12
Summary and Recommendations

SUMMARY

In addressing its charge of whether asbestos exposure plays a causal role in the occurrence of pharyngeal, laryngeal, esophageal, stomach, or colorectal cancer, the committee reviewed a broad array of evidence from observational and experimental research. Its review emphasized epidemiologic studies of cancer rates in cohorts of asbestos-exposed workers and of risk factors in sets of individuals with cancer at the selected sites in comparison to the general population. The observational evidence was systematically identified and evaluated for its consistency and strength of association. The committee also considered the biologic plausibility of causal associations of asbestos with cancers at the specified sites, recognizing that asbestos is an established cause of mesothelioma and lung cancer. The full committee reviewed the final integration of the evidence to assure uniformity of application of the causal criteria across the sites.

Of the five sites considered, the committee found the evidence to be sufficient to infer a causal relationship for laryngeal cancer; to be suggestive for pharyngeal, stomach, and colorectal cancers; and to be inadequate for esophageal cancer. Most of the non-epidemiologic evidence does not indicate any particular site as being the target of carcinogenic action by asbestos in humans; that evidence and the complementary epidemiologic evidence do establish with certainty that asbestos is a human carcinogen. Although correspondence of tumor sites in humans and experimental animals would constitute intuitively appealing evidence and would likely be mechanistically consistent, it should be noted, however, that empirical con-



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12 Summary and Recommendations SUMMARY In addressing its charge of whether asbestos exposure plays a causal role in the occurrence of pharyngeal, laryngeal, esophageal, stomach, or colorectal cancer, the committee reviewed a broad array of evidence from observational and experimental research. Its review emphasized epidemio- logic studies of cancer rates in cohorts of asbestos-exposed workers and of risk factors in sets of individuals with cancer at the selected sites in com- parison to the general population. The observational evidence was system- atically identified and evaluated for its consistency and strength of associa- tion. The committee also considered the biologic plausibility of causal associations of asbestos with cancers at the specified sites, recognizing that asbestos is an established cause of mesothelioma and lung cancer. The full committee reviewed the final integration of the evidence to assure unifor- mity of application of the causal criteria across the sites. Of the five sites considered, the committee found the evidence to be sufficient to infer a causal relationship for laryngeal cancer; to be sugges- tive for pharyngeal, stomach, and colorectal cancers; and to be inadequate for esophageal cancer. Most of the non-epidemiologic evidence does not indicate any particular site as being the target of carcinogenic action by asbestos in humans; that evidence and the complementary epidemiologic evidence do establish with certainty that asbestos is a human carcinogen. Although correspondence of tumor sites in humans and experimental ani- mals would constitute intuitively appealing evidence and would likely be mechanistically consistent, it should be noted, however, that empirical con- 230

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231 SUMMARY AND RECOMMENDATIONS sideration of epidemiologic and experimental findings for known carcino- gens have demonstrated that site-specificity is not necessarily the rule across species. Documentation of persistence of fibers at a target site would repre- sent important evidence in support of biologic plausibility. Although in- haled asbestos fibers clearly pass by the tissues in question in this report, either directly or by swallowing secretions following clearance from the respiratory tract, investigations on fiber persistence in the target organs with definitive findings proved to be unfortunately sparse. Consequently, the epidemiologic data did, in large part, influence the committee’s decision-making for these five sites. The inference of causality for laryngeal cancer reflects the consistency of the evidence from a substantial number of both worker cohorts and general-population case-control studies, an indication of greater risk among more highly exposed persons, and the finding of an association with expo- sure in studies that addressed potential confounding by tobacco-smoking and alcohol consumption. In considering biologic plausibility, the commit- tee noted that the epithelium of the larynx is similar to the respiratory epi- thelium lining the conducting airways of the lung. Inhaled fibers pass through the larynx and may deposit there; although fiber deposition and persistence in the larynx have not been studied extensively, there are reports of fibers and asbestos bodies being recovered from laryngeal tissues. For all the sites for which the evidence was classified as suggestive, the case-control information was less abundant than for laryngeal cancer. For stomach and colorectal cancers, there actually were a few more informative cohorts, but fewer than half as many cohorts provided data on pharyngeal cancer as had on laryngeal cancer. The committee’s review found less con- sistency among the findings of the individual studies for these sites and there was only limited indication of exposure-response relationships. As- bestos fibers could pass through the lumen of the pharynx, stomach, and colon and rectum, but it is uncertain how fibers might interact with the presumed target for carcinogenesis, the cells of the epithelium. Despite spo- radic reports of asbestos bodies or fibers being recovered from stomach and colon tissue, information was lacking on the fiber doses received by target cells in the gastrointestinal epithelium. Relevant animal evidence was avail- able from feeding studies, which showed the induction of colon polyps in rats but not the production of malignancy. The evidence was most sparse for cancer of the esophagus, for which the designation was inadequate. There was a suggestion of an exposure- response relationship from the available cohort studies, but the summary estimate of 0.99 for any asbestos exposure was indicative of no association. Only three case-control studies were identified, and investigation of poten- tial confounding was limited. Animal-feeding studies did not show produc- tion of esophageal cancers.

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232 ASBESTOS RECOMMENDATIONS This committee was charged with reviewing evidence on a widely used material that is known to cause respiratory malignancy. Asbestos has been extensively investigated as a cause of mesothelioma and lung cancer with epidemiologic and experimental approaches. However, its potential to cause malignancy at other sites that may also be exposed to substantial numbers of asbestos fibers has not been as extensively investigated; little effort has gone into determining delivered or effective dose at these extrapulmonary sites. Much of the information reviewed by the committee came from co- hort studies of workers that focused on investigating respiratory effects; information on risks of other diseases, including cancers at the site covered by this committee’s charge, was reported only incidentally. Other evidence came from case-control studies directed at the causes of the cancers at the sites of interest, but these studies were not specifically designed to address asbestos exposure and their exposure assessments varied in quality. The committee’s review identified limitations of the available evidence that contributed uncertainty to its conclusions. Although the committee was not charged with developing a research agenda to address the informa- tion gaps, its review found many research needs. Research should address the relevance of physical and chemical characteristics of asbestos fibers to carcinogenicity. Studies directed at doses of fibers received by organs other than the lung are needed; mechanistic studies directed at these organs could prove to be a useful complement to ongoing work on the respiratory carci- nogenicity of asbestos fibers. Studies involving animal models with high risk for cancer of the designated sites might also be useful. In addition, consideration should be given to approaches to strengthen the epidemio- logic information on asbestos exposure and risk of cancers at the sites in the committee’s charge. Information might be gained from further follow-up of some of the cohorts of asbestos-exposed workers; however, the committee is concerned that further study of these cohorts may no longer be possible in that most were initiated decades ago and their records may not have been maintained. Some effort might be made to determine whether key cohorts could be followed up or new studies started on potentially informative populations.