Document om4oDQbx4V0kqdRNVg9mMeDYr

GEORGE L DELCLOS, MD, MPH PATRICIA A. BUFFLER, PhD, MPH S. DONALD GREENBERG, MD MARCUS M. KEY, MD, MIH DENNIS M. PERROTTA, PhD CHARLES ALEXANDER, MD, DrPH R KEITH WILSON, MD Asbestos-associated disease: a review George L Deletes, MD, MPH, Pulmonary Sec* Uon, Dept of Medicine, Baylor College of Medi cine, Houston, and The University of Texas School of Public Health, PO Box 20186, Houston, TX 77225; Patricia Buffler, PhD, MPH. and Marcus M. Key, MD, MIH, The University of Texas School of Public Health, Houston; S. Donald Greenberg. MD, Dept of Pathology, Baylor College of Medicine, Houston; Dennis Pertotta, PhD. Division of Epidemiology, Texas Department of Health, Austin; and Charles Alexander, MD, DrPH, Bureau ofAIDS and STD Control, Texas De partment of Health, Austin; and R. Keith Wilson, MD, Pulmonary Section, Dept of Medi cine, Baylor College of Medicine, Houston. Send reprint requests to Dr Dddos. Asbestos and its potentialfor adversely affecting bestos increased dramatically until the mid-1970s health remain a source ofconcern to several sec when concern regarding health effects of asbestos tors ofsociety. Since it rarely occurs in the absence and the implementation of strict regulatory stan ofoccupational exposure to asbestos, and because dards resulted in a decrease in annual use (from ap it is potentially preventable, asbestosis was re proximately 800,000 metric tons used in the United cently defined as a reportable occupational disease States in 1973 to 210,000 metric tons in 1983). in Texas. An overview of the cardinal characteris Worldwide cumulative production of asbestos prod tics of the asbestos minerals and their associated ucts, however, has continued and it is estimated that health effects is presented. The role of the primary approximately 30 million metric tons of asbestos physician in diagnosis and counseling of indi are still in use in this country (4). viduals with asbestos-associated diseases is Isolated case reports of pulmonary fibrosis in addressed heavily exposed asbestos factory workers appeared KEY WORDS: ASBESTOS, ASBESTOSIS, OCCUPATIONAL DISEASE REPORTING. as early as 1906 (5) and increased rapidly thereafter (6). Although an association between asbestos ex posure, asbestosis, and lung cancer was suspected as early as 1935 (7), firm epidemiologic evidence in ferring causality was not reported until 1955 (8). In he occupational lung diseases are recognized I960, a causal association between asbestos ex Tby the National Institute for Occupational posure and mesothelioma, a malignant and invari Safety and Health (NIOSH) as heading the list ably fatal tumor of the pleura and/or peritoneum, of the ten leading occupation-related conditions winas reported (9) and thus further expanded the this country (1). When one considers prevalences,pectrum of asbestos-related diseases. potential disability, premature death, and preven- Asbestosis first became a recognized compensable tability, asbestos as a cause of pulmonary disease disease in 1931, in Great Britain under the Work continues to be a source of concern to industry, men's Compensation Act. In the United States, com labor, government, and the general public. This is pensation was first awarded to an asbestos weaver heightened by different medical, sociopolitical, and in 1927, through the Massachusetts Industrial Acci economic considerations. dent Board (10). The extent to which occupational In 1985, asbestosis, one of the asbestos-related diseases are covered in the United States varies ac diseases, was defined as one of the four reportable cording to each state's workers compensation laws. occupational diseases in Texas (Texas Civil Statutes, This inconsistency has led to numerous cases being Article 5182C) (2). The other three reportable con argued via tort litigation in the courts. ditions are elevated adult blood lead levels, silicosis, Initially, most cases of asbestosis described were and acute occupational pesticide poisoning (3). limited to workers in the mining, milling (11), and This review is one of a series of papers on the re manufacturing (12) sectors. End-product users (eg, portable occupational diseases in which an over insulators, pipefitters, shipyard workers, etc), were view of the historical, epidemiologic, mineralogical, not regularly reported as being at risk of asbestosis pathological, and clinical features of asbestosis and until the late 1950s and early 1960s (13), although the spectrum of asbestos-related conditions or dis isolated cases in this sector had been described as eases is presented. early as 1934 (6). From a medicolegal standpoint, the asbestos product use sector is of great interest, Modem history since the numbers of exposed workers in these Asbestos is a term that refers to a group of naturally- occupations are now considered to substantially occurring fibrous hydrated silicate minerals, useful to man because of their properties of enhanced outnumber those in the mining, milling, and manu facturing sectors. In the United States, it has been strength, flexibility, and resistance to physical and estimated that over 27 million persons have been chemical Insults. It was used sporadically for pro occupationally exposed to asbestos since 1940 duction of purses and lamp wicks for hundreds of (14). The potential medical, economic, and legal years. Widespread production and use of asbestos implications of these figures are readily apparent began in the late 19th century with the introduc Implementation of regulatory measures and safe tion of the steam engine. Unique properties of as workplace practices paralleled scientific knowledge; bestos--flexibility and virtual indestructibility-- the measures taken initially, such as those of the US were unmatched at the time by any other mineral Public Health Service, however, were limited and or man-made fiber and quickly led to its use in the left up to industry to implement and enforce (15). manufacture of a long list of construction materials A major step towards stricter workplace regulation and textiles, including cement, insulation products, took place in 1970 with the passage of the Occupa friction materials, electrical appliances, and protec tional Safety and Health Act and the subsequent tive garments. Worldwide production and use of as creation of the Occupational Safety and Health Ad- Texas Medicine DPMC-01742 LAM 008259 c "A s Is the controversy associated with die relationship of rheumatoid arthritis and malignancy. While inves tigators from Great Britain have reported an in creased risk for lymphoproliferative disorders in patients with rheumatoid arthritis (6,7), studies from the United States have failed to find a signifi cant association (8,9). Furthermore, our patient had received azathioprine (Imuran) and methotrexate for treatment of his rheumatoid arthritis in the three years prior to the discovery of lymphoma. Presenta tion of stage III malignant lymphoma as nocturnal lower leg pain is unusual. The patient in case 4 presented with unilateral sacroiliitis Interspersed with periods of remission. Sacroiliitis is most commonly seen in inflammatory spondyloarthropathies. Although pure unilateral sacroiliitis may be seen in seronegative spondyloarthritis, it is more suggestive of joint infection or neoplasm (10). Causes of unilateral sacroiliitis are listed in Fig 1. Of the infectious agents causing uni lateral sacroiliitis, staphylococcus is most common; in intravenous drug abusers P aeruginosa is com monest Unilateral sacroiliitis caused by Mycobac terium tuberculosis in a young man in continental North America is unusual. The initial evidence and closed-needle biopsy had suggested a diagnosis of malignant lymphoma, and the correct diagnosis was made after open biopsy and tissue cultures for my cobacteria. This stresses the importance of tissue culture in all cases suspected of tuberculous infec tion; staining for mycobacteria is not adequate to exclude tuberculous infection (11). Some diseases such as syphilis, diabetes mellitus, and tuberculous infections are known to be great mimics. Various malignancies can present in atypical fashions. Pain is a common symptom in rheumatic diseases and also in patients with malignancy. Physi cians should stay alert to the possibility of lymphomatous disorders masquerading as rheumatologic diseases. This is important not only for correct diag nosis but because of major differences in the treat ment and prognosis of these disorders. ACKNOWLEDGMENT We wish to thank Mrs EE Timm for her help in the prepa ration of this manuscript REFERENCES 1. Hollenhorst RW, Brown JR, Wagcner HP, ct al: Neu rologic aspects of temporal arteritis. Neurology 10:490498, 1960. 2. Moore PM, Cupps TR: Neurological complications of vasculitis. Ann Neurol 14(2):155-167,1983. 3. Hundcr GG, Hazlcman BL: Giant cell arteritis and polymyalgia rheumatica, in Kelley WN, Harris EDJr, Ruddy S, et al (eds>. Textbook of Rheumatology, ed 2. Philadel phia, WB Saunders Co, 1985, pp 1166-1173. 4. Fauci AS: Vasculitis, in McCarty DJ (ed>. Arthritis and Allied Conditions: A Textbook of Rheumatology, ed 10. Philadelphia, Lea and Febiger, 1985, pp 942-961. 5. Lakhanpal S, McLeod RA, Luthra HS: Insufficiencytype stress fractures in rheumatoid arthritis: report of an Interesting case and review of the literature. Clin Exp Rheumatol 4(2): 151-154,1986. 6. Prior P: Cancer and rheumatoid arthritis: epidemio logic considerations. Am J Med 78(1A):15-21,1985. 7. Symmons DPM: Neoplasms of the immune system in rheumatoid arthritis. Am J Med 78(IA):22-28,1985. 8. Katusic S, Beard CM, Kurland LT, ct al: Occurrence of malignant neoplasms in the Rochester, Minnesota, rheu matoid arthritis cohort Am J Med 78(1A):50--55,1985. 9. Fries JF, Bloch D, Spitz P, et al: Cancer in rheuma toid arthritis: a prospective long-term study of mortality. Am J Med 78(lA):56-59, 1985. 10. .Carrera GF: Computed tomography in the evalua tion of low back pain, in McCarty DJ (ed): Arthritis and Al lied Conditions, ed 10. Philadelphia, Lea and Febiger, 1985, pp 148-155. 11. Lakhanpal S, Linschcid RL, Ferguson RH, ct al: Tu berculous fasciitis with tenosynovitis. J Rheumatol 14(3): 621-624, 1987. I. Causes of unilateral sacroiliitis. Infection (Staphylococcus aureus Pseudomonas aeruginosa, Streptococcus pneumonococcus, Escherichia coli, Gonococcus Mycobacteria, fungi) Malignancy Osteomyelitis Ankylosing spondylitis Psoriatic arthritis Reiter's syndrome Inflammatory bowel disease Degenerative joint disease Rheumatoid arthritis Gout Still's disease Familial Mediterranean fever Volume 85 May 1989 DPMC-01743 LAM 008260 ministration (OSHA) in the Department of Labor. OSHA first regulated asbestos in 1971, setting a per missible exposure limit of 12 fibers per cubic cen timeter of air (free). Since then the level has been progressively lowered to the current threshold limit of 0.2 free (16). Present legislation specifies stan dards, not only on levels in maritime and general in dustry, but also for the construction sector, with specific norms for asbestos abatement projects, since these activities are considered to pose the potential for acute exposure to hazardous levels ofdust Recognition of asbestos-related diseases has in re cent times led to concern regarding the potential for population exposure to already existing asbestos in public buildings, particularly in schools. Legis lation set forth by the Environmental Protection Agency (EPA) required all US schools to examine their facilities for asbestos-containing materials and, if any were found, to notify both parents and em ployees (17). Subsequently, guidelines for dealing with asbestos, if found, were described (18). Al though cases of mesothelioma and benign pleural changes have been described as a result of nonoccupational exposure, these have generally been lim ited to immediate family members of asbestos work ers, or to individuals living near asbestos plants or naturally occurring asbestiform fiber deposits (19-- 22). Even so, cases of mesothelioma have been de scribed in which no obvious risk factors were iden tified. Epidemiologic data regarding the long-term effects of exposure to low levels of asbestos, such as those encountered in schools, are sparse. Risk as sessment of population exposure in these settings using measurements of fiber levels inside public buildings, extrapolation of data from occupational cohorts, and mathematical models has beat per formed recently. Estimates of excess lung cancers and mesotheliomas have varied in precision, mainly because of differences in underlying assumptions re garding levels of occupational exposure in the dif ferent cohorts analyzed (4,23--25). Mineralogy and the asbestos chain The asbestos minerals are classified into two distinct classes, serpentines and amphiboles. The serpentine class contains one member, chrysotile (white asbes tos), which accounts for 90% of commercial as bestos produced worldwide. In the United States, 95% of the commercial use of asbestos has involved chrysotile. There are five main types of amphiboles: crocidolite (blue asbestos), amosite (brown asbes tos), anthophyllite, actinolite, and tremolite. Serpen tine asbestos fibers, as their name implies, are long, wavy, and very flexible, whereas the amphiboles tend to be shorter and straighter; these properties are taken into account in the manufacture of asbestoscontaining products. The major asbestos mining countries are Canada (which mines almost exclu sively chrysotile). SouthAfrica (the majorproducer of crocidolite and amosite), and die Soviet Union (26). Although numerous trades in Industry have dealt with asbestos, the "asbestos chain" can be broadly categorized as described in Fig 1 (16). Knowledge of these different sectors of the asbestos chain is im portant because of differences in the nature of the exposure and the concomitant risk of disease. Most occupational asbestos exposure in Texas has oc curred in end-product use. Determinants of asbestos-related health effects Not all individuals exposed to asbestos will develop asbestos-related disease. Factors relating to both en vironment and host must interact to create the nec essary conditions for a pathologic response. Among these, we can distinguish fiber characteristics, indi vidual susceptibility, and the nature of the exposure. It is mandatory for fibers to be respirable (ic, of a size that, after inhalation, can reach respiratory bron chioles and alveoli). In general, this capability is lim ited to fibers with an aerodynamic diameter of 3 |tm or less, since larger diameter particulates tend to be trapped in more proximal airways. In addition, ani mal experiments suggest that asbestos fibers with a large aspect ratio (lengthrwidth ratio) appear to have more pathogenic potential than shorter, thicker ones (4). Similarly, at least with respect to meso thelioma, there is evidence of a differential risk gra dient byfiber type (28--32), with crocidolite posing the greatest risk, followed by amosite and, at the lower end of the scale, chrysotile and anthophyllite. Once a fiber has reached the alveolar level, it must persist long enough to cause an effect. Foreign particles in the lung are typically handled by two basic lung defense mechanisms, the mucociliary es calator and the alveolar macrophage or scavenger /. Common sources ofasbestos exposure. Mining and milling, in and around either open-faced or under ground mines. In this stage, fibers arc for the most part Initially intact in the rock, but subsequent crushing in the mill may gen erate large amounts of dust. Primary manufacturing, where raw asbestos fibers are received, introduced, and processed to make asbestos products such as ce ment, sheet, and paper. Secondary manufacturing, where products are received from pri mary manufacturers and further processed (including sawing,' pressing, and drilling) to fabricate other Intermediate or finished products. End-product use, involving the application of products, generally in the construction, insulation, electrical, automotive, and ship building industries. Nonocctipational or environmental exposure Since all persons may have some asbestos fibers In their lungs from general envi ronmental levels (27), the question of what constitutes signifi cant environmental exposure is still being debated. Volume 85 May' 1989 Asbestos-associated disease 52 cell The macrophage phagocytizes the particle and is subsequently transported away (cephalad) from the area by either the mucociliary escalator or drainage to the regional lymph nodes. With asbestos fibers, this task may be complicated by die fibers' peculiar dimensions and resistance to destruction, making them harder to engulf. Some of the fibers are eventually coated with an iron protein material which confers a club- or beaded-like appearance to the fiber (asbestos body). Evidence from in vitro and animal experiments suggests dial these coated fibers have been rendered less reactive than naked ones (33--35). Data have also shown that inhaled chrysotlle may in part disappear over time from the lung, possibly due to leaching of minerals and fiber fragmentation and dissolution, whereas the amphibolcs tend to persist in both coated and uncoated states (36,37). Asbestos bodies have been found not only in persons occupationally exposed to asbestos, but also in lungs of presumably nonexposed urban residents, examined at autopsy, although generally in much smaller numbers (27). Therefore, It is be lieved that the presence of asbestos bodies in the lung is a marker of asbestos exposure, not disease. This information suggests that for exposure to as bestos to produce disease, there must be some quan tity of retained uncoated asbestos fibers, possibly related to overwhelming of the normal lung defense mechanisms. Data concerning the pathogenesis of parenchymal injury at this stage are uncertain, but currendy favor the occurrence of an inflammatory response and release of cytotoxic enzymes, initially at the peribronchiolar level, which can ultimately lead to fibrosis (38). Bronchoalvcolar lavage analy sis has revealed the presence of increased numbers and types of inflammatory cells, as well as some im munological changes in asbestos-exposed subjects both with and without asbestosis, although many of these abnormalities are not specific to asbestos ex posure (39--41). Several studies have noted that the prevalence of smoking among asbestos exposed individuals is quite high. In vitro and In vivo studies have shown that particle clearance is Impaired in the presence of cigarette smoke, and epidemiologic data have found that the risk of lung cancer is increased markedly among asbestos-exposed smokers (42-44). In addi tion, smokers are at increased risk of other lung dis eases (eg, emphysema) which arc independent of an association with asbestos. Therefore, smoking may also be responsible for some of the symptoms and lung pathology present in asbestos-exposed subjects and needs to be taken into account during their clinical evaluation (45). The nature of exposure to this mineral is impor tant as a determinant of disease. When evaluating a potential causal link between a suspected toxin and an adverse effect, the demonstration of a dose- response relationship constitutes evidence in favor of the toxin's being the cause of that effect Numer ous studies have shown dose-response relationships between asbestos exposure and the established asbestos-related conditions and diseases (46). Autopsy series document correlations between lung fiber content and asbestosis and mesothelioma (46--48). The ability of epidemiological studies to demonstrate dose-response relationships depends in part on their precision in defining both exposure levels and disease. Unfortunately, the appropriate exposure data are not always available because of the long latency period between asbestos ex posure and onset of disease, the general lack of workplace dust level measurements, and the marked variation in Individual exposures (14). This limitation is particularly true when evaluating the risks in end-product users. Less direct measures of exposure, such as years since onset of first ex posure, duration of exposure, and job type provide in some instances a rough correlation between dose and response (46). Nonmalignant asbestos-related pathology PLEURAL CHANGES Asbestos exposure is associated with different types of nonmalignant processes involving the lungs and pleura. For medical and compensation purposes, it is necessary to carefully differentiate those changes associated with functional impairment and disability from processes not generally leading to disease or disability. Nonmalignant asbestos-associated pleural changes may be of three types: circumscribed pleural thick ening (plaques), diffuse pleural thickening, and pleural effusion. Pleural plaques are irregularly rounded, circumscribed lesions that are characteris tically bilateral and most commonly appear on the lower posterolateral aspects of the parietal pleura and central tendinous portion of the diaphragm. An exposure-response relationship has been demon strated between frequency of plaques and duration of exposure and years since onset of first exposure; plaques correlate less well, however, with cumula tive exposure (49). Plaques are uncommon in sub jects with less than 20 years elapsed since first exposure and have been reported in persons with nonoccupational exposure to asbestos (50). MacroscopiCally, pleural plaques appear as ivorycolored or grayish-white elevated, localized areas on the parietal pleura. The surface ofpleural plaques is generally smooth, but often can be nodular. Infre quently, calcification may be visible to the naked eye and tends to correlate with increasing years since first exposure as well as with the age of the plaque. Microscopically, plaques are composed of collagen fibers most often arrayed in a basket-weave pattern. Cellular elements are scarce, and calcium Texts Medicine DPMC-01745 LAM 008262 deposition at this level is common. mid- and lower-lung fields and may complicate Coated asbestos fibers (asbestos bodies) have not evaluation of the underlying parenchyma. Comput been described in pleural plaques. Likewise, un erized tomography of the chest can aid in its detec coated fibers arc not visible on light microscopy of tion (58). routinely prepared plaques, but have been reported Severe diffuse pleural fibrosis independently may when studying ashed specimens (51). cause abnormal lung function, characterized by a Radiographically, pleural plaques may be the most decrease in lung volumes and forced vital capacity. frequent asbestos-related abnormality described in In some cases, unilateral or bilateral decortication both cross-sectional and longitudinal studies has been necessary because of severe symptomatic (50,52>, prevalence is even higher at autopsy (53). extraparenchymal restrictive disease (59). When On the radiograph, pleural plaques are most com evaluating diffuse pleural fibrosis, one should also monly seen along the lateral aspects of the mid- consider other etiologies such as scarring secondary third of the chest wall and on the diaphragm. They to prior surgery, trauma, or infection. do not involve the apices or costophrenic angles Nonmalignant pleural effusions are the earliest unless they are very extensive. Plaques on the chest asbestos-associated changes to manifest themselves, wall can appear either in profile or en face, and not infrequently appearing in workers less than ten their presence can often be enhanced with the use years since first exposure. They are generally small, of oblique films (54). These lesions may or may not and thoracentesis yields an exudate that may be be calcified, but when present, calcium deposition blood-tinged. The effusions are usually unilateral, tends to appear in the center of the lesion. The ra but can recur and alternatively involve the oppo diographic appearance of pleural plaques can be site side. Although often asymptomatic, asbestos- confused with a variety of radiologic shadows, in exposed individuals may present with pleuritic pain cluding those related to subpleural fat, companion and dyspnea, with or without an accompanying shadows, rib fractures, post-thoracotomy pleural fever. The effusions tend to resolve spontaneously, thickening, serratus anterior muscle, or previous although occasionally they persist for long periods empyema of time. Since the cffrision itself is nonspecific, other Circumscribed pleural plaques are asyniptomatic. conditions associated with exudative effusion must Epidemiologic studies, in general, have not found also be considered, including differentiation from consistent associations between these changes and mesothelioma (60). clinically significant lung function abnormality. Simi larly, the presence of pleural plaques among asbes ASBESTOSIS tos workers does not appear to be an independent Asbestosis refers to a diffuse interstitial lung fibrosis risk factor for either parenchymal fibrosis or cancer, which results from significant asbestos exposure. Of when adjusted for age and exposure (55--57). At the nonmalignant asbestos-associated diseases, it is present, no evidence exists that these plaques de the only one which is a reportable occupational dis generate into mesothelioma. Because of the current ease in Texas (2). When it occurs, die fibrosis devel lack of evidence associating pleural plaques with ad ops insidiously and generally after a latency period verse health effects, it is believed that pleural plaques of usually 20 years and may progress after cessa indicate exposure to asbestos, but not asbestos- tion of exposure. In epidemiologic studies of those associated disease. Use of the term "pleural asbesto- industrial sectors where dust levels have been avail sis" is discouraged, in that it may contribute to con able for some time (ie, mining, milling, and manu fusion with other asbestos-associated processes that 1 facturing), good dose-response relationships do have functional consequences. Diffuse pleural fibrosis may be detected in some asbestos workers, although it is less common than 2. Asbestos-associated conditions. circumscribed plaques. Differentiation of pleural fi brosis from pleural plaques is important from both a medical and a legal perspective. Pathologically, dif Marker of Asbestos Exposure Asbcscosassodated Disease fuse pleural fibrosis consists most commonly of a variable degree of thickening of the visceral pleura. Its pathogenesis is unclear, but it can appear adja cent to areas of parenchymal fibrosis and possibly as a sequel to asbestos-related pleural effusions. Radio graphically, diffuse pleural fibrosis may also appear Nonmalignant: Asbestos bodies Pleural plaque Diffuse pleural fibrosis Pleural effusions Asbestosis Obstructive airways disease Yes Yes Yes Possibly Yes No No No Yes Yes Yes Possibly* in profile or en face. In-profile changes are mani fested by obliteration and thickening of one or both costophrenic angles, tapering cephalad. En face dif Malignant: Bronchogenic carcinoma Mesothelioma Possibly Yes Yes Yes fuse pleural thickening casts a milky haze over the Although unlikely to be of clinical significance. Volume 85 May 1989 Asbestos-associated disease 54 between duration or intensity of asbestos exposure and asbestosis have emerged (61 --63). Similarly, au topsy series have revealed a rough correlation be tween lung asbestos fiber content and parenchymal fibrosis (48) Unfortunately, the finding of similar dose-response associations in the end-product use sector is made difficult by the lack of adequate expo sure data. To date, there is no firm evidence that nonoccupational asbestos exposure produces asbestosis. Both chrysolite and the amphiboles appear to have similar fibrogenic potential although that of the latter may be more severe. The contribution of smoking to the fibrosis is unclear, with some studies purporting to show a higher prevalence of inter stitial disease among asbestos-exposed smokers (63--66) and others finding no such association (67-69). Because of the demonstration of consistent exposure-response curves, coupled with the obser vation of fewer and milder cases of fibrosis in work ers exposed to the lower dust levels of more recent times, it is believed that strict observation of cur rent permissible exposure limits, engineering and safety controls, and good workplace practices should make the appearance of future cases of as bestosis extremely rare (58). Macroscopic examination of the asbestotic lung reveals that the fibrosis almost always begins in the subpleural areas of the lower lobes and extends up ward as its severity increases. Patchy involvement Is common. The hallmark of microscopic diagnosis is the simultaneous presence of both fibrosis and asbes tos bodies. In advanced asbestosis cases, areas ofhon eycombing may appear in the affected lung areas. The most common presenting symptom in the pa tient with asbestosis is dyspnea. Rales--characteris tically bilateral, pan- or end-inspiratory, and best heard laterally or posteriorly--are present on physi cal examination in over 50% of patients, but are not specific. Clubbing is less common, nonspecific, and generally appears late in the course of the disease. Pulmonary function studies, when abnormal, typi cally reveal a restrictive lung pattern, with a reduc tion in vital and total lung capacities, and preserva tion of the FEV/FVC ratio. Lung diffusing capacity, although variable, may also be low, and relative hypoxemia can be present in advanced stages of the disease. The radiologic appearance of asbestosis is charac terized by the presence of bilateral small, irregular interstitial opacities beginning in the lower lobes. The concentration or "profusion" of these opacities increases with the severity of the disease and corre lates roughly with both cumulative exposure (63) and a reduction in lung volumes (46,70), particu larly at higher grades of profusion. A gradient for profusion has been quantitated by the International Labour Office (ILO) (71), but interpretation of mini mal degrees of profusion can be particularly diffi cult Several factors contribute to this. First of all, interobserver variability is present in interpretation of radiographic changes, even when the standards set out by the 1980 ILO Classification of Radio graphs of the Pneumoconioses are used. Second, the positive predictive value of mild increases in inter stitial markings for asbestosis is low, and other fac tors should be entertained in the differential diagno sis. Some studies have found interstitial markings to be more prevalent among smokers and, indeed, in some cases, to regress at least partially after cessa tion of asbestos exposure and smoking (72). Lung function is generally normal or minimally impaired at this stage of disease. On the other hand, longitu dinal studies have suggested a progression of profu sion in those who develop asbestosis, if the disease worsens (73). Unfortunately, physicians are fre quently asked to make a judgment at a single point in time, which often is the case when evaluating compensation cases. While there would be little un certainty in the case of a symptomatic asbestos worker who presents with rales, dubbing, a restric tive lung defect, and a chest radiograph showing bilateral calcified pleural plaques and advanced in terstitial fibrosis, the majority of cases are not as straightforward. Recently, the American Thoracic Society and the American College of Chest Physi cians both recognized that characteristic radiographic changes, coupled with an adequate history of exposure, may be suffident to establish a diag nosis of asbestosis (58) The additional presence of rales, dubbing, lung restriction, or a low diffusing capacity increases the certainty of the diagnosis. It is generally accepted that, in the presence of a his tory of occupational asbestos exposure and com patible clinical-radiological findings, the benefit of the doubt weighs in favor of a diagnosis of as bestosis (58). Lung biopsy is not necessarily ob tained for diagnosis. When performed, however, tissue obtained by open lung biopsy is preferable to transbronchial biopsy because of the low yield of adequate tissue and nonspedfidty of the latter tech nique (27). Guidelines for the pathologic diagnosis of asbestosis have been published jointly by the Col lege of American Pathologists and NIOSH (74). OBSTRUCTIVE AIRWAYS DISEASE There exists some controversy as to whether chronic inhalation of asbestos fibers can also induce obstructive airways disease. Examination of the lungs of asbestos-exposed animals and humans has shown that the earliest injury occurs at the level of the respiratory bronchiole (75,76). Likewise, some epidemiologic studies have reported lower midexpiratory flow (MMF) rates, decreased flows at low lung volumes, and diminished closing volume (CV) values among asbestos workers, suggestive of "small Texas Medicine DPMC-01747 LAM 008264 airways disease" (77-79). This difference persisted after adjusting for smoking history in those studies where this was considered. However, MMF, CV, and decreased flows at low volumes are fraught with a great deal of variability (80) and are of uncertain long-term significance. Furthermore, dose-response relationships between exposure levels and degree of airflow abnormality have been difficult to docu ment. A higher prevalence of clinically significant airway obstruction, as reflected by decreases in the FEV1/FVC beyond that attributable to smoking alone, has not been consistendy observed in as bestos-exposed individuals (77,81). In general, obstructive lung defects in these populations appear to be the result of the high prevalence of smoking. Asbestos-associated malignancy LUNG CANCER Studies of asbestos-exposed workers have consis tendy demonstrated an excess number of lung can cer deaths (82-86). This risk is further increased among smokers, above that expected from a simple additive effect of both exposure and smoking (42). Occupational studies have shown a linear relation ship between cumulative asbestos exposure and lung cancer mortality (23). At low levels of ex posure, however, it is unclear whether a threshold exists below which there is no excess risk. This question is of considerable importance, particularly with respect to consequences of environmental ex posure to asbestos. Due to the lack of data on ex posure at these low levels, risk estimation studies (4,23,25) have in general assumed a linear nothreshold model for purposes of recommending standards, extrapolating from health effects at higher, generally occupational, exposures. The rationale underlying this assumption presumes a '`worst pos sible" situation on which to base subsequent risk estimates. Some uncertainty exists as to whether asbestos is a complete carcinogen (ie, able to initiate carcino genesis by itself), or if it acts as a tumor promoter or cocarcinogen, at least in the case of lung cancer (4). Proponents of the latter point to several obser vations (87,88). First, the excess number of lung cancer cases among asbestos-exposed nonsmokers (in those studies where these data are available) oc curs predominandy among workers with concomi tant evidence of asbestosis (8). Second, there is some evidence that the incidence of lung cancer in individuals with other fibrotic lung diseases (eg, idio pathic pulmonary fibrosis, pulmonary systemic scle rosis) is increased, suggesting that the fibrosis itself may be associated with subsequent malignancy (87). Some authors have noted that lung cancer in these patients preferentially arises in the lower lobes as does the fibrosis, unlike the usual situation of upper lobe predominance of bronchogenic tu mors (88). In the United Kingdom, bronchogenic carcinoma is attributed to asbestos only if there is also concomitant evidence of asbestosis. Laboratory studies of mutagenicity and carcinogenicity have produced somewhat conflicting results. Whereas a few studies have reported a weak mutagenic effect of asbestos in certain cell lines (89), most have failed to observe this (4,90). Animal studies of as bestos and carcinogenicity favor the role of asbestos as a tumor promoter or cocarcinogen, at least in the case of lung cancer (4). Most cases of bronchogenic carcinoma in asbes tos-exposed individuals appear after a latency pe riod of 20 years or more. While not all fiber types show the same risks, there does not appear to be a predominant fiber type responsible for the observed excess lung cancer rates (91). Likewise, there is no firm evidence of a predominant histologic type of bronchogenic carcinoma in asbestos-exposed popu lations (92), although earlier a slight predominance of adenocarcinoma was reported by some authors (93). MESOTHELIOMA There is little question as to the causal association between asbestos exposure and the occurrence of malignant mesothelioma. Several observations sup port this relationship. Mesothelioma is rare in the nonexposed population, although cases have been reported (94--96). Epidemiologic studies have consistently identified cases in asbestos-exposed groups, regardless of occupational setting (4,16,94). Clusters of mesothelioma cases among relatives of asbestos workers and individuals living near asbes tos plants have been described as well (19--21,94). Also, mesotheliomas have been produced in animal studies following inoculation and/or inhalation of as bestos (97,98). Finally, an exposure-response rela tionship has been reported between years elapsed since onset of exposure and appearance of these tu mors, although based on relatively few studies (99). This exposure-response curve appears to be expo nential, not linear, with most cases appearing after a latency period of 30 or more years (23). There is evidence supporting the existence of a differential risk gradient according to fiber type, with crocidolite posing the greatest hazard (23). Smoking does not appear to increase the risk of mesothelioma among asbestos-exposed subjects. As is the case with bronchogenic carcinoma, there is some debate (100) as to whether a threshold exists below which no excess mesothelioma deaths would be expected to occur, although risk estimates also are based on a no-threshold model (4,23,24). There are data, how ever, on mesothelioma cases appearing several years after relatively brief and probably lower exposures than those observed in the other asbestos-associated diseases (101). Volume 85 May 1989 55 DPMC-01748 LAM 008265 Asbestos-associated disease 56 The most common presenting symptoms of the patient with mesothelioma are unremitting chest pain and increasing dyspnea upon exertion. Chest radiographs may show a moderate or large effusion and pleural thickening encroaching on the inter lobar fissures and infiltration of the mediastinum, as the tumor progressively encases the lung and neigh boring structures. Establishing a pathologic diag nosis prior to death is frequently difficult Closedneedle biopsy of the pleura and pleural fluid analysis may have a low diagnostic yield; open- or thoracoscopically-guided pleural biopsy procedures pro duce better samples. Other tumors such as meta static adenocarcinoma may mimic mesothelioma, and frequendy a combination of gross pathology, microscopic study of specimens, and histochemical testing for the presence or absence of certain mucins and enzymes is required for a definitive diagnosis. OTHER MALIGNANCIES Although there is general agreement on the associa tion between asbestos and both lung cancer and mesothelioma, a consensus does not exist as to whether there is an increased ride of other tumors such as gastrointestinal, laryngeal, renal, and ovarian carcinomas in asbestos-exposed populations. Among these tumors, die epidemiologic evidence is most abundant for tumors of the digcsdve tract, with some studies reporting an increased risk, although not always statistically significant, among those ex posed to asbestos (85,102,103); other studies have not found such an increase (29,104). Exposureresponse relationships have not been documented in studies of asbestos exposure and tumors of nonresplratory sites, the biological plausibility of an effect has been questioned, and animal experiments have been unable to substantiate the association of gastrointestinal tumors with asbestos exposure (4,105). Doll and Peto (106) suggest that misclassification of cases of peritoneal mesothelioma as gastrointestinal cancer may account for most of the observed excess. Notwithstanding this, OSHA con sidered gastrointestinal cancer as probably asso ciated with asbestos exposure when it recently re vised its exposure limits (16). There are fewer data on the associations between tumors other than gastrointestinal and lung and as bestos exposure. Although some studies have sug gested an excess number of laryngeal carcinoma cases among asbestos workers, these studies were limited by problems with study design, lack of ade quate reference populations, and lack of adjustment for the confounding effects of smoking and alcohol intake (4,107). Even so, the likelihood of misdiag nosis of laryngeal carcinoma, particularly in casecontrol studies, is low, and an argument is made for the biological plausibility of such an association. This association, therefore, remains,unresolved and further study seems warranted (106). Role of the primary physician The primary physician has two important roles with respect to patients with a history of asbestos exposure: the identification and counseling of indi viduals at risk and the accurate diagnosis ofasbestosassociated diseases when present Obtaining a care ful occupational history, which includes a detailed description of onset of exposure and the duration and nature of exposures, cannot be overempha sized. Likewise, an accurate smoking history and careful review of radiographs for evidence of both malignant and nonmalignant pathology are essential. When identified, persons at risk should be accu rately informed as to possible complications deriv ing from their exposure and the health significance of any pulmonary changes. Baseline and periodic pulmonary function testing, as well as radiographs, may be helpful in this assessment When a possible asbestos-associated disease is identified, the patient should be informed, for purposes of compensation, of the existence of a statute of limitations from the date of notification. If a diagnosis of asbestosis is suspected or con firmed, the case should be reported cither to the local health authority or directly to the Epidemi ology Division, Texas Department of Health. Re ports are accepted by mail or toll-free telephone report (1-800-252-8239). These rules provide for strict confidential handling of case reports. To bet ter serve the purposes of surveillance, a precise case definition for asbestosis has not been established. However, the epidemiologic surveillance criteria for a case is stated as "a person in whom an occupa tional disease is diagnosed by a physician based upon clinical evaluation, interpretation of labora tory and/or roentgcnographic findings, and an ap propriate occupational history" (108). Pleural plaques do not require reporting. Mesothelioma, as well as any other cancer, is reportable under the Texas Cancer Control Act OSHA requires that a preplacement medical ex amination be performed prior to assigning an indi vidual to a job with potential for exposure to air borne asbestos. For active employees, an annual comprehensive medical examination is required. Chest roentgenographs should be offered "at 5 year intervals during the 10 years following any em ployee's first exposure to asbestos. After 10 years from the employee's first exposure, the age category of an employee will determine the frequency of x-ray testing: up until age 35, x-rays will be required at 5 year intervals; between the ages of 35--45 medical examinations will be required every 2 years; and above age 45, x-ray will be required on an annual basis" (16). DPMC-01749 Texas Medicine LAM 008266 Compliance with current exposure control mea sures, coupled with ongoing surveillance, scien tifically sound policy decisions, and heightened worker awareness should make the asbestos-associ ated diseases virtually obsolete in the near future. REFERENCES 1. Leading work-related diseases and injuries-- United States. Morbidity and Mortality Weekly Report 32(2):24-26, 32, 1983- 2. Texas Register, Texas Department of Health: Title 25. Health Service Part 1, chapt 99. Occupational Disease Reporting. Sept 27, 1985, (10 Texas Register, 3766-- 3767). 3. Key MM: Occupational disease reporting in Texas (Editorial). Tex Med 83(6):7, 1987. 4. National Research Council US, Committee on Nonoccupatlonal Health Risks of Asbestiform Fibers: Asbestiform fibers: nonoccupational health risks. Board of Toxi cology and Environmental Health Hazards, Commission on Life Sciences, National Research Council, Washington DC, National Academy Press, 1984. 5. Murray HM: Report of the Departmental Commit tee on Compensation for Industrial Diseases. London, HMSO 127-128, 1907. 6. Wood WB, Gloync SR: Pulmonary asbestosis: a re view of 100 cases. Lancet 2:1383-1385, 1934. 7. Gloync SR: Two cases of squamous carcinoma of the lung occurring in asbestosis. Tubercle 17:5--10, 1935. 8. Doll R: Mortality from lung cancer in asbestos workers. Br J Indust Med 12(2):81-86,1955. 9. WagnerJC, Sleggs CA, Marchand P: Diffuse pleural mesothelioma and asbestos exposure in Northwestern Cape Province. Br J Indust Med 17:260--271,1960. 10. Castlcman BI: Asbestos: medical and legal aspects, cd 2. Clifton, NJ, Law and Business Inc, 1986. 11. Simson FW: Pulmonary asbestosis in South Africa. Brit MedJ 1:885-887, 1928. 12. Mcrcwethcr ERA: The occurrence of pulmonary fi brosis and other pulmonary affections in asbestos workers. J Indust Hygiene 12:198, May; 239, June 1930. 13- Whipple HE, van Reyen PE (eds>. Biological effects of asbestos. Ann NY Acad Sci 132:1-766, 1965. 14. Weill H: Asbestos-associated disease. Science, pub lic policy, and litigation. Chest 84(5):601-608, 1983. 15. Dreesscn WC, DallaVallc JM, Edwards TJ, et al: A study of asbestosis in the asbestos textile industry. Public Health Bulletin 241, 1938. 16. US Department of Labor. Occupational exposure to asbestos, tremolite, anthophyllite and actinolite; final rules. Fed Reg 15(119):226l2-22790, 1986. 17. US Environmental Protection Agency. Asbestos; friable asbestos-containing materials in schools; identifica tion and notification. Fed Reg 47 23360-23389,1983- 18. US Environmental Protection Agency. Guidance for controlling asbestos-containing materials in buildings. Washington DC, Office of Toxic Substances, US EPA. EPA 560/5-85-024. 19. Anderson HA, Lilis R, Daum SM, et al: Asbestosis among household contacts of asbestos factory workers. Ann NY Acad Sci 330:387-399, 1979. 20. Vianna NJ, Poian AK Non-occupational exposure to asbestos and malignant mesothelioma in females. Lancet 1(8073): 1061-1063, 1978. 21. Wolf KM, Zdzislaw H, Piotrowsid ZM, et al: Malig nant mesothelioma with occupational and environmental asbestos exposure in an Illinois community hospitaL Arch Intern Med 147(I2):2145-2149, 1987. 22. Baris YL Saracd R, Simonato L, et ah Malignant mesothelioma and radiological chest abnormalities In two villages in Central Turkey. An epidemiological and envi ronmental investigation. Lancet 1(8227):984--987,1981. 23. Hughes JM, Weill H: Asbestos exposure--quantita tive assessment of risk (Review article). Am Rev Rcspir Dis 133(1):5--13, 1986. 24. McDonald JO Health implications of environmen tal exposure to asbestos. Environ Health Perspect 62: 319- 328, 1985. 25. US Consumer Product Safety Commission. Report to the US Consumer Product Safety Commission by the Chronic Hazard Advisory Panel on Asbestos. Washington DC, Directorate for Health Sciences, USCPSO July 1983. 26. Morgan WKC, Seaton A: Occupational lung dis eases, ed 2. Philadelphia, WB Saunders Co, 1984. 27. Churg A: Current issues in the pathologic and mln- cralogic diagnosis of asbestos-induced disease Chest 84(3):75--280, 198328. McDonald AD, McDonald JC: Malignant mesothe lioma in North America. Cancer 46(7): 1650-1656,1980. 29. Ncwhouse ML, Berry G, SkidmoreJW: A mortality study of workers manufacturing friction materials with chrysotilc asbestos. Ann Occup Hyg 26(l-4):899--909, 1982. 30. McDonald AD: Mineral fibre content of lung in mesothelioma tumours: preliminary report [ARC Sci Pub! 30:681-685, 1980. 31. Talent JM, Harrison WO, Solomon A, et al: A sur vey of black mineworkers of the Cape crocidolite mines. IARC Sci Publ 30:723-729,1980. 32. McDonald AD, McDonaldJC: Mesothelioma after crocidolite exposure during gas mask manufacture. Environ Research 17:340-346, 1978 33- Vorwald AJ, Durkan TM, Pratt PC: Experimental studies of asbestosis. AMA Arch Ind Hyg Occ Med X1): 1-43, 1951. 34. Suzuki Y, ChurgJ: Structure and development of the asbestos body. AmJ Pathol 55:79--107, 1969. 35. Kannerstein M, Churg J, McCaughey E, et al: Pathogenic effects of asbestos (Review article). Arch Pa thol Lab Med 10I(12):623-628, 1977. 36. Rowlands N, Gibbs GW, McDonald AD: Asbestos fibres in the lungs of chrysotilc miners and millers--a pre liminary report. Ann Occup Hyg 26( l--4):4l 1--415,1982. 37. Morgan A, Davies P, Wagner JC, et al: The biologi cal effects of magnesium-leached chrysotilc asbestos. BrJ Exp Pathol 58(5):465--473,1977. 38 Rola-Pteszczynsld M, Gouin S, Begin R: Asbestos- induced lung inflammation. Role of local macrophagederived chemotactic factors in accumulation of neutro phils in the lungs. Inflammation 8(1 ):53--62,1984. 39. Costabcl U, Brass KJ, Huck E, et al: Lung and blood lymphocyte subsets in asbestosis and in mixed dust pneu moconiosis. Chest 91(1): 110-112, 1987. 40. Deletes G, Flitcraft D, Brousscau K, et al: Gallium 67 lung scanning and bronchoalveolar lavage in asbestosis (Abstract). Amer Rev Rcspir Dis 135(4):A22, 1987. 41. Gcllcrt AR, Macey MG, Uthayakumar S, et al: Lym phocyte subpopulations in bronchoalveolar lavage fluid in Volume 85 May 1989 57 DPMC-01750 Lam 008267 Asbestos-associated disease 58 asbestos workers. Am Rev Rcspir Dis l32(4):824-828, 1985. 42. Hammond EC, Selikoff ([, Seidman H: Asbestos ex posure, cigarette smoking and death rates. Ann NY Acad Sci 330:473-490, 1979. 43. Cohen D, Arai SF, Brain JD: Smoking impairs long term dust clearance from the lung. Science 204(4392): 514-517, 1979. 44. Bohning DE, Atkins HL, Cohn SH: Long-term par ticle clearance in man: normal and impaired. Ann Occup Hyg 26(1--4):259--271, 1982. 45. Jones RN, Weill H: Asbestos effects in referred shipyard workers. Am Rev Respir Dis 135(4):A452, 1987. 46. Becklake MR: Asbestos-related diseases of the lung and other organs: their epidemiology and implications for clinical practice (Review article). Am Rev Respir Dis 114(1): 187--227, 1976. 47. Craighead JE, Mossman BT: The pathogenesis of asbestos-associated diseases (Review article). N Engl J Med 306(24): 1446-1455, 1982. 48. Roggli VL, Greenberg SD, Seitzman LH, ct al: Pul monary fibrosis, carcinoma, and ferruginous body counts in amosite asbestos workers. A study of six cases. Am J Clin Pathol 73(4):496--503,1980. 49. Jones RN, Diem JE, Glindmeyer H, et al: Progres sion of asbestos radiographic abnormalities: relationships to estimates ofdust exposure and annual decline in lung function. IARC Sci Publ 30:537-543, 1980. 50. Kiviluoto R: Pleural plaques and asbestos: further observations on endemic and other non-occupational as bestosis. Ann NY Acad Sci 132:235-239, 1965. 51. Roberts GH: The pathology of parietal pleural plaques. J Clin Pathol 24(4):348-353, 1971. 52. Hughes JM, Jones RN, Glindmeyer HW, et al: As sessment of lung function consequences of asbestos-re lated disease. Am Rev Respir Dis 135(4):A21, 1987. 53. Meurman L Asbestos bodies and pleural plaques in a Finnish series of autopsy cases. Acta Pathol Microbiol Scand 181(Suppl): 1-107, 1966. 54. Baker EL, Greene R: Incremental value of oblique chest radiographs in the diagnosis of asbestos-induced pleural disease. Am J Ind Med 3(1): 17--22, 1982. 55. Hillcrdal G: Pleural plaques and risk for cancer in the County of Uppsala. EurJ Respir Dis 107(Suppl): 111-117, 1980. 56. Harber P. Mohscnlfar Z, Oren A, ct al: Pleural plaques and asbestos-associated malignancy. J Occup Med 29(8):64l-644, 1987. 57. Wain SL, Roggli VL, Foster WL Jr: Parietal pleural plaques, asbestos bodies, and neoplasia. A clinical, patho logic, and rocntgenographic correlation of 25 consecutive cases. Chest 86(5):707-713,1984. 58. Murphy RL, Becklake MR, Brooks SM, ct al: The di agnosis of nonmalignant diseases related to asbestos. Am Rev Respir Dis 134:363-368,15186. 59. Miller A, Tcirstein AS, Selikoff 1): Ventilatory failure due to asbestos pleurisy. Am J Med 75(6):911-919, 1983. 60. Epler GR, McLoud TC, Gaensler EA: Prevalence and incidence ofbenign asbestos pleural effusion in a work ing population. JAMA 247(5):6l7-622,1982. 61. Becklake MR, Foumicr-Massey G, Rossitcr CE, et al: Lung function in chrysotiie asbestos mine and mill workers of Quebec. Arch Environ Health 24(6):401--409, 1972. 62. Weill H, Ziskind MM, Waggenspack C, et al: Lung function consequences ofdust exposure in asbestos ce ment manufacturing plants. Arch Environ Health 30(2): 88-97, 1975. 63. Finkelstcin MM, VingilisJJ: Radiographic abnor malities among asbestos-cement workers. An exposure- response study. Am Rev Respir Dis 129( 1): 17--22, 15184. 64. Berry G, GilsonJC, Holmes S, et al: Asbestosis: a study of dose-response relationships in an asbestos textile factory. BrJ Ind Med 36(2):98-l 12,1979. 65. Pearle JL: Smoking and duration of asbestos ex posure in the production of functional and roentgeno- graphic abnormalities in shipyard workers. J Occup Med 24(t):37--40, 1982. 66. Weiss W: Cigarette smoke, asbestos, and small ir regular opacities (Review article): Am Rev Respir Dis 130(2): 293--301, 1984. 67. Selikoff (J, Nicholson WJ, Lilis R: Radiological evi dence of asbestos disease among ship repair workers. Am J Ind Med l(l):9-22, 1980. 68. Liddell FD, Gibbs GW, McDonald JC: Radiological changes and fibre exposure in chrysotiie workers aged 60-69 years at Thetford Mines. Ann Occup Hyg 26(1--4): 889-898, 1982. 69. McMillan GH, Rossitcr CE: Development of radio logical and clinical evidence of parenchymal fibrosis in men with non malignant asbestos-related pleural lesions. Br J Ind Med 39(l):54-59, 1982. 70. Becklake MR, Foumicr-Massey G, McDonald JC, et al: Lung function in relation to chest radiographic changes in Quebec asbestos workers. L Methods, results and con clusions. Bull Physiopath Respir 6(3):637-659,1970. 71. International Labour Office. Guidelines for the use of ILO International Classification of Radiographs of Pneu moconioses. Rev Ed 1980. Occupational Safety and Health Series No. 22, International Labour Office, Geneva, 1980. 72. Gaensler EA,Jcdcriinic PJ, McLoud T: Progression of asbestosis (Abstract). World Conference on Environ mental Lung Disease. Montreal, Canada, Oct 1986. 73- Becklake MR, Liddell FD, Manfreda J, ct al: Radio logical changes after withdrawal from asbestos exposure. BrJ Ind Med 36(l):23-28, 1979- 74. The pathology of asbestos-associated diseases of the lungs and pleural cavities: diagnostic criteria and pro posed grading schema. Report of the Pneumoconiosis Committee of the College of American Pathologists and the National Institute for Occupational Safety and Health. Arch Pathol Lab Med 106:544-596, 1982. 75. Hourihane DO, McCaughey WT: Pathological as pects of asbestosis (Review article). Postgrad Med J 42(492):613--622, 1966. 76. Churg A, WrightJL: Airway changes with asbestos exposure: do specific lesions exist? (Abstract) Am Rev Respir Dis 125(Suppl Part 2 of 2):154, 1982. 77. Becklake MR, Ernst P: Asbestos exposure and air way responses, in Gee JB (ed): Occupational Lung Disease. Contemporary Issues in Pulmonary Disease, voi 2. New York, Churchill Livingstone, 1984. 78. Begin R, Cantln A, Bcrthiaume Y, ct al: Airway function in lifetime-nonsmoking older asbestos workers. Am J Med 75(4):631-638, 1983. 79. Mohserdfar Z, Jasper AJ, Mahrer T, et al: Asbestos and airflow limitation. J Occup Med 28(9):817-820, 1986. DPMC-01751 Texas Medicine LAM 008268 80. Cochrane GM, Prieto F, dark TJH: Intrasubject variability of maximal expiratory flow volume curve. Tho rax 32:171-176. 1977. 81. Lerman Y, Seidman H, Gelb S, et al: Spiromctric ab normalities among asbestos insulation workers. J Occup Med 30(3):228--233, 1988. 82. McDonald JC, UddeU FD, Gibbs GW, et al: Dust ex posure and mortality in chrysotile mining, 1910-1975. Br J Ind Med 37(1):11--24, 1980. 83. Hobbs MS, Woodward SD, Murphy B, et al: The in cidence of pneumoconiosis, mesothelioma and other respi ratory cancer in men engaged in mining and milling croddolite in Western Australia. IARC Sci Publ 30:615--625, 1980. 84. Newhouse ML, Berry G: Patterns of mortality in as bestos factory workers in London. Ann NY Acad Sci 330:53-60, 197985. Selikoff ty, Hammond EC, Seidman H: Mortality ex perience of insulation workers in the United States and Canada, 1943-1976. Ann NY Acad Sci 330:91-116, 1979. 86. Buntoni R, Vcrcelli M, Mcrlo F, et al: Mortality among shipyard workers in Genoa, Italy. Ann NY Acad Sci 330:353-377, 197987. Browne K: Is asbestos or asbestosis the cause of the increased risk of lung cancer in asbestos workers? BrJ Ind Med 43(3): 145-149, 1986. 88. Parkcs WR: Occupational lung disorders, ed 2. London, Butterworths, 1982. 89- Huang SL- Amosite, chrysotile and crocidolite as bestos are mutagenic in Chinese hamster lung cells. Mutat Res 68(3):265--274, 1979. 90. Browne K: A threshold for asbestos related lung cancer. Br J Ind Med 43(8):556-558,1986. 91. Brown RC, Chamberlain M, Davies R, et al: In vitro biological effects of glass fibers. J Environ Pathol Toxicol 2(6):1369-1383,1979. 92. Ives JC, Buffler PA, Greenberg SD: Environmental associations and histopathologic patterns of carcinoma of the lung: the challenge and dilemma in epidemiologic studies (Review article) Am Rev Respir Dis 128( 1): 195-- 209, 1983. 93. Churg A: Lung cancer cell type and asbestos ex posure. JAMA 253(20):2984--2985, 1985. 94. Greenberg M, Davies TA: Mesothelioma register 1967-68. BrJ Med 31(2):9l-104, 1974. 95. McDonald JC McDonald AD: Epidemiology of mesothelioma from estimated incidence (Review article). Prev Med 6(3)426-442, 1977. 96. Peterson JT Jr, Greenberg SD, Buffler PA: Nonasbestos-related malignant mesothelioma. A Review (Re view article). Cancer 54(5):951-960, 1984. 97. WagnerJC Berry G, Timbrell V: Mesothelioma in rats after Inoculation with asbestos and other materials. Br J Cancer 28(2):173-185, 1973. 98. Wagner JC Berry G, Skidmore JW, et al: The effects of the inhalation of asbestos in rats. BrJ Cancer 29(3):252--269, 1974. 99. Weill H, Hughes JM: Asbestos as a public health risk: disease and policy (Review article). Annu Rev Public Health 7:171-192, 1986. 100. Browne K: Asbestos-related mesothelioma: Epi demiological evidence for asbestos as a promoter. Arch Environ Health 38(5):26l-266, 1983. 101. Seidman H, Selikoff IJ, Hammond EC: Short-term asbestos work exposure and long-term observation. Ann NY Acad Sci 330:61-89,1979. 102. Henderson VL, Enterlinc PE: Asbestos exposure: factors associated with excess cancer and respiratory dis ease mortality. Ann NY Acad Sci 330 :117-126,1979. 103. Finkelstein MM: Mortality among employees of an Ontario asbestos-cement factory. Am Rev Respir Dis 129 (5):754--761, 1984. 104. Hughes J, Weill H: Lung cancer risk associated with manufacture of asbestos-cement products. IARC Sci Publ 30:627-635, 1980. 105. Edelman DA: Exposure to asbestos and the risk of gastrointestinal cancer: a reassessment BrJ Ind Med 45(2): 75-82, 198a 106. Doll R, Pcto J: Asbestos. Effects on health of ex posure to asbestos. London, HMSO, 1985. 107. Chan CK, Gee JB: Asbestos exposure and laryngeal cancer: an analysis of the epidemiologic evidence (Review article). J Occup Med 30(l):23-27, 198a 108. Texas Administrative Code. Section 99.1, Art 97, Title 25. For additional resources on this topis see tbe MORE ON THE SUBJECTS department in this issue 59 Volume 85 Mav 1989 DPMC-01752 LAM 008269 PROMOTE Ail>S EDUCATION AMA MEDICAL STUDENT SECTION T-SHIRT SALE Specify Adjunctive Wear the t-shirt that promotes AIDS education. The t-shirts' slogan "Spread the Word, Not the Disease - AIDS" reflects the Medical Student Section's ongoing commitment to AIDS education. The Section sponsors a community action program "AIDS Education: Medical Students Respond" through which medical students help educate adolescents about AIDS. The t-shirts are bright red and are available in sizes large and extra large. Please enclose a $10.00 donation (per shirt) to the AMAMSS/AMA-ERF International Scholars Fund. Price includes postage and handling. All proceeds will benefit the Scholars Fund. AMA-MSS/AMA-ERF International Scholars Fund P.O. Box 59473 Chicago, IL 60659 Please send me ______ t-shirts at $10.00 each. Size ____ Check enclosed for $ Name Address City, State Zip Each capsule contains 5 mgcblordiazepaxide HCtand 15 mgdidiiiiam bromide. Please consult complete prescribinginformation, a summary ofwhich follows: * Indications: Based on a reviewofthis drug by the National Acadenqrof Sciences--National Research Council andfor other information, FDA has classified die indications as follows: "Possibly" effective: as adjunctive therapy in the treatment ofpeptic pkf* and in die treatment ofthe irritablebovnd syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitis. Final classification ofthe Vcsa-tiian-effective indications requires further investigation. Contraindications: Glaucoma; prostatic hypertrophy, benign bladder neck obstruction; hypersensitivity to chiordiaxepcndde HC1 and/or didinium Be Warnings: Caution patients about possible combined effects with aloohol and other CNS depressants, and against hazardous occupations requiring complete mental alertness (&., operating machinery; driving). Usage in Pr^mmey: Use ofminor tranquilizers during first trimester should almost always be avoided becauseofincreased risk ofcongeni tal malformations as suggested in several studies. Consider possibility ofpregnancy when instituting therapy Advise patients to discuss therapy ifthey intend to or do become pregnant. As with all anticholinergics, inhibitionoflactation mayoccur Withdrawal symptoms ofthe barbiturate type have occurred after discontinuation ofbenzodiazepines (see DrugAbuse and Dependence). Precautions: In elderly and debilitated, limit dosage to smallesteffective amount to predude ataxia, overaedatioo, confusion (no more than 2 capsules/day initially-, increase graduallyaa needed and tolerated)Though generally not recommended, tfcombination therapy with other psychotropica seems indicated, carefully consi<kr pharmacology ofagents, particularly potentiating drugs such as MAO inhib itors, phenothiazine*. Observe usual precautions in presence ofimpaired renal or hepatic function. Paradoxical reactions reported in psychiatric patients. Employ usual precautions in treating anxiety states with evidence ofimpending depres sion; suiddal tendencies may be present and protectivemeasures necessary Variable effects on blood coagulation reported very rarefy in patients receiving the drug and oral anticoagulants; causal relationship not established. Inform patients to consult physician before increasing dooe or abruptly discontinuing this drug. Advene Reactions: No side effects or manifestations not seen with eithercom pound skme reported with Ubrax.When chlordiazepoxide KC3 is used alone, drowsiness, ataxia, confusion may occu^ especially hi dderty and debilitated; avoidable in most cases by proper dosage adjustment, but ata) occasionally observed at lover dosage ranges. Syncope reported in a few instances. Also encountered: isolated instances ofskin eruptions, edema, minor menstrual irreg ularities, nausea and constipation, extrapyramida! symptoms, increased and decreased Kbido--jll infrequent, generallycontrolled with dosage reduction; changes in EEG patterns may appear during and after treatment; blood <fyscrasias (including agranulocytosis),jaundice, hepatic dysfunction reported occasionally with chlordiazepoodde HO, nuking periodic Mood counts and liver function tests advisable during protracted therapy. Adverse effects reported with Lfljrax typical ofanticholinergicagents, ic, dryness ofmouth, blurring ofvision, urinary hesi tancy, constipation. Constipation has occurred most often when Librax therapy is combined with other spasmolytics and/or low residue diets. Drug Abuse and Dependence: Withdrawal symptoms to those noted with barbiturates and alcohol have occurred flowingabruptdiscontinuance ofchlor- diazepooride; more severe seen after excessive doses over extended periods; milder after taking continuously at therapeutic levels for several months. After extended therapy, avoid abrupt discontinuation and taper dosage. Carefully supervise addiction-prone individuals because ofpredisposition to habituation and dependence. at. 02ss Roche Products Roche Products Inc. Manati. ftierto Rico 00701 DPMC-01753 Texas Medicine LAM 008270 Mare on the Subjects Tbe TMA Memorial Library staffcompiled this bibliography for several of tbe major topics covered this month in Texas Medicine All of tbe listed resources are available in tbe li brary. For information, call tbe Memorial Library at (512) 477-6704. TMA members also may request research on any medical topic. Books, audiovisuals, and copies ofjournal ar ticles are available by calling or writing the library. In most cases, your request can be processed within 24 hours Johnson NJ, Donohoe TP: Anabolic steroids and sporting per formance [editorial] J Clin Pharm Ther 13(3):171-173, 1988. Moore WV: Anabolic steroid use in adolescence. JAMA 260 (23):3484-3486, 1988. Strickland AL: Steroids: do they enhance athletic performance? JSC Med Assoc 84(2):59-62, 1988. ADVERSE REACTIONS TO BLOOD TRANSFUSION Journal Articles Aronson DL, Menache D: Prevention of infectious disease transmission by blood and blood products. Prog Hematol 15:221-241, 1987. Brecher ME, Moore SB, Taswell HF: Minimal-exposure transfu sion: a new approach to homologous blood transfusion. Mayo CUn Proc 63(9):903-905, 1988. Windsor RE, Dumitru D: Anabolic steroid use by athletes. How serious are the health hazards? Postgrad Med 84(4):37-38, 41-43, 47-49, 1988. Books Strauss RH (ed): Drugs & performance in sports. Philadelphia, W.B. Saunders, 1987. Thomas JA (ed): Drugs, athletes, and physical performance. New York, Plenum, 1988. Grossman BJ, Grindon AJ: Transfusion-related HIV infection. J Med Assoc Ga 77(3): 165-167, 1988. Larson CJ, Taswell HF: Human T-cell leukemia virus type I (HTLV-I) and blood transfusion. Mayo Clin Proc 63(9): 869-875, 1988. Rubin RH, Tolkoff-Rubin NE: Post transfusion viral infections. Transplant Proc 20(6):H12-1117, 1988. Waymack JP: The effect of blood transfusions on resistance to bacterial infections. Transplant Proc 20(6): 1105--1107, 1988. ASBESTOS-ASSOCIATED DISEASE: A REVIEW Journal Articles Branson HK: Asbestos can be safe. Occup Health Saf 57( 10): 42, 44, 1988. Davis JM, McDonald JC: Low level exposure to asbestos: is there a cancer risk? Br J Ind Med 45(8):505--508, 1988. Guidotti TL: Quantitative risk assessment of exposure to air borne asbestos in an office building. Can J Public Health 79(4):249-254, 1988. Books Anstall HB, Urie PM: A Manual of hemotherapy. New York, John Wiley & Sons, 1986. Churchill WH, Kurtz SR (eds): Transfusion medicine. Boston, Blackwell Scientific Publications, 1988. ANABOLIC STEROIDS AND GROWTH HORMONE Journal Articles American Academy of Pediatrics Committee on Sports Medi cine: Anabolic steroids and the adolescent athlete. Pediatrics 83(1):127--128, 1989. Kilbum KH: Does the 1980ILO classification of pneumoconio sis need a facelift? Arch Environ Health 43(4): 261 --262,1988. Kipen HM: Asbestos-related disease. N J Med 85( 11 ):915-- 918, 1988. Kishimoto T, Okada K: The relationship between lung cancer and asbestos exposure. Chest 94(3):486--490, 1988. Books Antman K, Aisner J (eds): Asbestos-related malignancy. Or lando, FL, Grune & Stratton, 1987. Brower KJ, Blow FC, Beresford TP, et al: Anabolic-androgenic steroid dependence.) Clin Psychiatry 50(1):31--33, 1989. Buckley WE, Yesalis CE III, Friedl KE, et al: Estimated preva lence of anabolic steroid use among male high school seniors. JAMA 260(23):344l--3445, 1988. Drug abuse in athletes. Anabolic steroids and human growth hormone. Council on Scientific Affairs. JAMA 259( 11): 1703-1705, 1988. DPMC-01754 Texas Medicine LAM 008271