Document NVQJ3OaYaGLVpL1G3ZE2brnD

In IBS,* when it's brain versus bowel, IT'S TIME FOR THE In irritable bowel syndrome,* intestinal discomfort will often erupt in tandem with anxiety--launching a cycle ofbrain/bowel conflict. Make peace with Librax. Because of possible CNS effects, caution patients about activities requiring complete mental alertness. Librax has been evaluated as possibly effective as adjunctive therapy in the treatment ofpeptic ulcer and IBS. Specify Adjunctive Each capsule contains 5 mg chlordiazepoxide HC1 and 2.5 mg clidinium bromide. Copyright 1989 by Roche Products Inc. All rights reserved. Please see summary of prescribing informatton on adjacent page. DPMC-01755 LAM 008272 Vol. 320 No. 26 ASBESTOS-RELATED DISEASES -- MOSSMAN AND GEE 1721 66. Htwthonie studies. In: Mitchell I, Stein I, eds. The Random House ency clopedia. New Yoct Random House, 1983:2262. 67. Bumie JP, Odds PC, Lee W, Webster C, Williams JD. Outbreak of systemic Candida albicans in intensive care unit caused by cross infection. Br Med J 1985; 290:746-8. 68. Phelps M, Ayliffe GA, Babb JR. An outbreak ofcandidiasis in a special care baby unit the use of a resistogram typing method. I 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. Kelknnan J, Rigler D, Siegel SE. The psychological effects of isolation in protected environments. Am J Psychiatry 1977; 134:563-5. 71. Holland i. Plumb M, Yates i, et al. Psychological response of patients with acute leukemia to genn-free environments. Cancer 1977; 40:8719. 72. Stoutenbeek CP, vanSaene HK, Miranda DR, Zandstn DH. The effect of selective decontamination ofthe digestive tracton colonisation and infection rate in multiple trauma patients. Intensive Care Med 1984; 10:185-92. 73. Unextl K, Ruckdeschel G, Sdbmami HK, et al. Prevention of colonization and respiratory infections in long-term ventilated patients by local antimi crobial prophylaxis. Intensive Care Med 1987; 13:106-13. 74. dasencr HA, Voilaard El, vanSaene HK. Long-term infection prophylaxis by selective decontamination in leukopenia and in mechanical ventilation. Rev Infect Dis 1987; 9295-328. 75. Graham DR, Correa-Villasenor A, Anderson L, Vottman JH, Baine WB. Epidemic neonatal gentamicin-methicillin -- resistant Staphylococcia au reus infection associated with nonspecific topical use of gentamicin. J Pediatr 1980; 97:972-8. 76. Feeley TW, du Moulin GC. Herfley-Whyte l, BushneO LS, Gilbert JP, Fcingold DS. Aerosol polymyxin and pneumonia in seriously ill patients. N Engl J Med 1975; 293:471-5. MEDICAL PROGRESS ASBESTOS-RELATED DISEASES T.Brooke Mossman, Ph.D., and J. Bernard L. Gee, M.D. ASBESTOS is a mineral causing much controversy XV. 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 Pathology, University of Vermont College of Medicine, 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, Yak University School of Medicine, 5038 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 deteriorating 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 DPMC-01756 lam 008273 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, croddolite, amosite, anthophyllite, tremolite, and actinolite. Asbestos is often closely associated with other min erals in ores. For example, iron oxides and quartz are often found with croddolite and amosite asbestos, whereas chrysotile can be contaminated with forsterite, magnetite, brudte, 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 add and heat, and durability. Currendy, as bestos is incorporated into cement pipes, brake lin ings, packing and gaskets, thermal and electrical insulation, flooring and roofing products, paper, plas hes, and textiles. In the past, asbestos was sprayed onto building surfaces as an insulation material and fire retardant, but this process has been oudawed 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 asbestosassodated diseases. For example, naturally occurring minerals such as palygorskite and zeolites may occur as fibers but are not induded under the rubric of as bestos. Chrysotile, which has consistendy 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. 1A). Cross sections of the fibers resemble scrolled tubes. In simplistic terms, the macromolecular structure of chrysotile consists of parallel sheets of silica and bru dte (magnesium hydroxide) that are stacked with varying degrees of overlap and curvature.10 The other types of asbestos -- croddolite, 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 capadty for substitution. As a result, the chemical composition of the amphiboles is complex and may indude 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 croddolite, 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- DPMC-01757 LAM 008274 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 slighdy, 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 die padents, 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 mesothelial hyperplasia.24 When die tumor appears in a glandular or tubulopapillary pattern, it may be mis diagnosed as a metastatic adenocarcinoma. Advances in histochemistry, immunocytochemistry, 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 afford 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 add-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-produdng cells that are character istic of malignant mesotheliomas. Altemativdy, adenocardnomas (but not mesotheliomas) react avidly with antibodies to cardnoembryonic antigen. The uniqueness of the fine features of mesothelioma cells -- spedfically, 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 (Adriamydn) 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 years, with most deaths occurring in patients over 60 years of age.26 In insula tors, the inddence of mesothelioma is estimated as proportional to T3-5, where T is the time since the initial exposure to asbestos, regardless of age at first exposure.27 However, the inddence of mesothelioma among factory workers with limited exposure to asbes tos is directly related to the time since first exposure, but eventually the inddence tails off.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 LAM 008275 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 cells 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 epigenedcally. 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 frequently 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, for the reasons we have men tioned, it remains uncertain whether any type of asbestos acting alone can cause lung cancer in nonsmokers. 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 Cumulative Exposure (fibers/cm3 of 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 of the publisher.) DPMC-01759 LAM 008276 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.46 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 direcdy 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 Peto,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 on 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 Selikoff 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 dis 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. Frequendy, 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. DPMC-01760 LAM 008277 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 radiologic shadow enhancement. Classical pathology reports show that asbestosis develops in the terminal bronchiolar region.62 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 bronchoalveolarlavage 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 a,-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. Pleural plaques are currendy 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 frequendy 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 postcroanterior-view chest films, but lateral- and oblique-projection films may be helpful. Calcification occurs with time, but docs 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, including tuberculosis. When seen en face in the central portions of the posteroanterior 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 DPMC-01761 LAM 008278 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 variations 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 brcunnerite content may be involved.83 Sepiolite, a nonasbestos 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, mosdy 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 the 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 ofv prep arations of fibers of a number of sizes, fibers more than 8 ftm long and less than 0.25 fim 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 fun) 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 DPMC-01762 LAIW 008279 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 croddolite 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 Annual Mortality Rate no. per million Asbestos in schools Floods Aircraft accidents (1979) Drowning (ages 5 to 14) Home accidents (ages 1 to 14) Long-term smoking 0.02-0.37t 2 6 27 60 1200 *Reprinted from Weill rad Hughes*3 with the permission of the pub lisher. tData from six published risk estimates were used to estimate the total number of deaths over a lifetime from lung cancer and mesothelioma that were attributable to asbestos exposure per million students exposed in school to 0.001 mixed fiber per milliliter of air for five years, 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 mean estimate (range) Total Chrysotile Mixed fibers Not related to asbestos 0.6 (0.3-l.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 Weil!31 with the permission of the publisher, tEstimated number of lifetime deaths attributable to asbestos exposure per million students exposed to 0.001 fiber per milliliter for six years. DPMC-01763 lam 008280 Vol. $20 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 Perspect 198S; 62:319-28. 2. National Research Council, Committee on Noooccupatiooal Health Risks of Asbestiform Fibers. Asbestiform fibers: noooccupatiocal health risks. Washington, D.C.: National Academy Press, 1984. 3. Churg A, Wamock ML. Asbestos fibers in the general population. Am Rev Respir Dis 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; 112:314-8. 3. Com M. 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