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\ s-ff "E ;>*y. ng /'I'.-lf ASBESTOS-RELATED PLEUROPULMONARY DISORDERS KEITH W. CHANDLER, MD Assistant Professor Division of Pulmonary and Critical Care Medicine University of South Florida Tampa, FL Over 150 minerals occur in a fibrous form, in South Africa. Amosite was so named in 1918 and asbestos is a collective mineralogical term for the town near its discovery, Amosa, which that includes several hydrated silicate minerals is an acronym for the Asbestos Mining Organiza sharing certain properties. Asbestiform minerals tion of South Africa. Anthophyllite is largely contain easily separable fibers that are ag mined in Finland and has little commercial im gregated in parallel or radiating bundles. These portance outside this country of origin. Other /. fibers possess a high (ensile strength and an ex asbestiform minerals such as tremolite, an am- treme length:diameter (aspect) ratio. The term phibole with no industrial application, may con was bom in antiquity and refers to the fibers from taminate commercially valuable mineral asbestos rocks that were woven into perpetual deposits of taconite, talc, and chrysotile. wicks for the sacred lamps of vestal virgins The properties of asbestos that permit its in [aofitoxo = unquenchable). Although ancient dustrial use are its light weight, resistance to historians, geographers, and naturalists docu thermal and corrosive destruction, and its mented the use of asbestos in wicks, napkins, reasonable cost. Further, it is easily woven into ornamental dress, and crematory cloths, it was textiles or molded into various shapes when not until the late 19th century that large-scale mixed with cement or plastic, thereby increas commercial exploitation began. ing the tensile strength of the finished product. Four major varieties of asbestos are commer Some 3000 manufactured products contain cially important. Chrysotile, which comprises asbestos because of these desirable properties. 90% of the world production of asbestos, is a While asbestos has found application in such wavy (serpentine) fiber that has been mined and diverse uses as filters for gas masks and cigarettes milled in Quebec since 1877. The other three and as artificial snow in motion pictures, it has varieties are amphiboles--straight rather than primarily been used as an insulating material serpentine in their fibrous nature. Crocidolito and as a strengthening agent in asbestos cement. (literally woolly rock) has been mined since 1891 After World War II (until 1973, when the prac tice was banned in the United States by the En vironmental Protection Agency), asbestos was Rtiprint request* to Dr. Chnndlcr. James A. Haley Veterans Hospital. 13000 North 30th Street, UlC. Tampa. FL 33012. sprayed onto the structural supports of buildings as a means of insulation and fire retardation. kk- 46 COMPREHENSIVE THERAPY July 1986 Workers who have direct occupational exposure to asbestos include miners and millers of the relevant ores, insulators, asbestos textile and asbestos cement workers, and individuals who work with asbestos friction and gasket materials. Indirect occupational exposure frequently at tends those in the construction trades (pipe fitters, sheet-metal workers, welders, and electricians). Household exposure may occur when asbestos workers bring their heavily contaminated clothing home for laundering. Almost one of every five wives of asbestos factory workers has radiographic evidence of pleural thickening, suggesting substantial exposure. Neighborhood exposure may occur near asbes tos mines, mills, or factories. Over 100 residents of a mobile housing subdivision near Globe, Arizona, were evacuated when it was realized that their subdivision had been built on the property of an inactive asbestos mill. Mill tail ings had been used as landfill during the initial grading of the site, and household activities such as dusting generated unacceptably high concen trations of airborne fibers. Even in the absence of direct or indirect oc cupational exposure and household or neighbor hood exposure to asbestos dust, environmental contact with this ubiquitous mineral is unavoid able. Twenty-two states have natural asbestos outcroppings, and dust-generating recreational activity may lead to measurable contamination of the air with respirable particles of asbestos. Also, in the U.S. alone there are 320,000 km of water pipe containing 10% to 20% asbestos, and many buildings built during the critical period of 1946 to 1973 have sprayed-on asbestos insula tion. As many as 10,000 elementary and secon dary schools may harbor such insulation. As the asbestos surface is vandalized or undergoes spontaneous degradation, respirable-sized fibers may become airborne. The preponderant clinical manifestations of asbestos exposure are pleural or pulmonary (Table 1). Not all such manifestations represent diseases, since some do not lead to functional impairments or presage tire development of more serious complications. Pleural disorders include benign effusions, hyaline plaques, diffuse thickening, and diffuse malignant mesothe lioma. Pulmonary disorders include fibrosis (as- bestosis), bronchogenic carcinoma, small-airway abnormalities, and rounded atelectasis. To a greater or lesser degree these disorders are related to intensity of exposure, duration of expo sure, length of time since onset of exposure, fiber type, age at onset of exposure, and circumstances of exposure (mining or milling the ore as op posed to manufacturing asbestos products or working with the asbestos items produced).*'4 ASBESTOS-RELATED PLEURAL DISORDERS Benign Asbestos Pleural Effusions Pleural effusions are the only pleuropulmonary manifestation of asbestos exposure to ap pear within 10 years of exposure, and they are the most common form of asbestos-related pleu ral disease to occur within 20 years of exposure . Eisenstadt first described benign asbestos pleural effusions when he recounted the case of an in sulation worker with asbestosis, pleural plaques, and bilateral pleural effusions. He later reported finding effusions in other workers (welders, pipefitters, insulators, and boilermakers) who had been employed in the shipyards and oil refineries of Port Arthur, Texas. Such effusions may be subacute or chronic, symptomatic or asymptomatic, unilateral or bilateral. They char acteristically are small and asymptomatic. One quarter of affected individuals experience one or more recurrences, and as many as 5% of heav ily exposed workers may be affected at some time. The fluid is always exudative and may be serosanguineous or frankly bloody, but there are no salient pleural fluid findings or histologic Table 1 Pleural and Pulmonary Disorders Related to Asbestos Pleural Effusion Plaques Diffuse thickening Malignant mesothelioma Pulmonary Asbestosis Bronchogenic carcinoma Small airway abnormalities Rounded atelectasis 1 way pleural hallmarks that would serve to confirm should be excluded to the extent reasonably 0a the diagnosis. Generally accepted criteria for the possible, and the individual for whom this are diagnosis include the presence of an effusion in presumptive diagnosis is considered should be po- an asbestos-exposed worker who has no other followed carefully. ber disease known to cause pleural effusions and in ces whom no malignant tumor develops within Pleural Plaques and Pleural Thickening >P- three years of the appearance of the effusion.* Hyaline pleural plaques resemble articular or Obviously, this diagnosis is one of exclusion that cartilage and have a leathery consistency when 1 -4 can be upheld only retrospectively. dissected free from the underlying chest wall at IS Although the effusion is benign, affected necropsy. They form beneath the parietal pleura workers may ultimately develop more serious and may calcify They rarely extend over four in asbestos-related diseases. In a collected review tercostal spaces and seldom involve the lung 0- of 75 patients with benign asbestos pleural ef apices or the costophrenic angles. When seen > fusions, 9 patients developed diffuse malignant face on (en face) radiographically, they are faint, e mesothelioma 6 to 16 years later, and 2 others ill-defined, and have an irregular contour that 1- developed bronchogenic carcinoma.8 has been likened to a holly leaf or an archipelago At present the diagnosis of an asbestos pleural (Figure 1). 1 effusion should be considered in the appropriate They are radiographically underappreciated* setting. Other competing causes of effusion in that only 8% to 40% of those found at autop- Figure 1. (A) Chest radiograph demonstrating many ill-defined plaques that are better defined on (8) CAT. 48 COMPREHENSIVE THERAPY July 1986 sy can be seen on routine chest radiographs. Oblique views increase the likelihood of detec tion but only at the expense of greater observer unreliability. Computerized axial tomography (CAT) is a sensitive test for the detection of pleural plaques but only at the expense of much greater cost. No theory adequately explains induction of plaques by asbestos fibers. The current theory is that fibers exit the lungs and become em bedded in the chest wall, where they are en gulfed by macrophages that activate fibroblasts to mediate a characteristic fibrotic response. Because pleural changes occur at lower cumu lative fiber concentrations, they outnumber parenchymal manifestations of asbestos expo sure considerably. Cigarette smoking may poten tiate the development of pleural plaques. Pleural plaques are of little clinical relevance. They provide dramatic evidence of asbestos exposure, but they are associated with un important decrements in global pulmonary function. Hyaline pleural plaques are not pre cursor lesions to diffuse malignant mesothelioma. Groups of individuals with plaques may or may not demonstrate an increased incidence of bronchogenic carcinoma. Uncer tainty in this regard is fostered by die failure of published reports to differentiate plaques from diffuse pleural thickening and from the lack of any study that appropriately matched control subjects without plaques to case subjects with plaques for intensity and duration of asbestos exposure, cigarette smoking, and con comitant asbestosis. Distinct from the discontinuous hyaline pleural plaque is the very uncommon diffuse pleural thickening. Seemingly confluent plaques, infection, trauma, and pleural malig nancy may all give the appearance of pleural thickening radiographically. Extension of pul monary fibrosis (asbestosis) to the pleural sur face is an unlikely cause of diffuse pleural thickening. Most commonly, diffuse pleural thickening in the asbestos-exposed worker is the residual of a benign asbestos pleural effusion.6 Patients rarely may be so severely affected that the underlying lung is trapped, held en cuirasse by a thick rind of unyielding fibrotic pleura that impairs respiratory function to the point of respiratory failure. Such diffuse pleural thickening results in a restrictive ventilatory impairment, but the dif fusing capacity for carbon monoxide, when cor rected for the decrease in lung volume, is well preserved. This is In contradistinction to asbestosis, which likewise produces a restriction to full lung expansion but is associated with con siderably greater derangements in gas transfer. This separation is crucial, since the patient who is substantially impaired as a result of diffuse pleural thickening may benefit from resection of the diffusely thickened visceral pleural cortex, which is usually easily accomplished/ Diffuse Malignant Mesothelioma of Pleura Although diffuse malignant mesothelioma (DMM) was reported to be associated with as bestos exposure as early as 1946, it was not utt* til I960, when Wagner documented an upsurge in the occurrence of this disease in South African crocidolite miners, that the relationship became unquestionable. While radiation, man made mineral fibers, organic chemicals, viruses, and chronic inflammatory processes may play a role in the genesis of background cases of DMM, the relationship to asbestos exposure is so important that one half to three quarters of malignant mesotheliomas are- thought to be asbestos-related. Evidence suggests that amphibole varieties of asbestos, particularly crocidolite and to a lesser degree amosite, are much more capable of inducing DMM than is the serpentine chrysotile. Epidemiologic evi dence also suggests that increased exposure to asbestos increases the risk of DMM, but there is no threshold exposure below which mesothe lioma will not occur. To a certain degree, infor mation is difficult to come by, since 85% of patients develop their mesotheliomas at least 25 years after their initial asbestos exposure. The crucial diagnostic difficulty involves the separation of DMM from benign mesothelia! pro liferations and from pseudomesotheliomatous involvement of the pleural space by metastatic cancer. Certain features may be of help. Almost all patients with DMM present with chest pain, weight loss, and pleural effusion. Grossly, the tumor involves the pleural space as solid masses, sheets of tissue, or multiple nodules studding the pleural surfaces. Micro scopically, the tumor may be epithelial (tubu- Volume 12 Number 7 PULMONARY DISORDERS 49 lopapillary), resembling adenocarcinoma or sar comatous (mesenchymal or connective tissuetype), which may be so bland as to resemble benign fibrosis, or a mixture of these two types. Since hyaluronic acid may be secreted, quan titation of a high pleural fluid hyaluronic acid level (>200 mg/L) strongly supports the diagnosis of DMM. If biopsies of involved pleura are periodic acid-Schiff (PAS)-positive (confirm ing the presence of mucin or hyaluronic acid) and are negative when the stain is repeated after the application of diastase. DMM is suggested. Mucin-secreting adenocarcinomas remain PASpositive despite diastase digestion, since mucin is not subject to the action of diastase. If malignancy is unquestionably present, elec tron microscopy may permit the appreciation of qualitative subcellular findings that support the mesothelial nature of the cancer. Consequently, if DMM is suspected, a portion of the biopsy specimen should be preserved in glutaraidehyde for later electron microscopic inspection, should such an investigation be desirable. Nonetheless, the diagnosis of DMM remains elusive even for expert pathologists. In fact, when Charles Carrington chaired the U.S. Inter national Union Against Cancer Mesothelioma Panel, he preferred the final diagnosis of adenocarcinoma metastatic to the pleural space in one fifth of patients who were felt to have DMM by the panel at large.' Treatment decisions also remain problema tic. Some investigators favor policies of exten sive resection followed by radiation therapy to areas of residual disease. This is followed by multiagent chemotherapy with a doxorubicincontaining regimen. Early mortality is quite high, particularly when surgical resection en tails pleuropneumonectomy. Results are impos sible to assess because of the variable natural history of this malignancy and the reliance on historical controls for purposes of comparison. Most clinicians, citing the multicentric and diffusely invasive nature of DMM, conclude that heroic attempts at resection are counterproduc tive, that the least invasive surgical procedure that affords a diagnosis is the most appropriate, and that any invasive procedure, in view of the inherent incurability of this cancer, might be considered meddlesome. Further, they reserve palliative radiation therapy for intractable pain and for growth of tumor in surgical incisions and along chest tube or needle biopsy tracts. Finally, they consider chemotherapy to be investigational and of doubtful benefit.7 ASBESTOS-RELATED PULMONARY DISORDERS Asbestosis The first description of asbestos-related pul monary fibrosis is attributed to H. Montague Murray, who, in 1900 at London's Charing Cross Hospital, found severe lung fibrosis during the autopsy of a 33-year-old asbestos textile worker. Twenty-four years later, similar fibrosis in another asbestos textile worker was described by W. E. Cooke as asbestosis, thereby introducing the term into medical parlance. Asbestosis, like silicosis, was described as a pneumoconiosis, a term introduced by Zenker in 1866 to signify the ``dusty lungs" of workers with dust-induced lung diseases. As it is currently used, pneumo coniosis refers to an accumulation of dust in the lungs and the lung's non-neoplastic reaction to such dust with a permanent alteration in lung structure. Consequently, as a term that describes the pneumoconiosis associated with asbestos ex posure, asbestosis is best restricted in applica tion to asbestos-induced pulmonary fibrosis. Asbestosis characteristically follows intense, continuous exposure to asbestos but may at times follow indirect intermittent exposure. When it develops in those indirectly exposed, asbestosis seemingly causes less disability and progresses more gradually, suggesting that asbestosis is largely related to intensity of exposure. Even after cessation of exposure, existing abnormalities may progress and new abnormalities may ap pear. Cigarette smoking enhances the fibrosis produced by asbestos. Those with asbestosis manifest the signs and symptoms of diffuse interstitial pulmonary fibrosis, which asbestosis resembles clinically, radiographically, and histopathologically. A history of asbestos exposure, dyspnea, late inspiratory crackles (rales), a profusion of linear markings (small irregular opacities by the International Labor Organization International Classification of the Pneumoconioses) most pronounced at the lung bases with associated pleural thickening, and a restrictive ventilatory impairment are all characteristic (Figure 2). Substantial derange- 50 COMPREHENSIVE THERAPY July 1986 bodies per lung section* Asbestos bodies (also referred to as ferruginous bodies, since they rarely form on nonasbestos fibers) are typically beaded, sheathed, segmented, or knobbed with a clear central core fiber. The coat consists of fer ritin granules and amorphous proteins. The cores of most asbestos bodies consist of commer cial amphiboles. ' Much recent information places the finding of asbestos bodies or asbestos fibers in clinical context. Asbestos bodies may be found in expec torated sputum, bronchoalveolar lavage fluid, transbronchial lung biopsies, squeeze prepara tions of lung juice, routine and thick histologic sections of lung and lung biopsies subjected to potassium hydroxide (KOH) digestion, and \. ( membrane filter collection. The presence of f asbestos bodies confirms exposure but does not document disease. The presence of any asbestos bodies in a lung section suggests occupational exposure, since background exposure results in one asbestos body per 300 sections of lung, and the finding of an asbestos body in a lung sec tion suggests the presence of 5000 bodies/g of dried lung.910 Asbestos bodies may not be found in some i: Figure 2. Radiograph demonstrating asbestosis with workers with asbestosis. Pathologists may i. fine linear opacities and "shaggy-hearf border. routinely underdiagnose asbestosis because they 1 ; fail to appreciate asbestos bodies when they ap f ; pear in abundance. An iron stain stains asbestos bodies a bright blue and may lift them from the ,' merits in gas exchange as witnessed by background obscurity of a hematoxylin and a low carbon monoxide diffusing capacity or eosin stain. > arterial hypoxemia, which is most pronounced In addition, asbestos bodies may be com with exercise, are almost univers.il. Digital club pletely absent from the lung section of workers bing may rarely be present, and the finding of this sign may suggest the presence of lung whose lungs contain high counts of uncoated fibers. Such fibers may be quantitated by sub cancer in addition to asbestosis. jecting the lung biopsy to KOH digestion, mem In patients with these features, open lung brane filter collection, and electron microscopic biopsy merely to obtain diagnostic certainty is counting of fibers. Such workers with high fiber not necessary. However, when a history of ex posure is absent and diseases known to be associated with diffuse interstitial pulmonary counts but negligible numbers of asbestos bodies may be poor formers of asbestos bodies, may be rapid clearers of formed bodies, or may have an fibrosis or constitutional signs are present, or the disease is atypical for asbestosis in development, uneven distribution of bodies within the lung. Alternatively, the lung fiber burden may consist distribution, or progression, open lung biopsy exclusively of chrysotile, which is known to pro may be advisable to exclude other simulative diseases. If a lung biopsy can be performed, a histologic diagnosis of asbestosis is based on the finding vide a poor substrate for asbestos body formation. Since actual fiber counting is labor intensive, requiring one week of a trained technician's time Si of parenchymal fibrosis with at least two asbestos to count the fibers in three or four samples of JSi ? (also ! they ically (with of fer- The cr- ding nical :pecuid, >araogic d to and 5 Of not >tos nal ecof ne ay ey p os le id ls d Volume 12 Number 7 PULMONARY DISORDERS lung, it is of marginal clinical use. However, such are the pitfalls when using the asbestos body as a marker of the disease asbestosis. Once the diagnosis of asbestosis is estab lished, usually on clinical grounds, patients should bo treated with management of concomi tant airflow limitation, hypoxemia, and infec tion. They should cease smoking cigarettes and avoid further asbestos exposure. Pneumococcal and influenzal vaccinations are reasonable steps. Corticosteroids are thought to offer little hope in the restoration of function or in the preven tion of deterioration. Bronchogenic Carcinoma The first published report of lung cancer in an asbestos worker with asbestosis appeared in 1935. A series of case reports over the next 20 years culminated in the publication of an epidemiologic study that left no doubt that asbestos exposure and bronchogenic carcinoma were associated. Lung cancer as an occupationally related neoplasm of asbestos workers differs little from its asbestos-unrelated counterpart. With regard to clinical presentation, radiographic ap pearance and distribution, histologic type, and natural history, the two are indistinguishable. Since both asbestosis and lung cancer are diseases related to the intensity of exposure to asbestos, the presence of asbestosis in an in dividual with lung cancer confirms that an asbestos burden heavy enough to have caused lung cancer was inhaled. For the worker at risk for lung cancer, tobacco smoking should be strictly avoided. The multiplicative risk of cigarette smoking and asbestos exposure in the development of lung cancer has been known since 1968. Simply stated, if the risk of lung cancer in the nonsmok ing worker who is not exposed to asbestos is 1, the relative risk of lung cancer rises to 5 in the nonsmoking asbestos worker, to 10 in the worker who smokes and is not exposed to asbestos, and to 50 in the cigarette-smoking, asbestos-exposed worker. Beyond this admonition lies uncertainty. Since most cancers will develop in those smokers who were exposed to asbestos earlier than 20 years ago, some physicians recommend the policy of annually screening such patients with a chest radiograph and a cytologic examina tion of a pooled sputum specimen. The benefits of this approach are uncertain. Asbestos Airway Abnormalities Focal deposits of fibrous tissue and pigment around terminal and respiratory bronchioles (small airways) nro a nonspecific response to many types of inhaled inoiganic dusts. Such deposits may occur in asbestos-exposed in dividuals but are of no functional importance. Available evidence suggests that clinically im portant airflow limitation in an asbestos worker is unrelated to asbestos and is instead related to coexistent non-asbestos-related diseases such as asthma, chronic bronchitis, or emphysema." Whether the appreciation of such deposits in a lung biopsy specimen would confirm substan^ Hal asbestos exposure in an individual with lung cancer and thereby permit attribution of the cancer to asbestos exposure is contested. Since as many as one third of patients with lung cancer have focal pulmonary fibrosis attributable to tobacco smoke, identification of a unique asbestos-related peribronchiolar fibrosis may be impossible. Rounded Atelectasis Rounded atelectasis has been described under a variety of names (shrinking pleuritis, periph eral lobar collapse, Blesovsky's syndrome, atelectatic pseudotumor, pleuroma, subpleural atelectasis, folded lung) by various investi gators.'2 Radiographically rounded atelectasis consists of a rounded, parenchymal, pleuralbased mass that has a predilection to occur in the lung bases. There is adjacent pleural thicken ing, and curvilinear densities representing the bronchovascular bundle project toward the hilum (comet-tail sign). Bronchography may reveal displacement of bluntly obstructed bron chi (trees-bent-in-the-wind sign) (Figure 3). Rounded atelectasis presumably results from a pleural effusion that causes compressive atelectasis of that portion of lung that it displaces. The collapsed lung becomes adherent to adjacent parietal pleura, and when the effu sion is resorbed, this portion of lung is incapable of expanding because of these adhesions. This pleural-based mass of unexpanded lung remains as a residuum of the effusion. 52 COMPREHENSIVE THERAPY July 1986 Figure 3. (A) Blunting of posterior costophrenic angle suggests effusion. (B) A mass later develops posteriorly with features and bronchogram (C) diagnostic of rounded atelectasis. This condition is clinically innocuous, but pa tients with characteristic features of rounded atelectasis do not require thoracotomy for con firmation. Conversely, a patient with a peripheral cancer should not be denied a potentially curative resection in the mistaken assumption that the mass represents rounded atelectasis. At tention to the relevant radiographic features should permit the distinction to be accurately made. An appropriately obliqued tomographic projection may permit appreciation of the "comettail sign,'' and bronchography may at times be helpful. CONCLUSION In the 20th century, amosite factory levels of asbestos fibers greater than 5 pm in length averaged 20 fibers per mLair, and with removal of asbestos, logging peak fiber levels exceeded 3000/mL. The dawning recognition that various pleural and pulmonary abnormalities could be caused by breathing air contaminated with un controlled concentrations of asbestos fibers led to the imposition of fiber standards. The present asbestos standard recommended by the National Institute of Occupational Safety and Health is 0.1 fiber per mL. This standard, if adopted and enforced, may largely eliminate the problem of asbestosis and asbestos-related lung cancer. Since the relationship between DMM and fiber dose may be alinear, diffuse malignant mesothelioma may be more difficult to eliminate. Despite improved controls, physicians will continue to be called on to correctly diagnose asbestos-related disorders as greater numbers of directly and indirectly exposed workers pass through the to- to 40-year lag phase from initial Volume 12 Number 7 PULMONARY D1SORUERS 53 )US be m ed ;nt ial is id of r. ?r it 0 1 i exposure to manifest disease. Correct diagnosis rests on an understanding of the manifestations of asbestos exposure and on the willingness to take a thorough occupational-environmental history. Such a history should include all oc cupations ever held, including short-term jobs, summer employment, and military service. The occupations of household members, and residence near mines, mills, and factories, may be relevant. When a diagnosis of an asbestos-related con dition has been established, the patient should be so counseled. If the patient has been impaired by this condition, then he should be informed that he has a work-related disease for which compensation may be available. Obviously, such judgments must be based on sound reasoning and the attainment of a reasonable degree of medical certainty. Expert advice in reaching such conclusions may be essential. REFERENCES 1. Davis JMG: The pathology of asbestos-related disease. Thorax 1984; 39:801-808. 2. Becklake MR: Asbestos-related diseases of the lung and other organs: Their epidemiology and im plications for clinical practice. Am ftev Respir Dis 1970: 114:187-227. 3. Churg A: Current issues in the pathologic and minernlogic diagnosis of asbestos-induced disease. Chest 1983; 84:275-280. 4. Becklake MR: Asbestos-related diseases of the lungs and pleura. Am Rev HespirDis 1982: 120: 187-194. 5. Epler GR, McCloud TC. Gaensler EA: Prevalence and incidence of benign asbestos pleural effusion in a working population. JAMA 1982: 247:817-022. 6. Iltllerdal C: Non-malignant asbestos pleural disease. Thorax 1981; 38:009-675. 7. Goensler EA. McCloud TC. Carrington CD: Thoracic surgical problems in asbestos-related 54 COMPREHENSIVE THERAPY July 1986 disorders. Ann Thorac Surg 1985; 40:82-96. 8. Craighead JE. Abraham JL, Churg A, et ai: The pathology of asbestos-associated diseases of the lungs and pleural cavities: Diagnostic criteria and proposed grading schema. Arch Pathol Lab Med 1962: 106:544-596. 9. Churg AM. Warnock ML: Asbestos and other fer ruginous bodies: Their formation and clinical significance. Am / Pathol 1981; 102:447-456. 10. Churg A: Fiber counting and analysis in the diagnosis of asbestos-related disease. Hum Pathol 1982; 13:381-392. 11. Sue DY, Oren A. Hansen JE. Wasserman K: Lung function and exercise performance in smoking and nonsmoking asbestos-exposed workers. Am ftev Respir Dis 1985; 132:612-618. 12. Schneider HJ, Felson B. Gonzalez LL: Rounded atelectasis. A)R 1980; 134:225-232. opues Alzheimer's Victims Lack Chemical that Permits Response to Stress Scientists at The Johns Hopkins University Medical Institutions report that the brains of pa tients with Alzheimer's disease contain reduced levels of corticotropin-releasing factor (CRFJ, a chemical that enables the body to respond to stress. Although the finding has no immediate applications for treating Alzheimer's disease, team members say there is much to be learned about Alzheimer's by artificially raising or lowering brain CRF levels in animal studies, according to principal investigator Errol B. DeSouza, PhD, instructor of neuroscience at Johns Hopkins and research scientist at the National Institute on Drug Abuse, Addiction Research Center. In the future, testing for the absence of the compound might be used to diagnose the disease, and drugs resembling CRF might be used as a treatment. "What's going on in Alzheimer's disease is really more complex than we ever imagined," DeSouza says. "We don't know if this is part of the cause of the disease or just a consequence of it." The researchers' report was published in the February 13th issue of Nature. CRF is a neurotransmittcr--one of the many substances brain cells use to communicate with each other. Neurotransmitters fit into special sites, or receptors, on brain cells in much the same way a key fits into a lock. Different neuro transmitters convey different messages to brain cells, and, in turn, result in different brain func tions. For example, the neurotransmitter acetylcholine is involved in memory. Scientists have long known that in Alzheimer's disease--a condition marked by severe memory loss--the brain contains very low levels of acetylcholine. Similarly, brains of-* Alzheimer's patients have been found to contain fewer receptors for this neurotransmitter. In con trast, DeSouza and his collaborators found that while the brains of Alzheimer's patients also contain reduced amounts of CRF, they contain more CRF receptors than do the brains of nor mal persons. "The body really cares about CRF," DeSouza observes, "because it's trying to com pensate for this loss by increasing the number of locks." Now that scientists know the chemical struc ture of CRF, they can attempt to design drugs to fit the receptor, in hopes of treating Alzheimer's disease. DeSouza points out that injecting Alzheimer's patients with CRF would be inef fective because the neurotransmitter will not cross the blood-brain barrier, the physical mechanism that prevents potentially harmful substances from passing from the blood into the brain. Last year, DeSouza was part of a research team that discovered that CRF, as a neurotransmitter, has a direct effect on the brain. The substance also is a hormone that affects the pituitary. Other members of the research team were Peter J. Whitehouse, MD, PhD, assistant professor of neurology; Michael J. Kuhar, PhD, Johns Hopkins professor of neuroscience and chief of the neuroscience branch at the Addiction Research Center, National Institute on Drug Abuse; Donald L. Price, professor of neuropathology; and Wylie W. Vale, a scientist at the Salk Instititute in La Jolla, CA.