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/\^>bes+D^'5 mo What is Asbestosis? Dorsett D. Smith, M.D., F.C.C.P. (Chest 1990; 98:963-64) r) 'he term asbestosis has been defined as diffuse interstitial fibrosis of the lung parenchyma caused by exposure to asbestos.1 Controversy has raged over the site of pulmonary fibrosis. Beilis and others2 have considered the earliest lesion to be in the walls of the respiratory bronchioles and alveolar ducts. Churg1 and others believe that abnormal respiratory bronchioles and alveolar ducts are a separate and nonspecific reaction to many types of mineral dust exposures and that true asbestosis is a diffuse type of parenchymal fibrosis surrounding the small airways but not just limited to the small airways. Kilburn and Warshaw provide us, in this issue (see page 965), with a provocative study which concludes that small airways disease is present in individuals with asbestos expo sure who do not meet the standardized criteria for asbestosis: restrictive lung disease, or reduced diffu sion, abnormal gas transport, or ILO x-ray profusion abnormalities of 1/1 or greater that cannot be explained by some coexisting disease process such as diffuse pleural thickening, emphysema, malignancy, or some other disorder. These patients must also fulfill the criteria of having significant exposure to asbestos, as well as having an appropriate latency period since first exposure to asbestos before the diagnosis can be reasonably considered.3-5 If Kilburn's hypothesis of a continuum of asbestosrelated disease beginning in the small airways and progressing to diffuse interstitial fibrosis is correct, then pathologic proof should be available to support this hypothesis. The studies of Beilis et al2 have shown a lack of correlation between airway lesions and asbestos body and fiber counts. No correlation with pleural plaques was found. Pathologic examination demonstrates small airways disease in workers with asbestos exposure, with and without asbestosis.631 Data are lacking to establish any relationship between small airways disease and symptoms or functional impair ment. Perhaps the most elegant studies published were performed by Begin and co-workers.910 They were able to detect significant small airways impair- Clinica] Professor of Medicine, Division of Pulmonary Disease and Critical Care, University of Washington Medical Center. Seattle Reprint requests: Dr Smith, Respiratory Diseases, M/S^Rm 12, University of Washington School of Medicine, Seattle 98195 ment only in those patients who had restrictive lung disease, but were unable to detect reduced expiratory rates on the flow volume curves of lifetime non smokers with asbestosis. The study of Kilburn and Warshaw makes the common error of using a test with great variability and poor reproducibility to prove a hypothesis, ie, the FEF25-75 and FEF75-85.1'-'2 The data are further confounded by comparing apples with oranges, or industrial workers with multiple types of heavy dust or fume exposure to a control group from Michigan which consists mostly of rural healthy farmers. The proposed correlation between pleural plaques and small airways dysfunction will need further con firmation. Pleural plaques occur more frequently in smokers,13 presumably due to the effect of smoking on mucociliary function. Perhaps welding smoke and other dusts and fumes may also adversely affect mucociliary function and, hence, cause greater fiber retention and a greater frequency to form pleural plaques. If, at a standardized exposure, a population with welding fume and mineral dust exposure has a higher frequency of pleural plaques than the control group, one would anticipate that there might be other asbestos-related disorders also associated with the enhanced fiber retention. While the hypothesis has merit, an epidemiologic study is unlikely to provide an answer. On chest x-ray film, pleural plaques are seen in only approximately 15 percent of patients in whom they are found at autopsy.19 This means that the majority of patients who have pleural plaques have plaques which are not visible on x-ray examination. There is such great difficulty in finding plaques in a reproducible fashion on chest x-ray examination that any correlation with small airways disease would seem to be spurious. The gold standard is the pathologic correlation between pleural plaques found at autopsy and small airways disease noted in tissue sections. Most recent studies have found no correlation between small airways disease and pleural plaques at autopsy, and therefore, the data of Kilburn et al are interesting, but certainly not convincing of any true association. The medical/legal implications of the study by Kilburn and Warshaw are enormous if one accepts their hypothesis that small airways disease is the CHEST / 98 / 4 / OCTOBER, 1990 963 I I i jl ji ii i ;i I CAT-1016911 029 earliest stage of asbestosis and that pleural plaques pleural thickening. This is an arbitrary standard for r are a radiologic sign ofcoexisting small airways disease. epidemiologic purposes and is not meant to preclude If this were the case, then all lung cancers occurring the possibility of diffuse pleural thickening in the in patients with pleural plaques would be considered absence of blunting of the costophrenic angle. Hope attributable to asbestos exposure due to underlying fully, a perspective study with thin-slice, high resolu early asbestosis. Patients with pleural plaques could tion CT scanning should further clarify the interrela seek compensation for "fear of lung cancer," as well tionship between lung function abnormalities and as increased risk of lung cancer related to asbestos asbestos related pleural disease. exposure. Presently, the available data indicate that pleural plaques do not indicate disease, but simply References reflect a pleural injury related to asbestos exposure. 1 Churg A. The diagnosis of asbestosis. Hum Pathol 1989; 20: Exposure may be very remote and very small such as occurring in household contacts ofasbestos workers.15 Pleural plaques are not associated with abnormalities in pulmonary function or exercise impairment16 unless 97-9 ' 2 Beilis D, Andrion A, Delsedime L, Mollo F. Minimal pathologic changes of the lung and asbestos exposure. Hum Pathol 1989; 20:102-06 3 Craighead J, Abraham J, Churg A, Creen F, Kleinerman J, Pratt there is evidence of diffuse pleural thickening. Many other studieshave demonstrated small airways disease in asbestos-exposed workers, as well as other types of mineral dust exposure. Abnormalities of small airway function are nonspecific and may be caused by a E Pathology standards for the diagnosis of asbestos related diseases. Arch PathoJ Lab Med 1982; 106:541 4 Murphy R, Becklake M, Brooks S, Gaensler E, Gee B, Goldman A. The diagnosis of non-inalignant diseases related to asbestos. Am Rev Respir Dis 1986; 134:363 5 Smith D, Agostoni R The discriminatory value of the P(A-a)0. variety of industrial exposures,8 as well as being secondary to cigarette smoking Cigarette smoking may be remote as in household contacts of cigarette smokers.17 In patients with interstitial pulmonary disease ofany type, small airways disease is common,18 during exercise and the detection of asbestosis in asl>estos exposed workers. Chest 1989; 95:52-5 6 Churg A, Wright J. Small airways disease and mineral dust exposure. In: Sommers C, Rosen R eds. Pathology annual, 1983, part II. New York: Appleton-Century-Crofts. 1983; 233-51 7 Churg A. Asbestos fiber content of the lungs in patients with but since it is also commonly found in individuals and without asbestos airways disease. Am Rev Respir Dis 1983; without interstitial fibrosis, small airways disease means small airways disease and nothing more. There is no pathologic evidence and there is no epidemiologic 127:470-73 8 Churg A, Wright J, Wiggs B, Pare P, Lazar N. Small airways disease and mineral dust exposure. Am Rev Respir Dis 1985; 131:139-43 i evidence that small airways disease progresses to 9 Begin R, Cantin A, Berthiaume Y, Boiieau R, Peloquin S, Massd asbestosis in man. S. Airway function in lifetime-nonsmoking older asbestos work The other issue addressed by Kilburn and Warshaw is the possible relationship between pleural disease and lung function impairment. Recently, Schwartz et ers. Am J Med 1983; 75:631-38 10 Begin R, Boiieau R, Peloquin S. Asbestos exposure, cigarette smoking, and airflow limitation in long-term Canadian chrysotile miners and millers. Am J Indus Med 1987; 11:55-66 j al19 also reviewed the correlation between pleural 11 Buist AS. Current status of small airways disease. Chest 1989; disease and abnormalities in lung function in a similar 86.100-05 population of 1,223 sheet-metal workers. They noted an association between circumscribed pleural plaques and a fall in FVC, as well as a slight but significant 12 Berend N, Wright J, Thurlbeck W, Marlin G, Woolcock A. Small airways disease: reproducibility of measurements and correla tion with lung function. Chest 1981; 79:263-68 13 Finkelstein M, Vingilis. Radiographic abnormalities among increase in the FEV,/FVC ratio. This is the opposite asbestos-cement workers. Am Rev Respir Dis 1984; 129:17-22 conclusion to that of Kilburn and Warshaw who noted obstructive but not restrictive changes in their cohort. Schwartz and co-workers have also raised the question about the possible association between circumscribed pleural plaques and subclinical alveolitis, not visible 14 Hourihane D, Lessof L. Richardson P. Hyaline and calcified pleural plaques as an index of exposure to asbestos: a study of radiological and pathological features of 100 cases with a consideration of epidemiology. Br MedJ 1966; 1:1069-74 15 Kilburn K, Lib's R, Anderson H, Boylen T, Einstein H, Johnson S, et al. Asbestos disease in family contacts of shipyard workers. on a chest x-ray film, as the possible cause for these restrictive changes. An alternative explanation for these findings would be the coexistence of diffuse pleural disease in patients with circumscribed pleural plaques which spares the costophrenic angle. In my Am J Pub Health 1985; 75:615-17 16 Agostoni R Smith D, Schoene, Robertson H, Butler J. Evalua tion of breathlessness in asbestos workers. Am Rev Respir Dis 1987; 135; 812-16 17 White J, Froeb H. Small airways dysfunction in nonsmokers chronically exposed to tobacco smoke. N Engl J Med 1980; experience, it is not uncommon to find both diffuse pleural thickening and circumscribed pleural plaques occurring simultaneously in patients with asbestosrelated pleural disease and unexplained restrictive changes. The ILO Standards require blunting of the 302:720-23 18 Fulmer J, Robert W Small airways and interstitial pulmonary disease. Chest 1980: 77, 470-73 19 Schwartz D, Fuortes L, Galvin J, Burmeister L,Schmidt L, Leistikow B, et al. Asbestos-induced pleural fibrosis and im paired lung function. Am Rev Respir Dis 1990; 141:321-26 costophrenic angle to make a diagnosis of diffuse CAT-1016912 029 Vol.' 320 No. 26 ASBESTOS-RELATED DISEASES -- MOSSMAN AND GEE 1721 66. Hawihone studies, to: Mitchell J, Stein i, eds. The Random House ency clopedia. New Yoric: Random House, 1983:2262. 67. Bumie IP, Odds FC. Lee W, Webster C, Williams ID. Outbreak of systemic Candida albicans in intensive care unit caused by cross infection. Bt Med] 198S; 290:746*8. 68. PhclpeM, AyliffeGA.BabblR. An outbteak ofcandidiasis in a special care baby unit: the use of a resistogram typing method. J Hosp Infect 1986; 7:13 20. 69. Valenti WM, Menegus MA, Hall CB, Pincus PH, Douglas RH Jr. Nosoco mial vital infections. 1. Epidemiology and significance. Infect Control 1980; 1:33-7. 70. Kellerman J, Rigler D, Siegel SE. The psychological effects of isolation in protected environments. Am J Psychiatry 1977; 134:363-3. 71. Holland i. Plumb M, Yates J, et al. Psychological response of patients with acute leukemia to germ-free environments. Cancer 1977; 40:871 9. 72. Stoutcnbcek CP, vanSaene HK. Mitanda DR, Zandslre DH. The effect of selective decontamination ofthe digestive tract on colonisation and infection rate in multiple trauma patients. Intensive Care Med 1984; 10:183*92. 73. Unettl K, Ruckdeschel G, Selbmann HK, et al. Prevention of colonization and tespiiatoty infections in long-lenn ventilated patients by local antimi crobial prophylaxis. Intensive Care Med 1987; 13:106-13. 74. Clasener HA, Votlaard El, vanSaene HK. Long-term infection prophylaxis by selective decontamination in leukopenia and in mechanical ventilation. Rev Infect Dis 1987; 9293-328. 73. Graham DR, Conea-Villasenor A, Anderson L, Vollman JH, Baine WB. Epidemic neonatal gentaniicin-methicillin -- resistant Staphylococcia au reus infection associated with nonspecific topical use of gentamicin, i Pe- diatr 1980; 97:972-8. 76. Feeley TW, du Moulin GC, Hedley-Whyte J. Bushnell LS, GUbert IP, Eeingold DS. Aerosol polymyxin and pneumonia in seriously ill patients. N Engl 7 Med 1975; 293:471-5. w MEDICAL PROGRESS ASBESTOS-RELATED DISEASES Brooke T. Mossman, Ph.D., and J. Bernard L. Gee, M.D. A SBESTOS is a mineral causing much controversy l \ in today's society. Before the passage and enact ment of the Occupational Safety and Health Act of 1970, millions of Americans were exposed to relatively high concentrations of airborne asbestos in the work place. Other citizens -- including insulation installers, shipyard workers, and manufacturers of gas masks -- encountered asbestos during World Wars I and II, when it was produced at an accelerated rate. Although the importation and use of asbestos have decreased in the United States since 1970, and recendy the Envi ronmental Protection Agency (EPA) has proposed a ban on its use, asbestos remains an important prod uct internationally in construction and as a friction material. The incorporation of asbestos into thousands of U.S. buildings in the past has resulted in the release of asbestos fibers into urban air when those structures are renovated or demolished.1 Other fibers can be come airborne because of the wear of brake linings or roads composed of asbestos ores, as well as through the weathering or erosion of asbestos-containing rock. These phenomena and the documented presence of asbestos fibers in water supplies and food products2 have fostered concerns about the possible risks of ex posure to asbestos outside the working environment. Indeed, the presence of asbestos fibers in the lungs of members of the general population3 and children4 suggests that many of us are exposed to asbestos un knowingly and early in life. The asbestos used in building materials is nonres- From the Department of Patiwlogy, University of Vermont College of Medi cine, Burlington, Vt., and the Pulmonary Division, Department of Internal Medi cine, Yale University School of Medicine, New Haven, Conn. Address reprint requests to Dr. Gee at the Pulmonary Division, Department of Internal Medicine, Yale University School of Medicine, 2038 LMP, P.O. Box 3333, New Haven, CT 06510-8057. pirable unless its surfaces become disturbed or worn -- a situation that promotes the release of friable as bestos fibers into the atmosphere. The documentation of the presence of airborne asbestos in deterioradng school buildings has caused widespread concern that children will be afflicted with asbestos-related dis eases. In response to these fears, Congress recently passed the Asbestos Hazard Emergency Response Act, which requires the EPA to arrange with local education agencies for the inspection of all schools. Legislation is also pending that requires the monitor ing, labeling, and management of asbestos in build ings. In addition to the high costs of such surveillance, an estimated $100 billion to $150 billion will be spent for the abatement and removal of the mineral during the next decade.5 We address the effects of asbestos on health as doc umented in occupational cohorts, as well as the ad vances in the diagnosis and treatment of asbestosassociated diseases. In addition, we describe current basic-science and clinical research in order to eluci date the mechanisms of asbestos-related disease. Fi nally, we examine the results of several recent epide miologic studies and risk assessments in order to address the question of whether exposure to asbestos is a health problem outside the working environment. Since it has become increasingly clear that different types of asbestos differ in their pathogenic potential with respect to pleural abnormalities and malignant mesothelioma, we begin by describing the physical and chemical properties of asbestos. Identification and Types of Asbestos Asbestos is a family of crystalline hydrated silicates with a fibrous geometry (defined as a ratio of length to diameter, or aspect ratio, of more than 3:1). A commercial designation rather than a mineralogic : S. I i. J ..i CAT-1016913 029 1722 THE NEW ENGLAND JOURNAL OF MEDICINE June 29, 1989 term, the word asbestos can be applied to six chemi cally and physically distinct types of minerals -- chrysotile, crocidolite, amosite, anthophyllite, tremo- lite, and actinolite. Asbestos is often closely associated with other min erals in ores. For example, iron oxides and quartz are often found with crocidolite and amosite asbestos, whereas chrysotile can be contaminated with forsterite, magnetite, brucite, quartz micas, and feldspar.6 Tremolite asbestos is a contaminant of some Canadi an chrysotile deposits, as well as of industrial talc, vermiculite, sandstone, and other types of asbestos. During processing, asbestos fibers can adsorb both organic solvents, such as oils and hydrocarbons,7 and inorganic solvents used in the workplace. The use of asbestos in thousands of manufactured products is dictated by its strength, flexibility, resist ance to acid and heat, and durability. Currently, as bestos is incorporated into cement pipes, brake lin ings, packing and gaskets, thermal and electrical insulation, flooring and roofing products, paper, plas tics, and textiles. In the past, asbestos was sprayed onto building surfaces as an insulation material and fire retardant, but this process has been outlawed by the EPA. Although a number of replacements for as bestos have been proposed, none appear to be as at tractive and economical or to have as many industrial applications.8 Distinguishing various types of asbestos and other fibers is important in the consideration of asbestosassociated diseases. For example, naturally occurring minerals such as palygorskite and zeolites may occur as fibers but are not included under the rubric of as bestos. Chrysotile, which has consistently accounted for 95 percent of the world's production of asbestos, is a member of the serpentine group and consists of pli able, curly fibrils that may occur in bundles (Fig. 1 A). Cross sections of the fibers resemble scrolled tubes. In simplistic terms, the macromolecular structure of chrysotile consists of parallel sheets of silica and bru cite (magnesium hydroxide) that are stacked with varying degrees of overlap and curvature.10 The other types of asbestos -- crocidolite, amosite, anthophyl lite, tremolite, and actinolite -- belong to the amphibole group, a family of minerals with characteristic needlelike fibers (Fig. IB) and a crystalline structure composed of parallel chains of silica tetrahedra. The silicon tetraoxide chains are separated by a band of cations that vary in type, number, and capacity for substitution. As a result, the chemical composition of the amphiboles is complex and may include substan tial and variable amounts of monovalent, divalent, and trivalent metals. The majority of individual asbestos fibers in air and tissues are not visible on light microscopy, although ferruginous bodies (i.e., asbestos bodies) that encap sulate longer asbestos and asbestoslike fibers are often apparent. Chrysotile asbestos can usually be detected with confidence with transmission electron microsco py, but the identification of other fibers requires addi B Figure 1. Morphology of the Serpentine and Amphibole Types of Asbestos. Panel A shows the curly nature of chrysotile, a serpentine type, and Panel B shows the needle-like fibers of crocidolite, an amphibole. In these scanning electron micrographs, reference samples of asbestos (arrows) from the International Union against Cancer interact with bronchial epithelial cells in organ cultures of human bronchi. (Figure 1A is reprinted from Woodworth et al.9 with the permission of the publisher.) tional diagnostic tools, including selected-area elec tron diffraction, a procedure yielding crystallographic data, and x-ray energy dispersive analysis, which provides a blueprint of the chemical composition of fibers. The increased pathogenicity of the amphiboles, as compared with chrysotile asbestos, may be ascribed to a difference in the patterns of deposition and clearance of fibers, as well as to their insolubility in lung tissue. The larger fibers of chrysotile tend to occur in bundles and are readily intercepted at airway bifurcations be cause of their curliness.11 Alternatively, the straighter amphibole fibers can penetrate deeper into the lung. Over time, the longitudinal fragmentation12 and leaching13 of magnesium from chrysotile fibers are ob >. CAT-1016914 029 Vol. 320 No. 26 ASBESTOS-RELATED DISEASES -- MOSSMAN AND GEE 1723 served in the lung. Thus, these phenomena may ac count for the increased solubility of chrysotile and its less frequent occurrence in the lungs of exposed co horts, as compared with the amphiboles. Diseases Associated with Exposure to Asbestos Since the turn of the century, asbestos has been recognized as an occupational health hazard. Because of the documentation of asbestosis in the workplace in the early 1900s and the subsequent regulation of expo sure to asbestos, the disease is less important medical ly today than lung cancer and mesothelioma. Mesothelioma Mesotheliomas arise in the pleura and the peritone um. Asbestos exposure does not cause localized be nign, predominantly fibrous mesothelioma. In con trast, approximately 80 percent of diffuse malignant mesotheliomas occur in men exposed to asbestos in the workplace and sometimes in their family members or in persons who live near mines. The remaining 20 percent of men with malignant mesothelioma have no history of exposure to asbestos, and there is usually no excess of mineral fibers in their lungs. Smoking does not enhance the prevalence of malignant mesothelio ma in humans. . Of 17,800 asbestos-insulation workers who have been followed since 1967, 356 have been reported to have died of malignant mesothelioma (pleural or peri toneal).14 In women who manufactured crocidolite gas masks, all cases of malignant mesothelioma were observed at least five months after initial exposure.15 These cases involved heavy fiber loads in the lung, as observed at autopsy.16 In Rochdale, England, textile workers exposed to chrysotile and crocidolite,17 the risk of contracting malignant mesothelioma was ap proximately 25 times higher in workers employed for 10 or more years than in those employed for less than 10 years (Liddell FDK: personal communication). A recent study of mortality rates in miners and millers of crocidolite in Western Australia confirms that the de velopment of malignant mesotheliomas after intense exposure is dose-dependent. Two independent surveys done of the prevalence and geographic pattern of pleural malignant mesothe lioma from 1968 to 1984 show that the disease remains extremely uncommon in the United States.19,20 As compared with mortality due to lung cancer (approxi mately 130,000 cases per year), an average of 1500 cases of malignant mesothelioma are reported year ly.21 Whereas the mortality due to mesothelioma in women of all ages and in men under 65 has remained fairly constant or declined slightly, death rates in men 65 or older have increased steadily. There have been excess numbers of cases in several regions where asbestos was manufactured or where there were shipyards in the past, but the high mortality due to the disease in other geographic areas is not related to obvious occupational exposure. Patients with malignant mesothelioma may be asymptomatic at first, but they often have dyspnea or chest pain with pleural fluid of variable mobility.22 Pleural thickening or interstitial fibrosis is apparent on chest films in approximately 20 percent of the pa tients, and CT scans reveal calcifications of the tumor mass in almost half.23 Since malignant mesotheliomas vary histologically, ranging from epithelial to sarco matous and mixed forms, diagnosis by microscope is difficult. The tumors may be confused with those of metastatic cancer or, less commonly, with inflamma tory or reactive processes, including exuberant meso- thelial hyperplasia.24 When the tumor appears in a glandular or tubulopapillary pattern, it may be mis diagnosed as a metastatic adenocarcinoma. Advances in histochemistry, immunocytochemis- try, and electron microscopy have made possible earli er and more accurate diagnosis of malignant meso thelioma, if sufficient biopsy material is available. Generally, cytologic smears or needle-biopsy speci mens do not afTord an accurate identification, and only open thoracotomy yields tissue samples adequate for both the diagnosis of malignant mesothelioma and the determination of fiber counts in the lung.22 When pro cedures such as periodic acid-Schiff staining (a reac tion that stains diastase-resistant vacuoles) are used to detect mucopolysaccharides, positive staining invari ably suggests adenocarcinoma. Immunoperoxidase techniques that use antibodies to keratin proteins may identify.the keratin-producing cells that are character istic of malignant mesotheliomas. Alternatively, ade nocarcinomas (but not mesotheliomas) react avidly with antibodies to carcinoembryonic antigen. The uniqueness of the fine features of mesothelioma cells -- specifically, long microvilli and tonofilaments -- can be demonstrated by electron microscopy, a more definitive technique in the diagnosis of most malig nant mesotheliomas.25 . The prognosis of malignant mesothelioma is grim. Most patients survive for less than one year after diag nosis, although untreated persons have survived for as long as three years. A combination of radiation and doxorubicin (Adriamycin) is probably most helpful in prolonging survival,22 and thoracentesis can minimize dyspnea. The average latency period between the first expo sure to asbestos and the clinical diagnosis of malig nant mesothelioma is 35 to 40 yea^s, with most deaths occurring in patients over 60 years of age.26 In insula tors, the incidence of mesothelioma is estimated as proportional to T12, where T is the time since the initial exposure to asbestos, regardless of age at first exposure.27 However, the incidence of mesothelioma among factory workers with limited exposure to asbes tos is directly related to the time since first exposure, but eventually the incidence tails ofT.28 Several experimental studies give insight into the mechanisms of malignant mesothelioma in associ ation with exposure to asbestos. In a number of ex perimental systems, carcinogenesis occurs in sequen- 1724 THE NEW ENGLAND JOURNAL OF MEDICINE June 29, 1989 tial stages of initiation and promotion. Whereas initiating substances can interact with the DNA of ceils to produce heritable changes in the genetic mate rial, promoters, which favor the proliferation and ex pansion of the initiated cells in a manner that encour ages the development of malignancy, are thought to act epigenetically. According to these definitions, as bestos appears to be a complete carcinogen, possess ing both initiating and promoting properties with re gard to the induction of mesothelioma in rodents. For example, the intrapleural or intraperitoneal injection of asbestos fibers causes mesotheliomas to develop in a dose-dependent fashion.29,30 Lung Cancer The association between exposure to various types of asbestos and bronchogenic carcinoma has been demonstrated in a number of occupational settings.31 The average latency period of the disease from the time of first exposure to asbestos ranges from 20 to 30 years. The degree of association varies with the type of asbestos, fiber morphology, concentration, expo sure regimen, and such cofactors as smoking habits or the presence of certain other chemicals in the work place, but there is usually a dose-response relation (fibers per cubic centimeter of air times the number of years of exposure). Cohorts such as textile workers have a higher relative risk of disease than others, such as chrysotile miners and workers in plants that manu facture friction products (Fig. 2).31 Lung tumors are rare among asbestos workers who do not smoke. Although early epidemiologic studies indicated that the effects of asbestos and smoking combine in a multiplicative fashion to pro duce lung cancer,32 several recent surveys have sug gested that this model is inapplicable in some cohorts. For example, there is a weak interaction between the effects of asbestos and smoking in Canadian chryso tile miners and millers, as well as in British factory workers.33,34 The risk of lung cancer in nonsmokers with asbestos exposure can be assessed only in a very large cohort, because male asbestos workers are frequendy heavy smokers. The inaccurate classification of smokers as nonsmokers may disproportionately inflate the calcu lated risk of lung cancer among nonsmokers. Workers' estimates of their own cigarette smoking are also ques tionable, subject to faulty recall, and not always verifi able by independent questioning of friends and rela tives. Moreover, a high incidence of passive smoking in the presence of other workers whose smoking rates were higher than those of the general population could enhance the risk among nonsmokers. The data on as bestos workers who are nonsmokers have been sum marized recently.31 But, Tor the reasons we have men tioned, it remains uncertain whether any type of asbestos acting alone can cause lung cancer in non smokers. Several considerations are relevant to the question of a possible contribution of environmental asbestos to lung cancer among, members of the general popula tion. First, the numbers of coated asbestos fibers (fer ruginous bodies) in the lungs of persons with and' without lung cancer are comparable.35 Second, the correlation between the incidence of plaques -- an indicator of asbestos exposure -- and the increased risk of lung cancer is variable, weak, and inconclu sive.36,37 Third, recent epidemiologic studies of per sons with low exposure to asbestos either occupationally38"41 or environmentally42,43 provide little support for the concept that there is an increased risk of lung cancer when asbestos concentrations are at levels sev eral hundred or thousand times lower than those found in workplace situations in the past. In a recent British paper analyzing two very large cohorts, one working before and the other after the introduction of a new standard of asbestos regulation,44 the workers studied after the standard was imposed had no clear evidence of increased cases of lung cancer or asbestosis. As the authors point out, however, the follow-up period was short (12 years), and the latency period established for these diseases is far from over. A current controversy with important medicolegal ramifications concerns the possible causal role of asbestosis in the development of lung cancer. That scar cancers can occur at sites of fibrotic postinflammatory too 200 Cumulative Exposure (fibers/cm3 ol air--yr) Figure 2. Estimated Risks of Lung Cancer in Various Occupational Cohorts. The risk gradients for workers exposed to mixed fibers are several times steeper than those for workers in chrysotile mining and manufacture of friction products, but less steep than those for chrysotile textile workers. Exposure is expressed as fibers per cubic centimeter of air times the number of years of exposure. (Reprinted from McDonald and McDonald,31 with the permission ol the publisher.) . CAT-1016916 029 Vol. 320 No. 26 ASBESTOS-RELATED DISEASES -- MOSSMAN AND GEE 1725 disease (e.g., tuberculosis) has long been recognized.45 There is also evidence for the concurrence of fibrogenicity and tumorigenicity with various fiber types and clinical forms of pulmonary fibrosis in humans.40 Sev eral difficulties are inherent in dissociating asbestosis from exposure to asbestos without asbestosis as a cause of lung cancer in asbestos workers. First, since the development of both diseases is related to the amount of exposure to asbestos, the appearance to gether of lung cancer and asbestosis cannot be distin guished directly from the requirement for asbestosis as a precondition for the development of lung cancer. Second, by impairing the lung's ability to clear fibers, smoking may magnify the extent of fibrogenesis due to asbestos. Third, at levels of exposure that cause no detectable fibrosis, the epidemiologic difficulties in de tecting small increases in the risk of lung cancer are considerable, particularly when smoking is both prev. alent and heavy. A study of Quebec miners and mill ers suggests that "most, but not necessarily all, [pa tients with] lung cancer `attributable' to chrysotile have small (radiologic) parenchymal opacities before death."47 This study addresses indirectly the issue of distinguishing asbestosis-associated lung cancer from lung cancer in asbestos workers who smoke and who have little or no "clinical" asbestosis. In West Germany and the United Kingdom,48 lung cancer is attributed to asbestos if there is evidence of asbestosis on either chest films or pathological exami nation. Some reports have indicated that adenocarci nomas occur more frequently and more peripherally in patients with lung cancer who have'asbestosis.49 Others stress that the histologic types of the tumors are similar in patients with lung cancer with and with out fibrosis.50 Many asbestos workers with lung can cer51"53 have histopathological evidence of asbestosis on in-depth examination,51"53 though some have questioned this view.54 The diagnosis of asbestosis is made in living patients when radiologic and functional features associated with respiratory symptoms and clinical changes are present. There is no doubt that pathologically evident asbestosis can precede these di agnostic features, as is also 'true of idiopathic pulmo nary fibrosis. Thus, asbestos workers with lung cancer can also have occult minor asbestosis. However, with out an autopsy, one must still rely on the clinical evi dence of asbestosis in assigning a statistical proba bility to the relative contribution of asbestos and smoking. Cancers of the Gastrointestinal Tract and Larynx Certain cohorts of asbestos workers have been re ported to have an increased risk of cancers of the gastrointestinal tract, larynx, kidney, pancreas, ovary, and most recently the eye.55 An increased risk of lym phoma has also been suggested.56 Since these risks were first described -- in insulation workers in New Jersey who were heavily exposed to asbestos and in a few other cohorts -- considerable doubts have arisen, as more cohorts with different exposures in different industries have been followed for longer periods. Re cently the subject has been reviewed by Doll and Pelt),56 who generally discount the original concerns' about gastrointestinal cancers and those in some other sites. Although those investigators believe that asbes tos causes laryngeal cancer, they find the absolute risk to be much lower than that for lung cancer. Since this account, another review has argued that the risk of laryngeal cancer among asbestos workers is insignifi cant.57 Indeed, life-style factors, ethanol use, and smoking are clearly, much more important. Many available epidemiologic studies are based bn death certificates that refer to laryngeal cancer, rather than to actual cases of this far from universally fatal disease. , Whether asbestos causes gastrointestinal cancers is particularly important to the general population, since . asbestos-lined cement pipes carry much of the na tion's water supply. The magnitudes of the increased standardized mortality ratios (SMRs) originally re ported as statistically significant by SelikofT et al.58 have not been confirmed in studies of more than 30 separate cohorts. When elevated risks were observed for cancers of the gastrointestinal tract or for those of only the colon and rectum, the SMRs were about 2, lower than those in most studies of lung cancer. The majority of cohorts had no significant increase in SMRs.59 Asbestosis The general features of asbestos-induced pulmo nary fibrosis are well known. Diagnostic criteria for nonmalignant asbestos-related diseases have been published by the American Thoracic Society,60 as has a response thereto.61 Asbestosis is characterized by a history of exposure to asbestos and interstitial pulmo nary fibrosis manifested by dyspnea, cough, basal rales, late-stage finger clubbing with cyanosis, and ul timately, right-sided heart failure. Radiologically, the features are those of other interstitial fibroses -- namely, fine-to-coarse irregular opacifications that are initially basal, and irregular linear shadows. A formal classification for asbestosis, developed on the basis of the size and profusion of lesions, permits some inter observer standardization.60 However, lung-function tests remain essential in the detection and assessment of impairment. Diminutions of vital capacity, total lung capacity, residual volume, functional residual ca pacity, and commonly, low values for diffusing capac ity are the general hallmarks of restrictive lung disi ease. Perturbations of lung function caused by obesity must be considered. The first manifestation of asbes tosis may involve either radiologic or functional fea- . tures, but ultimately both become abnormal, and hy poxemia develops. Frequently, this classical picture is modified by the presence of chronic obstructive pul monary disease due to smoking. The pathological di agnostic criteria of asbestosis have been reported elsewhere.62 To date, there is no effective therapy for an established case of the disease. f i i CAT-1016917 029 1726 THE NEW ENGLAND JOURNAL OF MEDICINE June 29, 1989 From the 1930s to the mid-1950s, asbestosis was an occupational disease of overwhelming importance. Now its incidence in the workplace is declining, at least in North America. It is not a threat outside the working environment. In many newly diagnosed cases of asbestosis, the disease is relatively mild and prob ably will not progress -- particularly in cases in which the radiologic indexes of profusion are low.63 These observations imply that with adherence to good work practices and current standards of hygiene, asbestos workers need not leave their trade. Although workers with seriously restrictive disease probably should not work with asbestos, those with borderline abnormali ties in function and low profusion of radiologic abnor malities probably can continue.57 Though dyspnea is a symptom commonly reported by asbestos workers, an objective assessment is important for both casemanagement and medicolegal purposes. In one study of 120 asbestos workers seeking compensation, almost half had no ventilatory dysfunction.64 Small, irregular opacities seen on radiography, a common and minor feature of asbestosis, are more evident in asbestos workers who smoke.65 Similar re sults have been observed in those who work with as bestos insulation.66 However, since no data on lung function were included, it is unclear whether such changes imply function-reducing asbestosis or radio logic shadow enhancement. Classical pathology reports show that asbestosis develops in the terminal bronchiolar region. More recent studies have examined the occurrence in as bestosis of small airway disease. Apart from the gen eral difficulties inherent in making this diagnosis, recent data from a sheep model of asbestosis67 and from asbestos workers68,69 indicate that small-air way dysfunction that is related to exposure to asbes tos as opposed to cigarette smoke is minor and clini cally unimportant. A review of airway function in asbestos workers should be consulted for details.70 Symptoms of obstructive lung disease have been clearly identified with smoking rather than asbestos by Lerman et al.71 Some interesting studies have advanced our under standing of the pathogenesis of asbestosis. First, alveolar macrophages obtained from the lungs of as bestos workers by lavage spontaneously hypersecrete tissue-injuring oxidants and macrophage-derived growth factor and fibronectin.72 The latter two media tors synergistically promote the replication of fibro blasts, a prerequisite for fibrosis. Other studies, most recently from Australia,73 show a neutrophil-eosino phil alveolitis in patients with asbestosis and elevated numbers of both types of cells in bronchoalveolar- lavage fluid from these patients. The proportion of neutrophils recovered was correlated with the dura tion of exposure to asbestos. Neutrophils release a collagenase that is not inhibited by O|-antiprotease and that conceivably induces lung injury.74 The emphasis on neutrophils and eosinophils, in addition to macro phages, as inflammatory mediators of the fibrosing alveolitis of asbestosis suggests possible therapies. For instance, colchicine decreases the production in mac rophages of a fibroblast growth factor in vitro,75 and quinacrine decreases the flux of neutrophils into al veoli in rats in which silica is instilled.76 Other studies with bronchoalveolar lavage have indicated variable lymphocytosis in asbestos workers, with a depression of the ratio of helper to suppressor T cells.77,78 Al though lymphocytes produce fibroblast growth factors and have been shown by some studies to be increased in fluid recovered from asbestos workers by bron choalveolar lavage,79 these cells have not been demon strated to be directly involved in asbestos-related fibrogenesis. Benign Pleural Disorders Four types of benign pleural disorders are associat ed with asbestos: benign pleural effusions, pleural plaques, pleural fibrosis, and rounded atelectasis. How fibers are transported to the pleura and how cel lular mechanisms contribute to these reactive lesions remain an enigma.80 Benign pleural effusions occur in a small percentage of asbestos workers, usually less than 20 years after the initial exposure to high concen trations of asbestos.81 The diagnosis is based on the exposure history and the exclusion of other causes. Only about a third of affected persons are symptomat ic and have pleural pain, dyspnea, or both. A few effusions recur, but most resolve spontaneously. The fluid is usually an exudate, occasionally sanguineous. There is no evidence that benign pleural effusions cause pleural plaques, and workers who have only effusions probably do not now need to leave the work place. Pleura) plaques are currently the most common manifestation of exposure to asbestos. They occur as fibrohyaline nodular lesions, most often on the pari etal pleura, but also on the diaphragmatic pleura and less frequently on the pericardium. Their relatively discrete nature and parietal location together account for the virtual absence of decrements in lung function from such plaques. Plaques are best seen on the lower half of the lateral aspects of posteroanterior-view chest films, but lateral- and oblique-projection films may be helpful. Calcification occurs with time, but does not necessarily imply an enlargement of the le sions. Plaques need to be differentiated from fat pads (notably in obese patients), reactions to rib fractures, and in the case of unilateral plaques, other causes of pleural reaction, especially recurrent pneumothoraxes and inflammatory diseases, includin ; tuberculosis. When seen en face in the central port ions of the pos- teroanterior film, they can simulate tumors (when sin gle) or asbestosis lesions (when multiple and small). CT scanning is useful, because it shows more plaques than are revealed by conventional radiography and differentiates them from both fat pads and intrapulmonary lesions. At present, there is little evidence V CAT-1016918 029 Vol. 320 No. 26 ASBESTOS-RELATED DISEASES -- MOSSMAN AND GEE 1727 that pleural plaques on their own carry an increased risk of neoplasia or of the development of "function ally significant asbestosis" -- the latter term being re served by many, including the American Thoracic Society, for parenchymal as opposed to pleural abnor malities.60 The prevalence of plaques, particularly with calcifi cation, varies considerably. Plaques are very common in anthophyllite workers in Finland, for instance. Within Quebec, there is at least a twofold variation in the prevalence of plaques between the miners working at Asbestos and those at Thetford Mines,82 despite apparently similar techniques of mining "similar" chrysotile ores.82 Geographic variadons in pleural changes also occur among persons on a single island, Corsica.80 These variations are not explicable at pres ent, but they raise the possibility of differential spread of "asbestos" to the pleura or differences in the types of asbestos that cause plaques. These ideas are en dorsed by a report suggesting that differences in mica, talc, or breunnerite content may be involved.83 Sepiolite, a nonasbestps fiber, has been proposed as the cause of pleural calcifications endemic in Bulgaria.84 Thus, variations in the prevalence of benign pleural reactions may reflect mineralogic or morphologic dif ferences among fibers. Diffuse pleural fibrosis is a relatively rare manifesta tion that produces unilateral or bilateral pleural reac tions, mostly manifest laterally on posteroanterior chest films. Only rarely can it cause a cuirass effect, with restrictive changes in function that simulate those of asbestosis. Occasionally, the pleural changes encroach on the subjacent lung parenchyma and trap some lung tissue, simulating a tumor. In this event, CT scans suggest the correct diagnosis. Since their histologic appearance is similar, pleural fibrosis and plaques may have a similar pathogenesis.84 Characteristics of Asbestos Important in the Causation of Disease The variable physicochemical features of asbestos complicate attempts to evaluate the effects of different types of fibers on health. Because asbestos workers may be exposed over a lifetime to various concentra tions, sizes, aerodynamic features, and admixtures of chrysotile and amphibole fibers, the interpretation of epidemiologic data is sometimes difficult. However, a growing body of information supports the concept that the amphiboles crocidolite, amosite, and tremolite are largely, if not entirely, the cause of malignant mesothelioma in humans. For example, the mortality rate for pleural and peritoneal malignant mesothelio ma in male cohorts with occupational exposure to asbestos depends on the types of asbestos handled.85 Mortality is highest among those who work with the amphiboles alone (10.6 percent), lower among those who work with mixtures (3.6 percent), and lower still among those who work with chrysotile alone (0.2 per cent). Asbestos-related peritoneal malignant meso theliomas are invariably associated with exposure to the amphiboles. The few pleural malignant meso theliomas that result from the mining and mill ing of Canadian chrysotile are now attributed to the contamination of Thetford Mines and other Que bec ore with tremolite.85 Indeed, the relative risk of malignant mesotheliomas among workers handling chrysotile corresponds directly with the ratio of tremolite to chrysotile fibers in the lungs of these persons.86 Lung cancer and asbestosis87 may also be associat ed more commonly with the amphiboles than with chrysotile. Consistently lower rates of lung cancer oc cur in occupational cohorts exposed almost exclusive ly to chrysotile (Fig. 2).31 In comparison to chrysotile, the amphiboles are associated with a higher risk of . disease in miners, millers, and persons who work with building materials. Textile workers exposed to chryso tile have a higher risk gradient than other cohorts, including persons in a textile plant who handle mixed fibers. This high-risk group was exposed to chrysotile from the same source as Quebec miners and millers. Recent analyses of tissues at autopsy show equivalent concentrations and sizes of asbestos fibers, predomi nantly those of tremolite, in the lungs of persons from these two cohorts, even though the dust levels in the textile plant were an estimated one tenth of those in the mines and mills.88 Thus, the differences between the types, concentrations, and dimensions of fibers in thp lungs of the Quebec miners and millers and those of the textile workers do not account for the extreme differences in the risks of lung cancer between these groups. Under these circumstances, the solvents and oil sprays used in the textile industry seem to be im portant cocarcinogens. The concept that fiber size is an extremely im portant determinant of the pathogenic potential of asbestos was indicated initially in epidemiologic data. Malignant mesotheliomas were first described in the northwestern Cape region of South Africa, where long, thin crocidolite fibers were mined.89 In contrast, no tumors were observed in the Transvaal district, where workers were exposed to shorter and coarser crocidolite fibers. A number of experimental studies have confirmed these observations. After the intrapleural or intraperitoneal injection of prep arations of fibers of a number of sizes, fibers more than 8 pm long and less than 0.25 pm in diameter were found to be most potent in the induction of ma lignant mesothelioma, regardless of their chemical constitution.29,30 The intratracheal injection of longer fibers produced asbestosis in rodents, whereas shorter fibers caused no disease.90 Recently, long-fiber prep arations of amosite asbestos were compared with shorter fibers (less than 5 pm) in rats.91 Widespread asbestosis, pulmonary neoplasms, and malignant mes otheliomas developed only in animals that inhaled long fibers, although significantly more short fibers were retained in the lung over time. Thus, regardless i CAT-1016919 029 1728 THE NEW ENGLAND JOURNAL OF MEDICINE June 29, 1989 of the route of administration of asbestos, longer fi bers appear to carry greater risks. Risks of Nonoccupational Exposure to Asbestos and Regulatory Considerations Expert panels have debated at length the controver sial question of whether asbestos is a health risk to the population at large. There have been several well-doc umented cases of malignant mesothelioma in the vi cinity of crocidolite mines and factories, as well as in the families of asbestos workers. An increased prev alence of malignant mesotheliomas and asbestosrelated effects have been reported most recently in the residents of certain geologic regions, such as the Ana tolian part of Turkey,92 Cyprus, 93 and northeastern Corsica.94 However, one-would expect from the limit ed measurements reported that the concentrations of fibers in air in these situations were much higher than those observed in homes and public buildings today. Lacking direct evidence for the concept that nonoccupational exposure to asbestos poses a risk to the public, governmental agencies and scientists have addressed this question by using the process of risk assessment. From 1983 to 1986, seven estimates of potential lifetime risk of asbestos-induced lung cancer and mesothelioma appeared in the literature.2"21,95:100 In general, all were calculated according to similar mathematical models, based on extrapolation of mor tality data from occupational cohorts down to the theoretical levels of disease occurring at the concen trations of fibers found in public buildings and schools today. The final risk estimates and their degree of uncertainty varied from group to group, because of the selection of occupational cohorts and other vari- ables. One report95 examined these risk assessments comparatively and attempted to provide a perspective on the estimated lifetime risk of asbestos exposure in schools, as compared with other risks in our society (Table 1). Clearly, the total number of deaths due to asbestos is substantially lower than published risk es timates from common causes. In the light of current epidemiologic and experi mental data, it has become increasingly apparent that estimating the risk due to exposure to asbestos is more complicated than estimating the risk due to soluble chemical carcinogens. The types and sizes of fibers are important variables that must be considered. The lin ear dose-response model for the prediction of asbes tos-induced lung cancer is questionable, because it as sumes that any exposure to asbestos will result in some increase in disease -- an unproved hypothesis. More over, several studies of persons exposed to asbestos show no statistically significant excess cases of lung cancer when concentrations of fibers are low.38-43 Risk estimation is the basis of the governmental policies that regulate occupational and environmental carcinogens. However, it is inappropriate to assess the risks of asbestos without regard to the important vari ables. Despite the questionable assumptions of linear ity -- the absence of a threshold and unlimited linear extrapolation -- the derivation of the risks of exposure to various types of asbestos is possible (as illustrated in Table 2) and should be encouraged. Currently, U.S. regulatory policies do not distinguish between the amphiboles and chrysotile, despite compelling epi demiologic data that show the association of malig nant mesotheliomas with the amphiboles rather than chrysotile, which is by far the most common fiber-- a point of considerable importance with regard to as bestos exposure in schools. Although there is an oc cupational standard (0.2 asbestos fiber greater than Table 1. Published Estimates of the Risk of Death in the United States from Various Causes.* Cause Asbestos in schools Floods Aircraft accidents (1979) Drowning (ages 5 to 14) Home accidents (ages 1 to 14) Long-tenn smoking Annual Mortality Rate mo. per million G.02-0.37t 2 '6 27 60 1200 'Reprinted from Weill and Hughes93 with (he permission of the pub- . JUbcr. tDatt from six published risk estimates were used to estimate the total number of deaths over a lifetime from lung cancer and mesothelioma (hat were attributable to asbestos exposure per million students exposed id school to0.001 mixed fiber per milliliter of air for five yean, beginning at age 10, and assuming an average life expectancy of 75 years. 5 p.m in length per cubic centimeter of air collected over an eight-hour period), the EPA has no standards for action against asbestos in schools or public build ings, where the average airborne fiber counts are gen erally 1000-fold less.101 Thus, the decision to remove asbestos is made arbitrarily, often without sufficient information, by private and civic groups. Most alarm ing are recent publications that show an increase'in the asbestos concentrations in the air after fibers are removed from buildings -- a phenomenon that is due to disturbance of fibers and improper containment during the removal process.102,103 Although air moni toring in schools and public buildings has revealed infinitesimal amounts of airborne asbestos in com parison with conditions prevailing in the workplace in the past, governmental agencies, on the general Table 2. Risk of Cancer and Exposure to Chrysotile or Mixed Fibers.* Lung Cancer Mesothelioma Total mean estimate (rangt) Chrysotile Mixed fibers Not related to asbestos 0.6 (0.3-- 1 -2)t 0.6 (0.3-1.2) 32,000 0.9 (0.4-1.8) 4.4 (2-2--8.8) 140 1.5 (0.7-3.0) 5.0 (2.5-10) 32,140 -Reprinted from Hughes and Weill11 with the pemussios or Ihe publisher. tEsiinuted number of lifetime deaths attributable to asbestos exposure per million students exposed to 0 001 fiber pef milliliter for six years. Vol. 320 No. 26 ASBESTOS-RELATED DISEASES -- MOSSMAN AND GEE 1729 grounds of prudence, have advocated visual inspec tion and massive removal at great expense, instead of operational maintenance. We suggest that determinations of respirability, the airborne concentrations of fibers, friability, fiber size, and most important, the type of asbestos (particularly when the amphiboles are involved) are the prerequi sites for any rational determination of the need for asbestos abatement. In schools, where the risk of ma lignant mesothelioma may be far more pertinent, fo cusing on the presence of the amphiboles is critical. For lung cancer, an overall attack on smoking, as ad vocated by the Surgeon General, will be far more effec tive than asbestos removal in the reduction of risk. In the absence of epidemiologic data or estimations of risk that indicate that the health risks of environmen tal exposure to asbestos are large enough to justify high expenditure of public funds, one must question the unprecedented expenses on the order of $100 bil lion to $150 billion5 that could result from asbestos abatement. References 1. McDonald JC. Health implications of environmental exposure to asbestos. Environ Health Perepccl 1985; 62:319-28. 2. National Research Council, Committee oo Nonoccupational Health Risks of Asbestifonn Fibers. Asbestifonn fibers: nonoccupational health risks. Washington, D.C.: National Academy Press, 1984. 3. ChuigA, Wamock ML. Asbestos fibers in the general population. Am Rev Respir DU 1980; 122:669-78. 4. Haque AK, Kanz MF. Asbestos bodies in children's lungs: an association with sudden infant death syndrome and bronchopulmonary dysplasia. Arch Pathol Lab Med 1988; 112:514-8. 5. Corn M. Perspective on the potential risk and management options for asbestos in buildings. Presented at the 22nd International Congress on Occupational Health, 1989. 6. Mineral resources of the Union of South Africa. 4lh ed. Pretoria, South Africa: Government Printer, 1959:357-67. 7. Harington JS. Occurrence of oils containing 3:4-benzpyrene and related substances in asbestos. Nature 1962; 193:43-5. 8. Background information on substitutes for asbestos. Washington, D.C.: Environmental Protection Agency, Office of Toxic Substances, 1980. 9. Woodworth CD, Mossman BT, Craighead JE. Interaction ofasbestos with metaplastic squamous epithelium developing io organ cultures of hamster trachea. Environ Health Perapecr 1983; 51:27-33. (0. Pooley FD. Asbestos mineralogy. In: Amman K, Aisner J, eds. Asbestosrelated malignancy. Orlando, Fla.: Grune A Stratton, 1987:3-27. i I. Timbrel! V, Bevan NE, Davies AS, Munday D. Hollow casts oflungs for experimental purposes. Nature 1970; 225:97-8. 12. Roggii VL, Brody AR. Changes in numbers and dimensions of chrysotile asbestos fibers in lungs of rats following short-term exposure. Exp Lung Res 1984; 7:133-47. 13. Jaurand MC, Bignon J, Sebastien P, Coni J. Leaching of chrysotile asbes tos in human lungs: correlation with in vitro studies using rabbit alveolar macrophages. Environ Res 1977; 14:245*54. 14. RibakJ, LilisR, Suzuki Y, PennerL, Selikoff U. Malignant mesothelioma in a cohort of asbestos insulation workers; clinical presentation, diagnosis, and causes of death. Br J Ind Med 1988; 45:182-7. 15. Jones JSP, Smith PG, Pooley FD. The consequences of exposure to asbes tos dust in a wartime gas-mask factory. In: Wagner JC. ed. Biological effects of mineral fibres. Vol. 2. Lyon, France: International Agency for Research on Cancer, 1980:137-53. (lARC scientific publications no. 30.) 16. Jones JSP, Roberts GH, Pooley FD. The pathology and mineral content of lungs in cases of mesothelioma in the United Kingdom in 1976. In: Wagner JC, ed. Biological effects of mineral fibres. Vol. 2. Lyon, France: Interna tional Agency for Research on Cancer, 1980:187-99. (1ARC scientific publications no. 30.) 17. Peto J, Doll R, Hermon C, Bums W, Clayton R, Goffe T. Relationship of mortality to measures of environmental asbestos pollution in an asbestos textile factory. Ann Occup Hyg 1985; 29:305-SS. 18. Armstrong BK, de Klerk NH, Musk AW, Hobbs MS. Mortality in miners and millers of crocidoiite in Western Australia. Br J Ind Med 1988; 45:5 13. 19. Enter!ine PE, Henderson VL, Geographic patterns for pleural mesothelio ma deaths in the United States. 1968-81. JNC1 1987; 79:31-7. 20. Connelly RR, Spinas R, Myers MH, Percy CL, Fiaumeni JF Jr. Demo graphic patterns for mesothelioma in the United States. JNCI 1987; 78:1053-60. 21. Hughes JM, Weill H. Asbestos exposure -- quantitative assessment of risk. Am Rev Respir Dis 1986; 133:5-13. 22. Antman KH. Corson JM. Benign and malignant pleural mesothelioma. Clin Chest Med 1985; 6:127-40. 23. Grant DC, Seltzer SE, Antman KH, Finbcrg HI, Rosier K. Computed tomography of malignant pleural mesothelioma. J Comput Assist Tomogr 1983; 7:626-32. * 24. Craighead JE. Cunrtnt pathogenetic concepts of diffuse malignant meso thelioma. Hum Pathol 1987; 18:544-57. 25. Warhol MJ. Electron microscopy in the diagnosis of mesothelioma with routine biopsy, needle biopsy and fluid cytology. In: Amman K, Aisner J, eds. Asbestos-related malignancy. Orlando, Fla.: Grune A Stratton, 1987:201-24. 26. Bignon J, Sebastien P, Di Menza L, Payan H. French mesothelioma regis ter. Ann NY Acad Sci 1979; 330:455-66. 27. Peto J.SeidmanH, Selikoff U-Mesotbetioma mortality in asbestos work ers: implications for models of carcinogenesis and risk assessment. Br J Cancer 1982; 45:124-35. 28. Seidraan H, Selikoff D, Gelb SK. Mortality experience of amosite asbestos factory workers: dose-response relationships 5 to 40 yean after onset of shon-teem work exposure. Am J Ind Med 1986; 10:479-514. 29. Pott F, Friedrichs KH. Tumoren der Ratte nach i. p.-Injektioo fasetffir- tniger Staube. Naturwisscnschaften 1972; 59:318. 30. Stanton MF, Wrench C. Mechanisms of mesothelioma induction with asbestos and fibrous glass. JNCI 1972; 48:797-821. 31. McDonald JC, McDonald AD. Epidemiology of asbestos-related lung can cer. in: Antman K, Aisner J, eds. Asbestos-related malignancy. Orlando, Fla.: Gnine A Stratton, 1987:57-79. 32. Saracci R. Asbestos and lung cancer, an analysis of the epidemiological evidence cm the asbestos-smoking interaction, (nl J Cancer 1977; 20:323 31. 33. Idem. The interactions of tobacco smoking and other agents in cancer etiology. Epidemiol Rev 1987; 9:175-93. 34. Berry G, Newbouse ML, Antonis P. Combined effect of asbestos and smoking on mortality from lung cancer and mesothelioma in factory work ers.. Br J Ind Med 1985; 42:12-8. . 35. Churg AM, Wamock ML. Numbers of asbestos bodies in urban patients with lung cancer and gastrointestinal cancer and matched controls. Chest 1979;76:143-9. 36. Harbcr P, Mohsenifar Z, Oren A, Lew M. Pleural plaques and asbestos- associated malignancy. J Occup Med 1987; 29:641-4. 37. Bateman ED, Benatar SR. Asbestos-induced diseases: clinical perspec tives. Q J Med 1987; 62:183-94. 38. Berry G, Ncwhouse ML. Mortality of workers manufacturing friction ma terials using asbestos. Br J Ind Med 1983; 40:1-7. 39. Gardner MJ, Winter PD, Panned B, Powell CA. Follow up study of workers manufacturing chrysotile asbestos cement products. Br J Ind Med 1986; 43:726-32. 40. Obisou CG, Hogstcdt C. Lung cancer among asbestos cement workers: a Swedish cohort study and a review. Br J Ind Med 1985; 42:397-402. 41. Thomas HF, Benjamin IT, Elwood PC, Sweetnam PM. Further follow-up of workers from an asbestos cement factory. Br J Ind Med 1982; 39:273 6. 42. Churg A. Lung asbestos content in long-term residents of a chrysotile mining town. Am Rev Respir Dis 1986; 134:125-7. 43. CoidierS, Lazar P, BrochaidP, Bignon J, Ameille J, Pioteau J. Epidemio logic investigation of respiratory effects related to environmental exposure to asbestos inside insulated buildings. Arch Environ Health 1987; 42:303 9. 44. Hodgson JT, Jones RD. Mortality of asbestos workers in England and Wales 1971-81. Br J Ind Med 1986; 4.;: ^8-64. 45. Spencer H, ed. Pathology of the lung. Vol. 2. 4th ed. Oxford: Pergamon Press, 1985:885. 46. Kuschner M. The effects of MMMF on animal systems: some reflections on their pathogenesis. Ann Occup Hyg 1987; 31:791-7. 47. Liddell FD, McDonald JC. Radiological findings as predictors of mortality in Quebec asbestos workers. Br J ind Med 1980; 37:257-67. 48. Paries WR, ed. Occupational lung disorders, 2nd ed. London: Butter- worth, 1982:294. 49. Whitwell F, Newhouse ML, Bennett DR. A study of the histological cell types of lung cancer in workers suffering from asbeslcwis in the Vailed Kingdom. Br J Ind Med 1974; 31:298-303. 50. Churg A. Lung cancer cell type and asbestos exposure. JAMA 1985; 253:2984-5. 51. Baum GL, Gitter S, Goldsmith JR, et al. Advances in asbestos disease research: common practical problems -- panel discussion. Am J Ind Med 1986; 10:563-72. . CAT-1016921 029 1730 THE NEW ENGLAND JOURNAL OF MEDICINE June 29, 1989 52. Browne K. Is asbestos or asbestosi* the cause of the increased risk of lung cancer in asbestos workers? Br J Ind Med 1986; 43:145-9. 53. Kipen HM, Litis R, Suzuki Y, Vakiukas JA, Selikoff II. Pulmonary fibrosis in asbestos insulation workers with lung cancer, a radiological and histopathological evaluation. Br 1 lnd Med 1987; 44:96-100. 54. Wamock ML, Isenberg W. Asbestos burden and the pathology of lung cancer. Chest 1986; 89:20-6. 55. Enterline PE, Hartley J, Henderson V. Asbestos and cancer a cohort followed up to death. Br Jlnd Med 1987; 44:396-401 56. Doll R, Peto J. Other asbestos-related neoplasms. In: Amman K, Aisner J, eds. Asbestos-related malignancy. Orlando, Fla.: Grune & Stratton, 1987:81-98. 57. Chan CK, Gee JB. Asbestos exposure and laryngeal cancer: an analysis of the epidemiologic evidence. J Occup Med 1988; 30:23-7. 58. Selikoff U, Hammond EC, Churg J. Asbestos exposure, smoking, and neoplasia. JAMA 1968; 204:106-12. 59. Edelman DA. Exposure to asbestos and the risk of gastrointestinal cancer a reassessment. Br J lnd Med 1988; 45:75-82. 60. American Thoracic Society. Medical Section of the American Lung Asso ciation: the diagnosis of nonmalignant diseases related to asbestos. Am Rev Respir Dis 1986; 134:363-8. 61. Franzblau A, Lilis R. The diagnosis of noomalignant diseases related to asbestos. Am Rev Respir Dis 1987; 136:790-1. 62. Craighead JE, Abraham JL, Churg A, et al. The pathology of asbestos- associated diseases of the lungs and pleural cavities: diagnostic criteria and proposed grading schema. Arch Pathol Lab Med 1982; 106:544-96. 63. Gaensler EA, Jederlinic PJ, McLoud TC. Progression of asbestosis. Chest 1987; 91:305. abstract. 64. Agostoni P, Smith DD, Scboene RB, Robertson HT, Butler J. Evaluation of breathlessness in asbestos workers: results of exercise testing. Am Rev Respir Dis 1987; 135:812-6. 65. Weiss W. Cigarette smoke, asbestos, and small irregular opacities. Am Rev Respir Dis 1984; 130:293-301. 66. Ulis R, Selikoff U, Lerman Y, Seidman H, Gelb SK. Asbestosis: intersti tial pulmonary fibrosis and pleural fibrosis in a cohort of asbestos insula tion workers: influence of cigarette smoking. Am J bid Med 1986; 10:459 70. 67. Begin R, Masse S. Sebastian P, et al. Asbestos exposure and retention as determinants of airway disease and asbestos alveolitis. Am Rev Respir Dis 1986; 134:1176-81. 68. Begin R, Boileau R, Peloquin S. Asbestos exposure, cigarette smoking, and airflow limitation in long-term Canadian chrysotile miners and millers. Am J Ind Med 1987; 11:55-66. 69. Churg A, Wright JL, Wiggs B, Pare PD, Lazar N. Small airways disease and mineral dust exposure: prevalence, structure, and function. Am Rev Respir Dis 1985; 131:139-43. 70. Becldake MR, Ernst P. Asbestos exposure and airway responses. In: Gee JBL, ed. Occupational lung disease. New York: Churchill Livingstone, 1984:25-49. 71. Lerman Y, Selikoff ZJ, Lilis R, Seidman H, Gelb SK. Clinical findings among asbestos workers in U.S.: influence ofcigarette smoking. Am J Ind Med 1986; 10:449-58. 72. Rom WN, BioermanPB, Rennard SI, Cantin A, Crystal RG. Characteriza tion of the lower respiratory tract inflammation of nonsmoking individuals with interstitial lung disease associated with chronic inhalation of inorganic dusts. Am Rev Respir Dis 1987; 136:1429-34. 73. Robinson BW, Rose AH, James A, Whitaker D, Musk AW. Alveolitis of pulmonary asbestosis: bronchoalveolar lavage studies in crocidolite- and chiysotile-exposed individuals. Chest 1986; 90:396-402. 74. Gee JBL, Lwebuga-Mukasa J. Cellular and matrix mechanisms in occupa tional lung disease. In: Morgan WKC, Seaton A, eds. Occupational lung diseases. 2nd ed. Philadelphia: W.B. Saunders, 1984:163-95. 75. Rennard S, Bitterman B, Ozaki T, Crystal R. Colchicine blocks the release of mediators of fibrosis by human alveolar macrophages. Clin Res 1984; 32:246A. abstract. ' 76. Mikes PS, Polomski L, Gee JBL. Mepacrine but not mast cell active agents impair neutrophil migration into rat lungs. Clin Res 1987; 35:536A. ab stract. 77. Gcllert AR, Macey MG, Uthayakumar S, Newland AC, Rudd RM. Lym phocyte subpopulations in bronchoalveolar lavage fluid in asbestos work ers. Am Rev Respir Dis 1985; 132:824-8. 78. Costabel U, Brass KJ, Huck E, Guzman J, Matthys H. Lung and blood lymphocyte subsets in asbestosis and in mixed dust pneumoconiosis. Chest 1987;91:110-2. 79. Uigmm J, JuuruiKl M-C. Asbestos fiber toxicity and lung disease. In; Gee JBL, ed. Occupational lung disease. New York: Churchill Livingstone, 1984:51-73. 80. Bignon J, Gee JBL. Pleural fibrogenesis. In: Lung biology in health and disease. Vol. 30. Chrdlien J, Bignon J, Hirsch A, eds. The pleura in health und discuse. New York: Marcel Dckkcr, 1985:417-43. 81. Robinson BW. Musk AW. Benign asbestos pleural effusion: diagnosis and course. Thorax 1981; 36:896-900. 82. Rossiter CE, Bristol U, Cartier PH, et al. Radiographic changes in chryso tile asbestos mine and mill workers of Quebec. Arch Environ Health 1972; 24:388-400. .. 83. Gibbs GW. Etiology of pleural calcification: a study of Quebec chrysotile asbestos miners and millers. Arch Environ Health 1979; 34:76-83. 84. Stephens M, Gibbs AR, Pooley FD, Wagner JC. Asbestos induced diffuse pleural fibrosis: pathology and mineralogy. Thorax 1987; 42:583-8. 85. McDonald AD, McDonald JC. Epidemiology of malignant mesothelioma. In: Antman K, Aisner J, eds. Asbestos-related malignancy. Orlando, Fla.: Grune & Stratton, 1987:31-56. 86. Churg A, Wiggs B. Fiber size and number in workers exposed to processed chrysotile asbestos, chrysotile miners, and the general population. Am J lnd Med 1986; 9:143-52. 87. Wagner JC, Newhouse ML, Corrin B, Rossiter CE, Griffiths DM. Correla tion between fibre content of the lung and disease in east London asbestos factory workers. Br J lnd Med 1988; 45:305-8. 88. Sebastien P, McDonald JC, McDonald AD, Case B, Harley R. Respiratory cancer in chrysotile textile and mining industries: exposure inferences from lung analysis. Br J Ind Med 1989; 46:180-7. 89. Wagner JC, Sleggs CA. Marchand P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J lnd Med 1960; 17:260-71. 90. Kuschner M, Wright G. The effects of intratracheal instillation of glass fiber of varying size in guinea pigs. In: Occupational exposure to fibrous glass -- proceedings of a symposium. Rockville, Md.: National Institute for Occupational Safety and Health, 1976:151-68. (HEW no. (NIOSH) 76 151.) 91. David JM, Addison J, Bolton RE, Donaldson K, Jones AD, Smith T. The pathogenicity of long versus short fibre samples of amosite asbestos admin istered to rats by inhalation and intraperitoneal injection. Br J Exp Pathol 1986; 67:415-30. 92. Aitvinli M, Baris YI. Malignant mesotheliomas in a small village in the : Anatolian region of Turkey: an epidemiologic study. JNCI 1979; 63:17 22. 93. McConnochie K, Simonato L, Mavrides P, et al. Mesothelioma in Cyprus. In: Bignon J, Peto J, Saracci R, eds. Non-occupalional exposure to mineral fibers. Lyon, France: International Agency for Research on Cancer, 1989:411-9. (1ARC publication no. 90.) 94. Boutin C, Viallat JR, Steinbauer J, Dufour G, Gaudichet A. Bilateral pleural plaques in Corsica: a marker of non-occupaiional asbestos expo sure. In: Bignon J, Peto J, Saracci R. eds. Non-occupational exposure to mineral fibres. Lyon, France: International Agency for Research on Can cer, 1989:406-10. (IARC publication no. 90.) 95. Weill H, Hughes JM. Asbestos as a public health risk: disease and policy. Annu Rev Public Health 1986; 7:171-92. 96. Report to the U.S. Consumer Product Safety Commission by the Chronic Hazard Advisory Panel on Asbestos. Washington, D.C.: Consumer Prod uct Safety Commission, 1983. 97. Airborne asbestos health assessment update. Washington, D.C.: Environ mental Protection Agency, 1986. 98. Achesoo ED, Gardner MJ. Asbestos: the control limit for asbestos. Lon don: Her Majesty's Stationery Office, 1983. 99. Ontario Royal Commission. Report on matters of health and safety arising from the use of asbestos in Ontario. Toronto: Ontario Ministry of the Attorney General, 1984. 100. Doll R, Peto J. Asbestos: effects on health of exposure to asbestos. Lon don: Her Majesty's Stationery Office, 1985. 101. Com M. Issues related to the potential health hazard of asbestos-containing materials in buildings. Presented at the Symposium on Health Aspects of Exposure to Asbestos in Buildings, Harvard University, Energy and Envi ronmental Policy Center, Cambridge, Mass., 1989. 102. Massey DG, Foumier-Massey G. Asbestos removal from buildings: a re view. Hawaii Med J 1987; 46:153-7. 103. Sawyer RN, Rohl AN, Langer AM. Airborne fiber control in buildings during asbestos material removal by amended water methodology. Environ Res 1985; 36:46-55. CAT-1016922 029