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1480 THE NEW ENGLAND 1QURNAL OF MEDICINE June 17, 1982 The New Englan Journal of Medici Official Organ of The Massachusetts Medical Society Percy W. Wadman, M.D. President William B. Munier, M.D. Charles S. Amorosino, Jr. Extcutioe Vice-president Executive Secretary Published Weekly by the Committee on Publications of the Massachusetts Medical Society James F. McDonough, M.D., Chairman John I. Sandson, M.D. John C. Ayres, M.D. William H. Sweet, M.D., D-Sc. William . Schwartz, MJ). Frank E. Bixby, Jr., M.D. Samuel K. Stewart, M.D. Arnold S. Reiman, M.D., Editor Marcia Angell, M.D., Deputy Editor Edwin W. Salzman, M.D., Deputy Editor Associate Editors Jane F. Desforges, M.D. Norman K. Hollenberg, M.D., Ph.D. Ronald A. Malt, M.D. Morton N. Swartz, M.D. Franklin H. Epstein, M.D. Francis D. Moore, M.D., Book Review Editor * John C. Bailar, III, M.D., Statistical Consultant Joseph J. Elia, Jr., Manager of Editorial Operations Emily S. Boro, Assistant Editor Marlene A. Thayer, Editorial Office Manager Editorial Board Richard H. Egdahl, M.D. Paul Calabresi, M.D. Park Gerald, M.D. Aram V. Chobanian, M.D. Joseph B. Martin, M.D. John T. Harrington, M.D. Robert J. Mayer, M.D. Homayoun Kazemi, M.D. Frederick Naftolin, M.D. Kenneth McIntosh, M.D. Kenneth J. Rothman, Dr.P.H. David G. Nathan, M.D. Kurt J. Bloch, M.D. Lawrence G. Raisz, M.D. Thomas J. Ryan, M.D. John K. Iglehart, Special Correspondent Frederick Bowes, III, Director of Business Operations Ronald H. Brown, Manager of Advertising & Marketing William H. Paige, Manager of Production & Distribution Milton C. Paige, Jr., Consultant Prospective authors should consult "Information for Authors," which appears in the first issue of every volume and may be obtained from the Journal office. Articles with original materia] are accepted for consideration with the understanding that, except for abstracts, no part of the data has been pub lished, or will be submitted for publication elsewhere, before appearing in this Journal. Material printed in the New EnglandJournal ofMedicine is covered by copyright. TheJournal does not hold itselfresponsible for statements made by any contributor. Notices should be sent at least 30 days before publication date. Although all advertising material accepted is expected to conform to ethi cal medical standards, acceptance does not imply endorsement by theJournal. Reprints: The Journal does not stock reprints, and reprints of the MGH CPCs are not available. Subscription Prices: USA: $48 per year (interns, residents $33 per year; students $30 per year). Canada (U.S. funds only): $38 per year (interns, residents $43 per year; students $40 per year). Mail checks to Subscription Payments, P.O. Box 4772, Boston, MA 02212. Editorial Offices: 10 Shatiuck St., Boston, MA 02113. Business and Subscription Offices: 1172 Commonwealth Ave., Boston, MA 02134. XPGSURE TO ASBESTCf \?77> HUMAN DISEASE urIng the past two decades, ill health resulting from exposure to asbestos has been the subject of in tensive observation and research1 --probably more intensive than research on any other environmental agent.2 In the most direct target organ, the lung, and in its pleural coverings, there is a wide spectrum of response after exposure; not only acute and chronic inflammatory diseases but also cancer of these organs may occur. Research has been stimulated by the belief that the more complete our understanding of the mechanisms of pathogenesis, the better will be our ability to control the continued use of this mineral in today's complex technologic world.3 The review by Craighead and Mossman of the pathogenesis of asbestos-related diseases in this issue of the Journal * which covers recent work in cell biol ogy, is set in the context ofpathology but also discusses the use of these minerals and regulatory consider ations; it complements other recent reviews of the epi demiology of these diseases,3 their impact on public health,6 and current clinical issues.7 Also important is a recent report that provides criteria for grading the pathologic changes in the lungs associated withasbestos exposure.8 Systematization of pathological assess ments can only enhance the pooling ofexperience from different centers or countries by maximizing the com parability ofstudies. The international classification of radiographs of pneumoconiosis9 by the International Labour Office is an example of such systematization, and the dividends associated with its use are generally recognized. Perhaps the major contribution of the review by Craighead and'Mossman (and this may surprise read ers not familiar with the held) is the emphasis placed on the shortcomings of our present knowledge of the pathogenesis of asbestos-related disease. Considering first the fate of inhaled fibers in the lung, it is now evident that the dust burden of the lung is primarily in the form of uncoated asbestos particles,4 whether or not these conform to the definition of a fiber (i.e., a particle with a length-to-width ratio of 3:1). This defi nition probably originated rather arbitrarily from a need to standardize what was considered a fiber for purposes of industrial hygiene6; it is now widely be lieved that a much higher ratio, perhaps 10:1, would have been a better choice. Both fiber length10 and mineralogic type" are important determinants of whether a fiber becomes coated and so takes on the familiar appearance of the asbestos body. Most asbes tos bodies found in human lungs contain an amphibole fiber as a core," even though chrysotile accounts for the greatest use and presumably the most exposure.7 What permits some particles to lie apparently dormant in the lungs for long periods before evoking an organ response is not known, and there is no good explana tion for the fact that all the disease consequent to as bestos exposure (including fibrosis of the lungs and 15191830 Vol. 306 No. 24 EDITORIAL 1481 pleura as well as cancer of these organs) may appear long after exposure has ceased. Fibrosis of the lung (asbestosis) was recognized by the first decade ofthis century and has been the subject of much research in animal models. Nevertheless, Craighead and Mossman conclude that the patho genesis of asbestosis remains to be established,4 as does the importance of exposure dose as compared with individual "susceptibility" in the initiation and the progression of the fibrotic reaction. The finding of an acute inflammatory response in some early human lesions4 raises the issue of whether there is a reversible component to the acute response in human beings, as suggested by work in animals.12 Long-term studies in sheep13 may help to answer this question. As for whether asbestos acts as an initiator or as a promoter of lung cancer, the authors of the review4 favor the latter view; perhaps particles act as physical carriers of other environmental carcinogens to the basal epithe lial cells. It is also possible that more than one mecha nism is involved.7 There is perhaps even more uncertainty about the pathogenesis of pleural reactions than there is about parenchymal lesions. For instance, it is not dear how often acute exudative reactions, such as effusions (pre sumably usually clinically silent), precede the more chronic diffuse or localized fibrotic reactions ofvisceral or parietal pleura. It is also unclear how fibers reach the parietal pleura and concentrate there in such a way as to evoke plaque production after a long delay while leaving the visceral pleura intact; an adequate hypothesis for the pathogenesis ofpleural plaques is needed to explain all these features. 4 Perhaps even i nore puz zling is what determines whether the pleural reaction will be benign or malignant. Not all would agree with the view expressed in the article4 that malignant mesotheliomas are pathognomonic of asbestos expo sure: these tumors were described by European pa thologists in the 19th century -- long before major commercial exploration of the asbestos minerals15 -- and there is little evidence even today that asbestos is responsible for many cases in men or women outside industrial centers.3,15 What are described in the pres ent review as "casual" exposures (i.e., usually domes tic or neighborhood) arc exposures that are intermit tent but have often turned out to be to very heavy dust clouds of fine particles.3 In spite of considerable current interest in the topic,7 the issue ofwhether asbestos exposure is associ ated with airway abnormalities is not addressed by Craighead and Mossman. The involvement of small airways in the early stages of asbestos-related lung fibrosis has in all likelihood its clinical counterpart, although there is no evidence about whether these ab normalities are reversible or not. The association be tween asbestos exposure and other forms of airway response, such as bronchitis' or emphysema in the ab sence of asbestosis, also remains to be clarified, as do the confounding effects of cigarette smoking. Finally, there is the question of whether there are differences in the pathogenic potential of the various fibers in this mineral group. Of particular concern is whether chrysotile (which has accounted for over 90 per cent of commercial uses during the past several decades) differs from the two amphibole fibers, crocidolite and amosite, which were used extensively during World War II and in the postwar building boom. The issue has been bedeviled by problems of comparing like with like,5 by the difficulty of sorting out the rela tive contributions of exposure (duration, level, and particle size) and fiber type, and by the differences between exposure in the mining and milling of fiber and the secondary application of fibers in manufactur ing. Thus, although it is clear that the rates ofmesothe lioma are different in different exposed populations, it has usually not been possible to assess the extent to which these differences are due to fiber type or to other factors. Some clarification has come from the applica tion ofmodem methods oflung-dust analysis to autop sy material. In two case-control studies of mesotheli oma, an excess of amphiboles (amosite in North America and croddolite in the United Kingdom) was found in the lungs of the cases, whereas chrysotile contents were similar in cases and controls.5,16JSSB pathogenic potential is strongest for mesothelioma, with croddolite more strongly implicated than chryso tile, and amosite probably in between. The evidence is also reasonably strong for lung cancer, with crocidolite again more strongly implicated than chrysotile. For pleural reactions (pleural plaques and fibrosis), there may also be a fiber gradient, although other factors are almost certainly involved; for parenchymal fibrosis the evidence for a fiber gradient is minimal. At present it is believed that the biologic activity of asbestos partides relates to the degree of penetration and the amount of deposition in the lower respiratory tract, both of which depend mainly on their physical characteristics, in cluding their aerodynamic properties. Particle size (and particularly length and fineness) may also deter mine oncogenicity. However, biologic activity is likely to be modified by the length of time that particles survive in the lung without denaturing, which may be related to their chemical characteristics. The most plausible explanation for differences in the pathogenic potential of various fibers is that these differences re sult from differences in both the physical and chemical properties of the fibers. What is the clinical importance of the issues raised by the review in the Journal? Perhaps the most impor- 15191831 1482 THE NEW ENGLAND JOURNAL MEDICINE June 17, 1982 tant is that health risks in relation to exposure to asbes 10. Morgan A. Holmes A. Concentrations and dimensions of coated and uncoat tos vary according to environmental factors. Some of these factors (such as exposure dose, particle size, and fiber type) are known, but there are undoubtedly oth ers not yet recognized. Host characteristics probably also influence the response to exposure. Thus, in con ed asbestos fibres in the human lung. Br J Ind Med. 1980; 37:23-32. 11. Churg AM, Wsmock ML. Asbestos and other ferruginous bodies: their formation and clinical significance. Am 1 Pathol. 1981; 102:447-36. 12. Hiett DM. Experimental asbenosis: an investigation of functional and patho logical disturbances. I. Methods, control animals and exposure conditions. Br I Ind Med. 1978; 33:129-34. 13. Begin R. Plesrcrynski M. Masse S. et al. Asbestos-induced lung injury in sidering the individual padent with a disease known to the sheep model: the initial alveolitis. Environ Res. (in press). be related to asbestos exposure, the wise clinician 14. Hillerdal G. The pathogenesis of pleural plaques and pulmonary asbestosis: possibilities and impassibilities. Eur I Respir Dis. 1980; 61:129-38. should avoid regarding any parricular exposure as too 13. McDonald IC. McDonald AD. Epidemiology of mesothelioma from esti i short, too remote, or at too low a level (even ifenviron mated incidence. Prev Med. 1977; 6:426-46. 16. McDonald AD. McDonald IC. Pooley FD. Mineral fibre content of the lung ;! mental counts were in compliance with the present in mesothelial tumours in North America. Ann Occup Hyg. (in press). reguladons) to have accounted for the disease. Assess mm- ment of the importance of particular environmental exposures is often outside the clinician's expertise; it should be referred to appropriate consultants in indus trial hygiene, engineering, or physics. In lung cancer the statistical probability that a given case is attribut 18. Enter!ine PE. Attributability in the face of uncertainty. Chest. 1980; 78: Suppl (August):377-9. T9. "Wagner JC. Elmes PC. The mineral fibre problem. In: McDonald JC. ed. Recent advances in occupational health. Edinburgh: Churchill Livingstone, 1981:1-13. able to asbestos exposure may be estimated from expo sure-response data,18 which for practical purposes can probably be assumed to be linear, provided that the i data available are applicable to the industry in which j the subject was employed. Finally, the unpredictable SOUNDING BOARDS clinical course of these diseases demands vigilance by the clinician with respect to past exposures, and the AFTER LAETRILE, WHAT? most powerful indicator remains the careful, complete, Laetrile was moribund before Moertel et aj. laid it and precise occupational history.7 to rest with the recent report of their prospective clini ;< Whether the dust concentrations permitted by cur cal trial.1,2 It had been replaced in popularity by an i. rent regulations will in fact eliminate the future risk of approach unusual in the annals of unorthodox cancer asbestosis, as Craighead and Mossman suggest,4 re therapy -- one that represents more of a challenge mains to be established. Similar suggestions in the than did Laetrile or its predecessors. This is the "natu I! 1930s proved to be premature. Evaluation of the im ral" approach to malignant disease, which emphasizes ' r pact of present controls on health issues is an urgent cure through purification and the body's capacity to matter for research. Furthermore, a total ban on use heal itself. The currently popular alternative approach seems unlikely in technologic societies,3 in which it is rooted in homeopathic and naturopathic beliefs, may be considered preferable to retain these versatile Indian and Oriental philosophy, and 19th-century minerals for certain uses. Until it is established that theories of intestinal putrefaction. Promoters often asbestos substitutes do not carry health risks,19 re evoke the time-worn conspiracy dogma, which states T'll1 .1 search into the mechanisms by which asbestos parti cles produce ill health should be vigorously pursued. that the medical system, the Food and Drug Adminis tration, and the federal government withhold true McGill University cures from the public, thereby perpetuating therapeu Montreal, PQ H3A 2B4, tically useless and biologically harmful cancer treat ments in order to further the Establishment's econom 4 References 1. Acheson ED. Gardner M. Exposure limites -- tbc scientific criteria. In: ic interests.3,4 Alternative cancer therapies in vogue today differ McDonald JC, ed. Recent advances in occupational health. Edinburgh: importantly from Laetrile and from other unproved Churchill Livingstone. 1981:237-69. 2. Peter GA. Peters BJ. Source book on asbestos disease. New York: Garland STPM press. 1980:A1-K18. remedies of the past. Previous unorthodox treatments were "medicines" or at least "medicinal." Examples 3. Gloag D. Asbestos -- can it be used safely? Br Med J. 1981; 282:331-3. were Dr. Bye's Combination Oil Cure, Dr. Chamlee's S: 4. Craighead JE, Mossman BT. The pathogenesis of asbestos-associated dis remedy for removing cancer viruses from the blood, i j, eases. N Engl J Med. 1982; 306:1446-33. 3. McDonald JC. Asbestos-related disease: an epidemiological review. In: Wagner IC. ed. Biological effects of mineral fibres. Lyon: International Agency for Research on Cancer, 1980:387-601. (IARC scientific publica tion no. 30). Dr. Leach's Cancerol, Dr. Koch's glyoxylide, and many others that attained great prominence in their day. They came in ampules, vials, or syringes, mim 6. Liddell D. Asbestos and public health. Thorax. 1981; 36:241-4. icking standard medications, and they were sold and 7. Becklake MR. Asbestos related diseases of the lung and pleura: current administered in the usual clinical fashion by people in < clinical issues. Am Rev Respir Dis. (in press). 8. Craighead JE, Abraham JL, Churg A, et al. The pathology of asbestos- white coats. `.4 'o* associated diseases of the lungs and pleural cavities. Arch Pathol Lab Med. Today's alternative remedies explicitly reject associ (in press). ation with standard treatments, environments, and 9. International Labour Office. Guidelines for the use of the ILO International Classification of radiographs of pneumonconioses. Geneva: International paraphernalia. These are anti-medicines, emphasizing Labour Office, 1980:1-48. (Occupational health and safety series no. 22). purification through dietary regimens, detoxification 15191832 1 H.A. Eschenbach H. C. Duecker York: Alan R LUs, Attached is a summary article from the 17 June 1982 New England Journal of Medicine titled, "Pathogenesis of Asbestos - Associated Diseases" and an editorial based upon it. While the article has some rather technical sections, it is a good basic document. There is one item that requires further investigation. On page 1447 in the middle of the left column, the author states, without footnote, that Canadian chrysotile contains tremolite. In the editorial, page 1481, right column, middle, it is indicated that there may be a preferential clearance of chrysotile over amphiboles from the lung with an inference that tremolite and/or amphiboles may be more of a health problem than chrysotile. The reference given is "in press". uch. Vol. 1. Lyon: l-76. tndvds for height, s of puberty. Arch )hi thaUsuemia in erizaiion of sickle >d. 1981; 58:1057- te Hb-S concentnlood in sickle cell : oxygen affinity of vidual variation in sc. N Engl J Med. Fetal haemoglobin laudi Arabia. Br ) Harry Eschenbach cell disease. Gin eijeant BE. Comucklc cell disease. -I __ ____ .1 _ -------- D- w, '.mj e iw. KMmil L/J. sxipna thalassemia and homozygous sickle cell disease, in: Brewer GJ, ed. The red m cell. New York: Alan R Uss, 1980:781-6. 17. Sewell A, Millard D, Serjeant GR. The interaction of alpha thalassaemia s associated with ase. Br J Ophthal mol. ivsi; 29. Hawker H, Netlson H. Hayes RJ, Serjeant GR. Haematok>gical facton associated with avascular necrosis of the femoral head in homoz|gou$ 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 ofour most useful minerals. Over - 3000 manufactured products of contemporary asbestos cannot be replaced expeditiously in many 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 are 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 of manufactured goods the adverse effects of asbestos on health and provides a in the United States. At present, several million perspective on the pathogenetic mechanisms of the Americans are employed in industries that use asbes diseases associated with exposure. Since there are sev tos products, and countless millions of American citi eral different mineralogic types of asbestos, we will zens are 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.3"6 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 of min eralogic features into two groups: the serpentines and 15191834 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 ^3:1, 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 amositeare 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 asbestosjs not always mineralogi- cally pure.smaftamounq 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 bole minerals are distributed widely in geologic strata, but only two relatively small mines in Vermont and ASBCSTOS 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 of the 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 0). 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. Chrysotile currently accounts for over 90 per cent of 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 1). 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 15191835 1448 THE NEW ENGLAND JOURNAL OF MEDICINE June 17, 1982 Table 1. Consumption of Different Types of Asbestos in the United States in 1978.* Usa Typs Of Asurros Total AlUSTOS cxaytonu CHOODOUTI AMOSfTB 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 dels of Fagan.1 24.100 -- -- -- 100 -- -- -- -- 100 -- 100 -- 24,400 200 -- 200 -- -- -- -- -- -- -- -- -- 1300 1700 144,000 7,900 90,200 26,300 12,300 6,000 2,900 43,700 10,900 1,300 1,900 300 -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 foF 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. Asbesto-containing 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 Are protection. Because of its 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 coundess additional industrial uses of asbestos are 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 offibers 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, 1 Fibers with a relatively broad diameter are deposited in the upper respiratory tract, whereas thin fibers are carried peripherally into the parenchyma of the lung, where they lodge* in the terminal airways. Bifurcations are common sites for fiber impaction, since patterns ofair flow are altered at these sites. The shape of the fibers also has a role in transport. Aerodynamically, 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 amphiboles, 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 exposed to as bestos of different types.12 Three biologic mechanisms participate in the clear ance of fibers from the lower respiratory tract. By far, the bulk of the dust is removed by the mucociliary escalator of the tracheal bronchial tree, and the mate rial is either expectorated or swallowed.13'15 In the peripheral airways, short fibers are ingested by macro phages, and at least some of these ceils 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.18"20 This material accumulates in the interstitium and is carried to regional lymph nodes.17 In general, short fibers are cleared more readily than long fibers,17 which tend to be retained in the lumens of the respiratory bronchioles and the alveolar 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, Vol. 306 No. 24 ASBESTOS-ASSOCIATED DISEASES -- CRAIGHEAD AND MOSSMAN 1449 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 intrapulmonary deposition offibers. However, these fac tors are extraordinarily complex, in part because indi viduals appear to differ in their responses to inhaled dust.21'29 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 ofthese lobes are frequently thickened by a dense layer offibrous tissue. In advanced asbesto sis, 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.31'34 They consist offibers coated by complexes of hemosiderin and glycoproteins and are 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 are commonly known as asbestos bodies. The number of uncoated 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 uncoated. Since uncoated fibers are usually diffi cult or impossible to demonstrate by light microscopy, lung tissue must be digested and the residue examined by either phase or electron microscopy in order to carry out qualitative and quantitative studies of the fibers. Whereas relatively long fibers (>5 /Am) are found by light microscopical techniques, electron mi croscopy makes it possible to identify very small parti cles.40,4 Thus far, attempts to correlate the extent of disease with either the number of asbestos bodies or the overall content of fibers in the lungs have been difficult, although fibrosis is usually evident when 106 fibers per gram of lung (wet weight) are present. Quantitative studies pose many problems and are only a crude measure of exposure, partly because many fibers are cleared from the lungs and others fragment to increasingly smaller particles with time. Macrophages are a key element in the response of the host to asbestos. Whereas these cells phagocydze 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 fibrogenic 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 consistent 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 the production of collagen by cells. When chrysotile is added to cultures of fibroblasts in vitro, the cells elaborate reticulin 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 modem environmental controls have dramatically reduced exposure in 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. Plaques are curious lesions made up of hyalinizcd fibrous tissue located on the parietal pleura of the tho rax, diaphragaiyt^^^^^^i^^^ka^ium.50,51 exposure. ttsssbestos:58 Although the occurrence of plaques correlates with the duration and intensity of exposure,rtia-ComiBMt to finffinim in the absence of * t 15191837 1430 THE NEW ENGLAND JOURNAL OF MEDICINE June 17, 1982 _______ i d6 riot'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"55 it is not always clear in published reports whether plaques were differ entiated from the fibrous lesions of the visceral pleura that accompany pulmonary asbestosis. Since plaques are foundzMttefi^isf] DOMff*e'' -- ods^Tthm is 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.58^1 Malignant mesotheliomas of the pleural and perito neal cavities are considered pathognomonic of expo sure to asbestos, although in many patients a history 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.^5"67 TBe i liomasasat _ ___ is an tnwioiniribn went. 0n 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 oflarge 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 after 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 e 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 and 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, ut not the chemical composition, were found to be the tical determinant affecting the development of tu tors 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 crocidolite consisting predominantly of long,_thin fibers and the rarity of tumors in persons exposed to the com paratively blunt, shorter fibers of amosite and anthophyllite.65,72"74 A fibrous zeolite, erionite, has recently been associated with the occurrence of pleural fibrosis and mesothelioma in a rural area of Turkey where commercial mining of asbestos does not occur.61 Since the fibers of this mineral do not possess the chemical properties of asbestos but are morphologically similar to crocidolite fibers, the observation is consistent with the experimental findings of Stanton and his associ ates.70,71 The basis for the development of mesotheliomas in the peritoneum is uncertain. Presumably, fibers of as bestos in the lungs are transported in lymphatics to the abdomen, where they have been recovered from lymph nodes and other organs.75,76 Asbestos is also transport ed across the mucosa of the gut after ingestion.77,78 Whatever the mechanism for entry ofasbestos into the abdomen, it is assumed that the pathogenesis of the tumors in the peritoneal and pleural cavities is similar. Peritoneal mesotheliomas occur only in persons ex posed to amphibole asbestos. The gradual disintegra tion ofchrysotile in tissue may account for the relative ly uncommon occurrence ofmesotheliomas of both the pleural and peritoneal cavities in persons exposed ex clusively to chrysotile.79 The mechanism of malignant transformation of mesothelial tissues is obscure. Surprisingly little ex perimental information has accumulated, although there is reason to believe that the lesions may be com- 3.5191838 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. Cocarcinogenic substances and cigarette smoke do not aftpear 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 severity 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 Canada85 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 either 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,93 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 ofasbestos-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 Berenblum, carcinogenesis is a sequence ofevents 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 of a 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 ofasbestos 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 ofpulmo nary asbestosis. Asbestos has many of the properties of classic 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 ofcells106,107 and induces the syn thesis of. the polyamines 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 ofthe respiratory mucosa to carcinogens. However, alternative mechanisms are worthy of consideration. Asbestos cart be phagocytized by the bronchial epithelium and can be transported intracellularly both free in the cytoplasm and in phagolyso somes.20 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.1" There after, the hydrocarbons are converted by microsomal mixed-function oxidases to biologically active epox ides and diolepoxides, which can interact with the DNA of basal cells.110 Another (but less attractive) hypothesis involves the alveolar macrophage, which phagocytizes asbestos in the airways and possesses the 15191839 1452 THE NEW ENGLAND JOURNAL OF MEDICINE June 17, 1982 enzymatic capacity to convert polycyclic hydrocar bons to active metabolites.111 At present, the mecha nism of asbestos-associated carcinogenesis is unclear, although the mineral appears to act like a classic tumor promoter. The fibrous nature ofasbestos is criti cal, since exposure to nonfibrous oxides of silicon (for example, quartz) and a variety ofsilicates is not associ ated with an increased risk of bronchogenic carcinoma in human beings. Cancers of the Digestive System and Other Organs Asbestos is implicated in the causation of cancer in the upper and lower gastrointestinal tract and the kid ney. 115 Oropharyngeal and esophageal tumors oc cur more frequently in asbestos workers who smoke, whereas a direct relation between smoking and the development of carcinoma of the large intestine and the kidney has not been established. Selikoff and Hammond114 and Elmes and Simp son112 have reported a statistically significant twofold to threefold increase in the prevalence of tumors of the digestive tract in insulators, factory workers, and ship yard employees. Other surveys have either demon strated a smaller increase or failed to establish an asso, ciation between exposure to asbestos and neoplasms in this system.116 We believe that the evidence must be assessed cautiously because the associations thus far reported are relatively weak. Since death certificates are used to obtain data in most studies, it is possible that peritoneal mesotheliomas have been confused with metastatic carcinomas of gastrointestinal-tract origin. The general population is exposed to small amounts of asbestos in drinking water, beverages, food, drugs, and agricultural products. Potable water often con tains mineral fibers that are presumably derived from geologic deposits and refuse dumps. The finding of fibers of amphibole asbestos in the drinking water of Duluth, Minn., resulting from the disposal of taconite tailings into Lake Superior,117 prompted investiga tions to determine the concentration and characteris tics of mineral fibers in water supplies throughout the United States. Fibers with the properties of both ser pentine and amphibole asbestos were found in over half the samples of water studied (Table 2). Thus, Table 2. Concentrations of Asbestos-Like Mineral Fibers in the Water Supplies of Selected but Representative Commu nities in the United States.* Crr* Concentration no. offibers >5 pm/liter Atlanta Boston Duluth Dallaa Kansas City, Mo. New York Philadelphia San Francisco Seattle _____ -"Prepared from Table E-2 in Levine.1 5.7J 3.98 1.72 0 0.07 0 16.95 0.60 0.85 many Americans consume water containing asbestos like minerals. Mineral fibers have been detected in the urine of residents of Duluth in numbers corresponding to the concentration of asbestos in drinking water.118 Inter estingly enough, fibers have been found in the glomer uli and tubules of rats exposed in inhalation chambers to synthetic fibers.119 These observations suggest that asbestos migrates to the kidney after clearance from both the gastrointestinal and respiratory tracts. Whether , this has an influence on the occurrence of tumors in the gastrointestinal tract is unknown. When fed to laboratory animals, asbestos interacts with the mucosa of the gut.78 Fibers enter cells of the mucosa and prove cytotoxic.120 The experimental evi dence strongly suggests that ingested asbestos is dis seminated to abdominal organs by the lymphatics and blood vessels. This conclusion is supported by post mortem studies of occupationally exposed persons; these studies have demonstrated asbestos bodies and uncoated fibers in most major organs.76 How does the ingestion of asbestos induce gastroin testinal carcinomas in human beings? In efforts to ad dress this question, rodents were fed large amounts of asbestos over extended periods. With one exception,121 these studies failed to demonstrate an increase in the prevalence of tumors in the gut.122-124 The possible synergistic effects of asbestos on the induction of intes tinal neoplasms by chemical carcinogens has also been examined.126 Intragastrie administration of asbestos failed to augment tumor development in rodents fed azooxymethane, a recognized intestinal carcinogen. The carcinogenic potential of asbestos in the gastro intestinal tract appears to be low. The pathogenetic basis for the purported increase in the prevalence of carcinomas in certain occupational groups remains to be established. Pathogenic Potential of Asbestos Types As emphasized above, asbestos is not one but a fam ily of fibrous minerals, each of which has distinctive physical and chemical characteristics. Minerals from various parts of the world and geologic formations often have dissimilar physical properties, even though they are classified under a specific mineralogic type. These differences are relevant to our understanding of the effects of asbestos on health, since the characteris tics of the fiber have been fully defined in only a few epidemiologic and experimental studies. The problem of evaluating the effects ofdifferent types ofasbestos on health is compounded by the common practice of cus tom blending ofvarious minerals for specific industrial applications and the use of one type and then another, depending on availability and conditions of the market. Since the serpentine chrysotile is used extensively in industry today, it is important to ask whether its pathogenic importance is comparable to that of the amphiboles crocidolite and amosite. These latter min erals are of historical importance, particularly since Vol. 306 No. 24 ASBESTOS-ASSOCIATED DISEASES -- CRAIGHEAD AND MOSS MAN 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 of relatively 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 ofrelatively short, blunt fibers. A number of studies have been conducted in miners and millers in Quebec and Italy, where the serpentine chrysotile is,,extracted.7+'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 are exposed predominandy 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 of asbestos 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 ofdisease 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 are 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 either in the remote past or over a lifetime. The difficulties are 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 pan, collected by mechanical means. A concentration of five fibers per cubic centimeter ofair, 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 of two 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 pan 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. The conclusion that asbestosis fails to develop below a certain threshold dosage is based on physical exami nations and radiologic studies of workers and not on pathological examinations. By these criteria, it is prob ably impossible to be certain whether a fibrotic lesion in the lung is due to asbestos. With mesothelioma, the data are more controversial. Although a dose-response relation appears to exist, the threshold may be deter mined by the life span of the person exposed, because the latency period for these tumors is protracted. Since the problem cannot be answered with contemporary epidemiologic and experimental approaches, it must be resolved by practical rather than theoretical consid erations. References 1. Feder BJ. Asbestos injury suits mount with broad business impact. The New York Times. 1981 July 3:1. 2. Warning: asbestosis may cost you mom than money. Economist. 1981; 280:83-4. 3. Levine RV. ed. Asbestos: an infonturioa resource. 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J Environ Pathol Toxicol. 1980; 3(5&6):30I-I2. 126. Rubino GF, Piolano G, Newhouse ML, Scanaetti G, Aresini GA, Murray R. Mortality of chrysotile asbestos workers at the Balangero Mine, No. Italy. Br J Ind Med. 1979; 36:187-94. -- 15191843 version ** .. . I ource mass of 8-h sample,6 pg ref. /ggwss- f r- -, ^ products r<y ^.mmercial buildings -general standard" P-1- -- fcygiene standard 244 117 73 . 31 82 s82r (27) (27) (27) (5) (28) (10) ~>s "jn in length. 6 1.7 L/m sampling rate. ijdtp the analytical results as a consequence of the redeposition. j^nounts of chrysotile were deposited on 12 Millipore -- and 12 silver membrane filters (six filters at each peels; 100 and 150 Mg). The AA filters were then ashed r temperature asher and the residues redeposited on jembrane filters. The average intensities of the dif- j beams from the 12 redeposited samples were compared fibose of the 12 direct deposition samples and a two tailed showed that at a 5% level of significance (P = 0.466, A respectively) there was no difference in the means at Jflrr of the two levels of loading. Similarly, both sets of filters [-each of the two levels gave comparable standard deviations i%o tailed F-test, 5% level of significance P = 0.058,0.182, ! spectively) indicating that ashing and redeposirion does not (itroduce analytical bias or affect the precision of the method. Count to Mass Conversion. On July 1, 1976, the Oc cupational Safety and Health Administration (OSHA) pro mulgated a standard for occupational exposure to asbestos containing an 8-hour time-weighted average (TWA) con centration exposure limit of 2 fibers/cm3 longer than 5 Mm (26). To determine if this level is commensurate with the detection limit of the above method, it is necessary to obtain a count-to-mass conversion factor for chrysotile fibers. The results of several studies in which -conversion factors were Artermi:ion i percent e in this si analyte -necessary 'Ventages the pure re a prior reported are summarized in Table VI. Quite clearly, the results are at variance and reflect not only the variety in the sources or uses of the fibers but also the differences in techniques used by the original investigators. However, based on these correction factors, the minimum amount of material that would be collected in a personal sample exceeds by at least a factor of three the detection limit determined for chrysotile at a level of 1% in talc and exceeds by at least a factor of five the detection limit for pure chrysotile. assuming CONCLUSIONS * amount `hich will This study clearly demonstrates the substantial potential f-ing silver j of XRD as a routine technique for the quantitative deter critical in j mination of microgram quantities of serpentine asbestos. The n internal I utility of this method for both personal samples collected on filters and bulk samples is evident in its (1) specificity fcr i thod de-j chrysotile, (2) low detection limits, (3) excellent precision, c analysis J particularly in comparison to the interlaboratory precisions . attached of 30-100% (or greater) found using fiber counting methods 1.7 L/m. for non-occupational (4, 5, 8), occupational (6, 7), and lab f the face oratory generated samples (.9), (4) capability of making precise : inched to and accurate quantitative measurements on small quantities > inhomo- of chrysotile in the presence of large amounts of matrix mciples of neous de ns support collection d on silver "n homo- a study being in- ANALYTICAL CHEMISTRY, VOL. 51. NO. 4. APRIL 1973 525 material, a situation where the counting method is at best difficult, (5) potential for automation, and (6) ready adapt ability of the method to other asbestiform materials (e.g., tremolite) in different matrices. No method is without its drawbacks, the primary one of which in this case is the problem of interferences. Minerals such as antigorite, lizardite, members of the kaolinite group (kandites)i and possibly chlorite are potentially serious in terferences with chrysotile. Sample pretreatment and X-ray line profile, analysis are two approaches presently being ex plored in an attempt to reduce the adverse effects of inter ferences. ACKNOWLEDGMENT The authors gratefully acknowledge the guidance and assistance received during the program from J. V. Crable and from M. E. Cassinelli for her technical assistance. Special . thanks also go to M. T. Abell and D. D. Dollberg for their technical and scientific consultations. LITERATURE CITED (1) M. R. Becklake. Am. Rev. Respk. Dis.. 114. 187 ('978). (2) L. Bruckman. R. A. Rubino, and 8. Christine, Air PoBut. Control Assoc. J., 27. 121 (1977). (3) H. J. Woitowitz and H. Valentin. Staub-Reinhalt, Lutt. 36. 112 (1976). (4) M. J. Duggan and E. W. Cufley. 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"Worked Examples in X-Ray Analysis", Springer-Verlag, New York, 1970. p 51. (24) C. F. Gerald. "Applied Numerical Analysis', Addison-Wesley Puolishing Co,, Reading. Mass.. 1970, p 2. (25) "International Tables lor X-Ray Crystallography". Vol. 3. 3rd ed., Kynock Press. Birmingham, England, 1969, p 159. (26) U.S. Department of Labor. Occupational Safety and HeaKh Administration (1975); Occupational Safety and Health Standards. Fed. Reg.. 29 CPR 1910.1001. 1975. (27) J. R. Lynch, H. E. Ayer, and D. L. Johnson. Am. Ind. Hyg. Assoc. J., 31. 598(1970). (28) L. Bruckman and R Rubino. Ar PoBut. Control Assoc. J.. 25. 1207(1975) Rexeived for review October 19,1978. Accepted January 2, 1979. Mention of products or trade names does not constitute endorsement by the Public Health Service. 15191844