance of this issue, FDA employed a notice-and- eomment-type procedure to 

give the public an opportunity to participate in the Agency's analysis of its jurisdiction. None of the 

comments the Agency received identified a statutory requirement that would have compelled the Agency 

to follow any additional or different procedures. Thus, while the Agency endeavored in its publication of 

the Jurisdictional Analysis to provide notice, a supportive record, and a comment period sufficient to meet 

the procedural requirements of the AP A for informal rulemak:ing, the Agency was not bound by the AP A's 

informal rulemak:ing procedures with respect to the Jurisdictional Analysis. 

1228 Because the AP A in this context provides the public at least as much protection as the Due Process 

Clause of the Constitution, the Agency will address these procedural objections solely under the APA. See 

Forester v. Consumer Product Safety Commission, 559 F.2d 774,787 (D.C. Cir. 1977); Ass'n of National 

Advertisers, Inc., v. Federal Trade Commission, 627 F.2d 1151, 1166 (D.C. Cir. 1979), cert. denied, 441 

U.S. 921 (1981). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45275

VI.A.l. 

relied upon in the proceeding." 1229 In particular, these comments complained that the 

public was deprived of the opportunity to comment meaningfully on the Jurisdictional 

Analysis because, according to these comments, the Agency had relied on confidential 

documents and on substantial amounts of undisclosed data. One comment went so far as 

to claim that "a substantial portion" of the material FDA relied upon, both in the 

Jurisdictional Analysis and in the Proposed Rule, was not made available for public 

scrutiny. 

The record in support of the Jurisdictional Analysis provided the public not only 

with a "reasonable opportunity" for comment, but with an extraordinary opportunity to 

examine the Agency's position. The claim that the Agency withheld "a substantial 

portion" of the materials on which it relied is simply unfounded. 

1. The Administrative Record the Agency Assembled for This 

Proceeding Surpassed the Requirements of the APA 

Even in an informal rulemaking proceeding-which the Jurisdictional Analysis was 

simply modeled on-the AP A requires only that the "notice of proposed rule making" 

include a statement of the time, place, and nature of the proceeding, "reference to the legal 

authority under which the rule is proposed," and "either the terms or substance of the 

proposed rule or a description of the subjects and issues involved." See 5 U.S.C. 553(b). 

The AP A, thus, does not expressly require disclosure of the information on which the 

Agency relies in proposing a rule. 

1229 Joint Comments of the Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol. XII, at 1. See AR 

(Vol. 535 Ref. 96) 

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45276 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI.Al. 

Nevertheless, courts have implied under the AP A a requirement that an agency 

give notice of the information on which it actually relies to support a proposed rule, and 

make that information available to the extent it is not readily accessible to the public. See 

generally K. Davis, Administrative Law Treatise,§ 7.3 at 305-309 (3d ed. 1994) 

(discussing one of the seminal cases on disclosure of data relied on to support a 

rulemaking proceeding, Portland Cement Ass'n v. Ruckelshaus, 486 F.2d 375 (D.C. Cir. 

1973), cert. denied, 417 U.S. 921 (1974)). No court, however, has required the degree of 

public disclosure at the notice stage of a rulemaking proceeding that FDA undertook here. 

Indeed, the primary cases cited by the comments, namely, Portland Cement Ass'n, 

United States v. Nova Scotia Food Products Corp., 568 F.2d 240 (2d Cir. 1977), and 

United States Lines, Inc. v. Federal Maritime Commission, 584 F.2d 519 (D.C. Cir. 

1978), address agency conduct that bears little resemblance to FDA's efforts in this 

proceeding. While FDA has provided a remarkable degree of factual support and 

procedural openness, these cases involve instances in which agencies provided the public 

with no information whatsoever or otherwise excluded a study that was critical to the 

agency's decision. In Portland Cement Ass'n, the Environmental Protection Agency 

failed altogether to provide the public an opportunity to comment on the test results and 

procedures on which the agency relied as the "critical" basis for the emission control level 

adopted by the agency. That is, the agency set very specific technical control limits, but 

failed to make public until after the close of the comment period the details of crucial tests 

relied upon to determine the limits. 486 F.2d at 392. 

In Nova Scotia Food Products, "all the scientific research was collected by the 

agency, and none of it was disclosed to interested parties as the material upon which the 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45277

VI.Al. 

proposed rule would be fashioned." 568 F.2d at 251 (emphasis added). And in United 

States lines, where a common carrier challenged an order of the Federal Maritime 

Commission amending a contract between two competitors, the court found that the 

Commission had made "critical fmdings" on the basis of data which was neither identified 

in its decision nor included in the administrative record. Rather, the Commission based its 

decision on "reliable data reposing in the Commission's files." 584 F.2d at 533. The 

reviewing court simply had no idea of the factors or data on which the Commission had 

relied. Id. 

Thus, at most, the case law requires agencies to disclose studies and data actually 

relied upon by the agency. Even then, the cases that have struck down agency rulemaking 

are generally confmed to instances in which the agency provided woefully inadequate 

information to the public or failed to disclose a critical piece of information. See, e.g., 

Kennecott Corp. v. Environmental Protection Agency, 684 F.2d 1007, 1018-1019 (D.C. 

Cir. 1982) (agency acted arbitrarily and capriciously when it failed to include in the public 

docket during the comment period any documents supporting a particular proposed 

regulation); compare Personal Watercraft Industry Ass'n v. Depart~nt of Commerce, 48 

F.3d 540,544-545 (D.C. Cir. 1995) (while agency must disclose information critical to its 

decision to regulate a particular activity, absent prejudice an agency may rely on studies 

developed after close of comment period that are not critical to the underlying proposal). 

Finally, FDA's own procedural regulations require that the Agency include with a 

notice of proposed rulemaking, among other things, "references to all information on 

which the Commissioner relies for the proposal." 21 CFR 10.40(b)(vii) (emphasis added); 

see 21 CFR 10.3 (defming the term "administrative record" to mean the materials on 

621 
45278 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI.Al. 

which the Agency "relies to support the action"). Thus, even under the Agency's own 

procedural regulations, FDA is required-when it initiates infonnal rulemaking-to supply 

the public only with the materials the Agency is relying upon to support the proposed 

action. 

Here, the materials the Agency relied upon at the opening of this proceeding are 

the materials the Agency cited in the two August 11, 1995, Federal Register documents. 

Not only did the Agency provide these materials to the public, but it also provided the 

roughly 190,000 pages of factual and analytical materials the Agency considered but did 

not rely on and, hence, did not reference in either the Jurisdictional Analysis or the 

Proposed Rule. Moreover, the Agency provided over 1000 endnotes and footnotes 

directing readers to each document, including every study, government report, journal 

article, industry document, and Agency record on which FDA relied to support the 

Jurisdictional Analysis and the Proposed Rule. 

Out of all of this material, the only nonpublic materials on which the Agency relied 

in its Jurisdictional Analysis were two confidential documents1230 and two lines of text the 

Agency redacted from a document placed on the public Administrative Record.1231 None 

1230 The two confidential documents the Agency directly referenced, which are discussed in detail in the 

text, are the 1991 Handbook on Leaf Blending and Product Development (Confidential Document 75) and 

the unredacted summary of notes of FDA trip visits (Confidential Document 74). The summary was 

compiled from notes and handouts that are also designated as confidential (Confidential Documents 69, 

70, 71, 72 and 73). The Agency views the summary as a stand-alone document to the extent it distills a 

large volume of disparate handwritten notes and handouts. Also, the Agency cited only to the summary 

itself. Nevertheless, even if the summary were counted as five documents rather than one, the Agency at 

most relied for support on six confidential documents. 

1231 On page 255 of the Jurisdictional Analysis (60 FR 41716), the Agency redacted several lines of text 

along with a footnote that identified the sources for the redacted text The footnote consisted of references 

to two sources, both of which appeared on the agency's public docket Kiefer JE, Tennessee Eastman 

Company, Cigarette Filters for Altering the Nicotine Content of Smoke (Report No. 71 5003 7), Aug. 18, 

1971 at 1-2, See AR (Vol. 28 Ref. 463-1); and Curran Jr. JG, Miller EG, Factors influencing the elution 

of high boiling components of cigarette smoke from ftlters, Beitr. Tabaliforsch 1969;5:67, See AR (Vol. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45279

VI.A2. 

of these documents is pivotal in that none provides the sole or principal basis for the 

Agency's conclusion that cigarettes and smokeless tobacco are intended to affect the 

structure and function of the body under the Act. Further, as discussed below, the 

decision to keep these materials confidential did not undermine the quality of the public 

participation in the Agency's jurisdictional determination. In sum, the procedures the 

Agency followed in assembling a public record in support of this jurisdictional 

determination are not analogous to the facts described in cases like Portland Cement 

Ass'n, Nova Scotia Food Products, and United States lines. 

2. The Agency's Use of Confidential Documents 

a. Confidential Documents on Which the Agency Did Not Rely 

The Agency placed in a confidential docket 75 documents from the approximately 

210,000 pages of materials the Agency made available at the opening of the jurisdictional 

determination and the companion rulemaking proceeding. The Agency identified each of 

these 75 documents for the public in an index filed on September 29, 1995, on the public 

docket. See 60 FR 66981,66982 (Dec. 27, 1995). Of these 75 documents, 73 were not 

even relied upon by the Agency to support either the Proposed Rule or the Jurisdictional 

Analysis. 

Sixty-one of these 73 confidential documents consisted either of commercial 

information and trade secrets which the industry urged FDA to keep confidential 

(Confidential Documents 1-12, 16-21, 62-73), or unpublished manuscripts for which the 

Agency lacked the authors' permission, as of September 29, 1995, to publicly release 

28 Ref. 463-2). The Kiefer document appeared on the public docket with certain trade secret and 

confidential information redacted from the document The Curran document was made available to the 

public in full. 

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45280 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI.A.2. 

(Confidential Documents 22-52). The remaining twelve documents were either 

proprietary reports and other copyrighted information-such as fmancial reports 

generated by Dun and Bradstreet-which the Agency lacked permission to reprint 

(Confidential Documents 13-15, 53-58), or confidential documents that support a pending 

new drug application (Confidential Documents 59-61). 

Again, the Agency did not rely on any of these 73 documents as support for the 

Jurisdictional Analysis. Therefore, the Agency was not even required to include these 

documents in the administrative record. See 21 CFR 10.4<Xb)(vii). It likewise follows 

that because the Agency did not rely upon these documents, the decision to protect them 

cannot be said to have unfairly interfered with the public's ability to question the Agency's 

Jurisdictional Analysis. See Mid-Tex Electric Cooperative, Inc. v. Federal Energy 

Regulatory Commission, 773 F.2d 327, 344 (D.C. Cir. 1985) (agency's failure to disclose 

two studies was "manifestly harmless" because the agency did not rely on the studies to 

support any finding or conclusion); Conference of State Bank Supervisors v. Office of 

Thrift Supervision, 192 F. Supp. 837, 843 (D.D.C. 1992) (there is no violation of the 

AP A's notice requirements where the agency has declined to disclose materials on which it 

did not rely in proposing the rule); B. F. Goodrich Co. v. Dept. of Transportation, 541 

F.2d 1178, 1184 (6th Cir.) (only the basic data "upon which the agency relied in 

formulating the regulation" must be published for public comment), cert. denied, 430 U.S. 

930 (1976); K. Davis, Administrative Law Treatise,§ 7.3 at 307 (3d ed. 1994) ("If an 

agency does not attempt to support its fmal rule by reference to an undisclosed study, it 

seems apparent that the agency was not required to make the study available to potential 

commentators"). The fact that the Agency went well beyond existing requirements to 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45281

VI.A2. 

make publicly available thousands of additional documents for public review-in 

recognition of the uniqueness and public importance of this proceeding-should not be 

used now as a basis for suggesting that the Agency was under a legal obligation to 

disclose publicly all information that it had at hand. 

Finally, at the close of this jurisdictional determination and the companion 

rulemaking proceeding, the Agency will supplement the public docket with copies of those 

confidential items for which the Agency previously lacked permission to publish, but for 

which pennission has now been granted. Most of the unpublished manuscripts in the 

confidential docket-none of which were relied upon by the Agency to support last year's 

Jurisdictional Analysis-will be available through this addition to the public record. 

b. Confidential Information on Which the Agency Relied 

In support of the Jurisdictional Analysis, FDA relied on only 2 of the 75 

documents designated as confidential: a summary of notes taken by FDA investigators 

during site visits to manufacturing plants run by Brown & Williamson, Philip Morris, and 

R J. Reynolds (Confidential Document 74); and a 1991 Brown & Williamson handbook 

on leaf blending and product development (Confidential Document 75).1232 The Agency 

described the two confidential documents cited in the Jurisdictional Analysis in an index 

made available to the public on September 29, 1995. In addition, the Agency relied on 

1232 The Agency did not attribute ownership of the handbook in the Jurisdictional Analysis, or in the 

September 29, 1995, index to the administrative record. However, in a set of comments filed by Brown & 

Williamson, the company itself acknowledged publicly its ownership of the handbook. Brown & 

Williamson Tobacco Corp., Comment (Jan. 2, 1996), at 37-38. See AR (Vol 529 Ref. 104). 

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VI.A2. 

two lines of text that it redacted from a document regarding cigarette filters that the 

Agency placed on the public docket. 1233 

The Agency placed in the confidential docket the summary of notes at the request 

of Brown & Williamson, Philip Morris, and R. J. Reynolds, each of whom urged the 

Agency to keep confidential their commercial information and trade secrets. See 60 FR 

66981 (Dec. 27, 1995). Brown & Williamson likewise vigorously urged the Agency not 

to put its leaf blending handbook on the public docket.1234 These same companies have 

now commented that it was improper for the Agency to rely on this information because 

the information "cannot be subjected to comment by interested parties."1235 

The Agency disagrees that its decision to place in the confidential docket these two 

documents (out of 20,000 pages of documents the Agency cited in support of its position), 

or rely on two lines of redacted text from a document the Agency made available to the 

public, in any way undermined the public's ability to comment on the Agency's 

Jurisdictional Analysis. Nor does the Agency agree that its reliance in this proceeding on 

confidential commercial information or confidential industry trade secrets violated the 

APA. 

1233 See Kiefer JE, Tennessee Eastman Company, Cigarette Filters for Altering the Nicotine Content of 

Smoke (Report No. 71 5003 7), Aug. 18, 1971, at 1-2. See AR (Vol. 28 Ref. 463-1). Although the 

Agency also redacted from the document the confidential measurements of the effects of fllter additives on 

nicotine content in cigarettes smoke, the Agency did not directly rely on these measurements in the text of 

the Jurisdictional Analysis. 

1234 Letter from Krulwich AS (counsel to Brown & Williamson) to Porter MJ (FDA) (Jan. 11, 1996). See 

AR (Vol. 711 Ref. 38). 

1235 Joint Comments of Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol XII, at 14. See AR (Vol. 

535 Ref. 96). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45283

VI.A2. 

First, none of the authorities cited in the comments supports the proposition that 

agencies, even in a rulemaking context, are precluded from considering or relying upon 

privileged documents. To the contrary, several courts have indicated that reliance on 

protected documents in an informal rulemaking proceeding is permissible. See Home Box 

Office. Inc. v. Federal Communications Commission, 561 F.2d 9, 58 n.130 (D.C. Cir.) 

(stating, in dicta, that "it is conceivable that trade secrets ... if proffered as the basis for 

rulemaking, should be kept secret. Cf 5 U.S.C. 552."), cert. denied, 434 U.S. 829 

(1977); United States v. Nova Scotia Food Products Corp., 568 F.2d 240,251 (2d Cir. 

1977) ("We can think of no sound reasons for secrecy or reluctance to expose to public 

view (with an exception for trade secrets or national security) the ingredients of the 

deliberative process" (emphasis added)). 

Second, the Agency put the confidential materials on which it relied in sufficient 

context so that the public could comment on, and challenge, the Agency's use of the 

material. With respect to the handbook, the Agency quoted from the document in several 

instances in the Jurisdictional Analysis. See 60 FR 41453, 41710-41711; 60 FR 41453, 

41510-41511. The Jurisdictional Analysis also incorporated testimony before the House 

Subcommittee on Health and the Environment of the Committee on Energy and 

Commerce on June 21, 1994, in which the Commissioner discussed the content of the 

handbook and quoted from relevant portions. See 60 FR 41453, 41710-41711 and nn. 

443-447. In both settings, the Agency made the language from the handbook on which 

the Agency relied available, and carefully explained how these portions of the handbook 

were relevant to the overall proceeding. Thus, while the Agency kept the bulk of the 

document confidential, it provided as much actual content and context as possible to allow 

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VI.A.2. 

for meaningful public comment on the quoted passages. In the end, the only comments 

the Agency received regarding the decision to keep the handbook confidential were from 

tobacco industry trade associations with whom Brown & Williamson jointly submitted 

comments. No other commenter objected to the Agency's reliance on the handbook or 

the way the Agency safeguarded infonnation the industry regarded as confidential. 

As for the summary of notes (Confidential Document 74), the Agency assembled 

this document from handwritten notes recorded by FDA employees during site visits in 

March, April, and May 1994 to Brown & Williamson, Philip Morris, and R. J. Reynolds, 

as well as handouts distributed by R. J. Reynolds and Philip Morris during those visits. 

During these visits, company representatives requested that FDA employees not disclose 

certain confidential commercial and trade secret infonnation. The Agency, in an effort to 

accommodate this request, withheld from the public docket trade secret or confidential 

commercial information provided to the Agency. 

As with the handbook, the Agency is not persuaded that the public has been 

prejudiced by the decision to withhold this comparatively small amount of information. 

Again, the Agency presented the notes in context to allow the public to see precisely what 

points they were being used to support. See 60 FR. 411453, 41704-41719. The Agency 

also put on the public docket the original handwritten notes from these visits (less the 

redactions needed to protect infonnation the companies regarded as confidential), so that 

the public could see as much of what transpired as possible and understand the full context 

of the protected infonnation. As with the handbook, nonindustry commenters did not 

object to this procedure. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45285

VI.A.2. 

Finally, with respect to the Tennessee Eastman document, the Agency placed the 

document on the public docket, but redacted the two lines of text that identified the name 

of a manufacturer who used polyethylene glycol in cigarette filters, resulting in a higher 

nicotine delivery than from other cigarettes. The text that identified the name of the 

manufacturer (both as it appeared in the Jurisdictional Analysis and in the Tennessee 

Eastman document), was redacted from public view to protect that firm's confidential 

commercial information and its trade secrets. The balance of the text of the Tennessee 

Eastman document, as well as the balance ofthe text of the Jurisdictional Analysis, gave 

the public ample opportunity to comment on the Agency's findings regarding "the use of 

filter additives to enhance nicotine delivery." 60 FR 41453, 41715. 

In sum, the Agency carefully developed a mechanism to accommodate the 

industry's need to protect its confidential commercial information and its trade secrets, 

while at the same time providing ample notice to the public of the information on which it 

relied in this proceeding. Based on the quality and quantity of comments received, and 

based on the lack of objection from other commenters, the Agency is not persuaded that 

its decision to rely on confidential information prejudiced the public's ability to participate 

in the Agency's jurisdictional detemrination. Rather, the lack of comment from the public 

at large confirms that the Agency struck a reasonable balance between the need for public 

process, the need to protect trade secrets and confidential commercial information, and, of 

course, the need to protect the public health. 

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45286 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI.A.3. 

3. The Claim that FDA Relied on "Unknown" Undisclosed Data 

A tobacco industry comment claimed that the Agency withheld certain data and 

calculations used to construct a series of charts showing that nicotine and tar levels in 

smoke have risen steadily from 1982 to 1991. See 60 FR 41728-41731. 

As the comment acknowledges, the Agency relied on summaries of industrysupplied data gathered by the FfC to construct these charts. See 60 FR 41727-41731. 

The comment claims, however, that the Agency relied on "unknown" data to construct the 

tar and nicotine yields for the years 1982 and 1984-86.1236 According to the comment, the 

FTC did not generate data for these years. The industry comment also questions where 

the Agency obtained the sales figures used to calculate weighted averages, how the 

Agency calculated these averages, and why the Agency's figures did not always track 

those of the FfC. 

The industry raised precisely the same issues in a December 8, 1995, letter to the 

Agency. In a December 27, 1995, response, FDA identified the specific documents in the 

administrative record that address each concem.

1237 

The only issue not fully resolved by that exchange of correspondence is the 

industry's claim that FDA's figures for 1990 and 1991 reflect fewer brands than FTC 

reported on for those years. As the Agency stated in its December 27 letter, it is not 

apparent from the face of the charts what, exactly, the industry association is referring to. 

1236 Joint Comments of the Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol. XII, at 3. See AR 

(Vol. 535 Ref. 96). 

1237 See Letter from Schultz WB (FDA) to Merrill R (Covington and Burling) (Dec. 27, 1995). See AR 

(Vol. 711 Ref. 7). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45287

VI.A4. 

Although the association acknowledges this exchange of correspondence in its January 2, 

1996, comments, it failed to provide any greater specificity in its comments than it did in 

the December 8 letter. 

FDA based its charts on sales-weighted averages calculated by the FTC based on 

industry-supplied data. In most years, the FTC publishes this data in two reports: one on 

sales volume and one on tar, nicotine, and carbon monoxide content. Some 

manufacturers, however, fail from time to time to report to the FTC for each brand on all 

three of the values of interest to FDA, namely, tar, nicotine, and sales volume. The FTC, 

therefore, excluded from the sales-weighted averages it supplied to FDA any brand for 

which the manufacturer failed to supply data on any of the three values of interest to FDA 

That is why, in 1990 and 1991, the points FDA plotted on its graphs reflect fewer brands 

than the total number of brands that the FTC reported on in those years. See section 

II.C.6.c.ii., above. 

The decision to exclude in 1990 and 1991 brands for which FTC lacked complete 

data was reasonable. The slight variation between FDA's figures and FTC's figures for 

1990 and 1991 are not the result of FDA having relied on "unknown" or "undisclosed" 

data. Rather, FDA has made publicly available all of the information necessary to allow 

for meaningful comment on these charts. 

4. The Claim That FDA Failed To Include in the Record NDA Data on 

Which It Relied 

One comment elaimed that the Agency relied on studies in seven new drug 

applications (NDA's) for the proposition that a high proportion of smokers are addicted to 

nicotine, but failed to make adequate disclosure of these NDA's. In particular, this 

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VI.A.4. 

comment stated that the Agency failed to include any infonnation in the public docket for 

NDA 18-612 (Nicorette gum, 2 mg) and NDA 20-385 (Nicotine nasal spray), and 

included only summaries for five other NDA's the Agency cited. As discussed below, 

FDA did in fact include in the public docket sufficient infonnation regarding the NDA's on 

which it relied. As for the particular ND A studies the Agency referenced, the relevant 

data in support of these studies was recounted in sufficient detail in Appendix 1 to the 

Jurisdictional Analysis to provide the public a meaningful opportunity to comment. 

a. The Agency's Reference to Five NDA's 

With respect to NDA 18-612 (Nicorette gum, 2 mg), the Agency did not rely on 

the NDA for this product in either the Proposed Rule or the Jurisdictional Analysis. See 

60 FR 41549, n.62 (citing only to NDA 20-076 Habitrol, NDA 20-150 Nicotrol, NDA 19-

983 ProStep, NDA 20-165 Nicoderm, NDA 20-066 Nicorette, 4 mg); see also 60 FR 

41550, n.64 (citing only to the same five NDA's listed in footnote 62 of the Jurisdictional 

Analysis). Therefore, the Agency is under no obligation to include in the public record the 

NDA itself or a summary of the application. 

With respect to NDA 20-385 (Nicotine nasal spray), the Agency similarly did not 

rely on the NDA for this product in either the Jurisdictional Analysis or the proposed rule. 

See 60 FR 41549, n.62 and 60 FR 41550, n.64. While the Agency did discuss an aqueous 

nicotine nasal spray in the Jurisdictional Analysis, the Agency did not rely on the NDA 

itself to support its point Rather, the Agency relied on the discussion of the nasal spray at 

an August 1994 FDA Drug Abuse Advisory Committee meeting. The relevant portions of 

the transcript, cited in footnote 116 in the Jurisdictional Analysis, and the background 

materials provided to the advisory committee, cited in footnote 117, were included in the 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45289

VI.A.4. 

public record.1238 See 60 FR 41565, n.116 and n.ll7. The only other reference to the 

nasal spray in the Jurisdictional Analysis is at 60 FR 41569, where again the Agency relied 

on a statement offered at the August 1994 advisory committee meeting, not on the NDA 

itself. 60 FR 41569 and n.l26. Therefore, all the materials relating to the nasal spray on 

which the Agency relied in the to the Jurisdictional Analysis are in the public docket. 

As for the five NDA' s the Agency cited in footnotes 62 and 64 of the Jurisdictional 

Analysis, the Agency put into the administrative record an extensive summary, prepared at 

the time of approval, for each of these NDA' s.1239 Given the volume of materials that 

make up each of these NDA' s, and the limited purpose for which the Agency was relying 

on them, see 60 FR 41549-41550, it was appropriate for the Agency to include only the 

summaries. See National Ass'n of Pharmaceutical Mfrs. v. Department of Health and 

Human Services, 586 F. Supp. 740, 755-756 (S.D.N.Y. 1984). A complete NDA can run 

into the tens of thousands of pages, particularly when one includes the records which must 

be kept for each patient enrolled in each clinical trial. Putting this volume of materials on 

the record in this instance would serve no useful purpose. Instead, the Agency included 

on the record the summaries it prepared in anticipation of approving each of these 

smoking cessation products as safe and effective. The summaries themselves are peer 

reviewed within the Agency to ensure that they thoroughly and accurately discuss each of 

1238 Kramer ED, Transaipt of testimony before the Drug Abuse Advisory Committee (Aug. 1, 1994). See 

AR (Vol. 9 Ref. 116). 

FDA Drug Abuse Advisory Committee Background Information, Joint Abuse Liability Review of Nicotine 

Nasal Spray (Aug. 1, 1994). See AR (Vol. 9 Ref. 117). 

1239 NDA 20-076 Habitrol (CffiA); NDA 20-150 Nicotrol (Kabi); NDA 19-983 ProStep (Elan); NDA 20-

165 Nicoderm (Alza); NDA 20-066 Nicorette (Merrell Dow). See AR (Vol. 6 Refs. 62-63). 

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45290 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

Vl.A.4. 

the studies on which the approval is based. They generally provide more detail about a 

sponsor's underlying clinical data and methodology than one would expect to find in 

published peer-reviewed medical literature. 

As discussed in greater detail, below, notice is sufficient under the AP A when it 

provides the public a "reasonable opportunity" to participate in the proceeding. Forester 

v. Consumer Product Safety Commission, 559 F.2d 774,787 (D.C. Cir. 1977). This is 

not an instance in which the Agency failed to explain the technical basis for its position, 

failed to disclose its reasoning, or otherwise failed to identify and make available the data 

on which it relied to reach a particular conclusion. See Connecticut light and Power Co. 

v. Nuclear Regulatory Commission, 673 F.2d 525, 530-532 (D.C. Cir. 1982). Rather, the 

summaries the Agency placed on the public docket provided detailed access to the pivotal 

data on which the Agency relied in approving these NDA's. Even more, the summaries 

identified the very data on which FDA relied in this proceeding to support the position 

that nicotine replacement therapy helps reduce withdrawal symptoms in smokers trying to 

quit, and that participants enrolled in clinical studies of nicotine replacement therapy 

demonstrated addiction to nicotine. 60 FR 41453,41459-41460. This is also the data on 

which the Agency relied to support the position that the efficacy of nicotine replacement 

therapy shows that most smokers are indeed addicted to nicotine. Id. at 41459. Thus, 

these summaries provided the public with ample access to the information needed to 

comment meaningfully on the Agency's position. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45291

VI.A4. 

b. The Agency's Reference to Nineteen Smoking Cessation Studies 

FDA prepared Appendix 1 to the Jurisdictional Analysis to provide the public with 

background materials supporting the Agency's scientific judgments with respect to 

nicotine pharmacology. In that Appendix, the Agency discussed a number of smoking 

cessation studies, including 19 studies submitted in support of the NDA's for Habitrol, 

Nicotrol, ProStep, Nicoderm, Nicorette ( 4mg), Nicorette (2 mg), and nicotine 

nasal spray.1240 

The Agency referenced these studies as yet another way to demonstrate that 

nicotine obtained from tobacco products produces dependency. The efficacy of nicotine 

replacement therapy in reducing withdrawal symptoms strongly suggests this conclusion. 

To further demonstrate the point, the Agency supplied the public with efficacy data 

for each of the 19 studies. The incorporation in Appendix 1 of the relevant data from 

these studies in itself allowed for a reasonable opportunity to comment on the Agency's 

use of the studies. Again, the fact that the Agency has approved these products as 

smoking cessation aids, because of their effectiveness in relieving withdrawal from 

nicotine, supports the Agency's point that nicotine from certain tobacco products 

causes dependency. 

In addition to providing in the Appendix itself the data on which FDA relied, the 

Agency relied on studies that have been widely reported on in the medical and scientific 

literature. For example, each of the studies the Agency cited from the NDA' s for 

Nicorette (2mg) and nicotine nasal spray have been reported on in "refereed" or peer1240 See appendix 1 to Jurisdictional Analysis, at 62-85. See AR (Vol. 1 Appendix 1). 

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45292 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI.A.4. 

reviewed journal articles. 1241 See National Ass'n of Pharmaceutical Mfrs., 586 F. S upp. 

at 756 n.45 ("The public availability of infonnation not included in the administrative 

record is a factor to be considered in determining whether the record is inadequate for 

failing to include it") (citations omitted). Thus, to the extent Appendix 1 or the 

administrative record itself did not provide the public with enough information to 

comment on the Agency's analysis, the public had easy access to journal articles authored 

by the individuals who designed and conducted each of the studies. 

Finally, with respect to all but the five studies referenced from the NDA's for 

Nicorette (2mg) and nicotine nasal spray, the public had access to the "backup" for the 

data on which the Agency relied through the NDA summaries the Agency included on the 

public docket. For the Agency to put on the record further documentation to support this 

"backup" would have been excessive, given the limited purpose for which the Agency 

relied on these studies. 

1241 See Christen AG, McDonald JL, Olson BL, Drook CA, Stookey GK. ''Efficacy of a nicotine chewing 

gum in facilitating smoking cessation," Journal of the American Dental Ass'n 1984; 108: 594-597. See 

AR(Vol. 711 Ref. 25}. 

Jarvis MJ, Martin RAW, Russel MAH, Feyerabend C, "Randomised controlled trial of nicotine chewinggum, British Medical Journal1982; 285:537-540. See AR (Vol 711 Ref. 26}. 

Schneider NG, Olmstead R, Mody F, Doan K. Franzon M, Jarvik ME, Steinberg C, Efficacy of nicotine 

nasal spray in smoking cessation: a placebo-controlled, double-blind trial, Addiction 1995; 90:1671-1682. 

See AR (Vol 711 Ref. 27). 

Sutherland G, Stapleton JA, Russel MAH, Jarvis MJ, Hajek P, Belcher M, Feyerabend C, Randomised 

controlled trial of nasal nicotine spray in smoking cessation, Lancet 1992; 340:324-29; See AR (Vol 348 

Ref. 5511). 

Hjalmarson A, Franwn M, Westin A, Wiklund 0, Effect of nicotine nasal spray on smoking cessation, 

Archives of Internal Medicine 1994; 154:2567-2572. See AR (Vol. 711 Ref. 28). 

636 
Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45293

VI.A5. 

The Agency, then, referenced 19 studies to prove a single point. The public 

docket included detailed summaries, prepared for purposes of approving a drug product as 

safe and effective, of 14 of the 19 studies. For the tobacco industry to claim that it lacked 

adequate data with which to challenge the Agency's conclusion, which could have been 

supported by far fewer than 19 studies, is unreasonable. 

In sum, the complaint that FDA did not put on the public docket the "actual 

studies" used to support these NDA's is misplaced. When FDA relied on a specific NDA, 

it put a detailed summary of the NDA in the public docket; and when FDA relied on 

particular NDA studies, it provided the public with the data from those studies in the 

appendix itself. The Agency also took care to rely on studies which have been widely 

reported on in the medical and scientific literature. The comment from the tobacco 

industry that the Agency in this instance withheld crucial information is tantamount to 

arguing that for each journal article on which the Agency relies, it must also include in the 

record all the raw data discussed or analyzed in the article. This is a level of disclosure 

that exceeds reason, not to mention the basic tenets of notice under the AP A The 

Agency, therefore, is not persuaded that the industry, or any other interested person, was 

deprived of a meaningful opportunity to comment on the Agency's reference to certain 

smoking cessation studies or certain ND A's. 

5. The Agency's Reliance in the Final Jurisdictional Determination on 

New Materials 

In an ordinary informal rulemaking proceeding, the fmal administrative record 

must contain the proposed rule, including all information that the Commissioner identifies 

or files with the proposal, all comments received on the proposal, including all information 

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45294 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI.A.5. 

submitted as part of the comments, and the notice promulgating the fmal regulation, 

including all information that the Commissioner identifies or files with the final regulation. 

21 CFR 10.40(g). An agency may rely on information and data that was not included at 

the proposal stage that expands on or confirms information in the proposal or addresses 

alleged deficiencies in the pre-existing data, provided that no prejudice is shown:1242 

Otherwise, "[r]ulemaking proceedings would never end if an Agency's response to 

comments must always be made the subject of additional comments." Community 

Nutrition Inst., 749 F.2d at 58. Accordingly, the Agency has cited in the fmal 

jurisdictional determination a small amount of information that is needed to respond fully 

to comments or that otherwise supplements the information contained in or filed with the 

proposal. These documents include published scientific articles, reference texts, a Centers 

for Disease Control and Prevention memorandum and supporting data, letters to tobacco 

industry counsel, an abstract that the tobacco industry asked to include in the record, a 

small number of publicly released tobacco company documents, Congressional hearing 

transcripts, and newspaper articles. The Agency has placed this cited information in the 

administrative record for the jurisdictional determination. 

1242 See, e.g., Personal Watercraft v. Dep't of Commerce, 48 F.3d 540, S44 (D.C. Cir. 1995) ("Agencies 

may develop additional information in response to public comments and rely on that information without 

starting anew unless prejudice is shown."); Solite Corp. v. EPA, 952 F.2d 473,484 (D.C. Cir. 1991) 

("[C]onsis1ent with the APA, an agency may use 'supplementary' data, UDavailable during the notice and 

comment period, that expands on and confirms information contained in the proposed rulemaking and 

addresses alleged deficiencies in the pre-existing data, so long as no prejudice is shown."); Community 

Nutrition /nst. v. Block, 749 F.2d 50,57-58 (D.C. Cir. 1984) (agency may rely on information that 

"expanded on and confirmed" information in the proposal and addressed alleged deficiencies in the 

record); see also K. Davis, Administrative Law Treatise,§ 7.3 (3d ed. 1994). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45295

VI.B. 

B. ADEQUACY OF THE NOTICE 

Two industry comments argued that the public's participation in the jwisdictional 

determination, as well as in the rulemaking process, has been frustrated because the 

Agency presented a "one-sided" view of the Jwisdictional Analysis and the Proposed 

Rule. Although neither comment disagreed with the Agency's use of notice and 

comment-type procedures to reach a jurisdictional determination, both comments claimed 

that FDA failed to satisfy the AP A's notice requirement for informal rulemaking because 

the Agency neither disclosed nor discussed the supposedly "large body" of information 

"that is inconsistent with, or otherwise not supportive of, the Proposed Rule."1243 

Further, the Agency did not, in their view, provide a "reasoned explanation" for departing 

from past precedent on the issue of whether FDA should regulate all cigarettes and 

smokeless tobacco.1244 

These comments provided no legal authority to support the proposition that, 

assuming the Agency is bound here by AP A precedent governing informal rulemaking, the 

Agency was required at the notice stage to anticipate all challenges to its reasoning, and 

should have attempted in its notice to answer those challenges. Rather, at the notice stage 

of a rulemaking proceeding, the Agency's obligation is to include sufficient detail to allow 

for meaningful and informed comment. See American Medical Ass'n v. Reno, 51 F.3d 

1243 Joint Comments of Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol. XII, at 15. See AR (Vol. 

535 Ref. 96). See also Joint Comment of the Smokeless Tobacco Manufacturers, Comment (Jan. 2, 

1996), at33-38. See AR(Vol. 526Ref. 95). 

1244 Joint Comment of the Smokeless Tobacco Manufacturers, Comment (Jan. 2, 1996), at 38-39. See AR 

(Vol. 526 Ref. 95). 

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45296 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

1129, 1132 (D.C. Cir. 1995); Home Box Office, Inc. v. Federal Communications 

Commission, 567 F.2d 9, 35-36 (D.C. Cir.), cert. denied, 434 U.S. 829 (1977). 

VI. B. 

More specifically, in an informal rulemaking proceeding, the APA requires public 

notice of an Agency's intention to issue a regulation. 5 U.S.C. 553(b). The notice must 

include "reference to the legal authority under which the rule is proposed," and "either the 

terms or substance of the Proposed Rule or a description of the subjects and issues 

involved." 5 U.S.C. 553(b)(2) and (b)(3). FDA's own regulations require that a notice of 

proposed rulemaking include "a preamble that summarizes the proposal and the facts and 

policy underlying it, ... -all information on which the Commissioner relies for the proposal, 

... and cites the authority under which the regulation is proposed." 21 CFR 10.40(b)(vii). 

Under case law construing section 553 of the AP A, notice of informal rulemaking 

must be "sufficiently descriptive of the 'subjects and issues involved' so that interested 

parties may offer informed criticism and comments." Ethyl Corp. v. Environmental 

Protection_Agency, 541 F.2d 1, 48 (D.C. Cir.) (en bane), cert. denied 426 U.S. 941 

( 1976). Notice is sufficient under the AP A "if it affords interested parties a reasonable 

opportunity to participate in the rulemaking process." Forester, 559 F.2d at 787; accord 

State of South Carolina ex rel. Tindal v. Block, 717 F.2d 874, 885 (4th Cir. 1983), cert. 

denied, 465 U.S. 1080 (1984). And, insofar as the proposal to regulate relies on a 

technical study or specific data essential to an understanding of the rule, the notice should 

disclose this information to the extent needed to allow for "meaningful comment " 

Connecticut Light and Power Co. v. Nuclear Regulatory Commission, 673 F.2d 525, 530-

531 (D.C. Cir.), cert. denied, 459 U.S. 835 (1982). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45297

VI.B.l. 

In this instance, the Agency's Jurisdictional Analysis met both the APA's notice 

requirements (as interpreted by prevailing case law), as well as FDA's own procedural 

requirements. The Agency by any standard "fulfllled its obligation to make its views 

known to the public in a concrete and focused fonn so as to make criticism or fonnulation 

of alternatives possible." Air Transport Ass'n of America v. Civil Aeronautics Board, 732 

F.2d 219, 225 (D.C. Cir. 1984) (quoting Home Box Office, Inc., 567 F.2d at 36). 

1. The Agency Provided Adequate Notice of the Key Legal and Factual 

Issues 

Although the APA's notice requirements could have been met by a far briefer 

presentation, the Agency chose to supply the public with a discussion of its Jurisdictional 

Analysis that explored in full the wide range of factual and legal issues presented. In doing 

so, the Agency discussed a number of the issues that the industry commenters claimed 

were missing from the Jurisdictional Analysis. 

The comments contended that the Agency failed to discuss past instances in which 

it declined to exercise jurisdiction over cigarettes and smokeless tobacco products, 

including FDA's response to a 1977 citizen petition. One comment in particular insisted 

that such a discussion would have alerted the public to the idea that Congress enacted 

preemptive legislation in reliance on FDA's past pronouncements, legislation which the 

comments argue bars FDA from regulating these products. 

The Agency acknowledged in its Jurisdictional Analysis that it has in the past 

refrained from exercising jurisdiction generally over all cigarettes and smokeless tobacco 

products (provided claims were not made for the product). 60 FR 41482 n.5. Among 

other things, the Agency referred readers to the published decision in Action on Smoking 

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45298 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI.B.l. 

and Health (ASH) v. Harris, 655 F.2d 236 (D.C. Cir. 1980). That decision reviewed the 

Agency's rejection of the 1977 citizen petition, which one comment claimed the Agency 

"conscientiously avoid[ed]" in the Jurisdictional Analysis in order to "mislead[]" the 

public! 245 Not only does the ASH opinion discuss the petition and the Agency's position 

at that time with respect to exercising jurisdictional generally over cigarettes, it also 

recounts for the reader the Agency's historical position on the issue. 655 F.2d at 237-241. 

Moreover, the Agency placed in the administrative record copies of documents in which 

FDA declined to exercise jurisdiction, including FDA's response to ASH's 1977 citizen 

petition.1246 

In addition, the Agency attached as part of an appendix to its Jurisdictional 

Analysis, copies of the Commissioner's testimony before the House Subcommittee on 

Health and the Environment of the Committee on Energy and Commerce on March 25, 

1994.1247 At the outset, Commissioner Kessler stated: 

Although FDA has long recognized that the nicotine in 

tobacco products produces drug-like effects, we never 

stepped in to regulate most tobacco products as drugs. One 

of the obstacles has been a legal one. A product is subject 

to regulation as a drug based primarily on its intended 

use .... With certain exceptions, we have not had sufficient 

1245 Joint Comment of the Smokeless Tobacco Manufacturers, Comment (Jan. 2, 1996), at 35. See AR 

(Vol 526 Ref. 95). 

1246 See Letter from Kennedy D (FDA) to Banzhaf J (ASH) (Dec. 5, 1977). See AR (Vol. 503 Ref. 8882) 

(denial of 1977 petition). 

Letter from Goyan JE (FDA) to Banzhaf J (ASH) (Nov. 25, 1980). See AR (Vol 503 Ref. 8881). 

Public Health Cigarette Amendments of 1971, Hearings before the Consumer Subcommittee of the 

Committee on Commerce, U.S. Senate, 92d Cong., 2d Sess. at 239-246. See AR (VoL 503 Ref. 8894). 

1247 See appendix -7 to the Jurisdictional Analysis. See AR (Vol. 1, Appendix 7). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45299

evidence of such intent with regard to nicotine in tobacco 

products .... 

Mr. Chairman, we now have cause to reconsider this 

historical view ... This question arises today because of an 

accumulation of information in recent months and years. In 

my testimony today, I will describe some of the information. 

Vl.B.l. 

Appendix 7 at 1-2 (footnote omitted). This testimony, like the reference to the ASH 

decision, adequately put the public on notice of FDA's past position.1248 

Nor does FDA agree with the comment's argument that Congress, in reliance on 

past FDA pronouncements, enacted legislation precluding FDA from regulating tobacco 

products under the Act. As discussed in detail in sections IV. and V ., above, the Agency 

has never categorically disclaimed jurisdiction over tobacco products and Congress has 

never expressly forbidden FDA from asserting jurisdiction over these products. The 

Agency had no affirmative obligation to posit in the Jurisdictional Analysis arguments it 

believes are legally infirm. Cf. Florida Power and Light Co. v. United States, 846 F.2d 

765,771 (D.C. Cir. 1988), cert. denied, 490 U.S. 1045 (1989). 

Two tobacco industry comments also claimed that the Agency unfairly 

underplayed the complexity of issues such as "intended use," product categorization, 

1248 The Agency's decision not to include a prolonged discussion of past Agency decisions is also based on 

the fact that the Agency is operating under a different set of facts. See section IV., above. The Agency 

did not commit a procedural error by failing to chronicle exhaustively decisions it made in a factually 

distinguishable context 

One of the comments also faults the Agency for failing to give notice of the "several" citizen petitions illed 

since 1977 that request that the Agency regulate cigarettes. In fact. the Agency incorporated by reference 

into the docket for this jurisdictional determination all significant dockets opened since the conclusion of 

the ASH litigation that relate to the Agency's jurisdiction over cigarettes and other nicotine delivery 

systems. The index the Agency provided to the public on September 29, 1995, in conjunction with the 

public display of the administrative record (as of that date), included a description of 9 dockets the Agency 

incorporated by reference into the record supporting the Jurisdictional Analysis. See AR (Vol 504 

Ref. 8934). 

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45300 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI.B.l. 

regulatory authority over combination products, and the applicability of the medical device 

provisions of the Act to cigarettes and smokeless tobacco. Instead, one of these 

comments asserted that all the Agency had done was publish "a tendentious anti-tobacco, 

pro-FDA-regulation manifesto" and, as such, the Agency's notice was "fraudulent."1249 

The Agency disagrees with this characterization, whether it was directed at the Proposed 

Rule or at the Jurisdictional Analysis. More to the point, the Agency disagrees with the 

argument that the Agency somehow deprived the public of fair notice of its Jurisdictional 

Analysis. 

Again, to satisfy the AP A's notice requirement for informal rulemaking, the 

Agency must specify with particularity the legal authority on which its proposal is based. 

K. Davis, Administrative Lo.w Treatise (3d ed. 1994), at 299. Notice must be 

"informative" and must "fairly apprise" interested persons. Id. at 299-300. The Agency 

notes, however, that it need not unravel for the public each and every theoretical step in 

the analysis. See Chemical Waste Management, Inc. v. Environmental Protection 

Agency, 869 F.2d 1526, 1535 (D.C. Cir. 1989) (even where Agency statement in notice of 

rulemaking assumes rather than invites comments on an issue, notice is sufficient if it 

provides interested parties ''with a clear indication of the agency's intended course of 

action .... ");Center for Auto Safety v. Peck, 751 F.2d 1336, 1361 (D.C. Cir. 1985) ("It 

is simply not the case, however, that all of the essential postulates for an agency rule must 

be contained in the record"). 

1249 Joint Comment of the Smokeless Tobacco Manufacturers, Comment (Jan. 2, 1996), at 33. See AR 

(Vol. 526 Ref. 95). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45301

VI.B.l. 

Nevertheless, the Agency provided the public a detailed explanation of why it 

regards cigarettes and smokeless tobacco as drug/device combinations products, and why 

it believes the device provisions of the Act may, and should, be used to regulate these 

products. The Agency set forth its rationale for regulating these products as devices in 

both the Jurisdictional Analysis itself, see 60 FR 41521-41525, and in the Proposed Rule, 

see 60 FR 41348-41350. Further, the Agency identified for the public in the Proposed 

Rule the precise statutory provisions under which it proposed to regulate these products. 

60 FR 41346-41352, 41372. 

The Agency also put the public on notice, by referencing the lntercenter 

Agreement, see 60 FR 41521, that preloaded drug delivery systems are often regulated 

using the drug authorities under the Act. The Agency adequately explained-for notice 

purposes-why in this instance it proposed a different approach. 60 FR 41348-41350. 

With respect to the application of the concept of "intended use," the lengthy 

discussion in Part II of the Jurisdictional Analysis provided the public with full disclosure 

of the Agency's rationale for regulating cigarettes and smokeless tobacco based on the 

~'intended use" of these products. The core facts and precedents on which the Agency 

relied were displayed in a manner the Agency believes invited maximum public scrutiny. 

The Agency even provided the public with 11 different examples (9 from the 1980's and 

1990's) of the application of the intended use concept to the determination of whether a 

product, absent express claims, may be regulated as a drug or a device. 60 FR 41527-

41531. This level of explanation more than satisfied the requirements of the AP A as 

interpreted by the relevant case law. 

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45302 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI.B.l. 

Finally, the quantity and quality of comments the Agency received on the 

Jurisdictional Analysis and the proposed rule suggest that, in fact, the public was 

adequately notified of the relevant issues. The Agency received more comments on these 

two documents than it has ever received on any other subject, with over 700,000 

comments (including fonn letters) and over 95,000 distinct or unique sets of comments. 

More important, the Agency received hundreds of pages of comments on the very issues 

the Agency is said to have hidden from the public. Indeed, the two industry commenters 

who complained most vigorously about the supposed deficiencies in the Jurisdictional 

Analysis and the Proposed Rule themselves literally filed volumes of comments on the 

issues they claim the Agency concealed.1250 Even the comments of interested nonindustry 

persons evidenced fair notice of the Agency's historical position and fair notice of the 

Agency's reasoning for applying the device provisions of the act to cigarettes and 

smokeless tobacco. 1251 

In Chemical Waste Management, 869 F.2d at 1535, the plaintiff complained that 

the Environmental Protection Agency's notice of proposed rulemaking treated a certain 

controversial issue "as an accomplished fact." Like two of the comments here, the 

plaintiff in Chemical Waste Management argued that the AP A required the agency to 

1250 See, e.g., Joint Comments of the Smokeless Tobacco Manufacturers, Comment (Jan. 2, 1996), at 43-

73 (discussing the Agency's histOrical position on Agency jurisdiction over tobacco products), 99-258 

(discussing the Agency's application of the concept of intended use to tobacco products), and 259-307 

(analyzing the Agency's position that cigarettes and smokeless tobacco are combination products that may 

be regulated as restricted devices). See AR (Vol. 526 Ref. 95). Accord Joint Comments of Cigarette 

Manufacturers at. among other places, VoL I (discussing FDA's historical position on jurisdiction), Vol. 

II (discussing the concept of intended use), and Vol V (discussing the regulation of cigarettes as medical 

devices). See AR (VoL 535 Ref. 96). 

1251 See, e.g., Public Citizen Litigation Group, Comment (Jan. 2, 1996), at 29-43. See AR (Vol. 700 Ref. 

591 ); American Heart Association, Comment (Dec. 26, 1995). See AR (Vol. 700 Ref. 592). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45303

VI.B.l. 

highlight the fact that its position was subject to debate and to solicit comments on the 

issue. The United States Court of Appeals for the District of Columbia rejected this 

argument because EPA had provided notice of its intended course and because the agency 

in fact received numerous comments on the issue. Id.; see also Shell Oil Co. v. EPA, 950 

F.2d 741,757 (D.C. Cir. 1991) (recognition of a certain issue by commenters may be used 

to infer that adequate notice of the issue was given); Haralson v. Federal Home Loan 

Bank Board, 678 F. Supp. 925,926 (D.D.C. 1987) (same). 

As in cases such as Chemical Waste Management, the comments FDA received 

demonstrate that there is no serious claim to be made that the Agency has concealed issues 

from the public. Interested persons representing both sides in this controversial 

proceeding commented on the very issues the Agency supposedly underplayed in its notice 

of proposed rulemaking. 

At bottom, the comments that challenge the adequacy of the Agency's proposal 

confuse the merits of the issue with procedure. The supposed deficiencies in FDA's legal 

reasoning, and the supposed failure to discuss contrary authorities, raise substantive issues 

to be resolved during the comment and response-to-comment phase of the proceeding. 

The possibility that some of the Agency's legal conclusions may be subject to debate does 

not render the notice inadequate. See Chemical Waste Management, 869 F.2d at 1535; 

Natural Resources Defense Council, Inc. v. Hodel, 618 F. Supp. 848, 864-865 

(E.D. Cal. 1985). 

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45304 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI.B.2. 

2. The Agency Provided a "Reasoned Explanation" for Its Current 

Position 

Several tobacco industry comments also claimed that the Agency violated the 

AP A's notice provisions by failing to include a "reasoned explanation" for departing from 

past precedent on the issue of whether to regulate all cigarettes and smokeless tobacco. In 

their view, the Jurisdictional Analysis and Proposed Rule are procedurally inftrm because 

the Agency did not adequately explain its basis for past decisions not to regulate these 

products, and did not distinguish those decisions from its present position. One of these 

comments likewise asserted that the Agency was required to include in the administrative 

record each and every document "that formed the basis for, or was an expression or 

reflection of, FDA's consistent position over more than 80 years that it does lWt have 

jurisdiction to regulate cigarettes." The absence of this material, according to the 

comment, demonstrates that the Agency failed to consider "obviously relevant" contrary 

information in asserting jurisdiction and in proposing to regulate these products.1252 

The authorities cited in the comments require that, by the close of an 

administrative proceeding, the Agency must provide a "reasoned explanation" to the 

extent the Agency has departed from a prior formal position. See, e.g., International 

. Union, United Auto Workers v. NLRB, 459 F.2d 1329 (D.C. Cir. 1972) (challenge to fmal 

decision of labor board); Greyhound Corp. v. ICC, 551 F.2d 414 (D.C. Cir. 1977) 

(challenge to fmal order of the ICC); Baltimore and Annapolis Railroad Co. v. 

Washington Metro. Area, 642 F.2d 1365 (D.C. Cir. 1980) (challenge to final order of 

1252 Joint Comments of Cigarette Manufacturers, Comment (Jan. 2, 1996), Vol. XII, at 16. See AR (Vol. 

535 Ref. 96). 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45305

VI.B.2. 

transit commission); RKO Gen., Inc. v. FCC, 670 F.2d 215 (D.C. Cir. 1981), cert. denied, 

456 U.S. 927 (1982) (challenge to final order of Federal Communications Commission 

denying renewal of television license); see also Motor Vehicle Mfrs. Ass'n v. State Farm 

Mutual Auto Insurance, 463 U.S. 29,43 (1983) (challenge to fmal rule rescinding passive 

restraint seatbelt requirement contained in a Department of Transportation standard). 

None of these cases, which involve challenges to fmal Agency orders and final rules, holds 

that at the notice stage of a proceeding, when an Agency is proposing to depart from a 

prior position, the Agency must provide a comprehensive "reasoned explanation." 

The Agency nevertheless agrees that the rulemaking proceeding, taken as a whole, 

should clearly and rationally justify changes in existing policies. Thus, FDA included in its 

Jurisdictional Analysis ample reference to its prior policy and a more than ample 

discussion of the Agency's rationale for changing its policy. Indeed, the very intent of the 

Jurisdictional Analysis, the 622 footnotes supporting the analysis, its appendices, and the 

more than 13,000 documents put on the administrative record was to provide the public 

with a full view of the new evidence that supports the need for the Agency to take a 

different approach to the regulation of these products. 

As FDA made clear at the outset of its Jurisdictional Analysis, its decision to 

propose to regulate these products, when in the past it did so only when claims were 

made, is based on the fact that"[ t]he quality, quantity, and scope of the evidence available 

to FDA today is greater than any other time when FDA has considered regulation of 

cigarettes and smokeless products." 60 FR 41464, n.l. Footnote 5 of the Jurisdictional 

Analysis, in particular, made clear that: (1) The Agency in the past had declined to 

exercise jurisdiction generally over these products; and (2) the reason for taking a different 

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45306 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI.B.2. 

position today is that the evidence before the Agency regarding the intended use of these 

products "has changed dramatically." 60 FR 41482, n.5. In addition, the Agency 

repeatedly stated that its analysis was based on "evidence now available to the Agency," 

60 FR 41464, "current evidence," 60 FR 41466, evidence accumulated since 1980,60 FR 

41482, n.S, and evidence that has emerged since 1980 or was not widely known until 

recently, 60 FR 41483-41484, 41539. 

Neither the AP A nor the case law cited in the comments requires an agency to 

provide a thorough "reasoned explanation" for departing from precedent at the notice 

stage of a proceeding. Rather, the AP A at most requires that the Agency give notice of its 

proposal to take a different position or view, and give enough information to allow the 

public a reasonable opportunity to comment. Not until the close of the proceeding, after 

public comment has been received, must the Agency ensure that it has provided a full 

"reasoned explanation." The Agency believes in this instance that its discussion at the 

notice stage met the standard that courts ordinarii y do not impose until the close of an 

administrative proceeding. Nonetheless, the Agency has provided further, detailed 

discussion of the legal and factual bases for taking its current position in this document. 

See section IV., above. 

Finally, the Agency does not agree that it was required to include in the record, at 

the notice stage, each and every prior Agency "decision, statement, and fmding." Rather, 

the Agency appropriately included in the record of proposed rulemaking enough 

documentation to give the public notice of the Agency's prior position, and notice of the 

Agency's prior reasoning for declining to exercise jurisdiction generally over these 

products (absent express claims). For example, the Agency incorporated by reference into 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45307

VI. C. 

the administrative record for this jurisdictional determination all significant dockets opened 

since the conclusion of the 1977 ASH litigation that relate to the Agency's jurisdiction 

over these products. In addition, the Agency included in the record its response and 

supplemental response to the original ASH citizen petition. Those documents outline in 

detail the "contrary" view the Agency has allegedly concealed, including full discussions of 

the Agency's enforcement history with respect to tobacco products and the Agency's 

significant past pronouncements on the subject. In any case, the tobacco industry itself, 

through its comments, has introduced many of the Agency's earlier statements into the 

administrative record for this proceeding. Thus, unlike the facts presented in cases such as 

Public Citizen v. Heckler, 653 F. Supp. 1229 (D.D.C. 1986) and Walter 0. Boswell 

Memorial Hospital v. Heckler, 749 F.2d 788 (D.C. Cir. 1984), as referenced in the 

comment, the administrative record for this proceeding already contains the "adverse" 

infonnation claimed to be lacking, by virtue of the Agency's inclusion of documents in the 

record and the comments received by the Agency. 

C. ADEQUACY OF THE COMMENT PERIOD 

FDA received at least one comment urging that the comment period for both the 

Jurisdictional Analysis and the Proposed Rule was unreasonably short in light of the 

complexity of the Proposed Rule, the number of materials the Agency put on public 

display, and the possible impact of the rule on the tobacco industry. This comment argued 

that the Agency acted arbitrarily and capriciously in deciding to ''limit" the comment 

period to 144 days from the publication of the August 11, 1995, Proposed Rule and 

Jurisdictional Analysis and 95 days from the public release of the documents FDA 

considered but did not rely upon. 

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45308 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI. C. 

Far from having "limited" the comment period, FDA provided more than twice as 

much time for comment as the Agency's regulations require. See 60 FR 53560 (Oct. 16, 

1995) (extending comment period for Proposed Rule); 60 FR 53620 (Oct. 16, 1995) 

(extending comment period on Jurisdictional Analysis). 

The APA requires only that an agency "give interested persons an opportunity to 

participate in the rule making through submission of written data, views, or arguments ... " 

5 U.S.C. 553(c). This is all the APA requires; there is no statutory requirement 

concerning how many days an Agency must allow, nor is there a requirement that an 

Agency must extend the period at the request of an interested person. See Phillips 

Petroleum Co. v. Environmental Protection Agency, 803 F.2d 545, 559 (lOth Cir. 1986). 

FDA's own regulations generally afford the public 60 days to comment on a 

Proposed Rule, unless the Commissioner shortens or lengthens the period for good cause. 

21 CFR 10.40(b)(2). Executive Order 12889 implementing the North American Free 

Trade Agreement prescribes a minimum comment period of 75 days on certain proposed 

rules, except when good cause is shown for a shorter comment period. See 58 FR 69681 

(Dec. 27, 1993). 

Here, the Agency provided the public with 144 days from the publication of the 

Jurisdictional Analysis, 139 days from the release of the documents the Agency cited in 

support of the Jurisdictional Analysis (on August 16, 1995), and 95 days from the release 

of the materials the Agency considered but did not directly rely upon (on September 29, 

1995). Thus, even when counting from the date the Agency released additional 

documents on which it did not rely, the Agency provided much more time for comment 

than its regulations, or the Executive Order, require. 

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Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations 45309

VI. C. 

Further, on March 20, 1996, the Federal Register published notice of an additional 

30 day comment period limited to specific documents the Agency added to the docket in 

support of the Agency's analysis of its jurisdiction. See 61 FR 11419 (Mar. 20, 1996). 

Although the Agency expressly limited the scope of the matters on which interested 

persons could comment, the March 20, 1996, action did provide the public with yet 

another 30 days on which to comment on issues related to such core subjects as the 

manipulation of the nicotine content of cigarettes and smokeless tobacco. 

The Agency is not persuaded that any interested person has been unfairly 

prejudiced. First, FDA considers requests to extend the comment period on a case-bycase basis. Here, on the one hand, the commenter (the Tobacco Institute together with 

five major tobacco companies) presented in its request for additional time no compelling 

reasons to extend the period (such as a new, material study). On the other hand, FDA is 

faced with a matter raising serious public health concerns. For those reasons, the Agency 

denied the request to extend the period for as much time as the commenter had requested. 

See 60 FR 53560. 

Second, each of the five tobacco companies that submitted this joint comment also 

filed suit against FDA immediately after FDA's Jurisdictional Analysis and notice of 

proposed rulemaking went on public display. The timing appears to indicate that these 

frrms had been preparing to respond to an FDA proposal to regulate cigarettes and 

smokeless tobacco for some time. In any case, the cigarette manufacturers were able, 

jointly, to submit 2,000 pages of comments and 45,000 pages of exhibits and the 

smokeless tobacco manufacturers were able to jointly submit 474 pages of comments and 

3,372 pages of exhibits within the time allotted for commenting on the Jurisdictional 

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45310 Federal Register / Vol. 61, No. 168 / Wednesday, August 28, 1996 / Rules and Regulations

VI. D. 

Analysis and Proposed Rule. Their submissions far outweigh any others. The Agency, 

therefore, is not persuaded that these commenters suffered prejudice as a result of FDA's 

allowing twice as much time as the Agency's regulations require. See Conference of State 

Bank Supervisors v. Office ofThrift Supervision, 792 F. Supp. 837, 843 (D.D.C. 1992) 

(in light of the comments received, court declined to find that 30 day comment period was 

insufficient to allow opportunity for meaningful public participation); Phillips Petroleum 

Co., 803 F.2d at 559 (citing cases in which courts have upheld notice periods of 45 days 

or less). 

In sum, the Agency believes it provided ample additional time for commentsnearly 90 days more than is provided for in the Agency's own procedural regulation. 

Given that it received over 700,000 comments, including 95,000 distinct sets of 

comments, the Agency is not persuaded that the length of the comment period unfairly 

hampered the quality of the public debate on this matter. 

D. THE NEED FOR "ADDITIONAL PROCEDURES" 

Finally, one comment claimed that the Agency's use of William A Farone's 

statement1253 "and other similar documents" raises "serious issues of procedural 

fairness." 1254 The comment asserted that "FDA appears to treat" Farone as if he has 

current first-hand knowledge of internal company deliberations, and that FDA is using 

Farone's statement as "testimonial evidence." Based on this characterization of the 

1253 William A. Farone w~the director of applied research in the research and development department 

of Philip Morris U.S.A. See Farone W A. The Manipulation and Control of Nicotine and Tar in the 

Design and Manufacture of Cigarettes: A Scientific Perspective (Mar. 8, 1996), at 17. See AR (Vol 638 

Ref. 2). 

1254 Joint Comments of the Cigarette Manufacturers, Supplemental Comment on the Statement of William 

A. Farone (Apr. 19, 1996), at 15. See AR (Vol 700 Ref. 223). 

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VI.D. 

Farone report, the commenter argued that it should be allowed the opportunity to confront 

and cross-examine Farone on the record, examine any notes taken by FDA in interviews 

with Farone, and obtain an extension of the comment period in order to take Farone's 

deposition in a pending civil proceeding (to which FDA is not a party). 1255 

The Agency added the Farone statement and two affidavits from former tobacco 

industry employees as possible additional support (but by no means crucial) for the 

Agency's determination that it has jurisdiction over cigarettes and smokeless tobacco 

(because these products are intended for use as drug delivery devices). The comment 

failed to cite any legal authority to advance the proposition that, in making such a 

jurisdictional determination, the Agency must allow for cross-examination of witnesses 

and discovery of investigatory notes. 

A brief review of the procedures the Agency employed in reaching its final 

jurisdictional determination is in order. At the same time that the Agency published notice 

of its proposal to regulate nicotine-containing cigarettes and smokeless tobacco, see 60 

FR 41314, the Agency also published the results of its lengthy investigation into, and 

comprehensive analysis of, the Agency's jurisdiction over these products. See 60 FR 

41453. Because of the unique importance of the jurisdictional issue, the Agency made its 

analysis available to the public, put the administrative record in support of its analysis on 

public display, and invited comments from the public on its analysis. When the Agency 

later supplemented the record in support of its Jurisdictional Analysis with the Farone 

1255 In a letter to Grossi PT. Jr., counsel for Philip Morris Inc., from Schultz WB, FDA deputy 

commissioner for policy, dated Apr. 12, 1996, the Agency responded to these very arguments. In 

addition to the Agency's discussion in that letter, the Agency offers the response in the text of this 

document See AR (Vol 711 Ref. 44). 

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VI. D. 

report and two affidavits from former tobacco.industry employees, the Agency invited 

public comment on these documents. See 61 FR 11419. Interested persons thus were 

provided the opportunity to present written statements consisting of facts, data, expert 

affidavits, studies, argument, and other relevant information with which to challenge, if 

they chose, the Agency's Jurisdictional Analysis and documents such as the Farone report 

that support it. Finally, in this document, the Agency is responding to all pertinent 

comments to the Agency's Jurisdictional Analysis. 

FDA has primary jurisdiction to determine its jurisdiction. Weinberger v. Hynson, 

Westcott & Dunning, Inc., 412 U.S. 609, 627 (1973). At best, FDA must ensure that it 

meets "the rudiments of fair play" in determining its jurisdiction. /d. However, neither 

the Act nor the AP A directs the Agency to commence a rulemaking proceeding, or 

conduct a formal evidentiary hearing, before making a jurisdictional determination. 

Nevertheless, FDA chose to employ the process outlined above-a notice and commenttype procedure-as a means by which to give the public an opportunity to participate the 

Agency's analysis of its jurisdiction and, thereby, met the conditions of ''fair play." 

There is nothing about the Farone report or the affidavits from former industry 

employees that would now require that the Agency employ even more procedures. In an 

ordinary informal rulemaking proceeding, such as that by which the Agency is 

promulgating its regulations governing cigarettes and smokeless tobacco, see 21 U.S.C. 

37l(a), an interested person generally has no right to cross-examine witnesses. Compare 

21 U.S.C. 371(e) (enumerating those instances in which rulemaking under the Act may be 

subject to additional procedures, including the opportunity for a formal evidentiary hearing 

under sections 556 and 557 of the APA); see VeriTWnt Yankee Nuclear Power Corp. v. 

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VI. D. 

Natural Resources Defense Council, Inc., 435 U.S. 519, 524 (1978). Exceptions to this 

rule can be made where Congress has expressly, provided for additional procedures, see 5 

U.S.C. 553(c), or where the rulemaking proceeding is in fact a "quasi-judicial 

determination" in which "a very small number of persons are 'exceptionally affected, in 

each case upon individual grounds .... "' Vermont Yankee Nuclear Power Corp., 435 

U.S. at 542 (quoting United States v. Florida East Coast Ry. Co., 410 U.S. 224,242-245 

(1973), and holding that the APA established "the maximum procedural requirements" 

that courts can impose upon agencies in conducting rulemaking procedures and that the 

circumstances in which courts may require additional procedures, "if they exist, are 

extremely rare"); Lead Indus. Ass'n, Inc. v. EPA, 647 F.2d 1130, 1169-1170 (D.C. Cir.) 

(interested persons face an extremely heavy burden when they demand that an Agency 

provide procedures not required by statute, such as cross-examination), cert. denied, 449 

u.s. 1042 (1980). 

The comment FDA received did not seriously attempt to show that the Agency is 

in fact engaged in the type of individualized determination described in Vermont Yankee, 

nor did it reference any statutory provisions that would require additional procedures in 

this instance. Instead, the comment rested its argument on the ''testimonial" and "firsthand" nature of the Farone report. The mere labeling of evidence in this way does not 

change the nature of a proceeding. Indeed, the tobacco industry with their comments 

submitted statements of individuals as exhibits. Nor is the company-specific nature of the 

evidence determinative. 

The issue, instead, depends upon the purpose for which the Agency intends to use 

the evidence. See United Air lines, Inc., 766 F.2d at 1119; Ass'n of National 

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VI. D. 

Advertisers, Inc. v. FTC, 627 F.2d 1151, 1164-1165 (D.C. Cir. 1979), cert. denied, 447 

U.S. 921 (1980). Where, as FDA has done here, the Agency is relying on evidence to 

reach essentially legislative judgments, for prospective application, and for the purpose of 

regulating an entire industry, there is overwhelming authority that an evidentiary hearing 

with cross-examination of witnesses is not required. See, e.g., Vermont Yankee Nuclear 

Power Corp., 435 U.S. at 524; Lead Indus. Ass'n, Inc., 647 F.2d at 1169-1170; United 

Air lines, Inc. v. Civil Aeronautics Board, 166 F.2d 1107, 1116-1121 (7th Cir. 1985); 

Cleveland Elec. Illuminating Co. v. EPA, 572 F.2d 1150, 1160 (6th Cir.), cert. denied, 

439 U.S. 910 (1978); Miami Nation of Indians of Indiana, Inc. v. Babbitt, 887 F. Supp. 

1158, 1173 (N.D. Ind. 1995). 

The Agency is relying on documents such as the Farone report to support its 

jurisdiction over two broad categories of products (cigarettes and smokeless tobacco), and 

over all persons who manufacture, distribute, and sell these products. The Agency's 

inquiry into the operations of the leading tobacco flnns was intended not to restrict or 

punish particular ftnns based on individualized grounds, but rather was intended to 

support regulatory controls that extend to the entire industry. Thus, the Agency's Final 

Rule governing youth access to cigarettes and smokeless tobacco products is properly 

characterized as rulemaking proceeding "in its purest form." Vermont Yankee, 435 U.S. at 

542 n.l6; accord Lead Indus. Ass'n, 641 F.2d at 1171 n.119. The fact, then, that Farone 

at one time worked for a leading tobacco finn does not change the purpose of this 

jurisdictional determination or in any way trigger the need for additional procedures. See 

Commodity Exchange, Inc. v. Commodity Futures Trading Comm., 543 F. Supp. 1340, 

1351 (S.D.N.Y. 1982) (summarizing case law holding that "infonnal rulemaking could 

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VI. D. 

include an examination of past practice in order to prescribe future rules," and that "even 

when only one entity is the immediate subject of an Agency's action, this alone does not 

change its rulemaking nature ... "), aff'd, 703 F.2d 682 (2d Cir. 1983). 

The comment also complained that FDA's decision not to make available its 

interview notes with witnesses who have come forward with public statements (i.e., 

Farone, Rivers, and Uydess) raised issues of "procedural fairness." 1256 This concern, 

however, is offset by the confidential nature of such material and by the limited extent to 

which the Agency relied on the public statements of Uydess and Farone. The public is 

entitled to notice of, and the opportunity to comment on, all materials upon which the_ 

Agency has relied. For that reason, the Agency published notice of the three witnesses' 

statements, placed the statements on the public docket, and afforded the public an 

opportunity to comment on them. The former employers of these witnesses, in particular, 

had the opportunity to challenge the witnesses' statements by affidavit or rebuttal 

documentation. The Agency has decided to cite to the publicly-released Uydess affidavit 

and the Farone report in this jurisdictional determination only to the extent it has on hand 

information from other sources that corroborates or confirms the information that U ydess 

and Farone have given. 1m Therefore, the Agency has proceeded fairly in its use of these 

witnesses' statements. 

The comment's suggestion that there should be public access to the notes and 

transcripts of the confidential interviews with these witnesses raises a fundamental issue 

1256 Joint Comment of Cigarette Manufacturers, Comment (Apr. 19, 1996), at 16. See AR (Vol 700 

Ref. 223). 

1257 The Agency has decided not to rely on the Rivers affidavit in this document 

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VI. D. 

with implications that go beyond this jurisdictional determination. The Agency has broad 

authority to conduct investigations for the purposes of the Food, Drug, and Cosmetic Act. 

21 U.S.C. 372 and 374. In conducting these investigations, it may be necessary for the 

Agency to pledge confidentiality to individuals who provide certain information and who 

fear retaliation if their identities are disclosed. Such disclosure may occur, directly, by 

naming them, or indirectly, by disclosing information only they could have provided. It is 

essential to the overall mission of the Agency that it sustain a reputation for maintaining 

the confidentiality of information given to it in confidence. Otherwise, the Agency risks 

losing invaluable sources of information which the Agency must have to carry out its 

statutory responsibilities. Moreover, disclosure of underlying investigatory materials may, 

in some instances, reveal the Agency's investigatory techniques, procedures, and methods, 

that it is entitled to shield from the public. See 5 U.S.C. 552(b)(7). In other instances, 

underlying investigatory materials may include trade secrets or other confidential 

commercial information, which the Agency is obligated to keep confidential. See 5 U.S.C. 

552(b)(4). See generally 60 FR 66981, 66982 (Dec. 27, 1995) (the Agency's Statement of 

Procedures for Handling Confidential Information in Rulemaking); see also 5 U.S.C. 

552(b )( 6) and (b X7). Thus, an express, unequivocal waiver of confidentiality on the part 

of a declarant would not necessarily obviate the Agency's obligation to protect such 

investigatory materials. 

Information conveyed to the Agency during its interviews of these three witnesses, 

as reflected in the notes and transcripts of the interviews, includes the identification of 

other possible sources of information and other possible leads for the Agency to pursue, as 

well as trade secrets and other confidential commercial information. This information was 

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VI. D. 

conveyed to the Agency with the understanding that it would be kept confidential. The 

Agency is duty-bound to honor its pledge of confidentiality, without which its 

investigation in this matter would have been severely hampered, and maintain its 

reputation as a reliable protector of confidential sources and infmmation. The public 

interest is enhanced, and not harmed, by the Agency's commitment to honor this pledge, 

particularly where, as here, the Agency has afforded the public notice and an opportunity 

to comment on the only infonnation given by these witnesses that the Agency is citing in 

its jurisdictional detennination. Cf. Lame v. Department of Justice, 654 F.2d 917, 925 

(3d Cir. 1981) ("[O]nce there has been an expressed or implied assurance of 

confidentiality, a subsequent release or publication by the government of a portion of the 

infonnation does not negate the exemption for any of the infonnation originally given."). 

In light of the notice and opportunity for public comment afforded by the Agency 

with respect to the public statements of these three witnesses, the limited extent of the 

Agency's use of the Uydess affidavit and the Farone report, and the confidentiality 

concerns outlined above, the Agency properly declined to make its underlying interview 

notes and transcripts publicly available in the course of this proceeding. 

Finally, the Agency does not agree that it was in any way required to delay this 

important public health proceeding in order for Farone's deposition to be taken. The 

Agency is not a participant in the civil litigation in which Farone may be called to testify 

and has no ability to influence the procedures to be followed in that proceeding, let alone 

the schedule. In any case, the Agency has no statutory obligation to delay a jurisdictional 

determination in order to allow for the submission of cross-examination testimony from a 

wholly separate proceeding. 

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VI. E. 

E. CONCLUSION 

Because of the importance of the issues involved, the Agency took the unusual 

step of inviting public participation in the process of developing the fmaljurisdictional 

determination set forth in this Annex. The result is the most extensive administrative 

record in the history of the Agency. FDA employed procedures that exceeded all legal 

requirements and gave the public the opportunity for full participation. 

Dated:~ 1st 9. I <fj b .; 

J2='K~"'P David A Kessler, M.D. 

Commissioner of Food and Drugs 

662