The Case Against Nicotine

By Mark P. Robinson, Jr. and Kevin F. Calcagnie

INTRODUCTION

According to the U.S. Surgeon General, smoking is direfctly responsible for one out of every six deaths in the U.S.[1] Chronic use of tobacco causes a variety of serious diseases, and smoking has been described as the largest preventable cause of death in the United States. It is estimated that each year 80,000 deaths from lung cancer, 22,000 deaths from other cancers, 19,000 deaths from chronic pulmonary disease, and 225,000 from cardiovascular disease are caused by smoking.[2] Tobacco related health care and economic costs are estimated to exceed 68 billion dollars.

The percentage of adult American smokers has declined since the 1964 Surgeon General’s Report. Since then, millions of Americans have quit smoking. However, more than 50 million people continue to smoke cigarettes and more than 10 million people use smokeless tobacco products. Combined they account for 20 billion in revenues annually to an industry which spends about 2.5 billion dollars each year in advertising and marketing.[3] Of all individuals who actually attempt to quit smoking, less than 20% succeed on their first effort. After seven or more attempts, less than half succeed.[4]

Nicotine, a chemical substance which is a natural constituent of the tobacco leaf and is absorbed into the body during smoking, has proven to be highly addictive. In 1988, the Surgeon General warned that nicotine in tobacco plants is as addictive as controlled substances such as heroin and cocaine. Because of nicotine’s strong potential for physiological and psychological addiction, individuals persist in smoking despite repeated warnings and medical evidence of the harmful effects of tobacco. Tobacco kills more people than all other addictions combined, with more than one in four cigarette smokers dying prematurely due to their addiction. [5]

Although the F.D.A. regulates nicotine used in other products, it does not regulate tobacco products. It has been estimated that if the F.D.A. were to require manufacturers to reduce the quantity of nicotine in their products to non-addictive levels, 95% of all smokers would be able to discontinue smoking. This would mean that over 12 million lives would be saved just among smokers now living, not to mention the lives of thousands of non-smokers who die each year due to environmental tobacco smoke.

This article reviews the medical evidence of the severe consequences of smoking and the tobacco industry’s concealment of its knowledge regarding nicotine addiction and the health effects of cigarettes.

THE DANGERS OF TOBACCO

Nicotiana tobacum is a cultivated species of the genus Nicotiana, named after Gene Nicot, a French diplomat, who introduced the use of tobacco in France in 1560. The tobacco leaf contains numerous compounds including starches, proteins, sugars, alkaloids, hydrocarbons, phenols, fatty-acids, sterols, and organic materials. When burned at temperatures of 830-890 degrees centigrade, reactions occur which generate approximately 4,000 different compounds, which appear in cigarette smoke as gases or particulates. Gases include hydrogen cyanide, nitrogen oxide and carbon monoxide. Particulates in cigarette smoke are referred to as tar. These include a variety of hazardous substances including nicotine.

According to experts, the components most likely to contribute to health hazards of smoking are carbon monoxide, nicotine, and tar. Probable contributors to health hazards from smoking are acrolein, hydrocyanic acid, nitric oxide, nitrogen dioxide, cresols, and am phenols.[6] At least 43 compounds in cigarette smoke are known carcinogens, including polyaeromatic hydrocarbons, n-nitrosamines, aeromatic amines, and aldehydes. Other compounds, such as nicotine, HCN, zinc, cadmium, carbon monoxide, and others are not known to be carcinogenic but associated with other pathology including acute toxicity, psychoactivity, cardiovascular disease and cilia stasis.[7]

Lung Cancer – In 1964, the Surgeon General compiled a detailed report on cigarette smoking risks summarizing all the available literature. The Surgeon General concluded “cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors…The risk of developing lung cancer increases with duration of smoking and the number of cigarettes smoked per day, and is diminished by discontinuing smoking. For men who smoke more than 25 cigarettes a day, the risk of death from lung cancer is 25 times that for the non-smoker. [8]

Other Cancers – Cigarette smoking is strongly associated with other cancers, including cancers of the kidney, bladder, esophagus, pancreas, aerodigestive tract and oral cavity. Smoking has been found to result in a 3.1 fold increase in kidney cancer, with long term smoking resulting in a 7.2 fold increase. 70% of cancers among men and 30% of cancers among woman can be attributed to smoking.[9]

Cardiovascular Disease – In a 1983 report, the Surgeon General concluded that tobacco abuse is the strongest preventable cause of cardiovascular disease: “Thus the overall finding of this report is clear; cigarette smoking should be considered the most important of the known modifiable risk factors for coronary heart disease in the United States.”.[10]

Chronic Obstructive Lung Disease – Cigarette smoking is the major cause of chronic obstructive lung disease in the United States for both men and women. The contribution of cigarette smoking to chronic obstructive lung disease morbidity and mortality far outweighs all other factors. 10 million Americans suffer from chronic obstructive pulmonary disease and it is estimated that 60,000 Americans die every year from COPD. 80-90% of these deaths are attributable to cigarette smoking.[11]

Birth Defects – Nicotine has also been identified as a tereratogenic agent linked to spontaneous abortion and congenital defects in the off-spring of smoking mothers, as well as learning deficits, reduced fetal size and skeletal defects.[12]

SECOND-HAND SMOKE – ETS

Tobacco smoke also presents a health hazard to non-smokers who are exposed to second-hand smoke because of their proximity to smokers in the workplace, at home, and in public places. Second-hand smoke (also known as environmental smoke, or ETS), is chemically similar to the smoke inhaled by smokers and contains a number of carcinogenic compounds. Evidence from laboratory studies has demonstrated the ability of second-hand smoke both to cause cancer in animals and to damage DNA, which is recognized by scientists as being an instrumental mechanism in cancer development. [13]

The EPA estimates that approximately 3,000 American non-smokers die each year from lung cancer caused by second-hand smoke, and that every year an estimated 150,000 to 300,000 children under 18 months of age get pneumonia or bronchitis from breathing second-hand tobacco smoke. The EPA has also found that second-hand smoke is a risk factor for the development of asthma in children and worsens the condition of up to one million asthmatic children.[14]

The EPA has evaluated the respiratory health effects of breathing second-hand smoke and in a 1993 report, the EPA concluded that ETS causes lung cancer in adult non-smokers and impairs the respiratory health of children. The EPA report classified second-hand smoke as a Class-A carcinogen, a designation which means there is sufficient evidence that the substance causes cancer in humans. The Group A designation has been used by the EPA for only 15 other pollutants, including asbestos, radon, and benzene.[15]

OSHA has proposed regulation governing indoor air quality, and has identified cardiovascular disease as a major quantifiable risk to health in non-smoking individuals exposed to environmental tobacco in the work place. According to OSHA, epidemiologic literature regarding ETS exposure demonstrates that the relative risk of lung cancer in non-smokers due to chronic ETS exposure ranges from 1.2 and 1.5, while the corresponding relative risk estimate for heart disease ranges from 1.24 to 3.0. OSHA also concluded that there is a relative risk of 1.28 of heart disease among non-smoking workers exposed occupationally to ETS.[16]

The tobacco industry has criticized the epidemiologic studies on environmental tobacco smoke exposure and coronary heart disease mortality, which provide the primary data used by OSHA in concluding that work place ETS exposure increases the risk of heart disease mortality. The Tobacco Institute contends that there are important problems in the design and conduct of the studies and that ‘it is premature to interpret the few relevant studies that support the biological plausibility of an ETS/CHD effect when an association has not even been adequately established.’ Among the criticisms are publication bias, small sample size, inadequate methods, inappropriate comparison groups, inconsistent dose response, and weak association.

NICOTINE

Nicotine is a naturally occurring drug found in all tobacco plants, and the pharmacologically active ingredient responsible for tobacco addiction. It is also a deadly poison, widely used as an agricultural insecticide and as a parasiticide in veterinary medicine. A single 65 mg. dose of nicotine – the amount found in a pack of cigarettes – can prove fatal. In addition, nicotine has been medically linked to cardiovascular and chronic obstructive diseases and complications in pregnancy and infancy.[17]

One of the few natural alkaloids, substances which react with other acids to form salts, nicotine is readily soluble in water and forms water soluble salts. Changes that occur in the body after administration of nicotine are due to its actions on a variety of neuroeffector and chemosensitive sites, and the fact that nicotine has both stimulant and depressive effects. Nicotine stimulates the central nervous system and at certain levels will produce tremors which can be followed by convulsions.[18]

Nicotine has been characterized as “super toxic,” having a probable oral lethal dose in humans of less than 5 mg/kg or a taste (less than 7 drops) for a 70 kg (150 lb.) person. Maternal smoking during pregnancy is associated with increased risk of spontaneous abortion, low birth weight and still-birth. Acute exposure to nicotine may result in headache, dizziness, confusion, agitation, restlessness, lethargy, seizures, and coma. Victims may experience hypertension (high blood pressure), tachycardia (rapid heart rate), tachypenia (rapid respiration), followed by hypotension (low blood pressure), bradycardia (slow heart rate), and respiratory depression. Cardiac arrhythmias may also occur.[19]

Because nicotine is a small molecule that is both lipid and water soluble, it is rapidly absorbed through the skin or lining of the mouth and nose. Due to the large area for gas exchange in the alveoli of the lungs, nicotine delivered by smoke inhalation is almost immediately extracted from the smoke and travels from the alveoli into the pulmonary veins; then it is pumped through the left ventricle of the heart into the arterial circulation where concentrated nicotine laden blood reaches organs such as the brain.[20]

ADDICTION

In 1988, the Surgeon General defined addiction as the compulsive use of a drug that has psychoactivity and that may be associated with tolerance and physical dependence.[21] Cigarette smoking is a severe form of drug addiction, with a higher death toll than all other addictions combined. The persistence of cigarette smoking behavior is not explained simply by the tolerance that develops to nicotine, but rather, by a variety of effects on the body. These effects have been called the anatomy of nicotine addiction.[22]

Tobacco industry representatives cite personal choice as the primary reason why people continue to smoke. However, studies show that most smokers would like to quit if they could find a way. 60% have tried to quit, but more than 80% who tried to quit relapsed within the year. Although scientists have long suspected that nicotine, not just the act of smoking, is addictive, it was not until the 1970’s that experimentation into nicotine began. Several reviews of this body of research have concluded that nicotine is a potent drug and that it is an addictive and dependence-producing substance that can control behavior and modify physiologic functioning. This evidence applies to the effects of nicotine delivered by cigarette smoking as well as delivered orally from smokeless tobacco .[23]

The American Psychiatric Association has identified two medical disorders pertaining to nicotine addiction. The first of these is nicotine dependence, a type of psychoactive substance use disorder, the essential feature of which is a cluster of cognitive behavioral and physiologic symptoms that indicate that a person has impaired control and continues use of the substance despite adverse consequences. In the case of nicotine, the most common form is cigarette smoking, due to the rapidly onsetting effects of nicotine which facilitate the conditioning of an intensive habit. The second is nicotine withdrawal, which is a type of psychoactive substance-induced organic mental disorder. The essential feature is a characteristic withdrawal syndrome due to the abrupt cessation of or reduction in the use of nicotine containing substances that includes craving for nicotine, irritability, frustration, anger, anxiety, and other symptoms.[24]

Animal and human studies demonstrate that chronic nicotine administration induces changes in the brain and other parts of the nervous system by stimulating the expression of nicotine receptors on neurons. Nicotine also produces a variety of changes in the function of the central nervous system, brain metabolism and energy utilization in various regions, not unlike those produced by other addictive drugs. The physiological actions of nicotine lead to addiction by providing a variety of mechanisms by which behavior may be reinforced by tobacco use. Most people who smoke regularly have become dependent on nicotine, both physiologically and psychologically.[25]

The mechanism by which nicotine causes addiction has been established through studies involving experimental animals. Nicotine activates neurons in the mesolimbic system of the brain, which creates the cravings for certain foods, drinks, or other pleasurable activities. The mesolimbic system has been shown to be activated in rats addicted to cocaine. When the mesolimbic system is stimulated, the neurons secrete Dopamine, which produces a chemical award which results in euphoric conditioning. Cocaine blocks the re-uptake of Dopamine at the nerve endings and prolongs its action, enhancing its euphoric effects. Nicotine works on the same Dopamine releasing neurons by stimulating the release of Dopamine. Nicotine is an amine which at body pH crosses cell membranes. The absorption of nicotine from the lungs, and rapid distribution to the brain, permit psychological and behavioral changes from smoking and allow the smoker to modulate the pharmacological effects on the brain.[26]

Cessation of the use of tobacco may be followed by withdrawal syndrome. Cessation of smoking causes changes in the EEG, with a decrease in high frequency activity characteristic of arousal and an increase in a low frequency activity characteristic of drowsiness and hypoarousal. Decreases in performance on tests of vigilance and psychomotor performance and increases in hostility are detectable within hours. There is a decrease in heart rate and blood pressure, and peripheral blood flow increases.[27]

According to the Commissioner of the FDA: “It is fair to argue that the decision to start smoking may be a matter of choice. But once they have started smoking regularly, most smokers are in effect deprived of the choice to stop smoking…17 million Americans try to quit smoking each year. But more than 15 million individuals are unable to exercise that choice because they cannot break their addiction to cigarettes. My concern is that the choice that they are making at a young age quickly becomes little to no choice at all and it will be very difficult to undo for the rest of their lives.”.[28]

The National Cancer Institute strongly supports the position of the U.S. Food and Drug Administration that nicotine is a drug and that tobacco products – like all drug delivery systems – should come under the same strict regulatory controls as nicotine drug products used in the management and treatment of cigarette addiction. According to NCI director, Samuel Broder, M.D., “Until now, cigarette manufacturers have been free to add virtually anything in any quantity to cigarettes, and no regulatory mechanism existed which provided any minimal safeguards…Yet tobacco is the only consumer product on the market that when used as intended by the manufacturer, will kill 500,000 consumers this year. We are pleased that FDA is taking this position and we would be glad to assist them in any way possible.”[29]

Despite the clear evidence of the addictive nature of nicotine, the tobacco industry publicly denies what it has known and internally acknowledged for decades. The industry’s public position is best summarized by the testimony of a CEO of a major manufacturer: “The term ‘addiction’ has been used to describe everything from an enslavement to hard drugs to an inability to loose weight or watch less television, and Surgeon General Koop himself proclaimed in 1982 that children were ‘addicted’ to video games. In view of the radical differences between tobacco and hard drugs in their effects on behavior and the symptoms associated with quitting, and in view of the fact that more than half of all Americans alive who have ever smoked have quit – over 90% without professional help – equating cigarettes and hard drugs is nothing more than an rhetoric…Without nicotine, you don’t have tobacco. Without nicotine, cigarettes simply would not taste like cigarettes. The experience of another manufacturer indicates that consumers will not accept a cigarette without nicotine. Calls for legislation to eliminate nicotine amount to a call to ban cigarettes – not because the substance that allegedly satisfies ‘an addiction’ would be removed, but because the resulting product would taste nothing like a cigarette. We offer a range of products with a range of nicotine deliveries and the customer makes the choice.” [30]

On December 8, 1995, the Wall Street Journal reported that a confidential internal document obtained from the Phillip Morris Company acknowledges that cigarettes are “nicotine delivery systems,” that the main reason people smoke is to get nicotine into their bodies, and that nicotine is chemically “similar” to drugs such as cocaine. The 15-page Phillip Morris draft report likens nicotine to a drug in both its composition and its effects on the brain. In calling nicotine a “similar, organic chemical” to the drugs cocaine, morphine, quinine, and atropine, the document states that “while each of these substances can be used to effect human physiology, nicotine has a particularly broad range of influence.” [31] The article quotes a Phillip Morris spokesman as stating that the tobacco industry has acknowledged that nicotine has pharmacological effects “but that doesn’t mean that cigarette smoking is addictive.”

While the industry steadfastly denies that nicotine is addictive, at least one manufacturer of a nicotine product readily admits, and in fact, warns that it is. Ciba Self-Medication Inc., which markets Habitrol, a “nicotine transdermal system,” or nicotine patch designed to help people stop smoking, provides the following warning: “WARNINGS – Nicotine from any source could be toxic and addictive. Smoking causes lung cancer, heart disease, emphysema, and may adversely affect the fetus and the pregnant woman…”

THE BROWN AND WILLIAMSON DOCUMENTS

On May 12, 1994, Stanton Glantz, Ph.D., a professor of cardiology at the University of California of San Francisco, received from an unknown source approximately 4,000 pages of memoranda, reports, and letters generated by the Brown and Williamson Company (B&W) and its parent company, The British American Tobacco Company (now BAT Industries), covering a span of 30 years. BAT is the world’s second largest private cigarette manufacturer. The company sold 578 billion cigarettes in 1992, which was 10.7% of the total world out-put and more cigarettes than were consumed in the entire U.S. market that year.

In subsequent months, Glantz and his colleagues received several thousand pages of documents from Congressman Henry Waxman’s House Subcommittee on Health and Environment, as well as hundreds of documents from the estate of the chief scientist of BAT. All the documents were placed in the library at UCSF, and Glantz and his colleagues published several articles devoted to analysis of those documents in the Journal of the American Medical Association in July of 1995. The documents support the claim of civil litigants that Brown and Williamson has known for 30 years that nicotine is addictive and has drug-like qualities but has concealed that fact from the public. For example, a document obtained from the B&W files reveals that in 1963 Addison Yeaman, general counsel for B&W, wrote that based on scientific research, “nicotine is addictive,” and that B&W was in the “business of selling nicotine, an addictive drug.”.[32] Another B&W document reveals that in 1962, two years before the issuance of the Surgeon General’s report which describes smoking as a habit, not an addiction, Sir Charles Allis, an executive in research and development at BAT, gave a keynote address at an annual BAT scientific research conference where he stated that “smoking is a habit of addiction,” and he called nicotine a “very fine drug”.[33] This is in conflict with the congressional testimony of B&W former CEO, Thomas Sandefur, who stated that he did not believe nicotine was addictive and that nicotine is a very important constituent in the cigarette smoke for taste.[34]

The documents also reveal that Yeaman wrote in 1963 that the odds are “greatly against” proving that there is no etiological factor in cigarette smoke and that at the best, the probabilities are that some combinations of constituents of smoke will be found conducive to the onset of cancer or to create an environment in which cancer is more likely to occur.[35]

The JAMA articles reached several significant conclusions:

  1. The documents show a significant sophisticated legal and public relations strategy to avoid liability for the diseases induced by tobacco use. Documents show that lawyers steered scientists away from particular research avenues, which is inconsistent with the company’s purported disbelief in the causation and addiction claims; If the company had been genuinely unconvinced by the causation and addiction hypotheses, then it should have no concern that new research would provide ammunition for the enemy. Quite the contrary, the documents show that B&W and BAT recognized more than 30 years ago that nicotine is addictive and that tobacco smoke is ‘biologically active’ (e.g., carcinogenic).[36]
  2. During a period of 22 years (1962-1984), employees of B&W and BAT conducted research and commented on the pharmacology of nicotine. They consistently regarded nicotine as the pharmacological agent that explained tobacco use. In the early part of the period under study, officials of the companies wrote about nicotine addiction explicitly….The documents reveal an intention on the part of B&W and its corporate parent to effect the function of the body with nicotine.[37]
  3. The documents demonstrate that the tobacco industry, in general, and B&W in particular, were very concerned about the threat of products liability lawsuits, and they illustrate some of the steps taken by lawyers at one company to avoid the discovery of documents that might be useful to a plaintiff in such a lawsuit. These steps included efforts to control the language of scientific discourse on issues related to smoking and health, to bring all potentially damaging internal scientific documents under attorney work-product and attorney-client privilege to avoid discovery.[38]
  4. The involvement of tobacco industry lawyers in the selection of scientific projects to be funded is in sharp contrast to the industry’s public statements about its review process for its external research program. Scientific merit played little role in the selection of external research projects. The results of the projects were used to generate good publicity for the industry, to deflect attention away from tobacco use as a health danger, and to attempt, sometimes surreptitiously, to influence policy makers.[39]
  5. The industry’s strategy regarding passive smoking has been remarkably similar to its strategy regarding active smoking. It has privately conducted internal research, at least some of which has supported the conclusion that passive smoking is dangerous to health, although it has publicly denied that the hazards have been proven.[40]

In an editorial, the JAMA indicated that the reason it was publishing the articles was because the mission of the American Medical Association has been to promote the science and the art of medicine and betterment of public health, and “to remain silent about the B&W papers would be to deny our mission. Quite simply, we are publishing this research because it is the right thing to do.”[41]

B&W’S RESPONSE

In the same issue, the Journal published an article regarding B&W’s response to a summary of the conclusions about the documents. In a written statement, B & W argued, “We refuse to be drawn into media hysteria about these stolen, attorney-client privileged documents. Despite this, it is obvious that B&W and other companies will continue to be ‘tried in the media’ in advance and any proper form to address these issues. Dr. Glantz has admitted cooperating with plaintiffs’ attorneys and we seriously question his objectivity in addressing these issues. Lifting single phrases or sentences from 30 year old documents and using that information to distort B&W’s position on a number of issues in clearly what is occurring. B&W has done, and will continue to do, nothing to waive any privilege or confidentiality associated with these documents and we are taking every step necessary to preserve those rights. We continue to believe that nicotine is not addictive because over 40 million Americans have quit smoking, 90% of them without any help at all.”

A B&W spokesperson stated, “Our position continues to be that there are health risks statistically associated with smoking, but there is no conclusive evidence of a causal link between tobacco use and disease. When these issues are played out in the courts before juries, where our rights have been protected and respected, when we have been given a fair hearing, common sense has prevailed.” The article went on to say that the documents in question were stolen by a former paralegal before his dismissal from the company’s law firm and that they are now being used by unscrupulous plaintiffs’ attorneys hoping to gain an unfair advantage over the tobacco industry in product liability suits.[42]

CONCLUSION

In the absence of significant legislative or regulatory restriction on tobacco products, the courts are the only avenue for positive change, and the only hope for victims of the tobacco industry to obtain compensation. Almost a century ago, the Supreme Court of Tennessee recognized as undisputed fact that which tobacco manufacturers today continue to deny. In William D. Austin v. State of Tennessee[43], the court stated:

“Are cigarettes legitimate articles of commerce? We think they are not because they are wholly noxious and deleterious to health. Their use is always harmful, never beneficial. They possess no virtue but are inherently bad and bad only. They find no true accommodation for merit or usefulness in any sphere. On the contrary, they are wholly condemned as pernicious altogether. Beyond question, their every tendency is towards the impairment of physical health and mental vigor. There is no proof in the record as to the character of cigarettes; yet their character is so well and so generally known to be that stated above that the courts are authorized to take judicial cognizance of the fact.”

Despite past defeats and setbacks, actions against tobacco manufacturers, by private individuals as well as public entities seeking reimbursement for tobacco-related healthcare costs, will eventually succeed. Just as products liability litigation against auto manufacturers has resulted in safer cars and fewer traffic fatalities, tobacco litigation will also have a profound impact that will result in saving lives as well as immeasurable benefit to the safety and health of the American public.


[1] U.S. Department of Health and Human Services, Public Health Service, U.S. Report of the Surgeon General: The Health Consequences of Smoking (1982).

[2] Goodman and Gillman’s The Pharmacological Basis of Therapeutics, 6th Edition, McMillan Publishing Company 1980, Pages 558 and 559.

[3] K.E. Warner, Cigarette Smoking in the 1970’s, Science (1986), Page 211.

[4] U.S. Department of Health and Human Services, Public Health Service, Office on Smoking and Health, Document No. A44700, National Audio Visual Center (1986).

[5] M.E. Mattson, et al.: What are the Odds that Smoking Will Kill You? American Journal of Public Health, April 1987; 77(4); 425-431.

[6] Goodman and Gillman’s The Pharmacological Basis of Therapeutics, 6th Edition. McMillan Publishing Company 1980, Page 557.

[7] U.S. Department of Health and Human Services, Reducing the Health Consequences of Smoking: 25 Years of Progress, A Report of the Surgeon General, DHHS Publication Company No. (CDC) 89-841 (1989).

[8] Cancer: Principles and Practice of Oncology, Volume 1, 3rd Edition, JB Lippincott Company 1989, Page 182.

[9] J.K. McLaughlin, et al.: Cigarette Smoking and Cancers of the Renal, Pelvis, and Ureter, Cancer RES (1992 January) 15:52(2):254-7.

[10] U.S. Department of Health and Human Services, Public Health Service, Report of the Surgeon General: The Health Consequences of Smoking: Cardiovascular Disease (1983).

[11] U.S. Department of Health and Human Services, Public Health Service, Report of the Surgeon General. The Health Consequences of Smoking: Chronic Obstructive Lung Disease (1984).

[12] Shepard, Catalog of Teratogenic Agents, 4th Edition, Johns Hopkins University Press (1983).

[13] Setting the Record Straight: Second-Hand Smoke is a Preventable Health Risk; EPA 402-F-94-005, Page 2 (1994).

[14] Id.

[15] Respiratory Health Effects of Passive Smoking: Lung Cancer and other Disorders; EPA/600/6-90/006F (1993).

[16] 59 Federal Register 15968, April 5, 1994.

[17] National Cancer Institute, Office of Cancer Communications, Release February 28, 1994.

[18] Goodman and Gillman’s The Pharmacological Basis of Therapeutics, 6th Edition. McMillan Publishing Company 1980, Page 557.

[19] Sittig, Marshall, Handbook of Toxic and Hazardous Chemicals and Carcinogens, 3rd Edition, Noyes Publications (1991), Page 1194.

[20] Henningfield and Keenan, The Anatomy of Nicotine Addiction, Health Volume 17, No. 2, Page 12, March/April 1993.

[21] Department of Health and Human Services, Public Health Service. Health Consequences of Smoking: Nicotine Addiction, A Report of the Surgeon General (1988) DHHS Publication Company No. (CDC) 88-8406.

[22] Henningfield and Keenan, The Anatomy of Nicotine Addiction, Health Volume 17, No. 2, Page 12, March/April 1993.

[23] Cancer Principles and Practice of Oncology, Volume 1, 3rd Edition, JB Lippincott Company 1989, Page 186, quoting from the Health Consequences of Using Smokeless Tobacco : A Report of the Advisory Committee to the Attorney General, Pages 146-147 NIH Publication No. 86-2874 (1986).

[24] American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition (Revised), Washington D.C., American Psychiatric Association (1987).

[25] Henningfield and Keenan, The Anatomy of Nicotine Addiction, Health Volumes, Volume 17, No. 2, Pages 14 and 15, March/April 1993.

[26] Braitbar, Direct Effects of Nicotine on the Brain: Evidence for Chemical Addiction, Archives of Environmental Health, August 1995.

[27] Goodman and Gillman’s The Pharmacological Basis of Therapeutics, 6th Edition. McMillan Publishing Company 1980, Pages 559-560.

[28] Statement on Nicotine Containing Cigarettes by David Kessler, M.D., Commissioner of the Food and Drug Administration before the Subcommittee on Health and the Environment, U.S. House of Representatives, March 25, 1994.

[29] The National Cancer Institute, National Institutes of Health, Office of Cancer Communications, NCI Press Office Release, February 28, 1994.

[30] Statement of Thomas Sandefur, Chairman and Chief Executive Officer, Brown and Williamson Company, before the Subcommittee on Health and the Environment, House Energy and Commerce Committee, April 14, 1994.

[31] Wall Street Journal, December 8, 1995, Marketplace B1.

[32] Memo from Addison Yeaman, July 17, 1963, Control Archives, Digital Library of UCSF, Internet Document 1802.5.

[33] J. Slade, et al., The Journal of the American Medical Association, “Nicotine and Addiction: The Brown and Williamson Documents,” July 19, 1995, Volume 74, No. 3, at page 225.

[34] Testimony from the Health and Environment Subcommittee, Energy and Commerce Committee, House of Representatives, June 23, 1994.

[35] Memo from Addison Yeaman, July 17, 1963, Tobacco Control Archives, Digital Library at UCSF, Internet Document 1802.5.

[36] S.A. Glantz, et al., The Journal of the American Medical Association, “Looking through a Keyhole at the Tobacco Industry: The Brown and Williamson Documents,” July 19, 1995, Volume 274, No. 3, at page 219.

[37] J. Slade, et al., The Journal of the American Medical Association, “Nicotine and Addiction: The Brown and Williamson Documents,” July 19, 1995, Volume 274, No. 3, at page 225.

[38] P. Hanauer, et al., The Journal of the American Medical Association, “Lawyer Control of Internal Scientific Research to Protect Against Products Liability Lawsuits: The Brown and Williamson Documents,” July 19, 1995, Volume 274, No. 3, at Page 234.

[39] L. Bero, et al., The Journal of the American Medical Association, “Lawyer Control of the Industry’s External Research Program: The Brown and Williamson Documents,” July 19, 1995, Volume 274, No. 3, at page 241.

[40] D. Barnes, et al., The Journal of the American Medical Association, “Environmental Tobacco Smoke: The Brown and Williamson Documents,” Judy 19, 1995, Volume 274, No. 3, at page 248.

[41] Editorial, The Journal of the American Medical Association, July 19, 1995, Volume 274, No. 3, at page 257.

[42] The Journal of the American Medical Association, July 19, 1995, Volume 274, No. 3, at page 254-5.

[43] William D. Austin v. State of Tennessee (1898) 101 Tenn. 563 (affirmed 179 U.S. 343, 1900).

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