While diet and hormone alterations play major roles in the causation of human cancer, in most instances the exact mechanism resulting in such increased risk is not clear. In the abuse of to- bacco and tobacco products through smoking, chewing, and related uses, a more definitive caus- ative mechanism of human cancer has been clarified. Early observations in this century (cf. Hoffman, 1915) related cancer of the buccal cavity, and particularly of the lip, to smoking habits, especially with pipes. In this context, smoking was related to the use of the betel nut as a masti- catory for chewing, a habit that has been known since the fourth century A.D. in different parts of the world (Sharan, 1996). Over time, the form of mastication of the betel nut has changed de- pending on the social circumstances. Thus, the betel nut may be used alone or as a quid along with a variety of ingredients including perfumes, stimulants, and different types of tobacco. Extracts of the quid have been shown to be carcinogenic in the mouse and other species (Bhide et al., 1979). Extracts of the nut itself contain alkaloids that have been shown to be mutagenic in bacteria (cf. Sharan, 1996). Recently, there has been a decline in betel quid chewing, especially in the young, and a concomitant decline in oral cancer (Reichart, 1995). Related uses of tobacco include its use as snuff and for chewing without the other additives of the betel quid. Chewing tobacco, a form of smokeless tobacco, while popular around 1900, decreased dramatically in use until about 25 years ago, at which time there was a marked increase in sales and production of smokeless tobacco, used both for chewing and for snuff dipping (holding cut tobacco between the cheek or lip and gingiva or beneath the tongue) (Connolly et al., 1986). This type of expo- sure to tobacco, as well as the betel quid, has been deemed as carcinogenic for humans by the IARC (IARC, 1985). While the IARC has deemed the evidence for human carcinogenicity of chewing tobacco as limited, alkaloids extracted from smokeless tobacco during its use give rise to potent carcinogenic N-nitrosamines such as NNK (Chapter 3) (Hoffmann and Hecht,1988). Unfortunately, the use of smokeless tobacco today is most common in children and young adult males (Squier, 1988) as well as in young women who chronically dip snuff. In one study of this last population, the relative risk of oral and pharyngeal cancer approached 50-fold (Winn et al., 1981).
Tobacco smoking as a cause of lung and a variety of nonrespiratory cancers is largely a phenomenon of the twentieth century, especially the last two-thirds of the century. To a signifi- cant degree, this is probably the result of the ready availability and popularity of cigarettes. The mass production of cigarettes was made possible by the invention of the cigarette-rolling ma-chine in the latter part of the nineteenth century, followed by the development of safety matches. The result of these inventions is seen by the fact that in 1880 smokers averaged 40 cigarettes per year, while in 1977 this average increased to 12,854 (Bartecchi et al., 1995). Concomitant with the increasing consumption of cigarettes was seen the increasing mortality from lung cancer (Figure 11.5). Tobacco abuse is the leading preventable cause of death in the United States, ac- counting for about 20% of total deaths (Bartecchi et al., 1994). This figure includes not only cancer but also respiratory and cardiovascular diseases caused by tobacco abuse. A further sig- nificant factor in the popularity and consumption of cigarettes is the extensive advertisement of their use. Cigarette marketing expenditures increased from $491 million in 1975 to $3274 mil- lion in 1988 (Bartecchi et al., 1995). An even more alarming statistic, estimated by Peto et al. (1996), is that some 3 million deaths a year are attributable to smoking now, and this figure will rise to 10 million per year in 30 to 40 years from now. This indicates that about 200 to 300 million of today’s 3 billion adults can be expected eventually to die from tobacco abuse.
The results of tobacco abuse are not limited to its carcinogenic effects on the lung and upper respiratory tract. A significant proportion of a variety of other neoplasms can also be at- tributable to smoking in the United States (Figure 11.6). As with any chemical carcinogen, the risk of developing cancer of the lung and of the other organs noted in Figure 11.6 will vary with the number of cigarettes smoked per day. In a large study reviewing a number of reports, the relative risk of lung cancer versus the number of cigarettes smoked per day was essentially linear up to 40 cigarettes per day, which is as far as the study extended. However, the various reports differed in the relative risk seen from 10 to 40. Laryngeal cancer risk in a number of studies was even greater by far, but the spread was more extensive. For nonrespiratory cancers attributable to smoking, the relative risk was generally less than 10 for those who smoked 40 cigarettes per day (Dreyer et al., 1997). A more specific listing of the estimated cancer deaths caused by cigarette smoking in the United States in 1988 is seen in Table 11.8.
Not in the table, however, are at least two other types of neoplasms for which there is significant evidence of a causal relationship to tobacco abuse. One of these is hematopoietic can- cer, including leukemias and to a lesser extent lymphomas. Since cigarette smoke contains ben- zene and is a source of ionizing radiation (polonium 210), both known causes of leukemia, it is quite possible that the two- to threefold excess of leukemias seen in smokers is related to their habit (cf. Newcomb and Carbone, 1992). A more alarming association is that described by Gio- vannucci and Martinez (1996) on the relation between smoking and cancers of the large bowel in U.S. men. In 1950, age-adjusted colorectal cancer incidence and mortality rates were similar in
Figure 11.5 Relationship of cigarette consumption and total deaths from lung cancer in the United States 1900 to 1989. (Reprinted from an NIH publication entitled Smoking, Tobacco and Cancer Program,1990.)
Figure 11.6 Proportion of cancer deaths that can be attributed to smoking in the United States in 1985. (Adapted from Newcomb and Carbone, 1992, with permission of the authors and publisher.)
U.S. men and women. By 1986, however, incidence rates were 34% higher and mortality rates 44% higher in men. These authors conclude that the increasing ratio of male to female mortality from colorectal cancer over the latter half of this century may have resulted from tobacco use by men earlier in the century. If this thesis is correct, as many as 20% of the large bowel cancers in men may be attributable to smoking during the last two decades. All of this information leads to the conclusion that tobacco abuse in general and cigarette smoking in particular are definable and thus preventable causes of approximately one-third of the cases of potentially fatal human cancer (Doll and Peto, 1981).