Why does smoking change the human voice?

Why does smoking change the human voice?

We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

What happens to the biology of the voicebox of smokers? Women's voices can change to croaky men's voices, and vaper's voices develop "white noise" content, like a TV set to static, compared to their original voice which is closer to an oboe reed. I am curious why the white noise content and What happens to the voicebox and what happens to the sound of humans that smoke?

Smoke is hotter than air and passes through your vocal cords (before getting to your lungs), irritating them.

Irritation produces inflammation and inflammation produces mucus and general edema that could affect the biomechanics of your vocal cords, especially if you're a seasoned smoker.

The edema of the vocal cords is called Reinke's edema, which is classified as a benign polyp and will definetely make your voice more low-pitched.

I just saw that you added vaping in your question.

Since vape contains irritating chemicals too, I think its effects wouldn't be much better than smoke… obviously it depends on how often you smoke/vape.

Also, check this article:

Significant research has been conducted about the effect of cigarette smoking on the larynx and vocal cords. Several studies also suggest that exposure to electronic nicotine delivery systems can cause cellular hyperplasia (growth of cells) and metaplasia (change in cells) in mucosal lining in rats. It is theorized and likely that the same would occur in human tissue. Another experiment assessed the toxicity of vegetable glycerin, which is known to be harmless in liquid form. Its effects change in aerosol form. The experiment concluded that the substance led to squamous metaplasia of the epiglottis epithelium. Other research shows that nicotine in cigarettes is likely to lead to cancer, including in the mouth and larynx.

If the delicate lining of the vocal cords are exposed to hot, vaporized chemicals, the tissues are likely to undergo change and lose their ability to behave normally. This may produce hoarseness, loss of vocal range, voice fatigue, or vocal injury.

and finally:

These diseases and their effects on the voice can deeply affect singers and other people who use their voice for a living. The only option to avoid these is to abstain from vaping completely.

Biology of Addiction

People with addiction lose control over their actions. They crave and seek out drugs, alcohol, or other substances no matter what the cost—even at the risk of damaging friendships, hurting family, or losing jobs. What is it about addiction that makes people behave in such destructive ways? And why is it so hard to quit?

NIH-funded scientists are working to learn more about the biology of addiction. They’ve shown that addiction is a long-lasting and complex brain disease, and that current treatments can help people control their addictions. But even for those who’ve successfully quit, there’s always a risk of the addiction returning, which is called relapse.

The biological basis of addiction helps to explain why people need much more than good intentions or willpower to break their addictions.

“A common misperception is that addiction is a choice or moral problem, and all you have to do is stop. But nothing could be further from the truth,” says Dr. George Koob, director of NIH’s National Institute on Alcohol Abuse and Alcoholism. “The brain actually changes with addiction, and it takes a good deal of work to get it back to its normal state. The more drugs or alcohol you’ve taken, the more disruptive it is to the brain.”

Researchers have found that much of addiction’s power lies in its ability to hijack and even destroy key brain regions that are meant to help us survive.

A healthy brain rewards healthy behaviors—like exercising, eating, or bonding with loved ones. It does this by switching on brain circuits that make you feel wonderful, which then motivates you to repeat those behaviors. In contrast, when you’re in danger, a healthy brain pushes your body to react quickly with fear or alarm, so you’ll get out of harm’s way. If you’re tempted by something questionable—like eating ice cream before dinner or buying things you can’t afford—the front regions of your brain can help you decide if the consequences are worth the actions.

But when you’re becoming addicted to a substance, that normal hardwiring of helpful brain processes can begin to work against you. Drugs or alcohol can hijack the pleasure/reward circuits in your brain and hook you into wanting more and more. Addiction can also send your emotional danger-sensing circuits into overdrive, making you feel anxious and stressed when you’re not using the drugs or alcohol. At this stage, people often use drugs or alcohol to keep from feeling bad rather than for their pleasurable effects.

To add to that, repeated use of drugs can damage the essential decision-making center at the front of the brain. This area, known as the prefrontal cortex, is the very region that should help you recognize the harms of using addictive substances.

“Brain imaging studies of people addicted to drugs or alcohol show decreased activity in this frontal cortex,” says Dr. Nora Volkow, director of NIH’s National Institute on Drug Abuse. “When the frontal cortex isn’t working properly, people can’t make the decision to stop taking the drug—even if they realize the price of taking that drug may be extremely high, and they might lose custody of their children or end up in jail. Nonetheless, they take it.”

Scientists don’t yet understand why some people become addicted while others don’t. Addiction tends to run in families, and certain types of genes Stretches of DNA, a substance you inherit from your parents, that define characteristics such as your risk for certain disorders, such as addiction. have been linked to different forms of addiction. But not all members of an affected family are necessarily prone to addiction. “As with heart disease or diabetes, there’s no one gene that makes you vulnerable,” Koob says.

Other factors can also raise your chances of addiction. “Growing up with an alcoholic being abused as a child being exposed to extraordinary stress—all of these social factors can contribute to the risk for alcohol addiction or drug abuse,” Koob says. “And with drugs or underage drinking, the earlier you start, the greater the likelihood of having alcohol use disorder or addiction later in life.”

Teens are especially vulnerable to possible addiction because their brains are not yet fully developed—particularly the frontal regions that help with impulse control and assessing risk. Pleasure circuits in adolescent brains also operate in overdrive, making drug and alcohol use even more rewarding and enticing.

NIH is launching a new nationwide study to learn more about how teen brains are altered by alcohol, tobacco, marijuana, and other drugs. Researchers will use brain scans and other tools to assess more than 10,000 youth over a 10-year span. The study will track the links between substance use and brain changes, academic achievement, IQ, thinking skills, and mental health over time.

Although there’s much still to learn, we do know that prevention is critical to reducing the harms of addiction. “Childhood and adolescence are times when parents can get involved and teach their kids about a healthy lifestyle and activities that can protect against the use of drugs,” Volkow says. “Physical activity is important, as well as getting engaged in work, science projects, art, or social networks that do not promote use of drugs.”

To treat addiction, scientists have identified several medications and behavioral therapies—especially when used in combination—that can help people stop using specific substances and prevent relapse. Unfortunately, no medications are yet available to treat addiction to stimulants such as cocaine or methamphetamine, but behavioral therapies can help.

“Treatment depends to a large extent on the severity of addiction and the individual person,” Koob adds. “Some people can stop cigarette smoking and alcohol use disorders on their own. More severe cases might require months or even years of treatment and follow-up, with real efforts by the individual and usually complete abstinence from the substance afterward.”

NIH-funded researchers are also evaluating experimental therapies that might enhance the effectiveness of established treatments. Mindfulness meditation and magnetic stimulation of the brain are being assessed for their ability to strengthen brain circuits that have been harmed by addiction. Scientists are also examining the potential of vaccines against nicotine, cocaine, and other drugs, which might prevent the drug from entering the brain.

“Addiction is a devastating disease, with a relatively high death rate and serious social consequences,” Volkow says. “We’re exploring multiple strategies so individuals will eventually have more treatment options, which will increase their chances of success to help them stop taking the drug.”

The Science Behind Addiction, Successfully Quitting Smoking

New Year's Eve provides a benchmark for many Americans to take stock of their lives, and create goals and milestones for the upcoming year. It's at this time of year that many people add "Quit Smoking" to their list of New Year's resolutions. On average, it takes a smoker six to 11 quit smoking attempts before they are completely smokefree, and an overwhelming majority of smokers and non-smokers agree that quitting is difficult. Make this year's resolution stick by understanding why quitting smoking is so difficult, and identifying what proven steps you can take to quit for good.

According to the American Lung Association, there is a "three-link chain" of physical, social and mental components to smoking addiction. Smokers have a better chance of quitting and staying smokefree if they address all three parts of the chain:

  1. Physical: Cigarettes contain an addictive chemical called nicotine, that when inhaled causes the release of a chemical called dopamine in the brain and makes you feel good. Unfortunately, after the dopamine release depletes, these symptoms return which causes the smoker to crave another cigarette. Smokers also build up a tolerance and physical dependence on nicotine, meaning they have to smoke more to feel the same effect. Talk to a healthcare provider about quit smoking medications that can help with these symptoms.
  2. Mental: The act of smoking is often a part of one's daily routines. Smokers tend to light up at specific times of day—when drinking coffee or driving—or when they're feeling a certain way, like stressed or tired. Cigarettes can become a crutch, almost like a steady friend a smoker can rely on. Proven methods to quit smoking includes identifying these triggers, and relearning and adjusting behaviors through a quit plan.
  3. Social: Many smokers develop social groups around smoking—people will head out for a smoke break with friends or coworkers. Smoking can also be used as a social icebreaker by asking, "Got a light?" In that same vein, relying on social groups that support a quit smoking attempt can be helpful. In a recent survey, 80 percent of smokers reported that support from others, including friends, family, significant others and coworkers is very beneficial to successfully quitting.

"We know that smoking is the number one cause of preventable death in the United States, and the health benefits of quitting smoking are immediate and substantial," says Harold P. Wimmer, National President and CEO of the American Lung Association. "This month, we honor the millions of Americans that are affected by chronic lung disease through Lung Cancer and COPD Awareness Month, and know that we must do more to provide resources to help individuals quit smoking and reduce their risk of lung disease."

In addition to the in-person and online smoking cessation program Freedom From Smoking®, the American Lung Association has collaborated with Pfizer to create Quitter's Circle a new mobile app and social community designed to help smokers quit through educational, social and financial support. Within a few clicks, smokers can start a quit team with friends and family, personalize a quit plan and track progress, find resources to connect with a healthcare provider and start a quit fund – all in the palm of their hand.

"A quit plan developed in consultation with a healthcare provider can double the odds of successfully quitting smoking," says Dr. Albert Rizzo, Senior Medical Advisor to the American Lung Association. "Whether in-person, online or through a smartphone, the American Lung Association has over 30 years of experience in helping smokers quit, and it always starts with a quit plan."

Smokers&rsquo lungs vs healthy lungs

Smoking causes COPD

As we mentioned up above, the chemicals in cigarette smoke don&rsquot just irritate the airways that carry air to the lungs of a smoker, they damage the clusters of tiny air sacs deep down inside the lungs, the alveoli. 5

Over time, the thin walls of these air sacs fuse together, forming larger air spaces than normal.

This means smokers&rsquo lungs are less efficient at moving oxygen into the bloodstream, which reduces how much oxygen is transported around the body to the organs and tissues. 6

Eventually this causes emphysema, one of several Chronic Obstructive Pulmonary Diseases (COPD). 7

Common symptoms of COPD include: 8,9

  1. Chesty cough with phlegm
  2. General breathlessness
  3. Chest infections.
  4. Wheezing
  5. Lack of energy
  6. Chest tightness
  7. Shortness of breath, especially when exercising
  8. Unintended weight loss
  9. Swollen ankles, feet or legs

Smoking &lsquoparalyses&rsquo the lungs

There are millions of tiny hairs inside your windpipe and the airways that lead to your lungs. These hairs are called cilia, and they have a very important job &ndash to protect the lungs.

They do this by sweeping mucus, dirt and other particles away from the lungs and back out of the airways. 10

But one of the major effects of smoking on lungs is to paralyse these hairs, which enables mucus to build up over time.

This is one of the reasons for smoker&rsquos cough, and it can lead to chronic bronchitis, another COPD. 11

Smoking may lead to asthma

A 2013 study, published in the European Respiratory Journal, reported that smoking&rsquos impact on the lungs makes you more likely to develop asthma. 12

You&rsquore even more at risk if you&rsquore a woman &ndash a population study by the University of Ottawa in Ontario found that female smokers are nearly twice as likely to have asthma than non-smoking women. 13

Scientists think that the male hormone, testosterone helps protect men&rsquos lungs from the type of inflammation that causes asthma. 14

Smoking increases your risk of lung cancer

There are more than 60 substances that can cause cancer in cigarette smoke, which collect inside the tar that builds up in your lungs when you smoke.

It&rsquos close contact with these chemicals that increase your risk of developing lung cancer &ndash smoking causes 85% of all lung cancers in the UK. 15

So it&rsquos best to stop smoking sooner rather than later to help look after your lungs.


  • Smoking can lead to people developing Chronic Obstructive Pulmonary Diseases (COPD)
  • Common symptoms of COPD include a chesty cough with phlegm, chest infections and wheezing
  • Smoking can also paralyse the lungs, lead to asthma and increase the risk of developing lung cancer

You might also Like

I'm pretty sure once you have "killed" your cilia there is no way to make them functional again. Do you have sources for how quickly you claim that cilia damage can be reversed? anon950759 May 12, 2014

The tobacco companies put poisonous chemicals into cigarettes. Those chemicals are not in the marijuana plant. Yet you don’t usually filter marijuana as extensively as a cigarette there are still burnt plant tars and carcinogens within both plants once smoked. Fortunately, if marijuana plants are grown ethically, then there shouldn't be too much to risk, cancer wise, since the human body can naturally absorb and rid itself of the burnt plant material that was ingested into your lungs. Smoke from anything on earth can paralyze the cilia and cause its functions to cease until the cilia and lungs have been given time to re-grow and work again. I have been a marijuana smoker for over six years now and my only concern is the fact that I can’t put on extreme amounts of muscle from training at the gym due to the oxygen deprivation of smoke. (need oxygen to build muscle). Running isn’t even much of an issue for me, thankfully.

Cilia can grow back after smoking for however long, but what matters is if cancer has already developed. anon931887 February 10, 2014

Cannabis broad leaves have more carcinogens than tobacco broad leaves, but cannabis bud has one-third less, so it's not actually true that cannabis is more dangerous to smoke than cigarettes. After all who smokes cannabis broad leaves!? Juice them perhaps but sure don't smoke them. anon348628 September 18, 2013

@anon266713: Someone was smoking in the cabin below you? You get worse damage by walking around in any city with traffic than you do from secondhand smoke.

Some people would not be happy unless the whole world was regulated and sculpted to fit their world view only, with no thought or care for anyone else's opinions or life choices. anon327509 March 28, 2013

I am 60 years old and quit smoking after 38 years. I had a heart workup that was normal, and my chest X-ray was normal. I had a cough and mucus for years before I quit. This stopped with quitting, but I have moderate shortness of breath with exertion. I had pulmonary function tests that were good, showing no emphysema. I did not develop cough or mucus after quitting which I expected, just shortness of breath. The doctor said I have chronic bronchitis, and to use albuterol. I do not understand how I can have chronic bronchitis with no cough or sputum? anon308531 December 11, 2012

Good news. After you quit smoking, the cilia grows back. But if you start smoking, the smoke will literally kill the cilia, and your lungs will turn blackish grey, because they will be full of dirt, dust and other dirty things. Please read "It Couldn't Just Happen" chapter 15. It will explain things a lot better. I hope this helped! anon266713 May 7, 2012

I have serious, violent reactions to both cigarette smoke and marijuana smoke. I try to just stay away from it and give no business to any place that would expose my health to such dangers.

However, recently I was trapped on a ship with a rude chain-smoker in the cabin below our suite or maybe forward, and it came into our suite for seven days. Needless to say we'll no longer go on NCL and will cruise on a more luxury line with zero tolerance smoking programs.

I try to never take drugs of any sort, and was forced after three weeks into antibiotic world. Now we have a doctor who knowingly gave me something I'm severely allergic to. It's in his chart. I told him. I had a high fever and couldn't focus (again, thank you, smoker). After just one tab, I had a vicious rash.

Bottom line, smoking is costly to even healthy people and I really resent paying $12,000 for a cruise and coming home deathly ill, then resent doctors who are sloppy. Changing both doctors and cruise lines. anon266712 May 7, 2012

O.K., it only takes a minute to find this to be false. Marijuana has significantly more of certain dangerous poisons than cigarette smoke. No, there's no nicotine, but that doesn't matter.

Ammonia levels were 20 to 30 times higher in the marijuana smoke than in the tobacco smoke, while hydrogen cyanide, nitric oxide and certain aromatic amines occurred at levels three to five times higher in the marijuana smoke. Smoke is smoke. anon266211 May 4, 2012

I'd say that smoking marijuana does not affect the cilia as bad as smoking cigs do. That's just my guess, since I recently quit smoking cigs but still smoke weed.

I still have that smoker's cough letting me know the cilia are doing their thing. It's not like smoking marijuana gets rid of that cough as if another cig would. This is just a guess though, basing off of my experience. anon162664 March 24, 2011

how would you cite this article? anon150403 February 7, 2011

For the people asking what causes it: we talked about it in my Biology class and I believe the professor said the nicotine was a cause for it, though I'm sure it's possible for other substances to contribute to it too. anon143034 January 14, 2011

Question: I have been a smoker for about ten years, both pot and cigarettes. I recently quit a few weeks ago because I could not seem to clear my throat of mucus. It is horrible when i eat. It feels like the food is getting stuck in my throat. Can paralyzed cilia make it hard to swallow your food? anon123632 November 2, 2010

So is this caused by just the smoke or what it is you're smoking? anon108495 September 3, 2010

In regards to the question about the effect of smoking pot on the cilia. From experience I can give an unequivocal yes to your question. Smoking pot damages the cilia. Never smoked cigarettes in my life. Never. But smoked pot moderately for 30 years. Ended up with the same sort of damage to my cilia as a cigarette smoker. anon76099 April 8, 2010

Does marijuana affect the cilia in such a dramatic manner as cigarettes? trela February 22, 2010

does anyone know if nasal cilia can regenerate after quitting smoking. I've been smoking a pack to a pack and one half for twenty years. anon64287 February 6, 2010

What substances paralyze the cilia? anon49810 October 23, 2009

Does anyone know if the cilia in the fallopian tubes heal as quickly or at all as it does in the lungs? anon48868 October 15, 2009

Oxidative Stress in Chronic Obstructive Pulmonary Disease

There is considerable evidence, largely indirect, for increased oxidative stress in the lungs of COPD patients. As explained previously, oxidative stress can be measured in several ways, including direct measurements of oxidant burden, indirect measures using response to oxidative stress, and measurements of the effects of oxidative stress on target molecules (see 𠇊ssessment of Oxidative Stress” earlier in this chapter). Spin trapping, a technique by which a radical reacts with a more stable molecule, can be used to measure oxidants in biologic systems. The technique of spin trapping has been applied to measure BAL fluid in patients with COPD and has shown increased ROS (Pinamonti et al. 1998).

Numerous studies have shown that markers of oxidative stress are increased in the lungs of COPD patients compared not only with those in healthy persons but also with those in smokers having a similar smoking history who have not developed COPD (MacNee 2000). Patients with COPD have higher levels of H2O2 in exhaled breath condensate, a direct measurement of air space oxidative burden, than do former smokers with COPD or nonsmokers (Dekhuijzen et al. 1996 Nowak et al. 1998). Elevated levels of H2O2 in the exhaled breath of smokers are thought to derive partly from increased release of O2• − by alveolar macrophages (Hoidal et al. 1981).

NO has been used as a marker of airway inflammation and indirectly as a measure of oxidative stress. Increased NO in exhaled breath has been seen in some studies of patients with COPD, but the levels are not as high as those reported in asthma (Maziak et al. 1998 Delen et al. 2000). Other studies have found either normal or even lower-than-normal levels of exhaled NO in patients with stable COPD compared with those in healthy persons (Clini et al. 1998 Rutgers et al. 1999). Smoking directly increases exhaled NO levels, however, thereby limiting the usefulness of this marker in COPD. The rapid reaction of NO with O2• − , described previously, or with thiols may alter NO levels in breath (see “Generation of Reactive Oxygen Species” earlier in this chapter). Nitrosothiol levels have been shown to be higher in breath condensate in smokers and in COPD patients than those in nonsmokers (Corradi et al. 2001). ONOO − , formed by the reaction of NO with O2• − , can cause nitration of tyrosine to produce nitrotyrosine (Petruzzelli et al. 1997). Nitrotyrosine levels are elevated in sputum leukocytes of patients with COPD, and they are correlated negatively with FEV1 (Ichinose et al. 2000).

Exhaled carbon monoxide, as a measure of the response of heme oxygenase to oxidative stress, has been shown to be elevated in exhaled breath in persons with COPD compared with that in persons without COPD (Montuschi et al. 2001). Carbon monoxide is also present in cigarette smoke, however, which limits its usefulness as a marker of oxidative stress in persons who smoke.

Lipid peroxidation products such as TBARS or malondialdehyde are elevated in sputum from COPD patients, and the levels correlate negatively with FEV1 (Nowak et al. 1999 Tsukagoshi et al. 2000 Corradi et al. 2003). Urinary levels of 8-isoprostane, another lipid peroxidation product, are also higher in persons with COPD (Praticò et al. 1998). Levels of 8-isoprostane in breath condensate are also higher in persons with COPD than in healthy persons and smokers who have not developed the disease, and they correlate with the degree of airway obstruction (Paredi et al. 2000a). Isoprostanes may also reflect systemic effects caused by ROS (Morrow et al. 1995). Plasma levels of free F2-isoprostanes are higher in smokers than in nonsmokers and are decreased after cessation of smoking.

Lipid peroxides can interact with enzymatic or nonenzymatic antioxidants and can decompose by reacting with metal ions or iron-containing proteins, thereby forming hydrocarbon gases and unsaturated aldehydes. Hydrocarbons are thus by-products of fatty acid peroxidation (Paredi et al. 2000b). COPD patients have higher levels of exhaled ethane in breath than do persons in the control group, and these levels correlate negatively with lung function (Habib et al. 1995 Paredi et al. 2000b).

There is evidence that concentrations of these markers of oxidative stress are also increased in the lung tissue of COPD patients. The lipid peroxidation product 4-HNE reacts quickly with extracellular proteins to form adducts, which have been shown to be present at higher concentrations in airway epithelial and endothelial cells in the lungs of COPD patients than in those of smokers with a similar smoking history who have not developed the disease (Rahman et al. 2002). Other markers of oxidative stress, such as 8-OH-dG and 4-HNE, have been shown to have increased expression associated with emphysematous lesions in the lungs (Tuder et al. 2003c).

Pathogenesis of Chronic Obstructive Pulmonary Disease

Many studies have shown higher levels of biomarkers of oxidative stress in COPD patients than in healthy smokers. Furthermore, several studies show relationships between markers of oxidative stress and the degree of airflow limitation in COPD (Repine et al. 1997 MacNee 2000). However, the presence of oxidative stress and its relationship to airflow limitation may be an epiphenomenon because oxidative stress occurs in any inflammatory response. Cohort studies have not shown that the presence of enhanced oxidative stress relates to the decline in FEV1 or to the progression of COPD.

Protease-Antiprotease Imbalance

In COPD, the protease burden in the lungs is increased because of the influx and activation of inflammatory leukocytes that release proteases. It has been proposed that a relative �iciency” of antiproteases such as AAT, because of their inactivation by oxidants, creates a protease-antiprotease imbalance in the lungs. This hypothesis forms the basis of the protease-antiprotease theory of the pathogenesis of emphysema (Janoff et al. 1983a Stockley 2001). Inactivation of AAT by oxidants occurs at a critical methionine residue in its active site and can be produced by oxidants from cigarette smoke or oxidants released from inflammatory leukocytes, resulting in a marked reduction in the inhibitory capacity of AAT in vitro (Bieth 1985 Evans and Pryor 1992). In vivo study of the acute effects of cigarette smoke on the functional activity of AAT show a transient but nonsignificant fall in the antiprotease activity of BAL fluid one hour after cigarette smoking (Abboud et al. 1985). In addition, in vitro exposure of lung epithelial cells to proteases leads to increased release of ROS, suggesting that proteases increase oxidative stress (Aoshiba et al. 2001b).

Hypersecretion of Mucus

Oxidant-generating systems such as xanthine and xanthine oxidase have been shown to cause the secretion of mucus from airway epithelial cells (Adler et al. 1990 Wright et al. 1996). Oxidants are also involved in the signaling pathways for EGF, which has an important role in the production of mucus (Nadel 2001). In addition, H2O2 and superoxide have been shown to cause a significant impairment of ciliary function after short-term exposure at low concentrations (Feldman et al. 1994). These effects may have important implications in the pathogenesis of COPD.

Lung Inflammation

Oxidative stress is present wherever inflammation exists. It may also be a mechanism for enhancing the air space inflammation that is characteristic of COPD (Pauwels et al. 2001). Oxidative stress can result in the release of chemotactic factors, such as IL-8, from airway epithelial cells (Gilmour et al. 2003), and epithelial cells from COPD patients have been shown to release more IL-8 than those of smokers or healthy persons (Profita et al. 2003). Lipid peroxidation products such as 8-isoprostane can also act as signaling molecules and cause the release of inflammatory mediators such as IL-8 from lung cells (Scholz et al. 2003). The lipid peroxidation product 4-HNE can cause increased production of TGFβ (Leonarduzzi et al. 1997) and increased expression of the gene encoding for the anti- oxidant enzyme γ-glutamylcysteine synthetase (Arsalane et al. 1997).

An enhanced inflammatory response in the lungs is characteristic of COPD (Di Stefano et al. 2004 Hogg 2004). Oxidative stress may have a fundamental role in enhancing inflammation through the increased production of redox-sensitive transcription factors, such as NF-㮫 and AP-1, and also by activation of the extracellular signal-regulated kinase, C-JUN N-terminal kinase, and p38 mitogen-activated protein kinase pathways (Rahman and MacNee 1998 MacNee and Rahman 2001). Cigarette smoke has been shown to activate all of these signaling mechanisms.

Genes for many inflammatory mediators are regulated by NF-㮫, which is present in the cytosol in an inactive form linked to its inhibitory protein I㮫. Many stimuli, including oxidants, result in activation of I㮫 kinase, producing phosphorylation and cleaving of I㮫 from NF-㮫. The release of NF-㮫 is a critical event in the inflammatory response and is redox sensitive (Janssen-Heininger et al. 1999 MacNee 2000). Studies both in macrophage cell lines and in alveolar and bronchial epithelial cells show that oxidants cause the release of inflammatory mediators (e.g., IL-8, IL-1, and NO) and that these events are associated with increased expression of the genes for these inflammatory mediators and with increased nuclear binding and activation of NF-㮫 (Jiménez et al. 2000 Parmentier et al. 2000). The linking of NF-㮫 to its consensus site in the nucleus leads to enhanced transcription of proinflammatory genes and hence inflammation, which induces more oxidative stress, creating a vicious circle as enhanced inflammation and increased oxidative stress perpetuate each other.

Nuclear binding of NF-㮫 is increased in the airway macrophages and airway epithelial cells of COPD patients (Di Stefano et al. 2002). In a guinea pig model, exposure to cigarette smoke led to influx of neutrophils into the lungs and increased IL-8 gene expression, protein release, and NF-㮫 activation (Nishikawa et al. 1999). These increases and the neutrophil influx were reduced by pretreatment with superoxide dismutase, suggesting a role for oxidant stress. NF-㮫 is activated and translocated to the nucleus to a greater extent in lung tissue in smokers and in patients with COPD than in healthy persons (Szulakowski et al. 2006), and NF-㮫 activation in lung tissue has been shown to correlate with FEV1 (Crowther et al. 1999).

A study of gene expression in rat epithelium after exposure to cigarette smoke showed that smoke causes rapid induction of antioxidant stress-response genes and drug-metabolizing enzymes, such as heme oxygenase and quinone oxidoreductase, all of which had decreased expression after long-term exposure to cigarettes (Gebel et al. 2004). The protein kinase C signaling pathway is also sensitive to tobacco smoke and increases its activity by twofold to threefold when stimulated by 5-percent CSE (Wyatt et al. 1999).

A further event controlling gene transcription that may be affected by oxidative stress and may enhance lung inflammation is chromatin remodeling. Under normal circumstances, DNA is wound tightly around a core of histone residues. This configuration prevents access for transcription factors to the transcriptional machinery and also reduces access of RNA polymerase to DNA, thereby resulting in transcriptional repression and gene silencing (Rahman and MacNee 1998 MacNee 2001). Histone acetyltransferases (HATs) cause the acetylation of his-tone residues, resulting in a change in their charge and unwinding of DNA and allowing access for transcription factors such as NF-㮫 and RNA polymerase to the transcriptional machinery, thereby enhancing gene expression. This process is reversed by HDACs, enzymes that deacetylate histone residues, resulting in the rewinding of DNA and gene silencing. The exact role of oxidative stress in modifying HAT and HDAC activity is unknown, but it appears that oxidative stress can result in increased HAT activity and decreased HDAC activity (Gilmour et al. 2003), which would enhance gene transcription.

Oxidative stress results in HAT activity in epithelial cells (Tomita et al. 2003). Histone acetylation can be shown to occur after the exposure of epithelial cells to cigarette smoke and is prevented by the antioxidant therapy N-ace-tylcysteine, indicating that the process is redox sensitive (Anderson et al. 2004). Furthermore, in animal models, exposure to cigarette smoke results in increased acetylated histone in the lung and decreased HDAC activity, and both of these events would enhance gene expression (Marwick et al. 2002). In addition, HDAC activity in alveolar macrophages obtained from cigarette smokers has been shown to be decreased, which would also enhance gene expression (Ito et al. 2001). This event may be due to nitration of HDAC2 by ONOO − (Ito et al. 2001, 2004a). More recent studies have suggested that acetylate histone residues, such as H4, are present to a greater extent in lung tissue in smokers and in COPD patients who smoke. These increases in H4 are associated with a decrease in HDAC2 in COPD patients who smoke and in patients with severe COPD (Ito et al. 2005 Szulakowski et al. 2006). A correlation has also been shown between decreased HDAC activity in lung tissue and FEV1 in patients with COPD.


There are two types of cell death: apoptosis, which is organized and noninflammatory, and necrosis, which is unorganized, destructive, and proinflammatory. One hypothesis is that loss of alveolar endothelial cells by apoptosis may be an initial event in the development of emphysema (Tuder et al. 2003b). Apoptosis has been shown to occur to a greater extent in endothelial cells in emphysematous lungs than in lungs of nonsmokers (Kasahara et al. 2001).

Airway lymphocytes (Majo et al. 2001) and stimulated peripheral blood leukocytes (Hodge et al. 2003) from patients with COPD also show increased apoptosis. The process of endothelial apoptosis is thought to be under the influence of VEGFR-2 receptors. Decrease of VEGFR-2 has been shown to produce emphysema in animals, and reduced expression of VEGFR-2 is evident in emphysematous human lungs (Kasahara et al. 2001). Studies have also shown that the apoptosis and emphysema induced by VEGF inhibition in animal models is associated with increased markers of oxidative stress and is prevented by antioxidants, suggesting that oxidative stress is involved in this process (Tuder et al. 2003c).

Systemic Involvement

Although COPD predominantly affects the lungs, it has important systemic consequences, including cachexia and skeletal muscle function (Wouters et al. 2002 Langen et al. 2003). Increasing evidence suggests that similar mechanisms involving oxidative stress and inflammation in the lungs may also be responsible for many of the systemic effects of COPD (Langen et al. 2003).

Peripheral blood neutrophils from COPD patients have been shown to release more ROS than such neutrophils from unaffected persons (Rahman et al. 1996a). Products of lipid peroxidation are also increased in plasma in smokers and patients with COPD (Rahman et al. 1996a). In addition, increased levels of nitrotyrosine have been shown to occur in the plasma of COPD patients (Ichinose et al. 2000).

Patients with COPD often display weight loss, which correlates inversely with the occurrence of exacerbations and is seen as an independent indicator of outcome (Gray-Donald et al. 1996 Landbo et al. 1999). In addition, loss of fat-free mass results in peripheral muscle dysfunction, decreased exercise capacity, and reduced health status (Palange et al. 1995 Baarends et al. 1997 Engelen et al. 2000b). Several factors influence the loss of weight and fat-free mass in COPD patients, including malnutrition, imbalance in overall protein turnover and the hormones involved in this process, tissue hypoxia, and pulmonary inflammation (Jenkins and Ross 1996 Engelen et al. 2000b Eid et al. 2001 Wouters et al. 2002).

Oxidative stress may also have a role in the cachexia and loss of fat-free mass that occurs in COPD. Skeletal muscle is exposed continuously to changes in the redox environment that occur during exercise. Several studies have shown evidence of increased oxidative stress in patients with COPD both locally and systemically, particularly during exercise (Couillard et al. 2002, 2003 Langen et al. 2003). Presence of lipid peroxidation products in the serum, accompanied by an increase in the ratio of oxidized to reduced GSH, occur during exercise in COPD patients to a greater extent than in healthy persons (Sastre et al. 1992 Vi༚ et al. 1996 Heunks and Dekhuijzen 2000). Skeletal muscle cells adapt to oxidative stress by increasing production of antioxidant enzymes such as SOD, catalase, and GPX (Franco et al. 1999). Study findings also showed evidence of disturbed redox homeostasis in COPD associated with emphysema. GSH levels in skeletal muscle were lower in COPD patients with emphysema than in those who did not have emphysema and were associated with reduced concentrations of glutamate, an important substrate in the synthesis of glutamine and GSH (Engelen et al. 2000a). Other studies demonstrate a decrease in GPX activity, elevated GRX activity, and increased lipid peroxidation, which indicate oxidative damage in the skeletal muscle of experimental hamsters with emphysema (Mattson et al. 2002). These results suggest that GSH metabolism is impaired in COPD.

Increased ROS production in skeletal muscle during exercise may result from stimulation of the mitochondrial electron-transport chain by TNFα (Li et al. 1999), which is known to be elevated in the circulation of patients with COPD who lose weight (Di Francia et al. 1994). Leukocytes infiltrating skeletal muscles in COPD patients may be another source of ROS (Adams et al. 2002). In addition, exercise increases the activity of xanthine and xanthine oxidase, a further source of ROS (Andrade et al. 1998). ROS also contribute to oxidative stress in muscles, and inducible NO expression has been shown to increase in skeletal muscle in response to inflammatory cytokines and activation of NF-㮫 (Adams et al. 2002). Oxidative stress may directly compromise muscle function by decreasing contractility and by increasing the susceptibility of muscle to oxidants (Barclay and Hansel 1991 Andrade et al. 1998). ROS may also oxidize proteins in the contractile apparatus, such as sulfhydryl residues in the contractile proteins, which may impair muscle function (MacFarlane and Miller 1992). In addition to impairing muscle function, resulting in muscle fatigue, oxidative stress may induce muscle atrophy. Atrophy is the result of an imbalance in muscle protein metabolism, which has been described in studies showing that oxidative stress induced inhibition of muscle-specific protein expression (Buck and Chojkier 1996 Langen et al. 2004). Furthermore, oxidative stress may result in apoptosis of muscle cells, which has been described in skeletal muscle cells, and may contribute to muscle atrophy (Stangel et al. 1996).


Considerable evidence now exists for both local and systemic oxidative stress in COPD patients. Increasing evidence suggests that oxidative stress is involved in many of the pathogenic processes involved in COPD, as well as in systemic phenomena such as skeletal muscle dysfunction. Cigarette smoke provides an extraordinarily strong dose of free radicals to the lung, initiating processes of oxidative injury that involve multiple cell types and the entire lung. Local inflammation results and markers of inflammation are higher, both in smokers and in persons with COPD, than are those in nonsmokers. Oxidative stress unfavorably tips the protease-antiprotease balance toward protease, leading to tissue damage and COPD.


Phases of Tobacco Smoke

Smoke from a burning cigarette is a 𠇌oncentrated aerosol of liquid particles suspended in an atmosphere consisting mainly of nitrogen, oxygen, carbon monoxide and carbon dioxide” (Guerin 1980, p. 201). Researchers have also described cigarette smoke as a “lightly charged, highly concentrated matrix of submicron particles contained in a gas with each particle being a multicompositional collection of compounds arising from distillation, pyrolysis, and combustion of tobacco” (Dube and Green 1982, p. 42). Tobacco smoke is a complex and dynamic chemical mixture. Researchers have analyzed whole smoke or used chemical and physical means to separately examine the gas and particulate portions of tobacco smoke. The gas phase is defined as the portion of smoke that passes through a glass fiber filter of specified physical parameters, and the particulate phase refers to all matter captured by the glass fiber filter (Pillsbury 1969). Standard methods for analysis of tobacco smoke separate the two phases by using Cambridge glass fiber filters designed to collect aerosol particles of 0.3 micrometers (μm) or larger with an efficiency not less than 99 percent (Pillsbury 1969). Although these separate phases are an artificial construct, they are useful for describing the results of analysis of the components of cigarette smoke typically obtained by machine smoking. When people smoke cigarettes, the continuum of physical characteristics in smoke does not include the differentiation into specific fractions. The diameter of cigarette smoke particles constantly changes, and as the particles coalesce after their formation, they grow in diameter. However, in diluted smoke, loss of a volatile chemical matrix or other components may cause particles to shrink and changes in the particle size may alter the relative amounts of certain chemicals in the gas and particle phases (Guerin 1980).

Smoke formation occurs when the cigarette is lit and a puff is taken or when the cigarette smolders between puffs. Mainstream smoke is released from the butt end of the burning cigarette during puffing, and sidestream smoke emanates from the burning cigarette coal when it smolders (Guerin 1980). The air in the immediate vicinity of an active smoker contains a mixture of sidestream smoke, exhaled mainstream smoke, and any smoke that passes through the porous paper surrounding the tobacco (L཯roth 1989). A greater quantity of sidestream smoke is generated when the amount of tobacco burned during smoldering increases relative to the amount burned during puffing (Johnson et al. 1973b Perfetti et al. 1998). Thus, the way the cigarette is smoked (e.g., puff volume and time between puffs) can alter the relative levels of mainstream and sidestream smoke (Perfetti et al. 1998).

In addition, the ratio of the levels of chemical components in sidestream smoke to their levels in mainstream smoke can be altered by differences among cigarettes (Perfetti et al. 1998). These differences are related to the tobacco blend or type, the tobacco preparation (e.g., cut width, additives, and moisture level), the dimensions of the cigarette, the weight of the tobacco rod, the porosity of the paper, the presence of a filter, and the type of filter. Studies using a machine that simulates human smoking have determined that the change in the ratio of sidestream to mainstream smoke components after introducing a filter and ventilation primarily resulted from a decrease in the amount of mainstream smoke, because the amount of sidestream smoke does not change substantially with alterations in cigarette design (Perfetti et al. 1998). Examination of chemicals with similar properties revealed that those with a low boiling point had higher ratios of levels in sidestream smoke to levels in mainstream smoke and that compounds with a high boiling point had lower ratios (Sakuma et al. 1984). Studies indicate that compared with mainstream smoke collected under standard FTC/ ISO smoking parameters, sidestream smoke has higher levels of PAHs (Grimmer et al. 1987 Evans et al. 1993) nitrosamines (Brunnemann et al. 1977a, 1980 Hoffmann et al. 1979a Rühl et al. 1980) aza-arenes (Dong et al. 1978 Grimmer et al. 1987) aromatic amines (Patrianakos and Hoffmann 1979) carbon monoxide (CO) (Hoffmann et al. 1979b Rickert et al. 1984) nicotine (Rickert et al. 1984 Pakhale et al. 1997) ammonia (Brunnemann and Hoffmann 1975) pyridine (Johnson et al. 1973b Brunnemann et al. 1978 Sakuma et al. 1984) and the gas phase components 1,3-butadiene, acrolein, isoprene, benzene, and toluene (Brunnemann et al. 1990). With increased puffing intensity, the toxicant ratios of sidestream to mainstream smoke decrease (Borgerding et al. 2000).

The increase in the amount of tobacco burned during smoldering compared with tobacco burned during puffing is not the only factor influencing differences in the chemical content of sidestream and mainstream smoke. The burning conditions that generate sidestream and mainstream smoke also differ (Guerin 1987). Temperatures reach 900ଌ during a puff and fall to about 400ଌ between puffs (Guerin 1987). Puffing burns the tobacco on the periphery of the cigarette, and tobacco in the core burns between puffs (Johnson 1977 Hoffmann et al. 1979a). Thus, mainstream smoke depends on the chemical composition of the combustible portion of the cigarette near the periphery of the rod, whereas chemicals at higher concentrations in the central portion of the rod have higher levels in sidestream smoke than in mainstream smoke (Johnson 1977). Sidestream smoke is produced during conditions with less available oxygen (Guerin et al. 1987) and higher alkalinity and water content than those for mainstream smoke (Brunnemann and Hoffmann 1974 Adams et al. 1987 Guerin 1987). Ammonia levels are significantly higher in sidestream smoke, resulting in a more alkaline pH (Adams et al. 1987). Thus, the composition and levels of chemical species in mainstream smoke differ from those in sidestream smoke.

Levels of some compounds are higher in mainstream smoke than in sidestream smoke, and this difference may reflect chemical influences that are more complex than just changes in puff frequency. For example, mainstream smoke contains considerably more cyanide than side-stream smoke does (Johnson et al. 1973b Brunnemann et al. 1977a Norman et al. 1983). Sakuma and colleagues (1983) measured a series of semivolatile compounds in tobacco smoke and found that levels of phenol, cresol, xylenols, guiacol, formic acid, and acetic acid were higher in sidestream smoke, whereas levels of catechol and hydroquinone were higher in mainstream smoke.

Individual chemical constituents may be found in the particulate phase, the gas phase, or both (Guerin 1980). As cigarette smoke dissipates, chemicals may pass between the particulate and gas phases (L཯roth 1989). The gas phase contains gases and chemical constituents that are sufficiently volatile to remain in the gas phase long enough to pass through the Cambridge glass fiber filter (Guerin 1980), but as the filter becomes wet during the first puffs, hydrophilic compounds tend to adhere to it. The gas phase of cigarette smoke includes nitrogen (N2), oxygen (O2), carbon dioxide (CO2), CO, acetaldehyde, methane, hydrogen cyanide (HCN), nitric acid, acetone, acrolein, ammonia, methanol, hydrogen sulfide (H2S), hydrocarbons, gas phase nitrosamines, and carbonyl compounds (Borgerding and Klus 2005 Rodgman and Perfetti 2009). Constituents in the particulate phase include carboxylic acids, phenols, water, humectants, nicotine, terpenoids, paraffin waxes, tobacco-specific nitrosamines (TSNAs), PAHs, and catechols. Mainstream smoke contains only a small amount of nicotine in the gas phase (Johnson et al. 1973b Pakhale et al. 1997), but the fraction of nicotine in the gas phase is higher in side-stream smoke because of the higher pH (Johnson et al. 1973b Brunnemann and Hoffmann 1974 Adams et al. 1987 Pakhale et al. 1997). Brunnemann and colleagues (1977b) studied both mainstream and sidestream smoke and found that the gas phase of mainstream smoke contained more cyanide than did the particulate phase. Johnson and colleagues (1973b), however, showed that in sidestream smoke, cyanide is present almost exclusively in the particulate phase. Guerin (1980) concluded that both formaldehyde and cyanide may be present in both phases, and Spincer and Chard (1971) found formaldehyde in both the particulate and gas phases. The PAHs in the gas phase were only 1 percent of total PAHs, and the PAH distribution between gas and particulate phases varied with the boiling point of the PAHs (Grimmer et al. 1987). Because physical and chemical changes occur after tobacco smoke is drawn from the cigarette, some of the reported differences in PAH levels could result from differences in measurement techniques.

In summary, cigarette smoke is a complex and dynamic system. The concentration of smoke and the time after it leaves the cigarette can cause changes in particle size that may alter the relative amounts of certain chemicals in the gas and particle phases. Also, specific properties of the tobacco, the physical design of the cigarette, and the machine-smoking method that is employed to generate mainstream smoke for analyes can have a significant impact on the levels of both mainstream and side-stream emissions.

Nicotine and Free Nicotine

The tobacco leaf contains many alkaloid chemicals nicotine is the most abundant. Nicotine content varies, among other factors, by the leaf position on the tobacco stalk and also by the blend or leaf type used in a given cigarette or cigar (Tso 1990 Kozlowski et al. 2001). Plants such as tobacco that are characterized by high alkaloid content often possess a natural pharmacologic defense against microorganisms, insects, and vertebrates. For example, nicotine is toxic to many insects and, for many years, has been extracted from tobacco for use as a commercial pesticide (Domino 1999). Nicotine is addictive in humans because a portion of the nicotine molecule is similar to acetylcholine, an important brain neurotransmitter (Brody et al. 2006).

The alkaloids in tobacco leaf include anatabine, anabasine, nornicotine, N-methylanabasine, anabaseine, nicotine, nicotine N′-oxide, myosmine, β-nicotyrine, cotinine, and 2,3′-bipyridyl (Figure 3.1). In commercial tobacco products, nicotine concentrations range from 6 to 18 milligrams per gram (mg/g) (0.6 to 1.8 percent by weight) (International Agency for Research on Cancer [IARC] 2004 Counts et al. 2005). Together, the sum of the concentrations of anatabine, anabasine, and nor-nicotine equals approximately 5 percent of the nicotine concentration (Jacob et al. 1999). Many minor tobacco alkaloids are pharmacologically active in humans in one or more ways. Clark and colleagues (1965) observed that some of these alkaloids had physiological effects in a variety of animal tests. Lefevre (1989) reviewed the evidence and concluded that anabasine and nornicotine had demonstrated effects on smooth muscle fiber, blood pressure, and enzyme inhibition. The literature on potentially addictive properties of these minor alkaloids is limited. S(-)-nicotine, which is present in the tobacco leaf, is structurally similar to forms of several minor alkaloids also found in the tobacco leaf, such as S(-)-N-methylanabasine (Figure 3.2). Moreover, Dwoskin and colleagues (1995) reported that in the rat, anatabine, anabasine, N-methylanabasine, anabaseine, and nornicotine all release dopamine from striatal brain tissue. Overall, it is likely that some of the minor tobacco alkaloids could (1) be addictive if delivered alone at sufficiently high levels and (2) act together with nicotine during tobacco use to generate effects that are difficult to discern because nicotine levels are so much higher. In addition to addictiveness, both nicotine and minor secondary amine alkaloids are precursors of carcinogenic TSNAs (IARC 2004, 2007).

Figure 3.1

Figure 3.2

Structures of nicotine and minor alkaloid S(-)-N-methylanabasine in tobacco leaf.

The unprotonated nicotine molecule contains two nitrogen atoms with basic properties. The unprotonated nicotine molecule can thus add one proton to form a monoprotonated species or two protons to form the diprotonated species (Figure 3.3) (Brunnemann and Hoffmann 1974). The first proton added to nicotine attaches predominantly to the nitrogen on the five-membered (pyrrolidine) ring, because that nitrogen is significantly more basic than the nitrogen on the six-membered (pyridine) ring. Although protonated nicotine is not volatile, unprotonated nicotine is volatile and is able to enter the gas phase and readily pass into lipid membranes. Unprotonated nicotine is therefore free of the limitations that come with carrying an ionic charge, and the scientific literature and tobacco industry documents frequently refer to nicotine in this form as both 𠇏ree nicotine” and 𠇏ree-base nicotine.” In the tobacco plant and in the dried leaf, nicotine largely exists in its ionic forms otherwise, it would be rapidly lost to the surrounding atmosphere.

Figure 3.3

In water or in the droplets of particulate matter in tobacco smoke, the distribution of nicotine among its three forms depends on the pH of the solution. Increasing acidity of the solution increases the fraction of protonated molecules conversely, increasing basicity increases the fraction in the unprotonated (free base) form (Figure 3.3). Because all forms of nicotine are highly soluble in water, all of the nicotine entering the respiratory tract from one puff of tobacco smoke easily dissolves in lung fluids and blood. However, because unprotonated nicotine from tobacco smoke particles is volatile, whereas protonated nicotine is not, a higher percentage of unprotonated nicotine in a puff results in a higher rate of nicotine deposition in the respiratory tract (Pankow 2001 Henningfield et al. 2004). The exact nature and effects of the increased rate of deposition depends on the chemical composition and the size of particles in the tobacco smoke, as well as topographic characteristics of smoking, such as puff size and duration and depth of inhalation. Increased rates of deposition in the respiratory tract lead to increased rates of nicotine delivery to the brain, which intensify the addictive properties of a drug (Henningfield et al. 2004). The conventional view has been that a sample of particulate matter from tobacco smoke is not usually so acidic that the diprotonated form becomes important. In water at room temperature, the approximate dividing line between dominance by protonated forms or by the unprotonated form is a pH of 8 (González et al. 1980). At higher pH, the fraction of unprotonated nicotine (αfb) is greater than the fraction of protonated nicotine (Pankow 2001). At pH 8, the two fractions are present in equal percentages. At any lower pH, the fraction of protonated nicotine is greater.

Because a typical sample of particulate matter from tobacco smoke collected from a cigarette or cigar is mostly nonaqueous liquid, it is not possible to take conventional pH measurements to determine nicotine distribution between the monoprotonated and unprotonated forms (Pankow 2001). However, it is possible to measure the concentration of unprotonated nicotine in a sample of tobacco smoke particulate (cp,u), because that level produces a directly proportional concentration of unprotonated nicotine in the gas phase, which is measurable (Pankow et al. 1997, 2003 Watson et al. 2004). Measuring the concentration of nicotine in a sample of tobacco smoke in the particulate phase (cp,t) allows calculation of the fraction of unprotonated nicotine: αfb = cp,u/cp,t (Pankow et al. 2003). To simplify the discussion of αfb values in tobacco smoke, Pankow (2001) introduced the term �tive pH” (pHeff), which refers to the pH needed in water to obtain the αfb value in a sample of particulate matter from smoke. Reported values of αfb for smoke from commercial cigarettes at 20 o C were 0.006 to 0.36 (Pankow et al. 2003 Watson et al. 2004), which corresponds to pHeff values at 20 o C in the range of 5.8 to 7.8.

The fraction αfb for particulate matter in tobacco smoke is important because the rapidity with which inhaled nicotine from tobacco smoke evaporates from the particulate phase and deposits on the linings of the respiratory tract is directly proportional to the αfb value for the smoke (Pankow et al. 2003). According to numerous tobacco industry documents, increasing levels of unprotonated nicotine in tobacco smoke was known to increase smoke “strength,” “impact,” “kick,” and/or “harshness” (Backhurst 1965 Dunn 1973 Teague 1974 Ingebrethsen and Lyman 1991). Because of similar mechanisms, nicotine replacement therapy delivering gaseous nicotine caused throat irritation at delivery levels per puff that were similar to those reached by smoking a cigarette rated by using the FTC regimen at approximately 1 mg of total nicotine delivery thus, cigarette design is focused on a balance between smoke “impact” and irritation. Some researchers have suggested that the irritation and harshness of smoke at higher pH makes it harder for smokers to inhale this smoke into the lungs (Brunnemann and Hoffmann 1974).

The value of αfb for particulate matter in each puff of smoke from one brand of cigarette or cigar strongly depends on the overall proportion of acids to bases in the puff (Pankow et al. 1997). As already noted, nicotine itself is a base. The natural acids in tobacco smoke (e.g., formic acid, acetic acid, and propionic acid) can protonate nicotine and tend to reduce αfb from its maximum of 1.0. The natural bases (e.g., ammonia) tend to neutralize the acids and keep more nicotine in the unprotonated form.

Variability in the acid-base nature of commercially available tobacco leaf is considerable. Flue-cured (𠇋right”) tobacco is typically viewed as producing acidic smoke. Air-cured (𠇋urley”) tobacco is typically viewed as producing basic smoke. Simple adjustment of the tobacco blend can therefore produce a considerable range of acid or base content in tobacco smoke. In acidic smoke, αfb can be 0.01 or lower (e.g., 1-percent unprotonated nicotine), and in basic smoke, the αfb can be relatively high (e.g., 0.36 [36-percent unprotonated nicotine]) (Pankow et al. 2003 Watson et al. 2004).

Tobacco additives that are bases increase αfb values in mainstream smoke, and these additives are discussed extensively in tobacco industry documents (Henningfield et al. 2004). The documents reveal that a variety of basic additives have been considered, including ammonia and ammonia precursors. Conversely, some manufacturers also were interested in reducing harshness to a minimum and investigated acidic additives such as levulinic acid as “smoothing” agents. In that context, the natural basicity of a specific blend and the harshness of the smoke can be reduced by acidic additives such as levulinic acid, which tend to reduce αfb (Guess 1980 Stewart and Lawrence 1988).

In summary, nicotine in cigarette smoke exists in either a protonated or unprotonated form, depending on a number of factors, including the presence of natural acids and bases, the tobacco blend, tip ventilation, and the use of additives. Cigarette design ensures that the smoke has enough unprotonated nicotine to rapidly transfer nicotine into the body but not so much of it as to be too harsh for the smoker to continue to smoke.


N-nitrosamines are a class of chemical compounds containing a nitroso group attached to an amine nitrogen. There are two types of nitrosamines in tobacco and tobacco smoke: volatile and nonvolatile, including TSNAs (Hoffmann et al. 1981 Tricker et al. 1991 Spiegelhalder and Bartsch 1996 IARC 2007). The volatile nitrosamines include N-nitrosodimethylamine, N-nitrosoethylmethylamine, N-nitrosodiethylamine, N-nitro-sopyrrolidine, and N-nitrosomorpholine. The nonvolatile nitrosamines are 4-(N-nitroso-N-methyl-amino)butyric acid, N-nitrosopipecolic acid, N-nitroso-sarcosine, 3-(N-nitroso-N-methylamino)propionic acid, N-nitrosoproline, and N-nitrosodiethanolamine. The nonvolatile TSNAs (Figure 3.4) have been examined extensively in tobacco and tobacco smoke. They include N′-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N′-nitrosoanatabine (NATB), and N′-nitrosoanabasine (NAB). The levels of nitrosamines in tobacco products are higher than are those in other consumer products, such as cooked bacon and beer (Hecht and Hoffmann 1988), and smokers are exposed to higher levels of TSNAs than of the other nitrosamines (Hoffmann et al. 1981 IARC 2007).

Figure 3.4

Studies have been conducted to identify precursors of nitrosamines and to determine the conditions required for their formation in tobacco. The primary intent of this research was to identify ways to reduce nitrosamine levels in tobacco and tobacco smoke. Secondary and tertiary amines in tobacco, including the alkaloids, react with nitrosating agents to form N-nitrosamines (Hecht and Hoffmann 1988). Hecht and colleagues (1978) showed that both nicotine and nornicotine can react with sodium nitrite under controlled conditions to form carcinogenic NNN and NNK, but nicotine is considered more important because of its higher level in tobacco products. TSNAs are not present at trace levels in freshly harvested tobacco, but they are predominantly formed during processing, curing, and storage (Hoffmann et al. 1974, 1981 Chamberlain et al. 1984 Andersen and Kemp 1985 Bhide et al. 1987 Djordjevic et al. 1989 Fischer et al. 1989b Fisher 2000a). Aerobic bacteria play a major role in TSNA formation in air-cured tobacco (Hecht et al. 1975 Hoffmann et al. 1981 Parsons et al. 1986). In flue-cured tobacco, the curing conditions alter levels of nitrosamines (Fisher 2000a). Before the late 1960s and early 1970s, direct-fire curing in the United States did not produce high levels of TSNAs. When propane gas was introduced as the combustion source (Fisher 2000a), nitrogen oxides from the exhaust gases in tobacco barns reacted with alkaloids in the tobacco plant to form TSNAs. Hoffmann and colleagues (Hoffmann et al. 1981 Brunnemann and Hoffmann 1991) also revealed that N-nitrosodiethanolamine is formed from the diethanolamine used in the formulation of maleic hydrazide, which is applied to regulate suckers on tobacco plants.

Volatile nitrosamines are found primarily in the gas phase of tobacco smoke, and TSNAs are almost exclusively found in the particulate phase (Guerin 1980). Researchers suggest that about one-half of the nitrosamines in tobacco smoke are transferred unchanged from the tobacco to the smoke and that the remainder is formed from pyrosynthesis during smoking (Hoffmann et al. 1977 Adams et al. 1983). Other researchers have concluded that almost all TSNAs are transferred directly from the tobacco (Fischer et al. 1990b).

It is difficult to determine whether TSNAs are pyrosynthesized or transferred intact, because the most important factors in nitrosamine formation such as concentrations of preformed TSNA in tobacco or their precursor, as well as chemical and physical processes during smoking, could affect either mechanism. Morie and Sloan (1973) reported that the nitrate and amine content in tobacco determined the amount of N-nitrosodimethyl-amine formed in tobacco smoke. This finding has been widely duplicated by researchers looking at other nitrosamines (Hecht et al. 1975 Brunnemann et al. 1977a, 1983 Hoffmann et al. 1981 Adams et al. 1983, 1984 Fischer et al. 1989b Tricker et al. 1991 Atawodi et al. 1995 Spiegelhalder and Bartsch 1996). Other factors that influence nitrate concentrations in tobacco can also indirectly influence nitrosamine concentrations. Because TSNA content is strongly influenced by the use of stems that are naturally high in TSNAs in the cigarette rod, the increased use of stems leads to higher nitrosamines in the smoke (Brunnemann et al. 1983). Researchers have also found that the use of nitrogen fertilizer can contribute to the concentration of nitrosamines in tobacco and ultimately in the smoke (Johnson and Rhoades 1972 Tso et al. 1975 Brunnemann et al. 1977a Chamberlain et al. 1984, 1986). Other influential factors identified were tobacco growth conditions, storage times, storage temperatures (Andersen et al. 1982 Andersen and Kemp 1985), and the stalk positions from which the tobacco leaves are harvested (Chamberlain et al. 1986).

Another factor contributing to nitrosamine concentrations in tobacco is the type of tobacco used (Johnson and Rhoades 1972 Brunnemann et al. 1983 Fischer et al. 1989b,c). Oriental tobaccos are lowest in both nitrates and TSNAs (Fischer et al. 1989b), whereas burley tobacco contains the highest TSNA concentrations (Fischer et al. 1989b,c). The nitrosamine concentrations in bright tobacco are between those in oriental and burley and depend on the curing practices described earlier (Tso et al. 1975 Hoffmann et al. 1979a). The TSNA concentrations are higher in blended cigarettes than in those made from bright tobacco, because burley is included in the blend (Fischer et al. 1990a). In most tobaccos, NNN concentrations exceed NNK concentrations (Fischer et al. 1989b), but in bright tobacco, NNK concentrations exceed those of NNN (Fischer et al. 1989b, 1990a).

The preformed concentration of nitrosamines in tobacco leaves and stems is a major determinant of the levels in tobacco smoke (Fischer et al. 1990c Spiegelhalder and Bartsch 1996). However, for cigarettes that have the same concentrations of nitrosamines in the tobacco, the nitrosamine levels in the smoke were largely determined by the degree of ventilation and the use of cellulose-acetate filter tips in the cigarette. After examining machine-generated smoke, by the FTC/ISO method, from cigarettes containing the same type of tobacco, whether blended or bright only, researchers found that nitrosamine levels are correlated with tar delivery, which is primarily a function of filter ventilation (Adams et al. 1987 Fischer et al. 1990a). However, studies of cigarettes with different blends of tobacco have shown that tar is not an accurate measure of nitrosamine levels (Fischer et al. 1989c Spiegelhalder and Bartsch 1996 Counts et al. 2004). Studies have also shown that cellulose-acetate filter tips remove both volatile nitrosamines and TSNAs (Morie and Sloan 1973 Brunnemann et al. 1980 Rühl et al. 1980 Hoffmann et al. 1981). These findings indicate the importance of measuring TSNA levels in smoke, rather than using measured levels of tar or nicotine to predict levels of TSNAs in smoke on the basis of an average relationship between tar or nicotine and TSNAs.

Nitrosamine levels measured in the tobacco and the smoke from cigarettes that were purchased around the world vary widely because of the differences cited above. Historically, the ranges of levels of NNN (2 to 12,454 nanograms [ng] per cigarette), NAB+NATB (109 to 1,033 ng), and NNK (55 to 10,745 ng) in cigarette tobacco were wide (Hoffmann et al. 1974 Fischer et al. 1989b, 1990a,c Tricker et al. 1991 Atawodi et al. 1995 IARC 2004, 2007). More recent analyses have given more consistent results that depend on the blend of tobacco (NNN + NNK: 87 to 1,900 ng/g) (Ashley et al. 2003). Levels in mainstream tobacco smoke, as reported by the FTC/ISO machine-smoking method, have been reported at an order of magnitude lower than those in tobacco (NNN = 4 to 1,353 ng generated per cigarette) NAB+NATB = 10 to 82 ng and NNK = 5 to 1,749 ng (Fischer et al. 1989b, 1990a,c Tricker et al. 1991 Atawodi et al. 1995 Mitacek et al. 1999).

Using the ISO, Massachusetts (MDPH 45-mL puff volume, 30-second puff interval, 50 percent of ventilation holes blocked) and Canadian Intense (CAN 55-mL puff volume, 30-second puff interval, 100 percent of ventilation holes blocked) smoking regimens, Counts and colleagues (2005) reported the levels of TSNAs in mainstream smoke from Philip Morris cigarettes sold internationally. The investigators found that in mainstream smoke, NNN levels were 5.0 to 195.3 ng generated per cigarette for ISO, 16.3 to 374.2 ng for MDPH, and 20.6 to 410.6 ng for CAN. NNK levels were 12.4 to 107.8 ng generated per cigarette for ISO, 25.8 to 206.6 ng for MDPH, and 39.1 to 263.0 ng for CAN. NATB levels were 8.0 to 160.4 ng generated per cigarette for ISO, 31.9 to 295.3 ng for MDPH, and 43.5 to 345.1 ng for CAN.

The combined levels of NNN and NNK reported by Wu and associates (2005) are in good agreement with the ranges reported by Counts and colleagues (2005). This finding suggests that the more advanced analytical methods used in these later studies yielded more accurate measures for current cigarettes than did previous measures. Levels of volatile nitrosamines in mainstream tobacco smoke are typically lower than those of the TSNAs (dimethylnitrosamine = 0.1 to 97 ng generated per cigarette methylethylnitrosamine = 0.1 to 9.1 ng and N-nitrosopyrrolidine = 1.5 to 64.5 ng) (Brunnemann et al. 1977a, 1980 Adams et al. 1987).

Ashley and colleagues (2003) compared TSNA concentrations in tobacco from Marlboro cigarettes with those in locally popular, non-U.S. brands of cigarettes in 13 countries. For most of the countries, TSNA concentrations in the tobacco from Marlboro cigarettes were higher than those in tobacco from locally popular brands from that country. TSNA concentrations varied widely (20-fold overall) between and within brands from the same country and differed significantly from country to country. This study confirmed earlier work showing wide variations in TSNA levels in tobacco and smoke from products within a country and between countries (Hecht et al. 1975 Fischer et al. 1990c Spiegelhalder and Bartsch 1996 Gray et al. 2000). The basic findings from this study were confirmed by work from Wu and colleagues (2005), who examined combined levels of NNN and NNK in the mainstream smoke from cigarettes from the same 13 countries and also found a wide variation in this matrix.

Identification of growing, curing, and blending practices that alter nitrosamine levels in tobacco and smoke have led researchers to agree that low TSNA levels in smoke can be achieved by using particular varieties of tobacco and carefully controlling the factors leading to formation and transfer of TSNAs from tobacco into smoke (Brunnemann et al. 1977a Hoffmann et al. 1977 Hecht et al. 1978 Rühl et al. 1980 Andersen and Kemp 1985 Hecht and Hoffmann 1988 Fischer et al. 1990c Spiegelhalder and Bartsch 1996 Mitacek et al. 1999 Ashley et al. 2003 Burns et al. 2008). To reduce TSNAs, tobacco curing in the United States is undergoing a transition, and nitrosamine levels may change as curing and blending practices change (Counts et al. 2004 O𠆜onnor et al. 2008).

In summary, nitrosamines are found in tobacco and tobacco smoke at high levels compared with other consumer products. The levels of these compounds, which are formed during tobacco processing, curing, and storage, can be minimized by breeding and selecting tobacco lines with lower propensity for TSNA formation, and limiting the use of nitrogen fertilizer, the levels of nitrogen oxides in the atmosphere during curing, the amount of burley tobacco in the blend, and storage times. The impact of different practices is clearly seen by the wide global range of TSNA levels in tobacco and smoke.

Polycyclic Aromatic Hydrocarbons

PAHs are chemical compounds with two or more condensed aromatic and other cyclic rings of carbon and hydrogen atoms (Douben 2003). Recent studies (Rodgman and Perfetti 2006) have identified at least 539 PAHs in tobacco smoke. The U.S. Environmental Protection Agency (EPA) has identified 16 priority environmental PAHs on the basis of evidence that they cause or may cause cancer: acenaphthylene, acenaphthene, anthracene, benz[a] anthracene, benzo[a]pyrene (B[a]P), benzo[b]fluoranthene (B[b]F), benzo[k]fluoranthene (B[k]F), benzo[g,h,i] perylene, chrysene, dibenz[a,h]anthracene, fluoranthene, fluorene, indeno[1,2,3-cd]pyrene, naphthalene, phenanthrene, and pyrene (Figure 3.5) (USEPA 1980, 1986). The 16 PAHs, which have two to six fused rings and molecular weights of 128 to 278, were detected in the particulate matter of tobacco smoke (IARC 1986, 2004 Ding et al. 2006, 2007). PAHs range from highly volatile to relatively nonvolatile, and their distribution in the particulate and gas phases of tobacco smoke varies with the boiling point (Grimmer et al. 1987). However, the gas phase contained only an estimated 1 percent of the total PAHs found in tobacco smoke. The composition of PAHs in mainstream smoke is different from that in sidestream smoke (Grimmer et al. 1987), and the lipophilic characteristics range from moderate to high (Douben 2003).

Figure 3.5

Priority environmental polycyclic aromatic hydrocarbons.

PAHs are formed by incomplete combustion of natural organic matter such as wood, petroleum, and tobacco and are found throughout the environment (Evans et al. 1993 Douben 2003). In the burning cone at the tip of the tobacco rod, various pyrolysis reactions occur to form methylidyne (CH) radicals that are precursors to the pyrosynthesis of PAHs. Hoffmann and Wynder (1967) were the first to show that adding nitrate to tobacco reduced B[a]P levels. During smoking, nitrates form O2 and nitric oxide (NO), which intercept radicals and reduce PAH levels (Johnson et al. 1973a Hoffmann and Hoffmann 1997). Other researchers also reported that the presence of nitrate in tobacco decreases B[a]P levels in the smoke (Torikai et al. 2005). The pyrolytic conditions also favor the formation of PAHs from certain isoprenoids such as solanesol (IARC 1986), although other findings have disagreed with this assessment (Torikai et al. 2005). B[a]P is the most widely known and studied PAH (IARC 2004).

Differences in tobacco type can affect levels of PAHs in the smoke. Flue-cured (bright) or sun-cured (oriental) tobaccos have lower nitrate content than does air-cured (burley) tobacco. Pyrosynthesis of PAHs generates higher PAH levels in smoke from cigarettes made exclusively with flue-cured or sun-cured tobaccos than in smoke from cigarettes made with burley tobaccos (Hoffmann and Hoffmann 1997 Ding et al. 2005). Cigarettes made from reconstituted tobacco with cellulose fiber as an additive yield significantly reduced PAH levels. Evans and colleagues (1993) measured PAHs in mainstream and sidestream smoke and found that B[a]P, B[b]F, and B[k]F levels are related to tar yields in cigarette smoke that result from differences in cigarette ventilation.

Some studies reported the levels of B[a]P alone as a surrogate for the total PAH content. Ding and colleagues (2005) observed that total PAH levels in mainstream smoke from commercial cigarette brands varied from 1 to 1.6 μg generated per cigarette under FTC machine-smoking conditions. In the same study, individual PAHs ranged from less than 10 ng generated per cigarette (B[k]F) to approximately 500 ng (naphthalene) (Ding et al. 2005). Other researchers reported levels of B[b]F at 10.4 ng, B[k]F at 5.1 ng, and B[a]P at 13.4 ng generated per cigarette (Evans et al. 1993). In four of five brands tested, B[a]P concentrations in cigarette tar were about 0.5 ng/ mg of tar (Tomkins et al. 1985). Kaiserman and Rickert (1992) reported the levels of B[a]P in smoke from 35 brands of Canadian cigarettes by using the ISO method mean levels were 3.36 to 28.39 ng generated per cigarette. Although B[a]P levels were linearly related to declared tar values, the tar values and the B[a]P levels did not change at the same relative rate. In a study of PAHs in mainstream smoke from cigarettes from 14 countries, Ding and colleagues (2006) showed a significant global variation in levels. They also demonstrated an inverse relationship with TSNA levels at high PAH and low TSNA levels, possibly as a result of differences in nitrate levels.

In summary, PAHs result from the burning of biologic material, so they are present in the smoke from any form of burning tobacco. Factors that can affect PAH levels in tobacco smoke include the type of tobacco and its nitrate content. Because of divergent pyrosynthetic mechanisms, factors that increase the nitrate content of tobacco decrease PAH levels but may increase TSNA levels in cigarette smoke. However, a substantial reduction in PAH levels in cigarette smoke will be a challenge as long as tobacco smoke is generated from burning tobacco.

Volatile Compounds Including Aldehydes

When a cigarette is smoked, chemicals partition between the particulate and gas phases on the basis of physical properties including volatility and solubility (Hoffmann and Hoffmann 1997). Complete partitioning of any chemical to the gas phase of cigarette smoke is generally limited to the gaseous products of combustion, such as the oxides of nitrogen, carbon, and sulfur, and the extremely volatile low-molecular-weight organic compounds. There are between 400 and 500 volatile gases and other compounds in the gas phase (Hoffmann and Hoffmann 1997). The nearly complete combustion of the cigarette tobacco filler generates an effluent stream of gaseous chemicals residing almost exclusively in the gas phase portion of mainstream cigarette smoke. These chemicals, on the basis of weight, account for most of the mainstream smoke. In order by prevalence, these chemicals include N2, O2, CO2, CO, nitrogen oxides, and the sulfur-containing gaseous compounds.

CO and CO2 result from the combustion of tobacco. Other than N2 and O2, CO and CO2 are the most abundant compounds in mainstream cigarette smoke, representing nearly 15 percent of the weight of the gas phase. CO2 levels (approximately 50 mg generated per cigarette) are more abundant than are CO levels (approximately 20 mg), as determined by the FTC machine-smoking method.

Nitrogen oxide gases are formed by the combustion of nitrogen-containing amino acids and proteins in the tobacco leaf (Hoffmann and Hoffmann 1997). Mainstream cigarette smoke contains mostly NO with traces of nitrogen dioxide (NO2) and nitrous oxide. The formation of nitrogen oxides is amplified by combustion with nitrate salts, and the amount formed is directly related to the nitrate concentration of the tobacco leaf (MacKown et al. 1999). The mainstream cigarette smoke contains approximately 500 μg of NO generated per cigarette. Although fresh smoke contains little NO2, the aging of the smoke converts the reactive NO to NO2, which has an estimated half-life of 10 minutes (Borland et al. 1985 Rickert et al. 1987). These gases react with water and other components in cigarette smoke to form nitrate particles and acidic constituents.

Sulfur-containing gases result from the combustion of sulfur-containing amino acids and proteins (Horton and Guerin 1974). In mainstream cigarette smoke, H2S is the most abundant of these gases (approximately 85 μg generated per cigarette), and both sulfur dioxide and carbon disulfide are present in smaller quantities (approximately 2 μg).

In addition to the volatile gases, mainstream cigarette smoke contains a wide range of volatile organic compounds (VOCs) (Counts et al. 2005 Polzin et al. 2007). The formation of these VOCs results from the incomplete combustion of tobacco during and between puffs. The generation of VOCs, as well as the previously mentioned volatile gases, is directly related to the tar delivery of the cigarette, as evidenced by machine smoking under the FTC regimen (Hoffmann and Hoffmann 1997 Polzin et al. 2007). Therefore, factors altering the yield of tar (e.g., tobacco blend, cigarette filter, filter ventilation, paper porosity, and tobacco weight) directly affect the yield of VOCs. Under certain machine-smoking conditions, the use of charcoal filters (Williamson et al. 1965 Counts et al. 2005 Laugesen and Fowles 2006 Polzin et al. 2008), variations in the temperature in the burning zone, and the presence or absence of O2 can substantially alter the levels of VOCs generated in cigarette smoke (Torikai et al. 2004). The VOCs in mainstream cigarette smoke, as a result of their high biologic activity and levels, are among the most hazardous chemicals in cigarette smoke (Fowles and Dybing 2003 IARC 2004). In developed countries, the combined exposure of smokers to mainstream cigarette smoke and nonsmokers to secondhand smoke constitutes a significant portion of the population’s total exposure to certain VOCs. For example, more than one-half of the U.S. population’s exposure to benzene is from cigarette smoking (U.S. Department of Health and Human Services [USDHHS] 2002). The roughly 500 VOCs in the gas phase of mainstream cigarette smoke can be subclassified by structure. Among the most significant classes are the aromatic hydrocarbons, carbonyls, aliphatic hydrocarbons, and nitriles. Although other classes of volatile compounds (e.g., acids and bases) are present, these four classes of VOCs have been the most widely studied, because of their biologic activity and overall higher levels.

Aromatics are a class of compounds defined by their structural similarity to benzene. These compounds result from incomplete combustion of the organic matter of the cigarette, most notably sugars and cellulose (Chortyk and Schlotzhauer 1973). The most abundant aromatic compounds in mainstream smoke generated from full-flavored cigarettes with use of the FTC/ISO smoking regimen are toluene (approximately 5 to 80 μg generated per cigarette), benzene (approximately 4 to 60 μg), total xylenes (approximately 2 to 20 μg), styrene (approximately 0.5 to 10 μg), and ethylbenzene (approximately 1 to 8 μg) (Counts et al. 2005 Polzin et al. 2007).

Carbonyl compounds include the ketones and aldehydes. These compounds are studied because of their reactivity and levels, which approach 1 mg generated per cigarette. The most prevalent aldehydes in mainstream smoke from cigarettes, generated using the ISO regimen, are acetaldehyde (approximately 30 to 650 μg generated per cigarette), acrolein (approximately 2.5 to 60 μg), and formaldehyde (approximately 2 to 50 μg) (Counts et al. 2005). The most prevalent ketones in mainstream cigarette smoke, generated by using the FTC/ISO smoking regimen, are acetone (approximately 50 to 550 μg generated per cigarette) and 2-butanone (approximately 10 to 130 μg) (Counts et al. 2005 Polzin et al. 2007). Spincer and Chard (1971) identified formaldehyde in both the particulate and gas phases of tobacco smoke and found that much of the formaldehyde was associated with total particulate matter (TPM). These investigators determined that formaldehyde delivery was higher in smoke from bright tobacco than in that from burley tobacco.

On the basis of total mass, hydrocarbons represent the largest VOC class in mainstream cigarette smoke (Hoffmann and Hoffmann 1997). Both saturated hydrocarbons and olefins result from the incomplete combustion of cigarette tobacco. The most abundant hydrocarbons in cigarette smoke are methane, ethane, and propane, which represent nearly 1 percent of the total cigarette effluent. Unsaturated hydrocarbons are also present in significant quantities in mainstream cigarette smoke, as evidenced by using the ISO regimen, but the olefins isoprene (approximately 70 to 480 μg generated per cigarette) and 1,3-butadiene (approximately 6.5 to 55 μg) are the most abundant unsaturated hydrocarbons (Counts et al. 2005).

The volatile nitriles, which include compounds such as HCN, acetonitrile, and acrylonitrile, are important because of their toxic effects. The most abundant nitriles in mainstream smoke generated from cigarettes by using the ISO regimen are HCN (approximately 3 to 200 μg generated per cigarette), acetonitrile (approximately 100 μg), and acrylonitrile (approximately 1 to 12 μg) (Counts et al. 2005).

In summary, cigarette smoke is composed primarily of gaseous and volatile compounds. Thus, levels of these compounds are critical in determining the overall toxicity of tobacco smoke. Differences in the design of the cigarette can have a substantial effect on the levels determined in smoke, which makes the reproducibility of results challenging, but provides knowledge of possible mechanisms to reduce the exposure of smokers.

Heavy Metals

Metals and metalloids are among the many substances contained in tobacco smoke they are often loosely called “heavy metals” without regard to whether they are light- or heavy-mass metals or metalloids. Their chemical properties span a wide range. These substances are found as pure metals or as metals naturally associated or chemically bound to other elements that can significantly alter the chemical properties of the metals.

Although metals can be deposited on tobacco leaves from particles in the air and some fungicides and pesticides containing toxic metals have been sprayed on tobacco leaves or soils in the past (Frank et al. 1977), most of the metals present in plants are absorbed from the soil (Schwartz and Hecking 1991 Cheng 2003 Xiao et al. 2004a,b). Soils, therefore, including any amendments to the soil, such as sludge, fertilizers, or irrigation with polluted water have been the predominant source of metals found in tobacco grown in various geographic areas (Bache et al. 1985 Mulchi et al. 1987, 1991, 1992 Adamu et al. 1989 Bell et al. 1992 Rickert and Kaiserman 1994 Stephens et al. 2005). Cadmium and lead content in tobacco and smoke have been correlated with the content in the soil in which the tobacco was grown, after adjustment for the amendments to the soil (Bache et al. 1985 Adamu et al. 1989 Mulchi et al. 1991, 1992 Bell et al. 1992 Rickert and Kaiserman 1994 Stephens et al. 2005). In addition, Rickert and Kaiserman (1994) showed that heavy metals in the air can be important. For example, significant changes in the lead concentrations in the air between 1974 and 1988 accounted for most of the changes in lead levels in tobacco during that period. Researchers have associated the mercury content in tobacco with environmental factors and soil in geographic areas where the tobacco was grown (Rickert and Kaiserman 1994). Mulchi and colleagues (1992) have also suggested that consideration of soil pH is important to understanding the relationship between metals in the soil and metals in the tobacco leaf. Because of differences in the soil, air, and metal uptake by the tobacco plant, the metal content of tobaccos varies widely.

Most metals and metalloids are not volatile at room temperature. Pure metallic mercury is volatile, but only a few forms are volatile at temperatures lower than 100஬. The temperature of tobacco that burns at the tip of a cigarette may reach 900஬ (Baker 1981). A burning cigarette tip is hot enough to volatilize many metals into the gas phase, but by the time the smoke is inhaled or rises in a plume from the cigarette as secondhand smoke, most of the metals have condensed and moved into the particulate portion of the smoke aerosol (Baker 1981 Chang et al. 2003).

The range of levels of toxic metals found in tobacco smoke reflects differences in cigarette manufacturing processes, ventilation, additives, concentrations in the tobacco, and the efficiency with which the metal transfers from the leaf to the smoke. The transfer rate of metals from tobacco into smoke also depends on the properties of the metal (Krivan et al. 1994). Because tobacco plants easily absorb and accumulate cadmium from the soil, cadmium is found at relatively high concentrations in tobacco leaves. This accumulation, along with the high percentage of transfer from the leaves into the smoke (Schneider and Krivan 1993), yields high cadmium levels in tobacco smoke (Chiba and Masironi 1992). Kalcher and colleagues (1993) developed a model for the behavior of metals in mainstream smoke and found that most of the cadmium in tobacco smoke is in the particulate phase, whereas lead is equally partitioned between the particulate and gas phases. Cadmium levels have been reported to range from 10 to 250 ng generated per cigarette in the particulate phase (Allen and Vickroy 1976 Bache et al. 1985 Nitsch et al. 1991 Schneider and Krivan 1993 Krivan et al. 1994 Rhoades and White 1997 Csalári and Szántai 2002 Torrence et al. 2002) to a lower level of 1 to 31 ng in the gas phase (Nitsch et al. 1991). More recent studies of cadmium levels in particulate matter in smoke from commercial cigarettes smoked under FTC/ISO conditions reported a range of 1.6 to 101.0 ng generated per cigarette (Counts et al. 2005 Pappas et al. 2006). Not surprisingly, Counts et al. (2005) also showed that levels of cadmium in smoke generated using more intense smoking regimens such as MDPH (12.7 to 178.3 ng generated per cigarette) and CAN (43.5 to 197.1 ng generated per cigarette) were higher than when using FTC/ISO. This increase was also seen with other metals tested. These studies also demonstrated that changes in cigarette design, such as introducing filter ventilation, reduces the delivery of metals under FTC/ISO smoking conditions. In counterfeit cigarettes, levels of cadmium in particulate matter from mainstream smoke can be significantly higher, ranging from 40 to 300 ng generated per cigarette, under FTC smoking conditions (Pappas et al. 2007).

Lead also transfers well from tobacco to smoke (Schneider and Krivan 1993) measurements range from 18 to 83 ng generated per cigarette in the particulate phase (Allen and Vickroy 1976 Nitsch et al. 1991 Schneider and Krivan 1993 Krivan et al. 1994 Csalári and Szántai 2002 Torrence et al. 2002 Baker et al. 2004) and from 6 to 149 ng in the gas phase (Nitsch et al. 1991). More recent studies of lead levels in particulate matter in smoke from commercial cigarettes smoked under FTC/ISO conditions reported a range of 4 to 39 ng generated per cigarette (Counts et al. 2005 Pappas et al. 2006). Studies of cigarettes in the United Kingdom have documented concentrations of heavy metals in a number of counterfeit cigarette brands that were higher than those in domestic products (Stephens et al. 2005). These metals included arsenic, cadmium, and lead. In counterfeit cigarettes, levels of lead in mainstream cigarette smoke can be significantly higher, ranging up to 330 ng generated per cigarette, under FTC smoking conditions (Pappas et al. 2007). Studies have also found similar levels of nickel in both phases: particulate levels range from 1.1 to 78.5 ng generated per cigarette (Bache et al. 1985 Nitsch et al. 1991 Schneider and Krivan 1993 Torjussen et al. 2003), and gas phase levels range from 3 to 57 ng (Nitsch et al. 1991).

Tobacco smoke also contains lower levels of other metals. The range of levels found in the particulate phase includes cobalt, 0.012 to 48.0 ng generated per cigarette arsenic, 1.5 to 21.0 ng chromium, 1.1 to 1.7 ng antimony, 0.10 to 0.13 ng thallium, 0.6 to 2.4 ng and mercury, 0.46 to 6.5 ng (Allen and Vickroy 1976 Suzuki et al. 1976 Nitsch et al. 1991 Schneider and Krivan 1993 Krivan et al. 1994 Rhoades and White 1997 Milnerowicz et al. 2000 Shaikh et al. 2002 Torrence et al. 2002 Baker et al. 2004 Pappas et al. 2006). Gas phase levels depend on the volatility of the metals or metal complexes. Cobalt levels range from less than 1 to 10 ng generated per cigarette, and mercury levels range from 5.0 to 7.4 ng generated per cigarette (Nitsch et al. 1991 Chang et al. 2002). In a limited analysis, Chang and colleagues (2003) found arsenic and antimony in the gas phase but did not provide quantitative results.

Studies have identified radioactive elements in tobacco and tobacco smoke. Lead 210, a product of radioactive decay of radon, was found in tobacco (Peres and Hiromoto 2002) and is transported at low levels in tobacco smoke (Skwarzec et al. 2001). Most of the lead in tobacco smoke is the nonradioactive isotopes. Polonium, an element found only in radioactive forms, is also a product of radioactive decay of radon. Some researchers have found polonium 210 in tobacco (Skwarzec et al. 2001 Peres and Hiromoto 2002 Khater 2004), and others estimated transfer of 11 to 30 percent of the amount in tobacco to tobacco smoke (Ferri and Baratta 1966). The presence of a filter and the type of filter used can alter the amount of polonium transferred into mainstream smoke some filters remove 33 to 50 percent of the polonium from the smoke (Ferri and Baratta 1966).

In summary, the levels of metals in tobacco smoke are primarily a function of their content in the soil in which the tobacco is grown, added substances such as fertilizer, and the design of the cigarette. Study findings indicate that (1) growing conditions for tobacco contribute to the levels of metals in cigarettes manufactured worldwide and (2) some counterfeit cigarettes have higher levels of metals than do domestic commercial cigarettes. This evidence has proved that tobacco-growing conditions can alter the concentrations of metals in cigarette tobacco and therefore the levels in the smoke.

Aromatic Amines

Aromatic amines and their derivatives are used in the preparation of dyes, pharmaceuticals, pesticides, and plastics (Brougham et al. 1986 Bryant et al. 1994 Centers for Disease Control and Prevention [CDC] 1994) and in the rubber industry as antioxidants and accelerators (Parmeggiani 1983). Because of their widespread use, aromatic amines are prevalent and may be found as contaminants in some color additives, paints, food colors, and leather and textile dyes and in the fumes from heating oils and fuels. Studies that measured aromatic amines in the ambient environment detected their presence and determined concentrations in air, water, and soil (Birner and Neumann 1988 Del Santo et al. 1991 Ward et al. 1991 Skipper et al. 1994 Sabbioni and Beyerbach 1995). Aromatic amines consist of at least one hydrocarbon ring and one amine-substituted ring, but these agents have diverse chemical structures. Chemically, aromatic amines act as bases and most exist as solids at room temperature.

Some scientists have suggested that aromatic amines are present in unburned tobacco (Schmeltz and Hoffmann 1977) and are also formed as combustion products in the particulate phase of tobacco smoke (Patrianakos and Hoffmann 1979). Investigators determined levels of aromatic amines in both mainstream and sidestream smoke (Hoffmann et al. 1969 Patrianakos and Hoffmann 1979 Grimmer et al. 1987 Luceri et al. 1993 Stabbert et al. 2003a). The identified compounds include aniline 1-, 2-, 3-, 4-toluidine 2-, 3-, 4-ethylaniline 2,3-, 2,4-, 2,5-, 2,6-dimethylaniline 1-, 2-naphthylamine 2-, 3-, 4-aminobiphenyl and 2-methyl-1-naphthylamine. The most commonly studied compounds from this class are shown in Figure 3.6. Stabbert and colleagues (2003a) found that aromatic amines reside primarily in the particulate phase of smoke, except for the more volatile amines such as o-toluidine only 3 percent of o-toluidine was found in the gas phase. Studies have reported that sidestream smoke contains substantially higher levels of aromatic amines than does mainstream smoke, but these levels depend on the parameters for puffing the cigarette (Patrianakos and Hoffmann 1979 Grimmer et al. 1987 Luceri et al. 1993). For mainstream smoke, the levels of aromatic amines were reported to be 200 to 1,330 ng generated per cigarette (Luceri et al. 1993 Stabbert et al. 2003a), but studies have reported much higher levels in sidestream smoke (Luceri et al. 1993). More recently, one study reported the following levels of aromatic amines in mainstream cigarette smoke (Counts et al. 2005). Using the ISO regimen, these investigators determined that levels were 3 to 27 ng generated per cigarette for 1-aminonaphthalene 2 to 17 ng for 2-aminonaphthalene 0.6 to 4.2 ng for 3-aminobiphenyl and 0.5 to 3.3 ng for 4-aminobiphenyl. These levels increased on average by approximately 115 percent when the MDPH smoking regimen was used and by approximately 130 percent under the CAN smoking regimen.

Figure 3.6

Commonly studied aromatic amines in tobacco smoke.

Levels of aromatic amines in tobacco smoke are influenced by both the chemical constituents in the tobacco and the chemical and physical processes of the burning cigarette. Levels of aromatic amines in smoke from cigarettes made with dark tobacco are higher than those in cigarettes made from light tobacco (Luceri et al. 1993). For typical U.S.-blended cigarettes, there is a linear correlation between levels of aromatic amines and tar in the smoke (Stabbert et al. 2003a).

Sources of nitrogen in the tobacco also significantly influence levels of aromatic amines in tobacco smoke. Nitrate is a primary factor in altering the level of aromatic amines in tobacco smoke, and its presence is influenced by the use of nitrogen fertilizers (Patrianakos and Hoffmann 1979 Stabbert et al. 2003a). Protein in tobacco is known to be a good source of biologic nitrogen, and studies have reported that higher nitrogen content from elevated protein in tobacco increased the yields of 2-naphthylamine and 4-aminobiphenyl (Patrianakos and Hoffmann 1979 Torikai et al. 2005). Cigarette smoke from bright tobacco had lower aromatic amine levels than expected compared with the smoke of U.S. blended cigarettes, possibly because of the lower nitrogen content in bright tobacco (Stabbert et al. 2003a). Combustion temperature is also a factor in the generation of aromatic amines in tobacco smoke, because lower temperatures yielded lower levels of aromatic amines in smoke (Stabbert et al. 2003b). Other investigators have suggested that increased cellulose levels in tobacco can decrease aromatic amines in the smoke (Torikai et al. 2005), and in another study, celluloseacetate filters removed a substantial portion of aromatic amines from mainstream smoke (Luceri et al. 1993).

In summary, it appears that the nitrogen content in tobacco, either from protein levels or use of nitrogen fertilizer, is a primary determinant of aromatic amine levels in tobacco smoke. The type of tobacco used in the cigarette filler also alters these levels in tobacco smoke.

Heterocyclic Amines

Heterocyclic amines (HCAs) are a class of chemical compounds that contain at least one cyclic ring and an amine-substituted ring. HCAs act as basic compounds because of the amine functional group. HCAs can occur in food stuff, such as grilled meats, poultry, fish, and tobacco smoke (Sugimura et al. 1977 Sugimura 1997 Skog et al. 1998 Murkovic 2004). HCAs are classified in two groups: one is produced by the pyrolysis of amino acids and proteins through radical reactions, and the other is generated by heating mixtures of creatinine, sugars, and amino acids (Sugimura 1997 Murkovic 2004). The first group dominates when the pyrolysis temperature is high, whereas the second group is predominant at low temperatures commonly used to cook meat (Sugimura 1997). In tobacco smoke, the primary HCAs are 2-amino- 9H-pyrido[2,3-b]indole 2-amino-3-methyl-9H-pyrido[2, 3-b]indole 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) 2-amino-3-methylimidazo[4,5-f]quinoline 2-amino- 6-methyldipyrido[1,2-a:3′,2′-d]imidazole (Glu-P-1) 2-aminodipyrido[1,2-a:3′,2′-d]imidazole and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (Figure 3.7) (Kataoka et al. 1998).

Figure 3.7

Primary heterocyclic amines in tobacco smoke.

HCAs are not found in unburned tobacco they are present in tobacco smoke as a result of pyrolysis and are found in the particulate phase (Manabe and Wada 1990). The chemical composition of amino acids, protein, sugars, and creatine/creatinine in the tobacco filler influences the final HCA levels in the smoke. Other components that may alter the pyrolysis of amino acids can also change HCA levels in smoke. The usual levels of HCAs in tobacco smoke were reported to be 0.3 to 260.0 ng generated per cigarette (Hoffmann et al. 2001). Manabe and Wada (1990) reported levels of 0.29 to 0.31 ng of Trp-P-1 generated per cigarette and 0.51 to 0.66 ng for Trp-P-2 in smoke condensate from five types of cigarettes. Manabe and colleagues (1991) determined an average level of 16.4 ng generated per cigarette for PhIP in tobacco smoke condensate from cigarettes purchased in Japan, the United Kingdom, and the United States.

In summary, although HCAs are not specific to tobacco products, they are found at levels in tobacco smoke particulate that must be considered when assessing the harm from the use of burned tobacco. The concentration of nitrogen-containing compounds in tobacco influences the levels of HCAs that are found in the smoke, and reducing the nitrogen content may be a means of reducing HCAs.

Effect of Additives on Tobacco Smoke

Chemical additives are introduced into cigarette tobacco for a variety of specific purposes, including pH adjustment, maintenance of moisture (humectants), amelioration of the harshness of smoke, control of the burn rate, and impartation of desirable flavor to the smoke (Penn 1997). The taste and flavor of cigarette smoke is affected primarily by the tobacco blend and is further modified with additives. Specific additives are applied to mask the harshness of lower-quality tobacco (World Tobacco 2000). Early in the processing of burley and flue-cured tobaccos, a solution called �sing” is added to the shreds of tobacco lamina. The casing is a slurry containing humectants (e.g., glycerol and propylene glycol) and flavor ingredients with low volatility (e.g., cocoa, honey, licorice, and fruit extracts) that lend a pleasant aroma. After the tobacco is aged, a top-flavoring solution is added to the finished cigarette blend. Top flavoring is generally an alcohol- or rum-based mixture containing volatile compounds (e.g., menthol) and other ingredients (e.g., aromatic compounds, essential oils, and extracts) that are added immediately before packaging (Penn 1997 Fisher 1999).

Even though the specific ingredients added to individual cigarette brands are proprietary, a collective list of 599 additives used in U.S. cigarettes has been published on the World Wide Web (Indiana Prevention Resource Center 2005). The � list” contains individual chemical compounds and complex additives, such as essential oils, juices, powders, oleoresins, and extracts. Included in the list are complex natural extracts and essential oils, such as anise, cassia, cedarwood, chocolate, cinnamon, ginger, lavender, licorice, nutmeg, peppermint, valerian, and vanilla. The list also includes individual organic chemical compounds, such as 1-menthol, 3-methyl pentanoic acid, anethole, β-caryophyllene, caffeine, ethyl acetate, γ-decalactone, isoamyl acetate, methyl cinnamate, sucrose, and vanillin. The compounds in the 599 list have been approved by the U.S. Food and Drug Administration as generally recognized as safe for use in foods (Hoffmann and Hoffmann 1997). Virtually any material with this approval as a food additive is used in cigarette manufacturing (World Tobacco 2000). However, this use is based on the broad assumption that additives designated as safe for ingestion are safe to burn and inhale in cigarette smoke. Because of the detoxifying action of the liver on blood coming directly from the digestive tract and the movement of blood from the lungs into the general circulation without first passing through the liver, the toxic effects associated with ingesting a compound can differ from the toxic effects of breathing it. Studies indicated that eugenol, a compound found in many natural extracts and used as an additive in clove cigarettes, had an LD50 200 times lower in Fischer rats when administered intratracheally compared with gavage (LaVoie et al. 1986). Although this did not simulate inhalation, it did raise concern about increased toxicity of this compound to the lung.

Cigarette tobacco is a complex physicochemical mixture containing several types of tobacco and numerous additives (Hoffmann and Hoffmann 1997). The flavor compounds in tobacco can be transferred into the smoke by distillation, combustion, or pyrolysis (Green et al. 1989). Newly emerging flavored �ssert” cigarettes marketed under names such as Midnight Berry, Mandarin Mint, and Mocha Taboo (Carpenter et al. 2005) may represent new sources of exposure to harmful substances, but the qualitative and quantitative differences in smoke from these cigarettes have not been described.

One of the most common tobacco additives is menthol, a monoterpene alcohol (Burdock 1995) first used in cigarettes in the mid-1920s (Reynolds 1981) and subsequently added to most cigarettes (Eccles 1994). Natural sources of menthol include plants in the mint family, namely, peppermint (Mentha piperita) and corn mint (Mentha arvensis) (Burdock 1995). Flavorants derived from natural sources generally contain a mix of compounds, in contrast to flavoring compounds that are chemically synthesized. If menthol added to the tobacco is derived from natural sources, such as peppermint, constituents such as pulegone may also be present at low concentrations. Submicrogram concentrations of pulegone (0.024 to 0.29 μg/g) were measured in 12 mentholated brands but were not detected in nonmentholated brands (Stanfill and Ashley 1999). Menthol can be added on the tobacco, the filter, or the foil pack (Wayne and Connolly 2004). Menthol levels in smoke have ranged between 0.15 and 0.58 mg generated per cigarette for several brands (Cantrell 1990). Unlike most nonmentholated cigarettes, menthol cigarettes usually contain more flue-cured and less burley tobacco, along with reconstituted tobacco made without added ammonia.

Although they generally are regarded as safe for use in foods, certain flavor-related chemicals added to cigarettes and found in cigarette smoke (Stanfill and Ashley 1999) have known toxic properties. In an analysis of 12 flavor compounds in tobacco fillers from 68 U.S. cigarette brands, concentrations of compounds were 0.0018 to 43.0 μg/g (Stanfill and Ashley 1999). Also, 62 percent of the 68 brands contained detectable levels of 1 or more of the 12 flavor compounds. Piperonal and myristicin were present at the highest concentrations. Anethole, myristicin, and safrole were found in 20 percent or more of the brands pulegone, piperonal, and methyleugenol were each present in at least 10 percent of the brands. In four brands, safrole, myristicin, and elemicin were found together, which strongly suggests the presence of flavorings such as nutmeg or mace (Myristica fragrans) in the tobacco. Coumarin is a benzopyrone compound found in the tobacco of one menthol brand at a concentration of 0.39 μg/g. Pulegone, a monoterpene ketone found in peppermint, was present only in mentholated brands. Tentative identification of other compounds suggested the use of flavor agents such as cinnamon and ginger (Stanfill and Ashley 1999). In addition to tobacco analysis, mainstream smoke particulates from several brands were also analyzed for six flavor compounds: eugenol, isoeugenol, methyleugenol, myristicin, elemicin, and piperonal (Stanfill and Ashley 2000). Levels of these compounds in the smoke from eight U.S. cigarette brands were 0.0066 to 4.21 μg generated per cigarette. The measurements suggested that a portion of eugenol and isoeugenol in smoke from some cigarettes could be a by-product of the burning tobacco. Also, when filter ventilation holes in the cigarette were partially or fully blocked, the transfer of these compounds from tobacco filler to mainstream smoke particulates increased twofold to sevenfold.

In summary, the impact of flavor-related additives on the toxicity, carcinogenicity, and addictive properties of tobacco products has not been thoroughly studied. In addition to the known harmful properties of these compounds, they may potentiate the effects of other known smoke constituents or alter the way people smoke cigarettes. These additives may also increase the initiation and continuation of smoking in the population.

Delivery of Chemical Constituents into Tobacco Smoke

Various tobacco types are used in the manufacture of cigarettes and other tobacco products. Lamina from bright, burley, and oriental tobacco varieties, along with reconstituted tobacco sheet, is the main filler component used in cigarettes (Hoffmann and Hoffmann 1997). In addition to lamina, cigarette filler often contains puffed or expanded tobacco, tobacco stems, humectants, and various flavor additives (Hoffmann and Hoffmann 1997 Abdallah 2003a). One tobacco variety such as bright can be used, or several varieties can be mixed together in products with specific tobacco blends. Most commercial cigarettes are constructed primarily from bright tobacco or from a blend of mainly bright, burley, and oriental tobaccos, usually referred to as an American blend (Browne 1990). However, a few small geographic areas outside the United States (e.g., France) have regional preferences for cigarettes made exclusively from dark, air-cured tobacco (Akehurst 1981 Tso et al. 1982). Each type of tobacco has unique properties that influence packing density (Artho et al. 1963), burn rate (Muramatsu 1981), tar and nicotine delivery (Griest and Guerin 1977), and flavor and aroma (Davis 1976 Enzell 1976 Leffingwell 1976). Bright tobacco, also known as flue-cured or Virginia tobacco, has lower nitrogen content (i.e., less protein) and higher sugar content than do the other varieties. Burley and Maryland tobaccos are air cured and typically have higher nicotine content but reduced sugar content.

Sakuma and colleagues (1984) measured the smoke components in mainstream and sidestream smoke and found that nitrogen-containing compounds were abundant in smoke from burley tobacco, whereas the non-nitrogen-containing compounds were more abundant in smoke from bright and oriental tobaccos. Oriental tobacco is often included in blended varieties because of its unique aromatic properties (Browne 1990). Cigarettes such as light or ultralight varieties that deliver low yields of tar and nicotine by FTC/ISO machine measurement often contain puffed or expanded tobacco lamina with higher 𠇏illing power” (Kertsis and Sun 1984 Lewis 1990 Kramer 1991), which lowers the density of the tobacco rod, thus lowering the amount of tobacco in each cigarette. Several types of reconstituted tobacco sheet are also used to manufacture cigarettes (Abdallah 2003b).

Development of reconstituted tobacco was an attempt at 100-percent utilization of tobacco (Abdallah 2003b). Stems, ribs, and scrap lamina are combined with various binders and other additives to form a “reconstituted” sheet approximating the physical and chemical characteristics of a tobacco leaf (Browne 1990 Blackard 1997 Abdallah 2003b). A common additive in reconstituted tobacco is diammonium hydrogen phosphate, which is used as a pectin release agent that facilitates cross-linkage to form stable sheet material (Hind and Seligman 1967, 1969 Hind 1968). Reconstituted tobacco sheet containing this additive selectively adsorbs nicotine from surrounding lamina and enriches it in an environment abundant in ammonia precursors (Larson at al. 1980).

The stages of manufacturing a cigarette include processing the tobacco lamina and reconstituted tobacco materials and slicing them into shreds of a specific cut width. Tobacco cut widths vary from approximately 1.5 mm for a coarse cut to 0.4 mm for a fine cut (Hoffmann and Hoffmann 1997). Alternatively, the cut width may be expressed in units of cuts per inch, which range from approximately 14 to 48. Cigarettes made from fine-cut tobacco have faster static burn rates resulting in fewer puffs (Resnik et al. 1977). A consequence of using tobacco filler with a fine-cut width is that the ratio of filler surface area to void volume increases and may increase the efficiency of the tobacco column to filter large aerosol particles (Keith and Derrick 1960).

The papers used in cigarettes are generally flax or linen fiber and may contain additives (Browne 1990). Salts often are added to the cigarette paper as optical whiteners to achieve a target static burn rate and to mask the appearance of sidestream smoke (Schur and Rickards 1960 Owens 1978 Durocher 1984). A key physical property of the paper wrapper is its porosity. Papers with high porosity facilitate diffusion of gases in and out of the tobacco rod (Newsome and Keith 1965 Owen and Reynolds 1967). Volatile smoke constituents such as CO readily diffuse through a porous wrapper, so delivery to the smoker is lower than that with less volatile constituents. High-porosity papers also permit more O2 to diffuse inward, which increases the static burn rate and the air-flow through the tobacco column that dilutes the smoke. A faster-burning cigarette yields fewer puffs, reducing tar and nicotine delivery per cigarette (Durocher 1984). Porosity of the paper, filler cut width, filter efficiency, and tobacco density all make important contributions to reduction of pressure drop in the tobacco rod, which is a key index related to acceptance by smokers (Norman 1999). Smokers prefer a cigarette on which they do not have to draw too hard because of changes in pressure drop as a result of design. A separate but related parameter, filter pressure drop, is directly related to smoke delivery and filter efficiency (Norman 1999).

In 2006, cigarette lengths generally fell into one of four categories in the U.S. market: king-size filter cigarettes (79� mm accounting for 62 percent of the market) long (94� mm 34 percent of the market) ultra long (110� mm 2 percent of the market) and regular, nonfilter cigarettes (68� mm 1 percent of the market) (FTC 2009). The usual diameter of a conventional cigarette is 7.5 to 8.0 mm (Norman 1999), although some “slims” have diameters of 5 to 6 mm. The amount of tobacco consumed varies with the circumference of the cigarette, and in cigarettes with smaller circumference, delivery of constituents in the smoke to the smoker decreases accordingly (Ohlemiller et al. 1993). The greater surface of the wrapper in long cigarettes increases the opportunity for gaseous diffusion out of the cigarette, which can (1) reduce delivery of highly volatile constituents of mainstream smoke to the smoker, but increase delivery to the nonsmoker and (2) increase the static burn rate as more O2 diffuses inward (Moore and Bock 1968). However, long cigarettes generally facilitate delivery of higher tar and nicotine levels, because more tobacco mass is burned.

Before the 1950s, most cigarettes were about 70 mm long and unfiltered (Hoffmann and Hoffmann 1997). The addition of a filter tip to a cigarette can greatly reduce delivery of many chemical constituents of mainstream smoke as determined by the FTC/ISO machine-smoking method (Fordyce et al. 1961 Williamson et al. 1965). This reduction was attributed to filtering of the smoke particulate and reducing the amount of tobacco in each cigarette. Cost savings are also achieved because the filter material is less expensive than the tobacco (Browne 1990). Filters provide a firm mouthpiece and permit the smoker to avoid direct contact with the tobacco. Cigarettes with modern cellulose-acetate filter tips gained about 96 percent of the market share by the 1970s (Hoffmann and Hoffmann 1997). In the United States, cellulose-acetate filter tips are the most popular and can selectively remove certain constituents of the smoke, including phenols and alkylphenols (Hoffmann and Wynder 1963 Spears 1963 Baggett and Morie 1973 Morie et al. 1975). Typically, a bonding agent such as triacetin or glycerol triacetate is used to facilitate filter manufacturing (Browne 1990). The filtration efficiency is proportional to the length, diameter, size, and number of fiber strands and the packing density of the cigarette (Keith 1975, 1978 Eaker 1990). Flavoring agents or other materials can also be incorporated into the filter design.

Extensive research from the 1960s has examined the use of activated charcoal in the cigarette filter to efficiently remove volatile compounds (Newsome and Keith 1965 Williamson et al. 1965 Keith et al. 1966). The addition of activated charcoal significantly reduced levels of volatile compounds, such as formaldehyde, cyanide, and acrolein (Williamson et al. 1965 Spincer and Chard 1971). Charcoal filters reduced the delivery of H2S to mainstream smoke (Horton and Guerin 1974). Both cellulose-acetate and charcoal filters removed some of the volatile pyridines (Brunnemann et al. 1978). Coatings with metallic oxides were extremely efficient at removing acidic gases (Keith et al. 1966). Filter designs can also be tailored to selectively pass and not trap certain classes of targeted compounds. For instance, inclusion of alkaline materials in the filter inhibits filtration of gaseous nicotine (Browne 1990).

One key technology used to reduce FTC/ISO machine-measured tar and nicotine delivery is the inclusion of microscopic ventilation holes in the paper wrapper (Harris 1890) or the filter paper. These holes cause the mainstream smoke to become diluted with air (Norman 1974). Filter ventilation holes are usually located in one or more rings about 12 mm from the mouth end of the filter (Baker and Lewis 1997). The amount of filter ventilation ranges from about 10 percent in some full-flavored varieties to 80 percent in brands measured as having very low delivery by using the FTC smoking regimen (CDC 1997). Filter ventilation also contributes to control of the burn rate (Durocher 1984). The tiny perforations can be made by mechanical means, electrostatic sparking, or laser ablation. Paper permeability can also be used to increase air dilution, although as the cigarette is consumed, this effect becomes less important. Delivery of lower levels of the constituents of mainstream smoke, as measured under FTC machine-smoking conditions, occurs when smoke drawn through the cigarette rod mixes and is diluted with air drawn through filter ventilation holes. Under FTC machine-smoking conditions, filter ventilation is highly effective in reducing delivery of chemical constituents (Norman 1974). However, the fingers or lips of smokers may cover vent holes when they smoke cigarettes and reduce the amount of air available for dilution, which results in delivery that is higher than expected (Kozlowski et al. 1982, 1996).

Cigarette smoke is formed by (1) the condensation of chemicals formed by the combustion of tobacco, (2) pyrolysis and pyrosynthesis, and (3) distillation products that form an aerosol in the cooler region directly behind the burning coal (Browne 1990). During a puff, the coal temperature reaches 800ଌ to 900ଌ, and the temperature of the aerosol drops rapidly to slightly above room temperature as it travels down the tobacco rod (Touey and Mumpower 1957 Lendvay and Laszlo 1974). As the smoke cools, compounds with lower volatility condense first, and many of the very volatile gaseous constituents, such as CO, remain in the gas phase. The cooler tobacco rod acts as a filter itself, and some portions of the smoke condense (Dobrowsky 1960) as the smoke is drawn through the tobacco column during a puff.

Torikai and colleagues (2004) examined the influence of the temperature, the pyrolysis environment, and the pH of the tobacco leaf on the formation of a wide variety of constituents of tobacco smoke. Their findings showed that, in general, the yields of the chemical constituents in tobacco smoke that present health concerns increased as the temperature increased from 300ଌ to 1,000஬, but some compounds (e.g., acrolein and formaldehyde) reached their maximum yield at 500஬ and the yield remained approximately the same at higher temperatures. The presence of O2 in the pyrolysis atmosphere increased the yield of acrolein and other volatile organic compounds but lowered the levels of cyanide, phenol, and 1-aminonaphthalene. The pH of the tobacco had a mixed effect on the levels of toxic chemicals in tobacco smoke. Levels of B[a]P, cyanide, quinoline, resorcinol, and acrylonitrile increased with a lower pH, and hydroquinone and 1-naphthylamine levels increased with higher pH. The effects of the pH and pyrolysis atmosphere combine to influence the radical reactions that generate many constituents in tobacco smoke.

In summary, design features of the cigarette have a major influence on the yield of the constituents in smoke. Altering the tobacco blend, filter type and length, cut width, paper porosity, ventilation, and chemical additives alters the levels of many constituents of smoke.

Delivery of Chemicals to Smokers

In addition to cigarette design, the major factors that influence the delivery of chemicals to smokers are characteristics of puffing (puff volume, duration, and frequency), cigarette length smoked, and blocking air dilution holes on the filter tips of ventilated cigarettes (e.g., with the mouth or fingers). Testing cigarettes by using smoking machines or smokers in a laboratory setting can elucidate how certain design factors and smoking characteristics can influence the chemical components in smoke. However, the results obtained in a laboratory cannot be directly applied to populations of smokers because many factors influence the way a person smokes each cigarette.

In a laboratory setting, Fischer and colleagues (1989a) investigated the influence of smoking parameters on the delivery of TSNAs in mainstream smoke for six cigarette brands. The research included filter-tipped cigarettes with very-low-to-medium ISO/FTC yields of constituents of smoke and unfiltered cigarettes with high and very high ISO smoke yields. The major finding was that the puff profile and duration had no remarkable influence on TSNA delivery, but puff volume and frequency significantly increased TSNA yields. The dependency of TSNA delivery on the volume of smoke emitted from one cigarette (puff volume × number of puffs) was almost linear up to a total volume of approximately 500 mL. TSNA yield was equivalent for the same total volume whether the total volume was from a change in puff volume or puff frequency. Thus, the total volume drawn through a cigarette was the main factor responsible for delivery of TSNAs in mainstream smoke.

In another study, average levels of tar, nicotine, and CO per liter of smoke and per cigarette were determined for 10 brands of cigarettes smoked under 27 machine-smoking conditions (Rickert et al. 1986). Yields per cigarette were highly variable across smoking conditions, because of differences in the total volume of smoke. The results of a simple linear regression analysis indicated that up to 95 percent of the variation in tar yield per cigarette could be explained by variation in the total volume of smoke produced per cigarette. Puffing behavior (topography), especially the interpuff interval and total smoke volume per cigarette, which were influenced by puff volume, number of puffs, and length of the cigarette smoked, were the primary determinants of blood levels of constituents of cigarette smoke (Bridges et al. 1990).

The influence of machine-smoking parameters on levels of chemical constituents measured in smoke is well illustrated in the work of Counts and colleagues (2005). This research was performed according to the ISO, MDPH, and CAN regimens described earlier. The study examined levels of 44 chemicals emitted in cigarette smoke. Not surprisingly, the more intense smoking regimens resulted in higher levels of constituents in cigarette smoke. However, in some cases, the emissions of the constituents did not maintain their relative levels as a result of different burning properties of the tobacco under different regimens and because of breakthrough in charcoal filters in the more intense smoking regimens. Because the intensity of smoking changes, the delivery of chemicals to the smoker varies and cannot be assessed by using a single smoking regimen.

In studies of 129 female and 128 male smokers of contemporary cigarettes, Melikian and colleagues (2007a,b) reported data on smoking topography and exposure to toxic substances in mainstream smoke of cigarettes that deliver a wide range of nicotine as reported by the FTC/ISO method. Exposure was determined by the delivered dose and urinary biomarkers. The first study focused on whether differences in gender and ethnicity affect delivered doses of select toxicants in mainstream cigarette smoke, as a result of differences in smoking behavior or type of cigarettes smoked (Melikian et al. 2007b). Smoking topography differed significantly between females and males. Compared with men, women drew more (13.5 versus 12.0 p = 0.001) but smaller puffs (37.6 versus 45.8 mL p = 0.0001) of shorter duration (1.33 versus 1.48 seconds p = 0.002). Women also smoked a smaller portion of the cigarettes (36.3-mm butts [40.2 percent of cigarette length] versus 34.3-mm butts [39.2 percent of cigarette length] p = 0.01). Although smoke volume per cigarette did not differ between women and men (p = 0.06), the daily dose of smoke was significantly higher in men (9.3 versus 8.0 liters [L] p = 0.02), because men consume a greater number of cigarettes per day.

When data were stratified by race, no difference was found in puffing characteristics between European American and African American female and male smokers, except that African American women and men smoked equal lengths of the cigarettes (34.5- versus 33.9-mm butts p = 0.93). However, African Americans smoked fewer cigarettes, so the daily smoke volume was significantly higher among European American smokers (8.61 versus 7.45 L for women 10.6 versus 7.8 L for men). The emissions of select toxicants per cigarette, as determined by use of machine-smoking regimens that mimicked each smoker, were consistently greater among male smokers than among the female smokers, and they correlated significantly with delivered smoke volume per cigarette. The geometric means of emissions of nicotine from cigarettes were 1.92 mg per cigarette for women versus 2.2 mg for men (p = 0.005). Cigarettes smoked by women yielded 139.5 ng of NNK per cigarette compared with 170.3 ng for men (p = 0.0007). B[a]P emissions were 18.0 ng per cigarette for women and 20.5 ng for men (p = 0.01). Differences between women and men in delivery of toxicants in cigarette smoke to the smoker were more profound in European Americans than in African Americans. On average, African American men’s smoking behavior produced the highest emissions of select toxicants from cigarettes, and European American female smokers received the lowest amounts of toxicants.

The second study by Melikian and colleagues (2007a) investigated urinary concentrations of biomarkers in relation to levels of select toxicants in mainstream cigarette smoke, as determined by using machine-smoking regimens that mimicked the smoking behavior of each smoker. In this study of 257 smokers, the researchers determined levels of nicotine, NNK, and B[a]P in mainstream smoke and concentrations of the respective urinary metabolites: cotinine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and 1-hydroxypyrene (1-HOP). The smokers were assigned to groups according to the FTC yield of toxic substances in the cigarettes they smoked: low yield (0.1 to 0.8 mg of nicotine generated per cigarette, medium yield (0.9 to 1.2 mg), and high yield (ϡ.3 mg). Concentrations of urinary metabolites, expressed per level of parent compound delivered decreased with increased smoke emissions. In smokers of low-, medium-, and high-yield cigarettes, as measured by FTC methods, the respective ratios of cotinine (nanograms per milligram of creatinine) to nicotine (milligrams per day) were 89.4, 77.8, and 57.1 (low versus high p = 0.06). Ratios of NNAL (picomoles per milligram of creatinine) to NNK (nanograms per day) were 0.81, 0.55, and 0.57 (low versus high p = 0.05). Ratios of 1-HOP (picograms per milligram of creatinine) to B[a]P (nanograms per day) were 1.55, 1.13, and 0.97 (low versus high p = 0.008). Similarly, for smokers who consumed fewer than 20 cigarettes per day, the means of cotinine per unit of delivered nicotine were 3.5-fold higher than those for smokers of more than 20 cigarettes per day. Likewise, a negative correlation was observed between ratios of cotinine to nicotine and delivered doses of nicotine in subgroups of smokers who used the identical brand of cigarettes, namely a filter-tipped, vented Marlboro (r = -0.59), which is a popular brand among European Americans, and Newport (r = -0.37), a menthol-flavored cigarette without filter-tip vents that is preferred by African Americans. The researchers concluded that the intensity of smoking and the mouth levels of smoke constituents significantly affect the concentrations of urinary biomarkers of exposure and should be taken into account in evaluating human exposure to toxic substances in cigarette smoke.

Regarding the influence of cigarette type on urinary biomarkers of exposure to toxic substances in mainstream smoke, there is a slight difference in puff volume and puff frequency among smokers of low-FTC-yield versus medium-FTC-yield cigarettes, as measured under FTC conditions (Djordjevic et al. 2000). Smokers of low-FTC-yield brands drew somewhat larger puffs (48.6 versus 44.1 mL) and inhaled more smoke both per cigarette (615 versus 523 mL) and daily (9.5 versus 8.2 L). However, delivered doses of NNK and B[a]P were marginally higher among smokers of medium-yield cigarettes (NNK: 250.9 versus 186.5 ng per cigarette B[a]P: 21.4 versus 17.9 ng). On the other hand, Hecht and colleagues (2005) found no differences in urinary biomarkers of exposure to NNK and B[a]P among smokers of regular, light, or ultralight cigarettes.

Researchers have also suggested that blocking ventilation holes during smoking can result in increased delivery of smoke constituents. For example, when puff and inhalation parameters were allowed to vary, participants took significantly more and larger puffs from cigarettes with unblocked ventilation than from those with completely blocked ventilation (Zacny et al. 1986 Sweeney et al. 1999). Hoffmann and colleagues (1983) found that blocking air-dilution holes in seven brands of commercial filter-tipped cigarettes increased nicotine yields by 69 percent, tar yields by 51 percent, and CO yields by 147 percent. Another study examined a cigarette brand with tar and nicotine yields of 4.0 and 0.4 mg, respectively, under various conditions of machine smoking intended to reflect the wide range of smoking behaviors (Rickert et al. 1983). The researchers studied three levels of five smoking parameters (butt length, puff duration, puff interval, puff volume, and ventilation occlusion) and the effects on the number of puffs and TPM, and they estimated gas phase, particulate phase, and total yields of HCN. The HCN and TPM yields varied significantly under different smoking conditions. Ventilation occlusion had the most pronounced effect, accounting for 34 percent of the response variation in TPM yields and 42 percent of the response variation in total HCN yields.

Comparison of normal lip contact during smoking, which partially blocked filter vents, and smoking through a cigarette holder, which avoided blocking, showed higher nicotine boosts with normal lip contact (Hr et al. 1991). Exposure to other smoke constituents may vary with the degree of blocking. Sweeney and colleagues (1999) found that blocking the filter vents of cigarettes with ventilation levels of at least 66 percent led to significant increases in CO exposure. The same manipulation of filter vents in cigarettes with filter ventilation levels of 56 percent or lower appeared to have negligible consequences for CO exposure. In another report, CO exposure from completely blocked filter vents was twice as high as from the unblocked vents (8.96 versus 4.32 parts per million [ppm]) (Zacny et al. 1986). Blocking filter vents also resulted in higher CO exposure in a study by Hr and associates (1991). Blocking filter ventilation holes is not the only element of smoking topography that influences filter efficiency. More rapid or intense puffing increases flow rates, which results in less effective filtration, because the smoke passes through the tobacco column and filter material more quickly with less opportunity for adsorption on the filter’s fibers. This smoking behavior also reduced the time for highly volatile gaseous materials to diffuse outward through the cigarette’s paper wrapper.

An 𠇎lastic” cigarette is one that shows low levels of tar and nicotine when it is tested on a smoking machine but can potentially yield higher levels of emissions to smokers (Kozlowski et al. 2001). When cigarettes are elastic, smokers can extract as much nicotine as they need by changing their pattern of puffing on the cigarette. Analysis of tobacco from commercial American blend cigarettes purchased in the United States in 1990 revealed that the nicotine content did not differ substantially among brands that delivered a wide range of FTC-measured yields (Kozlowski et al. 1998). This cigarette design allowed delivery of virtually any amount of nicotine, depending on puffing behavior. Because there are similar amounts of other constituents in tobacco (e.g., TSNAs, metals, nitrates, and nitrites), regardless of the FTC ranking of the cigarette brand, more intense smoking to obtain a desired dose of nicotine leads to higher exposure to carcinogens. Historically, smokers have refused to use brands designed to reduce delivery of nicotine. For example, one company experimented with a modified cigarette containing denicotinized tobacco and a tar yield of 9.3 mg generated per cigarette but a nicotine yield of only 0.08 mg, as determined by using the FTC regimen, but this product was not successfully marketed (Rickert 2000).

Not all of the smoke volume delivered in the puff is inhaled by the smoker. Some escapes during mouth holding before inhalation. The depth of inhalation may be important for some smoke constituents but not for others, which is not surprising because of the complexity of the physics related to particle size that is involved with smoking and respiration. Finally, even very brief breath holding at peak inspiration can theoretically contribute to increased diffusion of some smoke constituents across alveolar membranes, as the intra-alveolar pressure increases.

There are considerable individual differences in inhalation patterns. In one study, inhaled smoke volume was measured by tracing the smoke with an isotope of the inert gas krypton (Woodman et al. 1986). The percentage of inhaled smoke (total inhaled smoke volume per total puff volume) averaged between 46 and 85 percent among persons in the study. Neither the mean inhaled smoke volume per puff nor the total inhaled smoke volume per cigarette was significantly correlated with any of the indices for puffing.

Evidence on the importance of inhalation patterns to total smoke exposure is mixed (Woodman et al. 1986 Zacny et al. 1987 Zacny and Stitzer 1996). Variations in results may be related to the small number of persons tested and to the difficulties inherent in accurately capturing the relationship between puffing indices and total inhaled smoke. Methods used include pneumography using a mercury strain gauge, whole-body (head and arms out) plethysmography, impedance plethysmography, inductive plethysmography, and inert gas radiotracers. The method most commonly used in U.S. laboratories that study smoking is inductive plethysmography, in which chest and abdominal expansions are measured by bands applied around the rib cage and the abdomen. Significant practical limitations include difficulties in accurate calibration of the systems and adequate integration of chest and abdominal expansions, especially because men tend to have greater abdominal expansion than women do. Measurement artifacts created by movement during measurement are another limitation. Studies of the accuracy of the systems have shown fair results in adults (Zacny et al. 1987). Errors in volume measurements were typically approximately 100 mL over a large number of respiratory cycles. Unfortunately, the attributes of the systems have not been well studied for the puff-by-puff evaluation of human smoking behaviors. In addition, the most useful information will come from integrating puff analyses with inhalation parameters on a puff-by-puff basis to assess mouth holding and breath holding at peak inhalation. Studies such as those cited above have shown that mechanical testing regimens cannot mimic the way people smoke cigarettes. These findings suggest the importance of expressing the levels of toxic constituents as a ratio with nicotine or puff volume in the denominator (Rickert et al. 1985 Burns et al. 2008).

The size of particles containing chemical species can affect their retention in the lung. Cigarette smoke is an aerosol formed as the vapors generated in the pyrolysis zone cool and condense. Cigarette design has been shown to control particle-size distribution in an aerosol, so particles become easier or more difficult to inhale (Str 1982 Ingebrethsen 1986 McRae 1990 Wayne et al. 2008). Burning finer-cut tobacco creates an aerosol with smaller particles, which are easier to inhale. Thus, changing the filler cut width can change the distribution of particle size in the aerosol and the chemistry. Particle size is also altered by air dilution. Dilution reduces the aerosol concentration and, thus, the coagulation rate. The particle size of the smoke is increased by increasing the coagulation rate or by condensing the moisture produced during combustion onto the smoke particles. According to Ishizu and colleagues (1987), the timed average particle size (equivalent diameter) for major chemical components in tobacco smoke was 0.03 to 0.5 μm, and constituents with higher boiling points tended toward larger particle sizes. Very small particles are more likely to be retained in the lungs. The overall equivalent diameter of particles of crude tar in tobacco smoke was 0.21 μm. Nicotine was usually present in small particles (e.g., 0.08 μm). Particle size influences how fast chemicals are transferred to tissue. Particles larger than 0.3 μm are more likely than smaller particles to be absorbed in the mouth and throat than in the lungs (Wayne et al. 2008).

Accurate measurement of particle size distribution in cigarette smoke is important for estimating deposition in the lung (Anderson et al. 1989). Most earlier studies (1960�) reported a median diameter of 0.3 to 0.5 μm, including a few ultrafine particles (π.1 μm). Using the electrical aerosol analyzer, Anderson and colleagues (1989) reported similar values for median diameter (0.36 to 0.4 μm) for the particles emitted in smoke from U.S. commercial filter-tipped cigarettes. But, there were also distinctly smaller particles, with a median diameter of 0.096 to 0.11 μm. This finding indicated the presence of many more ultrafine particles in the smoke than was previously recognized. It is notable that the low- and ultralow-yield filter-tipped cigarettes Merit and Carlton emitted smaller particles than did the full-flavored Marlboro cigarettes. Ultrafine particles are of toxicologic importance because their deposition in the respiratory tract was significantly higher than that of the 0.3- to 0.5-μm particles. Also, the relatively large surface-to-volume ratio of the ultrafine particles could facilitate adsorption and delivery of potentially toxic gases to the lung.

An alternative analysis of the impact of particle size on deposition in the lung suggested that growth in particle size may accelerate deposition in the respiratory tract (Martonen and Musante 2000). Because of their hygroscopicity, inhaled smoke particles may grow to several times their original diameter. This study suggested that mainstream cigarette smoke could behave aerodynamically as a large cloud (e.g., 20 μm in diameter) rather than as submicrometer constituent particles. The effect of cloud motion on deposition is pronounced. For example, an aerosol with a mass median aerodynamic diameter of 0.443 μm and a geometric standard deviation of 1.44 would have the following deposition fractions: lung, 0.14 tracheobronchial, 0.03 and pulmonary, 0.11. When cloud motion is simulated, the total deposition is concentrated in the tracheobronchial compartment, especially in the upper bronchi, and pulmonary deposition is negligible. Cloud motion produces a heterogeneous deposition resulting in increased exposure of underlying airway cells to toxic and carcinogenic substances. The deposition sites correlate with the incidence of cancers in vivo.

Although most of the smoke particles deposit in the periphery of the lung, the surface concentrations of deposited particles are not significantly greater in the periphery than in centrally located airways (Muller et al. 1990). Concentrations on the surface of the central airway are relatively independent of breathing patterns and airway geometry. This finding suggests that the effects of deposition of particles from cigarette smoke cannot be greatly reduced by changing the pattern of smoke inhalation. Efforts to manipulate particle size in smoke have been described in greater detail in a report by Wayne and colleagues (2008). Their study draws on internal tobacco company documents to assess industry consideration of the role of smoke particle size as a potential controlling influence over inhalation patterns and exposure of lungs to harmful substances. The researchers reported that tobacco manufacturers evaluated manipulation of particle size to control physical and sensory attributes of tobacco products and to reduce health hazards related to exposure to tobacco smoke. Examples of design features of tobacco products that relate to potential effects on generation of particle size and distribution of particles include puff flow rate, tobaccos and experimental blends, combustion, circumference, rod length, and ventilation (Wayne et al. 2008).

In summary, smoking behavior (puff volume, number of puffs per cigarette, and percentage of ventilation holes blocked) has a major impact on the levels of toxic, carcinogenic, and addictive compounds delivered to the smoker in cigarette smoke. The puffing patterns of smokers vary considerably from person to person. To completely understand the effect of specific harmful chemical constituents on smokers, further research is needed to explore how cigarette design and the chemical makeup of cigarettes influence use of the product.

Effects on the Mouth, Larynx and Pharynx

Hot gases and particulate inhaled during cigarette smoking contact the tissue and mucous membranes that surround the mouth larynx, or voice box and pharynx, or throat. These areas suffer continual irritation from smoking, and tobacco users may develop symptoms such as hoarseness, coughing and wheezing due to inflammation.

As the National Institutes of Health report, cigarette smoke contains more than 60 cancer-causing compounds. The U.S. Surgeon General has linked mouth, larynx and pharynx cancers with tobacco use.

  • Hot gases and particulate inhaled during cigarette smoking contact the tissue and mucous membranes that surround the mouth larynx, or voice box and pharynx, or throat.

Exposure to Tobacco Smoke Causes Immediate Damage: A Report of the Surgeon General

“How Tobacco Smoke Causes Disease” 1 is the 30th tobacco-related Surgeon General's report issued since 1964. It describes the specific mechanisms and pathways by which tobacco smoke damages the human body and leads to disease and death. While previous Surgeon General's reports on tobacco have focused on which diseases are caused by tobacco smoke, this report explains in detail how tobacco smoke damages every cell in the body.

The 700-page report incorporates the contributions of 64 health experts its messages are simple and powerful. The report concludes that any exposure to tobacco smoke, even occasional smoking or exposure to secondhand smoke, causes immediate damage to your body. That damage can lead to serious illness or death. The report describes in detail how tobacco smoke reaches every organ in the body and how it affects those organs.

Tobacco smoke is a toxic mix of more than 7,000 chemicals and compounds. These chemicals and compounds reach a person's lungs quickly every time the person inhales. The blood then carries the toxicants to every organ in the body.

Exposure to tobacco smoke quickly damages blood vessels throughout the body and makes blood more likely to clot. The chemicals in tobacco smoke damage the delicate lining of the lungs and can cause permanent damage that reduces the ability of the lungs to exchange air efficiently. This can ultimately lead to chronic obstructive pulmonary disease, including emphysema.

Many Americans have some degree of coronary heart disease, and often they don't know it until they experience chest pain or present to the hospital. This report found that even brief exposures to tobacco smoke harm blood vessel linings and increase the likelihood of blood clotting. In people with coronary heart disease, this effect could trigger a heart attack.

Chemicals in tobacco smoke cause inflammation and cell damage. The body makes white blood cells to respond to injuries, infections, and cancers. White blood cell counts tend to stay high while a person continues to smoke, as the body is constantly trying to fight against the damage being caused by smoking.

The chemicals and toxicants in tobacco smoke also damage a person's DNA, which can lead to cancer. At the same time, however, smoking can weaken a body's ability to fight cancer. With any cancer𠅎ven a cancer not related to tobacco use—smoking can lessen the benefits of chemotherapy. Exposure to tobacco smoke can, therefore, both cause cancer and make it difficult to stop tumors from growing.

Smoking also makes it harder for people with diabetes to regulate their blood sugar. That's why smokers with diabetes have a higher risk of kidney disease, peripheral arterial disease, eye disease, and nerve damage that can result in amputations, poor vision, and even blindness.

It is never too late to quit smoking. When smokers quit, the risk for a heart attack drops sharply after just one year of not smoking. Stroke risk can fall to about the same level as a nonsmoker's risk after two to five years of being smoke-free. Risks for cancer of the mouth, throat, esophagus, and bladder are cut in half five years after quitting smoking. And the risk of dying from lung cancer drops by half after 10 years of being smoke-free.

The report confirms that tobacco smoke is addicting, and determines that cigarettes are designed for addiction. Nicotine is the key chemical compound responsible for the powerful addicting effects of cigarettes, but many ingredients (e.g., sugar and moisture enhancers) are added to reduce harshness and improve taste and consumer appeal. Chemical ingredients (e.g., ammonia) convert the nicotine into what is called 𠇏ree nicotine,” which more quickly crosses the blood brain barrier. Ventilation holes in filters make smoke easier to inhale deeply into the lungs and also convert more of the nicotine into free nicotine. These design features work together to enhance the addictive “kick” and pleasure a smoker feels. Today's cigarettes deliver nicotine and chemicals more quickly to the brain.

Evidence suggests that psychosocial, biological, and genetic factors may also play a role in tobacco addiction. In addition, adolescents may be more sensitive to nicotine and more easily addicted than adults. This helps explain why about 1,000 teenagers become daily smokers each day, and why it often takes several attempts to quit. 2

Tobacco use in the U.S. has declined by almost half since the first Surgeon General's report on tobacco was released in 1964. However, since 2003, smoking rates have not declined. One in five American adults continues to smoke, as do one in five adolescents. Tobacco use remains the leading cause of preventable death in the U.S. and is responsible for more than 440,000 premature deaths each year.

Fortunately, there are things we can do. The U.S. Department of Health and Human Services has developed an action plan called 𠇎nding the Tobacco Epidemic: A Tobacco Control Strategic Action Plan,” 3 with the goal to reach the Healthy People 2020 4 objective of reducing the adult smoking rate from 18.4% to 12.0% by 2020.

We know what works. When we increase the price of tobacco, smoking rates decline. When we enact smoke-free policies, we reduce exposure to secondhand smoke, prompt smokers to quit, change social norms, support healthy decisions, and reduce heart attacks. And when we educate the public with aggressive media campaigns, we inform them of the risk of smoking, encourage tobacco users to quit, and prevent young people from starting.

Evidence shows that smoking rates decline when states implement comprehensive tobacco-control programs, and the longer the investment, the greater and faster the impact. For example, California is home to the longest-running state tobacco-control program in the country. Lung cancer incidence has been declining four times faster in that state than in the rest of the nation. California has the potential to become the first state in which lung cancer is no longer the leading cause of cancer death.

It is important for those of us in public health to note that doctors and other clinicians can play an important role in helping people quit smoking. We know that patients who are advised by their doctors to quit smoking have a 66% higher success rate. We have a responsibility to encourage every patient to stop smoking and to tell them ourselves, not rely on others to do it.


Benowitz, Neal L., ed. Nicotine Safety and Toxicity. New York: Oxford University Press, 1998.

Bolliger, Christoph T., and Karl-Olav Fagerström, eds. The Tobacco Epidemic, Vol. 28. New York: Karger, 1997.

Fiore, M. C., et al. Treating Tobacco Use and Dependence: Clinical Practice Guideline. Rockville, Md.: U.S. Department of Health and Human Services, Public Health Service, 2000.

Gilbert, David G. Smoking: Individual Differences, Psychopathology, and Emotion. Washington, D.C.: Taylor and Francis, 1995.

Kassel, J. D., L. R. Stroud, and C. A. Paronis. "Smoking, Stress, and Negative Affect: Correlation, Causation, and Context Across Stages of Smoking." Psychological Bulletin 129 (2003): 270–304.

Mayhew, K. P., B. R. Flay, and J. A. Mott. "Stages in the Development of Adolescent Smoking." Drug and Alcohol Dependence 59 (2000): Supp. 1: S61–S81.

Orleans, C. Tracy, and John Slade, eds. Nicotine Addiction: Principles and Management. New York: Oxford University Press, 1993.

Shiffman, S., et al. "Smoking Behavior and Smoking History of Tobacco Chippers." Experimental and Clinical Psychopharmacology 2 (1994): 126–142.

Shiffman, Saul, and Thomas A. Wills, eds. Coping and Substance Use. Orlando, Fla.: Academic Press, 1985.

Slovic, Paul, ed. Smoking: Risk, Perception, and Policy. Thousand Oaks, Calif.: Sage, 2000.

U.S. Department of Health and Human Services. Reducing Tobacco Use: A Report of the Surgeon General—Executive Summary. Atlanta, Ga.: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2000.

Wagner, Eric F., ed. Nicotine Addiction Among Adolescents. New York: Haworth Press, 2000.

physiology the study of the functions and processes of the body.

dysphoria a feeling of unhappiness and discomfort being ill-at-ease. Cigarette smokers can experience dysphoria when deprived of cigarettes.