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-st.-mrtaMai- aantigf s,i,M i lap The New England sD Jir.t Journal of Medicine ^ la 1U1 at TL HUT ENGLAND JOSUUI. OF JCEDICINE AMD SDBGEKY ' VOLUME 306JUNE 17, 1982NUMBER 24 Original Articles Family Management in die Prevention of Exacerbations of Schizophrenia: A Controlled Study............................ -......... I. R. H. Falloon, J. L. Boyd, C. W. McGill, j. Razam, h. b. Mou, and a m. gildekman 14S7 The Interaction ofAlj^ThJsemia and _D. H,,R.o,,Hmigogzsy',gBo. u_Es. A.Slidcrkildeg-eC, Je,.llrLDamisse.J,a. s_Be. .C_...l.e..g..g., D.J. Weatherall, R.J. Hayes, Y. Grandson, Y. Lowrie, K. P. Mason, B. E. Serjeant, and G. R. Serjeant 1441 Editorial Exposure to Asbestos and Human Disease........................................................... M. R. Becklake 1480 Sounding Boards After Uetrile, What?.......................................... B. R. Cassleth A Future Shortage of Residency Training Positions: Dilemma or Opportunity?... d a Kindio and n. c. Dunham 1482 1484 The Pathogenesis of Asbestos-AssocISSS Diseases........................................................ J. E. Craighead and B. T. Mossman --~ --------- -- Medical Intelligence Drug Therapy: Atenolol and Timolol, Two New Systemic 0-Adrenoceptor .J Antagonists.................................................. W. H. Frbhman _., . -- , T,. Discordant Cortisol Response to Exogenous ACTH and Insulin-Induced Hypoglycemia in Patients with Pituitary Disease.............................. G. C. Borst, H. J. Miciienfelder, and J. T. O'Brian Intraventricular Hemorrhage in the Premature Infant: A Changing Outlook ............................................................ S. Shixnar, R. A. Moltem, K. Gammon, B.J. D'Souza,J . Altman, and J . M. Freeman Heterozygote Detection in Cystinosis, ?S2.*S2S?S!!?.r................. Correspondence Haanl of Ophthalmic Timolol.............................. 1446 J Aplastic Anemia after Parenteral Chloramphenicol: Warning Renewed........... Thrombosis after Pulmonary-Artery .................... iodo 1462 1464 ,<*' 1468 Factitious Sckle-Cell Trait .................................... Levels ."Inflammatory Bowel Disease ... Thyrotropin-Releasing Hormone....................... Pouib|e Alteration of Metronidazole Metabolism by Phenobarbital____ Y................................................ Case 7-1982: Sarcoidosis and Cancer.................... R,,io of Arm Span to Height not Usually Increased in Klinefelter's Syndrome............. Visualization of "Cold" Thyroid Nodules with Nonradioactive Iodine................................... A Good Little Antacid............................................... Musical Bottles....................................................... Do Water Pipes Prevent Transmission of Fungi from Contaminated Marijuana?..................... Methadone Maintenance Programs....................... Financing Long-Term Care...................................... Computerized Matching Algorithm for ThirdYear Medical-School Courses....................... Lack of Interpersonal Communication in Programmed Learning................................... 1485 1486 i486 1487 1488 1488 1490 1490 1490 1491 1492 1492 1492 1493 1494 1495 1495 H R. Steinherz, F. Tietze, T. Triciie, a. Modesti, VV. A. Gaul, and J. D. Sciiulman Case Records of the Massachusetts General Hospital 1 A 51-Year-Old Woman with Chronic Asthma and Hemoptysis........................ 1471 N. M. Braslow and E. J. Mark Books Received................................................ 1499 Notices................................................................ Special Report _w The Modular Medical Integrated Curriculum: An Innovation in Medical Education............................... A. J. Cvlri.rt, E. H. Blaustein, andJ, l. Sandson 1501 1502 Owned, Published, and Copyright**!, 1982, by the Massachusetts Medical Society Tat Nrw England Journal o MtntciNr (ISSN is published urekK fi.,m editorial ofiitci at 10 Shauurk Street. Boston, MA 02115. Subscription pntr S4H 00 |rr year. Scmi*t |.t\ postage p.nd at Boston and ai additional mnilnn* ofhers POSTMASTER. Send aiUlroi chain**:* to 1172 lanumoimraUh A\rnue. Boston, MA 02134 NEJMAG 306(24) 1437-1504 (1982) DU 038546 B*WWW'milWMIBW'MWBBIBItiMMMMiiWWMHW-ll BIMBmfffglffSi 14-16 THE NEW ENGLANDJOURNAL OF MEI)If:lNE June 17, 1082 3, N*ttC. Failure of the n-<hi*ieiiiu gene >*crered reuoily of ickk celt anemia. Blood. 1978; 51:1163-8, 6. Huiunan THJ. Siekic cell anemia as a syndrome: a review of diagnostic features. Am i Hcmatoi. 1979; 6:173-84. 7. Felice AE. Webber B. Miller A. et al. The zvvkivlionof tickle cdl anctnsa with betenuygoua and homozygous a-thalaasemia-2; in vitro HB dram synthesis. Ami Hemalol. 1979;691-106. I. Powars DR. Schroeder WA. Weiss JN. Chan LS. Aien SP. Lack of ioftoence of fetal hemoglobin levels or erythrocyte indices on the severity of sickle cell anemia, i Clin Invest. 1980; 65:732-40. 9. Ahay C, Gravely ME. Joseph BR. Williams DF. Atpha-thalassemia-2 and die variability of hematological values in children with sickle cell anemia. Pcdtatr Res. 1981; 15:1093-6. 10. Embury SH. Dozy AM. Miller J. et al. Concurrent sickle-cell anemia and -thalassemia: affect on severity of anemia. N Eagl J Med. 1982; 306:2704. 11. Higgs DR. Pressley L. Serjeant GR. Clegg JB. Weatherall DI. The generics and molecular basis of alpha dulittarmia in assoriatioa with HbS inJamaican Negroes. Br J Haematol. 19(1; 47:43-56. 12. Serjeant GR. Serjeant BE. Milner PF. The irreversibly tickled cell; a deseruom of haemolysis ia tackle cell anaemia. Br ] Haematol. 1969; 17327- 33. 13. Lathe GH.Ruthven CRJ. Facson affecting die rase of coupling of bilirubin and conjugated biitrubts m the van den Bcrgh rcactxxi. i CUa Pathol. 1958; 11:155-61. 14. Millard DP. Mason K. Serjeant BE. Serjeant GR. Comparison of haemsao- logical features ofthe fi 0 and ft* thalassaemia ttaits hi Jamaican Negtoa. Br J Haematol. 1977; 36:161-70. 15. Bctke K. Marti HR, Schlicht 1. Estimation of small perrentagrt of foetal haemoglobin. Nature. 1959: 184:1877-8. 16. Serjeant GR. Higgs DR. Aldndge B. Hayes RJ. Weatherall DJ. Alpha dialasscmia and homozygous sickle cell disease. In: Brewer GJ.ed. The red cell. New York: Alan R List. 1980.781-6. 17. Sewell A. Millard D. Serjeant GR. Use interaction of alpha thilaararmis. -with SS disease. In: Brewer GJ. ed. The rod celt. New York: AJaa R Liss. 197893-102. It. Bsesknv NE. Day NE. Statistical methods of cancer research. VoL l .Lyon: learnt stain rl Ageney for Research on Cancer, 1980:162-76. 19. Tanner JM. Whnchiwse RH. Clinical longitudinal standarda for height, eight, height vekreity. weight velocity, and the stages of puberty. Arch Dis Child 1976:51:170-9. 20. Higgs DR. Pressley L. Clegg JB. et al. Detection of alpha thalassaemia in Negro infants. Br J Haematol. 1980:46:39-46. 21. Noguchi CT. Schechtct AN. The muaccnutar polymerization of sickle hemoglobin aad its relevance to sickle cell discaie Blood. 19(1; 58:1057- 68. 22- SaakitvsM. Gibbs WN. Milner PF. Betties IF. Erythrocyte Hb-S concentra tion: an impunam feciur ia tbe knv oxygen affinity of Mood in sickle cell anemia. J dm Invest. 1973:52:422-32. 20. May A. Hnehns ER. The coneeiaration dependence ofdseigygcn affinity of haamoglobio S. Br I Haematol. 1975: 30917-35. 24. Dover GJ. Boyer SH. Characbc S. Ikisczrlrnaa K. Individual variation io the produetioa and aorvivai of F cell* ia aickk-ccd disease. N Engl J Med. 1978; 299:1428-35. 25. Pimbrey ME. Wood WG. Weadrend DJ. tariae RP. Feu! haemoglobin production and die sickle gene in We Mam nf msfent Saudi Arabia. Br J Haesmsol. 1978:40:415-29. 26. Sctjeant GR. Fetal haemoglobin in himtigrnn siddc ceU disease, dm Haematol. 1975;4:109-22. 27. Sctjeant GR. Sommetana A, Stevenson M. Mason K. Serjeant BE Coropariaoo of sickle cell-fl * tbiiatsaenuj with homozygous sickle cell disease. Br J Haematol. 1979;41:83-93. 28. Hayes RJ. Condon PI. Sctjeant GR. HaemaSDiogical factors associated with proliferative retinopathy in homozygous sickle celt disease. Br J Ophthal mol. 1981; 6329-33. 29. Hawker H, Neihoa H. Hayes RJ, Serjeant GR. Haematological factors rrvx-irtH with avascular necrosis of die femoral head in homozygous sickle cell disease. Br J Haematol. 1982; 30:29-34. MEDICAL PROGRESS THE PATHOGENESIS OF ASBESTOS-ASSOCIATED DISEASES E. M.D., T. P .D.John Craighead, and Brooke Moss^an, h 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 arc also the suits have been brought against 260 companies by basis for the use of the mineral in friction equipment workers, their families, and members of the general and in a wide variety of consumer items requiring a public.1,2 The spectrum ofliability has now widened to relatively inexpensive insulation material that is lighi involve the federal government for alleged negligence and subject to molding. Since the turn of the century, in establishing adequate environmental standards. about 3x 107 tons of asbestos have been used in con This review summarizes our current knowledge of struction and in the fabrication ofmanufactured goods 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 arc employed in industries that use asbes diseases associated with exposure. Since there arc sev tos products, and countless millions of American citi^ eral different mincralogic types of asbestos, we will icns arc exposed to asbestos cryptically in the course of attempt to assess the extent to which findings with one their daily lives. type can be applied to another. Detailed analyses of Public concern over the effects ofasbestos on health the issues addressed in this paper have been published is mounting. Although a total ban on its use in this elsewhere.3'0 country has been proposed, most would agree that Mineralogy From the Department of Pathology, University of Vermont College of Medi cine. Burlington. VT 0540S. 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 niineraiogic features into two groups: the serpentines and DUP 0947251 DU 038547 i^a^aiialiiM^aaaa^^ 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 mincralogic designation. Although the length:\vidth ratio ofthe mineral fiber known as asbes tos is by definition 2=3:1, the individual fibers making up the materials used in commerce vary substantially in width and length (Fig. 2). Chrysotilc is the only serpentine of commercial im portance. It is composed of pliable, curly fibers made up of fibrillar subunits. These fibrils arc 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 difTer 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 mineralogically 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 die 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 arc 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 UtiSTOS Figure 1. Types ol Asbestos of Commercial and Medical Impor tance and Their Chemical Compositions. C0 Figure 2. Differing Structural Features of Serpentine (Chrysotile) and Amphibole (Croddolite) Asbestos. These scanning electron micrographs of International Union gainst Cancer reference samples of chrysotile (Panel A) and croddolite (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 croddolite (Panel D). Note the dimensions of the fibers in com parison to the cilia. Photomicrographs were furnished by Mr. Craig Woodworth, Department of Pathology, University of Vermont Col lege of Medidne. California arc 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. Croddolite 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 DU 038548 DUP 0947252 1448 THE NEW E\c;i..\XI) JOU RNAL OF MEDICINE Jane 17, 198*2 Table 4. Consumption of Different Types of Asbestos in the United States in 1978.* u Tmor Assnrot Tout Asm*to* CKKwmu csoemouTt mmikti mmHetmi Ajbeuoi cement pipes Asbestos cement sheeting Flooring products Roofing products Packing and gasket] Insulation, therms! Insulation, electrics! Friction products Coatinp and compounds Pkutict Textiles Paper Other 119,700 7,900 90.000 26.500 12300 6.000 2.900 43.700 10.900 L200 1300 400 9,000 Total 332300 *ModiM from tfcc 4tU f Fafio.' 34.100 -- -- -- too -- -- 100 -- 100 -- 34.400 300 200 -- -- -- _ -- -- -- 1300 1700 144.000 7.900 90.200 26300 12300 ,, teooo 2.900 43.700 10300 1300 1,900 300 10.600 336.700 matches asbestos in providing tensile strength and moldability as well as resistance to fire, heat, and cor rosion. In addition, many of the manufactured substi tutes are comparatively expensive.8 About 25 per cent of the asbestos consumed in the United States is incorporated into cement piping for water mains and sewage lines. Over 320,000 km of pipe, containing about 10 to 20 per cent asbestos, is believed to be in use in this country. Asbestos-contain ing cement is employed widely in corrugated and flat sheeting, panels, tiles, and moldings for the construc tion industry. The mineral is used extensively in roof ing and paneling and as a filler in architectural dead spaces. In the past, suspensions of asbestos were sprayed onto the structural steel of buildings to pro vide insulation and lire protection. Because ofits thermal stability, asbestos is well suit ed for use in friction material and is applied to molded brake linings. Although substitutes arc being increas ingly employed in disk brakes, as in the aircraft indus try, a drum-brake lining for passenger cars that docs 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 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 engittes, 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 ofasbestos result from the inhalation of fibers suspended in tlic ambient air. The occurrence ofdisease 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 th* Lungs Timbrcll 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 parpnehyma of the lung, where they lodge in the terminal airways. Bifurcations are common sites for fiber impaction, since patterns ofair flow arc altered at these sites. The shape of the fibers also has a role in transport!; -Aerodynamicaliy, chrysorile 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 ncedlc-Iikc am- /' phiboles, which arc transported more readily to the ' periphery of the lung. These theoretical and cxperimental considerations have been verified by analyses l of the lungs of rodents experimentally exposed to as- 7 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 cither expectorated or swallowed.,3', In the peripheral airways, short fibers arc ingested by macro phages, and at least some of these cells probably mi grate across the wall of the bronchioles and acini.10'18 Asbestos fibers arc 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 arc 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 panicles 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 arc two phases of clearance through the tracheobronchial tree. About half the as bestos is removed within a few days. Subsequently, DUP 0947253 DU 038549 5 Vol. 306 No. 24 ASBESTOS-ASSOCIATED DISEASES -- CRAIGHEAD AND MOSSMAN 1449 clearance continues for extended periods. The bulk of Quantitative studies pose many problems and arc only it EI this material is excreted in the feces.15 A variety of extraneous influences such as cigarette smoke and air pollutants aflcct the clearance and in- a crude measure of exposure, partly because many fibers arc cleared from the lungs and others fragment to increasingly smaller particles with time. trapulmonary deposition offibers. However, these fac -Macrophages arc a key element in the response of tors arc extraordinarily complex, in pan because indi the host to asbestos. Whereas these cells phagocytizc viduals appear to differ in their responses to inhaled short fibers and remove them from the airways, they 1 dust.21'" cannot encompass and transport the longer fibers. Al Asbestosls though retention of these long fibers in the distal air ways appears to be an important consideration in the Diffuse pulmonary fibrosis is the typical lesion asso causation of pulmonary fibrosis,18,30 the pathogenesis ciated with prolonged, heavy exposure to asbestos.30 It of the lesion is not understood. Incomplete phagocyto develops slowly over a period of years and seems to sis of asbestos fibers in the airways -could result in progress in the absence ofcontinued exposure to asbes spillage of lysosomal enzymes42 and release of soluble t tos. Initially, fibrosis is found in and around the respi fibrogcnic factors from macrophages.43 On the other i ratory bronchioles and alveolar ducts, where relatively hand, oxygen free radicals liberated by macrophages long fibers deposit. With time, the fibrotic lesion pro and other inflammatory cells might also injure lung gresses in a seemingly centrifugal manner, so that in tissue. This idea is supported by our observations that creasing numbers of respiratory units arc involved. superoxidc dismutasc, an inhibitor of biologic oxi Fibers ofasbestos tend to accumulate preferentially in dants, protects cultured respiratory epithelial cells the lower lobes and adjacent to the visceral pleura. from the cytotoxic effects of chrysotile (Mossman BT, Fibrosis is usually prominent in these regions, and the Landesman JM: unpublished data). Chrysotile is cy pleural surfaces ofthese lobes are frequently thickened totoxic in vitro presumably because the magnesium of by a dense layer offibrous tissue. In advanced asbesto- the fibers interacts with the plasmalcmma and dam sis, the fibrotic pulmonary tissuctontracts and is reor ages it, along with lysosomal membranes of cells.44'45 ganized to form the new air space typical ofthe honey It is unclear whether this is an important mechanism comb lung. of tissue injury, however, since pulmonary macro Ferruginous bodies arc the histologic hallmark of phages and epithelial cells in the lungs of animals ex exposure to asbestos.31'34 They consist offibers coated posed to aerosolized chrysotile fail to reveal ultrastruc- by complexes of hemosiderin and glycoproteins and tural evidence of injury.18,19 are believed to be formed by macrophages that have Other biologic phenomena may prove important in phagocytizcd the particles. Asbestosis can exist when the causation ofpulmonary fibrosis. Asbestos activates ferruginous bodies arc difficult to demonstrate in the complement by the alternative pathway4" -- a reac lungs by light microscopy. On the other hand, ferru tion that may be expected to rcsuil in the accumulation ginous bodies can often be found in the absence of of leukocytes in the tissue and the release of lysosomal serious parenchymal disease.33'36 Thus, their presence enzymes. This observation is consistent with the find alone is probably not a stimulus for the proliferation ing of an acute inflammatory response in some early of fibrous tissue. Although they have been shown to lesions.30,47 Finally, consideration must be given to the form from foreign inorganic and organic fibers of possibility that asbestos stimulates the production of many different types,37 ferruginous bodies in most collagen by cells. When chrysotile is added to cultures human lungs have asbestos as a core.36 For this rea of fibroblasts in vitro, the cells elaborate rcticulin and son, the structures arc commonly known as asbestos collagen at an accelerated rate.4"'49 bodies. Although the hypothetical mechanisms mentioned The number of uncoated fibers in the lung greatly above could account for the deposition offibrous tissue exceeds the number of asbestos bodies in the tis in the lungs, the pathogenesis of asbestosis in human sue.3"'3'3 It is not known why some fibers arc coated beings remains to be established. The question may be and form the typical asbestos bodies, whereas others moot, however, since modern environmental controls arc uncoatcd. Since uncoalcd fibers arc usually diffi cult or impossible to demonstrate by light microscopy, have dramatically reduced exposure in the work place. The dust concentrations permitted by current regula lung tissue must be digested and the residue examined tions will probably not induce substantial pulmonary by either phase or electron microscopy in order to fibrosis during the lifetime of an industrial worker. carry out qualitative and quantitative studies of the fibers. Whereas relatively long fibers (>5 ftm) arc Pleural Lesions found by light microscopical techniques, electron mi Plaques are curious lesions made up of hyalinizcd croscopy makes it possible to identify very small parti fibrous tissue located on the parietal pleura of the tho cles.411'4 Thus far, attempts to correlate the extent of rax, diaphragm, mediastinum, and pericardium.50*51 disease with cither the number of asbestos Ixidies or They arc usually but not invariably associated with the overall content of fibers in the lungs have been exposure to asbestos.3" Although die occurrence of difficult, although fibrosis is usually evident when 10" plaques correlates with the duration and intensity of fibers per gram of lung (wet weight) arc present. exposure, it is common to find lesions in the absence of DU 038550 \\y> THE NEW ENC.IAXUJOURX/U. OF MEOICIXE June 17, 1962 obvio z-*ease of the pulmonary parenchyma. Thus, rclu'r.-r. '.Tiail amounts ofdust can induce the devel opm':.-. plaques. These benign lesions do not appear to d'r.* -- :nio malignant mesotheliomas. Chi - i '.-.enstically, plaques are located in the inter costal t va'.es on the anterior and posterior lateral as pects </ thorax and on the dome of the diaphragm at sites '-.'.ere the visceral and parietal plcuras approxirr,i`.e during respiratory excursions. The config uration vf the plaques is highly variable. For example, on the '..'.rs: wall they usually follow the contour ofthe rib, whereas on the diaphragm they are customarily either d-sk-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 entiates: from the fibrous lesions of the visceral pleura that accompany pulmonary asbestosis. Since plaques are found most often in persons ex posed 'occupationally to asbestos for extended peri ods,54's'- their overall prevalence in the United States is low.1' In Eastern Europe and Asia Minor the lesions are frequently found in older members of the general population who lack documented exposure to asbes tos. The presence of fibrous minerals in soil and in local construction materials may account for the common occurrence of pleural plaques in these re gions. 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 publichealth standpoint because they arc thought to occur in persons who have had either transient or indirect ex posure to asbestos.65"6. The development of mesothe liomas as a consequence ofcasual exposure, however, is an uncommon event. On the other hand, the preva lence of the tumor in workers who have had heavy exposure over extended periods is about 2 to 3 per cent and has beer, reported to approach 10 per cent.68,69 It is difficult to determine how often mesotheliomas actu ally occur, because the latency period is usually 20 years or longer and can often be as long as 40 to 50 years. Some suggest that an epidemic of mesothelio mas will appear in the late decades of this century, consequent to the exposure of large numbers of work ers during World War II. The pathogenesis of the pleural lesions associated with exposure to asbestos is not known, but it is a topic of considerable contemporary interest. Fibrosis of the visceral pleura, plaques of the parietal pleura, and mesothelioma probably develop by different mecha nisms, although a rigorous defense of this conclusion would be difficult. As mentioned above, asbestos is deposited preferentially in the periphery of the lung 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 on the visceral pleura to irritation by the physical pres ence of fibers on or near the surface. This mechanism might also explain the occurrence of plaques in the parietal pleura. Alternatively, the lesions may repre sent an organized fibrinous exudate resulting from the physical movement of die 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 ofthe visceral pleura or adhesions between the pleural surfaces. In addidon, 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, but not the chemical composition, were found to be the critical determinant affecting the development of tu mors in rats. Long, thin fibers of a variety of types proved carcinogenic when introduced into the pleural space, whereas short fibers and those with a relatively broad diameter failed to induce mesotheliomas. These findings are consistent with epidemiologic observa tions documenting the relatively common occurrence of tumors in populations exposed to grades of 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.63 '2'74 A fibrous zbolitc, erionitc, has recently been associated with the occurrence of pleural fibrosis and mesothelioma in a rural area of Turkey where commercial mining ofasbestos does not occur.61 Since the fibers of this mineral do not possess the chemical properties of asbestos but arc morphologically similar to crocidolitc 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.7j,7b 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 amphibolc asbestos. The gradual disintegra tion of chrysotilc in tissue may account for the relative ly uncommon occurrence of mesotheliomas of both the pleural and peritoneal cavities in persons ckposcd ex clusively to chrysotilc.79 The mechanism of malignant transformation of mcsothclial tissues is obscure. Surprisingly little ex perimental information has accumulated, although there is reason to believe tkat-ritc lesions may be com- pUP 0947255 DU 038551 LiXULi* SS iaeiaaafJiramt.^-- -ijriMMKir ^ffl Voi. 306 No. 24 ASBESTOS-ASSOCIATED DISEASES -- CRAIGHEAD AND MOSSMAN MSI 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 arc made up of malignant serosal cells, where as others have the histologic features of fibrosarcoma. Mesothclial 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 mesothclial cells to asbestos. Cocarcinogcnic substances and cigarette smoke do not ap pear to be pathogenetic factors in vivo. Bronchogenic Carcinoma Epidemiologic studies have documented an associ ation between bronchogenic carcinoma and occupa tional exposure to asbestos.82"87 The prevalence of tu mors is higher in persons working with the finished products (such as insulators) than in miners and mill ers. The severity ofthe 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 oftumor, 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 chrysotilc in Canada8'1 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 chrysotilc has been suggested by studies ofoccupational groups exposed to either type of asbestos or to the two in combination.92 Mortality among chrysotilc workers is increased 2.4fold, whereas it is five times higher than normal among miners of both chrysotilc and crocidolite. Surveys of the smoking habits of insulators,93 fac tory workers,94,95 and miners and millers90 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 oflung 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 efTecls 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 Bcrcnblttm, 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 cither acts di rectly with the DNA of the cell or requires metalrolic activation by cellular enzymes. A promoter is general ly neither mutagenic nor carcinogenic, although it is required ifthe 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 cfiects 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 of pulmo nary asbestosis. Asbestos has many ofthe properties ofclassic tumor promoters, such as the phorbol esters.104 Proliferation and squamous metaplasia are induced in the respira tory mucosa of rodents in vitro.105 Asbestos interacts with the membranes ofcells100,107 and induces the syn thesis of the polyamincs that accompany cell divi sion.108 Since cigarette smoke also contains a host of substances with promoter effects, the inhalants may act in either an additive or a synergistic fashion to enhance the susceptibility ofthe respiratory' mucosa to carcinogens. However, alternative mechanisms arc worthy of consideration. Asbestos can be phagocytizcd by the bronchial epithelium and can be transported intraccllularly 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.109 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.11" Another (but less attractive) hypothesis involves the alveolar macrophage, which phagocyli/es asbestos in the airways and possesses the DU 038552 DUP 0947256 l i ! I 1452 THE NEW EXCIANI) JOURNAL OF MEDICINE June 17, 1982 enzymatic capacity to convert polycyclic hydrocar many Americans consume water containing asbestos bons to active metabolites.'" At present, the mecha like minerals. nism of asbestos-associated carcinogenesis is unclear, Mineral fibers have been detected in the urine of although the mineral appears to act like a classic residents of Duluth in numbers corresponding to the tumor promoter. The fibrous nature ofasbestos is criti concentration of asbestos in drinking water.118 Inter cal, since exposure to nonfibrous oxides of silicon (for estingly enough, fibers have been found in the glomer example, quartz) and a variety ofsilicates is not associ uli and tubules of rats exposed in inhalation chambers ated with an increased risk of bronchogenic carcinoma to synthetic fibers.119 These observations suggest that in human beings. asbestos migrates to the kidney after clearance from Cancers of the Digestive System and Other Organs both the gastrointestinal and respiratory tracts. Whether this has an influence on the occurrence of Asbestos is implicated in the causation of cancer in tumors in the gastrointestinal tract is unknown. the upper and lower gastrointestinal tract and the kid When fed to laboratory animals, asbestos interacts ney. 2-1 ls Oropharyngeal and esophageal tumors oc with the mucosa of the gut.78 Fibers enter cells of the cur more frequently in asbestos workers who smoke, mucosa and prove cytotoxic.120 The experimental evi whereas a direct relation between smoking and the dence strongly suggests that ingested asbestos is dis development of carcinoma of the large intestine and seminated to abdominal organs by the lymphatics and the kidney has not been established. blood vessels. This conclusion is supported by post Sclikoff and Hammond114 and Elmes and Simp mortem studies of occupationally exposed persons; son112 have reported a statistically significant twofold these studies have demonstrated asbestos bodies and to threefold increase in the prevalence of tumors of the uncoatcd fibers in' most major organs.76 digestive tract in insulators, factory workers, and ship How does the ingestion ofasbestos induce gastroin yard employees. Other surveys have cither demon testinal carcinomas in human beings? In efforts to ad strated a smaller increase or failed to establish an asso dress this question, rodents were fed large amounts of ciation between exposure to asbestos and neoplums in asbestos over extended periods. With one exception,121 this system.116 We believe that the evidence must be these studies failed to demonstrate an increase in the assessed cautiously because the associations thus far prcvalence'of tumors in the gut.122'124 The possible reported are relatively weak. Since death certificates synergistic effects ofasbestos on the induction of intes are used to obtain data in most studies, it is possible tinal neoplasms by chemical carcinogens has also been that peritoneal mesotheliomas have been confused examined.12;> Intragastric administration of asbestos with metastatic carcinomas of gastrointcsunal-tract failed to augment tumor development in rodents fed origin. azooxymcthanc, a recognized intestinal carcinogen. The general population is exposed to small amounts The carcinogenic potential ofasbestos in the gastro of asbestos in drinking water, beverages, food, drugs, intestinal tract appears to be low. The pathogenetic and agricultural products. Potable water often con basis for the purported increase in the prevalence of tains mineral fibers that arc presumably derived from carcinomas in certain occupational groups remains to geologic deposits and refuse dumps. The finding of be established. fibers of amphibolc asbestos in the drinking water of Duluth, Minn., resulting from the disposal of taconite Pathogenic Potential of Asbestos Types tailings into Lake Superior,117 prompted investiga As emphasized above, asbestos is not one but a fam tions to determine the concentration and characteris ily of fibrous minerals, each of which has distinctive tics of mineral fibers in water supplies throughout the physical and chemical characteristics. Minerals from United States. Fibers with the properties of both ser various parts of the world and geologic formations pentine and amphibolc asbestos were found in over often have dissimilar physical properties, even though half the samples of water studied (Table 2). Thus, they arc classified under a specific mincralogic type. Table 2. Concentrations of Asbestos-Like Mineral Fibers in the Water Supplies of Selected but Representative Commu nities in the United States.* These differences arc 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 Cnt COSCFNTftATtON ofevaluating the effects ofdifferent types ofasbestos on AUjtUa Boston Duiulh Dallas KansasCii>. Mo. New York Philadelphia San Francisco Seattle ho. offibtrs >3 pm/ltter 5.75 3.98 1.72 0 0.07 0 16.95 0.60 0.85 health is compounded by the common practice of cus tom blending of various 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 chrysotilc is used extensively in industry today, it is important to ask whether its pathogenic importance is comparable to that of the amphiboles crocidolitc and amositc. These latter min Prepared from Table L-2 in Levine.* erals arc of historical importance, particularly since DUP 0947257 DU 038553 a*iA. :... - imiftilli Vol. 306 No. 24 ASBESTOS-ASSOCIATED DISEASES -- CRAIGHEAD AND MOSSMAN 1453 they were used widely during and immediately after World War II and arc 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 arc in dependent considerations. Ofall the types, croddolitc is clearly the most strongly associated with the occur rence of the tumor. But there arc interesting differ ences in prevalence, related to the physical character of this fiber type. For example, in Northwest Cape, South Africa, and western Australia, mesotheliomas occur commonly in persons with occupational or casu al exposure to crocidolite.65 The mineral mined in these regions is composed ofrelatively long, thin fibers. In contrast, mesotheliomas arc rare in the Transvaal of South Africa, where the crocidolite fibers are much coarser. Another amphibolc, amosite, is associated sporadi cally with mesothelioma, whereas the tumor rarely if ever occurs in workers exposed to anthophyllite. Both these latter types arc made up ofrelatively short, blunt fibers. A number of studies have been conducted in miners and millers in Qucbec^and Italy, where the serpentine chrysotile is.cxtraeted.74,126 Although the results are debated, the bulk of the evidence indicates that chrysotile is not an important cause ofmesotheli 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, arc 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 arc clouded by uncertain ty because ofthe prolonged latency period ofmesothe liomas. Considerable effort has focused on determin ing whether the various types ofasbestos differ in their capacity to induce bronchogenic carcinoma and fibro sis of the lung. Unfortunately, there is no good answer to these questions at present, since dose-related differ ences in the prevalence 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 arc exceptionally difficult to develop, because it is necessary to use data on morbidity and mortality doc umenting disease retrospectively in members of occu pational groups who have had heavy exposure either in the remote past or over a lifetime. The difficulties arc compounded by the long latency period ofasbestosis and the asbestos-associated cancers. Although recommendations for levels of asbestos in the air of occupational settings in this country were formulated in the 1940s, it was not until 1970 that federal regulations were promulgated as a result ofthe passage of the Occupational Safety and Health Act -and the Clean Air Act. The initial standard was based on the light microscopical count offibers ofa length of 5 fim, collected by mechanical means. A concentration of five fibers per cubic centimeter of air, averaged over an eight-hour period, was deemed permissible, with stipulations for transient excesses above that concen tration. In 1976 the contemporary standard of two fibers per cubic centimeter was established, and more recently a level of 0.5 fiber per cubic centimeter has been proposed. Is the current limit oftwo fibers per cubic centimeter sufficiently rigorous to prevent disease in the future? Is it appropriate to base regulation exclusively on deter minations of fibers of >5 fun 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 arc 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 dosc-responsc 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 arc 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 mourn with brood business import. The New York Times. 1981 July 3:1. 2. Warning: asbestosis may cost you more Uian money. Economist. 1981; 280.83-4. 3. Levine RV, ed. Asbestos: an information resource. Washington. D C.: U.S. Government Printing Ollicc, 1978. (DHEW (NIH) Publication no. 78-1681). 4. Simpson W. ed Asbestos: final reports of the advisory committee on asbestos. London Her Mjjcsty's Stationery Olhce. 1980 3. 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Auerbach O, Conston AS, Carfinkel L. Parks VR, Kaskrw HD. Hammond EC. Presence of asbestos bodies in orfans other than the lung. Chest. I960; 77:133-7. 77. SebastienP. Masse R.Bignon 3. Recovery ofingested asbestos fibers fiom the gastrointestinal lymph in tits. Environ Res. 19(0; 22:201-16. 78. Westlake GE, Spjut HA. Smith MN. Penetnuon of colonic murori by asbestos panicles. Lab Invest. 1965; 14:2029-33. 79. Jaurand MC, Bignon J, Sebastien P, Goni I. Leaching of chrysotile asbes tos in human beings; correlation with in vitro studies using rabbit alveole macrophages. Ermroo Rea. 1977; 14:245-54. (0. Jaurand M-C, Kaplan H, ThioUetJ, PincheoM-C, Bcmaudin3-F, Bignoo J. Phagocytosis of chrysotile fibers by pieunl mesothelisl cells m enhsre. Am 1 Pathol. 1979; 94:529-38. 81. RajanKT, Wagner JC.EvansPH. The response of human pleura in orgao culture to asbestos. Nature. 1972; 238:346-7. 12. Doll R. Mortality fiom lung cancer in asbestos workers. Br J Ind Med. 1955; 12:81-6. 83. Enterline P, de Coufle P, Henderson V. Respiratory cancer in relation to occupational exposures among retired asbgstos workers. Br J Ind Med. 1973; 30:162-6. 84. Selikoff U. Hammond EC. Qrurg 1. Carcinogenicity of mnosite aabestos. Arch Environ Health. 1972: 25:183-6. 85. McDonald 3C, Uddell FDK, Gibbs GW, Eyssen GE, McDonald AD. Dust exposure and modality in chrysotile mining. 1910-75. Br3 Ind Med. I960; 37:11-24. 16. Selikoff U, Hammond EC. Scidman H. Latency ofasbestos disease among insulation workers in the United States and Canada. Cancer. 19(0; 463736-40. (7. Blot WJ, Harrington JM. Toledo A. Hoover R, Heath CT( Jr, Fraumeni JF Jr. Lung cancer after employment in shipyards during Vfreid War U. N Engl J Med. 1978; 299:6204. 18.Ctemet-Sluis GK. The relationship between asbestoais and branchial can cer. Chest 1980; 78380-1. >9. SelikoffU, Bader RA, Bader ME, Churg J, Hammond EC.Asbestotisand neoptasil. Am 1 Med. 1967; 42:487-96. 90. Kanaentein M. Churg J. Pathology of carcinoma of die lung associated with asbestos exposure. Cancer. 1972; 30:14-21. 91. Whitwell F, Kewhouse ML, Bennett DR. A study of the histological cell types of hmg oncer in workers suffering from asbestoais in the United Kingdom. Br J Ind Med. 1974; 31:298-303. 92. EntcriinePE, Henderson V. Type of asbestos and respiratory cancer in the asbestos industry. Arch Environ Health. 1973; 27:312-7. 93. Selikoff U, Hammond EC, Churg J. Asbestos exposure, smoking, and neoplasia. JAMA. 1968; 204:104-10. 94. Selikoff U, Seidman H. Hammond EC. Mortality effects ofcigsrette smok ing among amosite asbestos factory workers. J Nad Cancer Inst. 1980; 65:507-13, 95. Berry G. Newhouse ML, Turok M. Combined effects of asbestos exposure sod smoking on mortality from lung cancer in factory workers. Lancet. 1972; 2:476-9. 96. Meurman LO. Kiviluoto R. Hakama M. Combined effect ofasbestos expo sure and tobacco smoking on Finnish anihophylhtc miners and milters. !n:\ pp. 491-6. 97. Sarecci R. Asbestos and lung cancer: an analysis of the epidemiological evidence on the asbestos-smoking interaction. Int J Cancer. 1977; 20:32331. 98. Berenbluml. Irritation and carcinogenesis. Arch Pathol. 1944:38:233-44. 99. Marx 1L. Tumor promoters: carcinogenesis gets mote complicated. Sci ence. 1971;201:515-8. 100. Chamberlain M. Tmy EM. Asbestos and glass fibers in bacterial mutation rests. Muut Res. 1977:43:159-64. 101. Huang SL- Amocire. chrysotile and cmcidolite asbestos are mutagenic in Chinese hamster hmg cells. Mutat Res. 1979; 61:265-74. 102. Price-Jones Ml. Gubbings G. Chamberlain M. The genetic effects of croci- dolitc asbestos: comparison of chromosome abnormalities and sistcr-chro- rnatid exchanges. Muut Res. 1980; 79:331-6. 103. Sincock A. Scabright M. Induction ef chromosome changes m Chinese hamster cells by exposure lo asbestos fibres. Nature. 1975; 257:56-8. 104. Mosanan BT. Landesman JM. Craighead JE. Asbestos exhibits properties of a classical tumor promoter on hamster tracheal epithelial cells. Proc Am Assoc Cncer Res Am Soc Clin Oncol. 1981:22:129. abstract. 105. Mossman BT. Craighead JE. MacPhcrson BV. Asbestos-induced epithelial __ changes in organ cultures of hamster trachea: inhibition by retms I mcthsl ether. Science. 1980; 207:311-3. 106. Woodworth CW, Mossman BT, Craighead JE. Comparative effects of fibrous tod auofihrous minerals on cells and liposomes. Environ Res. (in press). 107. Mossmtn BT, Halleron PA. Craighead JE. Simulation of Ni'-K' ATPasc activity in tracheal epithelial cells after exposure so crocidoltte asbestos. J Cell Biol. 1979; 83: Suppl: Hit. abstract. 106. Mossman BT. Landesman JM. Craighead JE. Asbestos stimulates orm- thioe dccarboaylaie (ODO activity in hamster trachea! epithelial cells. J Ceil Biol. 1980: g7: Suppl: 307a. abstract. 109. Lakowicz JR, Bcvan DR. Benio[a|pytenc uptake into ret liver microtomes: effects ofadsorption of betuo(a)pyrene to asbestos and non-fibrous mineral paniculate*. Cbem Biol Interact. 1980; 29:129-38. 110. Mossman BT, Craighead JE. Mechanisms of asbestos carcinogenesis. En viron Res. 1981; 25369-80. 111. Autntp H, Harris CC, Stoner GD. Selkirk JK. Schafer PW. Trump BF. Metabolism of ['Hlbenzofajpyrene by cultured human bronchus and cut- treed human pulmonary alveolar macrophages. Lab Invest. 1978; 38:21724. 112. Ebnet PC, Simpson MJC. Insulation workers in Belfast. 3. Mortality 1940- 66. Br J Ind Med. 1971; 28326-36. 113. Hammond EC, SelikoffII, Churg J. Neoplasia among insulation workers in the United States with special reference to inua-abdoreinal neoplasia. Ann NY Acad Sci. 1965; 132:519-25. 114. SeUkoffU. Hammond EC. Multiple risk factors in etiology ofenvironmen tal cancer. In: Fraumeni JF, ed. Persons at high risk of cancer: an approach 115. 116. to cancer etiology and control. New York: Academic Press, 1975:467-83. SelikoffU, Hammond EC, Seidman H. Mortality experience of insulation worker! in the United States and Canada. 1943-1976. In:*. pp. 91-116. Miller AB, Asbestos fibre dust and gastrointestinal malignancies. Review of literature with regard to a cause/effect relationship. J Chronic Dis. 1978; 31:23-33. 117. Cook PM. Glut GE, Tucker IK. Asbesriform amphibole minerals: detec tion and measurement of high concentrations in municipal water supplies. Science. 1974; 115:853-5. 118. Cook PM, Olson GF. Ingested mineral fibers: elimination in human urine. Science. 1979; 204:195098. 119. Cunningham HM, Moodie CA, Lawrence GA, Pontefract RD. Chronic effects of ingested asbestos in rats. Arch Environ Contam Toxicol. 1977; 6:50703. 120. Jacobs R. Humphrys J, Dodgson KS, Richards RJ. Light and electron microscope studies of the rat digestive tract following prolonged and short- term ingestion of chrysotile asbestos. Br J Exp Pathol. 1978: 59:443-53. 121. Gibe! W, Lobs Kh, Horn K-H, Wildncr GP, Hoffmann F. Tierexperimen- telle Untersuchungen fiber cine kanzerogene Wirkung von Asbestfiherma- terial Bach otxlcr Aufnahme. Arch Geschwulstforsch. 1976; 46.437-42. 122. Gross P, Harley RA, Swinburne LM, Davis JMG, Greene \VB. ingested mineral fibres: do they penetrate tissue or cause cancer? Arch Environ Health. 1974; 29:341-7. 123. Smith WE. Hubert DD. Sobcl HJ. Peters ET. Doerfler TE. Health of experimental animals drinking water with and without amosite asbestos " and other mineral particles. J Environ Pathol Toxicol. 1980, 3(54:6). 277- 300. 124. Smith WE, Miller L, Elsasser RE. Hubert DD. Tests for carcinogenicity of asbestos. Ann NY Acad Set. 1965, 132:456-88. 125. WardJM, Frank AL, WenkM.DevorD.TaroneRE. Ingested asbestos and intestinal carcinogenesis in F344 rats. J Environ Pathol Toxicol. 1980; 3(5&6):30l-12. 126. Rubino GF. Piolatto G, Newhouse ML, Scansctii G, Aresini GA. Murray R. Mortality of chrysotile asbestos workers at the Balangero Mine. No. -- Italy. Br J Ind Med. 1979; 36.187-94. ac a o tuo -s-l fO 0o> Du 038SS6 A % $ c.rt. rev e-BC trtAiL'ShtjiE:: E. 1. du Pont de Nemours & Company INCORPORATED Wilmington, Delaware EMPLOYEE RELATIONS DEPARTMENT /- ^ CC: B. W. Karrh, M.D./ J. C. Bonnett, M.D. July 12, 1982 TO: PAUL WYCHE, PUBLIC AFFAIRS DEPT. D-8078 FROM: BURFORD W. CULPEPPER, MEMO FOR RECORD Tom Heinz, Asst, to Jeremy Main of Fortune Magazine, called me on 8 July 1982 requesting confirmation on state ments to be made in the magazine article concerning: asbestos latency period (15-40 years) lead, fibers, silica, asbestos, etc., as old hazards in industry N-hexane, polyvinyl chloride, benzene, carbamates, some sulfa compounds as new hazards. A question of teratogenicity was raised concerning the new hazard chemicals and I suggested that the significant toxic property of those chemicals was not teratogenicity. However, I would review it and call him back. A second call was made to me on 9 July 1982. I con- ` firmed that teratogenicity was not the most significant hazard of the chemicals listed; ref. "Patty's Industrial Hygiene and Toxicology" and "Chemical Hazards In The Workplace." The chemicals were described to him as follows: N-hexane - solvent industrial glue. Neurotoxic hazard. Polyvinyl chloride - basic material for synthetic resins. Has been associated with increased incidence of tumors. Benzene - industrial solvent and byproduct in many processes. Associated with blood diseases. Carbamates - fungicides, rubber accelerator, etc. Some evidence for teratogenicity in animals; i.e., rats and mice at high doses. Sulfa compounds - a large category of chemicals, in cluding many compounds that cannot be specifically categorized as a group. DUP 0947263 He appreciated the help and did not seem to know much about the chemicals, the properties of the chemicals, or the pronunciations. BWC/mch DU 038557 o c *0 o (O fO o> ** DU 038558 atf i i i * t 4> Topics in Radiology / Diagnostic Radiology Harold G. Jacobson, MO Section Editor E. Robert Heitzman, MD, Section Coordinator Radiology of Asbestos Disease i Lawrence R. Goodman, MD ALTHOUGH the hazards of asbestos exposure were first reported in the early 1900s, the full extent of its effects is still being evaluated. Per sons with occupational exposure to asbestos have a higher incidence of pulmonary fibrosis (asbestosis), vari ous pleural disorders (plaque, thick ening, and effusion), and neoplasms (lung, pleura, and gastrointestinal). In recent years, attention has turned to asbestos as an environmental pol lutant. Household contacts of asbes tos workers, persons living near asbestos plants, and urban dwellers frequently have asbestos fibers in the lungs at autopsy. The chest roentgenogram often offers the first evidence of asbestos exposure, because a history of asbes tos exposure is difficult to obtain or is not sought Therefore, it is important for both the radiologist and clinician to understand both the radiological findings of asbestos exposure and the significance of each change. The final diagnosis of asbestosis (pulmonary fibrosis) rests on a com bination of pulmonary lesions on the roentgenogram, bibasifar rales, and reduced lung function in a patient with the appropriate exposure histo ry. Microscopic verification is usually not obtained.1-1 The diagnosis of asbestos-related pleural disease relies more heavily on the radiological changes (see below). Roentgenograms demonstrating the typical lateral pleural changes in the absence of old trauma or empyema have a 0.81 correlation with prior exposure to asbestos.' A rough correlation exists between the degree of asbestos exposure and the type of disease produced. Pulmo nary fibrosis (asbestosis) and malig nant neoplasms of the lung and gas- From the Dspsrtmsnt of Diagnostic Radiology. Hahnamam Madieal CoSaga and Hospital. Phitadalphia. Raprirtt raquaata to tha Dapartmant of Diagnoatic Radtology, Hahnamann Medical Colaga and Hospi tal. 230 N Broad St, Ptiiadatptiia. PA 1S102 (Dr Goodman). trointestinal tract are most likely to develop in those individuals with the heaviest exposure. Those persons with mild to moderate exposure are more likely to contract benign or malignant pleural disease. These rela tionships are complex and depend on the type of fiber, pattern of exposure, and time since initial exposure. Usu ally. a 15- to 20-year latency period occurs between the initial exposure and the first radiological or clinicaT evidence of disease. Cigarette smoking potentiates both the fibrogenic and carcinogenic effects of asbestos.1 For both epidemiologic studies and the individual patient, good-quality 120-kV posteroanterior and lateral roentgenograms usually provide the necessary radiological information. Oblique roentgenograms may accen tuate questionable pleural changes. Although computed tomography (CT) will demonstrate lesser degrees of fibrosis, pleural plaques, and pleural calcification, routine use of it hardly seems justified. The major value of CT appears to be in distinguishing focal plaques (benign) from intraparencbymal nodules (presumably can cer) and determining whether large lesions are lung masses, solid pleural lesions (presumably mesotheliomas), or focal pleural fluid collections. In patients with proven lung cancer and mesothelioma, CT is a valuable aid in determining the extent of the lesion both for planning of treatment and determining prognosis. Asbestosis (Pulmonary Fibrosis) The radiological changes of pulmo nary fibrosis may precede, be associ ated with, or follow the onset of pulmonary symptoms. Unlike most other pneumoconioses (with the ex ception of talcosis), the predominant radiological lesions involve the lower half of the lungs. These are usually small, irregular, poorly defined linear opacities. Pinpoint opacities, thick ened septal lines, gross linear strand ing, and honeycombing are less fre Fig 1.--In this posteroanterior film of right hemithorax, reticular nodular interstitial infil trate is present throughout lungs (asbestosis) in this patient with emphysema. Observe mild pleural thickening along lateral chest wall and minor fissure. Small calcified plaque is noted as well (black arrow). Spheroid, pleural-based mass (white arrow) was not present on previous films, proving at surgery to be adenocarcinoma involving lung, pleura, and chest wall. quent (Figs 1 and 2, left). (Their severity is scored on a 12-point scale adopted by the International Labor Office.) Lung volumes tend to be normal or diminished. Associated obstructive lung disease is more likely caused by smoking than by asbestos. Conglomerate masses (progressive massive fibrosis), a well-known com plication of silicosis and coal workers pneumoconiosis, are extremely rare in asbestosis. When it does occur in asbestosis, it tends to be in the lower lobes, the area of predominant pulmo nary fibrosis. Therefore, any focal lung density appearing in a patient with exposure to asbestos should sug gest a carcinoma rather than a con glomerate mass.1,4 A recently recognized entity that may mimic lung cancer or the rare Section Coordinators: Thomas C. 8a* navsntano. k (Cass of tha Month); Juan A. dst Ragato, MO (Tharapautic Radiology); Jack Edaikan, MO (Diagnostic Radiology); Barry B. Goidbarg, MD (Ultrasonography); E. Aobart lialtxman, MO (Diagnostic Radiol ogy); Stanisy S. Sisgatman. MD (Computad Tomography); Edward B. Silbaratain, MD (Nuctoar Racfiotogy). 644 JAMA, Feb 4. 1983--Vol 249, No. 5 Radiology in Asbestos Disease--Goodman i jt i $ I I I I i DUP 0947265 DU 038559 Fig 2.--Left, In this poataroanterior roantganogram of chest, considerable danaa, Inaar, intaratttial thickaning is notad in lower half of right lung (aabaatoais). Coatophranic angla la biuntad and piaura is thickened to iavai of postarior sagmant of third rib. On laft sida, uppar loba nodufa aa wak as homogeneous opacification of lung base is prasant. Oiffarantial diagnosis included locuiated affusion, masothaiioma, and lung cancer. Right, Computed tomographic scan through lung base demonstrates large, left lower loba lung mass (M), bilateral piauril thickaning, and calcification (arrows) (oat call carcinoma, laft lower lobe). lower lobe progressive massive fibro sis is the pulmonary pseudotumor (rounded atelectasis). This is usually a swirl of atelectatic parenchyma adjacent to thickened pleura. Tomo grams or oblique films may demon strate a "tail" to the medial aspect of the mass, and CT may show clearly the atelectatic nature of the lesion. Thus, one can often distinguish between round atelectasis and a tumor.'J Lung Cancer Asbestos and cigarette smoking are cocarcinogens. Lung cancer is 70 times more likely to develop in a smoking asbestos worker than in a nonsmoker without asbestos expo sure. The malignant neoplasms are most frequently peripheral and at the bases of the lungs as opposed to the more frequent upper lobe predomi nance. The tumor frequently arises in a background of interstitial fibrosis or pleural disease, making detection of a small neoplasm difficult (Fig 1). Any change identified on serial films should be viewed with great suspi cion, because fibrosis and plaques often take years to demonstrate radiological progression. Tomograms or CT may be helpful in distinguish ing overlapping shadows, a lung nod ule, or a pleural massu (Fig 2). Benign Pleural Disease Pleural disease may take several guises. Asymptomatic, focal, bilateral pleural thickening along the midlat eral thoracic wall are characteristic of pleural plaque due to moderate asbestos exposure. Plaques may also be discerned along the mediastinal pleura, the pericardium, and the dia phragm. They tend to spare the lung apexes and costophrenic angles. The majority are not calcified, and most are noted in the absence of pulmonary fibrosis. When calcification occurs, it is in the parietal pleura in a charac teristic distribution along the surface of the diaphragm and the lateral chest wall (Figs 1 and 3). Plaques do not undergo malignant degeneration. but are an indicator of significant asbestos exposure. When these characteristic plaques are present, the vast majority of patients have a his tory of asbestos exposure.1 Asbestos wprkers with pleural plaques, but no fibrosis, have a 2)4-fold increase in lung cancer.1-* Diffuse pleural thickening with involvement from the apex to the base may also be due to asbestos exposure. Unlike pleural plaques, this radiological appearance may be ob served in a variety of diseases (Fig 2, left). Pleural effusions are frequently harbingers of pleural or pulmonary malignant neoplasms. Any patient with a notable asbestos history and at least ten years since initial exposure should be presumed to have a malig nant neoplasm until proved other wise. However, effusions may be benign in nature. Epler et at* have recently shown that benign effusion was the most common asbestosrelated abnormality during the first twenty years after exposure. Mesothelioma Mesothelioma is approximately three to five times more frequent in asbestos workers than in nonasbestos workers. Because it is a relatively rare tumor, however, its incidence is considerably less than lung cancer. Exposure to asbestos is often mild to moderate, and frequently a 30- to 40-year latency period ensues be tween initial exposure and develop ment of the mesothelioma.u Mesotheliomas may arise from any mesothelial surface, but the vast majority are located in the pleura or pericardium. Symptoms include the insidious onset of pain, dyspnea, and weight loss. The most frequent radio logical manifestation is that of pleu ral effusion. The effusion is often large and may obscure the pleural JAMA, Feb 4, 1983--Vol 249, No. 5 Radiology in Asbestos Disease--Goodman 645 i i DUP 0947266 t !5Er DU 038560 He" - * tumor. Large effusions may cause the mediastinum to shift to the contralat eral side or mediastinal pleural involvement may "freeze" the medi astinum and prevent mediastinal shift (Fig 4). When the mesothelioma is visible, it usually appears as a lobular mass between the lung and the chest wall. It may be localized in a small area or may encase a large portion of the lung. The volume of the involved hemithorax may be diminished. Sec ondary invasion of the chest wall, lung invasion, or lung metastasis are frequently observed late in the course of the disease (Fig 4). Computed tomographic examination frequently discloses the tumor to be more exten sive than initially appreciated. Me diastinal invasion and contralateral or subdiaphragmatic spread are fre quently demonstrated by CT exami nation. Fig 3.--Posteroantarior chest roentgenogram shows lobular pleural plaques along each lateral chest waf (arrows). Lung apexes and costophrenic angles are spared. Calcified pleural plaque is noted on left diaphragm (arrowhead). Little or no interstitial fibrosis is present (asbestosiapleural plaques). Fig 4.--In this posteroanterior roentgenogram of chest, large right pleural effusion obscures extensive malignant mesothelioma. Lateral portion of right third rib (upper arrows) is destroyed, and upper segment of trachea is deviated to left. Two nodules observed over left upper lobe represent calcified pleural plaques en tace. Diaphragmatic, mediastinal pleura and lateral pleural calcifications are also present (lower arrows). Nonoccupational Lung Disease Concern for the effects of asbestos on the general population arises from multiple sources. Families of asbestos workers have a higher incidence of asbestos-related lung disease. The air in most urban areas contains small numbers of asbestos particles. Autop sies of adults in urban centers fre quently show asbestos bodies in the lung, although at a much lower con centration than in asbestos workers.1 The disease-producing potential of inhalation of asbestos in a low con centration in the general population is still unknown. It has been sug gested that the lateral pleural thick ening occasionally observed in nonas bestos workers may be related to lew levels of asbestos exposure.' Rafarencag 1. Preger L: Asbestos-Related Disease. New York, Grune & Stratton Inc, 1978. 2. Becklake ME: Asbestos-related diseases of the lung and other organs: Their epidemology and implications for clinical practice. Am Rev Respir Dis 1976;114:187-227. 3. Albelda SM, Epstein DM. Gefier WB, et a! Pleural thickening: Its significance and relation ship to asbestos dust exposure. Am Rev Respir Dis 1982;126:621-624. 4. Souter CA, Simon G, Turner-Warwick M: The radiology of asbestos-induced disease of the lungs. BrJ Dis Chest 1974;68:235-252. 5. Mintzer RA, Cugell DW: The association of asbestos-induced pleural disease and rounded atelectasis. Chest 1982;81:457-460. 6. Epler GR, McLoud TC, Gaensler EA; Preva lence and incidence of benign asbestos pleural effusion in a working population. JAMA 1982; 247:617-622. 7. Ochs CW, Smith JP: Chronic pleural thick ening: Some observations on cause and patho genesis. Military Med 1976;141:77-81. 646 JAMA. Feb 4. 1983--Vol 249, No. 6 Radiology in Asbestos Disease--Goodman t i ! i l * i i i DUP 0947267 DU 038561 PERMISSIBLE REUSABLE RESPIRATOR FOR DUSTS AND MISTS MSHA j NIOSH MINE SAFETY AND HEALTH ADMINISTRATION NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH APPROVAL NO. TC-21 C-170 ISSUED TO NORTON COMPANY, SAFETY PRODUCTS DIVISION CRANSTON, RHOOE ISLAND, U.S.A. LIMITATIONS Approved lor respiratory protection against dusts and mists having a timaweighted average not less than 0.05 milligram per cubic metar or 2 msion particles per cubic foot. Not for use in atmospheres containing toxic gases or vapors or in atmospheres containing less than 19.5 percent oxygen. CAUTION Clean respirator filter in accordance with manufacturer's instructions. This respirator shall be selected, fitted, used, and maintained m accordance with Mine Safety and Health Administration. Occupational Safety and Hearth Administration, and other applicable regulations. MSHA -- NIOSH Approval TC-21 C-170 issued to Norton Company. Safety Products Division. December i. 1976. The approved assembly consists of the following Norton part number 7170 respirator. PERMISSIBLE RESPIRATOR FOR DUSTS AND MISTS MSHA NIOSH MINE SAFETY AND HEALTH ADMINISTRATION NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH APPROVAL NO. TC-21 C-170A ISSUED TO NORTON COMPANY, SAFETY PRODUCTS DIVISION CRANSTON. RHODE ISLAND, U.S.A. LIMITATIONS Approved for respiratory protection against pneumoconiosis and fibrosis producing dusts and mists. Not for use in atmospheres containing less than 19.5 percent oxygen or in atmospheres containing toxic gases or vapors. CAUTION This respirator shall be selected, fitted, used, and maintained m accordance with Mine Safety and Health Administration, Occupational Safety and Hearth Administration, and othtr applicable regulations. Follow manufacturer's instructions for fitting the respirator to the face. Discard and replace the respirator if it becomes damaged or breathing resistance is excessive. MSHA -- NIOSH Approval TC-21C-170A Norton Company, Safety Products Division. December 1,1976. The approved assembly eoneuts of the following Norton part number 7170 respirator Dust Respirator Disposable and Reusable Model No. 7170 MSHA/NIOSH APPROVAL TC-21 C-170 AND TC-21C-170A WARRAtfflM--Om eemnwcMI navoonaumar products are warranted io be free from defects. Our only oblgalttttv oommeiCMf ueeriMN be at cur opeon. to replace sny porson proving defective or to refund fte purchase price hereof The commercial user assumes aU other nek. rf any We make We warranty to the commanaal user m leu of the warranties of merchantability, fitness tor partftoiar ptapoee and afi other wananaet, express or implied. No davtaoon a auttcraed. Norton Company consumer products are sold only with warranties implied by law. DUP 0947268 DU 038562 RESPIRATOR APPLICATIONS Disposable Respirator... Approved for respiratory protection against pneumoconiosis-producing and fibrosis-producing dusts and mtsts. This respirator is approved for use in atmospheres containing asbestos dusts and mists. Reusable Respirator.-ApDroved for respiratory protection against toxic dusts and mists, including systemic poison dusts and mists, having a permissible time-weighted average (TWA) concentration not less than 0 05 milligram particulate matter per cubic meter of air or not less than 2 million particles per cubic foot of air. RESPIRATOR DESCRIPTION The Norton Modal 7170 Respirator is a compact. lightweight, particulate-filtering respirator which protects against inhalation of dusts and mists, it is designed for application both as a Disposable Respirator and as a Reusable Respirator RESPIRATOR INSPECTION 1. Inspect respirator thoroughly before use to insure that it <s <n satisfactory operating condition. Discard respirator if damaged or if parts are missing, f DONNING, FITTING, AND Vqw 1; WEARING RESPIRATOR > i 1. Remove respirator from plastic film bag and examine it to insure that it has not been jff " ( damaged. Save Dag for reuse. \ v-^ \ 2. Position respirator on face so that wide y portion of facepiece is over chin and narrow portion of facepiece is over nose 3. Place (ewer headband straps around head below ears and fasten hook and catch together. 4. Place upper headband straps around head above ears and fasten hook and catch together. 5. Adjust tension in headband straps to provide tight seal of facepiece to face and yet allowing comfortable wearing of respirator. a. Tension n straps may be increased while wearing respirator by grasping ends of headband straps between thumbs and forefingers and puiiing on straps or by holding hook or catch with thumb and forefinger of one hand and puffing strap through hook or catch with thumb and forefinger of other hand. b. Tension m straps may be decreased while wearing respirator by holding hook or catch with thumb and forefinger of one hand and pulling strap through hook or catch with thumb and forefinger of other hand. 6. Use finger tips to form adjustable metal strip to shape thisr section of facepiece to fit nose. 7. Check for tightness of seal of facepiece to face by inserting tip of small finger through circular hole in respirator valve guard and pushing exhalation valve flap against exhalation valve seat. Exhale gently while keeping exhalation valve dosed, if leakage of exhaled air is detected to be passing between facepiece and face, readjust position of facepiece on face, reform shape of adjustable metal strip, and/or readjust tension of headband straps, and then retest for tightness of seal of facepiece to face. Repeat procedures until seal of facepiece to face is adequate. 8. Periodically check tightness of .seal of facepiece to face while wearing respirator and make adjustments if necessary. ^ CLEANING AND SANITIZING RESPIRATOR 1. Clean and sanitize respirator after each day of use. 2. Remove deposits of dust or mist particulate matter from outer surface of respirator filter by brushing off particulate deposit (clean paint brush is suitable). Carry out brushing operation inside ventilated hood to prevent inhalation of dust or mist particulate matter. 3. Use clean, non-iinting cloth wetted with Norton Cleaner-Sanitizer or any suitable cieaner-sanifizsr solution to clean and sanitize respirator Use wetted cloth to wipe surfaces of respirator facepiece, adjustable metal stnp. headbands, exhalation valve guard, exhalation valve, and inhalation valve by wiping. 0o not wipe surface of filter 4. Use clean, non-lmting cloth wetted with clean water (preferably distilled or demineralized water) to rinse surfaces of respirator facepiece, adjustable metal strip, hea&ands. exhalation valve guard, exhalation valve, and inhalation valve. Do not nnse surface of filter. 5. Allow respirator to dry in dean air at normal room temperature STORING RESPIRATOR AFTER CLEANING AND SANITIZING 1. Place cleaned and sanitized respirator into plastic film bag. 2. Store respirator so that it is protected against Oust, chemicals, moisture, excessive heat, and physical damage. Prevent distortion of respirator during storage. RESPIRATOR REPLACEMENT (Discard respirator and replace it with new respirator if breathing becomes difficult due to piuggmg of filter by retained dust or mist particulate matter. -- WARNING This respirator mutt not be used in atmospheres containing oxygen at a partial pressure less than 148.2 mm mercury (19.5% By volume oxygen at sea level). This respirator should not be used In atmospheres which contain harmful vapors or gases or lor protection against volatile dusts which emit vapors or gases. It must not be used in poorly ventilated areas, in enclosed spaces, for abrasive blasting, or for fire fighting. This respirator is approved for use in atmospheres contain ing asbestos under TC-21C-170A. No non-powered air-purifying respirator totally eliminates asbestos fibers from the breathing zone. Better protection against asbestos is provided by high-efficiency filters used with elastomeric facepieces such as the Norton #7580 or equivalent. -- Made m USA Norton Company. Safety Products Division, Cranston, R.l. 02920 U.S.A. 40-700208 REV. E DUP 0947269 DU 038563