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Institute of Medicine (US) Committee on Asbestos: Selected Health Effects. Asbestos: Selected Cancers. Washington (DC): National Academies Press (US); 2006.

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Asbestos: Selected Cancers.

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9Esophageal Cancer and Asbestos

NATURE OF THIS CANCER TYPE

The esophagus is a muscular tube that carries food and liquid from the mouth to the stomach (Figures 7.1 and 9.1).

FIGURE 9.1. Anatomy of the esophagus, colon, rectum, and other digestive organs.

FIGURE 9.1

Anatomy of the esophagus, colon, rectum, and other digestive organs. SOURCE: Copyright 2005 American Cancer Society, Inc. Reprinted with permission from www.cancer.org.

The American Cancer Society (Jemal et al. 2006) has estimated that 14,550 new cases of and 13,770 deaths from esophageal cancer (ICD-9 150; ICD-O-3 C15.0-15.9) will occur in the United States in 2006. Esophageal cancer ranks 19th in numbers of cases of cancer in the United States and sixth in developing countries (Kleihues and Stewart 2003).

The incidence is nearly 4 times higher in men than in women in the United States and slightly higher among blacks than among whites. The incidence has increased among men by an average of 1.7% per year since 1975, although the predominant histologic type and location of cancers in the esophagus have changed since the 1970s in most economically developed countries. Historically, the most common form of esophageal cancer worldwide was squamous-cell carcinoma, which occurred largely in the upper two-thirds of the esophagus (Blot 1994). Since the 1970s, the incidence of adenocarcinoma of the lower one-third of the esophagus and the junction with the stomach has increased by a factor of more than 5 among white and black men in the United States, whereas the incidence of squamous-cell carcinoma has decreased moderately. Rates of adenocarcinoma are also rising in women but are much lower than in men. Adenocarcinoma now makes up more than half of the esophageal cancers in white males, whereas squamous-cell carcinoma remains the predominant histologic type among black people and in high-incidence populations worldwide (Blot and McLaughlin 1999).

The incidence of carcinoma of the esophagus varies widely among countries. In regions extending from Iran through the steppes of Central Asia, Mongolia, and the northern portion of China, cancer frequencies are 10-100 times higher than in the countries at lowest risk. Squamous-cell carcinoma still predominates in the areas of high endemic risk, whereas adenocarcinoma now makes up about 50% of all cases in the low-risk areas of the United States, Europe, South Africa, Southeast Asia, and Japan.

The known risk factors differ somewhat for the two major histologic types of esophageal cancer. Known risk factors for squamous-cell carcinoma include all forms of tobacco-smoking (cigarettes, cigars, pipes, and bidis), use of chewing tobacco or snuff, and excessive consumption of alcohol. The combination of tobacco use and alcohol consumption potentiates the risk of either factor alone. Factors known to increase the risk of adenocarcinoma include chronic esophageal reflux (regurgitation of stomach acid and bile through the lower esophageal sphincter into the lower esophagus), obesity (which contributes to reflux), smoking, and achalasia (a type of esophageal dysfunction).

Adenocarcinoma of the esophagus develops from Barrett’s esophagus, a premalignant condition in which normal squamous epithelium of the lower esophagus is replaced with metaplastic columnar epithelium. The main cause of Barrett’s esophagus is thought to be chronic gastroesoph ageal reflux. People with Barrett’s esophagus are at increased risk for developing cancer of the esophagus and should be followed closely by their doctors. Even though they are at greater than average risk, most people with Barrett’s esophagus do not develop cancer of the esophagus.

EPIDEMIOLOGIC EVIDENCE CONSIDERED

Cohort Studies

The cohorts that presented usable information on the risk of esophageal cancer were indicated in Table 6.1. Their histories and design properties are described in Table B.1, and the details of their results concerning cancer at this site are abstracted in Table D.3. The results of both the cohort and case-control studies are summarized in Table 9.1, and Figures 9.2 and 9.3 are plots of relative risks (RRs) for overall exposure and for exposure-response gradients from the cohort studies reviewed.

TABLE 9.1. Summary of Epidemiologic Findings Regarding Cancer of Esophagus.

TABLE 9.1

Summary of Epidemiologic Findings Regarding Cancer of Esophagus.

FIGURE 9.2. Cohort studies: RR of esophageal cancer in people with “any” exposure to asbestos compared with people who report no exposure.

FIGURE 9.2

Cohort studies: RR of esophageal cancer in people with “any” exposure to asbestos compared with people who report no exposure.

FIGURE 9.3. Cohort studies: RRs of esophageal cancer among people in extreme exposure category compared with those with none (◆ = more than one exposure gradient reported in citation, so the plot contains both highest and lowest estimates of risk for extreme category over all gradients).

FIGURE 9.3

Cohort studies: RRs of esophageal cancer among people in extreme exposure category compared with those with none (◆ = more than one exposure gradient reported in citation, so the plot contains both highest and lowest estimates of risk for extreme (more...)

Few studies presented data explicitly on esophageal cancer, because of its rarity. Therefore, observed numbers, and hence statistical precision, were low. Only UK asbestos-factory workers (Berry et al. 2000) and North American insulation workers (Selikoff and Seidman 1991) showed strong evidence of increased risk with any asbestos exposure. A suggestion that risk might be dose-dependent was seen among Finnish anthophyllite miners (Meurman et al. 1994) and UK textile workers (Peto et al. 1985). The aggregate estimated risk for all 25 cohort populations with information on esophageal cancer risk following any exposure to asbestos was neutral (RR = 0.99, 95% CI 0.79-1.27).

Case-Control Studies

The three case-control studies retained for thorough evaluation after excluding studies that did not assess exposure to asbestos or did not meet other exclusion criteria are listed Table 6.5 according to quality of their exposure assessment. The details of the design aspects of these studies are presented in Table C.1 and their detailed results are abstracted in Table E.3. The findings of the studies are summarized in Table 9.1; data were inadequate to perform a meta-analysis.

There were two large, well-designed studies with asbestos exposure well assessed and analyses that adjusted for smoking, alcohol consumption, and other risk factors. Parent et al. (2000) assessed the relationship between esophageal cancer and occupational exposures as part of a large, population-based case-control study of men 35-70 years old in the Montreal area. A small excess was observed in esophageal cancers of all types, which decreased slightly when only substantial exposure was considered. A larger excess was observed for squamous-cell cancers specifically, which disappeared when only substantial exposure was considered. Although 21 cases were assessed as having some association with exposure to chrysotile asbestos, there were very few cases with substantial exposure (two overall, including one squamous-cell). Gustavsson et al. (1998) conducted a case-control study of occupational exposure and squamous-cell esophageal cancer among Swedish men 40-79 years old. No association was found with either low or high exposure.

The remaining study had an unusual design. Hillerdal (1980) conducted a case-control study of gastrointestinal cancer among participants in a general health survey conducted in Uppsala County, Sweden, in 1968-1972. Overall, 65-75% of the general population of the region and 80% of people with gastrointestinal cancer participated in the survey, which required a chest x-ray. Cases were identified through the Swedish Cancer Registry, and three controls, matched on age, were chosen for each case. Participants with bilateral pleural plaques were considered exposed. Results were presented as a ratio of observed exposed cases to expected, based on the rate in controls. One of the 21 people with esophageal cancer cases had pleural plaques vs 0.35 expected.

EVIDENCE INTEGRATION AND CONCLUSION

Evidence Considered

Both case-control and cohort studies of esophageal cancer were reviewed. Only three case-control studies met the criteria for inclusion, and so there were too few for a useful quantitative meta-analysis. There were relevant results from 25 cohort populations, although the number of cases was often small. The mortality studies did not distinguish between histologic subtypes, so associations could have been obscured. In assessing biologic plausibility, the cell type, potential dose at the target tissues, results, and possible mechanisms were considered. Findings related to the response to asbestos by esophageal tissues were evaluated from several well con ducted chronic rodent studies, four with inhalation exposure and six with dietary administration.

Consistency

The three case-control studies did not have consistent results, and the number of exposed cases was generally small. Two incorporated adjustment for tobacco and alcohol consumption; one of these observed an excess risk of squamous-cell cancer without evidence of a dose-response relationship, and the other found no evidence of an excess. A third, older study found an excess based on a single case, which was difficult to interpret.

Because of the relative rarity of esophageal cancer, few cohort studies presented data explicitly on this endpoint; and when they did, the statistical precision was routinely low. The results of the 20 citations that presented information on esophageal cancer in 25 cohort populations were mixed. Berry et al. (2000) and Selikoff and Seidman (1991) saw strong evidence of increased risk with any exposure, while Meurman et al. (1994) and Peto et al. (1985) found some evidence of a dose-response relationship. Findings from the remaining studies either were close to null, presented mixed or inconsistent results, or indicated lower than expected risks.

Strength of Association

There were too few case-control studies for a meaningful combined analysis. Several cohort studies did observe a dose-response relationship based on relatively small numbers; but when all 25 cohort populations were considered in the meta-analysis, no increase in RR was observed. Some studies did observe excess risks, but overall there was little consistency in the epidemiologic data.

Coherence

The most common histologic type of cancer arising in the upper two-thirds of the esophagus is squamous-cell carcinoma. That is probably the most common histologic type encountered in the epidemiologic studies of workers in the 1970s and earlier. The major risk factors are tobacco-smoking and tobacco-chewing, snuff use, and alcohol consumption. Since the 1970s, the major histologic type of esophageal cancer has been adenocarcinoma arising in the lower one-third of this anatomic region. Major risk factors for this type of esophageal cancer are reflux, obesity, achalasia, and tobacco-smoking. Although the combination of asbestos exposure and tobacco-smoking is an established risk factor for lung cancer, there is no epidemiologic or experimental evidence addressing whether asbestos is a cofactor with tobacco use or alcohol consumption in the development of esophageal cancer.

Asbestos bodies have been identified in the esophagus (Kobayashi et al. 1987), but contamination during collection or processing of tissue samples is a possibility, as discussed in Chapter 4.

No increase in esophageal tumors has been observed in animals exposed chronically to asbestos either by inhalation (Hesterberg et al. 1993, 1994; McConnell 2005; McConnell et al. 1994a,b, 1999) or by oral feeding (HHS 1983, 1985, 1988, 1990a). There is no other experimental evidence that asbestos fibers act as a direct or indirect carcinogen specifically in the esophagus.

Conclusion

Some studies have found an association between asbestos exposure and esophageal cancer, but the overall results of epidemiologic studies are mixed. In addition, what little evidence there is from animal experiments about asbestos’s carcinogenic potential specifically on esophageal tissues does not support biological activity at this site. On the basis of those observations, the committee concluded that the evidence is inadequate to infer the presence or absence of a causal relationship between asbestos exposure and esophageal cancer.

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