Document RpX3J7EKzMKYyO0na0096M5jB

j! STUU'J' 'i I J THE NEW ENGLAND JOURNAL OF MEDICINE June 17. 1982 9 SC. Fta*f too-toliaimiii--iotoeiwktoMvtniyofBekk cell mu. Blood. 1979; St. 119)4. * Hiuamaa TKJ. Skkk cell anu u a ivtow: a (enter of ilii|onuir foam. An I llanid. 1*7*; 0:17944. 7 Falice AE. WtMerB. Milkr A. nil. The auociano* of nckk cell Km wk hcuroayyoua and komeiyyaua tdiilaumu-i. m noa HI ckau '>m0na. Am J llunaul. 1979. 691-100 I Foeui OK. Sdeoodm WA. Wnu JN. Chto LS. Am $9. Lack of inlKenct of Inal M--ylaMa kwk or trwaracy wton on 9u ueamy of uctk call --mu J Clin law. 1910: 05:7)2-40. 9 Ahay C. Gnei) ME. JokpA IK. Wiliia-- OF. Mptii rtiilMmrai 7 and ilu <nMf( of hmaaoioyicil ahua u ctiilitna wto uckk coll --nan. FedianlUa. 1911: 15.1093-0. 10. Emawv SH. Ooay AM. Millar I. at aI. Conor** actla-oaO --ana and a-ihalaaaoaai: aflon on mm of anaauA N Ea|i 1 Mad. 1912:30570a 11 Hifp OR. Funky L. Scqaam OR. CW|f IB. Wcadunll 01 Tin fanaun a/U mokcalaf baaa ef alplii inalaaaaaaua anocianoo m> HI S limai an Napaat. If 1 Humuid 1911:47:43-50. 12. Sanaaw OR. Siiya-- BE- MiloarFF. The inenniMy ncMad call: a da-- muiau of liaamoma n nckk call aaaanui Br J Hatmunl 1909: 17J27- 33 13. LotoGH. RudnaaCXJ. Fanon affaeoni die me of cooMuf ofhiliran and coajufaud bilmOan m to van dan BatfO leacoon. J din Fadui. 1951: II 159-01. 14 MiUaidDF. Maaoo K. Scqaau BE. SaqcaoaOR. Campaauonaf fen--- loftcal faaoaea ofto $ and f~ ihalanumia oena Jamaican f'apooi Br J Hatmaim. 1977. 30:101-70 13. Bnic K. Man HR. Scfclki* 1. Baonaaon of email of foaaal haemofloOm. Naoaa. 1959 114:11774. 10 Scncam OR. Hi(fi DR. Aldndra B. Kayoa RJ. Watonll DJ. Alpha tnalauamia and Nomoiy|oua nckk call diacaae la: Biaear GJ. ad. The rad call See York. Alan R Liu. 1990:7514. 17. Sewell A. Millard 0. Scqaani OR. The inaeacm of alpha Hialaaiaamia wen SS duo--. In: Brawn GJ. ad. The rad call. New Yon: Alan R Lot. 197143-102. II. BrtaJou ME. Day NE. Siaanucal mahoda of ca--riaacarct. Vol. I. Lyon. Imamauonal A|cncy to Rmarra on Cancer. 1990:102-70. 19. Tanner JM. Whncno-- RH. Clinical tonpmidinal uandards to hatfla. waifm. hcipM vtlocny. weiphi wiociry. and tha acapaa of pahany Aran Du Child. 1976.51:170-9 20. Hippa DR. Fiaaaky L. Qf| JB. at al. Ocaaruon of alpha tola-- in Seym ufaau. Br J Haamaaol. 1990.40:3940. 21. Nofudn CT. Schochaar AN Tha mcartlhilar pnljmanimin of uckk hcmoplohm and ca lekaanee u udk call itneaae. Blood. 1911:99.1037- 91. 21 Seat--M. OihOt WN. Mil--FF. Btnlai IF. Erydancyu Hh-S rowraoara Don: an imp--Factor dk low oaypan aflbnty of Mood a aaehk cell antoaa. 1 Clui Inwa. 1973: 32:422-32. 23. May A. Huchna EX. The tuncjonaiioo dapcndanca of dk oayyon iftony of hacmoplohui 3 Br J Haematol, m3: 30-.3I7-15. 24. Dover GJ. Boyar SH. Charachc S. Hraudman K. Indmduai vananon in dm production -- nmval ef F ctlla nrkk-crll dinur. N Enfl J Mod. 1979:2991429-35. 23. Famhtay ME. Wood WG. Wcadunl DJ. fame RF Fetal harmoplohu preducueo and On uckk pone u to --a of eoaura Saudi Arabia. Br J Hi Mini. 1979. 40:413-29. 20. Seqtam OR. Fatal haamoylohtn in homorvyona aickk call due--. Clin Haematol. 1975:4:109-22. 27. Serjeant GR. Soounerena A. Sir-- M. Maaon K. Sarjaaaa BE. Com pan-- of aickk ecU-B dialiiiaamia wto homoryyoua nckk call -*------r J Haamaaol. 1979. 41:15-93. 29. Hayea RJ. Condoo FI. Saqoiot GR. Haamnoloyical factora uionaud wed prahtoaaivt faunepuhy u homoayfoua aickk call duo--. Br J Ophdialnul. 1991: 03:29-35. 29 Hawker H. Nciboa H. Hayaa RJ. Saryano GR. Hantmalopcal farart uioriaiod widt avaacular aacmtia of to famonl hand u homoayyona uckk call dueaee. Br 1 Huaaul. 1991 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 - iOOO 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.1,3 The spectrum ofliability 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 3* 10; tons of asbestos have been used in con This review summarizes our current knowledge of struction and in the fabrication ofmanufactured goods the adverse effects ofasbestos 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 arc sev tos products, and countless millions of Americai. 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. country has been proposed, most would agree that Mineralogy Fmm to Oaparnntm of Faahotoyy. Ummrury of Vnrnom Colkf* of Mo*rat. BiMmp--. VT 03403. whom mprat mquno U--Id ke wlftrviMd a Ik. Cimynud. 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 DOW 06685 V nL 306 .Vj. 24 ASBESTOS-ASSOCIATED DISEASES - CRAIGHEAD AND MOSSMAN 1447 the amphiboies (Fig. I). 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 asbestot is by definition >3:1, (he 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 posidve charge to the fiber, is an integral component of the lattice. The amphiboies 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 amphiboies differ from chrysotile in both physical and chemical makeup. There are several types ofamphibole, but croddolite 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 mineralogicallv pure. For example, Canadian chrysotile contains small amounts of an amphibole fiber, tremolite. In addition, industrial grades ofasbestos 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 x majos 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 A C0 Figure 2. Differing Structural Features of Serpentine (Chryeottie) and Amphibole (Croadolite) Asbestos. These scanning electron micrographs of International Union against Cancer reference samples of chrysotile (Panel A) end croaooute (Panel B) asoestos illustrate me 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 me straight rodUika form of croadolite (Pinal D). Note the dimensions of the fibers in companson to the cilia. Photomicrograohe ware furnished by Mr. Craig Woodworth, Department of Pathology, University of Vermont Col lege of Medians. motw Figure t. Types of Asbestos of Commerosl and Medical Impor tance and Their Chemical Compositions. 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 currendv 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, iu commercial importance has decreased over the past several dec ades (Table 1). Uses or Asbestos The unique physical properties of asbestos dictate iu 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 ! ii ! t-m Mois-i. DOW mu THE NEW ENGLAND JOURNAL OF MEDICINE June 17. 1982 T*oi t. Consumption of Oifforsnt Typos of Asoostos m ttto Unitod Statss in 1978-* III Tin or Aiaum Tot *4 rn<unu CMCIOOUTI oMOSITt Asbestos cment pipes Asbestos cement shccun| Fioonn| products Roofinf products Psckmf and insists Insulation. thermal Insulation, eiccincal Fnciiofl products Cosiinp and compounds Flatties Textiles Paper Otncr Total 110.700 7.900 90.000 :.soo 13400 1.000 :.9oo 11.700 . 10.900 1400 1.900 400 9.000 113400 frwa u* iia tt Fi|u. --1- 34.100 -- -- -- too 300 300 -- too too -- 34.400 1300 1700 144.000 7.900 90.300 31400 13400 6400 3.900 41.700 10.900 1.100 1.900 0 10.100 1)1.700 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.* 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 of its thermal stability, asbestos is well suit ed for use 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 are of concern because they can be overlooked by the manufacturer and unrecognised 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 or 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 ttw Lungs Timbrel! et at.* 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. l0-,` 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. Aerodynamical!)', 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.1' 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.1S*15 In the peripheral airways, short fibers are ingested by macro phages. and at least some of ihcse cells probably mi grate across the w all of the bronchioles and acini.1**1* .Asbestos fibers arc also taken up by the epithelial cells lining the airways and appear to move between cells of the mucosa.IW0 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.11 There are two phases of clearance through the tracheobronchial tree. About half the as bestos is removed within a few days. Subsequently, ji STUU'J' 'i I j' DOW 06687 YuL 30b So. 34 ASBESTOS-ASSOCIATED DISEASES -- CRAIGHEAD AND MOSSMAN 1*4* clearance continues for extended period*. The bulk of ihu material is excreted in the feces.1* 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 dust.*1'*'*' Aaboatoaia 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 asbestosis. the fibrotic pulmonary tissue contracts and is reor ganized to form the new air space typical ofthe honey comb lung. Ferruginous bodies are the histologic hallmark of exposure to asbestos.31'34 They consist of fibers 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.34,30 Thus, their presence a'nnc 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.35 ferruginous bodies in most human lungs have asbestos as a core.30 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 dssue ja.jv jt j, 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 cam- out qualitative and quantitative studies of the fibers. Whereas relatively long fibers (>5 itm) are found by light microscopical techniques, electron mi croscopy makes it possible to identify very small parti cles.404' 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 10 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 phagocytize 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.10,30 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 fibera interacts with the ptasmalemma and dam ages it, along with lysosomal membranes of cells.44,43 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 ultrastnictural evidence of injury. Other biologic phenomena may prove important in the causation of pulmonary fibrosis. Asbestos activates complement by the alternative pathway40 -- 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.30,45 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.40,4* Although the hypothetical mechanisms mentioned above could account for the deposition of fibrous 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 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. PtouralUaioM Plaques are curious lesions made up of hvalinized fibrous tissue located on the parietal pleura ofthe tho rax, diaphragm, mediastinum, and pericardium.30,41 They are usually but not invariably associated with exposure to asbestos.30 Although the occurrence of plaques correlates with the duration and intensity of exposure, it is common to find lesions in the absence of snsfioois 1430 THE NEW ENGLAND JOU RNAL OF MEDICINE June 17. 1982 obvious disease of the pulmonary parenchyma. Thus, surface. One is tempted to attribute the fibrous lesions I relatively small amounts of dust can induce the devel on the visceral pleura to irritation by the physical pres opment of plaques. These benign lesions do not appear ence of fibers on or near the surface. This mechanism to develop into malignant mesotheliomas. might also explain the occurrence of plaques in the I Characteristically, plaques are located in the inter parietal pleura. Alternatively, the lesions may repre i costal spaces on the anterior and posterior lateral as pects of the thorax and on the dome of the diaphragm sent an organized fibrinous exudate resulting from the physical movement of the lungs against the pleural 4l at sites where the visceral and parietal pleuras ap surface of the thorax. t proximate during respiratory excursions. The config However, these hypotheses are not fully consistent I uration of the plaques is highly variable. For example, with the pathological observations. For example, on the chest wall they usually follow the contour of the plaques are often found without fibrosis ofthe visceral rib, whereas on the diaphragm they are customarily pleura or adhesions between the pleural surfaces. In I either disk-shaped or geometrically shaped and have a addition, the lesions are localized and do not occur in nodular surface. Over time the lesions become calci the apexes or in the costophrenic angles. The patho fied. permitting easy recognition on x-ray films. Al genesis of the lesions cannot be defined at present, in though most of the available epidemiologic informa part because plaques occur only in human beings and tion is based on radiologic surveys,5Z'U it is not always experimental models have not been developed. clear in published reports whether plaques were differ- Experimental studies by Stanton et al.70,71 provide emu ted from the fibrous lesions of the visceral pleura an intriguing basis for speculation about the patho that accompany pulmonary asbestosis. genesis of mesothelioma. The dimensions of the fiber, Since plaques are found most often in persons ex but not the chemical composition, were found to be the posed occupationally to asbestos for extended peri critical determinant affecting the development of tu ods,**" their overall prevalence in the United Sutes mors in rats. Long, thin fibers of a variety of types is low.17 In Eastern Europe and Asia Minor the lesions proved carcinogenic when introduced into the pleural are frequently found in older members of the general space, whereas short fibers and those with a relatively population who lack documented exposure to asbes broad diameter failed to induce mesotheliomas. These tos. The presence of fibrous minerals in soil and in findings are consistent with epidemiologic observa local construction materials may account for the tions documenting the relatively common occurrence common occurrence of pleural plaques in these re- of tumors in populations exposed to grades of croddo- gUMlS.44"4* lite consisting predominantly of long, thin fibers and Malignant mesotheliomas of the pleural and perito the rarity of tumors in persons exposed to the com l neal cavities are considered pathognomonic of expo paratively blunt, shorter fibers of amosite and antho- i i sure to asbestos, although in many patients a history of contact with the mineral cannot be elidied.4*"44 These rare tumors are of particular concern from a public- phyllite.45,72"74 A fibrous zeolite, erionite, has recently been associated with the occurrence of pleural fibrosis and mesothelioma in a rural area of Turkey where health standpoint because they are thought to occur in commercial mining ofasbestos does not occur.41 Since persons who have had^ either transient or indirect ex the fibers of this mineral do not possess the chemical posure to asbestos.4*"47 The development of mesothe properties of asbestos but are morphologically similar liomas as a consequence of casual exposure, how-ever. to crocidolite fibers, the observation is consistent with is mu uncommon event. On the other hand, the preva the experimental findings of Stanton and his assod- lence of the rumor in workers who have had heavy ates.70-71 exposure over extended periods is about 2 to 3 per cent The basis for the development of mesotheliomas in and has been reported to approach 10 per cent,44,4* It the peritoneum is uncertain. Presumably, fibers of as is difficult to determine how often mesotheliomas actu bestos in the lungs are transported in lymphatics to the ally occur, because the latency period is usually 20 abdomen, where they have been recovered from lymph years or longer and can often be as tong as 40 to 30 nodes and other organs.71-74 Asbestos is also transport years. Some suggest that an epidemic of mesothelio ed across the mucosa of the gut after ingestion.77,7* mas will appear in the late decades of this century, Whatever the mechanism for entry ofasbestos into the consequent to the exposure of large numbers of work abdomen, it is assumed that the pathogenesis of the ers during World War II. tumors in the peritoneal and pleural cavities is similar. The pathogenesis of the pleural lesions associated Peritoneal mesotheliomas occur only in persons ex with exposure to asbestos is not known, but it is a topic posed to amphibole asbestos. The gradual disintegra of considerable contemporary interest. Fibrosis of the tion ofchrysotile in tissue may account for the relative visceral pleura, plaques of the parietal pleura, and ly uncommon occurrence of mesotheliomas ofboth the mesothelioma probably develop by different mecha pleural and peritoneal cavities in persons exposed ex* nisms, although a rigorous defense of this conclusion dusiveiy to chrysotile.7* would be difficult. As mentioned above, asbestos is The mechanism of malignant transformation of deposited preferentially in the periphery of the lung mesothelial tissues is obscure. Surprisingly little ex *fter inhalation. It penetrates the visceral pleura and is perimental information has accumulated, although Tied in the pulmonary lymphatics to the pleural there is reason to believe that the lesions may be com- ynsfifinis DOW 06689 Vd. J06 No 24 ASBESTOS-ASSOCLATED DISEASES --CRAIGHEAD AND MOSSMAN I4SI parable to the foreign-body sarcomas induced subcu is a sequence ofevents that can be divided into steps of taneously in- animals by sheets of plastic, glass, and initiation and promotion." An initiator interacts with metal. The cell of origin is not certain, since some the DXA of the target cell -- an event that can result tumors are made up of malignant serosal cells, where in malignant change. The carcinogen either acts di as others have the histologic features of fibrosarcoma. rectly with the DXA of the cell or requires metabolic Mesothelial cells phagocytize asbestos10 and prolifer activation by cellular enzymes. A promoter is general ate when exposed to asbestos in vitro,11 but malignant ly neither mutagenic nor carcinogenic, although it is transformation has not been demonstrated after expo required if the neoplasm is to develop. For example, if sure of cultured mesothelial cells to asbestos. Cocar- the skin ofa mouse is painted with a small amount ofa dnogenic substances and cigarette smoke do not ap chemical carcinogen, such as a polycyclic aromatic pear to be pathogenetic factors in vivo. hydrocarbon, tumors fail to develop unless a phorboi Bronchogenic Carcinoma ester is subsequently applied to the site: Promoting substances cause cellular division and proliferation as Epidemiologic studies have documented an associ well as biochemical changes in the cell that appear to ation between bronchogenic carcinoma and occupa be essential for neoplastic transformation." tional exposure to asbestos.*2"*7 The prevalence of tu Although epidemiologic data link exposure to asbes mors is higher in persons working with the finished tos with bronchogenic carcinoma in human beings, the products (such as insulators) than in miners and mill precise role of the mineral in the process has yet to be ers. The severity of the pulmonary parenchymal fibro defined. Since asbestos is not a potent mutagen100 and sis correlates with an increase in the number of neo inconsistently causes chromosomal aberrations in plasms.11'19 However, the incidence of tumors is also cells,101'103 a mode of action comparable to that of a increased in asbestos workers who lack radiologic evi classic chemical carcinogen is unlikely. It therefore dence of asbestosis. seems more plausible to suggest that asbestos increases Some controversy exists over the most common his the susceptibility of epithelial cells of the bronchi and tologic type of tumor, but among persons with asbesto- their branches to transformation by carcinogens in the sis, adenocarcinomas predominate.90'91 The lesions environment. tend to occur more frequently in the lower lobes in What biologic mechanisms account for the synergis conjunction with severe degrees of fibrosis.10 Atypical tic carcinogenic effects ofasbestos and cigarette smoke - hyperplasia of bronchiolar epithelium and multifocal in the respiratory tract? A plausible hypothetical con-' adenocarcinomas are often found in these sites. struct should be consistent with the apparent lack of a ( A linear dose-respotue relation between the cumula threshold in human beings and the occurrence of neo tive dosage of asbestos and the development of bron plasms in the absence ofappreciable degrees ofpulmo chogenic carcinoma has been reported in miners and nary asbestosis. millers of chrysotile in Canada1* and factory workers Asbestos has many of the properties ofclassic tumor in the United Kingdom.13 In the former study, those at promoters, such as the phorboi esters.104 Proliferation greatest risk were exposed to concentrations of asbes and squamous meuplasia are induced in the respira tos in the sir that were higher than the current regula tory mucosa of rodents in vitro.103 Asbestos interacts tions of the United States Occupational Safety and with the membranes ofcells10*'107 and induces the syn ^ Health Administration permit. A higher carcinogenic thesis of the polyamines that accompany cell divi potential for crocidolite than for chrysotile has been sion.1" Since cigarette smoke also contains a host of suggested by studies ofoccupational groups exposed to substances with promoter effects, the inhalants may either type of asbestos or to the two in combination.92 act in either an additive or a synergistic fashion to Mortality among chrysotile workers is increased 2.4- enhance the susceptibility of the respiratory mucosa to fold, whereas it is five times higher than normal among carcinogens. miners of both chrysotile and croddolite. However, alternative mechanisms are worthy of Surveys of the smoking habits of insulators,93 fac consideration. Asbestos can be phagocytized by the tory workers.94,93 and miners and millers91 have con bronchial epithelium and can be transported intracel- sistently shown that bronchogenic carcinoma is un lularly both free in the cytoplasm and in phagolyso common in those who do not smoke. Whereas there is somes.20 These fibers may serve as a physical carrier of only a slight increase in the prevalence of lung cancer the carcinogens in cigarette smoke to the basal cell, the among nonsmokers, heavy users of cigarettes (those presumptive progenitor of the neoplasms. Transfer of smoking more than 20 per day) have an 80-lold to 90- polycyclic aromatic hydrocarbons to and through bio iold greater predisposition to cancer of the lung.93*94 logic membranes occurs promptly and efficiently when Thus, the combined effects of asbestos and smoking the hydrocarbon is adsorbed to asbestos.1" There appear to be multiplicative rather than additive.97 after, the hydrocarbons are converted by microsomal What is the mechanism ofasbestos-induced carcino mixed-function oxidases to biologically active epox genesis in the respiratory tract? A consideration of ides and diolepoxides, which can interact with the contemporary concepts ofneoplastic transformation is DXA of basal cells.110 Another (but less attractive) appropriate in developing an answer to this question. hypothesis involves the alveolar macrophage, which As initially recognized by Berenblum, carcinogenesis phagoevtizes asbestos in the airways and possesses the I 1I ~n US.0.LUIS. DOW 06690 1437 THE XE'V ENGLAND JOl'RNAL OF MEDICINE Jun* IT. IMS enzymatic capacity to convert polycyclic hydrocar bons to active metabolites.1" 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. Caneara of tNs Otgaathra System and Other Organa Asbestos is implicated in the causation of cancer in the upper and lower gastrointestinal tract and the kidneyOropharyngeal 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. SeiikofT and Hammond"4 and Elmes and Simp son"2 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 betw een exposure to asbestos and neoplasms in this system."6 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 Ouluth. Minn., resulting from the disposal oftaconite tailings into Lake Superior,1" prompted investiga tions to determine the concentration and characteris tics of mineral fibers in water supplies throughout the L'nited 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. Tact* 2. Concentrations of AsOMtoa-Liko Mineral Fibers in tne Water Supplies of Selected Put Representative Commu nities in me United States.* Cm Cmhiuiiw tiftm Hwltar AliMMJ lottos Dvlttik D*iU> X-nuiCm. Ms. N York niiiaSctpBi* Sm Frescoes Sauk Inm Tieu l ; m Lmm J.7J 3.N 1.73 0 0.01 0 l*. 0*0 0.13 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."1 Inter estingly enough, fibers have been found in the glomer uli and tubules of rats exposed in inhalation chambers to synthetic fibers."* 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 turnon in the gastrointestinal tract is unknown. When fed to laboratory animals, asbestos interacts with the mucosa of the gut.;* Fibers enter cells of the mucosa and prove cytotoxic.130 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.7* 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,1,1 these studies failed to demonstrate an increase in the prevalence of tumors in the gut.,JJ',J4 The possible synergistic effects of asbestos on the induction ofintes tinal neoplasms by chemical carcinogens has also been examined.133 Intragastric administration of asbestos failed to augment tumor development in rodents fed azooxymethane. a recognized intestinal carcinogen. The carcinogenic potential ofasbestos 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 or Asbestos Tms .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 para 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 ofasbestos on health, since the characteris tics of the fiber have been fully defined in only a fewepidemiologic and experimental studies. The problem ofevaluating the effects ofdifferent types ofasbestos on health is compounded by the common practice ofcus tom blending ofvarious minerals for specific industrial applications and the use ofone type and then another, depending on availability and conditions of the market. Since the serpentine chrysolite 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 6 I 49C001S , DOW 06691 Vof 30b No. 24 ASBESTOS-ASSOCIATED DISEASES - CRAIGHEAD AND MOBSMAN I4S3 they were used widely during and immediately after the air of occupational settings in this country were World War II and are probably responsible for a sub formulated in the 1940s, it was not until 1970 that stantial proportion of the disease occurring today. federal regulations were promulgated as a result of the Much current debate centers around the question of passage of the Occupational Safety and Health Act whether alt types of asbestos possess the capacity to and the Clean Air Act. The initial standard was based induce mesothelioma. Experiments in animals yield an on the light microscopical count of fibers of a length of affirmative answer, but the results ofthis work may not 3 (tm, collected by mechanical means. A concentration be applicable to human beings, since pathogenic po of five fibers per cubic centimeter of air, averaged over tential and intrapulmonary transport of fibers are in an eight-hour period, was deemed permissible, with dependent considerations. Ofall the types, crocidolite stipulations for transient excesses above that concen is clearly the most strongly associated with the occur tration. In 1976 the contemporary standard of two rence of the tumor. But there are interesting differ ences in prevalence, related to the physical character fibers per cubic centimeter was established, and more recently a level of 0.5 fiber per cubic centimeter has HI t1 of this fiber type. For example, in Northwest Cape. been proposed. South Africa, and western Australia, mesotheliomas Is the current limit oftwo fibers per cubic centimeter occur commonly in persons with occupational or casu sufficiently rigorous to prevent disease in the future? Is I al exposure to croddolite.u The mineral mined in it appropriate to base regulation exclusively on deter these regions is composed ofrelatively long, thin fibers. minations of fibers of >5 tun when the bulk of the In contrast, mesotheliomas are rare in the Transvaal dust in air consists of fibers of a shorter length? Be of South Africa, where the crocidolite fibers are much cause standards are based on extrapolations from dau coarser. * accumulated among workers exposed to relativcly 1 Another amphibole, amosite, is associated sporadi heavy concentrations of dust in the past, predictions cally with mesothelioma, whereas the tumor rarely if must be based on analyses that assume that there are ever occurs in workers exposed to anthophyllite. Both no thresholds below which the disease fails to occur. these latter types are made up of relatively short, blunt Within the ranges usually found in the occupational i fibers. A number of studies have been conducted in setting, there appears to be linearity in the dose-re miners and millers in Quebec and Italy, where the sponse relation, at least with regard to bronchogenic serpentine chrysotiie is.extracted.,4',J* Although the carcinoma. However, the likelihood that cancer will, results are debated, the bulk of the evidence indicates occur is influenced substantially by cigarette smoking, \ that chrysotiie is not an important cause of mesotheli since the risk in the nonsmoker who has heavy expo : oma in these workers. sure to asbestos is increased only a few fold. Thus, the i However, the data from certain occupational risk for the nonsmoking asbestos worker is substantial groups, such as workers in the textile industry and ly lower than the risk for a member of the general insulators who are exposed predominantly but not ex population who smokes two or three packs ofcigarettes clusively to chrysotiie, are not as definitive. The risk each day. appears to increase as the mineral is processed or when The conclusion that asbestosis (ails to develop below dust concentrations cannot oe evaluated critically. a certain threshold dosage is based on physical exami Unfortunately, most epidemiologic studies concerned nations and radiologic studies of workers and not on i ' with this important question are clouded by uncertain pathological examinations. By these criteria, it is prob ty because of the prolonged latency' period of mesothe ably impossible to be certain whether a fibrotic lesion liomas. Considerable effort has focused on determin in the lung is due to asbestos. With mesothelioma, the t/T i ing whether the various types of asbestos differ in their data are more controversial. Although a dose-response capacity to induce bronchogenic carcinoma and fibro relation appears to exist, the threshold may be deter sis of the lung. Unfortunately, there is no good answer mined by the life span of the person exposed, because to these questions at present, since dose-related differ the latency period for these tumors is protracted. Since ences in the prevalence ofdisease have not been estab the problem cannot be answered with contemporary lished. epidemiologic and experimental approaches, it must Regulatory Considerations be resolved by practical rather than theoretical consid erations. 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 Reverences I. Mv BJ. Attorna rnymyimm mam <ntb trad kw--n Tht New Yort Tbw, IWI My 1:1- _____ _ UChlK 7CB*yoB* mamy. J. Ltcm KV. at. Aitessr. m mtmmran mom. Wahiasioii. D C.: U S. Cnom Pnauas Office. 1974. (OMEW (NIH) RiMkwm a. 7S-I4SI). 4 Sintpwn W. ot. Artnwe: Owl tepora of Ha atfxton fenemei m vOmot Undoe: Her Mamo i Sioiwery Office. I9S0. }. Schkoff U. Ut DHK. Aitnn led 4mm. New Yak: Academic Pm. 1974. 0669? 1434 THE NEW EXCUS'D JOURNAL OP MEDICINE June IT. 1982 Sehkoff U. Nmml EC. adr Kcakfc huarda of lifer-- Itpk<aai. Am VY Aad Sei 1*7* Voi. 330. *rwi. 1*12. 6110 t Bectpreund information <m luatnaaet for aikanot Wmhmpscn. DC Lnwd Siam EatuonmcmaJ Frotectioa Apane). Ofnre of Taim Juhnances. 14*0 * Timonril v. Ira NE. Dm AS. Mu--* DC. Hoik* cawof tap far eiptnmcaui purport Naoaa. 1*70 223:674. 10 Timanil v The inrnlsnm of Hm 4uan Aaa NY Ant So. 1*63: 132233-71. II Hama RL Jr. TimhmU V The mftuencc of Sbn dupe m kntp Orpoar* tma -- matnemaocsl aaomaita. la: Waken WH. ad. lakalad pammt IV. Pm 1 Otford Ptrpimon Hau. 1977.734*. i:. Wapam JC. BerryG. Skidant JW.TMacll V Theeffectsatdianfeala uo of utsessos m no Sr J Caneur 1*74; 2*2324* i) E*ana JC. I>m RJ. Holmes A. at al. Soiditaon dmdtposaieaaf nhalad Ihrout matanalt in dia nspmury ooct of dm m and us luhsequaai dearidea usinp ndwacnn ancar mrhaupni. I. LTCC enmdolMa ataestes. Eat-- Rat 1973: 6:110-201. i* Merpam A. E*aaa JC. Hoinms A. Drpoamoa aad dun-- of ofeekd Ibrous nuaanlt ta dir Ml. Sradiai mmf ndmacOM tracer irrm--CT la: WaJtoa WH. ad. Inhaled pamcka IV. Fan I. Oxford. Nrpiaaa n*at. 1*77.239-74 13. Muppenaurp BA. Boactar IB. Dial JH. 3atpas MB. Observation! a* dM leap mention af ndulad. ntaOMly msoluhk. tavmauntaaallv-mknd par- ucka. Oms. 1*11: 101*6203. 1. Kanauoa K. Iirtnci MSC. Canar RL. Roa FJC. Mipanoa af aafet-- **ns from nnaroou aaaa a a--. Br J Cancer 1*70. 2**6-106. IT Lae KF. Bama CE. GnJM FD. Wanu RD Pulmonary nipaaaa aad mmoufnooa af morpanic 60m fey admin-- upttut. Am J Fafeof. 1*11: I02JI4-2J. II. Brady AX. Hill LH. Adtaat B Jr. O'Cemar RW Chyamsk mfer-- utlulauati a nu arposMieapaonaaadmamonef i/veotmcpanelamtaad pulmonary macrephapts Am Re* Raapir Dia. 1*11: 123:676*. I Sucukt Y. Goaf J. Oao T. Phapocyoe anjvwy af tfer alveolar ep--feel ctllt pulfaeaao mWnlnsm. Am J Pmhat. 1*72 6*37341. 20 Moasmalt IT. Kctakr JB. Lay |W. Cmphcad JE. laattmioa af crondc lisa aafeaama aom feamaar laappawts mucoae m Qipao citfeara. Lat laaaat. -1977; 36-IJ!.*. :i Lppmao M. Alban R. Peterson HT Jr Tfca rvpionaJ deposition of iohakd aerosols m man. In: Wafeon WH. ad. Infcalad Particles III. Surrey. Eapland. lii BioiOan Lonaad. 1*71:103-22. Autrfeack 0. Hammond EC. Gartakcl L Olaapts at branchial apiditlaad in relation to apaetaa tmehjnp. 1*33-1*60 a. 1*70-1*77. M Enpl J Mad. 1979: 300 3114 23. .Smwoarunr BE. Kltusenaaa J. Riot DB PadwkficchaaftindmpenpW ml airways of younp cipartne smokers. N Enpl J Mad. 1974.291.7334. 24 Umfe D. Raid L. Morn* mm. (ofelai can increase and hiitorhemml cha/tpes m amis ta ms bronchial apohalmm dump aapoaiaa so lalpfeor dioiida J Famol Bacianol. 1961. *6:97-111. 23. Dowell AR. Kilfeara KH. Aw FC. Short-turn aapoaom m amo|ta dioadr: effects an pulmonary almaoutnot. compliance. and On mrfantm s.sirm. Arc* Intern Mad. 1*71: 121:7*40. 2*. E-ana MJ. Caonl U. Siapaana RJ Fmamao C. Reaml of alMalar spimrliom da mi toUonsai aspoama to NO|. Am J Fasaal. 1*73. 7017341 27 Frnrmai C. Jufeoi IT. Fanoti NJ. Matsandan R. Stapfeani RJ. Enna MJ FanoloO of pulmonary disoaaa from aapoaura le maMapandam amXu cases fnmonaa dmaida aad oaootl. Am* Emnroa Haafefe. 1*74:29J0J- 210. 21 n srr GA. Mans* RX. Himoektancal nama| aad la tor* spmadiaf af *uma* pulmonary alonlmomnop*i|U: vanafeslay ana* o|manasaiaaaM surua. J RaocoloandodMl Sac. 1*71. 23J342. 20. Biody AX. Ciu(*cad JE. Cyaaptaiaac mrioarona as psdBtoaary aucm pnapaa af eipmafla imndma. Life Ibmsi. 1*73: 32:123-32. JO. Cminaad JE. Afemfeam JL. Ond* A. as al. Tha padiolopy of ufeaam utonmad disoaaaa af IM femfa aad plaunJ camaaa. Am* FMal Lafe Mad. tin pnatL 31. GIomo SB. Thr fnmunna af Me aifeaamu feady ia 4a fem*. TMimH. 1*31. 113*6*01. 12. Suaufel Y. Chari J. Soucrum sad ds lalupniaar of l*a aMamas feady. Am J Famol. 1*69; 33:76107. 31 Gaanaiar EA. AOdinysoa 6TW. Aafeeam or firmpianus feadia*. N Ea*l 1 Mad 1*6*. 2*04*6*2. >4. tormanea of aafeanot bodies Eap Mol Famol 1*70 13:3*63* 33 Bipnoa J. Com J. Bonnaud G. Jaurand MC. Dolour C. Ffesdm* MC Inaidanca of pulmonary farruyinout femlrn m Fraaca. Emnroa Rat. 1970 34MM2 30. Cfeurp AM. Waraocfe ML. Asfeanm ml odrar fetrupmous kodiat: Oa* famanon aad cluneal npmVanra Am J Fadnd. 19(1. 102:447-36. 37 Gnat F. Cralky U. 4aTraviila RTF "Askarnot* kodma dm maapacinciry Am lad Hyp Assoc J. 1*67. 2tJ4|.2. II. Churp A. Pulmonarv aaattm burdaa m pamnti anm ptasdil plapima. Am Rav Rcaprr Du 1911: 123 Suppl: 133. afeamcr 3* Satuauaa F. Fandsmara A. Bipnaa J. Mone*aua G. Parkardai J. Beaaadd G. Tnpopraplue Oinnbuuon af nhaiim 6km feuaua kmp ia rtlaikm m occupational aad nea ocnipauonal capoasot. la: Wataa WH. ad. laaaled parnclaa IV. Fan 2. Otford Farpamoa Fraas. 1*77:433-46. 40. Millar A. Tcimata AS. Lanpar AM. SaJitofT U fiiknurmrepinl aadao- taa dfeata and dnaaaa N Enpl J Mod 1973; 29111*3. *1 Hard* HL. Submicreacopieal aibttMi Ikon aad diaaaaa. N Enpl J kfad. 1*73:2*111** 42. Bants F. Allison AC. AcUrmaa J. luRtrlSaid A. Wipiama S. Aakaam mducas salara** mlaaaa af lyaaomal asuymtt Aon mononuctaar pAa*o> rytat Nanua. 1*74; 231*23-3 43. HappWuoa AC. Srylct JA. Aeonry of a macsopkapa farm a collapee formation fey silica .Naam. 1*67: 214:321-2. 44 Cnipkcad JE. India- SJ. Moatnum BT. Camp--w soadias on 6w spam. 1*10. 34:37.0*. 43. Kannpson J$. Allison AC. Badami DV Mineral Ikon: chemical, pfeyra chemical and ktolopscal prop--a. Ad* Aaroiaeol Qumodur. 1*73: 112*1-402. Wtlad* MR. Gaumv KX. Sal*a(|io JE. Acovaudo of *e aJumaoMcamplameoi pathway and pamnooa of ahaoiataaua faoora ky atkaana. J AJlarpy Oin Immunol. 1977.1021621 47. Dodaon XF. Williama MG Jr. Hont GA. Early mponeofBoa aaway colli dispamm a-ny analmi. lamp. 1*10 137:143-34 41. Hut FM. Richams RJ Biochcmal allin af aakaaafam mmarala ao luap MreMaa cuhum. Br J Eap Fit/iol. I *71: 37:211-3. Richards RJ. Jacee* F Li|hi mjcrtncopu srudmon the effaesa afrkn seats IIfeedot and Itm plait at dm morpholep) and mnculm tomoaoa df cuhurtd Eunp IbmMaaa. En*ooa Roa. 1*76: 11:112-21. 30. Maurman LO. Asbrnos kodma and pleural ptapom at a HamaO smses af autopsy cases Acu Pathol Mmsokwl Seand. 1*66: Suppl 111:1-107. ' 31. Rohasta GH. The pedioto(y of panetal ptesoil piapuaa. J dip Fadml. 1*71: ' 2434633. 31 Maurman LO. Flaunl Ibrocalcila plaques and asbeitna aapnaum. Ennioa Rea 1961: 2:3646 33. MaaaooS-B. RmppnstT. FWunl plapuaa and aspcaioc ta atfetnga. ScaiM J Raspv Dit |Suppl!- >970. 73:MI. 34. Gib6t GW. Euoiops of ptaunl calciliman: a nudy of Quthar rtr)uaiH iikeana miners and millers. Am* En*dn Heafeh. 1*79; 34:7613. 33. Hilleidal G. Lindpen A. Flaunl plapuea: comtlaooa of lutapiy 6adupt to radiopaphm ladinps and owvpaiionil ktaaory. Ear J Ra^ Du. 19*0: *1:316*. 36. Heunhana DO'S. Usaef L. Rmhardaon FC. Hyaline and cakilc plaiail plaques as an mdea af aaposun ta aafeanot: a study of ndiolofseal aad pauiolofmal faanots of 100 caaot umt a oauudenuen afap--uotopy. Br MadJ. 1966: 1:106674. 37. Rafemtea JJ. Flaunl plaques tad iptouc ctpaulm sclerosis m adult Rule autoptits. Amb Flthdl. 1971 *3:11622. 31. Hmaafe J. Lwpt salt tandaaet af cfeaaia--a pleinl ckanpa ia cm- tana af dm saoat sacoan af dm toamr JiMave tepm. Roafel Tkfeak Namucacfe Film. 1962: 22*03-9 39. Naonul M. Tnppf F ftavalenee af phtail caktfcaoaa ia persons, as- Environ Rat. 1971 3.2166. 10. BimlkevT. Michattova L. Asfeasaat a afdm soil soda ssfeestosit. Envooa Ras 1970: 3 *4631. 61 Artvmli M. 8sn Y! Maiipsiant masadmliamm in a maafl Ulapt ia *a AiutehM septaa of Tuna* an apidamialaim soufy J No* Caoa lam. 1*7*; *3:17-21 61 Godum MC. Japaoc J. Asfeasua and asm--tanim. Em-- Rot. 1*70. 3.3*1-416. 63 Acfetsoa ED. Gardner MJ. Matothclionu aad cspoturn to mua-- of chrysctilc aad anpfeiOsM aafeasaoa. Aich Emn-- HaaMi. 1979.34 240- 64. EfencsFC. Mcsodulmmaa.maamah.aadaumm-- mamadlba.Theroa. HtO: 33:3*1-3. 63. Wapnar K. Stepps CA. Matchaad 9. Dilfima p--M --li-- md asfeasiot captnat m North Warn Capa Fltrvma. Br J hd Mad. I960; 17.2*0-71. ** WWwuBF. SeaoJ. GnnuhawM Ralanomhip karwaaa aaeup-- aad arfeaaid Ifen ooamat of dm kmp m patmaoi -- pleural man--liams. kmp caacar. and admr disaaam. Tkorma. 1977: 21377-16. *7. EpkrGR.FiuGmkldMX.GaaaatarEA.OinapaaCl.Aaku-- ml-- dia-- bom hmmckoM aaposun. Rmpomna. I*60. J9:229-40. *B. Scbkaff U. Lilm R. Nmho-- WJ. Ashe-- dnaaaa m Ua-- Sum ktpyards la:*, pp 293-JII. oo --4 C3 C_~ DOU 06693 Vol. 306 No. 24 ASBESTOS*ASSOCIATED DISEASES -- CRAIGHEAD AND MOSSMAN MSS 49. Ntebpaia ML. lory 0. hwlironaaaf manala? frog --nOnhil mmn a aabnn faonr? ratal Er J Id Md. ink U: 147-51. 10. Sumon MF. Int C. Merhiamra at atnoddmi tducima null dn ad Skma pirn J Sal Cucb Iml 1972 4:797-t:i. 71. Samoa MF. Layard M. Ttftm A. Miller E. Ml) M. Kant E. Camaefe* non? ef 6braa (laaa: pkunl napem a* m a itiaood io (Ibar Ina. rat. J Nd Cara lad. 1977; 51217403. 72 Mremne LO. Kmluaa K. Hat amt M. Morula? ad aerMiiy aaaaf the rahia| pupulaina of amopayibai aatamaa amn fiaiad. Er J Id Mai mi; >1:105-12. TJ. McOoaaM AD. McOdaM JC. Haintiilian afar craodelk dnaf M> maak nasfacaat. Earaoa Raa. mt; 17:3404. 74. McDoaaM AD. Mrf>mtli11C. Malipi Caaea. 1990. 44:1650*6. TJ Lppmaaa M. Yam DO. Alban EE. Drpourn. t at idald poseka. kJIdMM. I960: 5721742 T*. AuaromO. Comae AS. GartnkelL. Fob* VR.Kiilow HD. Hammed EC. hoacactefmbembedMiuianmattadmdabmt. Om. IMO; TT:1JJ*7. 7T. Sebaaaea F. Maaaa R. Itpoe J. Raeomy af mftad aabaataa Iban tad he taatraaaaaaaai lympb m fin Earaoa Raa. IMO; 22201*10. . Wamiaka GE. Iff! HA. Sad MN. hueworn af aoiaak aaaaaa bp attain paracka. Lab laraaa. IMS; 14 2024-JJ. TO. lamed MC. Oifooa i. Sabaaaas F. Oaa J. Laadaat af ebryaeok aahaa* mai ni|fii|a Earaoa Ra. ml; |4:liS-Si. lend M-C. Kepiaa K. Thalia 1. Fiacbaa M-C. Bataadia l*F. Bif J. ftatocynk af rhryaeak IbnbypkaolmainlMliilammi Am I Fabal. 1979: 94229*1*. II. Ram KT. WapaalC. Eraaa FH. Tha laapoaaa af ha calBBt aabaan. Nam. im DU4.I. C. DoO R. Moratory tarn hat earn a aabaan arataa. Ir 1 Id Mad. 1995; 1211*4. U. Eaaarln F. da Code F. Haadaraa V. Rtipncry caaam ia iiltnaa occupaooaal aipnaiaaa aaaeat mud aabaan mhait. Ir 1 Id Mad. inj. JO: 102*4. 64. Sahheff U, Hammed EC. Oarf I. Omaaforigr af taimia ubtan Arch Earaoa Head. I9Q; 25:104. tJ. McDonald 1C LiddO FCK. Cibba GW, Eytaaa GE. McDoaald AD. Ida aipotun ad morality a chryiouk euaaf. 1910-75. Ir J lad Mad. IMO; *7:11*24. H. Scbkefftf. KaaaadEC. SaidaaaH. Loeacyof aabaan diataaaaaeat -----*- ratal a ma Laud San ad Canada. Caaea. IMO; 44:27J4-aO. *7. la W|. Kanafn IM. Talada A. Koorar R. Haab CW Ir. Fnaaaai IF ft. Loaf caaea aAa imphi)maB atopyoda dm| Warid Wa 0. N Ea|l I Md. ini; 299:6204. n. Crrar-Stuu CK. The nlancnabip bcrncoa tthtinii ad am Chao. IMO: TIJIOI. e. Salikaff I. ladar Ra. lata ME. Qa| I. Homed EC. moploote. Am I Mad. IMT: 42:4*746 o. Kaaaanam M. Choi I. Fathom*? of carenooai of the hm| ram aabaan cipoom. Caaea. 19T2; 30:14-21. i. Whimll F. Newham ML. Imnco DR. A nd? of ho hierlotical eaO typm of hm| caaea in woatm teihriaf ftom aabaemu m ma Land Kiatdom. Ir I Id Md. 19T4; 11J96503. n. Butrina ft. Handenao V. Type of aabaan ad mpinmq Maata aibanat ladaao?. Arab Earaoa Head. 1973. 27212*7. . SciikefT D. Hammed EC. Chat I- Aabaan eapeam. tonkin, ad aaoplaaaa. 1AMA. I9M; 204:104*10. 94 SahhaffB.SmdmaaH. Hammed EC MonaB?ogaeaafciprana nab* of ament ********* aaboaaea factory woman. I Nall Caan lam. 1900; 69207* lJ. ft. Itrr? G. Savhtraa ML. Teat M Combaii aflecn af a t9T2 2416.9. M. Maoamd LO. Krrikm R. Hakaaa M. la:`.M 491*4. 97. Sanaa R. lihraot ad hmt M. 99. > IL. Tam . 1911; 20121S4. AmbFudi. 1944; 31233*44. Sea* 100. M. Tom? Bd. Aabaan ad fin ihm m bactnl a Im. 1971; 43:15944. 101. Hiaaaf SL. aahena am raa Chant hmt calk. Muua Raa. 1919; 66245*74. 102 Fnct-loam Ml. Gebbufl C. ChiHtharliti M. The faac tffa of c Man Rat. 1M0: 79231*4. I0J. Strack A. Seabn|M M. ladnrnoa of < hamua edit b? tiptaun mhan Ibra. Non. IMS; 397244. 104. Moumd IT. Laadcaan IM. Cnifhad IE. Aabaan aabtbaa pepann of a claaaml aaom pnramr aa hamaa otebeal tpubabai calk. Mac Am Aim Caaea Rm Am Sac CNa Oacai IMt; 22129. IDS. Mnaimoa IT. CmpbtdJE. MacFhmaa IV Aabctn-u ebatfoa otaa cubtea af hamaa cachet. latubtoao a? ira?l can. Soon. IMO; 207:311*3. 106. Woodworm CW. Mam IT. Outbid IE. fninpainvo affara af 6breua ad aaalbram miaanlt aa mill ad lipeacmi Earaoa laa. (ia 101. T. Halhroo FA. Cni|had IE. Sawnland af Na**X* ATFm aesra? ia atrhttl tpnbdtoil ctlla after tiponm m craaddfau aabera. 1 Cell Ed. 1979; S3: Suppi 211a man. too. Moaunae IT. Landnmaa IM. Cr*i|had IE. Aibem < mine dacamaa?lm (OOO aesra? a l 1 Cell Id. 1910: 17: Suppi: 307a. abaoocL 101. LakewKi JR. leraa DR. laaae(a)p)iRaa uptake imnr Sva efface af tdinrpim of bcaao|e|pyan m aabaan ad Doe-ltraa a pamealan. Cham Id Imanci I9R3.29129-lt. 10. *'------ *- '--inrnil rr llirhaamm nf a rasa Rea INI: 25:36940. 111. Atmsp H. Kama CC. Seem GD, ScQort IK. Scbofa FW. Tin RF. Mwtbnliam af [*7f1baaae(e)p?>cai b? caimmd boon hmba m ad aaad bmaa lailmnaar? alveolar marmpbatii. Lab tavern. 1971; 31211. 2d. 112 Elam FC. Siiapwe MIC. InanUnne ratin a Malm. 3. Mcrabn 19dfr. 66. Er J Id Md. mi; 212636 113. Hammed EC. Sctikdffll. Chat 1. Naapliaiiameat maaladderabmib da Iliad Sun earn ipaaal itfuraa to min iimtaiinal aaadama. Aaa NY Aed to. 1965; 112519-25. 114. SaliieffU. Hammond EC. Multiple nakfaoan ia nolop ofmraonca- uJ cancer. Ia: Fratuanti IF. d. Fineaa at hi|h nak of eaacar m dimacb m caaea caelof? ad coosol. New Yen. irtdtmic Flam. 1975:46743. 11J. Sclikeff II. Hammed EC. Scidmaa H. Manila? taptrioei af iualiM wun ia At Urntad Sian md Canada. I94J.I976. Im'. yp. 91*116. 116. Milla A*. Aabaan 4bn dm ad fraw'daaaaal auli|aaacn. Ravin ------------- * ~|--'------------- ----rr`iitirmlii inennrtia 1971; )I2>. in. Cook FM. Glau GE. Tucker IH. Aahaadaim a Sen sad mattunmrw of hifb c Socaca 1974: 1I5U3-3. in. Cook FM. Olaea GF. Ia|tnad miaanl iban: i Scmm. 1979; 204:I9J*!M. 119. Cunaatham KM. Mood* CA. Laraace CA. hall hart RS. rkima effaro of tattaad aabaan ia ma. Arch Earaoa Caara Tamdi 1977; 4207*13. 120. Jamba R. Heapbr?! 1. Dodfm KS. RJcharda Rl. U|ta m------ 1 mooacapa taidiaa of da m dtfeasva son feUewtaf praleatod ad ba? torn taiaaoea af cbr?aaolt aaamn. It 1 Eap Food. 1971:59:443-53. 121. Gibtl W. Laba Xh. Han KH. WildmGF. Hafftnaaa F. Tdup talk L'aanuebuB|ta bbanaa kaaicmtm Wiriamf raa I nil am enkr Aohabn. Arab CnetmMenek. 1976; 44c4Jl42. IS. Gnu P. Hark? RA. Swtabom LM. Dan IMC. Gnra Wl. bftam nuitoil ibrrt: 6a do? ptaatna aam a taut rararl Amb laraaa Haakb.. W*. 29 341*7. IS. Sam WE. Hahan DO. Sabtl HI. Frai CT. Damia TE. Hand af eapoimtaitl tatmala 6riakiat wear wab ad latwa amaut aabaan ad ma miaanl parocki. J Earaoa Fdd Toucel. I960; JUMP. 277* 300. 124. **"-* ----- *' --* ----- , liiiij ,f aabaan. Ad NY AcdSct. 1963: 132:45641. IS. WardJM.FinakAL. Weak M.DararD.Tanaa RE. lattndaabnnaad mnaaal ninatnina 1344 mu. 1 Earaoa Fmai TaudL IMO; 3(5M):301*I2 IS. RubumCF. PialaoG.NeehemML. ScuaeaG.AratmGA. Mm? R. Manila? of rtrrvoak mbera wntkmi a da lakaiaao Mm. No. kli). Ir 1 Id Mad. 1979; 36117-94. 2iS.Cfl01S.- ai DOW 06694 LSTUU05U3 1480 THE NEW ENGLAND JOURNAL OF MEDICINE June 17. 1903 The New England Journal of Medicine Official Or*in of TV Manachtuctu Medical Soartv fern W. Wadman. M.D. Pnniim William B. Munacr. M.D. Charln S. Atnoroiino. Jr. uuin In^mM Euntfur Srrman Fi-blomu M'ksiy r tm( Committo on Pi-aucanoNt or tn( MAflacNuum Mcoicaj. Soarrv James F. McDoooufh. M.D.. Ckainaaa John I. Sandtoa, M.D. John C. Avm. M.D. William H. Sweet. M.D.. Die William B. Schwarts. M.D. Frank E. Binby, Jr., M.D. Samuel K- Siewan. M.D. Arnold S. Reiman. M.D-. Eorroa Marcia Anjtll. M.D.. Duvrv Eorroa Edmn W. SaUman. M.D.. DcrvTr Eorroa Aaaoaart Eorroas Jane F. Deifortn. M.D. Nortnan K. Hollenberf. M.D.. Ph D. Ronald A. Mail. M.D. Morton N. Swam. M.D. Franklin H. Epstein. M.D. Franda D. Moore. M.D.. Book Renew- Eorroa John C. Bailar. Ill, M.D.. Stathtical Coniuitakt Joseph J. Elia. Jr.. Managcs or Eotroauk Ortaanona Emily S. Boro, Assistant Eorroa Marlene A. Thayer. EorroaiAL Once Manaus Eorroaut. Boaso Richard H. EfdahL M.D. Paul Calabresi. M.D. Park Gerald. M.D. Aram V. Chobanian. M.D. Joseph B. Martin. M.D. John T. Hamneton. M.D. Robert J. Maver. M.D. Homayoun Kaaemi. M.D. Frederick Naftoiin. M.D. Kenneth McIntosh. M.D. Kenneth J. Rothman. Dr.P H. David G. Nathan. M.D. Kurt J. Bloch. M.D Lsw-rracr G. Ratss. M.D. Thomas J. Rvan. M.D. John K. lelrhart. Setcut. CoaauroNOCNT Frederick Bowies. III. Discerns or Bvsmus OruATlONS Ronald H. Brown. Manacis or Aovta-nstNO 0 MAaam.ee William H. Paiee. Makacis or PaoocenoN 0 DtSTatatmox Milton C. Pup. Jr.. Conhitant Panseacnva amhon rhould eanauli "Information for AuiAon." winch appean m the let awe d every reliuue and Ml be obtained from the JunultAo. .kartells with onpiaal manrial are accept'd V cotwdcration with ike mOeniandme that cacept for abetnOK an pan of the Oau has been pu^ btlwd. r wii be rubnuticd for pubhevapa efoewbete. before appeanne m thw Jtmmtl. MsrtaiAi pnmed m ibe Anr Jmnai ifMttiam it catered b> coptneht. TbcJkona/doct apt bold luetfiesponnhlc foe ttateptema mode by am nwnfowr. Nonets tbauid be rent at ban JO dan briber publication due. AimoucM ad adieruuaf autenal accepted rtpeeled to conform to ethw cal medical tmndaedt. acceptancedoes act uaptvtadonemenibv ibeJmmtl. Strarrrr. The Jmrul dam am stack irpnaa. sad teprutta cf tit MGH CPU an am available. St-cecalmo* Pun* USA: M per year Imterar. teudtnu SIS per rear, ttudrmi ISO per vear) Canada lU-S. fonds onh-i: lM per tear imemt. trudmia MS per win tudtnu Ml per irsr; Mail chcckt M Subacnptam Pauaeau. P O. Boa 4772. lotion. MA 0912 Cotmaui Omcu: Id Skauwck St.. Buuon. MA 021 IS. Bt-mcar cue Scmcatmo* Orncxa- 1177 Commonwealth At*.. Batten. MA 02134. EXPOSURE TO ASBESTOS AND HUMAN DISEASE During the past two decades. iJI health resulting from exposure to asbestos has been the subject of in tensive observation and research* -- probably more intensive than research on any other environmental agent.2 In the most direct target organ, the lung, and in iu 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 (he continued use of this mineral in today's complex technologic world.1 The review by Craighead and Mossman of the pathogenesis of asbestos-related diseases in this issue of the Jtunul * 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,2 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 with asbes tos exposure.* 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 ofthe lung is primarily in the form of uncoatcd 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 hygiene*; 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 chrysotiie 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 I1 I I l I l DOW 06695 Vol. M6 No 24 EOtTOMAL 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 of this 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 docs 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.13 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 an 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 clear 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 hypoth esis for the pathogenesis ofpleural plaques is needed to explain all these features.'4 Perhaps even more 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 patholbgists in the 19th century -- long before major commercial exploration of the asbestos minerals13 -- and there is little evidence even today that asbestos is responsible for many cases in men or women outside industrial centers.313 What are described in the pres ent review as "casual" exposures (i.e., usually domes tic or neighborhood) are 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.' 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 in clinical counterpart,' although there is no evidence about whether these ab normalities arc 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, croddolite 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.3 by the difficulty ofsorting out the rela tive contributions of exposure (duration, level, and panicle 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 dear 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 croadolite in the United Kingdom) was found in the lungs of the cases, whereas chrvsotile contents were similar in cases and controls.3'1* In a study of chrysotile miners in Quebec, almost as much tremolite (an amphibole contaminating some of the mined rock deposits) was found in the lungs as chryso tile, although the latter was dearly the main environ mental contaminant.17 These results are consistent with what has long been believed on the basis of more tenuous evidence -- that there is preferential clear ance ofchrysotile, as compared with amphibole fibers, from body tissues and that this may contribute to the differences in the pathogenic potential of the minerals. Epidemiologic evidence for a fiber gradient in pathogenic potential is strongest for mesothelioma, with aocidolite 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 ofwhich depend mainly on their physical characteristics, in cluding their aerodynamic properties. Partide 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 partides 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- 1483 THE .NEW ENGLAND JOURNAL MEDICINE June 17. I M3 rant is that health risks in relation to exposure to asbes tos vary according to environmental factors. Some of these factors (such as exposure dose, particle site, and fiber type) are known, but there are undoubtedly oth ers not yet recognised. Host characteristics probably also influence the response to exposure. Thus, in con sidering the individual patient with a disease known to be related to asbestos exposure, the wise clinician should avoid regarding any particular exposure as too short, too remote, or at too low a level (even ifenviron mental counts were in compliance with the present regulations) to have accounted for the disease. Assess 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 able to asbestos exposure may be estimated from expo sure-response data,** which for practical purposes can probably be assumed to be linear, provided that the data available are applicable to the industry in which the subject was employed. Finally, the unpredictable clinical course of these diseases demands vigilance by the clinician with respect to past exposures, and the most powerful indicator remains the careful, complete, and precise occupational history.7 Whether the dust concentrations permitted by cur rent regulations will in fact eliminate the future risk of asbestosis, as Craighead and Mossman suggest,4 re mains to be established. Similar suggestions in the 1930s proved to be premature. Evaluation of the im pact of present controls on health issues is an urgent matter for research. Furthermore, a total ban on use seems unlikely in technologic societies,7 in which it may be considered preferable to retain these versatile minerals for certain uses. Until it is established that asbestos substitutes do not carry health risks," re search into the mechanisms by which asbestos parti cles produce ill health should be vigorously pursued. McGill Cmaut Monacal. PQ HJA ZB*. Canola ,, ,_ MaRGARET R. BeCKLAKE, M.D. Rirauxas I. Atlitim CD. GmObb M. Ci--i tanana -- On it--lit cmana la: McOoaaM 1C. al. Racial aiT-aarci acoaoaooaaJ butt. IbiMurffi: Clmidall bnQiiiai. INI:237>44. I- Prat GA. foan BJ. Sam Cant m aaOanaa Oanaaa. Nam Yaric GactaaR STPM arm. 1M0-.AI.K1I. ]. Gloat D. AaOaaaaa-- cm a kt aaaS uMy? Be MaS 1. IM1: ZUJSI-3. fucfTtafl J Mat. IW1 JOfciaaMSTM"*" ,,t,r,T u,"ri,,rf 5 McOoaaM JC. HM-- Ml--M Oaaaac: an rqifiiifULiliirel 1C-- la: w(|nar JC. at I--real aft-- at -- lam Lyea: tn--nnaal A|*acr far Rciccica aa Caa--. ISRttSfTMOI. (IaRC mamtt patbea- aca m. Ml. . I LMdellO A-- aal --Ik butt. Ttana. IMI: 34:241-4 T. Beeblebe MR. Aala-- -- -- at Me Mat *M ffaun: carnal cluneal ana. Am In Reoyv Die. in pnml. S. Ciai|haat JE. AOm-- JL. Oauf A. t al TM platan at -- aaion-- Onaaaai effae leap aM ptianl ermaa. Aw* PMwIUa Mat, ir mail. * --11 ----"**-- y-i-1-1--'--*- -- 1-- ClaiuAeama at ntfjofncm at pieii--uoiei. Geneva: bucmauonal LaOour Office. IMO:1At. ifli i miaiieial butt aaO lefety tana ao. Ml. 10. Moryaa A. HoOnet A. Cnnreamnnui -- dioitw-- at coand anC aacoai. ad aianiM Mai <* tte km-- huiy Br I Ind Mat. IMO. 37.23-32. 11. Ones AM. Wamoct ML. AiOeaoa -- cuter lTu|mouf boCica: tbaa fauna-- ant ttiaicai upuAcance Ant I PmM IMI. lOJ aat.j* 12. "-- rT---------1 --------r i--------i-------**---------u aitaiitm loftcal 4--ten. I. MtotoCx. con-- anioiili -- tipown cooOioooa. Bel lat Met. 1471. 33:121.34 13. Bryn R. Ptautznaki M. Maaae S. a al. A---- loaf a>ay m ta Urp moatl: Me lanal alt--iot. Ear-- Rea. la pmal. le. Hiltartai G. Tke petMftntM at pleml pfa--a -- yuli--aiy ufciaiTiti pamOiinel -- aapouiOtliota. Ear I Rnotr 0. IMO. (1:124.31. 13. McOoaaM JC. McOa-- AO Epamualon at n--u --a amtmaun a--, hat Mat. 1477; 6 *26-** IS. McOoaaM AD. McOoaaM JC. Pooler PO Mmanl fibre con--of ate I-- in n--iial a--n a Mom America. Ana Occup Hjr| la pmal. 17. Rowlaada N. GibOa GW, McOoaaM AO Aaacuaa (ban a Pta luayi at cfayiaoie amen -- atttan -- a praJuanury report Ana Occup Hy| In pmil. II. Emerltor PC. An--lay n da face at aaccnaaay. Ckta. IMO: 71: Suppl IAopaai.377.4 14. Wcyacr JC. Clam PC. The ananl fibre prcMcat. la: McOoaaM JC. aa. Receai aatcaiei a accepenatat heetui. rilinftirin fteeraill I neiyinaa IMI:M3. SOUNDING BOARDS AFTER LAETRILE, WHAT? Laetrile wrs moribund before Moertel et al. laid it to rest with the recent report of their prospective clini cal trial.1-* It had been replaced in popularity by aa approach unusual in the annals of unorthodox cancer therapy -- one that represents more of a challenge than did Laetrile or its predecessors. This is the "natu ral" approach to malignant disease, which emphasizes cure through purification and the body's capacity to heal itself. The currently popular alternative approach is rooted in homeopathic and naturopathic beliefs, Indian and Oriental philosophy, and 19th-century theories of intestinal putrefaction. Promoters often evoke the time-worn conspiracy dogma, which states that the medical system, the Food and Drug Adminis tration, and the federal government withhold true cures from the public, thereby perpetuating therapeu tically useless and biologically harmful cancer treatmenu in order to further the Establishment's econom ic interesu.*-4 Alternative cancer therapies in vogue today differ importantly from Laetrile and from other unproved remedies of the past. Previous unoruiodox treatmenu were "medicines" or at least "medicinal." Examples were Dr. Bye's Combination Oil Cure, Dr. Chamlee's remedy for removing cancer viruses from the blood, Dr. Leach's Cancerol, Dr. Koch's glyoxylidc, and manv others that attained great prominence in their day.1 They came in ampules, vials, or syringes, mim icking standard medications, and they were sold and administered in the usual clinical fashion by people in white coau. Today's alternative remedies explicitly reject associ ation with standard treatments, environmenu, and paraphernalia. These are anti-medicines, emphasizing purifleation through dietary regimens, detoxification DOW O6697