83 - Chronic Pulmonary Emboli

Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.

Title: General Thoracic Surgery, 6th Edition

Copyright 2005 Lippincott Williams & Wilkins

> Table of Contents > Volume II > Section XVI - Carcinoma of the Lung > Chapter 98 - Lung Cancer: Epidemiology and Carcinogenesis

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Chapter 98

Lung Cancer: Epidemiology and Carcinogenesis

Lynn T. Tanoue

Richard A. Matthay

Carcinoma of the lung is the leading cause of cancer death in the United States and around the world. The sheer magnitude of the lung cancer epidemic is staggering. Jemal and colleagues (2003) projected that 171,900 new cases of lung cancer would be diagnosed in the United States in 2003. At present, more persons in this country succumb annually to lung cancer than die from cancers of the colon, breast, and prostate combined. Pisani (1999, 2002) and Parkin (1999, 2001) and their colleagues have reviewed the most recent available global cancer estimates for the International Agency for Research on Cancer (IARC). Because these statistics reflect data from 1990, they likely underestimate the current global lung cancer threat. In 1990, lung cancer was the most common cancer worldwide, both in terms of incidence and mortality. Lung cancer was the largest single contributor to new cases of cancer diagnosed (1,037,000 new cases, equaling 12.8% of total new cancer cases) as well as to mortality from cancer (921,000 deaths, equaling 17.8% of total cancer deaths).

In the United States, lung cancer incidence in males has been decreasing since the early 1980s. Incidence and mortality rates for lung cancer tend to mirror one another, because most persons who are diagnosed with lung cancer eventually succumb to it. Jemal and colleagues (2003) in their review of cancer statistics for 2003 noted decreases in death rates from lung cancer in men averaging 1.8% per year from 1990 to 1998 (Fig. 98-1). In women, lung cancer incidence rates have been stable since 1991. On an optimistic note, incidence rates among women younger than 65 years declined from 28.3% per 100,000 women in 1991 to 22.7% per 100,000 women in 1998. Unfortunately, lung cancer death rates among women have not decreased. However, mortality rates appear to be reaching a plateau, which represents an encouraging change from the steep rise witnessed in the 1970s to 1980s (Fig. 98-2). Cancer of the lung and bronchus still accounts for 31% of cancer deaths in men and 25% of cancer deaths in women in the United States.

The lung cancer situation in the United States is a harbinger for the situation globally. Lung cancer incidence and mortality are highest in the United States and the developed countries of Europe. In contrast, lung cancer rates in underdeveloped geographic areas, including Central and South America and Africa, are relatively low (Fig. 98-3). However, the World Health Organization (1997) estimates that lung cancer deaths worldwide will continue to rise, largely due to increasing global tobacco use. The enormity of the lung cancer problem mandates examination of the epidemiology of the disease. Currently, despite the availability of new diagnostic technologies, advancements in surgical techniques, and the development of nonsurgical treatment modalities, the overall 5-year survival rate for lung cancer in the United States remains a dismal 14%. The situation globally is even worse, with 5-year survival in Europe, China, and developing countries estimated at 8%. Given this, prevention should be a major focus of the efforts currently being made in this field. Understanding the epidemiology of lung cancer, including the identification of risk factors, is critically important because the modification of risks should affect the development of this disease.

This chapter focuses primarily on a discussion of modifiable risk factors, including tobacco smoking, exposure to occupational carcinogens, exposure to ionizing radiation, and diet. The molecular and genetic aspects of carcinogenesis are discussed separately in this text.

TOBACCO SMOKING

Tobacco has been a part of the cultural and economic structure of this country since the time of Columbus. Originally chewed or smoked in pipes, cigarettes became widely available after the development of cigarette wrapping machinery in the mid-1800s. Prior to World War I, cigarette use in the United States was modest. Wynder and Graham (1950) estimate that in 1900 the average annual adult cigarette consumption was less than 100 cigarettes per person. In 1950 this number rose to approximately 3,500 cigarettes per person per year and reached a maximum of approximately 4,400 cigarettes per person per year in the mid-1960s.

Fig. 98-1. Annual age-adjusted cancer death rates for males by site, United States, 1930 2000. From Jemal A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5, 2003. With permission.

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In 1964 the U.S. Public Health Service published the Surgeon General's landmark report on smoking and health. The principal findings of this report were as follows:

  • Cigarette smoking was associated with a 70% increase in the age-specific death rates of men and a lesser increase in the death rates of women.

    Fig. 98-2. Annual age-adjusted cancer death rates for females by site, United States, 1930 2000. From Jemal A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5, 2003. With permission.

    Fig. 98-3. Age-adjusted incidence rates of lung cancer in men (A) and women (B) by geographic region. Micro/Poly, Micronesia/ Polynesia; NZ, New Zealand; Temp, temperate; Trop, tropical. From Parkin DM, Pisani P, Ferlay J: Global cancer statistics. CA Cancer J Clin 49:33, 1999. With permission.

  • Cigarette smoking was found to be causally related to lung cancer in men. The magnitude of the effect of cigarette smoking far outweighed all other factors leading to lung cancer. The risk of developing lung cancer increased with duration of smoking and the number of cigarettes smoked per day. The report estimated that the average male smoker had an approximately 9- to 10-fold risk of developing lung cancer, whereas heavy smokers had at least a 20-fold risk.

  • Cigarette smoking was believed to be much more important than occupational exposures in the causation of lung cancer in the general population.

  • Cigarette smoking was found to be the most important cause of chronic bronchitis in the United States.

  • Male cigarette smokers had a higher death rate from coronary artery disease than nonsmoking men.

At the conclusion of the report, the following statement was made: Cigarette smoking is a health hazard of sufficient importance in the United States to warrant appropriate remedial action. Since the submission of this report, yearly per capita consumption of cigarettes has declined in the United States (Fig. 98-4), although it is estimated that 25% of all Americans continue to smoke, a figure that has been stable since about 1990.

Fig. 98-4. U.S. adult cigarette consumption during the 20th century, and the influence of select social factors. From U.S. Department of Health and Human Services: Reducing Tobacco Use: A Report of the US Surgeon General. Washington, DC: Centers for Disease Control and Prevention, Office on Smoking and Health, 2000, p. 33.

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At the turn of the 20th century, lung cancer was an uncommon disease. In 1912 Adler performed an extensive review of autopsy reports from hospitals in the United States and western European countries and found 374 cases of primary lung cancer. This represented less than 0.5% of all cancer cases. Adler concluded that primary malignant neoplasms of the lung are among the rarest forms of disease. Over the next several decades a number of authors in the United States and abroad noted an increase in the incidence of carcinoma of the lung. In a series of 185,434 autopsy cases collected between 1897 and 1930, Hruby and Sweany (1933) noted that the incidence of lung cancer had increased disproportionately to the incidence of cancer in general.

In the early decades of the 20th century, it was postulated that the observed increase in lung cancer might be due to a variety of etiologies, including influenza, tuberculosis, irritating gases, atmospheric pollution from industrial plants and coal fires, and chronic bronchitis. The appreciation that tar could produce lung carcinoma when applied experimentally to the skin of animals raised preliminary concern that inhalation of tar products originating from automobile exhaust or the surface dust of tarred roads could be important factors in the observed rise in lung cancer incidence. As early as 1930, Roffo concluded from observations made in patients and experimental studies done in animals that tobacco tar liberated from the burning of tobacco was a carcinogenic agent. By the 1920s and 1930s, a number of uncontrolled series called attention to the potential role of cigarette smoking in the observed increase in lung cancer incidence. Fahr (1923), Lickint (1935), McNally (1932), Roffo (1930), Ochsner and DeBakey (1939), Tylecote (1927), and Levin and colleagues (1950), among others, voiced a growing concern that the increase in lung cancer was due to the growing use of cigarettes. In 1941 Ochsner and DeBakey stated in a review of carcinoma of the lung, It is our definite conviction that the increase in the incidence of pulmonary carcinoma is due largely to the increase in smoking.

In 1950 two landmark epidemiologic studies evaluating the role of tobacco smoking as an etiologic factor in bronchogenic carcinoma were published. Wynder and Graham (1950) in the United States reported a case control study examining 605 cases of lung cancer in men compared with a general male hospital population without cancer. The most striking finding was that 96.5% of lung cancers were found in men who were moderate to heavy smokers for many years compared with the general population, which had a smoking rate of 73.7%. Several important conclusions were drawn in this study: (a) Excessive and prolonged use of tobacco was an important factor in the induction of lung cancer, (b) the occurrence of lung cancer in a nonsmoker was a rare phenomenon, and (c) a lag period of 10 years or more between smoking cessation and the clinical onset of carcinoma could be observed. This report was closely followed by a similar case control study done in the United Kingdom by Doll and Hill (1950). Six hundred forty-nine male and 60 female lung cancer subjects were interviewed at 20 London hospitals and compared with 1,029 subjects who had cancer in organs other than the lung and 743 general medical and surgical patients matched for age and sex. In this study, 0.3% of men and 31.7% of women with lung cancer were nonsmokers, compared with 4.2% of men and 53.3% of women without cancer. Like Wynder and Graham, these authors concluded that an association between carcinoma of the lung and cigarette smoking did indeed exist and that the effect on development of lung cancer varied with the amount of cigarette use.

Cigarette smoke is a complex aerosol composed of both gaseous and particulate compounds. It is broken down into mainstream smoke and sidestream smoke components. Mainstream smoke is produced by inhalation of air through the cigarette and is the primary source of smoke exposure for the smoker. Sidestream smoke is produced from smoldering of the cigarette between puffs and is the major source of environmental tobacco smoke. The primary determinant of tobacco addiction is nicotine. Tar is defined as the total particulate matter of cigarette smoke after nicotine and water have been removed. Tar exposure appears to be the major link to lung cancer risk. The Federal Trade Commission determines the nicotine and tar content of cigarettes by measurements made on standardized smoking machines. However, it is clear that the composition of mainstream smoke can be quite variable depending on the intensity of inhalation, which differs among individual smokers. Although filter tips decrease the amount of nicotine and tar in mainstream smoke, the effect of filter tips can also be variable, because compression of the tips by lips or fingers has been shown to affect the composition of inhaled smoke.

More than 4,000 individual constituents of cigarette smoke have been identified. Hoffmann and Hoffmann (1997) and Burns (1994), in extensive reviews of cigarettes and smoke composition, note that 95% of the weight of mainstream

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smoke comes from 400 to 500 individual gaseous compounds. The remainder of the weight is made up of more than 3,500 particulate components. This does not include additives such as flavorings, which are considered trade secrets and often are unknown.

It is clear that mainstream smoke contains a large number of potential carcinogens, including polycyclic aromatic hydrocarbons, aromatic amines, N-nitrosamines, and miscellaneous organic and inorganic compounds such as benzene, vinyl chloride, arsenic, and chromium (Table 98-1). Compounds such as the polycyclic aromatic hydrocarbons and N-nitrosamines require metabolic activation to reach carcinogenic potential. Detoxification pathways also exist, and the balance between activation and detoxification likely affects individual cancer risk. Radioactive materials such as radon and its decay products, bismuth and polonium, are also present in tobacco smoke.

The agents that appear to be of particular concern in the etiology of carcinoma of the lung are the tobacco-specific N-nitrosamines (TSNAs) formed by nitrosation of nicotine both during tobacco processing and smoking. Eight TSNAs have been described, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is known to induce adenocarcinoma of the lung in experimental animal models. Other TSNAs have been linked to cancers of the esophagus, bladder, pancreas, oral cavity, and larynx. Of the TSNAs, NNK appears to the most important inducer of lung cancer. It has carcinogenic effects with both topical and systemic administration. Inhalation of tobacco smoke containing TSNAs results in direct delivery of carcinogens to the lungs. Because these compounds are also absorbed systemically, hematogenous delivery to lung via the pulmonary circulation occurs as well.

Tobacco carcinogens such as NNK can bind to DNA, creating DNA adducts. Repair processes may remove these DNA adducts and restore normal DNA, or cells with damaged DNA may undergo apoptosis. However, failure of the normal DNA repair mechanisms to remove DNA adducts may lead to permanent mutations. As outlined in a schema by Hecht (1999), mutations in critical oncogenes or tumor suppressor genes may contribute to the development of lung cancer (Fig. 98-5).

The International Agency for Research on Cancer has identified at least 50 carcinogens in tobacco smoke. It is important to note that the dosage of smoke constituents to the smoker can be highly variable, depending not just on the cigarette itself but also on the pattern of smoking. Specifically, the duration and intensity of inhalation, the presence and competence of a filter, and the duration of cooling of the smoke prior to inhalation can all change smoke composition. Over the last several decades the nicotine and tar contents of cigarettes have been lowered. However, the primary factor determining intensity of use of cigarettes is the smoker's nicotine dependence. Thus, although cigarettes now contain less nicotine and tar than previously, to satisfy their nicotine need smokers tend to smoke more intensively, with higher puffs per minute and deeper inhalations. In such situations the measurements of tar and nicotine content made by smoking machines may significantly underestimate individual exposure.

Wynder and Hoffmann (1994) proposed an intriguing hypothesis as to how low-yield filtered cigarettes might be a contributing factor to the observed increase of adenocarcinoma versus squamous cell carcinoma of the lung over the last several decades. As stated previously, the nicotine-addicted smoker will smoke low-yield cigarettes far more intensively than older nonfiltered higher-yield cigarettes. With deeper inhalation, higher-order bronchi in the peripheral lung will be exposed to carcinogen-containing smoke, as opposed to the major bronchi alone. These peripheral bronchi lack protective epithelium and are being exposed to carcinogens, including TSNAs, that are linked to induction of adenocarcinoma. Data from several laboratories, including those of Hoffmann (1993), Belinsky (1989), and Ronai (1993) and their colleagues, have documented that NNK is associated with DNA mutations resulting in the activation of K-ras oncogenes. Rodenhuis and Slebos (1992) reported that K-ras oncogene activation has been identified in 24% of human lung adenocarcinomas. Of note, Westra and colleagues (1993) have reported that K-ras mutations are present in adenocarcinoma of the lung found in ex-smokers, suggesting that such mutations do not revert with the cessation of tobacco smoking. This may in part explain the persistent elevation in lung cancer risk in ex-smokers even years after discontinuing cigarette use.

There is no doubt that tobacco smoking is the most important modifiable risk factor for lung cancer. Pisani and colleagues (1999) estimated that 20% of all cancer deaths worldwide could be prevented by the elimination of tobacco smoking. It is clear that individual susceptibility is also a factor in carcinogenesis. Although over 80% of lung cancers occur in persons with tobacco exposure, fewer than 20% of smokers will ever develop lung cancer. The variability seen in susceptibility must presumably be influenced by other environmental factors or by genetic predisposition.

Spitz and colleagues (1998) recently reviewed markers of susceptibility in lung cancer. They point out that factors that affect the absorption, metabolism, and accumulation of tobacco or other carcinogens in lung tissue will also affect cancer susceptibility. For example, the cytochrome P-450 multigene family, glutathione S-transferase gene families, and the genes determining N-acetylation (rapid, intermediate, or slow acetylator phenotypes) may all be involved in activation or detoxification of tobacco carcinogens. These genes themselves are subject to genetic polymorphisms, which may alter the levels of these metabolizing/detoxifying enzymes, thus affecting relative risks for cancer. Furthermore, susceptibility to carcinogenic agents may also be affected by individual differences in mutagen sensitivity. Mutagen sensitivity can be measured by assaying the frequency of bleomycin-induced chromosomal aberrations in lymphocytes, as outlined by Hsu and colleagues (1989).

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X. Wu and associates (1995) demonstrated that the presence of mutagen sensitivity is associated with an increased risk of lung cancer. Furthermore, Spitz's group (1998) noted that the combined risk for lung cancer was greater in individuals with mutagen sensitivity who smoked than in individuals with either smoking or mutagen sensitivity, and greater than in nonsmokers with mutagen sensitivity alone. Alterations in cytogenetics as well as variability in the ability of the individual to monitor and repair DNA damage may also affect cancer susceptibility.

Table 98-1. Tumorigenic Agents in Tobacco and Tobacco Smoke

Agent Evidence for IARC Evaluation of Carcinogenicity
Processed Tobacco (per gram) Mainstream Smoke (per cigarette) In Lab Animals In Humans
PAH
   Benz[a]anthracene   2 70 ng Sufficient NA
   Benzo[b]fluoranthene   4 22 ng Sufficient NA
   Benzo[j]fluoranthene   6 21 ng Sufficient NA
   Benzo[k]fluoranthene   6 12 ng Sufficient NA
   Benzo[a]pyrene 0.1 90 mg 20 40 ng Sufficient Probable
   Chrysene   40 60 ng Sufficient NA
   Dibenz[a,h]anthracene   4 ng Sufficient NA
   Dibenz[a,i]pyrene   1.7 3.2 ng Sufficient NA
   Dibenzo[a,l]pyrene   Present Sufficient NA
   Indeno[1,2,3c,d]pyrene   4 20 ng Sufficient NA
   S-Methylchrysene   0.6 ng Sufficient NA
Aza-arenes
   Quinoline   1 g NA NA
   Dibenz[a,h]acridine   0.1 ng Sufficient NA
   Dibenz[a,j]acridine   3 10 ng Sufficient NA
   7H-Dibenzo[c,g]carbazole   0.7 ng Sufficient NA
N-Nitrosamines
   N-Nitrosodimethylamine ND 215 ng 0.1 180 ng Sufficient NA
   N-Nitrosoethylmethylamine   3.13 ng Sufficient NA
   N-Nitrosodiethylamine   ND 25 ng Sufficient NA
   N-Nitrosopyrrolidine ND 360 ng 1.5 110 ng Sufficient NA
   N-Nitrosodiethanolamine ND 6,900 ng ND 36 ng Sufficient NA
   N-Nitrosonornicotine 0.3 89 g 0.12 3.7 g Sufficient NA
   4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 0.2 7 g 0.08 0.77 g Sufficient NA
   N-Nitrosoanabasine 0.01 1.9 g 0.14 4.6 g Limited NA
   N-Nitrosomorpholine   ND 690 ng Sufficient NA
Aromatic amines
   2-Toluidine   30 200 ng Sufficient Inadequate
   2-Naphthylamine   1 22 ng Sufficient Sufficient
   4-Aminobiophenyl   2 5 ng Sufficient Sufficient
Aldehydes
   Formaldehyde 1.6 7.4 g 70 100 g Sufficient NA
   Acetaldehyde 1.4 7.4 mg 18 1,400 mg Sufficient NA
   Crotonaldehyde 0.2 2.4 g 10 20 g NA NA
Miscellaneous organic compounds
   Benzene   12 48 g Sufficient Sufficient
   Acrylonitrile   3.2 15 g Sufficient Limited
   1,1-Dimethylhydrazine   60 147 g Sufficient NA
   2-Nitropropane   0.73 1.21 g Sufficient NA
   Ethylcarbonate 310 375 ng 20 38 ng Sufficient NA
   Vinyl chloride   1 16 ng Sufficient Sufficient
Inorganic compounds
   Hydrazine 14 51 ng 24 43 ng Sufficient Inadequate
   Arsenic 500 900 ng 40 120 ng Inadequate Sufficient
   Nickel 2,000 6,000 ng 0 600 ng Sufficient Limited
   Chromium 1,000 2,000 ng 4 70 ng Sufficient Sufficient
   Cadmium 1,300 1,600 ng 41 62 ng Sufficient Limited
   Lead   8 10 g Sufficient Inadequate
   Polonium 210 0.2 1.2 pCi 0.03 1.0 pCi NA NA
IARC, International Agency for Research on Cancer; ND, no data; NA, evaluation has not been done by IARC; PAH, polycyclic aromatic hydrocarbon.
From Burns DM: Tobacco smoking. In Samet JM (ed): Epidemiology of Lung Cancer. New York: Marcel Dekker, 1994, p. 15. With permission.

Fig. 98-5. Schema linking nicotine addiction and lung cancer via tobacco smoke carcinogens and their induction of multiple mutations in critical genes. PAH, polycyclic aromatic hydrocarbons; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. From Hecht SS: Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91:1194, 1999. With permission.

Smoking has been shown to be associated with mutations in the p53 tumor suppressor gene. Mutations in this gene are the most common genetic alterations seen in human cancers. Work by a number of investigators, including Ryberg (1994a), Field (1991), Koch (1995), Wang (1995), and Kawajiri (1996) and their colleagues, has demonstrated that specific exposures may be associated with specific mutations, thus establishing a link between environmental agents and chromosomal abnormalities. In particular, p53 mutations have been associated with a history of heavy tobacco use. Work by several groups has demonstrated increased frequencies of p53 mutations in heavy smokers as compared with persons with lower levels of tobacco exposure or nonsmokers. However, as noted by Brennan and associates (1995), endogenous, or at least non-tobacco-related, p53 mutations have also been identified, underscoring the point that tobacco is only one of multiple factors leading to lung cancer.

Lung cancer susceptibility is thus determined at least in part by host genetic factors. Persons with genetic susceptibility might therefore be at even higher risk if they also smoke cigarettes. As technology advances, it may be possible to target subgroups identified as genetically at high risk for lung cancer for specific interventions, including intensive efforts at smoking cessation, screening, and prevention programs.

Prevention of smoking initiation would be the most logical intervention because it would prevent the sequence of events leading to cancer outlined in Fig. 98-5. However, despite intensive antismoking campaigns and widespread public awareness of the risks associated with smoking, there appears to be a committed smoking cohort in this country that includes a staggering 25% of the population. There is no question that smoking cessation can decrease the risk of lung cancer in this group. Peto and colleagues (2000) reported two large case-control studies from about 1950 and 1990 in the United Kingdom. In 1990, cessation of smoking had nearly halved what would have been the anticipated number of lung cancer cases. Lung cancer risk also appeared to be related to age at smoking cessation. For men who had stopped smoking at age 60, 50, 40, and 30, the cumulative risks of lung cancer by ages 70 were 10%, 6%, 3%, and 2%, respectively. In contrast, the cumulative risk of death from lung cancer by age 75 in 1990 in male cigarette smokers was 16%.

Although these statistics appear to be hopeful, Jemal and colleagues (2001), in an evaluation of data collected by the National Center for Health Statistics in the United States, identified a slowing in the rate of decrease of the birth-cohort trend in lung cancer mortality for whites born after 1950, which they interpreted as a reflection of the impact of increasing teenage smoking. Although there has been some debate as to whether age at initiation of smoking is an independent risk factor for lung cancer, this report would support data reported by Wiencke and colleagues (1999) that patients in the youngest quartile of age at smoking initiation (7 to 15 years) have the highest DNA adduct levels.

Thus, while a frustratingly large percentage of persons in the United States and an increasing number of persons worldwide continue to smoke, efforts to prevent smoking initiation, particularly in children and teenagers, should be supported. Further, smoking cessation as the other method of primary prevention needs to be continually reinforced.

CONTRIBUTION OF OTHER FACTORS

Other Lung Diseases and Airways Obstruction

Several nonmalignant lung diseases have been associated with an increased risk of lung cancer. Of these, the strongest association has been shown with chronic obstructive pulmonary disease (COPD). Tobacco smoking is the primary cause of both lung cancer and COPD. A study by A. Wu and colleagues (1995) of women with lung cancer who had never smoked demonstrated a statistically significant association between the presence of airflow obstruction and the development of lung cancer. A number of other groups, including Cohen (1980), Skillrud (1986), and Tockman (1987) and their colleagues, have also presented evidence that airflow obstruction itself constitutes a risk for lung cancer. This conclusion is further supported by the outcomes observed by Anthonisen and associates in the Lung Health Study (1994), in which a total of 5,887 male and female smokers with spirometric evidence of mild to moderate COPD were monitored over a 5-year period with or without intervention of smoking cessation or bronchodilator therapy. One of the notable findings from this study was that mortality from lung cancer exceeded that from cardiovascular disease by nearly 50%. Lung cancer was the most

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common cause of death, accounting for 38% of all deaths among study participants.

Several diseases causing pulmonary interstitial fibrosis have also been associated with an increase in lung cancer risk. Hubbard and colleagues (2000) evaluated 890 patients with cryptogenic fibrosing alveolitis (CFA, idiopathic pulmonary fibrosis) and 5,884 control subjects and found that the incidence of lung cancer in study patients was markedly increased even after adjustment for smoking. Patients with CFA had an odds ratio for lung cancer of 8.25 compared with control subjects. Other fibrosing diseases, including asbestosis and scleroderma, also appear to have an increased association with lung cancer. Asbestos-related disease is discussed later in this chapter. The association of scleroderma with lung cancer is weaker. In a study of 248 patients with scleroderma reported by Abu-Shakra and colleagues (1993), a 2.1-fold increase in cancer incidence in patients with scleroderma relative to a general population was demonstrated, with the most frequent types being cancer of the lung and breast.

Although the mechanisms by which pulmonary interstitial disease may predispose to malignancy are not clear, various hypotheses have been raised, including malignant transformation related to chronic inflammation, epithelial hyperplasia, and impaired clearance of carcinogens.

Gender

Since 1950 a greater than 600% increase in lung cancer mortality has been noted in women. Although most of this increase is attributed to the dramatic increase in the prevalence of smoking among women since the 1940s, several disturbing facts have emerged that fuel the controversy as to whether women are more or less susceptible than men to the carcinogenic effects of cigarette smoke. The first is whether dose for dose women have an enhanced susceptibility to carcinogens in cigarettes when compared with men, which may translate into an increased risk for lung cancer. The American Cancer Society Cancer Prevention Study II (CPS-II), which followed 1 to 2 million subjects between 1982 and 1988, reported an overall risk of lung cancer in women smokers of 11.94, compared with 22.36 in male smokers, and took into account intensity of smoking (Halpern et al., 1993). However, a number of studies, including those by Zang and Wynder (1996) and Lubin and Blot (1984), as well as by Risch (1993), Brownson (1992), and McDuffie (1987) and their colleagues, all suggest that women may be more vulnerable to tobacco carcinogens than men. Specifically, in a case-control study of male female differences in lung cancer covering the period 1981 to 1985 in Ontario, Canada, Risch and associates (1993) demonstrated that with a history of 40 pack years of cigarette smoking relative to lifelong nonsmoking, the odds ratio for women developing lung cancer was 27.9 versus 9.6 in men. Similarly, another large case-control study by Zang and Wynder (1996) showed that dose response odds ratios for the development of lung cancer in women were 1.2- to 1.7-fold higher in women than men. In both studies the increase in lung cancer risk was true for all major histologic types of cancer.

The observed gender difference in susceptibility may be related to a number of factors, including sex-related differences in nicotine metabolism or in metabolic activation or detoxification of lung carcinogens. Such gender differences in clearance of plasma nicotine by cytochrome P-450 enzymes have been described. Moreover, several reports have commented on gender differences in lung cancer observed at a molecular level. Ryberg and colleagues (1994b) noted that women with lung cancer have higher DNA adduct levels than men. Patients with higher DNA adduct levels might be anticipated to be more susceptible to carcinogens, which might explain why women appear to develop lung cancer with lower-intensity cigarette exposure. Further, hormonal factors may also play a role in susceptibility. In a case-control study, Taioli and Wynder (1994) reported that estrogen replacement therapy was significantly associated with an increased risk for adenocarcinoma (odds ratio 1.7), while the combination of cigarette smoking and estrogen replacement increased that risk substantially (odds ratio 32.4). Conversely, early menopause (age 40 years or younger) was associated with a decreased risk of adenocarcinoma (odds ratio 0.3).

The second issue is whether cigarette smoking may be associated with a higher risk of the development of nonmalignant lung disease in women than men, including obstructive airway disease. Neither of two very large population studies, the British Physicians Study in the United Kingdom reported by Doll and Peto (1976) and Doll and colleagues (1980) or the Lung Health Study in the United States as reported by Tashkin and colleagues (1992), demonstrated gender differences in mortality from smoking-related COPD. However, other studies, including that reported by Chen and colleagues (1991), suggest that cigarette smoking may be more harmful in its effects on pulmonary function in women than men. In this study, changes in forced expiratory volume in 1 second (FEV1) and maximal midexpiratory flow rate (MMFR) and the slope of phase III of the single-breath nitrogen test increased with increasing pack years more rapidly in women smokers than their male counterparts. These changes were independent of age, height, and weight. Similar results have been reported by Buist (1979) and Detels (1981) and their associates. Furthermore, Beck and colleagues (1981) in a study of 4,690 Caucasians found that for a given level of smoking, female subjects demonstrated changes in FEV1 and maximal expiratory flow at 25% and 50% of vital capacity at a younger age (15 to 24 years) than male subjects (40 to 45 years). Similar results have been reported by Carter and associates (1994). Since persons with tobacco exposure and spirometric evidence of airway obstruction are at higher risk for developing lung cancer, the suggestion that women may have

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increased susceptibility to cigarette-induced airway disease may be important in the consideration of their risk for lung cancer as well.

Finally, whereas women may have enhanced susceptibility to the carcinogenic effects of tobacco, it also appears that lung cancer occurs more commonly in nonsmoking women than in nonsmoking men. In their early report of tobacco smoking as a possible etiologic factor in lung cancer, Wynder and Graham (1950) noted that a greater percentage of cancers in nonsmokers occurred in women than men. However, the number of women in that study was relatively small, and few women had at that time smoked for a duration of decades. Thus, no definite conclusion regarding an altered risk of lung cancer related to tobacco smoking in women could be made on the basis of their observations. Subsequently, however, it has become clear that women never-smokers are more likely than male never-smokers to develop lung cancer. In a case-control study by Zang and Wynder (1996) of 1,889 lung cancer subjects and 2,070 control subjects, the proportion of never-smoking lung cancer patients was more than twice as high for women than for men. The reasons for this are not clear, but speculation has been raised regarding the potential of women having greater susceptibility to nontobacco environmental carcinogens or increased exposure to environmental tobacco smoke, or of the existence of sex-linked differences in the metabolism of nontobacco environmental carcinogens.

Environmental Factors

A tremendous amount of epidemiologic work has been directed toward understanding lung carcinogenesis resulting from environmental factors other than tobacco, as well as interactions among factors. In particular, the combined effects of tobacco smoke with occupational carcinogens have received much attention. An additive or multiplicative risk of lung cancer has been demonstrated when cigarette smoking is present in the setting of exposure to asbestos, radon, arsenic, silica, and nickel, among others. The role of nutrition in cancer development has also increasingly received attention. The carcinogenic potential of occupational exposures, including asbestos and radon, and the influence of diet are discussed separately in this chapter.

Environmental Tobacco Smoke

In 1972 and 1989, the Surgeon General's reports on the health consequences of smoking raised concerns about hazards relating to smoke exposure (U.S. Public Health Service, 1972, 1989). Because nonsmoking persons exposed to environmental tobacco smoke (ETS) are observed to have an increased rate of smoke-related problems, including upper respiratory symptoms and eye irritation, and there is an observed increased frequency of respiratory illnesses in children, it logically follows that the acknowledged carcinogenic effect of active tobacco smoking might also be present in those involuntarily exposed. This was followed by reports by Hirayama (1981) and Trichopoulos and associates (1981) demonstrating an increased risk of lung cancer in nonsmoking women married to smoking men. In 1986 the National Research Council commissioned a review of the effects of ETS as a potential causal agent of lung cancer in nonsmokers exposed to household cigarette smoke. Review of all available evidence yielded an overall odds ratio of 1.34. In nonsmokers this translates into an approximately 30% increase of risk for lung cancer. More recently, an analysis by Hackshaw and colleagues (1997) of 4,626 cases of lung cancer in nonsmokers from 37 published epidemiologic studies indicated that the excess risk of lung cancer in nonsmokers living with smokers was 26%. This should be interpreted from the perspective that the background risk of lung cancer in a nonsmoker is very low and contrasted appropriately with the 1,000% increase of lung cancer in lifelong active smokers. In 1986 the U.S. Department of Health and Human Services released a report on the health consequences of involuntary smoking. On the basis of available evidence, this report concluded that involuntary smoking is a cause of disease, including lung cancer, in healthy nonsmokers.

The Environmental Protection Agency (1993) and the IARC (2002) now both classify ETS as containing lung carcinogens. A study by Cardenas and colleagues (1997) examined lung cancer mortality and ETS within the context of the American Cancer Society's Cancer Prevention Study. These authors performed a prospective comparative evaluation of 133,835 never-smokers with smoking spouses versus 154,000 never-smokers with nonsmoking spouses. These authors concluded that the relative risk of lung cancer in women with smoking husbands was 1.2, which represents an increase in lung cancer incidence of 20%. The relative risk in nonsmoking men with smoking wives was somewhat less but still elevated at 1.1. These figures are in agreement with data from prior studies evaluating lung cancer risk due to ETS. Pershagen (1994) evaluated pooled data from eight such studies in the United States from 1981 to 1991 and found a relative risk of lung cancer in nonsmokers living with smokers of 1.23.

Environmental tobacco smoke consists of both mainstream (exhaled) smoke and sidestream smoke from smoldering tobacco. A number of carcinogens have been identified in ETS, including benzene, benzo[a]pyrene, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Hecht and associates (1994) reported that male nonsmokers exposed to sidestream smoke generated by machine smoking of cigarettes demonstrated metabolites of the latter carcinogen in urine collected after exposure. In the third National Health and Nutrition Survey conducted between 1988 to 1991, Pirkle and colleagues (1996) reported that 88% of non-tobacco-users had detectable serum cotinine levels, presumably from exposure to ETS.

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Thus, the presence of ETS is pervasive and harmful. The effects of limitations placed on smoking in public places may be of benefit in this regard. However, with 25% of the American adult population still smoking, it should be obvious that ETS is a major public health issue. Although the exact number of cases of lung cancer due to involuntary smoking is difficult to calculate, Beckett (1993) estimates that the number of lung cancer deaths in the United States attributable to ETS is comparable to the annual number caused by asbestos or radon.

OCCUPATIONAL CARCINOGENS

Several workplace substances have been implicated as or proved to be carcinogens in the lung. The IARC has identified a number of such agents, including arsenic, asbestos, beryllium, cadmium, chloromethyl ethers, chromium, nickel, radon, silica, and vinyl chloride. The occupations associated with exposure to these agents are outlined in Tables 98-2 and 98-3.

Table 98-2. Occupational Carcinogens and Associated Occupational Exposures

Known Carcinogen Occupational Exposure
Arsenic Copper, lead, or zinc ore smelting
Manufacture of insecticides
Mining
Asbestos Asbestos mining
Asbestos textile production
Brake lining work
Cement production
Construction work
Insulation work
Shipyard work
Beryllium Ceramic manufacture
Electronic and aerospace equipment manufacture
Mining
Chloromethyl ethers Chemical manufacturing
Chromium Chromate production
Chromium electroplating
Leather tanning
Pigment production
Nickel Nickel mining, refining, electroplating
Production of stainless and heat-resistant steel
Polycyclic aromatics Aluminum production
Hydrocarbon compounds Coke production
Ferrochromium alloy production
Nickel-containing ore smelting
Roofing
Radon Mining
Silica Ceramics and glass industry
Foundry industry
Granite industry
Metal ore smelting
Mining and quarrying

Table 98-3. Suspected Occupational Carcinogens and Associated Occupational Exposures

Suspected Carcinogen Occupational Exposures
Acrylonitrile Textile manufacture
Plastics, petrochemical manufacture
Cadmium Electroplating
Pigment production
Plastics industry
Formaldehyde Formaldehyde resin production
Synthetic fibers Insulation work
Insulation production
Vinyl chloride Plastic production
Polyvinyl chloride production

Asbestos

Asbestos has historically been the most widely appreciated and most common occupational cause of lung cancer. Asbestos is a class of naturally occurring fibrous minerals consisting primarily of two groups: serpentine (chrysotile) and amphibole (amosite, crocidolite, tremolite, and others). Used commercially since the late 1800s, their fire-retarding qualities and strength have made them useful in construction and insulating materials. Hughes and Weill (1994) point out that asbestos was noted to be a lung carcinogen as early as 1943 in Germany. However, the wide recognition of its carcinogenicity dates to reports in the United Kingdom in the 1950s, including that by Doll (1955). It is widely recognized that asbestos exposure can result in a number of pleural and pulmonary manifestations.

Asbestos-related pleural disease may present as effusion or pleurisy or both. Chronic pleural involvement is seen as areas of pleural thickening (pleural plaques), usually involving the parietal pleura and often calcified. The presence of pleural plaques is not felt to herald development of mesothelioma and has not been definitively proved to be a marker of increased risk for lung cancer.

Inhalation of asbestos fibers can result in parenchymal lung disease, specifically interstitial lung disease ( asbestosis ). All the major types of asbestos can cause interstitial lung disease, although amphibole fibers may be more fibrogenic than chrysotile. The presentation of asbestosis is essentially identical to nonspecific interstitial lung disease as well as idiopathic pulmonary fibrosis. Symptoms typically include dry cough and dyspnea. Physical examination and chest radiograph are consistent with a bilateral basilar distribution of fibrotic changes. The distinction between asbestosis and nonspecific interstitial lung disease lies in a history of heavy occupational asbestos exposure. In a statement by the American Thoracic Society (1986) on the diagnosis of nonmalignant diseases related to asbestosis, the following were considered necessary to the clinical diagnosis of asbestosis: (a) a reliable history of exposure, (b) an appropriate time interval between exposure and detection, and (c) clinical evidence of interstitial lung disease, including

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chest radiographic abnormality, restrictive pulmonary physiology, abnormal diffusing capacity, and abnormal physical examination consistent with fibrosis.

In a review of the pathogenesis of asbestosis and silicosis, Mossman and Churg (1998) note that the development of asbestosis occurs above a threshold fiber dose of approximately 25 to 105 fibers per mL per year. This threshold dose is usually reached only in workers with heavy occupational exposure, including asbestos insulators, miners, millers, and textile workers. As is the case with other inorganic dusts, including silica, the development of interstitial fibrosis usually requires prolonged exposure over months to years. Disease can also follow shorter, more intense exposure, such as occurred in shipyard workers employed inside ship compartments during and after World War II. The latency period from exposure to presentation of disease is inversely proportional to exposure level. Thus, the less the exposure, the longer the latency period. It is important to note that most persons with occupational asbestos exposure never manifest any evidence of interstitial lung disease.

The distinction between asbestos exposure and asbestosis becomes extremely important because of controversy as to which represents the actual risk factor for lung cancer. Two reviews discussing the extensive available epidemiologic data illustrate this controversy. Jones and colleagues (1996), in an extensive literature review, highlight several important points. First, it is widely recognized that lung fibrosis of many causes is associated with an increased risk of lung cancer. This is true of idiopathic pulmonary fibrosis as well as interstitial lung disease associated with connective tissue diseases. Second, these authors point out animal experiments in which asbestos-exposed animals that developed lung cancer did so only when they also developed pulmonary fibrosis. Third, pleural plaques, a marker for asbestos exposure, have not proved a reliable marker for increased risk of lung cancer. These authors conclude that the issue of whether asbestosis is a necessary precursor to asbestos-attributable lung cancer cannot be definitively settled. However, their assessment was that the available data strongly support that hypothesis. In contrast, another review of the available medical literature by Egilman and Reinert (1996) arrives at the opposite conclusion. In their extensive assessment of the available epidemiologic data, these authors conclude that asbestos meets accepted criteria for causation of lung cancer in the absence of clinical or histologic parenchymal asbestosis. Their evaluation of pathologic and epidemiologic studies resulted in the conclusion that asbestos can act as a carcinogen independent of the presence of asbestosis.

The question of whether asbestos exposure alone or asbestosis per se represents the risk factor for lung cancer remains an area of debate. However, from a public health perspective, the issue is of particular significance because of concern about lung cancer risk related to asbestos in the general environment. As noted by Hughes and Weill (1994), all persons living in industrialized countries have accumulated asbestos fibers in their lungs; in adults the number of fibers is estimated to be in the millions. However, as stated, asbestosis requires prolonged and intense exposure to asbestos and is not observed with the level of asbestos fibers encountered from everyday exposure. It should be firmly stated that the risk of developing lung cancer from nonoccupational asbestos exposure in the general environment is extremely low. Moreover, Hughes and Weill point out that if, as postulated, asbestosis is a necessary prerequisite to the development of cancer, the extrapolation of risk of lung cancer related to occupational asbestos exposure to risk from exposure to asbestos in the general environment would substantially overestimate that risk.

Another area of controversy in the area of asbestos and lung cancer is whether all types of fibers are carcinogenic. Epidemiologic and experimental data have suggested that amphibole fibers are more carcinogenic than chrysotile. In the United States, chrysotile has been by far the most commonly used type of asbestos. Thus, although all fibers may be carcinogenic, public concern about low-level asbestos exposure and lung cancer should be appropriately tempered.

Whether asbestos exposure alone or asbestosis is the actual risk factor for lung cancer, and whether or not all types of asbestos fibers are carcinogens, tobacco smoking clearly potentiates the observed carcinogenic effect. The magnitude of the combined effect of asbestos and cigarette smoking, however, is not clear. Debate exists as to whether the interaction of these two agents results in an additive or multiplicative increase in the risk for lung cancer. The increase in relative risk for lung cancer in smokers is approximately 10-fold. Hammond and colleagues (1979) estimated that the relative risk for lung cancer among smoking asbestos workers increases by a factor of at least 15, but that the increase may be as much as 50-fold. Thus, the exact nature of the interaction in terms of relative risk is not defined. What is clear is that most lung cancers occur in asbestos-exposed workers who smoke. Smoking cessation should therefore be the most important goal of cancer prevention programs in this population, with particular targeting of the subgroup of workers with asbestosis.

With recognition of the health risks related to asbestos, its use has precipitously declined in the United States since the 1970s (Fig. 98-6). Assuming that occupational exposure continues to decline, in future years the risk of asbestos-related lung cancer will become increasingly small.

Radon

Mining

Mining is the oldest identified occupation associated with lung cancer. Agricola (1950) described a wasting pulmonary disease of miners and metal smelters associated with early mortality. Known as miners' pthisis, the cause of

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this illness was variably attributed to dust or metal exposure, tuberculosis, or even to inbreeding among mining communities. However, in 1879 Harting and Hesse performed an autopsy study of miners exposed to ores in the central European mines of Schneeberg and Joachimstahl in the Erz Mountains and documented that the process was actually neoplastic. Of note, Frank (1982) points out that these same mines produced the material from which Marie Curie later isolated radium. Although the etiologic factors causing the increased lung cancer risk were originally speculated to be dust-related pneumoconioses, arsenic, or cobalt, the actual carcinogens have been identified as radioactive materials, primarily radon and its decay products.

Fig. 98-6. United States asbestos use, 1973 1990. Modified from Hughes J, Weill H: Asbestos and man-made fibers. In Samet JM (ed): Epidemiology of Lung Cancer. New York: Marcel Dekker, 1994, p. 185. With permission.

Radon (radon 222) is a naturally occurring decay product of radium 226, itself a decay product of uranium 238 (Table 98-4). Uranium and radium are ubiquitously present in soil and rock, though in highly variable concentration. At usual temperatures, radon is released as a radium decay product as an inert radioactive gas. Radon itself decays with a half life of 3.82 days into a series of radioisotopes known as radon decay products (or radon daughters) that have half-lives measured in seconds to minutes. These products include polonium 218 and polonium 214, which emit alpha particles. Alpha radiation is highly damaging to tissues. Inhalation of these radon decay products and subsequent alpha particle emission in the lung may cause damage to cells and genetic material. Ultimately, radon decay produces lead 210, which has a half-life of 22 years.

The concentration of radon gas in an environment varies depending on two factors: the richness of the source of radium, and the degree to which the air around that source is ventilated. Thus, although the gas is present in ubiquitous fashion in the general environment, certain sites may be more likely to have a high radon concentration, with the

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prototypical situation being underground mines with poorly ventilated passageways.

Table 98-4. Principal Decay Products of Radium

Decay Product Half-Life
Radium 226
   
1,620 years
Radon 222
   
3.82 days
Polonium 218
   
3.05 months
Lead 214
   
26.8 months
Bismuth 214
   
19.7 months
Polonium 214
   
0.000164 seconds
Lead 210 22 years
Adapted from Samet JM: Radon and lung cancer. J Natl Cancer Inst 81:745, 1989. With permission.

Since Harting and Hesse's (1879) description of lung neoplasms in miners, an increased risk of lung cancer associated with exposure to radon decay products has been demonstrated in a number of different population studies of underground miners. These have included studies based in the United States by Samet (1989), Hornung and Meinhardt (1987), and Archer and colleagues (1974, 1976); in Sweden by Radford and associates (1984); in Canada by Howe and coinvestigators (1986); in China by Lubin and collaborators (1990); and in Czechoslovakia by Sevc and colleagues (1988). While not all miners will have increased risk of lung cancer, both uranium and nonuranium mines may have high radon concentrations, and the risk of lung cancer in such settings is raised. Darby and Samet (1994) and Samet and Hornung (1990) emphasized the following points in reviews of these studies:

  • In general, the relative risk of lung cancer increases with estimated cumulative exposure to radon. The occupational measure of cumulative exposure to radon decay products is the work-level month (WLM). The work level (WL) is any combination of radon decay products in 1 liter of air that results in the release of 1.3 105 MV of potential alpha energy. The number of hours worked in a month is defined as 170 hours. The WLM is a product of radon decay product concentration in WL and the duration of working months. In miners with cumulative exposures of 0 to 500 WLM, excess relative risk of lung cancer increases in approximately linear fashion to the amount of exposure. In miners with cumulative exposure of over 1,000 WLM, the excess relative risk becomes nonlinear and decreases. Darby and Samet (1994) suggest this decrease in excess risk at high cumulative radon exposure may reflect cell sterilization as opposed to genetic mutation.

  • Excess relative risk reaches a maximum approximately a decade after exposure and then declines with time.

  • The rate of exposure to radon affects lung cancer risk. Higher excess relative rates per unit exposure are associated with lower average exposure rates. In other words, among miners with equivalent cumulative exposure to radon, those exposed to lower levels for longer periods of time have a higher risk for lung cancer (Table 98-5).

  • An increased risk of lung cancer is seen in smoking miners compared with nonsmoking miners. The Committee on Biologic Effects of Ionizing Radiation (BEIR IV) concluded in 1988 that radon and smoking increased lung cancer risk in multiplicative fashion. However, a more recent review by Darby and Samet (1994) suggests that the two act only additively. Regardless, the combination of exposure to the two carcinogens is clearly worse than exposure to either alone.

    It should be noted that the numbers of lung cancer cases reported in nonsmoking miners is small due to a high prevalence of cigarette smoking in this working population. However, in a study of white underground uranium miners from Colorado by Waxweiler and colleagues (1981), nonsmoking miners had a higher relative risk for lung cancer as compared with all miners. This finding was also seen in a study of fluorspar miners in Newfoundland reported by Morrison and colleagues (1988). Such work emphasizes the potential importance of radon as a carcinogen in the nonsmoking population at large.

Uranium mining has now ceased in the United States. However, radon exposure continues to be an occupational concern in nonuranium mining and underground work in this country as well as in uranium and nonuranium mines around the world. In the United States, occupational exposure to radon is legislatively controlled. Individual exposure records are mandated for all workers in areas where the concentration of radon exceeds 0.3 WL, with an annual cumulative exposure limit of 4 WLM. The BEIR IV (1988) study estimated that a 40-year exposure at this level would increase a person's lifetime risk of lung cancer twofold. However, this is at best a rough estimate. Continued longitudinal evaluation of occupationally exposed persons is clearly necessary to improve our understanding of the carcinogenic effects of radon.

Table 98-5. Relative Risks and Average Exposure Rates in Miners Exposed to Radon

Mining Cohort Average Radon Exposure Rate (WLM/yr) Relative Risk of Lung Cancer (% per WLM) Reference
Malemberget, Sweden (iron) 5 3.6 Radford and Renard (1984)
Ontario, Canada (uranium) ~10 1.3 Muller et al. (1983)
Eldorado Port Northwest Territories, Canada (uranium) 109 0.27 Howe et al. (1986)
WLM, work-level month.
Modified from Darby SC, Samet JM: Radon. In Samet JM (ed): Epidemiology of Lung Cancer. New York: Marcel Dekker, 1994, p. 223. With permission.

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General Environment

The National Council on Radiation Protection and Measurements (1984) has identified radon and its decay products as the largest component of environmental radiation to persons living in the United States. Furthermore, radon is now recognized as the primary source of natural radiation to the bronchial epithelium (Table 98-6). These findings in conjunction with extrapolation of data collected in groups with high occupational radon exposure have escalated concern about the risks of lung cancer related to domestic radon.

The concentration of radon gas in the environment is usually expressed as the number of disintegrations of radon gas in a given volume of air over a given time period. This is usually expressed in Becquerels per cubic meter (Bq/m3), where 1 Bq/m3 equals one disintegration per second per cubic meter of air. Alternatively, radon concentration can be expressed in picocuries per liter (pCi/L). One pCi/L is equal to 37 Bq/m3. The average concentration of radon gas in the environment is 0.2 pCi/L. In a 1991 survey of homes in the United States, Samet and colleagues (1991) reported a mean indoor radon level of approximately 1.25 pCi/L. In this survey, the range of indoor radon levels was quite broad. Most homes had levels only slightly higher than outdoor environmental levels, but a few had levels ranging in excess of 100 pCi/L. The primary factor determining radon gas concentration in homes is the concentration of radium in the soil and rock beneath those structures. Building materials, well water, and natural gas are less common sources, usually contributing only minimally to indoor radon concentrations. Indoor-to-outdoor air exchange may also affect radon concentration within the home.

Broad concern for the public health implications of domestic radon exposure has been heightened by the documented carcinogenic effect of radon in miners. However, the potential for mutagenic and carcinogenic effects of low-level alpha radiation has been an area of controversy. A number of studies examining lung cancer risks from domestic exposure have been performed. A meta-analysis of eight such studies was reported by Lubin and Boice (1997). This analysis included 4,263 lung cancer and 6,612 control subjects. These authors concluded that greater residential exposure levels were associated with an increased relative risk of lung cancer. The overall estimated relative risk with exposure of 150 Bq/m3 was 1.14. This is consistent with extrapolation of risk from studies performed in miners as well as with actual calculated risks in miners with low cumulative radon exposure. It is important to note that this meta-analysis did not demonstrate any greater increase in lung cancer risk than what would be extrapolated from radon exposure in miners. This is important in that an inverse exposure-rate effect has been reported in miners by a number of groups, including Lubin and colleagues (1995), Darby and Doll (1990), Hornung and Meinhardt (1987), and Sevc and colleagues (1988). This effect describes the observation that for a given total radon exposure, lung cancer risk in miners increases as the duration of exposure increases and the exposure rate decreases. However, based on the results reported by Lubin and Boice (1997), concern that the exposure-rate effect might cause a relative increase in the carcinogenic effect of long-term, low-level domestic radon exposure appears to be unfounded.

Using miner-based risk models, it is now estimated that domestic radon may account for 7,000 to 36,000 lung cancer deaths in the United States per year. However, studies disputing this projection or demonstrating no increased risk even with high indoor domestic radon levels have also been reported, including those by Auvinen (1996), Blot (1990), Letourneau (1994), and Alavanja (1994) and their colleagues. Cohen (1995) concluded that use of a theoretic linear no-threshold relationship to extrapolate known risks in miners with high radon exposure levels to risk in persons with residential radon exposure grossly overestimates lung cancer risk. Cohen pointed out that the effects of low-dose, low-rate radiation have never been adequately evaluated, and he contested the assumptions inherent in extrapolation of high radon exposure to domestic situations.

Table 98-6. Estimated Annual Average Dose Equivalents from Natural Radiation in the United States

Source of Radiation Average Annual Dose Equivalent (mSv) Annual Effective Dose Equivalent Whole Body (mSv)
Bronchial Epithelium Other Soft Tissues Bone Surface Bone Marrow
Cosmic 0.27 0.27 0.27 0.27 0.27
Terrestrial gamma 0.28 0.28 0.28 0.28 0.28
Cosmic radionuclides 0.01 0.01 0.01 0.03 0.01
Inhaled radionuclides (mainly radon) 24.00 2.00
Other radionuclides in the body 0.36 0.36 1.10 0.50 0.39
All sources ~25.0 0.9 1.7 1.1 ~3.0
From Darby SC, Samet JM: Radon. In Samet EM (ed): Epidemiology of Lung Cancer. New York: Marcel Dekker 1994, p. 230. With permission.

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A study by Hei and co-workers (1997) addresses this issue. Using a novel and unique technique of microbeam irradiation of cell nuclei, the biologic effects of a single or known number of alpha particle traversals on genetic mutation and cytotoxicity were evaluated in single cells. Heretofore, the effect on cells of a traversal by a single alpha particle had been controversial, as noted by Cohen (1995). Hei's group (1997) points out that a single alpha particle hit to a cell is the most relevant to the general population, because environmental radon exposure levels make the probability of multiple traversals in a single cell very low. In their study, this group makes several important observations. The first is that 80% of cells traversed by a single alpha particle survive that exposure. This answers earlier speculation that a single alpha particle traversal would likely cause cell death rather than result in genetic mutations. Hei and colleagues (1997) were able to show that 10% of cells survived even up to eight alpha particle traversals. The second important observation was that in cells surviving alpha particle exposure, the frequency of gene mutation after a single traversal was enhanced twofold. The third was that the frequency of mutation was further increased in cells traversed by up to eight alpha particles, although multiple hits were associated with higher cytotoxicity.

The National Research Council Committee on Health Risks of Exposure to Radon (1994) estimates that 1 in 107 bronchial cells will be subject to alpha particle exposures per year. Given this, the results of the work by Hei and colleagues (1997) would indicate that a small number of bronchial epithelial cells are at significant risk of radiation-induced mutation. Assuming that genetic mutation may be an early step in induction of cancer, these data suggest that environmental and indoor radon exposure does indeed constitute a significant public health problem in its potential contribution to the development of lung cancer. Thus, further evaluation of the effects of domestic radon on the lung cancer epidemic would appear to be justified and warranted.

Other Occupational Carcinogens

Asbestos and radon are the best known of the known occupational lung carcinogens. A number of other lung carcinogens have been identified, relating to a wide array of occupations (see Tables 98-2 and 98-3). Steenland and colleagues (1996) from the National Institute for Occupational Safety and Health (NIOSH) estimated that approximately 9,000 to 10,000 men and 900 to 1,900 women per year in the United States develop lung cancer related to exposure to occupational carcinogens. Although over half of these are related to asbestos, a substantial number remain that are attributable to other exposures. Further, because these figures apply only to known carcinogens, they likely underestimate the actual number of lung cancer cases related to occupational exposures and represent another area in which prevention may play an important role.

DIET

It is generally accepted that diet may be a significant cofactor in the development of cancer. Retinoids, including retinol (vitamin A) and its precursor carotenoids, such as -carotene, have been the most intensively studied. One of the most widely cited reports of the effect of diet on the development of cancer was a prospective survey of 2,080 men aged 40 to 55 employed by the Western Electric Company performed by Shekelle and colleagues (1981). Detailed dietary histories of these men were taken in 1957. The cohort was then followed over 19 years. In this study, -carotene intake was inversely related to lung cancer incidence. Subsequent studies, including those by Cade and Margetts (1991) and Stryker and colleagues (1988), demonstrated that smokers have lower serum -carotene levels than nonsmokers. These and other studies have suggested that vitamin A and -carotene may have a protective effect against lung cancer. Byers (1994) evaluated 27 such studies published prior to 1994 and concluded that persons in the lowest quartile of carotene intake had an approximately 50% to 100% increase in lung cancer risk as compared with persons in the highest quartile. Thus, by 1994 the cumulative information suggested that -carotene and vitamin A might be useful as cancer chemopreventive agents.

Three important large-scale epidemiologic studies were performed to address this possibility. The Alpha-Tocopherol, Beta Carotene Cancer Prevention (ATBC) Study (1994) was a randomized, double-blind, placebo-controlled trial designed to determine whether daily supplementation of alpha-tocopherol, -carotene, or both could reduce the incidence of cancers, including cancer of the lung. The study enrolled 29,133 male smokers aged 50 to 60 in Finland. Unexpectedly, a higher than expected mortality, primarily due to lung cancer and heart disease, was observed in the group receiving -carotene. Omenn and colleagues (1996a, 1996b) then reported results of the Beta-Carotene and Retinol Efficacy Trial (CARET), also a randomized, double-blind, placebo-controlled study. The study was intended to determine whether dietary supplementation with -carotene, vitamin A, or both would decrease the incidence of lung cancer. It enrolled 18,314 men and women felt to be at increased risk for lung cancer. The CARET study (1996) was stopped 21 months early because of clear evidence of no benefit and substantial evidence of harm. As compared with placebo, the group that received both vitamin A and -carotene experienced a 17% increase in mortality and a 28% increase in the number of lung cancers.

A third randomized, double-blind, placebo-controlled trial, the Physicians Health Study reported by Hennekens and colleagues (1996), evaluated the effect of -carotene in 22,071 male physicians. Eleven percent were current smokers and 39% former smokers at the onset of the trial. Over 12 years of follow-up, neither benefit nor harm in terms of malignancy or cardiovascular disease was demonstrated. Of note, the dose of -carotene in this trial was lower than both the ATBC trial and the CARET study.

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Based on a large body of epidemiologic studies, a balanced dietary intake of fruits and vegetables, including those containing -carotene, should be encouraged. Ongoing efforts to identify food components that may be protective against cancer continue. On the basis of the findings of the ATBC and CARET trials, the use of supplemental -carotene and vitamin A should be discouraged. The final word about the role of dietary supplementation in cancer chemoprevention is not out. However, these studies should serve as a reminder that indiscreet and excessive intake of vitamins or other chemicals can be potentially harmful.

CONCLUSION

At present, the 5-year survival rate for lung cancer is only 14%. This is in stark contrast to the 5-year survival rates for the other leading causes of cancer death in the United States, including cancers of the colon (63%), breast (86%), and prostate (90%). The absolute number of lung cancer cases continues to be alarming, with the continued rise of lung cancer in women a particularly disturbing feature. The role of tobacco as an etiologic factor in lung cancer has been convincingly established. Likewise, ionizing radiation and certain occupational exposures have been recognized as carcinogenic. The challenge in the future will be to modify the impact of these identified external sources of risk while continuing to expand our knowledge of the genetic and molecular basis of carcinogenesis.

It is clear that early diagnosis of lung cancer should be considered imperative, because the 5-year survival rate for treated stage I lung cancer is substantially better than for stages II to IV. The issue of benefit related to lung cancer screening is being actively revisited. The American Cancer Society does not currently recommend routine screening for lung cancer. Prior trials from the 1970s and 1980s demonstrating no reduction in cancer mortality despite screening by chest radiograph effectively eliminated such testing. Petty (1997) points out that groups at high risk, specifically heavy smokers with spirometric and clinical evidence of airflow obstruction, can be easily identified. Many clinicians feel that screening with chest radiograph and sputum cytology in such groups might be justifiable. It is hoped that ongoing trials evaluating chest radiography, chest computed tomographic scanning, and sputum cytology will clarify this controversial issue.

At present, with a quarter of the American population still smoking cigarettes, continued efforts must be directed at smoking cessation and at preventing persons from becoming addicted to smoking. Although work in the field of lung cancer treatment remains extremely important, the dismal mortality associated with this disease demands that the medical profession contribute to efforts aimed at limiting its primary cause. If tobacco smoking could be eliminated, or at least severely curtailed, we might then be able to return lung cancer to its designation by Adler at the turn of the 20th century as among the rarest forms of disease.

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General Thoracic Surgery. Two Volume Set. 6th Edition
General Thoracic Surgery (General Thoracic Surgery (Shields)) [2 VOLUME SET]
ISBN: 0781779820
EAN: 2147483647
Year: 2004
Pages: 203

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