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PLAINTIFF'S EXHIBIT DUP-2218 l W \ ,\ . JO'. KN \|, ')y \j j\f A t *mi c Fulm of N>uimu pc* 9^KTt^t r* ^tmy af wet* =*fl uxrm 9m .9*1: )i . iaJ.I 4 Hmmw HO StfkJ* Mil went* < ttAtf/cac 4 rr`< of dUfM 'cjnm a i him iyt* * J r4*ct At VM I Mill* 4. TV utucution of **kc crt ana** . * nrwtyfox .(****;. i* *'J9 rio cmu tyMMtu a*j Hmum 439, 9t.;c I *>* 0* SOnilir *A. *m JN Qtm J. <n Sf Laci erf e.4u* cn of te^OwuiJiMa o* or frvajMo <* na** <m ift* M%riy of uette CBl unu. . C* rtvttt 19*Q, iJ.Ti; *uj 4 AUy C. Srtvcly Ml. I*. WJJu Qf Alp*-1 4 < sg/tetkr* or*M<Mo|ic vgf*, ,, iral+m *,* UClm cat! warnc Art .911. 1 j >0134 !0 hfimn *H 0way AM Mite 1. u. c**w* i*vk<.i m a* *** alTaet oa w>ncy t uxmt s Ei0 j vim .*:. 304 27&. it Hijfi0#. fcwMty USorwajMGI. fioff il *aMnii0i TVfruuw U6 noitulMUMtof *l*u M mimimm ** H9 S .a I4M CM If J Kjmum Hi 47 4J.J* !2. Sa^tM Cl. SuTCM It Mtlav^f D uctJM e*il 1 6em< ww of haawat) u .a u<Ut cod Meayg If j Kiaite l *t , ? JI7* 33 J J Ute GK. IrAxaCW F%aan tffannf n*c af ecupiiaf of fciaMa iM e*nfu|a Muum >a w . Ota Barpi ctat i C* Paaat. :9JI. 14 MUUHOI, Mamr K. toyTM* It. ten-Ct Cmmw af hiwaw ofmf feararaaftM0*w4$* iwiwaa *iia Htfra**. Ir / Hi--I 1977; J4J4I-K3 13 Brtk* K. Mara HI. ScMmMi L laaaai af uull ptretaafat of tarai hamoftotm 1mm, IW i4 11774 SarycM Cl. Hie* 0*. AhMft I. Ha>n tl wtanil 0i. iraiimwi mk ^amirifaiM imta nit imtaa ia. >*a*arQ.a4 TMte nii W fan. til I Lm. IVIO 7ti4. 17 swal A. MkOaN 0. Injnm CM. TV uwinaa af U*a iMafmi-- '* SS *--------ta tra( Cl *4 TV* ta en s vna>.ia: < 4. a * Smia* S( QayAf Staaineu maoat of cm* *ta vu, arvi0MI Afncr V ftaMann oa Cmm *10 143 *4 7na/ .M. ATutaMuM IK Gtof aafSMuW (UM4a x *a . *af v -ateay. aarpa a4any, m 01a wn of p^} vea Quid. ,r*. Jl (704 30 H,a P*u*f l. C*u 19. m il Semtxm of tip* uulx *p* afMu Ir / HiiwmJ 9*> *4 j%m lJ s*fsAi CT kMcar Ah amextear wv/^rruoui af Vmofiaaia md m 11 ta tteba c liwu Skaaa .yi il .lii- U Suua*M .Xitaar^f Bartlat;! 6wwriHWSfaews. tw. hi '.acaai <aa <*iw M>|ai Mftjwv of iim gi i*c* raj 4mia 1 Ok Iamk iff) 31422.)]. 2i May a. HimAjuCX. TTiacuacaKrttna itaaiMaaca af fit otvyaa Uhnx', * nmm+fjut S Ir I Hmrnmm 9J;JO;)t' )5 24 Da>ar Ot loy 5M. GUrtCM S. Haiaunmaa K 'rSt'^Gai * M aradMim t*4 virf f F trlh * ueU<D mm K ]au / mm tn. it*-142105 U firrmny MI. *aoa WG, Wasterti 2J. Sr-na 17 Pnu 3*waa M w Mcaia (ana <a x* mm* of luiaa Sau Anii Ir I Hmwxam 471. *> 415*59. 21. S)mi Gft fatal fcaawiflatw n 7aao<yf9ia tickja c*J tiH^ Oia Hmm I97S. 4 109-11 27 teraac CM. SManama A. Ittua M, rfaw JC Wtut 3E ton- Mitaa af Mklaai(-i*tlaUuaia u ia4>fa ticu **i on^ua Ir 1 Himihi 1979. 4|.t>91 Zt HrrmFJ.Cmmmn.UrnmCM. H--upmtmw* uvxiarti.* jawrfanaMt aaifMi9 a aMaayfaaa ucUa U <lmam fr, opwui*ai 1911; 9t9*U 29 Hawiar H. NnfcM H. Haw KJ. itrymm Ct HMiAaaMf 'wurv ataoM aa mrnmtm mrnmm aftef--anl leaf itau* m taua cal MM. Ir I Mataunf. t9t J0-J9-M. MEDICAL PROGRESS THE 9ATHOCENESH OF ASIESTOS-ASSOCIATED DISEASES John E. Ciuuchzao. M.D., amo B*oo T. Momman, Ph.D. A SBESTOS i* on of our mci umTu! minerml*. Over aV 3000 manuOeiurad ixodueu of oontcmporarv imporunc* contoin it. Ajbanaf il employed in con* nruction material* became it m remtant to thermal and eorroava dtrarrina aad increaaa the temik itrenfth of the praMam. These ptopertiea are alao the basil for the uae of the mineaal in friction equipment and ia a wida variety of eoatumer itema requiring a relatively inrtpenaive inaularion material that 11 light and tubjeci to tnoidiaf. Since the turn of the century, about 3x tO7 too* of aibato* have been used in conitruetioa and ia the Sabncatsoa ofmanufactured fooda in the United Seatea. At present, several million Americana are employed ia industries that use asbes tos product!, aad countless millions of American d ti ters* are expaaod to asbestos cryptically in the course of their dailv lives. Public concern over the eflecti of aibeatoi on health ia mounting. Although a total ban on its use in this country haa been proposed, most would agree that NaUiemn Slam. Umuairiv--nrmaataOUM daa.lmwpt VT MM*, rt--nymi QI-- owuaa. i. Or. cr.u aabaaaos cannot be replaced expeditiously in rnanv products. Litigation baaarf ou personai injurv conse* quent to pulmonary fibrest* and cancer is an increas ing problem for companies involved In the manufac ture, use, aad distribution of asbestos. About 12.CX30 suits have been brought against 260 companies bv workers, their families, and members of the genersi public. The spectrum ofliability has now widened to involve the federal government hr alleged negligence in establishing adequata environmental standard*. Thu review summarises our current knowledge of the adverse effects ofasbestos on health and provides a perspective on the pathogenetic meehamtms of the diseases associated with exposure. Since there are set cral different minersiogk types of asbestos, we well attempt to assess the extant to which findings with one type can be applied 10 another. Detailed anahses of the isaues addressed ia this paper have been published elsewhere.'"* MiNOULOor Asbestos it not one auaerai but a family of fibrous hydrmani MBcasaa thru are divhkd on the basis of nuneraiogk Ian terse !nm two groups: the serpentines and DUF 0934469 DU 036899 <SE.VTOn-AiaOCIATtO 0(5C.^SC3 _CIt-V(CHE.V0 VNO \tOV,M,t.\ the xmphtboies (Fig. 1). The term "ubestta" refers to tne commercial product tiler mining and processing ind it not a mineraiogie designation. Although the lengthiwidth nets'of the mineral fiber known as asbes tos is by deflrudon >3:1, the individual fibers making up the matenaia ujed in commerce vary subatantiaiiy n width and length (Fig. 2). Chrvsooie ii die only serpentine of commerdai im portance. it :> compoied of pliable, eurty fiber* made up of fibrillar subunits. There fibrils are arranged in pieudonexagonii array* sempoeed of tiiieoa oxide sheen termed mto scroll-tike structure*. The magne sium ion, which unpara a strongly poaidvt charge to the fiber, is an integral component ef the lathee. The amphibole* are straight, rodlike then consist ing of double chains of tetrahedral groupe having a basic silicon oxide compoeihoss and linked by one or more cadona. The amphibole* differ from ehryaonle in both physical and chemical makeup. Thee are several types ofamphibole, but croririollte and amotin are the two mineral* of major important*. Although an isburnt type la classified on the basis of it* mineralogic characteristic*. the products of dif ferent mines are not areatardy the same. Moreover, a commercial type of aabesue is not always miner*logi cally pure. For example, Canadian chryaocile contain* small amount! of an amphibole fiber, trtmolite. In addition, industrial grades of asbestos art contaminat ed with excransous inorganic and organic substances that are acquired either naturally or during proc essing. Deposits of terpentine and amphibole arc ubiqui tous in the eruat of the earth. Outcrop* art found in many geologic formation* and probably account for the mineral fibers commonly found in turiact water. .Asbestos is also found with other minerals of commer cial importance, such aa tho iron oca (manat-- aad in dustrial-grade tale. Canada aad Seam AMa am tho major suppliers in the uter world, although mines of limited commensal importance are (band in many countries, In the Uaksd Scat-- serpeanat aad aaiphi- bole minerals are distributed widely ia geologic strata, but only two relatively sanal afoirlnVMjai a ml 1. Type* <* Ase-aos at Commowsd me Memo vnaen tenca iM Then cnamaa C--n--ane. C0 npure tfai>n Sauoaea Fiara or Sen-- (Chy--) sna amanaaa lews--| . Than# seaming ------ ffsepogmm* tt Mams--i ikaon sqm Canoar iUvmm weks or dvywM (kata A) ve areas--a (Penal PI Manaueaa-- me na--ante* or mar* in Pam Senpai ena aomacer. tdwaorasAa er tw nanwar vaoiaai nan--an --ar n--us In --a --urn *ineaa woaiy. OMiniVVI||V^DIi(rV--Wm<imfVi'w<Mlwn orcm*--* am Ok mm me --on* or ns mart a --aperU-ama--a. W--i -- m--W antika--aayMr.C--o Wiamurn.nsi--in--Pam----;unmar--rtav--nereCal- ia--<r naaawno. Cahfcrs-- an --Mi Thr a--r af **--ne pr-- due-- in dm-- IMoamd dw Psopfo's Eepabheaf Chhm for --ad* that cm-- hi tin Warn Ghryaodfot--t--liyaaram--fooaarDp--ea--of tha tool --ban-- a--rbe--d hi thia eouiury and abroad. CroddoUea ia tha noat widely uaad amplubole, but far reasons rowsiderad below, its onmmereial impoetaaea has daereaasd over the pate several decad- (Table 1). If-- or A tncrrm The unique physical properti-- of asbestos dictate its continued use by industry, despite contemporary concerns about its effects on health. Although vario-- sun irti-f- and oaturaliv occurring m--tamest have been developed -- --hens-- for --heat--, aoae DUt 0934470 DU 036900 ~iC s;-A :\n:A'i.ruvii. or v,l;i,,.;vf tott i. ionjutrotion of ~*st 31 sarnies m me -"-'d Steles r '971 r< J Idil'Si jfkv UUI*M -fbllMhU fiecMun -etJVTT moirid <M kjeM<fini pion MwttotcwMat jiftturt* noonn< prodwtl otulpf sroduen 9tckif infi |iuu uuifiiio*. ihcrnui *i Killian. (Moncil prduu Catt-np ltd coaipofofttt "mimt P04T Ottar Tai 1 > `00 * M0 W-000 U.JOO u 4 XB 1 00 4J.JC* 0.900 XX3 I.9Q0 a *JX iJlXB u 'oo _ _0_0 _ n_a _90 OO -- 24 *00 :_oo ;_o_o _ _ __ MO l *00 44.000 * WO JOJOO U.XO 12. M0 4.000 2.M0 4J.*00 O.MO M0 MO 500 ;o.too ja.Mo -UeeVee tree M Ml4 M' ftmjL matches ubesto* in providing tensile ttrength uid moldability u well u resistance to fire, fleet, tnd cor rosion. Ia addition, many of the manufactured tubestutet are comparatively expensive.* About 23 per cent of the aabeatoa oonaumed in the United Stater ia incorporated into cement piping for water matna and sewage Unco. Over 320.000 km of pipe, containing about 10 to 20 per cent asbestos, ta believed to be in uae in due country. Ajbeetoe-contam ing cement ia employed widely in corrugated and fiat sheeting, panda, dim, and moldings for the cenetnjclion industry. The mineral it need extensively in roof ing and paneling and ai a filler in architectural dead ipacea. In the past, suspensions of aabeatoa were tpraved onto the itructural neei of buildings to pro vide insulation and fire protection. Because ofit* thermal eeabdity, nhassna la well suit ed for uae in Diction material and ia applied to molded brake iiniaft. Although tubadrates arc being incressingiv employed in disk brakes, aa ia the aircraft indue* try, a drum-brake lining for paeetager ears that dam not contain aabeatoa ia not available commercially. Teetiiae and pleads of a variety of types and appli cations comma ahbamsm in various concentration*, unee it imgnni'MdNmatnfco aaad enrreaoa as well u tendla eomhpft wkbem hueaBnaiaty altering the properdm rfdM pmdani or incramtig ia weight The esuadem addidonsi induetnei uses of asbestos are of concarn heeluae they can be overlooked by the manufacturer and unraeogiuaed by the consumer. Al though aabeew was known to industry before the nun of the century, iu use in the United States iaertased dramatically during the mobilisation that accompa nied World War !L Aahaaoa was empfoyod liberally in the tonatraeden and rseondltiealng of ihips and tn tueh diverse war industries ae the manufacture ofair craft anginas, eamhat vahidee, and gas masks. Al though worldwide production has continued to in crease dace the war, consumption in this country has CtODDCd iubttintn.lv during the nut sccise. TV,, tre-.u can or c-tpcc:ed to continue. Since tne ttenev serod for tr.c d.ieucr associated wun user tot 1 .u. i.lv 20 veara or longer, moit pauenu seen todav were ntuiily eaootcd in the 1940a and l9J0t. wnen control Tenure* were often not ngorous. Dilutes or ths RxsriRATOKY Tract and Thorax TSe mijor pathologic effects of asbestos result from the tnhilation of fibers tutpended in the ambient air. The occurrence of disease is influenced bv the tvpe of mtnerai and the dimensions of the fibers that consti tute it. as well aa by the concentration of fibers ana the duration of exposure. DosoaSleii ana Transport In ttw Limps Timbrell et *1.* itudied the deposition of fibers of asbestos in the respiratory tract, using a cut of the porcine tracheobronchial tree. The diameter of die in dividual fiber* proved important; length wii a less important determinant-'0'11 Fiben with a relatively broad diameter are deposited in the upper respiratory tract, whereas thin fiber* arc earned peripherally into the parenchyma of the Iung, where they lodge in the termtnal airway*. BdurcaQoni art common ate* for fiber impaction, since patterns of air flow are altered at these suet. The shape of the fibers also has a roie in transport. Aerodynamicalty, chryviule has t relatively arge theoretical ernes racoon *1 diameter because of its curiod configuration. Thus, fibers of this type tend to be depotstad store pcosmaily than the needle-like iraphiboie*, which an transported more readily so the periphery of the luag. These theoretical and expenmental considcntiona have been verified by analyses of the lungs of rodent* experimentally exposed to as bestos of dtSerant type*.'* ` Three biofogk oaeehaahum* participate in the clear- arte* of 1ban from the lower respiratory tract. Bv far. the hufli of the dust is removed by the mucoaiiary rareislor of theIreehad broockial tree, and the macenai it either expectorated or swallowed.11 In the peripheral airway*- abort (base are ingested by macro phages. end at lean some of these adIs probably mi grate across the wail of the bronchioles and acini. Aabanoi Iban art also takes up by the epithelial cell* lilting the airway* and appear to move between ceils of the timedm.1*'* Thi* material accumulate* in the interstiaum and ia carried ta ragieaai lymph nodes.ir In genml, aJtarc fibers an dearari men readily chan long Shorn,17 which tend so be retained in the lumen* of the respiratory bronchiole* and the alveolar duett. About a third of the tnhaiad parridca initially lodge io the distal airway*. Howtvw, ooiy about a quarter of this koideu is retained ia the rapiratory tract one month laser.11 Then an two phases of clearance through the tracheobronchial trot. About half the a*benos is removed widria a few day*. Subsequently. DU 0934471 DU 036901 ! , :i ^Eixos-^iscciArsa oisE.t-.es -- ;x...che.'0 i.-o .,cw.;a.\ clearance amuiua for extended periods. The bulk of dm material is excreted in the feet*.'1 \ variety of extraneous influences such u cigarette imoke wd ir pollutants affect tae clearance ir.a israpuimocary deposidaa offiben. However these fiacton ire extraordinarily complex, .n part occxt.se indi viduals Ippexr to differ in inetr response* to innucd bUJC.'3'35 ASbestOSl* Diffuse pulmonary fibrous is the tvpicxi lesion ssso* hated with prolonged, heavy exposure to noetic*. ft develops slowiy over i period of years xnd seems to progress in che absence ofcontinued exposure to ssbe* tos. Imaailv. Sbrosu is found in and around the respt- rstory oroticdioles and alveotarduccs, where relatively lon( fibers deposit. With ame, the fibrouc lesion pro* pates in a seemingly ocmmugaJ manner, to that in creasing numbers of respiratory units are involved. Fibers of ajbestoa tend to accumulate preferentially in the lower iobea and adjacent to the visceral pleura. Fibrosis is usually prominent in these regions, and the pleural surfaces of these lobes are frequently thickened ova dense lever of fibrous tissue, [a advanced asbeatm sis. the fibroac pulmonary tissue contracts and is reor ganized to form the new air space typical of the honey comb lung. Ferruginous bodies are the histologic haUmar'- of exposure 10 asbestos.11'3* They consist of fibers coated bv complexes of hemosiderin sad giyoopcottstu and are believed to be formed by macrophages that have phagocytued the parades. Ashestorn can exist when ferruginous bodies art difficult to demonstrate in the ' lungs by light microscopy. Oa che other hand, ferru ginous bodies can often be found in the absence of serious parenchymal disease.33"34 Thus, their presence aione is probably not a aoeuiiua for the proliferation of fibrous nwiii Although they hsvo been ho%vn to form from foreign inorganic- and organic ftben of many different typo,3' fcrragiaous bodies im moat human lunge have asbesee a* a core.* For thia rea son. che structures are commonly knsw at tehetsoi bodies. ' The number of uocoetad (bams-at die lung greatly exceeds the number ad ebroem bedim in the ut- sue. It it no< kaqen* fltal era eoued snd form the typed*! mbdeledbodle*. sstarea* others ire uneoated. Since uneoettd fibers ere usually diffi cult or impossible to demonstrate by light microscopy, I ung tissue mutt be digested and the residue examined by either phase or etectroa microscopy in order to earry out qualitative and quantitative iIndies of che fibers. Whereas relatively long fibers (>5 nm) are found by light microscopical technique*, electron mi croscopy makes it possible to identify very small parti cle*."1`1 Thu* for. attempts so eoeteiMe the extent of disease with etcher the number of ashrams bodies or the overall eoutent of fiber* In the lung* have been difficult, although fibrosis i* ueuettv evident when 10^ fibers per gram of lung (wet weight) are present. Quinciilitve studied pose manv problems sna ice cn.v i crude Tenure pf exposure, p.imv Peciuj* -runv fibers ire Cleared from me lungs and otners fragment o .mreiaingn imailer particles a.in time. Macroonages ire i kev element in the response of the nose to labesto*. Whereas these ceils phigoevure more fibers ino remove them from the sarwavs. they cannot encompass and transport use longer fibers. Al- tnough retenuon of these tong fibers m the diatai air ways appears as be sis important consideration us use causation of pulmonary fibroaii, 430 the oathogenesia of the iestoa is not understood. Incomplete phagocyto sis of asoestos fibers us tae airways could result in tptiUge of Ivioiomai enrymesand release of rotubie fibrogenic factors from macrophages,'3 On the other hand, oxygen free radicals liberated by macrophages and other inflammatory cells might also injure iung tisaue. This idea d supported by our observations that superoxtde dismutase, an inntbttor of bioiogse oxi dants, protects cultured respiratory epithelial cells from toe evtotoxic effects of chrvsoule I Mossman 3T, Lxndesman JM: unpublished data). Chrvtouie is ev totoxic in vitro preaumabiy because the magnesium of the fibers interacts with the plaamalemma and dam ages it, along with lysosomal nvemorxnes of ceils.** ** It is unclear whether this is an important mechanism of tissue injury, however, since pulmonary macro-' phages and epithelial cells in che lungs of animals ex posed to aerosolized chrvsoule fail to reveal ultrastructural evidence of injury, *-1* Other biologic phenomena mav prove important it the causation ofpulmonary fibroeix. Aabestoe actavatat complement bv the alternative pathway14 -- a reac tion that may be expected to result in the accumulation of leukocytes in che tissue and the release of lvtoecreal entyne*. This observation is consistent with che find ing of an acute inflammatory response in some early iesioae.**"*3 Finally, consideration must be given to the ponubsiity that aebeeee* sdmnlaut the production of coUagca by cell*. When chrysolite is added t* cultures of fibroblasts in vitro, the ctils elaborate reticulin and collagen at an acodernced race.'4"'4 Although the hypochedcal mechanisms mentioned above could account for che deposition offibrous tissue in the lungs, die pertsngessesis of sabracoaie he human being* remain be established. The question mav be moot, however, stnee modern environmental controls have drtnuacsUy reduced exposure in the work place. The dust concentrations permuted by current regula tions will probably not induce substantial pulmonary fibroai* during the lifetime of an industrial worker. ' ' Ptauref Last--* Plaques are curious lesions made up of hyalinbed fibrous tissue located on the parietal pleura of the tho rax, diaphragm, mediasnaam. and pericaidium.*'-31 They are usually but not invariably associated with exposure to asbestos.34 Although the occurrenee of plaque* correlate* with the duration and intensity of exposure, it it common to find lesions ut the absence of OOP 0934472 DU 036902 rwe sca CM.t \M) dl.^' -ri.ic :sr obvious a i scale of :ne auimontrv oircncbs-nt Thus, relatively until amounts of du ctn induce :ne devel opment of plaques. These benign lesions ao not appear to develop into malignant mesotneiiomaj. luriscc One is 'erupted :o attribute tne fibrous even on the visceral pleura io imtinon ov the pnvucaj -ret. ence of fibers on or near the surface. Thu mechanism might siso exolun ihe occurrence of ptaques ;n ..-t Chameteruueiily, plaques ire loctted in the rntercottti sptcet on the interior tnd postenor lateral as parietal pleura. Auemativelv. the lesions msv retire. sent in orginised fibrinous exudate resulting from me pects of me moru tnd on the dome of the diaphragm physical movement of the lungs against the oieursi it suet where the vtieeni tnd pinetti pieurtt sp- surface of the thorax. ' proximate during respiratory excunioni. The configurttion of the plaques is highly vtntoie. For example, on tne cncst will thcv usutily follow the contour of the However, these hypotheses are not fully consistent with ihe pathological observations. For example, plaques are often found without fibroin of the visceral nb. w.ncreti on the diapnragm they tre customtrily cither disk-shtped or geometrically sniped tnd hive t noduitr surftce. Over time the letiont became etld- pleura or adhesions between the pleural surfaces, in addiuon. the lesions are loraiirrri and do not occur in the apexes or m the eestophrente angles. The patho Sed, pcrmittinf ctsy recognition on t-rty Alms. Al genesis of the lesions eannot be defined tt present, m though most of the tvtiltble epidemiologic informa part beeausc plaques occur only m human beings and tion it bated on radiologic surveys,1J1' it n not ilwayt experimental models have not been developed. dear in published report! whether plaques were differ- Experimental studies by Stanton et al. 1 provide emitted from the fibrous lesions of the visceral pleura an intriguing basis for speculation about the patho thit teeomptny pulmontry uocsiotit. Sinea plsiquei are found most often in persons ex genesis of mesothelioma. The dimensions of the fiber, but not the chemical composition, were {bund to be the posed oeeupanonaily to ssbestoe for extended peri critical determinant affecting the development of tu ods,their overall prevalence in the United Ststea rnon in rata. Long, thin Shots of a variety of types is low." In Eastern Europe tnd Asia Minor the letiont proved eareaogsnic when introduced into the pleural tre frequently found in older members of the general pace, whereas short fiben and those with a reigttv^y population who lack documented exposure to asbes broad diameter (ailed to induce mesotheliomas. These tos. The presence of fibrous minerals in soil and in findings are consistent with epidetnsoiogie observa local construction materials mmv account for the tions documenting the relatively common occurrence common occurrence of pleural plaques in these re of tumors is populations exposed to grades oftroado- gions.4*41 Malignant mesotheliomas of the pleural and perito lite consisting prwhsnininriy af long, thin fibers and the rarity of tumors in persons exposed to the esm- neal eavitaea are considered pathognomonic of expo parativelv blunt, shorter fibers of tmotite and antho- sure to aahestoe, although in many patients a history of phyUite.`J-n''* A fibrous seoiite, eriomte. has recently contact with the mineral cannot be dialed.**"** These been associated with the occurrence of pleural fibrosis rare tumors are of particular concern from t public- and mesothelioma in a rural area of Turltsv where health standpoint because they are thought to occur in commercial milting of asbestos does not occur.*1 Since persons who have had denar transient or indirect ex the fibers of this mineral do not possets the chemical posure to asbeetoe.*'"4' The development of elaasrhs properties of ssbestoe but tre morphologically similar liomas at a consequence of casual esponura. however, to crocsdoiitt fibers, the observation is consistent with I is an uncommon event. On the other head, the preva the experimental findings of Stanton and his aatoa- lence of the tumor tm wortwes who haws hod heavy atea.'*51 . exposure ovar extended periods in atom 2 to S per caw end has been reported to approach 10 per cent.**4* It The basis fisc the development of nnsnthcHotnn in tbs r-"---- is uncertain. Presumably, fibers ef as- is difficult to determine hots often mesotheliomas actu beams io the tangs are traasportnd in lymphatics to the ally occur, because dee hsesy is usually 20 abdomen, where they have bean recovered from lymph yean or tager tad on oft** be aa bang u 40 to 50 nodes and other organs.75'7* Asbestos is alto transport yean. Soot auggaFtos as qpiriwmis of mmorhnlio- ed across the mucosa of the gut after ingestion.'u* mat will appor lei dm iMa decades af this eeatury, consequent so the epnwe ef large email an of weekera dusiag World War IL Whatever the modunasm fer entry ofasbestos into the abdomen, is is aauamd chat the pafringeurns of the rumors in the peritimml tad pleural caviuea ts umiiar. ^ . \ The lathngmadi af the pteani Mon associated Perimoaal rassnrbrlVami occur only in pesoni ex- "*r% with exposure so aahanaaii nos kssotra, bus it is a topic pasad smpbihnle asbeam*. The gradual diuntegra- of considerable contemporary interest. FThron of thn visceral ptema, plagues ef the parietal pleura, tad masothsHnsna preheMy devetep by difeeat meckn- uon ofchrysotilt in tiasoc may account for the relative ly uncommon occurrence of mesotheliomas ofboth the pleural and parimotai cavraea in persona exposed ex mama, although a rigorous defense of this conclusion clusively to ehrysotila.'* would be difficult. As mentioned above, asbestos is The marhiairm ef mnligmee transferawoea of deposited preferentially in the periphery of the lung metochcbal tsasnea is obscure. Surprisingly little ex I after inhalation. It penetrates the visceral pleura tnd is perimental intormxnon has accumulated, although carried in the pulmonary lymphatics to the pleural there is reason to believe that the lesions may be eora- DUP 0934473 DU 036903 `*01. 2CS 24 ^aST0S-ASS0ClATt3 0iSE.a3-CR.\iCHL*.0 kso MCSSWA.' parable to the fbftifTvbody jarcomaj induced jubcutaneouaiy in anunaii by sheet* of piajnc, $!iis, jnd metal. Tile cell ot onfin is toc ceruin. ur.ce tome cumon are made up of rruUfBuit serasai ceils, -fnere* as otnen have the histotofic features of fibrosarcoma, Mesothdiai cells phafocytue asbestos10 and proi.fer* ate when exposed to asbestos in vitro.1' Put rul.^nam transformation nas not seen demonscriced after expo sure of cultured mesochetiat cetU to asoescns. Cocarcmofemc suoscances and cigarette smoke do not ap pear to be pauofenetic facwn m viva roncnogsms Carcinoma Eptdemiclofic studies have documented an usod- auoa between bronchogenic carcinoma and occupa tional exposure to ubestoa.*4r The prevalence of tu rnon t* higher in person* workiflf wtth the finished products (such as insulators) thaa in nruners and mill ers. The seventy of the pulmonary parenchymal fibro sis correlates with an increase in the number of neo plasm*.1*49 However, the madenc* of tumors s also increased in asbestos workers who lads radiologic evi dence of asbestosi*. - Some controversy exists over the most common his tologic type oftumor, but among persons with asoesto- sis. adenocarcinomas predominate.*91 The lesions tend to occur more frequently in the tower lobes in conjunction with severe degrees of fibrosis.* Atypical hyperplasia of bronchiole/ epithelium and multifocal adenocardnomas are often found us these sites. A linear dose-response rtiaaoa between the cumula tive dosage of asbestos tad the development of bron chogenic cardaoma has been reported in miners und millers of chrysotde tit Canada9* and factory workers m the United Kingdom.** In the former study, those at greatest nsk were exposed to concentrations of asbes tos in the air that were higher chaa the current regula tions of the United States Occupational Saiety and Health Administration permit. A higher eardnogenie potential far croodoAif thaa far chryiook has been suggested by studies ofoccupational groups exposed to either type of asbestos or to the two in combination." Mortality among chrysodic workers is increased 2.4fold, whereas it is five times higher than normal among miners of both chrysotile sad etoddoiilc. Surveys of the smoking habits of insulators,n fac tory workers,MJ* and (users sad miUers** have eon- nstencly shown thsi hmMfasgseic evosesa is un common in dune wha da noe isrti. Whereat there is only a slight inrrsan is Um pruvakaea oflung cancer imonf aanuBOtes, heavy users a( agartetes (those imokinf more than 20 par day) have an *0-fed to 90 fold greater predispoatoca a, eaacar <rf tha lung.*** Thus, the combined afccta of asbetma tad imokinf appear so ba eaailipikadva rather than additive.* Whatthe mechanism ofmbeaeae-siidtiesdeareino- genctis in the respiratory tract? A consideration of contemporary ounce pts of neopiasdc traajfcnnanon is appropriate ia developing in answer to this question. As initially recognised by Berenbium, carcinogenesis , a sequence ot ever.u that can be civiaed into step, of nitiatton and Dromotion. - An initiator interacts with the ONA of the target cell -- an event that can retuit n malignant change. The carcinogen either acts di rectly with the DNA of the ceil or requires metabolic activation bv cellular eruvmes. A promoter is generai- v neither mutagenic nor carcinogenic, although it is required if the neoplism is to develop. For example, if :he ikiri of. mouse is painted with a small amount of a cnemical carcinogen, ,uch as a polycyclic aromatic nvdrocarbon. tumors fail to develop uniesa a pnorbol ester is iubequentiy applied to the site. Promoung substances causa cellular division and proliferation as well as biochemical change, in the cell mat appear to be essential for neoplastic transformation.'* Although epidemiologic data tinis exposure to asbes tos with bronchogenic carcinoma m human oemgs, :he precise role of the mineral in the process has vet to be defined. Since asbestos is not a potent mutagen 00 and inconsistently causes chromosomal aberrations m ceils, ui'ios , nod, of action comparable to that of a classic chemical carcinogen is unlikely. It therefore seems more plausible 10 suggest that asbestos increase* the susceptibility of epithelial ceils of the bronchi and cheir branches to transformation by caranogess in the environment. ** What biologic mechanisms account for the synergis tic carcinogenic effects of asbestos and cigarette smoke in the respiratory tract? A plausible hypothetical con struct should be consistent with the aoparenc lack of a threshold in human beings and the occurrence of neo plasms in the absence of appreciable degrees of pulmo nary asbestoais. .Asbestos has many of the properties ofclassic tumor promoters, such u the phorboi esters.104 Prolifenooa and squamous metaplasia are induced ia the respira tory mucosa of rode.es in vitro.100 .Asbestos interacts with th* ra*rabran*s ofcells1*--laf and induces the syn thesis of the poiyamiaes that accompany ceil divi sion. ;0* Since dgaeenc moke also contain a hoar of lubstinraa with promoMr effects, the inhalants mav act in either aa additive or a synergistic faalsou to enhance the suacepeafaiUcy ofthe respiratory mucosa carcinogens. However, alternative mechanisms art worthy of consideration. Asbestos can be phagocyused by the bronchial epithelium and can be transported tmracei- lulartv both free in the cytoplasm and in phagolyso some*. a These liber, may serve as a physical earner of the carcinogens tn cigarette smoke to the basal ceil, the presumptive progenitor of the neoplesau. Transfer of polycyclic aromatic hydrocarbons to and through bio logic membranes occurs promptly and efficiently when the hydrocarbon ia adsorbed to asbestos. 0* There- atler. the hydrocarbons arc converted by microsomal mixed-function oxidase, to biologically active epox ide, and diolcpoxides. which can interact wtth the of haul ceil,." .Another ibut leu attractive) hipotlicsis involve, the alveolar macrophage, which pliaguuviixcs asbestos in the atrwuvs and posscucs the DOF 0934474 DU 036904 the E'.ct.t.vD.'Oi g.vw. or mentctvc cnrvmatie capacity to convert oolvevcltc -ivdrocarbom to ictrve metabolites.'" At proem, the mediantsrn of asbestos-aisoaated carcinogenesis it unclear, although the mineral appears to act like a clinic itunor promoter. The fibroui nature of nbesto* u criti cal, since exposure to nonfibrous oxides of silicon t for example, quarts) and t vinery of silicates is not usooited with an therelied ns* of bronchogenic carcinoma m human beings. Caewara of the OlgaatKa Syetera me othar Organa Asbestos is implicated in the causation of cancer in the upper and lower gastrointestinal tract and the kid ney. '"* Oropharyngeal and esophageal tumors oc cur more frequently in asbestos workers who smoke, "nereis s direct reiauon between smoking and the development of carcinoma of the large intestine and the kidney haa not been established. Selikoff and Hammond'** and Elmea and Simpion11* have reported a itatisdcallv 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 us establish an asso ciation between exposure to asbestos and neoplasms in this system.1 " We believe that the evidence must be incased cautioualv because the association* thus far reported are relatively weak. Since death certificates are used to obtain data in moat studies, it is possible that peritoneal mesotheliomas have been confused with metastatic carcinomas of gastreinteitiaal-tract origin. The general population is exposed to small sueam of asbessot ia driiddng water, beverages, food, drugs, and agricultural product*. Potable water often con tains mineral fibers that are presumably derived hem geologic deposits and refuas dumps. Tbs hading of fibers of amphibala asbestos in the dhabing wstw of Duluth, Mian., resulting from the disposal of taeontte tailings into Lake Superior,"' prompted mvesngations to dmermine the concentration and characteris tic* of mineral fibers ia water aupphsa throughout the United States. Fibers with the properties of both ser pentine and amphibole sshnsma were fottad ia over half the sealpias of weaar sredsnd (Table 2). Thus, Table 1 CimiHMfiiM rn AMMHhUU UMerai mere to me Water Supoaea ek tel terns but fisaritcaiariti Csenv tuueo m ms uuism Staton* ^snv Amcncans consume water containing jiockcilike minerila. Mineral fibers have been detected .n the -nne ;f residents of Duiuth in numbers corresponding to me concentration of asbestos in drinking water,''* Inter estingly enough, fibers have been found in me glomer uli and tubules of rats exposed in inhaiauon chsmDers to svntheue fibers. "* These observations suggest that asbestos migrates to the kidnev after clearance irom tioth the gsstrointeionai and resptratorv tracts. Whether this has an influence on me occurrence of tumors in ihe gastrointestinal tract is unknown When fed to laborstorv animals, isbestoi nteracts with the mucosa of the gut." Fibers enter ceils of me mucosa and prove eytotaate.,JU The experimental evi dence itrongiy suggests that ingested asbestos is dis seminated to abdominal organs by the Ivmpnatics and blood vessels. This conclusion is supported bv post mortem studies of occupationally exposed perions: these studies have demonstrated asbestos bodies and unearned fibers in moet major organa. * How does the ingestion of asbestos induce gastroin testinal earanomts in human Dongs? In efforts to ad dress this question, rodents were fed large amqunu of labelins over extended periods. With one otcepaon,1*1 these studies failed to demonstrate an incrtise in the prevalence of tumors in the fut.'B"11* The possible synergistic effects of asbestos on the induction of intes tinal neoplasms by chemical carcinogens has slao been examined.'** Intngistnc administration of asbestos failed to augment tumor development in rodents fed aaooaymcthane. a recognised intestinal carcinogen. The can snugssiic pomrial ofaahesnas ia the gaatroiasesrinsl tram appears m bn low. The pethogencuc bane far the purported increase m the prevalence of carcinomas in certain occupational groups remain* to bn estabdabed. , Pansoaotse Forrasmai. or Asnorroa Try** As eaphatisod above, ubessa* is not one but a fam ily of fibraon auaerak, each of which has distincuve phyiieal aad chemsral characteristics. Minerals from varimts parts of the world and geologic formations often have diatimiinr physical properties, even though they are riteaWad under a specific mineraiogK type. Thcae dilfcrrnrrs sit relevant to our undentanding of the effneta of ashessas on health, tinea the charactenstica of the fibar have baeo Aslly defined in only a few i pulwiclogic aad sstperimental ttudia. The problem ofevaluating the effects ofdifferent types ofasbestos on health in compounded by the eeosmen practice of cus tom Meadtafefvarioon amenis far specific industrial applications Shdthe use ofone type and then another, depending on availabiUty and conditions of the marina. Sean the ampaMfarehrraosCt is read extnorveiy in iatiaasry sadop) it ia important to ask whether its patbogtaae iapectaaca is amtparabhMo that of the erai* are of hisaoricai importance, particularly since DDF 0934475 DU 036905 ;o sv 4S8ESTOS.4iSCCI.4rEO 0UE.4SES --CS-vrCHEAO 4.40 '.ICSS\(.4.N S3 thev were used widely during End immediately alter Wortd War II and are procabiy responnbl* for a sub stantial proportion of d dime occurring today. Much cunspt debite centers around the question of whether id types of isbestoi possess use emptnty to induce mesothelioma. Experiments m animus yield in affirmative answer, but the results of this work miv not be applicable to human Beings, since pathogenic potentiii ind intrapu.monirv transport of fibers ire in dependent consideration!. Of all the types, croddoiite j clearly tne most stroeijly associated with the occur- -er.ee of the tumor. But there are interesting differ ences in prevalence, related to the physical character of this fiber type. For example, in Northwest Cape, South Africa, and western Australia, mesotheliomas occur commoniy in persona with occupational or caaual exposure to crocidolite.u The mineral mined in these regions is composed ofrelatively long, thin fibers. . In contrait, mesotheliomas an rare in the Transvaal of South Africa, where the croddoiite fibers are much coarser. Another amphiboie, anotice, is associated sporadi cally with mesothelioma, whereas the tumor rarely if ever occurs in workers exposed to anthophyUit*. Bods these latter types are mad* up of niatsvtiy skorx, bluat fibers. A number of studies have been conducted us miners and millers in Quebac and Italy, where the serpentine chrvsonle ^extracted.'*'1* Although the results are debated, the built of the evidence iadstates that ehrysooie is not an important csusat of mesotheli oma in chase workers. However, the data from certain occupational groups, such is workers in the textile industry usd insulators who are exposed predominantly but nor ex clusively to chrvsoule, an not as definitive. The risk appears to tncreaae aathe mineral is processed or when dust concentrations cannot be evaluated critically. Unfortunately, most epidemiologic studies concerned with this important question are clouded by uacartaiaty because of the prolonged laiency period of moothe- liomas. Considerable eubrt has ftcuead on determin ing whether the varioua types ofasbestos dtffcr in their capacity to induce bronchogenic careincrna tod fibro us of this lung. Unfortunately, there is ao good answer us these questions as praam, ahacs doac-eeiacad differ ence* in the prrvalrac* ofdiww* have not beta esab- lished. Kaotximar CasBiButww No topic la marc eosnpia and subject ao oonsroversy then the exsMaskaacM of eriaaria ea which so w--staadards lor air quality ta tin wesrk place. Regula tions are exceptionally difficult to develop, because it is necessary to us* data on morbidity sad mortality doc umenting disease retrospectively ia members of occupaoottai groups who have had heavy expaaunt either in the remote past or over a lifetime. The difficulties are compounded by the long lateaev period ofasbestosts and the asbestoo-associated cancers. Although ircommcndationa for levels ofaahcstoi ia me sir of occupational settings n uhis round-* ,,5rt formulited in tne '.940s, it was not mul 19 70 ;.ut federal .-eguiationi were promulgated as a result of-he passage of the Occupational Safety ind Health Act tna me Clean Air Act. The initial standard was based on the light microscopical count of fibers of a iengthof 5 nm, collected by mechanical meant. A concentration of five fibers per cubic cendmeter of air, avenged over an eight-hour period, was deemed permiisioie, with itipuutions for transient excesses above mat concen tration. In i975 the contemporary standard of two fiben per cubic centimeter was established, and more recently a ievei of 0,5 fiber per cuoic centimeter his been proposed. Is the current limit oftwo fibers oer cubic centimeter sutficiemiv rigorous to prevent disease in me future? is t topropnate to baje regulation exciuitvriv on determutations of fibers of >5 *im when tne bulk of the dust in air consista of fibers of a shorter length? Be cause standards are based on extrapolations from data accumulated among workers exposed to rdauvely heavy concentrations of dust in the past, predictions must be baaed on analyses that assume that there are no thresholds beiow which the diseaie fails to occur. Within the ranges usually found in the occupational setting, there appears to be linearity us the dose-ce- spotue relation, at lease with regard to bronchogenic caranoma. However, the likelihood that cancer wsil occur a infiucactd substantially by cigarette smoking, since the risk in the nenimokcr who has heaw expo sure to asbestos is increased only a few fold. Thus, the risk for the nonsmoking asbestos worker is substantial ly tower than the risk for a member of the general population who smokes two or three pecks ofcigarettes each day. The eonduaion that aabestoais (ails to develop beiow a certain threshold dosage is based on physical examsnation* sad radiologic studiss at workta and tux on patheiogieal examinations. By these criteria. It is prababiy impossible to be certain whether a fibrooc lesioo in the lung is due to asbeaaoa. With mesothelioma, the data are more controversial. Although a doae-tesponse celadon appears so oast, the threshold may be deter mined by eke lift spaa of the person exposed, because the latency period for these cumors is protracted. 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