The Toxicology of Cigarette Smoke and Environmental Tobacco Smoke

by

Stephen Mulcahy, 9224076

Report Assignment - Biochemical Toxicology BC4927

Introduction

Cigarette smoke contains over 4,700 chemical compounds including 60 known carcinogens. No threshold level of exposure to cigarette smoke has been defined but there is conclusive evidence to indicate that long-term (years) smoking greatly increases the likelihood of developing numerous fatal conditions.

Cigarette smoking is responsible for more than 85% of lung cancers and is also associated with cancers of the mouth, pharynx, larynx, oesophagus, stomach, pancreas, uterine cervix, kidney, ureter, bladder and colon. Cigarette smoking has also been linked to Leukaemia. Apart from the carcinogenic aspects of cigarette smoking, links to increased risks of cardiovascular diseases (including stroke), sudden death, cardiac arrest, peripheral vascular disease and aortic aneurysm have also been established. Many components of Cigarette smoke have also been characterised as Ciliotoxic materials that irritate the lining of the respiratory system resulting in increased bronchial mucus secretion and chronic decreases in pulmonary and mucociliary function.

A 1992 report by the Environmental Protection Agency (EPA) examined the effects of Passive Smoking (also known as Environmental Tobacco Smoke (ETS) or Second-hand smoke) and concluded that it posed a similar risk to direct cigarette smoking. The report actually resulted in cigarette smoke being classified as a "group A" carcinogen by the EPA, a category reserved for the more potent known human carcinogens.

Cigarette smoke itself may be broken down into two categories of smoke - Mainstream smoke (MS) and Sidestream smoke (SS). MS is that smoke which is inhaled by the smoker from the cigarette during a puff. SS is that smoke which is emitted by the burning cigarette between puffs. The chemical compositions of both types of smoke are qualitatively similar since they are both derived from burning tobacoo, however, there are some significant quantitative differences between MS and SS. The temperature at which MS is formed is much higher than the temperature at which SS is formed, since the smoker is actively inhaling from the cigarette during the generation of MS. A result of this is that SS contains larger quantities of many organic chemical compounds than MS. One study has tentatively suggested that SS may be more carcinogenic than MS at the same concentrations.

Regulations governing Cigarette smoking have been increasingly strict since July 1957, when Dr. Leroy E. Burney (US Surgeon General) issued the first Public Health services statement on cigarette smoking - smoking was identified as a cause of lung cancer. This observation was based more on epidemiological data than specific scientific evidence that identified carcinogenic materials in cigarette smoke, however research in the last 30 years has confirmed the epidemiological observations made previously. ETS has become the latest aspect of cigarette smoking to come under regulation with the realisation that ETS does contribute to increased risk of lung cancer amongst exposed non-smokers. Most US states have legislation controlling or restricting smoking in public areas including restaurants. Many states have or are implementing complete bans on smoking in or within the vicinity of public areas, while many businesses have adopted non-smoking policies. In Ireland, legislation has not reached the same level, but it is inevitable and currently, the Public Health Act restricts smoking in public areas and on public transport services.

Cigarette Smoke Chemical constituents

As mentioned previously, cigarette smoke contains over 4,700 chemical compounds of which about 60 are carcinogenic. The following tables, sourced from US Surgeon General Reports on the Health Consequences of smoking summarise the toxic components of cigarettes.

Primary Toxic and Carcinogenic components of Cigarette Smoke including vapour-phase and particulate phase components
Agent Toxic Ciliotoxic Carcinogenic Co-carcinogenic
/ Promoter
Carbon Monoxide x
Nitrogen Oxides (NOx) x
Hydrogen Cyanide x x
Formaldehyde x x
Acrolein x
Acetaldehyde x
Ammonia x
Hydrazine x
Vinyl Chloride x
Urethane x
2-Nitropropane x
Quinoline x
Benzo[a]pyrene x x
Dibenz[a,h]anthracene x x
Benzo[b]fluoranthene x x
Benzo[j]fluoranthene x x
Dibenzo[a,h]pyrene x x
Dibenzo[a,i]pyrene x x
Dibenz[a,j]acridine x x
Indeno[1,2,3-cd]pyrene x x
Benzo[c]phenanthrene x x
Benz[a]anthracene x x
Benzo[e]pyrene x x
Chrysene x x
Methylchrysene x x
Mehtylfluoranthene x x
Dibenz[a,c]anthracene x x
Dibenz[a,h]acridine x x
Dibenzo[c,g]carbazole x x
Mehtylnaphtalenes x
1-Methylindoles x
Dichlorostilbene x
Catechol x
3-Methycatechol x
4-Methycatechol x
4-Ethycatechol x
4-n-Propylcatechol x
Nitrosodimethylamine x
Nitrosoethymethylamine x
Nitrosodiethylamine x
Nitrosodi-n-propylamine x
Nitrosodi-n-butylamine x
Nitrosopyrrolidine x
Nitrosopiperidine x
Nitrosomorpholine x
N'-Nitrosonornicotine x
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone x
N'-Nitrosoanabasine x
N'-Nitrosoanatabine x
Aromatic Amines x
Aromatic Nitrohydrocarbons x
Polonium-210 x
Nickel x
Arsenic x
Cadmium x

While it is not possible to examine all the compounds and their respective toxicological effects, this report will focus on the primary carcinogens found in cigarette smoke. The primary cancer causing agents found in cigarette smoke may be broadly categorised as follows,

Carcinogenic

Promoters

Co-carcinogens / Potentiators (not present in Cigarette smoke)

Polycyclic Aromatic Hydrocarbons (PAH)

Aromatic compounds that have rings which share at least one side are described as Fused-ring systems or Polycyclic Aromatic Hydrocarbons. There are many PAHs in cigarette smoke including Benzo[a]pyrene, Dibenz[a,h]anthracene and Benz[a]anthracene (see table).

These are reactive compounds that tend to form epoxides when metabolised becoming extremely genotoxic. They act as tumour initiators. Benzo[a]pyrene is a particularly good example of a cigarette smoke PAH which has been studied extensively. About 40 of it's oxygenated metabolites have been isolated and characterised with at least one of them being a potent mutagen. The resulting epoxide metabolite, benzo[a]pyrene-7,8-diol-9,10-epoxide forms an adduct with DNA in mouse embryo cells, indicating that the diol-epoxide is the metabolic intermediate responsible for reacting with DNA.

N-nitrosamines

N-nitrosamines are formed by the nitrosation of amines. Cigarette smoke contains two major types of N-nitrosamines, Volatile N-nitrosamines (VNA) and Tobacoo Specific N-nitrosamines (TSNA). Practically all Volatile N-nitrosamines are retained by the respiratory system upon cigarette smoke inhalation. Typical cigarette smoke VNAs include N-nitrosdiethylamine (NDEA) and N-nitrosodimethylamine (NDMA), both of which are classified as potent environmental carcinogens.

As of the International Agency for Research on Cancer's (IARC) 1986 report, these substances had not been classified as Human carcinogens due to lack of scientific research, however, on the basis of large amounts of research on laboratory animals indicating carcinogenicity it is generally felt that they should be regarded as carcinogenic to humans. In a 1968 study for instance, in which 36 Syrian Golden Hamsters were given a single dose of only 6 mg of NDEA, 29 suffered Tumours of the respiratory trace.

Studies of N-nitrosamines indicate that it is a metabolically activated carcinogen which disrupts DNA. The metabolic activation is brought about by the demethylating enzyme Cytochrome P-450 which requires NADPH and O2. The presence of alcohol seems to enhance N-nitrosamine metabolism to it's carcinogenic metabolite. This would appear to indicate that alcohol potentiates the effects of N-nitrosamines as carcinogens and would explain the observed increased incidence of cancer of the oral cavity and oesophagus in smokers who also drink large amounts of alcohol.

Aromatic Amines

Epidemiological studies of dye workers have documented that certain aromatic amines such as 2-naphthylamine and 4-aminobiphenyl are human bladder carcinogens. 2-naphthylamine is converted to an N-hydroxy derivative metabolic intermediate, which is capable of forming adducts with guanine in nucleic acids.

Trace Metals

While it is generally felt that the quantities of Cadmium, Nickel, Arsenic and Polonium-210 found in cigarette smoke do not significantly contribute to an increased risk of lung cancer or other smoking-related cancers, their role as potentiators or co-factors has not been researched to-date in any great detail.

These metals tend to accumulate in the body and could possibly act as promoters in conjunction with carcinogens in cigarette smoke. Cadmium for instance (several forms of which are suspected carcinogens) is only present at concentrations of 50-100 ng in cigarette smoke but it has been suggested that a heavy smoker will retain up to 1.5 g of it per day leading to a lifetime accumulation of 0.5 mg.

The importance of Arsenic as a toxic component of cigarette smoke has diminished following the removal of Arsenic containing compounds from the list if recommended pesticides in the US for the control of hornworms on tobacco. This has resulted in a large decrease in the amount of Arsenic in tobacco and consequently cigarette smoke. A review by the International Agency for Cancer (IARC) suggested that arsenic compounds could potentially act as human skin carcinogens.

Nickel, classified as a suspected human carcinogen (IARC, 1986) is present in concentrations up to 80 ng in cigarette smoke (MS). Nickel has been shown to induce sarcomas by subcutaneous injection in laboratory animals. Nickel Subsulphide (Ni3S2) has been shown to have even greater potency, inducing a high rate of renal carcinomas in rats after exposure to only a single 5 mg dose (Intravenally injected).

Polonium-210, a radioactive material that emits -particles, accumulates at a higher rate in the parenchyma and bronchial mucosa of smokers. Studies on Syrian Golden Hamsters using multiple intratracheal instillations of Polonium-210 have revealed a dose-response relationship with bronchocarcinomas and adenocarcinomas in the respiratory system.

Environmental Tobacco Smoke (ETS)

The 1986 report by the US Surgeon General on Involuntary Smoking came to the following conclusions,

  1. Environmental Tobacco Smoke is a cause of disease including lung cancer in healthy non-smokers.
  2. Children exposed to ETS (due to the fact that one or both of their parents were smokers) have an increased frequency of respiratory infections, increased respiratory problems and a slightly reduced rate of increase in lung function as they develop.
  3. The separation of smokers and non-smokers in the same airspace may result in reductions, but does not eliminate exposure of non-smokers to ETS.

As mentioned in the opening paragraph, cigarette smoke can be categorised as either Mainstream smoke (MS) or Sidestream smoke (SS). ETS is derived mainly from SS which is qualitatively similar to MS. However, due to the lower temperature of formation of SS, it actually contains higher concentrations of toxic and carcinogenic agents than MS. Laboratory tests on animals have indicated that SS is more carcinogenic than MS. It must, however, also be borne in mind that while SS may be more toxic/carcinogenic, ETS is essentially a diluted form of SS so one cannot directly correlate the toxicity of SS to ETS.

ETS, like cigarette smoke, is undoubtedly a causative agent for a number of human diseases including various cancers and diseases of the respiratory tract aswell as middle ear infections in exposed children. Non-carcinogenic lung disease may be broken down into two major areas, disease of the lung airways (inflammation of the airways, increased bronchial mucus secretions,etc.) and disease of the lung parenchyma (alveolar tissue damage resulting in emphysema). Non-smokers exposed to ETS generally do not suffer from lung parenchyma disease unless they have a genetic predisposition to weakened lung tissue, however, disease of the lung airways can be induced by much smaller doses of cigarette smoke. With regard to Lung cancer, there is a tentative dose-response relationship which indicates that higher ETS exposure levels increases the risk of lung cancer but lower doses could also result in cancer.

Studies have been conducted on the effects of ETS on both children and adults. With regard to ETS, the main risk group is children and infants, particularly up to the age of 2 years.

Effects of ETS exposure on children

ETS exposure due to parental smoking, especially the mother's, contributes to 150,000 to 300,000 cases annually of lower respiratory tract infection (pneumonia, bronchitis, and other infections) in infants and children under 18 months of age. ETS exposure is also associated with increased respiratory irritation (cough, phlegm production, and wheezing) and middle ear infections, as well as upper respiratory tract symptoms (sore throats and colds) in infants and children. Two other infant-specific conditions known to be linked to ETS exposure have been researched in recent times, these being middle ear infections (MEI) and sudden infant death syndrome (SIDS).

A report in May, 1995 entitled Passive Smoke Exposure and Otitis Media sought to clarify the link between ETS exposure in infants and occurrence of otitis media (middle ear infections). It concluded that a significant increase in MEI risk was caused by exposure to ETS with the threshold being a maternal smoking level of 20 or more cigarettes a day. The mechanisms by which MEI are brought about by ETS include increased general risk of infection in individuals exposed to ETS and increased mucus secretion and ciliostasis effects bringing about an accumulation of mucus and bacteria in the middle ear region.

Sudden Infant Death Syndrome is a significant cause of death in infants aged from 1 month to a year and studies have established a conclusive link between it's occurrence and maternal smoking. Increased maternal smoking which results in increased ETS exposure to infants leads to a higher risk of SIDS independently of other confounding risk factors including low birth weight and low gestational age (both of which, incidentally are associated with maternal active smoking during pregnancy).

Effects of ETS exposure on adults

Estimates that ETS exposure causes 3,000 lung cancer deaths annually have been made. This is the primary area of risk associated with ETS exposure to adult non-smokers. The 1992 report by the EPA Respiratory Health Effects of Passive smoking: Lung Cancer and other Disorders classified ETS as a Group A carcinogen - a category reserved only for the most dangerous cancer-causing agents in humans. The risks of other cancers due to ETS exposure have not currently been evaluated in great detail at this stage but it seems likely that most cancers linked to cigarette smoking will be linked to ETS following suitable study. Other effects of ETS exposure in adults include chronic coughing, phlegm and wheezing; decreased pulmonary function (a 1980 report on 2100 adults found that the magnitude of the effects of ETS on pulmonary function was comparable to active smoking of 1 to 10 cigarettes per day) and bronchoconstriction.

Asthmatics appear to have a heightened sensitivity to ETS exposure, with studies showing 25% decreased lung function in asthmatics exposed in the laboratory to levels of ETS that had no effect on smokers.

Conclusions

Cigarette smoke appears to be one the main, preventable causes of disease in the modern world and it seems likely that conventional cigarette smoking will become increasingly restricted as public awareness of the effects of ETS increases and other dangers of smoking become more apparent. Cigarette smoking as a habit is also threatened by the US Food and Drug Administration (FDA) which is currently contemplating reclassification of cigarettes as a drug delivery device, this would inevitably result in much tighter controls on cigarette sales. Environmental Tobacco Smoke exposure presents a definite health risk, particularly to young infants and high-risk groups (including groups with genetic predispositions to ETS exposure risk and workers dealing with materials such as asbestos which appears to potentiate the effects of carcinogens in cigarette smoke) and it is the responsibility of smokers to ensure that they do not provide unnecessary health hazards to non-smokers. It has so far been impossible to define a threshold level below which ETS or direct cigarette smoker exposure can be deemed safe and free from risks since it the whole concept of whether a carcinogen can possibly have a safe threshold level is currently under debate.

References:

  1. The Medical Effects of Tobacco Consumption, Scientific American. May 1995
  2. Harrisons' Principles of Internal Medicine, 10th Ed. Petersdorf, Adams, Braunwald Isselbacher, Martin and Wilson. Chap 244:1302-1305
  3. The Health Consequences of Smoking - Cancer, a report of the Surgeon General. US Department of Health and Human Services, 1982.
  4. The Health Consequences of Involuntary Smoking, a report of the Surgeon General. US Department of Health and Human Services, 1986.
  5. Organic Chemistry, 2nd Ed.. Ege, S. Published by D.C. Heath and Co.
  6. Biochemistry, Voet, D., Voet, J. G.. Published by Wiley
  7. National Cancer Institute World-Wide-Web site

Copyright © 1997 by Stephen Mulcahy (stephen@skynet.ie )