Chemistry Of Tobacco Smoke

When cigarette tobacco is burned, mainstream smoke and sidestream smoke are generated (IARC, 1986; Hecht, 1998b). Mainstream smoke is the material drawn from the mouth end of a cigarette during puffing. Sidestream smoke is the material released into the air from the burning tip of the cigarette plus the material which diffuses through the paper. The material emitted from the mouth end of the cigarette between puffs is sometimes also considered as sidestream smoke.

The mainstream smoke emerging from the cigarette is an aerosol containing about 1 x 1010 particles ml-1, ranging in diameter from 0.1 to 1.0 p.m (mean diameter 0.2 p.m) (IARC, 1986; Hecht, 1998b, 1999). About 95% of the smoke is made up of gases, mainly nitrogen, oxygen and carbon dioxide. For chemical analysis, the smoke is arbitrarily separated into a vapour phase and a particulate phase, based on passage through a glass-fibre filter pad called a Cambridge filter. This retains 99.7% of all particles with diameters of > 0.1 p.m. Individual smoke components, of which more than 50% appear in the vapour phase of fresh mainstream smoke, are considered volatile smoke components whereas all others are considered particulate phase components. The particulate phase contains more than 3500 compounds, and most of the carcinogens. Standardized machine smoking conditions have been used for measurement of cigarette smoke constituents. These conditions are also arbitrary and it is recognized that each smoker may puff in ways that are widely different from the standardized conditions, thereby changing the yield of individual smoke constituents. In addition to nitrogen, oxygen and carbon dioxide, the gas phase contains substantial amounts of carbon monoxide, water, argon, hydrogen, ammonia, nitrogen oxides, hydrogen cyanide, hydrogen sulfide, methane, isoprene, butadiene, formaldehyde, acrolein, pyridine and other compounds. Some major constituents of the particulate phase include nicotine and related alkaloids, hydrocarbons, phenol, catechol, solanesol, neophytadienes, fatty acids and others. Many of the components are present in higher concentration in sidestream smoke than in mainstream smoke; this is especially true of nitrogen-containing compounds. However, a person's exposure to sidestream smoke is generally far less than to mainstream smoke because of dilution with room air.

Among the many compounds in tobacco smoke are carcinogens, which are agents capable of inducing cancer in laboratory animals or humans. There are 55 carcinogens in cigarette smoke that have been evaluated by the International Agency for Research on Cancer (IARC) and for which there is 'sufficient evidence for carcinogenicity' in either laboratory animals or humans (Hecht, 1999). The types of carcinogens, based on their chemical classes, are listed in Table 8. Carcinogens specifically associated with lung cancer are listed in Table 9. The 20 compounds included in this list have been found convincingly to induce lung tumours in at least one animal species and

Table 8 Summary of carcinogens in cigarette smoke. (From Hecht, 1999, Journal of the National Cancer Institute, 91, 1194-1210.)

Type

No. of compounds

Polycyclic aromatic

1O

hydrocarbons (PAHs)

Azaarenes

3

N-Nitrosamines

l

Aromatic amines

3

Heterocyclic

8

aromatic amines

Aldehydes

2

Miscellaneous organic

i5

compounds

Inorganic compounds

l

Total

55

have been positively identified in cigarette smoke. The structures of the organic compounds are shown in Figure 3. These compounds are most likely involved in lung cancer induction in people who smoke.

PAHs are condensed ring aromatic compounds that are formed during all incomplete combustion reactions, such as occur in the burning cigarette. Among the PAHs, benzo[a]pyrene (BaP) is the most extensively studied compound. Its ability to induce lung tumours upon local administration or inhalation is well documented (Hecht, 1999). It causes lung tumours in mice, but not in rats, when administered systemically. In studies of lung tumour induction by implantation in rats, BaP is more carcinogenic than several other PAHs of tobacco smoke. In analytical studies, it has often been used as a surrogate for other PAHs and extensive data on its occurrence in cigarette smoke are available (IARC, 1986; Hecht, 1999). Thus BaP is a potent lung carcinogen, the occurrence of which is well documented. The vast literature on BaP tends to distract attention from other PAHs. However, PAHs such as dibenz[a, A]anthracene, 5-methylchrysene and dibenzo[a, z]pyrene are substantially stronger lung tumorigens than BaP in mice or hamsters, although the levels of these compounds in cigarette smoke are lower than those of BaP (Hecht, 1999).

Azaarenes are nitrogen-containing analogues of PAHs. Two azaarenes, dibenz[a,^]acridine and 7^-dibenzo-[c,g-]carbazole, are pulmonary tumorigens when tested by implantation in the rat lung and instillation in the hamster trachea, respectively (Hecht, 1999). The activity of dibenz[a,^]acridine is significantly less than that of BaP, whereas that of 7#-dibenzo[c, g-]carbazole is greater than BaP. The levels of both compounds in cigarette smoke are relatively low.

^-Nitrosamines are a large group of potent carcinogens formed by nitrosation of amines. Among the ^-nitrosa-mines, ^-nitrosodiethylamine (NDEA) is an effective pulmonary carcinogen in the hamster, but not the rat (Hecht, 1999). Its levels in cigarette smoke are low compared with those of other carcinogens. The tobacco-specific ^-nitrosamine 4-(methylnitrosamino)-1-(3-pyr-idyl)-1-butanone (NNK) is a potent lung carcinogen in rats, mice and hamsters (Hecht, 1998a, 1999). NNK is called a tobacco-specific ^-nitrosamine because it is a chemical derivative of nicotine, and thus occurs only in tobacco products. It is the only compound in Table 9 which induces lung tumours systemically in all three commonly used rodent models. The organospecificity of NNK for the lung is remarkable; it induces tumours of the lung, mainly adenoma and adenocarcinoma, independent of the route of administration and in both susceptible and resistant strains of mice (Hecht, 1998a, 1999). The systemic administration of NNK to rats is a reproducible and robust method for the induction of lung tumours. Cigarette smoke contains substantial amounts of NNK (IARC, 1986; Hecht, 1998b) and the total dose experienced by a smoker in a lifetime of

Table 9 Pulmonary carcinogens in cigarette smoke. (From Hecht, 1999, Journal of the National Cancer Institute, 91, 1194-1210.)

Carcinogen class

Compound

Amount in

Sidestream/

Representative

mainstream

mainstream

lung

cigarette smoke

ratio

tumorigenicity

(ng/cigarette)

in species

PAHs

Benzo[a]pyrene (BaP)

20-40

2.5-3.5

Mouse, rat, hamster

Benzo[b]fluoranthane

4-22

Rat

Benzoljjfluoranthane

6-21

Rat

Benzo[k]fluoranthane

6-12

Rat

Dibenzo[a, /jpyrene

1.7-3.2

Hamster

Indeno[l,2,3-cd]pyrene

4-20

Rat

Dibenz[a,b]anthracene

4

Mouse

5-Methylchrysene

0.6

Mouse

Azaarenes

Dibenz[a,b]acridine

0.1

Rat

7H-Dibenzo[c,g]carbazole

0.7

Hamster

N-Nitrosamines

N-Nitrosodiethylamine

ND-2.8

< 40

Hamster

4-(Methylnitrosamino)-l-

80-770

1-4

Mouse, rat, hamster

(3-pyridyl)-l-butanone (NNK)

Miscellaneous

organic compounds

l, 3-Butadiene

(20-70) x 103

Mouse

Ethyl carbamate

20-38

Mouse

Inorganic compounds

Nickel

0-510

13-30

Rat

Chromium

0.2-500

Rat

Cadmium

0-6670

7.2

Rat

Polonium-2l0

0.03-1.0 pCi

1.0-4.0

Hamster

Arsenic

0-1400

None

Hydrazine

24-43

Mouse

Benzo[a]pyrene (BaP)

Dibenzo[a,/]pyrene

Benzo[b]fluoranthene

Indeno[1,2,3-cd]pyrene

Benzo[j]fluoranthene

Benzo[j]fluoranthene

Benzo[k]fluoranthene

^CH3 5-Methylchrysene

^CH3 5-Methylchrysene

Dibenz[a,h]acridine

CH2=CH-CH=CH2 1,3-Butadiene

7H-Dibenzo[c,g]carbazole

7H-Dibenzo[c,g]carbazole

h2n-C-och2ch3

Ethyl carbamate

CH3CH2NCH2CH3

N-Nitrosodiethylamine

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

Figure 3 Structures of organic pulmonary carcinogens in tobacco smoke.

smoking is remarkably close to the lowest total dose shown to induce lung tumours in rats (Hecht, 1998a). Levels of NNK and total PAHs in cigarette smoke are similar (IARC, 1986; Hecht, 1998b).

Lung is one of the multiple sites of tumorigenesis by 1,3-butadiene in mice, but is not a target in the rat (Hecht, 1999). 1,3-Butadiene is a component of the vapour phase of cigarette smoke, but in most inhalation studies, the particulate phase shows more overall carcinogenic activity. Ethyl carbamate is a well established pulmonary carcinogen in mice but not in other species (Hecht, 1999). Nickel, chromium, cadmium and arsenic are all present in tobacco and a percentage of each is transferred to mainstream smoke; arsenic levels have been substantially lower since discontinuation of its use as a pesticide in 1952 (Hecht, 1999). Metal carcinogenicity depends on the valence state and anion; these are poorly defined in many analytical studies of tobacco smoke. Thus, although some metals are effective pulmonary carcinogens, the role of metals in tobacco-induced lung cancer is unclear. Levels of polonium-210 in tobacco smoke are not believed to be great enough to impact lung cancer significantly in smokers (Hecht, 1999). Hydrazine is an effective lung carcinogen in mice and has been detected in cigarette smoke in limited studies (Hecht, 1999).

Considerable data indicate that PAHs and NNK play very important roles as causes of lung cancer in people who smoke. The other compounds discussed above may also contribute, but probably to a lesser extent.

PAHs and A-nitrosamines such as NNK and A-nitro-sonornicotine (NNN) are probably involved as causes of oral cavity cancer in smokers (Hoffmann and Hecht, 1990). A-Nitrosamines such as NNN and NDEA are likely causes of oesophageal cancer in smokers (Hoffmann and Hecht, 1990). The risk of oral cavity cancer and oesophageal cancer in smokers is markedly enhanced by consumption of alcoholic beverages. NNK is also believed to play a prominent role in the induction of pancreatic cancer in smokers, whereas aromatic amines such as 4-aminobiphenyl and 2-naphthylamine are the most likely causes of bladder cancer (Hoffmann and Hecht, 1990).

Cigarette smoke is also a tumour promoter (Hecht, 1998b). The majority of the activity seems to be due to uncharacterized weakly acidic compounds. Substantial levels of cocarcinogens such as catechol are present in cigarette smoke (Hecht, 1998b). Co-carcinogens enhance the activity of carcinogens when administered simultaneously. Other co-carcinogens in tobacco smoke include methylcatechols, pyrogallol, decane, undecane, pyrene, benzo[e]pyrene and fluoranthene. In addition, cigarette smoke contains high levels of acrolein, which is toxic to the pulmonary cilia, and other agents such as nitrogen oxides, acetaldehyde and formaldehyde that could contribute indirectly to pulmonary carcinogenicity through their toxic effects (Hecht, 1998b, 1999).

Whereas cigarette smoke is extraordinarily complex, unburned tobacco is simpler. With respect to carcinogens, the tobacco-specific nitrosamines NNK and NNN are the most prevalent strong cancer-causing agents in products such as smokeless tobacco (IARC, 1985). A mixture of NNK and NNN induces oral tumours in rats, and consequently these compounds are considered to play a significant role as causes of oral cavity cancer in people who use smokeless tobacco products (IARC, 1985; Hecht, 1998a).

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