Document 7g393oj2J2ekXpr5nka26akB

PLAINTIFF'S EXHIBIT DUP-2218 (WC \>v . NL,..vV;>JOIK\m. f)y \j-h< ,\r t *mi c fulm of N>uimu pca iw ^tmy arf wet* =fl UK#m 9M .9**: 51 .l*J4 4 tfmmu HO S<Ut aid arena < 'cjnm a i 4 tt'x* of eUfWR* T rti*ci At Vcofcar I Mite A. TV btucution ofi*k ert *n* *wwf*T4* * nrw<y|a m **'jo rifl enij tyMMtu arh Ht*Mi >919, 9t.;c I *>* 0* tOniHr <*A. *m IN Q<*0 nS. Attn Sf Lnci erf e.4u- cn of fMOwufjiWa ota or nKxa 04 * M'oriy of uette eel umax.. C *vt i9to, 45.71; au 9 AUy C. Sf*i*ly Ml. >Mf* It. WjJa OK AI0*4-<JU*4 < ea/ufttlu* tr^Moyic vtho ,1 iTui+m .* uclm ctl wk KM .911. lj >09)4 !0 hfimn JH 0w> AM, Mite i. u. c*w*w* ixvk-.l m M rrct o uOTtyiMfiti s e0 j vim ,:. w*:io- it Hifl0K. KmmyUSm*jMCK. CitffJI <xJMfiiiOJ TV|*w UK -noteuteluuof *u fthwu mwii >* H4 S l4iu cm IflHiWMI %l 47 4J.J* !2. Suvm CK. SsotM IE. MtlavKf D *?*#*( tictfcK e*il 1 MW of tetel) u > u<Ut C0J Kiif4 tr l Koite I *9 ,7 in- 55 J 5 Ute GK. KrKxt CW Horn* 4ff* te w of cMptt** of *Ww u emfufMK Muum w > n lorpi om i C* Kate. :939, : 1.1 J>41 14 MiteK Of. Mmkw K. Imytmt It. Ct ter-fi-- *t Mwm ofmf (umi of da 0 * <nK <T Kwiwru uw m lunsate Nofrat*. Ir / Hoomwt 1977; 541*1-70, 15 SHU K. Mm tft. Mmm L bnwu K uui pmMn> K tarai hwfto 1mm, IW i4 11774 SoncM G*. Hia* 0*. AhMft I. Ko> Ki wKunO 05. a*w telim-- mik Trcurrwiw imrf riH imw 4. K**Q.oK TtonK nii He* ran. AtU K Lm. 1990 7I4. 17 Sowoti A. MteK 0. Injnm CM. TV uwirm of Ufto iQifmMm '* (S -------!a tir Cl *4 TSt t en s < 4. t vmoj.ia: 8mio sf DtyAf Saaineu mto0t of cjk-mki vu, 1.^ ntmtimm Afncr lm bVMi oo Cmm *93 ii: *4 7***/ .M. ATutolMUM KM GiOial toafSoKuW (UMaKa x *t . Vi 0M*y. orr otony, JIM rum of >mn} vea G< GuiK. ,r*. 51 (704 30 H,a Kattitr u a*fl . 1 Oaauoo of uuUm*. X oCuu Ir / HnwwM 'HO; 4JAK ^ s**fAi CT kMca Ah otnaHJmr wv/^rruoui of *<t,x Mmotooi mk m 11 to ticbo c rfivw tM *%! st .cjr. U SmjumM .MilaorKf Bortlot;K &wwnt`<WSfews. tw. HI MRIM '.aOOi <JW <*IW M>|ai KftAM* Of tlM Ul |*C* ta 4mio 1 Ok IatM i?7i >2.422-|J li Mv a. HimAjuCX. rtocwMCtowno OopmKneo of tx ftMPOfiooia S Ir 1 Hhm 97J;JO;it' )5 tihnx', 9 24 0r> Ol loy 5M. awvM S. Hoikutmoo K '0*v^iwi .uism Jrf orodMim *4 hm*| of F?*b uciit-eoJ mm k &* 1 mm tri. 299-142*05 li frrmty ME. *d WC, Wtstew OJ. Sr-nt Pnu 5Ohto* MO w Mttio *om xt hw ai umi Soup Ansi* &r I Hrnwxam 47|. t6 415*59. 21- Sajapi GK Foul Hmm If75. 4 109-12. n somatifom tickjo c*i tiH^ Oi 27 !g]uw CM. lowwaitt A. M, Muso jc 3E ton- MI09K of OKfcltOll(-A*tloUtMO U A4>t Ir 1 HiwoiiiI 1979. tl U-75 t| tSivuit Zt HtyrnMi.Cmmn.UmmCM. Hur--'ipciif^an uvxiart** paifonavt mrnt$mr/ to Motyfow ucUo U 4lmuo. It t Oprwuiol l9l;l*j-lJ. 29 Howior M. Nnfci H. How KJ. ittymm Gt HwafKM 'wurv MiiuoK Mil oHoooolar uoroi* tfMf--onl looK tbrnt* m >uo m MW. r 2 HatfMHl. (9C: J0-J9-J4. A MEDICAL PROGRESS THE PATHOGENESIS OP ASBESTOS*ASSOCIATED DISEASES John E. C&aicmzab. M.D., and B*oou T. Mohman, Ph.D. A SBESTOS ii on* sfoitr melt awful miner*la. Over 3000 manuOeturad prodacu os' eontempenry importanc* contain it. Aitanm ii employed in oon* hruction materials beeatue it m resatant to tfaenonl and cairoavd dTrunin* and inereaac* the tensik strenfth of the prodne*. These properties are also the basis for the use of the mineral in friction equipment and in a and* variety of consumer items requiring a relatively inntpenaiv* inaularion material that is iifht and subsea to moidiaf. Since the turn of the century, about 3X tO7 tons of ubesto* have been used in con struction and in tb Gsbocation ofmanufactured food* in the United States. At present, several million American* are employed in industries that use esbet* tu* product!, and coumleai millions of American citi zen* are espoeod to aibettoe eryptteail' in the course of their daiiv liva. Public concern ewer the efleeti of isbeaux on health is moumatf. Although a total ban on ia us* in this country had been proposed, most would agree that hen Ob Onumau at MUtp, Usmsms et vsna Caas*s at na <n.WnnrtMi.MiemsneuhMMs>. Ci'Tn*- esbeaaoe cannot be replaced espeditiousiy in msnv product*. Litigation based oe personsi injurv conse* quent to pulmonary flbraen and cancer it an nc.-cuing problem for companies involved in the msnufsc. ture, use, and distribution of asbestos. About 12.CX30 suits have been brought against 260 companies bv workers, their families, and members cf the general public.IJ The spectrum ofliability has now widened 10 involve the federal government for alleged negligence in establishing adequate environmental standards. Thu review summarises our current knowledge of the advene effects ofasbestos on health and provides a perspective oa the pathogenetic meehanitmt of the diseases associated with exposure. Since there are set cral different minerslogic types of asbestos, we will attempt to assess the extent to which findings with one type can be applied u another. Detailed anahses of the issues addressed ia this paper have been published elsewhere-1-* Hpnaiuor Ashman it not am xiioeral but t family of fibrous hydrmad dliciH* that are dtvidad on the basis of nuoeraiogk ienrarse inm two group*: the serpentines and DUB 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 --a- perU-ama--a. W--i -- m--W antika--aayMr.C--o Wiamurn.nsi--in--Pam----;unmar--rtav--nereCalia--<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< jfkv UUI*M ntiMhu ftecMun s -etJVTT moirid <M pion Mmiog cmucat (h*u*c noonn< prodwtl otulof sroduen 9tckif infi |ium Mii4ito<1. ihcrnui "Itllfiliftfl. (Moncil prduu Catt.f'p aad eoapowiti Pint Oitar Tatfii l > `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 suited 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 eamppft 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 cleararte* 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 Ibere 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*. Howtvv, ooiy about a quarter of this koideu is retained ia the respiratory 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. mmr DU 0934471 DU 036901 ! , :i ^Eixos-^iscciArsa oisE.t-.es -- ;x...che.'0 i.-o .,cw.;a.\ clearance amuiua for extended periods. The buik of dm material is excreted in the feet*.'1 \ variety of extraneous influences iuc.i u cigarette imoke wd ir pollutants affect tae clearance and n- 'rapmmocarv depcsidaa offiben. However these lieton ire extraordinarily complex, .n part occxt.se indi viduals Ippexr to OitTer in cnetr response* to innucd blue.'3'35 AtbSStSSlS Diffuse pulmonarv fibrous is the tvpicxi lesion ssso* hated with prolonged, heavy exposure to uSescos. ft develops slowiy over i period of years xnd seems to progress in che absence ofcontinued exposure to asbe*- tos. Imaailv. Sbrosu is found in and around the reaps- rstory oroticdioles and alveotarduces, where relatively lon( fibers deposit. With ame, the Sbrotic lesion pro* pates in a seemingly centrifugal 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 aabeatm 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 soeusius 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 them-at die long greatly exceeds the number ad ehrawm bedta* in the us- sue. It it no< koqwm (tal e coated snd form the typtad mbdeledbodle*. sstarea* others ire unearned. Since uneoettd fibers ere usually diffi cult or impossible to demount* by light microscopy, I ung tissue must be digested and the residue examined by either phase or etectroa microscopy in order to earry out qualitative and quantitative ttudies of che fibers. Whereas relatively long fiber* (>5 ism) are found by light microscopical technique*, electron mi croscopy makes it possible to identify very small parti cle*."1`1 Thus for. attempts so eosteiue the extent of disease with etcher the number of ubeuae bodies or the overall coetens of fiber* In the lungs have been difficult, although fibrosis i* uauett* evident when 10^ fibers per gram of lung (wet weight) are present. Quar.ciiait'.e uudiedpoie manv problems sna ice cn.v i crude -r.euure pf exposure, p.imv lecause -runv fibers ire Cleared from toe lung* and otners fragment o .mreiaingu imailer particles w.tn time. Macroonages ire i kev element in the response of the nose to labesto*. Wheress these ceils phigocvuze more fibers ino remove them from the sarwavs. they cannot encompixj ind transport use longer fibers. Altnough retenuon of these tong fibers in the distal air ways appears as be sis important consideration us use causation of pulmonary fibrosis, 430 the oathogenesia of the iestoa is not understood. Incomplete phagocyto sis of asoestos fibers in tae airways could result in totilsge of Ivsoiomai enrymesano release of rotubie fibrogenic factor* from macrophages, On the other hand, oxygen free radicals liberated by macrophages ind other inflammatory cells might also injure iung tissue. This idea u supported by our observations that superoxtde dismucase, an innibttor of btoiogic oxi dants, proceed cultured respiratory epithelial cells from tae cvtoioxic effecu of chrvsouie I Mouman 3T, Landesman JM: unpublished data). Chrvsouie is cvtotoxie in vitro preaumably because the magnesium of the fibers interacts with the plaamalemma and dam ages it, along with lysosomal memoranes 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 chrvsouie fail to reveal ultrastructural evidence of injury. *'* Other biologic phenomena mav prove important ia the causation ofpulmonary fibrosis. Asbestos activates complement bv the alternative petitwav'* -- a reac tion that may be expected to result ia the accumulation of leukocytes in che tissue and the release of lvsoaoreal cnayeses. This sbstrvscioa it consistent with che find ing of an acute inflammatory response in sons* esrlv iesioas.**"*3 Finally, consideration must be given to the powsibilicy that asbaseea sdmnlasss tbn production of coUagea by cell*. When chrysolite a added t* cultures of fibroblast* in vitro, the ctil* elaborate reticuiia and collagen at an accelerated rate.'4"'* Although the hypothetical mechanisms mentioned above could account for che deposition offibrous tissue in the lungs, tbs pathogenesis at stbrstosis in human being* remnant to be established. The quesooa may be moot, however, since modern environmental controls have dramaacaUy reduced exposure in the work place. The efuat concentrations permuted by current regula tions will probably act indue* substantial pulmonary fibroai* during the lifetime of an industrial worker. Mourn! Last--s Plaques are curious lesions made up of hyalinned fibrous uasuc located on the parietal pieure of the tho rax, diaphragm, madiasnaem. and perfoaidium.30-31 They are usually but not invariably associated with exposure to asbestos.34 Although the occurrence of plaque* correlate* with the duration and intensity of exposure, it is common to find lessons ut the absence uf OOP 0934472 DU 036902 rwe SCA cm,I \M) (it. *s V -ri.ic :s,- obvious disets* of :he autmoatn. oircnchsm* Thus, relatively smell amounts of du un induce :ne devel opment of plaques. These benign tenons ao not sppcar to develop into malignant mesomeiiomas. turticc One ;j ;ernpteq to attribute tne fibrous event on the visceral pleura io imtanon ov the pnvucaj -res. enee of fibers on or near the surface. This mechanism might aiio exolain ihe occurrence of ptaquej in the Chametenjucaily, plaques are located in the inter costal spaces oa the anterior and posterior lateral as pects of me moraz and on the dome of the diaphragm parietal pleura. Aitemativelv. the lesions may retiresent an organised fibrinous exudate resuittng from tne phvitcit movement of the lungs against the nieural at ittes where the vticenl and parietal pleurae ap surface of the thorax. proximate during respiratory eaeunionj. The config uration of the plaques is highly variable. For example, on tne cncst wall thcv uiuaily follow the contour of the However, these hypotheses are not fully consistent with the pathological observations. For example, plaques are often found without fibrosis of the visceral nb. w.ncreas bn the diapnragm they are customarily cither disk-shaped or geometrically snaped and have a nodular surface. Over time the leaiona become calci pleura or adhesions between the pleural surfaces, in addtuon. the lesions are loraiirod and do not occur in the apexes or in the eostophreme angles. The sstho- fied, permitting easy recognition on x-ray films. Al gertesis of the lesions cannot be defined at present, m though most of the available epidemiologic informa part because plaques occur only m human beings and tion is based on radiologic turveyi,"1* it is not always experimental model* have not been developed. dear in published reports whether plaques were differ Experimental studies by Stanton et al.70-71 provide entiated from the fibrous lesions of the visceral pleura an intriguing baht for specuiadon about the patho- that accompany pulmonary asbcatoais. [encau of mesothelioma. The dimensions of the fiber, Sine* piaiquta art found molt oftan in persona ex but not the chemical oompocitioa, were found to be the posed oeeupanonaUy to asbestos for extended peri- critical determines! affecting the development of tu ads,1*"*4 their overall prevalence in the United State* rnon in rats. Long, thin fibers of a variety of types ts low." In Eastern Europe and Asia Minor the lesions proved earaaograk when introduced into the pleural are frequently found in older memben of the general pace, whereas short fiben and those with a relaitv^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 cpidetnioiegie observa local construction maceriaia mav account for the tions documenting the relatively common occurrence common occurrence of pleural plaques in these re of turnon is population* exposed to grids oftroado- gions.1*41 lite conxuung prnVirnlruntty of long, thin fiben and Malignant mesothelioma* of the pleural and perito the ranty of turnon la persons exposed to the esm- neal cavines are considered pathognomonic of expo pantsveiv blunt, shorter fiben of imotite and antho* sure to asbestos, although tn many patients a history of phyUite."-n'7* A fibrous eeoiita, eriomte. has recendy contact with the mineral cannot be etiated.**"** These been associated with the occurrence of pleurti fibrosis rare tumors are of particular concern from a public- and mesothelioma us a rural ana of Turkev where health standpoint because they are thought to occur in commerctal mining of asbestos does not occur11 Since persona who have had citner transient or indirect ex the fiben of thie mineral do not poaseas the chemical posure to asbestos.w'4' The development of fstrip properties of asbeetoe but are morphologically itmilar home* as a eonaequeact of atauai expaeun. however, to crocsdoiiie fibers, the observation it consistent with I is an uncommon event. On the other head, the preva the experimental findings of Stanton and his associ lence of the tumor tm workers who hove bed heavy ate*.7'*1 exposure over extended period* ia about 2 to 3 percaat The basis fixr the development of maeotheHomn In and has been reported to approach 10 per cent/*'** It the |e-tewTM ia maisls. Ftieunuabiy. fiben of ss- is difficult to determine hot* often mcaothriiomas actu heeeoe io theinnga are transported as tynsphadca to the ally occur, because dee Saaarry BfWi is usually 20 abdomen, where they have been recovered from lymph yean or tagv tad out o&ra be a* long u 40 to 50 nodes and other organ*.75'7* Asbests* ts also transport yean. Some suggapto* aal qpirimmie of eranthelin- ed term the mucosa of the gut alter ingestion.'u* mas will appew hi dm laae dare dsn ef this oratury, Whatever the mechanism fcr entry ofasbestos into the consequent so she mpnenra ef large --has of work- abdomen, ic is assumed due the paafaegasserie of the en durtag World War IL tumors ia the peritnarail ead pteani cavities a similar. i The idthugmehe ef the p&eani Mon associated Perioaoml woshrUnmsi oocar only ih persons ex- /, with exposure ashaems is am kaoara, but it is a topic pond ta amphihnt* aabemoa. The gradual dlaintegra- <7-u of considerable contemporary interest. Fibrosa of tho uon ofchrysodlt in daauc may account for the relative- viseoral pUwu, plague* of the parietal pleura, tad msaothahisraa prahsMy devskrp by ddferat snecka- ly unoonunoa oecarrracs of mcaothdioiiua ofboth the pleural and peritoneal cavities is persons exposed ex mama, although a rigorous defense of this concluason clusively to chrysodle.7* would bo difficult. As oseanoned above, asbestos is The arhsaiim of malignant transfermabea of deposited preferentially ia the periphery of tho luag meaochchai tana* is obecura. Surprisingly little ex i altar inhalation. It penetrates the visceral pleura and is perimental iniormanon has accumulated, although carried in the pulmonary lymphatics to the pleural then it rratna to believe that the lesions may be eom- 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, $!iu, jnd metal. Tile ceii ot onfin is toc ctruun. ur.ce tome cumon are made up of rruUfBuit serasai ceils, ^nere* as otnen have the histotofic features of fibrosarcoma, Mesothdiai cells phafocytue asbestos10 and proi.fer* ate when exposed to asbestos tn 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 roncrtogsms Carcinoma otdemioloftc studies have documented an usodauoa 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 asoestosis. 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 ehrysotik sad erobdolite. Surveys of the sonkiaf habits of insulators,n fac tory workers,MJ* and (users sad miUers** have eonnstencly shown thsi hmMfasgseic evosesa is un common in dune wha da noe isrti. Whereat there is only a slight inrrsan is Um pruvakaea of ha* cancer imonf aanuBOtes, heavy umh a( agareaes (those imokinf more than 20 par day) have an *0-fed to 90fold greater predispoatoca a, cssear of tht lung.*>* Thus, the combined afccta of ashram tad imokinf appear to be meidpttcsdve rather than additive.* What is the mechanism ofaabtstoa-'ndacad esrdno- (enesa in the rrapirasory tract? A consideration of contemporary ounce pts of neoptasdc transformation is appropriate ia developing in answer to this question. As initially recognised by Berenbium. carcinogenesis , a sequence ot ever.u that can be divined into steps of nitiatton and Dromotion. - An initiator interacts with the ONA of the target cell -- an event that can remit n malignant change. The carcinogen either acts di rectly with the DNA of the ceil or requires metabolic activation bv cellular eiuvmes. A promoter is general- v neither mutagenic nor carcinogenic, although tc is required if the neoplism is to develop. For example, if the ikin of. mouse is painted wtth a small amount of a cnemicai carcinogen, tuch as a polycyclic aromatic nvdrocarbon. tumors fail to develop umesa a pnorbol ester is iubequentiy applied to the site. Promoung iu os Lances causa cellular division and orolifenaon as well as biochemical change, in the cell mat appear to be essential for neoplastic transformation.* Although epidemiologic data unit exposure to asbes tos wtui bronchogenic carcinoma m human oemgs, the precise role of the mineral in the process has vet to be defined. Since ashescos is noe a potent mutagen 00 and tneonautentiy causes chromosomal aberrations ;n ceils, ui'ios , of action comparable to thas 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 their branches to transformation by caronogens in the environment. ** What biologic mechanisms account for the synergis tic carcinogenic rtfecu of asbestos and cigarette smoke m the respiratory tract? A plausible hypothetical con struct should be consistent with the aoparent lack of a threshold in human beings and the occurrence of neo- piisms in the absence of appreciable degrees of pulmo nary asbestaaia. Asbestos has many of the properties ofclassic tumor promoters, such u the phoeboi esters.104 froliferaooa and squamous metaplasia are induced ia the respira tory mucosa of radcsis in Vitro.104 .Asbestos interacts with th* ra*rabran*s ofcells14--laf and induces the syn thesis of the pofyaminra that accompany ceil divi sion. ;0* Since dgarenc moke also contain a host of substance* with promoMr effects, the inhalants mav act in either aa additive or a synergistic fashion to enhance the suaceptibsHcy ofshe respiratory mucosa carcinogens. However, alternative mechanisms art worthy of consideration. Asbestos can be phagocyused by the bronchial epithelium and can be transported tmracei- lularlv both free in the cytoplasm and in phagolyso some,. a These liber, may serve as a physical earner of the carcinogens m cigarette smoke to the basal ceil, the presumptive progenitor of the neoplasms. Transfer of polycyclic aromatic hydrocarbons to and through bio logic membranes occurs promptly and efficiently when the hydrocarbon ia adsorbed to asbestos. 0* Thtre- atler. the hydrocarbon* arc converted by microsomal mixed-function oxidase, to bioiogtcally active epox ide, and diolcpoxides. which can interact with the of haul ceil,." .Another ibut leu attractive) hvpntltesu involve, the alveolar macrophage, which pliagtsiviixcs asbestos in the sirwavs and possesses ihu DOF 0934474 DU 036904 the E'.ct-t.'.D.'Ot g.vw. or mentctvc cnrvmatie capacity to convert oolvevcltc nvdrocarbom to active metabolites.'" At proem, the mecha nism of asbestos-associated carcinogenesis it unclear, tkjpoufh the mineral appears to act like a clinic minor promoter. The fibroui nature of nbesto* u criti cal, since exposure to nonfibrotts oxides of silicon t for example, quarts) and t vinery of silicates is not usooited with an therelied n of bronchogenic carcinoma m human beings. Caewara o the Olgesttvn Syetera me othar Organa Asbestos is implicated in the causation of cancer in the upper and lower gastrointestinal tract and the kid ney. 2'"* 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 Simpion112 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 gastreinteadnal-tract origin. The general population is exposed to small sueam of asbessot ia drinking water, beverages, food, drugs, and agricultural product*. Potable water often con tains mineral fibers that are presumably derived hem geologic deposits and rtfiias dumps. Tbs hading of fibers of amphibole asbestos in the drinking watw af Duluth, Minn., resulting from the disposal of taoontts tailings into Lake Superior,"' prompted mvesngations to dmermine the concentration and characteris tic* of mineral fibers ia water supplies throughout the United States. Fibers with the properties of both ser pentine and amphUnde ashiwma were found ia over half the samples of weaar traded (Table 2). Thus, Table 1 CiniiHb'HM AMMHhUU MMeM rant* to me Wmm fiuopdat sk fieHcaad but nsernsmerl'is Csreuse natea m ms umtM Stems.- ^snv Americans consume water containing ssociictlike minerals. Mineral fibers have been detected .n the -nne if residents of Duiuth in numbers corresponding to me concentration of asbestos in drinking water,''* Intereinngly enough, fibers have been found in me glomer uli and tubules of rats exposed in intiaiauoa chsmDeri to tvntheue fibers. "* These observations tuggesi that asbestos migrates to the kidnev after clearance from doth the gsstrointeionii and resptratorv tracts. Whether this has an influence on tne occurrence of tumors in the gastrointestinal tract is unknown When fed to Laboratory animals, aibestoi r.teracts with the mucosa of the gut." Fibers enter ceils of me mucosa and prove eytotaaie.,JU The experimental evi dence strongly suggests that ingested asbestos is dis seminated to abdominal organ* by tnc Ivmpnatics and blood vessels. This conclusion is tupperted bv post mortem studies of occupationally exposed perior.i; these studies have demonstrated asbestoe bodies and unearned fibers in moet major organa. * How does the ingestion of asbestos induce gastroin testinal carcinomas in human Pengs? In efforts to ad dress this question, rodents were fed large amounts of asbestos over extended periods. With ooe exception,'21 these studies foiled to demonstrate in incrtise in the prevalence of tumors in the gut.'B"11* The possible synergistic effects of asbestos on the induction of intes tinal neoplasms by chemical carcinogens has slao been examined.'2* Intragastnc administration of asbestos failed to augment tumor development in rodents fed aaooxymcthanc. a recognised intestinal carcinogen. The can snugssisc pomnil ofaahesnss ia the gaatroiatastiaal tnei appears m be low. The pethogencuc basil for the purported inertase in the prevalence of carcinomas in certain occupational groups remains to be estabdabad. Fansooeme Forearm**. or Aanorroa Trass At sraphaaiied shove, asbestos is not one but s fam ily of fibrous enacrata, each of which has distincuve physical aad chemirsl characters*ties. Minerals from various para of the world and geologic formations often have dforindler physical properties, even though they are ritesMad under a specific mineraiogK type. These dffltrrneet tit relevant to our undemanding of the efiecta of asbestos oa health, since the characteris tic* of the fiber have been folly defined in only a few i pulticlogic tad expennvpttal studies. The problem ofcvnhudag the effects ofdifferent types ofasbestos an health in compounded by the eeouoea pracoce of cus tom Mending efvariooa mioerai* for specific industnal appBcttfcwi aad the use ofone type and then tnotber, depandiag on nveilabfUcy and conditions of the marina. Sant the smpeMfarcfcrraosCe in toad extoniveiy in tadnesry tedagf k it important to ask whether its pathogenic importance is comparable^ to that of the enin are of huaerfoni importance, particularly itnce DO? 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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