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The New England Abstracts in the advertising Journal of Medicine Ectablihd Im 1812 u The NEW ENGLAND JOURNAL OF MEDICINE AND SURGERY VOLUME 306 JUNE 17, 1982 NUMBER 24 Original Articles Family Management in the Prevention of Exacerbations of Schizophrenia: A Controlled Study.................................... I. R. H. Falloon, J. L. Boyd, C. W. McGill, J. Razani, H. B. Moss, and A. M. Gilderman The Interaction of Alpha-Thalassemia and Homozygous Sickle-Cell Disease......... D. R. Higgs, B. E. Aldridge, J. Lamb, J. B. Clegg, D.J. Weatherall, R. J. Hayes, Y. Grandison, Y. Lowrie, K. P. Mason, B. E. Serjeant, 1437 1441 Medical Progress The Pathogenesis of Asbestos-Associated Diseases.................................................. J. E. Craighead and B. T. Mossman 1446 Drug Therapy: Atenolol and Timolol, Two New Systemic /3-Adrenoceptor Antagonists............................................. W. H. Frishman 1456 Discordant Cortisol Response to Exogenous ACTH and Insulin-Induced Hypoglycemia in Patients with Pituitary Disease........................... 1462 G. C. Borst, H. J. Michenfelder, and J, T. O'Brian 1 Intraventricular Hemorrhage in the Premature Infant: A Changing Outlook.................................................. S. SttiNNAR, R. A. Molteni, K. Gammon, B. J. D'Souza, J. Altman, andJ. M. Freeman 1464 Heterozygote Detection in Cystinosis, Using Leukocytes Exposed to Cystine Dimethyl Ester......................... R. Steiniierz, F. Tietze, T. Triciie, A. Modesti, W. A. Gahl, andJ. D. Schulman 1468 Case Records of the Massachusetts General Hospital A 51-Year-Old Woman with Chronic Asthma and Hemoptysis....................... N. M. Braslow and E. J. Mark 1471 Editorial Exposure to Asbestos and Human Disease...................................... M. R. Becklake Sounding Boards After Laetrile, What?.................................. B. R. Cassileth A Future Shortage of Residency Training Positions: Dilemma or Opportunity?.. D. A. Kindio and N. C. Dunham 1480 1482 1484 Correspondence 1 of Ophthalmic Timolol................................. plastic Anemia after Parenteral Chloramphenicol: Warning Renewed............ Thrombosis after Pulmonary-Artery Catheterization via the Internal Jugular Vein................... .................. Factitious Sickle-Cell Trait........................................ Folate Levels in Inflammatory Bowel Disease ... Thyrotropin-Releasing Hormone............ ................ Possible Alteration of Metronidazole Metabolism by Phenobarbital.................................................... Case 7-1982: Sarcoidosis and Cancer...................... Ratio of Arm Span to Height not Usually Increased in Klinefelter's Syndrome.............. Visualization of "Cold" Thyroid Nodules with Nonradioactive Iodine........................................ A Good Little Antacid................................. ................ Musical Bottles................................................................ Do Water Pipes Prevent Transmission of Fungi from Contaminated Marijuana?....................... Methadone Maintenance Programs............ Financing Long-Term Care ........................................ Computerized Matching Algorithm for ThirdYear Medical-School Courses.......................... Lack of Interpersonal Communication in Programmed Learning......................................... Book Reviews............................................. Books Received Notices. 1485 1486 1486 1487 1488 1488 1490 1490 1490 1491 1492 1492 1492 1493 1494 1495 1495 1495 1499 1501 Special Report The Modular Medical Integrated Curriculum: An Innovation in Medical Education................ ........... A.J. Colbert, E. H. Blaustein, andJ. I. Sandson 1502 Owned. Published, and {Copyrighted. 1982, by the Massachusetts Medical Society The New England Journal of Medicine I ISSN 0028-4793) ts published svcekls from editorial othces at 1U Shattuck Street. Boston, MA 02115. Subscription price: 548.00 per vear. Second-class postage paid at Boston and at additional mailing otHces. POSTMASTER: Send address changes to 1172 Communsvealth Avenue. Boston. MA 02134. 6113 21326 1446 THE NEW ENGLAND JOURNAL OF MEDICINE June 17, 1082 5. Natta C. Failure of ihe a-dialacremta gene to decrease the severity of sickle cell anemia. Blood. 1978: 51:1163-8. 6. Hmsman THJ. Sickle cell anemia as a syndrome: a review of diagnostic features. Am J Hematol. 1979: 6:173-84. 7. Felice AE. Webber B. Miller A. et al. The association of sickle ceil anemia with heterozygous and homozygous o-thalassemia-2: in vitro HB chain synthesis. Am J Hematol. 1979: 6:91-106. 8. Powars DR. Schroeder WA. Weiss JN, Chan LS. Azen SP. Lack of influ ence of fetal hemoglobin levels or erythrocyte indices on the seventy of sickle cell anemia. J Clin Invest. 1980: 65:732-40. 9. Altay C. Gravely ME. Joseph BR. Williams DP. Alpha-thalassemia-2 and the vanabtlity of hematological values in children with sickle cell anemia. Pediatr Res. 1981: 15:1093-6. 10. Embury SH. Dozy AM. Miller J, et al. Concurrent sickle-cell anemia and a-thaiassemta: effect on seventy of anemia. N Engl J Med. 1982:306:2704. 11. Higgs DR. Pressley L. Setjeant GR. Clegg JB. Weatherall DJ. The genetics and molecular basis of alpha thalassaemta in association with Hb S in Jamai can Negroes. Br J Haematol. 1981: 47:43-56. 12. Serjeant GR. Serjeant BE. Milner PF. The irreversibly sickled cell: a deter minant of haemolysis in sickle cell anaemia. Br J Haematol. 1969; 17:52733. 13. Lathe GH, Ruthven CRJ. Factors affecting the rate of coupling of bilirubin and conjugated bilirubin in the van den Bergh reaction. J Clin Pathol. 1958; 11:155-61. 14. Millard DP. Mason K. Serjeant BE. Serjeant GR. Comparison of haematological features of the 0 0 and J3' thalassaemia traits in Jamaican Negroes. Br J Haematol. 1977; 36:161-70. 15. Betke K. Mam HR. Schlicht I. Estimation of small percentages of foetal haemoglobin. Nature. 1959: 184:1877-8. 16. Serjeant GR. Higgs DR. Aldridge B. Hayes RJ. Weatherall DJ. Alpha thalassemia and homozvgous sickle ceil disease. In: Brewer GJ. ed. The red cell. New York: Alan R Liss. 1980:781-6. 17. Sewell A. Millard D. Setjeant GR. The interaction of alpha thalassaemia with SS disease. In: Brewer GJ, ed. The red cell. New York: Alan R Liss 1978:93-102. 18. Breslow NE, Day NE. Statistical methods of cancer research. Vol. I. Lyon: International Agency for Research on Cancer. 1980:162-76. 19. Tanner JM. Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and the stases of puberty Arch Dis Child. 1976: 51:170-9. 20. Higgs DR. Pressley L, Clegg JB. et al. Detection of alpha thalassaemta in Negro infants. Br J Haematol. 1980: 46:39-46. 21. Noguchi CT. Schechter AN. The intracellular polymerization of sickle hemoglobin and its relevance to sickle cell disease. Blood. 1981:58.1057. 68. 22. Seakins M. Gibbs WN. Milner PF, Betties JF. Erythrocyte Hb-S concentra tion: an important factor in the low oxygen affinity of blood m sickle cell anemia. J Clin Invest. 1973; 52:422-32. 23. May A, Huehns ER. The concentration dependence of the oxygen affinity of haemoglobin S. Br J Haematol. 1975; 30:317-35. 24. Dover GJ. Boyer SH. Chatache S. Heintzelman K. Individual variation in the production and survival of F cells in sickle-cell disease. N Engl J Med. 1978; 299:1428-35. 25. Pembrey ME. Wood WG. Weatheral DJ, Petrine RP. Fetal haemoglobin producuoa and the sickle gene in the oases of eastern Saudi Arabia. Br J Haematol. 1978; 40:415-29. 26. Setjeant GR. Fetal haemoglobin in homozygous sickle cell disease. Gin Haematol. 1975; 4:109-22. 27. Serjeant GR, Sommereux A. Stevenson M, Mason K, Serjeant BE. Com parison of sickle cell-B 0 thalassaemia with homozygous sickle cell disease. Br J Haematol. 1979: 41:83-93. 28. Hayes RJ. Condon PI. Setjeant GR. Haematological factors associated with proliferative retinopathy in homozygous sickle cell disease. Br J Ophthal mol. 1981; 65:29-35. 29. Hawker H. Neilson H. Hayes R3, Serjeant GR. Haematological factors associated with avascular necrosis of the femoral head in homozygous sickle cell disease. Br J Haematol. 1982; 50:29-34. MEDICAL PROGRESS THE PATHOGENESIS OF ASBESTOS-ASSOCIATED DISEASES John E. Craighead, M.D., and Brooke T. Mossman, Ph.D. ASBESTOS is one of our most useful minerals. Over __asbestos cannot be replaced expeditiously in many - 3000 manufactured products of contemporary products. Litigation based on personal injury! conse importance contain it. Asbestos is employed in con quent to pulmonary fibrosis and cancer is an increas struction materials because it is resistant to thermal ing problem for companies involved in the manufac and corrosive destruction and increases the tensile ture, use, and distribution of asbestos. About 12,000 strength of the product. These properties arc also the suits have been brought against 260 companies by basis for the use of the mineral in friction equipment workers, their families, and members of the general and in a wide variety of consumer items requiring a public.1,2 The spectrum of liability has now widened to relatively inexpensive insulation material that is light involve the federal government for alleged negligence and subject to molding. Since the turn of the century, in establishing adequate environmental standards. about 3X 107 tons of asbestos have been used in con This review summarizes our current knowledge of struction and in the fabrication ofmanufactured goods ____thc adverse effects ofasbestos on health and provides a in the United States. At present, several million perspective on the pathogenetic mechanisms of the Americans arc employed in industries that use asbes diseases associated with exposure. Since there arc sev tos products, and countless millions of American citi eral different mineralogic types of asbestos, wc will zens arc exposed to asbestos cryptically in the course of attempt to assess the extent to which findings with one their daily lives. type can be applied to another. Detailed analyses of Public concern over the effects of asbestos on health the issues addressed in this paper have been published is mounting. Although a total ban on its use in this elsewhere.7'0 country has been proposed, most would agree that Mineralogy From the Department of Pathology. University of Vermont College of Medi cine. Burlington. VT 05405, where reprint requests should be addressed to Dr. Craighead. Asbestos is not one mineral but a family of fibrous hydrated silicates-that are divided on the basis ofmincralogic features into two groups: the serpentines and r n tfvN, H r\j vo c ( Figt II Vol. 306 No. 24 ASBESTOS-ASSOCIATED DISEASES -- CRAIGHEAD AND MOSSMAN 1447 the amphiboles (Fig. 1). The term "asbestos" refers to the commercial product after mining and processing and is not a mineralogic designation. Although the length'.width ratio of the mineral fiber known as asbes tos is by definition 3=3:1, the individual fibers making up the materials used in commerce vary substantially in width and length (Fig. 2). Chrysotile is the only serpentine of commercial im portance. It is composed of pliable, curly fibers made up of fibrillar subunits. These fibrils are arranged in pseudohexagonal arrays composed of silicon oxide sheets formed into scroll-like structures. The magne sium ion, which imparts a strongly positive charge to the fiber, is an integral component of the lattice. The amphiboles are straight, rodlike fibers consist ing of double chains of tetrahedral groups having a basic silicon oxide composition and linked by one or more cations. The amphiboles differ from chrysotile in both physical and chemical makeup. There are several types ofamphibole, but crocidolite and amosite are the two minerals of major importance. Although an asbestos type is classified on the basis of its mineralogic characteristics, the products of dif ferent mines are not necessarily the same. Moreover, a commercial type of asbestos is not always mineralogi- cally pure. For example, Canadian chrysotile-contains small amounts of an amphibole fiber, tremolite. In addition, industrial grades of asbestos are contaminat ed with extraneous inorganic and organic substances that are acquired either naturally or during proc essing. ,, Deposits of serpentine and amphibole are ubiqui tous in the crust of the earth. Outcrops are found in many geologic formations and probably account for the mineral fibers commonly found in surface water. Asbestos is also found with other minerals of commer cial importance, such as the iron ore taconite and in dustrial-grade talc. Canada and South Africa are the major suppliers in the western world, although mines of limited commercial importance are found in many countries. In the United States serpentine and amphi- bolc minerals are distributed widely in geologic strata, but only two relatively small mines in Vermont and AStHTOS ( 9.1H,0) l9.OHj.Hjil Figure 1. Types of Asbestos of Commercial and Medical Impor tance and Their Chemical Compositions. CD Figure 2. Differing Structural Features of Serpentine (Chrysotile) and Amphibole (Crocidolite) Asbestos. These scanning electron micrographs of; International Union against Cancer reference samples of chrysotile (Panel A) and crocidolite (Panel B) asbestos illustrate the heterogeneity of fibers in both length and diameter. Micrographs ofthe hamster tracheal epithelium after exposure in vitro to asbestos illustrate the curly, pliable nature of chrysotile (Panel C) and the straight, rod-like form of crocidolite (Panel D). Note the dimensions of the fibers in com parison to the cilia. Photomicrographs were furnished by Mr. Craig Woodworth, Department of Pathology, University of Vermont Col lege of Medicine. California are active. The amount!of asbestos pro duced in the Soviet Union and the People's Republic of China far exceeds that extracted in the West. ^hrvsotilf^currentlv accounts for gj^SUjijrcentof the total asbestos marketed in this country' and abroad. Crocidolite is the most widely used amphi bole, but for reasons considered below, its commercial importance has decreased over the past several dec ades (Table l). Uses of Asbestos The unique physical properties of asbestos dictate its continued use by industry, despite contemporary concerns about its effects on health. Although various man-made and naturally occurring substances have been developed as substitutes for asbestos, none 6113 21328 mmmrnm I +48' THE NE\V ENGLAND JOURNAL OF MEDICINE June 17, 1982 Table 1. Consumption of Different Types of Asbestos in the United States in 1978.* Tvrtor Assestos Total Asbestos CHtYSOTtU CROCIOOLITE AMOStTI metric tons Asbestos cement pipes Asbestos cement sheeting Flooring products Roofing products Packing and gaskets Insulation, thermal Insulation, electrical Friction products Coatings and compounds Plastics Textiles Paper Other Total 119.700 7.900 90.000 26.500 12.200 6.000 2,900 43,700 10.900 1.200 1,900 400 9,000 332.300 Modified from the data of Fagan.' 24,100 -- -- 100 _ -- -- 100 -- 100 -- 24,400 200 -- 200 -- -- __ -- -- -- -- 1300 1700 144.000 7,900 90,200 26,500 12,300 6,000 2,900 43,700 10,900 1,300 1,900 500 10,600 358,700 matches asbestos in providing tensile strength and moldability as well as resistance to fire, heat, and cor rosion. In addition, many of the manufactured substi tutes are comparatively expensive.8 About 25 per cent of the asbestos consumed in the United States is incorporated into cement piping for water mains and sewage lines. Over 320,000 km of pipe, containing about 10 to 20 per cent asbestos, is believed to be in use in this country. Asbestos-contain ing cement is employed widely in corrugated and flat sheeting, panels, tiles, and moldings for the construc tion industry. The mineral is used extensively in roof ing and paneling and as a filler in architectural dead spaces. In the past, suspensions of asbestos were sprayed onto the structural steel of buildings to pro vide insulation and fire protection. Because ofits thermal stability, asbestos is well suit ed for use in friction material and is applied to molded brake linings. Although substitutes are being increas ingly employed in disk brakes, as in the aircraft indus try, a drum-brake lining for passenger cars that does not contain asbestos is not available commercially. Textiles and plastics of a variety of types and appli cations contain asbestos in various concentrations, since it imparts resistance to fire and corrosion as well as tensile strength without inordinately altering the properties of the product or increasing its weight. The countless additional industrial uses of asbestos arc of concern because they can be overlooked by the manufacturer and unrecognized by the consumer. Al though asbestos was known to industry before the turn of the century, its use in the United States increased dramatically during the mobilization that accompa nied World War II. Asbestos was employed liberally in the construction and reconditioning of ships and in such diverse war industries as the manufacture of air craft engines, combat vehicles, and gas masks. Al though worldwide production has continued to in crease since the war, consumption in this country has dropped substantially during the past decade. This trend can be expected to continue. Since the latency period for the diseases associated with asbestos is usu ally 20 years or longer, most patients seen today were initially exposed in the 1940s and 1950s, when control measures were often not rigorous. Diseases of the Respiratory Tract and Thorax The major pathologic effects of asbestos result from the inhalation of fibers suspended in the ambient air. The occurrence of disease is influenced by the type of mineral and the dimensions of the fibers that consti tute it, as well as by the concentration of fibers and the duration of exposure. Deposition and Transport in the Lungs Timbrell et al.9 studied the deposition of fibers of asbestos in the respiratory tract, using a cast of the porcine tracheobronchial tree. The diameter of the in dividual fibers proved important; length was a less important determinant.10,11 Fibers with a relatively broad diameter are deposited in the upper respiratory tract, whereasjthin^fibeuj are carried peripherally into the parenchyma of the lung, where they lodge in the terminal airwavs. Bifurcations are common sites tor fiber impaction, since patterns ofair flow are altered at these sites. The shape of the fibers also has a role in transport. Aerodynamicaily, chrysotile has a relatively large, theoretical cross-sectional diameter because of its curled configuration. Thus, fibers of this type tend to be deposited more proximally than the needle-like am- phiboles, which are transported more readily to the periphery of the lung. These theoretical and experi mental considerations have been verified by analyses of the lungs of rodents experimentally exposied to as bestos of different types.12 mmmmmm | Three biologic mechanisms participate in thejelear- ance <ff fibers from the lower respiratory tract. By far,' the bulk of the dust is removed by the mucociliary f escalator of the tracheal bronchial tree, and the mate rial is cither expectorated or swallowed.13'15 In the peripheral airways, short fibers arc ingested by macro- X phages, and at least some of these cells probably mi grate across the wall of the bronchioles and acini.16*18 Asbestos fibers are also taken up by the epithelial cells - lining the airways and appear to move between .cells of the mucosa.ia'J0 This material accumulates in the interstitium and is carried to regional lymph nodes.17 In general, short fibers arc cleared more readily than long fibers,17 which tend to be retained in the lumens of the respiratory bronchioles and the ialvcolar ducts. About a third of the inhaled particles initially lodge in the distal airways. However, only about a quarter of this burden is retained in the respiratory tract one month later.13 There are two phases of clearance through the tracheobronchial tree. About half the as bestos is removed within a few days. Subsequently, 6113 21329 Vol. 306 No. 21 ASBESTOS-ASSOCIATED DISEASES -- CRAIGHEAD AND MOSS MAN 1149 clearance continues for extended periods. The bulk of this material is excreted in the feces.15 A variety of extraneous influences such as cigarette smoke and air pollutants affect the clearance and in* trapulmonary deposition of fibers. However, these fac tors arc extraordinarily complex, in part because indi viduals appear to differ in their responses to inhaled jjhist.2'-29 Asbestosis Diffuse pulmonary fibrosis is the typical lesion asso ciated with prolonged, heavy exposure to asbestos.30 It develops slowly over a period of years and seems to progress in the absence ofcontinued exposure to asbes tos. Initially, fibrosis is found in and around the respi ratory bronchioles and alveolar ducts, where relatively long fibers deposit. With time, the fibrotic lesion pro gresses in a seemingly centrifugal manner, so that in creasing numbers of respiratory units are involved. Fibers of asbestos tend to accumulate preferentially in the lower lobes and adjacent to the visceral pleura. Fibrosis is usually prominent in these regions, and the pleural surfaces of these lobes are frequently thickened by a dense layer offibrous tissue. In advanced asbestosis, the fibrotic pulmonary tissue contracts and is reor ganized to form the new air space typical of the honey comb lung. Ferruginous bodies are the histologic hallmark of exposure to asbestos."`'34 They consist of fibers coated by complexes of hemosiderin and glycoproteins and arc believed to be formed by macrophages that have phagocytized the particles. Asbestosis can exist when ferruginous bodies are difficult to demonstrate in the lungs by light microscopy. On the other hand, ferru ginous bodies can often be found in the absence of serious parenchymal disease.35,36 Thus, their presence alone is probably not a stimulus for the proliferation of fibrous tissue. Although they have been shown to form from foreign inorganic and organic fibers of many different types,37 ferruginous bodies in most human lungs have asbestos as a core.36 For this rea son. the structures arc commonly known as asbestos bodies. The number of uncoatcd fibers in the lung greatly exceeds the number of asbestos bodies in the tis sue.38,39 It is not known why some fibers are coated and form the typical asbestos bodies, whereas others are uncoatcd. Since uncoatcd fibers are usually diffi cult or impossible to demonstrate by light microscopy, lung tissue must be digested and the residue examined by cither phase or electron microscopy in order to carry out qualitative and quantitative studies of the fibers. Whereas relatively long fibers (>5 jurn) arc found by light microscopical techniques, electron mi croscopy makes it possible to identify very small parti cles.40,41 Thus far, attempts to correlate the extent ol disease with cither the number of asbestos bodies or the overall content of fibers in the lungs have been difficult, although fibrosis is usually evident when 10 fibers per gram of lung (wet weight) arc present. Quantitative studies pose many problems and arc only a crude measure of exposure, partly because many fibers arc cleared from the lungs and others fragment to increasingly smaller particles with time. "Macrophages are a key element ih the response of the host to asbestos. Whereas these cells phagocytizc short fibers and remove them from the airways, they cannot encompass and transport the longer fibers. Al though retention of these long fibers in the distal air ways appears to be an important consideration in the causation of pulmonary fibrosis,18,30 the pathogenesis of the lesion is not understood. Incomplete phagocyto sis of asbestos fibers in the airways could result in spillage of lysosomal enzymes42 and release of soluble fibrogcnic factors from macrophages.43 On the other hand, oxygen free radicals liberated by macrophages and other inflammatory cells might also injure lung tissue. This idea is supported by our observations that superoxide dismutase, an inhibitor of biologic oxi dants, protects cultured respiratory epithelial cells from the cytotoxic effects of chrysotile (Mossman BT, Landesman JM: unpublished data). Chrysotile is cy totoxic in vitro presumably because the magnesium of the fibers interacts with the plasmalemma and dam ages it, along with lysosomal membranes of cells.44,45 It is unclear whether this is an important mechanism of tissue injury, however, since pulmonary macro phages and epithelial cells in the lungs of animals ex posed to aerosolized chrysotile fail to reveal ultrastructural evidence of injury.18,19 Other biologic phenomena may prove important in the causation ofpulmonary fibrosis. Asbestos activates complement by the alternative pathway46 -- a reac tion that may be expected to result in the accumulation of leukocytes in the tissue and the release of lysosomal enzymes. This observation is consisteht with the find ing of an acute inflammatory response in some early lesions.30,47 Finally, consideration must be given to the possibility that asbestos stimulates tfye production of collagen by cells. When chrysotile is added to cultures of fibroblasts in vitro, the cells elaborate rcticulin and collagen at an accelerated rate.48,49 Although the hypothetical mechanisms mentioned above could account for the deposition'offibrous tissue in the lungs, the pathogenesis of asbestosis in human beings remains to be established. The question may be moot, however, since modern environmental controls have dramatically reduced exposure irt the work place. The dust concentrations permitted by current regula tions will probably not induce substantial pulmonary fibrosis during the lifetime of an industrial worker. Pleural Lesions Plaques'.arc curious lesions made Up of hvalinizcd fibrous tissue located on the parietal pleura of the tho rax, diaphragm, mediastinum, and pericardium.'0,51 They arc usually but not invariably associated with exposure to asbestos.38 Although the occurrence of plaques correlates with the duration And intensity of exposure, it is common to find lesions ih the absence of 6113 21330 1450 THE NEW ENGLAND JOURNAL OF MEDICINE June 17. i0HJ obvious disease of the pulmonary parenchyma. Thus, relatively small amounts of dust can induce the devel opment ofplaques. These benign lesions do not appear to develop into malignant mesotheliomas. Characteristically, plaques are located in the inter costal spaces on the anterior and posterior lateral as pects of the thorax and on the dome of the diaphragm at sites where the visceral and parietal pleuras ap proximate during respiratory excursions. The config uration of the plaques is highly variable. For example, on the chest wall they usually follow the contour of the rib, whereas on the diaphragm they are customarily either disk-shaped or geometrically shaped and have a nodular surface. Over time the lesions become calci fied, permitting easy recognition on x-ray films. Al though most of the available epidemiologic informa tion is based on radiologic surveys,52'53 it is not always clear in published reports whether plaques were differ entiated from the fibrous lesions of the visceral pleurai that accompany pulmonary asbestosis. f Since plaques are found most often in persons ex posed occupationally to asbestos for extended peri ods,54*56 their overall prevalence in the United States is low.57 In Eastern Europe and Asia Minor the lesions are frequently found in older members of the general population who lack documented exposure to asbes tos. The presence of fibrous minerals in soil and in local construction materials may account for the common occurrence of pleural plaques in these re gions.58'61 Malignant mesotheliomas of the pleural and perito neal cavities are considered feathognomonic^of expo sure to asbestos, although in manypanentsamstory of contact with the mineral cannot be elicited.62'64 These rare tumors are of particular concern from a public- health standpoint because they are thought to occur in persons who have had either transient or indirect ex posure to asbestos.65'67 The development of mesothe liomas as a consequence of casual exposure, however, is an uncommon event. On the other hand, the preva lence of the tumor in workers who have had heavy exposure over extended periods is about 2 to 3 per cent and has been reported to approach 10 per cent.68,69 It is difficult to determine how often mesotheliomas actu ally occur, because the latency period is usually 20 years or longer and can often be as long as 40 to 50 years. Some suggest that an epidemic of mesothelio mas will appear in the late decades of this century, consequent to the exposure of large numbers of work ers during World War II. The pathogenesis of the pleural lesions associated with exposure to asbestos is not known, but it is a topic of considerable contemporary interest. Fibrosis of the visceral pleura, plaques of the parietal pleura, and mesothelioma probably develop by different mecha nisms, although a rigorous defense of this conclusion would be difficult. As mentioned above, asbestos is deposited preferentially in the periphery of the lung alter inhalation. It penetrates the visceral pleura and is carried in the pulmonary lymphatics to the pleural surface. One is tempted to attribute the fibrous lesions on the visceral pleura to irritation by the physical pres ence of fibers on or near the surface. This mechanism might also explain the occurrence of plaques in the parietal pleura. Alternatively, the lesions may repre sent an organized fibrinous exudate resulting from the physical movement of the lungs against the pleural surface of the thorax. However, these hypotheses are not fully consistent with the pathological observations. For example plaques are often found without fibrosis of the visceral pleura or adhesions between the pleural surfaces. In addition, the lesions are localized and do not occur in the apexes or in the costophrenic angles. The patho genesis of the lesions cannot be defined at present, in part because plaques occur only in human beings anti experimental models have not been developed.' Experimental studies by Stanton et al.70,71 provide an intriguing basis for speculation about the patho genesis of mesothelioma. The dimensions of the fiber, but not the chemical composition, were found to be the critical determinant affecting the development of tu mors in rats. Long, thin fibers of a variety of types proved carcinogenic when introduced into the pleural space, whereas short fibers and those with a relatively broad diameter failed to induce mesotheliomas. These findings are consistent with epidemiologic observa tions documenting the relatively common occurrence of tumors in populations exposed to grades of crocidilite consisting predominantly of long, thin fibers ate the rarity of tumors in persons exposed to the com paratively blunt, shorter fibers of amosite and antluphyllite.63''2"4 A fibrous zeolite, erionite, has recent:been associated with the occurrence of pleural fibroand mesothelioma in a rural area of Turkey w in-: commercial mining of asbestos does not occur."' bin the fibers of this mineral do not possess the chcmu properties of asbestos but are morphologically sinn. to crocidolite fibers, the observation is consistent V: the experimental findings of Stanton and his asates.70-71 The basis for the development of mesotheliomathe peritoneum is uncertain. Presumably, fibers oi . bestos in the lungs are transported in lymphatics to t> abdomen, where they have been recovered from lyryi; nodes and other organs.Asbestos is also transpir ed across the mucosa of the gut after ingestion.Whatever the mechanism for entry ofasbestos into t. abdomen, it is assumed that the pathogenesis of ti tumors in the peritoneal and pleural cavities is similePeritoneal mesotheliomas occur only in persons i posed to amphibole asbestos. The gradual disintegi. tion of chrysotile in tissue may account for the relattv ly uncommon occurrence of mesotheliomas of both ti. pleural and peritoneal cavities in persons exposed eclusiycly to chrysotile.'9 The mechanism of malignant transformation mesothclial tissues is obscure. Surprisingly little ev perimcntal information has accumulated, alihouei. there is reason to believe that the lesions mav be coin- 6113 21331 Vol. 306 No. 24 ASBESTOS-ASSOCIATED DISEASES -- CRAIGHEAD AND MOSSMAN 1451 parable to the foreign-body sarcomas induced subcu taneously in animals by sheets of plastic, glass, and metal. The cell of origin is not certain, since some tumors are made up of malignant serosal cells, where as others have the histologic features of fibrosarcoma. Mesothelial cells phagocytize asbestos80 and prolifer ate when exposed to asbestos in vitro,81 but malignant transformation has not been demonstrated after expo sure of cultured mesothelial cells to asbestos. Cocarcinogcnic substances and cigarette smoke do not ap pear to be pathogenetic factors in vivo. Bronchogenic Carcinoma Epidemiologic studies have documented an associ ation between bronchogenic carcinoma and occupa tional exposure to asbestos.82"87 The prevalence of tu mors is higher in persons working with the finished products (such as insulators) than in miners and mill ers. The seventy of the pulmonary parenchymal fibro sis correlates with an increase in the number of neo plasms.88,89 However, the incidence of tumors is also increased in asbestos workers who lack radiologic evi dence of asbestosis. - Some controversy exists over the most common his tologic type of tumor, but among persons with asbesto sis, adenocarcinomas predominate.90'91 The lesions tend to occur more frequently in the lower lobes in conjunction with severe degrees of fibrosis.30 Atypical hyperplasia of bronchiolar epithelium and multifocal adenocarcinomas are often found in these sites. A linear dose-response relation between the cumula tive dosage of asbestos and the development of bron chogenic carcinoma has been reported in miners and millers of chrysotile in Canada83 and factory workers in the United Kingdom.83 In the former study, those at greatest risk were exposed to concentrations of asbes tos in the air that were higher than the current regula tions of the United States Occupational Safety and Health Administration permit. A higher carcinogenic potential for crocidolite than for chrysotile has been \ suggested by studies ofoccupational groups exposed to ^ cither type of asbestos or to the two in combination.92 Mortality among chrysotile workers is increased 2.4fold, whereas it is five times higher than normal among miners of both chrysotile and crocidolite. Surveys of the smoking habits of insulators," fac tory workers,94,95 and miners and millers96 have con sistently shown that bronchogenic carcinoma is un common in those who do not smoke. Whereas there is only a slight increase in the prevalence of lung cancer among nonsmokers, heavy users of cigarettes (those smoking more than 20 per day) have an 80-fold to 90fold greater predisposition to cancer of the lung.93,94 Thus, the combined effects of asbestos and smoking appear to be multiplicative rather than additive.97 What is the mechanism of asbestos-induced carcino genesis in the respiratory tract? A consideration of contemporary concepts of neoplastic transformation is appropriate in developing an answer to this question. As initially recognized by Bercnblum, carcinogenesis is a sequence of events that can be divided into steps of initiation and promotion.98 An initiator interacts with the DNA of the target cell -- an event that can result in malignant change. The carcinogen either acts di rectly with the DNA of the cell or requires metabolic activation by cellular enzymes. A promoter is general ly neither mutagenic nor carcinogenic, although it is required if the neoplasm is to develop. For example, if the skin ofa mouse is painted with a small amount ofa chemical carcinogen, such as a polycyclic aromatic hydrocarbon, tumors fail to develop unless a phorbol ester is subsequently applied to the site. Promoting substances cause cellular division and proliferation as well as biochemical changes in the cell that appear to be essential for neoplastic transformation.99 Although epidemiologic data link exposure to asbes tos with bronchogenic carcinoma in human beings, the precise role of the mineral in the process has yet to be defined. Since asbestos is not a potent mutagen100 and inconsistently causes chromosomal aberrations in cells,101'103 a mode of action comparable to that of a classic chemical carcinogen is unlikely. It therefore seems more plausible to suggest that asbestos increases the susceptibility of epithelial cells of the bronchi and their branches to transformation by carcinogens in the environment. What biologic mechanisms account for the synergis tic carcinogenic effects of asbestos and cigarette smoke in the respiratory tract? A plausible hypothetical con struct should be consistent with the apparent lack of a threshold in human beings and the occurrence of neo plasms in the absence ofappreciable degrees of pulmo nary asbestosis. Asbestos has many of the properties ofclassic tumor promoters, such as the phorbol esters.104 Proliferation and squamous metaplasia are induced in the respira tory mucosa of rodents in vitro.105 Asbestos interacts with the membranes of cells106,107 and induces the syn thesis of the polyamincs that accompany cell divi sion.108 Since cigarette smoke also contains a host of substances with promoter effects, the inhalants may act in either an additive or a synergistic fashion to enhance the susceptibility of the respiratory mucosa to carcinogens. However, alternative mechanisms are worthy of consideration. Asbestos can be phagocytized by the bronchial epithelium and can be transported intracellularly both free in the cytoplasm and in phagolyso somes."0 These fibers may serve as a physical carrier of the carcinogens in cigarette smoke to the basal cell, the presumptive progenitor of the neoplasms. Transfer of polycyclic aromatic hydrocarbons to and through bio logic membranes occurs promptly and efficiently when the hydrocarbon is adsorbed to asbestos.109 There after, the hydrocarbons arc converted by microsomal mixed-function oxidases to biologically active epox ides and diolcpoxides, which can interact with the DNA ol basal cells.110 Another (but less attractive) hypothesis involves the alveolar macrophage, which phagocytizes asbestos in the airways and possesses the 6113 21332 Vol. 306 No. 21 ASBESTOS-ASSOCIATED DISEASES -- CRAIGHEAD AND MOSSMAN 1453 they were used widely during and immediately after World War II and are probably responsible for a sub stantial proportion of the disease occurring today. Much current debate centers around the question of whether all types of asbestos possess the capacity to induce mesothelioma. Experiments in animals yield an affirmative answer, but the results ofthis work may not be applicable to human beings, since pathogenic po tential and intrapulmonary transport of fibers are in dependent considerations. Of all the types, crocidolite is clearly the most strongly associated with the occur rence of the tumor. But there are interesting differ ences in prevalence, related to the physical character of this fiber type. For example, in Northwest Cape, South Africa, and western Australia, mesotheliomas occur commonly in persons with occupational or casu al exposure to crocidolite.65 The mineral mined in these regions is composed ofrelatively long, thin fibers. In contrast, mesotheliomas are rare in the Transvaal of South Africa, where the crocidolite fibers are much coarser. Another amphibole, amosite, is associated sporadi cally with mesothelioma, whereas the tumor rarely if ever occurs in workers exposed to anthophyllite. Both these latter types are made up of relatively short, blunt fibers. A number of studies have been conducted in miners and millers in Quebec and Italy, where the serpentine chrysotile ^extracted.74,126 Although the results are debated, the bulk of the evidence indicates that chrysotile is not an important cause of mesotheli oma in these workers. However, the data from certain occupational groups, such as workers in the textile industry and insulators who arc exposed predominantly but not ex clusively to chrysotile, are not as definitive. The risk appears to increase as the mineral is processed or when dust concentrations cannot be evaluated critically. Unfortunately, most epidemiologic studies concerned with this important question are clouded by uncertain ty because of the prolonged latency period of mesothe liomas. Considerable effort has focused on determin ing whether the various types ofasbestos differ in their capacity to induce bronchogenic carcinoma and fibro sis of the lung. Unfortunately, there is no good answer to these questions at present, since dose-related differ ences in the prevalence of disease have not been estab lished. Regulatory Considerations No topic is more complex and subject to controversy than the establishment of criteria on which to base standards for air quality in the work place. Regula tions arc exceptionally difficult to develop, because it is necessary to use data on morbidity and mortality doc umenting disease retrospectively in members of occu pational groups who have had heavy exposure cither in the remote past or over a lifetime. The difficulties arc compounded by the long latency period ofasbestosis and the asbestos-associated cancers. Although recommendations for levels of asbestos in the air of occupational settings in this country were formulated in the 1940s, it was not until 1970 that federal regulations were promulgated as a result of the passage of the Occupational Safety and Health Act and the Clean Air Act. The initial standard was based on the light microscopical count of fibers of a length of 5 /am, collected by mechanical means. A concentration of five fibers per cubic centimeter of air, averaged over an eight-hour period, was deemed permissible, with stipulations for transient excesses above that concen tration. In 1976 the contemporary standard of two fibers per cubic centimeter was established, and more recently a level of 0.5 fiber per cubic centimeter has been proposed. Is the current limit oftwo fibers per cubic centimeter sufficiently rigorous to prevent disease in the future? Is it appropriate to base regulation exclusively on deter minations of fibers of >5 (i.m when the bulk of the dust in air consists of fibers of a shorter length? Be cause standards are based on extrapolations from data accumulated among workers exposed to relatively heavy concentrations of dust in the past, predictions must be based on analyses that assume that there are no thresholds below which the disease fails to occur. Within the ranges usually found in the occupational setting, there appears to be linearity in the dose-re sponse relation, at least with regard to bronchogenic carcinoma. However, the likelihood that cancer will occur is influenced substantially by cigarette smoking, since the risk in the nonsmoker who has heavy expo sure to asbestos is increased only a few fold. Thus, the risk for the nonsmoking asbestos worker is substantial ly lower than the risk for a member of the general population who smokes two or three packs ofcigarettes each day. 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