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. f Htprinttd from Che Arohfvtt of Environment*/ Hoa/th Oetodar 1973. Vo/un* 27 Copyright 1973, Anmiem JWerfcef Aaocmtion PLAINTIFFS I EXHIBIT The Locus of Pathogenicity of Asbestos Dust A Theory Paul Grot*. HD, Kusmll A- Barit], Jr, HD, Charlatan, SC Docsmerrtetf upirinulil tvidMCt, as A theory based on chemical struc veil u tftt mufti of preliminary xptrisnts, an presented which indicsta a re duction in pathogenicity ai fee poljrfil*wntom envtgsment of ntitin putt particles it replaced by a moncfitamentous strvetin. On the batit rf this evidence, K h proposed that tha lacut of psthogtnicity ot atbntat dust particles resides in their palyfiiamenteus s&vcturs. ture became unsatisfactory when synthetic chrysotile, which has the same chemical composition as the natural produet, produced no fibropnic response in the lunp.1 This nonfibrogenic response in tbs lunp of rats to synthetic chrysotile else de stroyed the validity of the theory that the aystalline character of the asbes tos fibers determined their pathoge Asbestos minerals art silicates, but the pathogenicity ot their nicity. It ia to be noted that synthetic chrysotile has the same eystalline itnati is_u tunatrhad by that at anystructure as the natural product since Other silicate, and tha fibrogenicity is ft yields tha asms roentpnographic equalled only by that ot crystalline and electron diffraction pattern; and. silica. There has been much specula like natural chrysotile, it also exhib tion retarding the reason for this its a tubular eystalline structure high degree of pathogenicity of the under the electron microscope.* dust of the asbestos minerals, but The presence of trace metals on the today no satisfactory hypothesis re asbestos particles has also been con mains. sidered s possible cause for their Similar to the theories proposed for pathogenicity.4 However, in s recent the pathogenic potential of lilies investigation, when neither the re dust, the first theory was a mechani moval nor the addition of tract met cal one baaed on the notion that in als altered the pathogenicity of as haled asbestos particles tend to pro bestos dust, this theory had to be duce Cxictotraumata by piercing and abandoned (P. Gross, MD and R.A. impaling delicate lung cells. Ibis Harley, Jr., MD, unpublished data). concept proved untenable when the Tha discovery that, when asbestos dust of fibrous glass' and ceramic b ground to a fiber aim less than 5m aluminum silicate fibers* were shown long its fibrophidty for the lunp to be nonfibrogenic in the lunp. disappears,* astounded the scientific community. This finding, subse Pwkmtiled tor publication Marti X, UTX aocapwp April IS From tha Oapanmant W Palholafv. tMical Ueiwtsii? at South Carolina. Charlniaik SC. lUpnnt ntimu la SI Maui Cinck. Kapk*. FLUMOlDr. Crtoal. quently confirmed,*** proved to be an enigma that ultimately resulted in a new concept of the locus of pathoge nicity of asbestos dust. Although the new concept rests 2*0 Arch Environ Heslth/Vol 27. Oct 1973 Locus of Pathogenicity/G'Ots h Harley . \ ' * -* m MHBM *_ i an embarrassingly obvious k .`tun! characteristic of asbestos, It is supported by uncontested docu mented experimental findinp as well as by dsU from some promising pre liminary experiment*. The latter, however, require confirmation Theory and Supportive Data . The oew theory Is simply this: the locus of pathoffeaidty of asbestos dust resides in the polyfilamontous struc ture of its fibrous particles. Various data support this theory. Man-made miners] fibers, in con trast to polyfilaaentous asbestos ' fibers, an monofilamentous. The dust of those monofilamentous fibers (fibrous glass,1 ceramic aluminum sil icate,' and silicon carbide whiskers*) that have been studied have proved to be nonfibrogenic when inhaled or in jected intratracheal]/. Synthetic chryselile is uonfibrogenie when it is injected intratracheally. It is monofilamentous. It dif fers from nstunl chrysotile in that tubular crystals an discrete and > does parallel apposition to aacii other, as is the case with the natural product. When a grinding force is applied to asbestos fibers, they tend to split lon gitudinally nther than to firsetun transversely. Consequently, asbestos that has been ground to a fiber length of less than 5m will consist largely of fibers that are monofilamentous. Those bundles of fibers still remain ing will be greatly reduced in thicksees and will approach the monofilanentous state. It is the fact that most f the fibers in such finely ground isbestos are either monofilamentous tr nearly so, that offers a logical esilanation of its nonfibrogenioty. When asbestos is heated to 1,000 C, ts pathogenicity is either lost or aeerely reduced (P. Cross, MD end LA. Harley, Jr., MD, unpublished ata). At this temperature, the fibrils ompoeing the bundles tend to beome fused into unitary structures, :, the fibers tend to become monofilalentous (Fig 1). Although chemical a--es do occur es a result of the e: uch changes hive no bearing njhe resulting loss of pathogenieity_ inet it has been shown (with syn- Fig 1.-Asbestos. heated for tee hours in n electric muffle furnace tt 900 to LQOQ t fleft). Chrysotile heated to 900 C. At* thow|h fibrous itrucnne it retained, UtfiH are eeliterated by rounded homogeneities of different density, separated from one nether by less dense eMfts. (Top right). Cmodouts. heated to X.000 C. OeudUibe densities and ran factions oOliterate fibni. Ur structure of fibers. IBottom ngfiti Amosite, heated to 950 C. 0Orus fusion of eonstituentt in fiber btridUs has formed giebs of electron-dense material thereby tearing ether portions of fibers relatively bfectren-trensperent (cetgtnof magnifiesuon aTl.COOi. thstic chrysotile) that the chemical composition of asbestos is not respon sible for its pathogenicity. By cementing the fibrils ef asbestos fiber bundles together chemically, it is possible to convert the polyfilamentous structures into monofilamentous ones. This has been successfully ac complished with various silicates such as those of lead, iron, and mag nesium. The use of other water-insol uble cementing substances, such as those of magnesium and calcium py rophosphate, calcium hypophosphate, and calcium metapbosphate, is con templated. The method has been to suspend finely ground asbestos in a dilute so lution (1% to 5%) of an appropriate soluble metal salt Head nitrate, iron chloride or magnesium chloride). Af ter wishing the asbestos free of all eseess salt, it is suspended in a 1% eolution of sodium silicate. The latter rig 2.-Chrysolite fibers cemented erth teed Scale. Presence of lead silicate indicated Oy electron dense stippling with* lumen a* me flbhU and elsewhere (engine! magnifcstcn a 143,000). mh Ervnron HiaitWVol 27. Oct 1973 Locus of Psthogenieity/Oross L Harley 241 ! r% 3.-Alt injeaed irtntr*eh*(*T with 10 ng inn tikicaiwonwmrt tt\ry%cn<i. tend ga*d w rnemfa Istef. Highly cellulw inflammigpry tocut wrreundi lenranif braneruei*. An season*! glint call it present anfour' *' dfpmmg region many giant ea*!i were 06ainte. There is early hprasit (hemateeytirw emm. eng>nai magnitoataon a 500). melt with the adsorbed metal emit to --eripitate the insoluble silicate, m electron photomiaofrephs (Fig . appem that aolutes are capable a penetrating not only between the fibrils but also within the tubular lumen of chrysotile crystals. "Tli j~ " ' j ' 1. tin leu! lil icste- and ferric silicate-cemented asbestos were injected intratracheally into a few rat*. Their lungs were examined three months after the in tratracheal injection. The predomi nant pulmonary lesion produced by the l*ad<emented asbestos was mini ma! in character, consisting of promi nent giant cells, few histiocytes, little Teticulin, and no collagen fibers (Fig 3). In contrast, the lesions of the same age produced by the unaltered asbes tos consisted of mllagen as well as retirulin fibers and histiocytes. Foci consisting of the minimal reaction, as were noted secondary to the "cementad" asbestos, were not found in lungs injected with the unaltered asbestos (Fig 4). In an in vitro study it was found fig d.-ltat died 5*. mentfis after having Seen infected mtrarrsehnitfy with 7 mg unit tered chrysolite. Arta of utiigefwui fibrous m adjacent to respiratory bronchiole also inwfved in fibrosis. Tha fibrosis differs from that in Tig 3 as it it mere cWiagtneu* and Iaaa cellular. ia Match more advancad. Granular matanaf in oaflaen is broan pigment Cheovitgayfm aoairv. wirnst magnificatien a?C0). that lead silicate-cemented crocidolite caused only 30% hemolysis of human red blood cells whereas, under identical conditions, the unaltered creddolite caused 100% hemolysis. Iron silicate wasItM '~eneiu ve^a (educing the pathogenic potential of chryaotile than was lead eilicau. The season for this was a gradual disap pearance of the iron from the asbestos stored in the lungs. However, as ob served in a tall glass cylinder, the iron silicate-cemented chryaotile stains a deep blue color erith acidic potassium ferncyanide and retains this blue color. It settles rapidly, teavlag a colorless supernatant which remains colorless over many months. Because of obvious inadequacies in these experiments with cemented asbestos, the results can be termed only suggestive. But in cortjunction with the other findings, they tend to eupport the thesis that when polyfilementoui asbestos dust particles are converted toward a monofilamentous state, a reduction in their pathogenic ity takes place. An extensive inhalation study with cemented and unchanged asbestos will soon be initiated, as well as an investigation ef the comparative fibregenic and canetrogenic potential of the polyfiiamentoua, emus the cemented asbestos dust injected in- trspleurally. Thus, the documented evidence points to a sharp difference in patho genicity between polyfilamentous dusts on the one hand and monofila mentous dusts on the other, and * * significant reduction in the pathoge nicity ef asbestos dust whan its parti cles are rendered monofilamentous cither by grinding or by thermal fu sion of fibrils. Preliminary uncon firmed experiments suggest that a similar reduction in the pathogenici ty of asbestos dust may be accom plished by chemicsl fusion of fibrils, k, the deposition of insoluble cement ing materials between the fibrils of the fiber bundles- Thi* imetifMiaa wan up*wt4 by Amman Cmw Sacraiy laniiuuaaal raw rat grain 1N301. References X. Grau P. ef at Tt yalamiy aeti u kigti caarmuatioBi ml Sbraua (tea dual Anh -------- ---------------1 ini irn t Grau f, m 1: Ttm ificii W t eynthetir trvaeiic (bar Suit upon If* htnp ml lau. AHA Arch 1mA Smith 13:1CMM. 1(53 a Grau P. si Profclinu in th* pathology ef anfcwuou is Shpira KA ladr. PinnmiiMU. Amiiilfi ef lAr ImltnmlmmH Cmmfrmrt, Jmlmjmmhurt. 19ft. Cap* Taws, Ot/nfS Uniamity Pmu. 1(70. pp 193-199. 4 Cm P. et aJ: Ciponmonul i^minii TV* do-ralopmom ft lung cancor ia ran with pulmonary Sipwiu mi cHryaotiU uAnta* Sul* ArtA rnwian Smith 1S-JO-133. Ml. S. Wobdar I: The palhogenuit ml hIhuu in Shapiro HA *ed> Piwumorwiiuu. Pirawrf. Mp of thm Imummaamml Cmmftmtm. Jmhmmmm hmrg, 1969. Cnpr Tuna. Oilmri l/nivmity Prow. 1(70. pp 117-11( ft Hibchor W. el tl Zuaamioonhanf* secti on Aabnlaoe and Faaorlangi Smurtmurntmmchafln ST J34-M7. 1(70 7. Craw P. el a!. Aafeoouo Uenbfteauon ml IWn* panicle* ia lanp. J Oanp 4fd 14.737n*. 1(72. a Gnu P, at a) The pulmonary maw* la tbraua duel* ml dirotw umyniUM Am tmtI M/S Aura J 91:133-132,1(70. 1*5 Arch Environ HejltiWol 27. Oct 1973 Locus of Pathogenicity/Gross A Hsrley Armntf urt AvW'Ute m era Unite Waiai W Arrmntt I REC'D Asbestos-Induced Intrathoracic Tissue Reactions AuJ Gnu, UD, Ruutll A. HarUy, Jr, MD, Charituon.. SC RCD JR------------------------TO--------------------------------- hmathorscie injection of different type* without producing lung cancer, it was ml nbmtto* modifirfi 6y difterent method* gtaeraUj caused drfferen&iteC malignant chest tumen ia rati and undifferentiated tumor* in hamsters. Twenty-five malignant insathoracie rat turner* vert classified as ftbresarcomas; four as mesotheliomas; three as rhabdomyosarcomas; bee at os teogenic sarcomas; and one as fttaroiipo- wna. Tissues ether than mesothalium thought that there was something unujual about the asbestos exposure that gave rise to lung cancers. Chemi cal analysis disclosed that by hammer-milling, the asbestos fibers had acquired increased contents of nickel, cobalt, and manganese from the steel alloy of which the hammer mill was >usJy may site develop mat parti tu composed. A working hypothesis, mors and sU tuners arising from the chest trill art net necessarily mesotheliomas. Asbestos dusts heated to 900 to 1,000 C vert associated with only about 10% of the -tcmorlyiHOLM-liw'-V. . . '7*211 heated at desses dusts. Since the rvmoval Of trace metals from or their addition to asbestos dust caused no significant differ* exes in tumor production, the tnee-metal hypothesis for tht meehsnitm ef ashestesieducad cancor ns abandoned. therefore, was adopted in which it was assumed that the increased amount of nickel--a known pulmo nary carcinogen, was responsible for the development of 'lung usjilw wi mas and rats when exposed unduly to asbestos dust. The report by Wagner et al* estab lished that exposure to eocidolite asbestos wax exsodsted with the de velopment of mesotheliomas of the pleura. Thi* documentation was im portant, not only because it focused lthough the development oflung attention on an additional carcino A cancer ia man secondary to as genic potential of aabesios, but also bestos dust exposure is well estabbecause it alerted the general pathol lished. only one laboratory reported ogist to a hitherto very rare malig the development of lung cancer is nant tumor that within a relatively rats following exposure to asbestos short period, was encountered with dust1 Inasmuch as other laboratories frightening frequency in regions had also exposed rats to asbestos where croddolite asbestos exposures had occurred. Since the publication ef Wagner's A--arpi-i far pwbliutiee April 71. It13 From the InOuttntl H**hh foundation, Inc. hi I u burp lOr Cmji. and lha Dvpanment tl ICft! LTK>*TJly ot South Careltartesian. SC iDn Cnu and Harloyl. Dr. .1 praaant addrana u 21 Maui Cirrla. Napin. 7X23040. ^ItrpPinl raquaou to 21 Maui Circle. Noplaa. rL230lDr.Caw report, the designation mesothelioma of pleura or peritoneum has become s "popular* diagnosis clinically as well as experimentally The strictures and criteria for making the diagnosis of mesothelioma, as laid down.by Wil lis,' largely have been ignored. For instance, is many of the cases of one reported aeries, the diagnosis was based only on biopsy material--often acanty, without substantiation by a complete autopsy.' Experimentally, a similar lack ef critical judgment is evident where all turnon arising from the pleural cavity following the intrathoracic injection of asbestos have been classified as mesothelio mas.M This swing of the pendulum to the far left has reached the ultimate is the finding ef "mesotheliomas' arising in assodation with ground experimental intrathoracic turnon seeds to be accurate lest it cause un desirable alarm is illustrated by a recently published "expression ef concern" with regard to fiber glass in which various types of fibrous glass, ioduxive of glass wool, were tabulat ed as producing mesotheliomas? One purpose ef this paper is to re port the results of an attempt to test the trace-metal hypothesis for the development of asbestoe-induced lung cancer. Another purpaee is to docu ment the occurrence of malignant intrathoracic turnon following intra pleural injections ef different types of asbestos and to study whether tome, if not the majority, of these intratho racic turnon may arise from cells other than those of the mesothelia! surface. Methods and Materials Samples ef Canadian chrysolite. amoaiLe.and eroo'doliU were each prepared by A/ch Petnoi/Voi 96. Oct 1973 Asbestos-Induced Intrathoracic TumonAVou 1 Harley 24S ; t I i i j r< l.-iiturn after having peon heated to 900 te 1.000 C left. Amenta Obscured fibrillar 'tings ertf pipb* of 0KH mater# (ongin*) megnitcatwn a 70.000). Center. Chrysolite. Fiprwi* iCturt preserved. but ne fifenliar memnp (anginal magnification a 11.000). HifM. CrnCiOOiite franJucncj and opacities uucutae with iou of fibniier marainp (original magnification 1.000). #va different methods far intrapleural injection. Ona sample of each *u ham* mar-milled for 12 hour* (hammer mil) da* ambod *7 Halt ot al*l. Tlw purpose of tha prolonged hammar-millutg *u la coat tha aabaataa with tha micfcai<aauining alloy at which tha hammer sill waa rnmpiaart la a previous study, tfcia harrmar-milltng tea u Itad ia th* addition ta tha aabaataa ot tS% taara nickel. 14*% mera eobaJt, aad *4% mere chromium. all derived ba the metal of the hammer mill* Ane*her sample ot aaeh kind rt aabaataa waa bell-milled fa tarn hour* aad thee boated ia aa electne muAe furnace for two hour* at *00 C far chryaotila, at *60 C far erocidolite, aad at 1,000 C far aaifeiu. Tha beating did aet dmuny tha Ebtoua atnictera, although it altered the chemical aa wall aa tha crystalline structure af tha aabaataa (Fig 1L A third sample ot each, after batl*miH* tag, waa treated with ague irfio tor aaa boor, waahad, treated with 2% adrQC acid ia 1M potassium hydroxide far another hour, and washed until the pH waa 7.0. It was than milled ia a ahating-type ball till (Spex Mill* for 3 to 15 mlmiiaa ao that tha malerial would easily paaa through aa 15-gaug* needle. This chemical traatmant area intended to remove trace metals, par* ticularly nickel that is present within tha mineral crystal*. Tbe fourth aampla af each type of aahaa* tea waa treated ia a manner similar te tha .................... ` * !!> e mil irinimm^-- hi pieurof inflammatory tissue From a rat ease 11 monmt sftw an intra pleural mjectwn ot netted cnryietite <50 mg) inamatoeyfin sown, anginal nagnrfcanon a 250). rig J.-Pleura) urTact ia corwwd by karaflnisng sretiRad aouameua epithelium that roati on an inflammatory coUaganous tissue From a rat dead 15V. months eftw an intrapleural injection ot SO mg at treated crocidofitt (hamatoiytin-amm. eriginaf magnification a 1001 24C Arch Psthol/Vet 9& Oct 1973 Asbestos-Induced Intrathoracie Tumen/Cma i Harley ' 4.--UPiorantiatae ptaomerph* aarsoma imcfinj eht watt anfl t of namatar Oaac 18 Vi nmtM oftar an imraptawral miction of a fret arranta (hamataryim inn. 2501. (hanotetyiirvoajrv, onjinai magmfcatn s 250). Tig 8.- Mmottrafiema eharactahtae by naopiaatic fibre* ctroma eo**toimn* acmar atnxftim. From rat miactaO imrapiaurpOr vrth SO m| .evyaobit ane aaae 20 momtu ttwraanar (hamauxytmwm. ordinal magnification a"250). Fig 7.--Small portion o1 papilla^ maaetfiotioftia ttiot awfreO much ef pfevrp) turfacta. From rat owe 22 merits attar irnraptaurar mfaction of SO mf Kammar-mJioe amnia (hamatoaylin am in. ordinal magnification *250). Arch tottoi/Vof 96. Oct 1973 A*5wtoa>lnduc*0 Intrstftorpcic Tumera/Srou & Hirtojr 267 Table L-Incidence of Dust-R*<ted Tumor* in Animals surface of the luap seemad unineolved, interlobar leaions ware often noted. la its moat severe form, the tis Meow* at Mrvssrsdss a. % a SL Tsw/ra*) Asm . __ _ 4/12 23 i/16 31 2/6 23 11/34(32) Treated 2/11 M*ti (res k/10 Hsetsd - bis- Heeled and heated ins . 7/17 10 39 0- 0/17 7 0/16 41 23 -0 0 . 4/14 29 13/42 (31) V6 16 iff! (36) -via- - - 1*4(2) . 0/12 0 1/43 (21 Taut tru 19* U/7S 20* U4 15* 35/112118) Hamsters Hemnw masd 2/15 13 Treated V6 13 Uetet-tfM 7/1* 0 Heated VIS 7 Noted end noted VI5 6 0/7 V* 2/6 0 13 S3 on oonn 0 0 ona 0 0/13 0 0/15 0 0/12 0 2/23 (9) 2/19(11) 9/20(45) V44C2) . 1/43 (2) Tat# ia/M ir a/M .6* 1/21 0 time no) .. rifeared pwtuiBu ef tumor incMnci sue reaction consisted ef ovoid noduke of dense collageaous tissue bor dered by a vascular aad highly eellu Ur granulation tisane containing - asbestos, as well ae muliiaucleatad giant cells and histiocytes. la many animals. Urge center* ef aggregated . asbestos and necrotic material wr* surrounded by vascular and cellular granulation tissue continuous with that surrounding th* previously men tioned ovoid nodular collagen - The visceral pleun was often alightly thickened by edematous fibrillar tissue poor in cells The pari Table 2.- Effect ef Heating All Three Types of Asbestos Dust on Tumor Incidence Am Mims etal pleural involvement frequently extended into the skeletal muscle as a histiocytic and collagenous inflam Mettled at Pnaaoti-- Hasted Heeiac end Oeated Total Hammei nulled Treated Meteutree etal He. 1/48 1/43 2/11 11/34 13/42 9/25 33/101 2 2 2* 32 31 36 33' He. 1/46 1/43 m 2/22 2/19 9/20 13/61 % 2 2 r 9 11 45 21* mation. In the superficial portions of th* chest wall, it was often apparent that proliferation ef the meeothelial cells had occurred This was demonctrabl* as a surface covering of oowded plump cells--occasionally ar ranged in two or more layer*. Th* Overall percental* el tumor mcieanes. pleural involvement was also seen as third sample, but *u subsequently alee heated in the aaa* manner a* the second Triple Fer the fifth aampl*. a chunk 0T th* min sters similarly ipjected, only 157 survived T%4 months or longer. Of th* hamsters in jected with chrysolite, only 26 survived. gland-like structures within the in flammatory tixsus (Fig 2). Another very interesting finding (noted in only two rats) was squamous mete- eral ere of each type of eabesto* was de nuded of iu superficial fibers en one sur face with th* us* of a piece of broken (laaa. Additional deeper-lying fibers vers then handpieked with the eid rf1 sharp flea* pastured and allowed to live out their lives. Result* Thar* eras a considerable early cells--even with the formation of keratin (Fig 3). These meeothelial changes were found predominantly en the chert wall. Th# animals inject fragments to preride eabaetce fibers that had no select with e metal These fibers were then Spcs-milled for 20 to 30 min ute* with th* ue* ef plastic eeetainan and plastic bails. Th* sample* are her*after termed `metalfrea." Standard aqueous tuspeneiens were med* of each sample ae that each con tained SO mg/mi. With mal* rats wi|hing ISO to 200 gm under ether anesthesia, 1-ml ameunta at the suspensions (50 mg each) were injected mortality at the doaagt level amployed in several groups so that in order to obtain a reasonable number of rats surviving at least six months, 45 rats war* injected in the met*]free unosita group and 40 in the treated chrysotile group Disregard ing the deaths that occurred prior to six months, the average survival in the various groups ranged from 9 to 24.8 months, with an average ef 16.7 ed with the heated, or the treated and heated, varieties of asbestos gener ally showed less sever* sad leas ex tensive inflammation than the ani mals injected with asbestos treated in other way*. In some animals there was a transi tion from the cellular granulation tis sue to tissue that was manifestly neoplastic. A total of 35 and 15 malig nant tumor* in rats and hamster*, sttrmihorseicaJly in the right arilla with th* uMefa 5-mm lS-g*uf% needle. Ham sters were similarly injected, but her* the amount of dust was only 25 mg in 0.5 mL Injection* into th* right thorax were adm:,'-(irrcd to a total ef 430 rata. Of thee*. >ert injected with aaeeite, 175 with -ocidoliu, and 139 with chrysolite. The ember ef rate per tempi* ranged from"20 to <5 because ef early deaths, which were promptly replaced. Of a total ef 239 ham months. However, the deaths ef the animals were not necessarily related to the intrapleural injections of asbes tos, since two separate epidemics of pneumonia occurred among the rats. One of the more interesting obser-* vaiions pertains to the infrequency of obvious involvement of the visceral pleura as compared with the parietal pleura. In some animals when the respectively, originated from the in flammatory tissue associated with the injected asbestos. Th* earliest tumor was seen in a rat thst survived 13 months and in a hamster that sur vived 7 months after the injection. Consequently, in snsidering the in cidence of these turnon, only those animats were counted thst survived the number of months at which the 24g Arch Hathol/Vol 96. Oct 1973 Asbestos-Induced intrethorecic Tumors/Gross i Hsriey ' At tumor waa found, bulation of the tumor* found in the .arious group*. (Table* I and 2) suggests that th* animal* can b* ar ranged ia two contrasting ssries: on* ia which th* asbestos had beta hast ed, or treated and heated, aad th* other that iDeluded all the remaining Th* animal* Injected with th* dust* that had been heated-- * whether treated additionally with aqua regia or not--had a low tumor iotidenc*. around 2%, whareaa the tumor incidence of the combined injected with dusts treated differently wea approximately tan times greater-21% and 33% for hamsters aad rats, respectively. The tumors found in the rati were, with few exceptions, well-differen tiated. Thee* ia th* hamsters were undifferentiated sarcomas (Fig 4). Of the 35 tumors ia the rats, 25 were fibrosarcomas (Fig 5k, four were mes otheliomas (Fig 6 aad 7k three were rhabdomyosarcomas (Fig 8 aad 9); two were osteogenic sarcomas or / searccmas with bone formation w * 10); aad one was a fibroliposarcl (Fig 11). The mesotheliomas were identified on the basis of discrete papillary s^xucturas covered by mesotheliumlike cells or tha presence g-piugrp cells resembling those of meaothelium, associated with otherwise welldifferentiated fibrous tissue. Glandlike structures were also found (Fig 7). The tumors diagnosed as fibrosar coma adaiittadly may also include a few mesotheliomas. We do not know how to diaoimiaaie between a welldifferentiated fibrous mesothelioma and aa equally well^ifferentiated fibrosarcoma ia the absence of tissue suitable for electron microscopic study or tissue culture. The incident* of turnon la both pedes of animals was least with ehrysotils. So far as th* ether two types of asbestos are concerned, they tended to produce about the same in cidence oftumors ia the chests of rats, but ia hamsten smosit* caused ahigher iaddenes of tumors than crutidolita. Comment It is apparent from the results ob tained that no significant difference exists ia the incidence of turnon pro duced ia the chests of rats or hamsten injected intrapleurally erith the dif ferent modifications of unhealed as bestos. This lack of difference ia the iaodenoe of tumors held whether mors tram metals had been added to the asbestos dusts by hammer-mill ing, whether metals had beca re moved by aqua regia aad edetie add or trace metals had neither beta add ed aor subtracted. The trace-metal hypothesis must therefore be aban doned. Another conclusion that is readily apparent from these results is that prolonged heating of the three most T..i i 1 -types of asbestos will diminish their pathogenic potential inasmuch as the tumor incidence as sociated with the heated asbestos is about ou tenth of that aasodatsd with the unheated types. The fibregvaidty of the former also eermari less, since the inflammation was not ed to be less aevere aad less extensive than that seen with the latter. The present results also have rele vance to the tendency to make the di- gnosis of r raothelioma without ex cluding the .flexibility that tbs tumor fas question is metastatic or, la ease of experimental intrathoracic turnon, without considering a possible origin of the tumor from ths submssothsUal or ths inflammatory connective tis sue. Tha occurranos'ia this aariss of rhabdomyosarcomas, osteogenic sar comas, and fibroliposarmmaa sug gests that ths tissues of the ehsst wall other than mesothelium alas have ths potential to give rise to malignant tumors' when stimulated by intisplturally iqjscted asbestos dust. It is therefore likely that some, iC not many, of the reported nonpapiIIC7 fibrous tumors designated as meso theliomas wars in reality fibrosarco ma* This is also a probability erith respect to tha "mesotheliomas" ob served ia aaaodatioa erith fibrous glass.1 * * * V * * * * X Ia contrast to the usually well-dif ferentiated tumors ia the rat's chest cavity, the intrathoracic tumors ia hamsters are highly cellular, undif ferentiated aareomax It is presump tuous to designate such undifferen tiated tumors as mesotheliomas The relative resistance of the vis ceral pleura to ths damage caused by the injected asbestos represents inter esting incidental information second- ar7^^WvX5sm==h*s*fi9d.-Aa expla nation far the phenomenon ia not available, but it seems to have its clinical counterpart in the hyaline plaque* observed with increased fre quency ia people exposed to asbestos dust." These hyaline plaques also occur preponderantly oa the peristal pleura. riiii auidy mm upwi ad hy Public Health Sams fra EC 00313. la OH 00331 References V Cram f.maL ExfunAaatal afrwinn Tha danWpwni at lua| eanoar ie rsu with |*Jmenjj7 Srpmita af t&rj-aouU aibntaa dim. Ank wuw Hmitk 15*0J45,1CT. X Waow JC. Sinn CA. Karehand P DifKm yWural wiiirhal^ma aad aakuataa HW wis in tha bwthwwiara Capa tVvnaea. Mr J Wioa Wad 17 .260-371. 1*60. X WilUa tA. Tka Spmad afTamoan ia IV Hu"<aaMadj Leaden. j & A ChurtAiU. 1*34, pp 7*-*0. A Liabaw J. PwLawh* K. kbaetheiiama and Www etpGMirw Are* gamma Hmitk ItJSS M3.1M7. X Wafuar JC; CtpwiwaoLaJ yiadun ian at WeaethaUal tumor* at the pWurt hj implants* lion at Jump ie Uhoraiary animals Haturw IM; IK-ltUNl X Smith WE. et at Teat* br srtinofvnieity at aaUaua. Aaa NY Aaad Sn 13X466-4**. teas. 7. Suntan SC. VrmS C. Hwhaaiaa ef BMothaiieeia induruoa with aafcoetei aad threw (iua J Hail Caanr laat 44 7*7431. 1*7X X SalikoX U. Warkwe. anminu held this* talk* mi haaltfc haaarda laaalatma Hjgtaaa PrafrHrp*:\ (Na 3) 1*72. t. Hell IT. ml; Early rfiai at dirywcib akwiae Sum m Uw ret larv* J faJkai Matt 17 XX33.l**4. IX Kwnntii LQ-. kjJmmm hediw aad elmuml Pnim ie a tisnufc mtim at auwpaj mu. Ana faOmi Hurmk* Soaad Sappi 1*1 1-107. tsex 250 Arch Patnol/Vol 96. Oct 1973 Asbestos-Induced tntrathoracic Tumors/Gross X Harley t.-RhjDOcrnyowtom* ortonding ime tuPP>our*( *yc<r Hum. rot daad 19 fnontm wHm intropituroi injoaen of SO mg nommor& ,wa>tfwrn>tniji'H wim 1351. ?ig faen* formation in an otfcorwiM poor*j difforortiatad *arTO frgrn pwuW c**itj of fW daad 19V. mentrn aftor MropJowrol Injachon of 50 m* nammor m*ac amsitt (hamataryfin matin, a 1251. r ll.-NoopfMtic ptauraf tiuwa of oofvdlffarartiatad fibroadipoM tknn oAondS into air apacaa. From rot daad 23'H martm offor antroptauroi injacbon of SO mg hamnoramflad onaru (NoMtoar*1*1 --in. *2501. Are* ftilhol/Voi 96. Oct 1973 Aftbodtoo-lndwcod Introttorocic TumorVCro** i Kaflejr 241