Document 4QyV518pqrgJN681Vg8akjYbR

rp*r3*nt*l Ctudi* by TS2 SARAXAC LL30RATOET 2Jii2 UTS, 23JC TCSX Export to tb* JCEJS-UmiLLS COSPORATIOI m TOEC, 20W TOE* 3>pt--bur 30, IS48 2. Introduction 3. Asbestos Minerals I, ABSTRACT , , Hj Exparlaental liethoda 17. CTSEffiSXAL ASBESTOSIS 6. Spcfciea 5uscgpti.blli.ty ?- Fcculisr Characteristics of Aabestcg 9. Rate of Tissue Reaction to Asbestos Fibers ?. Aabeet-.-sis Bodies I. BHAUXIOa EXPSlBffaTS n. Sing** Floats Asbestos'Dust 12. Dusting Material 13. Dust Composition U*. Dust Concentration 1$. Reaction in Animals 16. Guinea Pigs 17, Pate and Type of Reaction 18. - iTqprmrifltt 1$. Infection Coicddtnfc sith. Dust Inhalation 20. Infection after Dust Inhalation 21. Asbestosis Bodies 22. Rabbits 23. Rats 21*. Suoaorr sad Ioterpretaiics u Pace 1 2 ? U 3 3 6 7 7 8 8 9 8 9 '9 9 ID ID n 12 12 12 13 cO. Dustinc Liiterlal 27. dust. Composition 23 Dual. Concentration 2?. Size-frequency of Dust 30. Reaction in irrt avals 31. Guinea Pi^a 32. Sate and Type of Reaction 33. Progression 3U. Asbestosis Bodies 35. Rata 36. Rate and Typ* of Reaction 37. Cate 38. Rate and Type of Reaction 39. X-ray Chances uo. Asbeatosta Bodies la. . Rabbits U2. Rate and Typo of Reaction 1*3, JLsbeelosia Bodies Uli. Saneiy end Interpretation u5. 1JCO Per CenV' Bsll-lled Asbestos Dost U6. Dustins Ueterial U7. Dust Cocspositicn U8. Durt Concentration 1*9. Size-fretpiancy* of Dust ill . 111 15 15 15 15 15 15 17 17 18 18 15 19 19 20 20 20 20 21 21 21 22 22 23 so. Reaction in Aninals Otdr.ee Pi^s 52. Rate and Type of Reaction 53. Progression SU. Lymph Kode Involvesent 55* Asbesteals Bodies 56, Rate and Hies 57. SvmsMrj and Interpretation 50. Long-fiber Asbestos Dust 59. Dusting Ibterisl 60. Dost Composition ol. Dust Concentration 62, Size-frequency of Dust 63. Reaction in Ini ails 614. ' Guinea Riga 6$. Rata and Type of Reaction. 66. Procreation 67. LjfTtph fcds rrcrolreaent 63. Aabestosia Bodies 69, r<t TO. Rat* and Type of Reaction 71. Z-cy Chances 72. Rats 73. Bate and Type of Reaction . ' . It Pace 23 23 23 2k 2lx 2k 2k 25 26 26 26 26 27 27 27 27 28 29 29 30 30 30 30 31 Uic* 73-. Roto ard T;*p* of Reaction ?6. C.Leuary nd 7*iterpr5tAt.-,oa injection sxrxp.r-rsjts ?2. intratracheal Srporiarscts 7?- Conparison of fibrous and Non-fibrous Dusts ?C. Comparison of Various Lonn-fiber Dusts Si. Comparison of Lone-fiber and Short-fiber Eusts 62. Intravenous raiperisxnts 33. Ir.traperitcnecl Experiment3 lcot/. * ardTi zz ni.zhii 35* Protectire Action of A.l:rrfmaa Cccptursd 36. Icnaation of Asbestosia ladies ' L^tevn. Tvnr^.T iFJiimf action LEEVUI. CUK'laCiTIDKS :.(9. Infection `TO* Susceptibility to tuberculous Infection 71. Susceptibility to Ncn-tuberculous Infection 92. 'leoplaj rein, conctcsiora 2CIY, TABLES- xcv. ?i?3uass * T Paste 31 31 32 32 32 33 3b 3b 35 35 35 36 37 3? 36 38 39 bO U3 - 71 72-75 jubentoei* ia a pulaonstr disease aaxued by th inhalation of asbestos dt:st* Ih anissls it i* characterised try 4 peribronchiolar flbrosia *hich **tacB to b* the result of aechsnical, rather than chemical, irritation of tho tissue by asbestos fibers. Only the Ion* fibers produce a typical reaction* short fibers are relatively inert* 'The filaawitod structure of the fibers is an essential factor in the nsechnnisa of irritation. A character istic tlasue response esa be produced by ncn-eilicaaua as -mil as siliceous fibrous ninarals. Inhalation of asbestos dust apparently does not alter significantly tfi* course of experimental tuberculosis in guinea pigs. The asbestosia body, erhich is a specific concealtint of aabeatoeis and forai soon after tha entrance of the asbestos fiber into the lane, is believed to prrrast further damage to the tiaras by the fiber nd thus to limit pro gression of the reaction etvsn exposure ceases* Aluminas does not exert a protectire action against the tiwue irritation of asbestos fibers as it dot* against that of quarts particles. Introduction AS33T03I5 that of a particular mineral but Is a tarn applied .to a rriaber of different nunerala who is characteristic feature la a structure composed of lor, par allel, fleccible fibers. This structure la unique because the fibers are capable of repeated longitudinal subdivision to unit.y of molecular pre-portions In length the fibers Tiry froc a few microns to sir. or more inches. Son varieties are stiffer than others but many arc sufficient!;- flexible to '> ypun into yam and woven on modified textile n&chiner;*, 3. Asbeatos lfinarals ' The asbestos tdnerals are r.illcctes of variable composition anc belong to the serpentina and the amnhibclo jproups. Listed belov are the more coasuot: varieties.. Arrtbophyllit-a (Mg, Fe) silicate Acxisitfl ('ig, Fa, H) silicate Imphiboxe (Ca, Vg, fo, klf Ka, K) silicate Tr*aolito (Ca, Vs) cilica.te AcfciroUt* (Ca, Ug, re) silicate Crocidolit* (Xar Fe) silicate Fe silicate derDentlrua Grouo Chr75otil ug silicate (hydrous) -2 The bulk of tha asbestos of comsrco is chrys'. :Lle. } '-C.2SiC2.2H2O, vhich is niimd in the Thatford reston of the frcr/unoo cf ~ibec. Croc idclits and arorita ar also used cocrcaroiaLly but ir. t.-.t so.tiler amount*. Chryvotile occur? juc reins in serpentina, z. ,air.era! ~.i-J !.. - in ciianical cocrposilicn to chiysotiic but r.hich exists in oaseiv ';v,ir. and is ends irp 0f Edcrcacopic fibers vithaat tha parallel orientation chtracioriatic of chrysotila. The meetre blue bl&ck eerpeatir.a, -which in r.oeth \r.d soupy to the touch, is traversed by vein* of fibrous chrrsotlio Tarying in ridih fren a barely perceptible line to sir or sore inches, The fibers run across tha vein and not lengtheise vith the formation. Attention is directed to the sinaral brucite, ^C.F.^O, uhich 13 oftea found in the *asw fornications -with serpentina ?nd chrysotilo and nay be fibrous is stnjcturs It has rta coarersial value at present because its fibers are not sufficiently fltrible to be used in textiles but they era capabla of repeated Isnsitudir-i-l yubdirisicn. Unlike othsr asbestlfora minerals, brucite la not a silicate cod for this reason it has boon a valuable tool in an experimental evaluation or the action of fibrous cineralo upon luns tissue. IP- EDTEHUIEHTAi iSBESTGSIS For cany yssrs studies h*r* been carried on by the Saranac laboratory in an tnvtitticn of tb* casw, nature and development of asbtstosia. The present re port i devoted tc EzpsriasatAl Asbestosis. In it are described tha aniisai ex periment# with various kted* of acbeeten dust. Another report, to bs pr-epars-d and isswaid latr, sd.il b-? ccr.cvmnd vrl.t-h Hunan .U'osttoala Wtd Till cover tha health aarpanta of rorterh stvo hns h+*n errvos#rA to asbestos dust in an industrial wrrirotsnenb* _. - - - --- '-i cor? Tp^cxiS of Ani~a.. charactar-- Lrttc ttssui* change -rnich ar* stoHar to the leaicns of human asbeetoau. Slaca the Ufa-roan of tha expari-vniMl ar.issl is rsstlatiivTil^ short, It 1-t not possible to dmtlop the caaract eristic lesions in anlsels 'order tha usual industrial con dition*. ConaqurauiyT to obtain a cosmlsts evaluation of the tissue rospoase to inhaled particulate and fibrous uateri&l. it Is necessary to accelerate the reaction by employing higher coccantra.tionn of dust than wjuld ordinarily b so~ countarfld in industry. ffhila condition* of exposure ar* thus different, the infcmation yielded by ssperinant* vith vdsala Is iamtlmbla in furnishing a better ucdaarstasding of the reaction of the huasa organ.'* sa to inhaled asbestos dust. 5. fmeriaental Ikthoda for lxrrestlg&ting the biological, reaction of the experimental arlaa.1 to tfc*~ r&rleus asbestos sdnsrsla, trwo types of technique hare bean essployed, namely, the inhalation setbod and the injectica eethed. In inhalation experiasnte, groups of anicals - up to 100 or sere guinaa pig* and eoamtina* saallsr trafcsra of rabbits, cats, dogs, rats or sica - are kept for sight hour* a day in a cubical dart roca, eight ft ir> diasnaion,. in 'which a cloud of asbestos dust is aaintairard. , it irttarral* during tbs expeerismt, . tew tniaals srt sacrificed end the tiara* fxasdaed to dstsrsirs the nature sad extent of tha dust reaction- 3om anicala r* exposed for periods tip to thrsaj years. The injection experiarnts, in -which the dust, either dry err yospsrdgj. .to. fluids is introdoesd into the an 1 sal by the iatrsreocus, intrsperitcrnaal or into*toaciVMti pg^cedurt: r used to dstsrain* irhether or not a particular dust *. pcrt^atial car-set ty to prodaca tissue ruction* Long~terr. inhalation experiments'fta-ni.ill inforrution upon Ttiich great reli ance Is placed whan estimating the degree to vvich a dost might be hazardous to industrial workers. 7Jhather cr not atoospheric dust, area though potentially dangerous. can be inhaled, pass the ivaturil dofense barriers and reach the pulraonary tissue In quantities sufficient it causo dans&rs can be deterrdr^-d only by inhalation procedures* Injection experiments arn useful fceesus* in them contact between the dust particlaa and tissues la assured end the potential capacity of the dust tj produce reactloo cun be estimated accurately, Uhc dealing with fi brous minerals Idle asbestos, the intratracheal nethed is raluabla aims it per mit* deferring the sifret cf the fibers on pulnonary tissue. 6, Speciea Susceptibility Unlike free silica, srbe-ctoa do as cot. smart- its specific affect in ail organs of all spociaa of smisal (Table 1). Injection of fina quarts into various organs of the guinea, pig, rabbit, rut, cat, dog, chicken and even tadpole will produce silicotic ordulsa. Kcwrer, similar injection* of long or short fiber asbestos hare resulted in i fibrems reaction in the lung urn, to a lesser extent, in the peritoneum but nest in ether organs. 7 Peculiar Quractarlgticg of iabaetaa Experience hba dcocrcsrtrat^d that raezt of the psrticulats aattar inhaled into the lungs of asa sad is ID aicro&s or lasr In Ecaddasa. diasatsr. Larger partieLes apparently ar* cciadd by tbs protect!"9 s^echAni sa of th* upper ra3pir- ctorr tract. Is. the <M*e of fibrous ssierUIs, hOTerrer, this restriction dosa act apply 4rsd fiber* 100 M rrsn ?0G Etcrons in Length bar* been found In. tbs tsrsdJb- *1 air #p*c** of hroaaa lungs* In mall laboratory animals eaepoeed to aabasto* dust the length of fib-.r Zomd in the lung r**i>* exasds 60 microns. Rot every kind of fibrous eatcriil ia inhaled **itt\ e^iil rwrtinaasj for axsstpU, the synthetic libers of glass wool apparently are too inflexible to pus easily throwrh the nose, pharynx, trachea and bronchi and celdoa roach tha terminal bronchioles and alveoli. Inhaled particulate natter cartes to rest throughout the terminal air spaces (alveolar duct, atria, alveoli) th all ports of the luaae; inhaled asbestos fibers are first retained in the respiratory bronchioles. These very antall tube* are immediately distil to bronchioles lined 07 ciliated epitheiiua. their erro essen tial lining' is * lor cuboidal type of epithaliun but, as their name Implies, they actually function in respiration through Lateral alreoli given off &e pouches along their valla. Either these pouches, or the abrupt change in the character of tha lining epithelium, or the decrease in diameter nf the tube, or perhaps the combination of all three factors is responsible for local retention of the inhaled fiber* Only after asbestos!s is veil established are appreciable numbers of fi bers carried into the sore peripheral air spaces. 6. Rata of Tissue Reaction to Asbestos Pibera Tha rate of tissue reaction to asbestos la touch sore rapid than to an active dust like quart*. Evidences of tissue response appear as soon a* fibers nave localised in sufficient concentration in specific rtu. In rate receiving asbes tos fibers by intratracheal injection this evidence is risible us early as t*o week* after infection! fer quarts dust, th* latent period sd^it be t-ro ro-.ttw or wore. Th* beiueviar of ths tissue reaction to inhaled dust ,\ftr the tcrairutioa of exposure is not ths ia* in' silicceia as in asbestosis. In silicosis, the young nodule-s bscccsa Larttrj in asbestoeis, young ecar tissue, t-hat coy.have formed,con tracts send becomes ear dense but the area, of icrolTeoent decreases in site. If exposure to asbestos dust is tsrdmted after a brief period, the recently-inhaled fibers in th* lung zsf cnuss the fibrous tissue response to continue for & shore tics#, until the fibers )'*? tssn coated. This progression is of only a. slight degroe wxi of little cigaiflcanc*. $, Asbestogis Bodies The pecuLLtr structurs kmien ae tin? aybctrtosic body or curious body la specific concoadtartt of asbeatosis. The typical bc*Jty is a goIdaTv-f-ellevj beaded or hauatrated rod rhich bst be either straight or curved. Oftca cr or both me are bulbous Hire a dusfa-b^H.* ths fcodisa vary considerably in length, and di ssensions up to 250 dcrons her been recorded* It la believed that wbsst-oais bodies are cua to a deposit of protein end. iron pigjasnt 'upon the surface of Inhaled fibers* In guinea piga they fans after about 60 dare of contact with. the tiasrwr., They arc abundant in roin aid tha guinea pig (5** Table 1; but are rxch Itrgiw In th* ferraer, probably bacauae tha l&rgcrssd air tube* adult fiber? o* greater diasnslon. In cats, ra&bita and alee th*r la an atypical co&fcir- of a .few of the fiber* after ranch Laager residence in the lungs * In rat end dogs no bodies could be discovered. Although the sridsice is inconplete, it appear? that th.a fcmnslion of the asboot-oais body prevents dssaga tc ths. tissue by the fiber. I. HK1UIICH EXPERIKSflS Four eoatcruhsciir^ Inbalitlon wqysrirasrrta hitvs beer, conducted at the Saranac laboratory sith various ferss of asbestos dust. In each .of these imrerttigstions oar? than 160 saisfii* 'vie? us=sd ard the aqperiaaats -swire carried an for periods ranging frm 2 to sard. than 5 Tb* four Vlnds of tsbsfsrtos duct espio7?d are ldaatLCied m ICl^4? flcaU, abort, fiber, 100 par cant fcsJU^silLsd, 4ad lon*~Ibr asbestos dost* 11. Inhalation Experiment -rdth n%lrig-'s flouts1* /labegtoa Curt the first inhalation experiment conducted at the Saranac Laboratory" with asbestos duirt was begun Is I?2o. Aainala inhaled, the dust for periods up to nearly three Tears and seme guinea pigs lived for about four years after their first exposure to dust* 1 preliminary report giving observations after 29 months of exposure appeared in the February, 1931 issue of 7KS JOORHit OP USDSSTRlkL KTCIEHE.* it that tine observations covered a period of only 2-1/U years and the conclusion* M to the ultimate effects of inhaled asbestos dust ware provisional. Results of the completed study show that most of the conclusions dr*sn la the preliminary report vers substantiated. i complete review of this experijusnt follows. 12. the dust inn; material was a coosarcial variety of asbestos dust known ' as Xing's floats and res composed of short fibers and particles of variable sine. It was obtained froct tte That ford, Quebec plant- of tbs Isbeatos Corporation of Aseriwu 13. Thg~do8t cocesosltioa (table 2) reveals that the amount of fibrous chrysc-- tile was only lii per cant, a rather lew value. However, there was suf* 1 cleat fibrous material to produce a characteristic fibrosis, lit. The dust coocectrstlg* at first quite lor and for impinger samples taken soon after the experiment vnui started, the average light fluid count* by the standard technique v*^ only 6.0 *&ilion particles per cubic foot of air. In appreciable amber of larg* particlw (or fibers) also nrt present, u STUDIES OH EXPOTfflfTiL FHECJOCCSIOSIS. 71. Inhalation of Aabestot Dust., Oardner, I.C., md OaalAgs, D.E, J. Ind, Hy*., 13* 65-tfl, 97-Uii, 1931. shorn by an arerage count of 0.8 n.1 U.lon far particle* greater than 10 cd.crons. After th* Inhalation ixparixent had been under wey for about two y**ra, the epoad of t-b rotating paddle in tho dusting machine wma increased and for the remain ing 9 or 10 oenths of t-h* experittsut considerably nor* dust waa diaperaed into the atsjoaphoro. dost counts for impinger samples collected after this change rare 53.7 atliicn for the ucutl light-field arthod, and 1.6 million for particles larger than IQ microns. - 15. Reaction in Animals to Inhale floats * Asbestos Dust. Resnlta of the inrestigaticn, briefly susrjariied in Table 3# aho<r that inhala tion of King' e floats asbert-aa duat produced a typical peribronchiolar fibrosis in guinea pigs but not in rabbits or rats. 16. Quine* Rigs. Serea croups of guinea pigs were used. In three groups the effect of a continuous soul of an interrupted dust exposure studied? in two other groups th# relationship between infection and dust exposure ns iirrertlgated. The retaining tec groups were infection controls. 17. Rate and Type of Raaction. Quins* pigs Inhaling this dust for period* up tc 33 norths dtreloped * charactertstic fibrosis .occurring in conical patches shout the respiratory bronchioles. During thi.e exposure th* peripheral aiTeoli wre not itrrolTwi-. The particulate slecents in the dust were transported to the lymphatic aysrtea where they caused no signi ficant reaction} the fibrous elesanta rsajainsd fixed at the site of original Localisation and were teldoei detected ia the lyspfcoid tissua. Plsuriar and fi brosis in the sept* were ebssrred only whan infection complicated the procaaa. After exposure of opprcadznftteiy a y^r, a srsvtll amount of cellular reaction had been produced about jeery respiratory broncaialee. As mors dust was inhaled, i it continued to accuaolatc in the sane location and later stages of the diseaao consisted of extensions of the original lesions. Hem zj-aaj wr* not involved. Apparently, the inhaled fibers rere caught in the packst-like l7cali that aro given off front the lateral walla of tha respiratory bronchioles. There thsy ware phagocytixed and oaoy of then: were carried into tha -sail by nigratory cells. Uooortucloar leucocytes attracted to the area caused an appreciable thickening of the bronchial vail. After 16 months a delicate librosis naha its appearance. The proceae evolved so gradually that sitotie division of fibroblasts could rarely be discovered} nevertheless, the ntnber of fine intercellular collagenous fibers (fibrosis) steadily increased. As this fibrosis contracted, it partially closed the alveoli, and with this atelectasis the lining gpitheliua its eabryordc cuboids! fora, the result vas the adenoca-lik* appearance that liillla described in guinea pigs inhaling ailicon carbide. Tha longer expomures resulted only in nor* thickening of the Trails of the air space*, largely due to an in crease in the ooour.t of fibrosis. The fibrous tissue always remained cellular and never showed the hyalinisation characteristic cf silicosis. 18. Progrossioa. The reaction produced in exposed guinea pigs did not pre gross significantly during: a subsequent period of 37 swaths whan the enisxlr livwd in a aortal atewephars. Betxeen 8 and 11 cwntha after exposure ceased, tha cellular reaction had been completely replaced by thin strands of fibrous tissue. Observed still longer, the scar tissue decreased in amount bat in the last sniaal sacrificed, 37 months after discontinuing dust exposure, *oa* fibrosis mas still risible* IS* Infection coincident *ith post-Inhalation. Of the group of LO guinea. pigx infected with atten uated tubercle bacilli (R^ strain) 31 died or were sacrificed before two years of dust exposure and tw* reported in the paper b7 Gardner and Cunninga mentioned above. Seventeen.cf_th3 died Trotn intercorrent- pneumonia. Briefly, the re sults wr* as follows! 10 revealed sotin evidence c t spread of the tuberculous FTocess; in 6 oi these it was confined to the lungs and in the other u the abdominal viscera also wr involved. UsualIf a slight local extension, of the tuberculous infection had occurred but cub3conceit heeling had resulted in fi brosis of both the pulnonary lesions and the secondary lesions in other organs. The healed pulmonary lesions snowed oora fibrasie than is characteristic of either tuberculosis or asbestosis alone. The 9 aniaalji which were still alive after two rears of dust exposure vers sacrificed at intervals durinc the followinc Tear. In U of then the prlscrr foci of infection had healed with fibrosis and even calcification end there was no evidence of progression. In the other $ the tuberculous foci showed erid*nc of haring previously'spread locally: in U of thao it had healed, by the tiae of autopsy, with escasaire fibrosis 5 in the other anical there vaa a generalized chronic tuberculous pnauacmix in one lob# and isolated primary tubercles, tiled per* still active but had not spread, in the other lobes. Evidence of extension of the infection was first sasn after 7 months cf dust Lnh&lationj daring the next 20 eonths oars than half of the aalnala showed an actirely spreading tubercruleedla and in 3 of then small cavities had d ere loped. During th* last S sooth* no ardnals exhibited any evidence of active infection although In half of that th* .haaLed fibrous scare of previous extensions ^sre cu rious. Sixty per ccci of tN* guira*. pic* with oprsaiing paiaonary tuberculosis a harped thbgrcnloeia of tha spleen and liver. 20. Infection 3ccperiiBpoaed Open an SatabHehad jabegtoels. '?Taire guinsa pigs, aft*? in haling aabeatoa dust for nearly 26 sonthe, hut* infected wdtft tubercle bacilli and then resserved to nomal air. The subplarural tubercles In the dusted aninala w* r.s ccr rnrtrcu4 than is ron-dur.ted controls, but a considerably mmh*- ^er<i found in the depth* of the lunt7 about foci of asbfstjfiiA. The reaction to ini ac tion shewed only* slight local extension abci.it the original eifcea .in the lur.es and trachftobronchiaJL lymph robes. 'Che oMoninal r'isesrs. rtere involved in coly one snioal. Caseation *&s found in tubercles 1-1/2 worths rid bat by J-l/2 months it had completely disappeared, leaving only scru* tissue. The latter still persisted In the last anioalf vhich tikw VrUlad lii uonth* altar infocticn, 21. Asbestosis Bodies, ^odor&b* rasabers of aslXKtt-caia tediaa occurred in the lungs of the guinea pigs, beccsing sara nuauttu* and core distinctly segausntsd in later months. 22. Rabbits. Rabbits exposed to the asbestos dust for periods up to 19 months developed a Lrr-grad* foreign-body type of reaction but no fibrosis, 11 though t-hoir.lungs contained particulate elesssots of the dust, fibers vsrs not present, indicating th=,t tb# upper rospiratarx sstchaniais of the _\ rabbit is adequate to exclude fibrous foreign bodies. Too rabbits, after inhaling dust for 6 and IS isoaths, lived La normal air far more than txo yssrs* it, autopsy neither aJvimtl sh-re-ri any aviesne* of cellular reaction or fibrosis in the tasut* Inal bronchioles cor ^sere there any fesbeeteffia hodi**. 23. Rat*, ill the sTdto rat* had acquired ta inaction, realising ir. ths formtico of pulmonary abactsscwt* before they can* to autopsy;. Apparently, sc such hftry tocos obstructed their branch! that very f.ra fibers could her entered thair lungs. In a (ent o? t-hp rs.t-s} an occasional asbestos!o body vas diacorensd but there vas no filirccif. ' Sunraarr and Interpretation of Inhalation Leerricant with Floats Dujst The findings ia the expari.Tnnt with King's floats dust can he susneirised 'under three heading** A. Effect of the inhalod dust on normal aniraJ-3. The flog's float* dust caused a charac teristic peribronchiolar fibrosis in guinea pigs bat not in rabbits or rats, Tte fibrosis did not progress aftar the dost exposure was discontinued. and the guinea pigs transferred to noraal air* 3, Sffect of the inhaled dust on tuberculosis in guinea nigs. In guinoa. pigs in fected with attenuated tuberclo bacilli snd then placed ia tha dart roce, the results were sorts Turiabli than ia usual'in an experinerrt of this type, l few sr.lsnls showed co sign of progression; in .-cost of then there was eridsr.es c tea-. v Fcrcrp progression frith ?.?ibsequant hnalir.gy in one animal there was continuous / progression to death. In contrast, when guinea pigs, after being infactsd, are exposed to quart; instead of asbestos dual, the infectious procasa continues to progress and srwr.tua.llr senses the death of the aninala.. Gn the other hard, ex posure of infected aniswi* to .% hamlces dust liV.s cdlcite or gjpsrn do not load, to anr progression e? tbs infection. Guinea. pigs infected with atuenttat^d tubercle bacilli following ths tamioAfcion of shout two rears' exposur-e to *sbeato dust did net darreinp proersasirs disease;. The onlj modification of the infection wa5 in its Local! action, *, few b7.ci.1lX being reta.in.od in the fibrous tcrcinil bronchiole? snd forairu? tubercles there in addition to the usual foci beneath tha pleura. In view of this Yarisbilitp, the unusual nature of the response and tha high proportion of dwtths froa intamj.rrtfflfc pacnxapla. it is felt that deficit* condi tion* as t/> ths influence cf this duafc os ths course of tuberculous infection are not justified- C . Iffact of tub<rrc.ilDujf tnlactlor. on the ration t-q J.% Infection cgepilcating a^rbeetoaw accentuated the taadancy of the dust to produce fibrous tissue. TTii? charge occurred whether or not the bacterial lesion tw in contact with tho asroa of duet reaction.. O. Inhalation Eroariaent frith Shorty-fiber isbeartog Dugt. Since baxtu dons dusts Lite quarts are sect effective in producing fibrosis 'd.en the partic] 45 are 3 aicrcce and lee* in aira, an Inhalation crperisant va* carried on to determine vhethsr this condition i true also for asbestos dust. It wu thought that by using a short-fiber jjebeirtou dart consisting also** entirely of fibers and particle* saa.13.sr then 3 edcror* aa accelor*ted tissue response be initiated and r< advanced reanticr* obtained in 9, short tins. The previous Inhalation erperlaent vith Xing's floats esbeatoa, **hieh contained fibers fresa 1 as- to 1 dorort or less in length &a veil an a great deal of perticuLat* natter Ktd vhich produced a topical peribronchiolar .fibrosis in exposed guinea. pigs, eerrod as a basis of conpariaon. 26. The dusting material for this expuricssit rus foi'vurded Iron ilia temrille plant of the iohr^uJirrillG Carporatioa. It n*s the remain of libam collected ia dust blits after a carding operation and careened to pass 200 cesii. Since the waterriil as received coatLnd rany Long fibers, l.t. m gremtii in & steel ball gill to reduce practically all the particles 'to 3 nicroas or leas in six*. Them tansd slooo in & standard dusting sachins, this finely-^ytmid asbestos tended to pack in the hopper and it becasse arcusitrr to 2is one vclaaa of the ucercicd saterial T?ith three volncsa cf the ground to j^snarat-e a satiafactcnry dost cloud. The addition of the asall quantity of ungrotmcS 3.5b*rtou urua unfurtyjaat* beceaee it confused the intcrprutstic^ of results. Probably the adrer encraat of reaction that developed ' ' ? to the lao$ fibers in the oJbcture although ths ' data of l&d# xperlaa&t.do not prota the point* U 7. Tha coapositlaan of the 8hort-fib~rr asbestos os received lc disclosed hr 3^* chmirgl apd petrographic analyses given in Tahlo It. S^vplea taken before andiatftar griztftag yielded about the same rolues on analysis, indicating that ther*ifBS uc coofcSmBinatioa Crocs, tha sill cr loss ox* water content- <4 26. duet cssfflBatration variod somewhat during-the crperlrent and light e count* for ft-tasospheric saspleo collected inside the animal cages * with the i^Lhger spperaetua ranged from 63 million to 18? million. The average of counts m 20 ailligp or the first pear of the ecqporiasntj 13U million far the second ysaer lu*O rdlli*ou for t*he third year. * 25. S^a-frosturecTj aessnreoenta of air-floated duat frea insids tha cages C (t,x nagnifixasbico of 1300X revealed a great preponderance of fine par- ticlas (Tab3j| 5) fc-ariy 90 per cent of the particles seen were smaller than 3 microns. : 30. Reaction in Astnals to Inhaled Short-fiber Aatrrotoa Dust. Four spscico of-anirals - guinea pigs, white rate, cats and rabbits - were used in t this experiment. The rarulte of tha durt exposure, which are euoaarised in Table 6, will be coc*&ardi sore in detail below. 31. Gutnea Pig*. Sigfcty guinea pigs were originally placed in the dust room : but 21 af tbss a*re later ellr.lnatod front the experlasot and killed bacmw of eclarjed lyapd oodte, Of the other 55 anioala, U5 remained ia tha dust rcoa until tb*y wart sacrificed or died frets natural causes and 13, after being exposed to dust for 20 month*, were tranaferrod to a narnal atmosphere. 32. Rate and Type of Reaction. Th* type of tit sue reaction to the inhaled start-fiber asbestos nas sasentinliy the saoa as that already cbasrrad in the axperineut with Xirtg1 c float* Asb-ston. The rtU of reaction also was approxi mately tha s*oe tot the arteirt of involrcwnb uitli the snort-fiber dust xsls ray raich less aad after 16 to 2U c^onth:: of exposure only a vary ex .hmH feel of reaction, which generally required microscopic erara'nation for detection, were produced la the gedaea pigs. Until expo.rtres had continued for approximately can year, there was little tendency for dust-cer.taining phagocytes to collect ir.tc cluspe. By 16 nonths phagocytes had bofun to collect about tha walla of a far of the respiratory bron chioles with a little proliferation or infiltration of eononuclear cells ia these wall*. There Tren^also aotoa cultinuciaatsd cells but they >sre always of tha inert foreign-body type. It 20 to 2U ronths the cellular ciueps were sctoatlaa* quite a&rhed and soastiacs changes in the epithaliusi resuitad in tha edencesa-liks or "sdercaRtoid<' appearance ^rrericusly described in Section 17. la rest of the subsequent Mahers of the 3erics, the reaction remained cellular in type. Ia a fsfff howsTer, fibrous element* dotsirated the picture. In the latter case, t'ne collagen 1**3 in color and tenuous ^Lth no hearry swoHsn hyalLnisatioa. is in the rats described balnsr, the alveolar -alXj sight bo cade up of a bead of collagen supporting isyse of epdtheliiat, hut with m contained capiUxriea. In the trachecbroncfelal lyupfa nodes th* reaction 1=5.3 eors pronounced in this experi ment than ia the prrri/ss* cta xith King'3 floats asbestos, probably because of the transportation of m sxc-ets of fine particle to thfi nodes in ands-sis inhaling nhcrt-flber tebeeto.t., 7h rwetion tzjs *s.mtiaUy increase in reticulua, rattier then jl fIfcrosie; T'ith preservation of tiuj original cell# bstrs'ern tha thickened reticular fibers. Ciffuss chronic plour4 ithout evidence of pulmonary infection u present ia 4 far v~: js. r-rofywgicry. +i oontfts follcrring tivs crasatioa o f 20 aoatha' exposure to dust-, arogressinn of diseaue was not definitely denonatratfrd but neither could it- he absolutely disproved, owing to the varia bility of the response in different inirce- ' it the end of the dust exposure of 20 mntha two pd.ES were--read ca and one as 2+. iaong the 13 removed from dust the finding* 'were variable t in 2 the roaction vta ; in k it -mu *; in 3 it -*** J+j in 3 it was h*j and in one aniaaJL it ms 5*. It is quite poeiibla that those with the wart oarlced changes had already darolnpod. acre reaction than the racain- der by- the tiro sspeurars ceased,. Since tha mors oTsr-e roacticaa occurred spora dically and borv no relationship to tha length of tics after ce&sstlas of expo* sure the differences -wore attributed to variation in individual sciscaptibility. This view received support frea the chaoical analyses (Table ?), which often re- raaled ccaparablo anounts of ash and silica in lungs with widely different fncunts of tissue change. For exaapls, the ash and silica vsince were quite eirbLUr for three aniials in dust 20 souths snd thoo la normal air 13-3/h nontha, yet the tLa rue reaction for one aniaal was Uf for another, *j and for the third, only . 3li. labestoeis Bodies. Ths fortsation of aa'oe*tods bodies au at first xtreessly lisdtod* After 5 Booths* azpoeur* only a tst rare short body could be found, usually inside of cells. Ironed the finest Intracellular pcrticle* there *srs yellow depoeit* haring the iwua* color &s the wsbeatosiB body. Scpotnsr* of one year had psroitWd tn aocuaalAtloa or aeny longer fibers about which the sabsetesis-bedy coating dcvolopod. Tfost cf these vra still short enough to be partially or entirely within phagocytic celle. Dy tha 20th conth and thsreaftsr, they -mere caasparatively aursreus altbcu^i still rare in coopsariaon -with tha findings in tha ting's float# qp*rleat. -17- 35. Kbit* Rata. Ssverrcy-three white rata were exposed to atooapharic short-- fiber asbestos dust for periods up to 32 oorsths. Sacri ficing:? duri.-- the first 10 tenths were rsad<a btronthly and Tor the reminder of tha experlaer.i at lass frequent intervalst ' 3^. Rataand Tyr-g of Reaction. The dost cells until 8 conths war6 widely scattered and axLsted in feel only aporedically. RsactiaBi was Hotted to occasional alight thlckaningo of the septa about snail accurai laSioas of dust colls. In & fee rata at 1C teemtha, there was a sug- fastloo of early fibrosis but tha change was so alight that it would probably b# crrsrlooiced wittout the clasp of dust cells to attract attention to the area. Only 30 aniaais Tara arpoeed fro* 12 to 32 Months, la each of then the lung* showed adnata patches of well-defined fibrosis distributed Ilk* that of asbestoaia but without aebsstesis bodies. The lesions, visible only at a oagnification. of 150 diasetera or sore, consisted of patches along alveolar ducts in which the walls of the air space* were retry thick, due to swollen collagen franework. Coiojactive tissue and Foot-JBielachcnrsid. silver preparations revoalod coxplale loss of capil lary bed locally. Quteid* tha collagen a thin layer of epithelial cells. This did not rateable tha 'edenoxatoid" changa <xhar*ctrljrtc of guinea pig ae- bestosia, tto pleurisy waa present. Hoar tha lesions tha air spaces ware filled with phagocyte* containing grey to y&llow particulate dust md a rare long naked asbestos fiber. Careful aaarci failed to reveal even t suggestion of an ab*sto~ sis body. The tracheobronchial codas showed cosrpact focal collection* of cono-- cytic call* at 12 Month* and, at <0 months, acre* diffuse thickening of tha reticulna. In a few rat* there ns dsflnits fibrosis along the margins of the nods and arttndlrg into tha nadiartirial areolar timrua. Coapared with tha response to active dust* like qparta and chart tha reaction to rficrt-fibar asbestos was negligible. Result* of chesicsl analyses race on the white rats are given in Table 3 and the average values have been tabulated in Table 9 Tor conr&riscn with siailar values for rata Inhaling other dusts. The concentration of atsoapheric particles to which the and cals were exposed vaa approximately the *aa for asbestos and quart*; for the gypsvra-qu&rt* oixfcure, it was about tiri.ce as high and for chart fire tires as high. It rill be noted t!iat the percentages for asbestos are lower than those for quarts or chart but are siadlar to those for the gypsua-quarta mixture, in which atmospheric agglutination tended to reduce the asount of duet inhaled. It cdght be inferred that the total.quantity of asbestos dust inhaled was low or that it had been eliminated from or dissolved within the lungs.. In the present state of our knowledge evaluation of these hypotheses Is not possible. 37* Cats. Twenty cats wars used in this inhalation experiment with, the Short-fiber asbestos. Eighteen were kept in the dust roos until death, the exposure period ranging Iron one raonth to naarly lu-1/2 years, and two, after a dust exposure nf 31-1/2 months, were removed to normal air. One of these was sacrificed $ months, and the other 2li aonths, later. 33. Hate and type of Reaction* The reaction was essentially that to an inert dust, even after mere than Is years of expo sure. The tissue nwrpoaae in this species was confined to adcroacopic foci of fibrosis is the rails of groups of aubpleural alveoli, rather than in the peri bronchiolar areas. In one ardtral the change ** extensive enough to be vijsuaiiied on gross inspection of the section. ' 3$. X-fiar Change*. Only in the animal with the longest exposure did the I-ray reveal definitely abnormal shadows. After 29-3A cooihs the picture was negative; after k$ oonth* a faint Bottling could be detected tlu'O'Ughout both lungs. It autopsy, 5 months later, there was only microscopic fibrosis ir the eutxilsnral con* plus he.rrr lymphocytic infiltration about, s^all bronchioles. liO. Asbcetosis Sadies.- On pro.lor.gc4 search a fsv yellorr atypical a^v- .-osis bodisfo. snooth and without vsuurtratio.-uj> ^rc found in two aeiaais exposed for oora thin a yvar. Ill* Rabbits* Sight rabbits aere exposed to dust fer periods arteexiing free on to oora than fire years* The Isnt anisi&l was reoored fr the dust roo &xi loft in normal air 6 taouths bafora being sacrificed, h2 Rata end Typo of Reaction, Thera was ncrer enough fibreate to be de tected grossly and there ema no chronic sdhesiTe plsurir/, ilicroscopic evident of alveolar vail thickening was first detected After about 3 rears of grpcgvtre and u seen in all fire animals exania&c thereafter. In ens anlnal that died of paralysis after nearly four mars of ex posure the reaction was extensive enough to be risible cn gross inspection of tissue aectidhs* The possibility af piUsonary infection in this Ar.isal could nct~ be exclndM, Koxsrrw* in another ar,iisl dying t-no years later tha focal fibrosis wsa not r-ajcrly as obrlous or ss Advanced, Areas of Lrrrolvcncnt, ehich vers largely visualise. b*csn of phagocytic reaction rithin the air spaces> tsud&d alcrwrcopically to toccga aora .fibrin* with th* psjs-sage of tine but there vas r*tt such *Rcrochwtt upon th# lursm of tir space* and the archItecturo of th* lung sua prsaerrad, U3, Agbeatoals Sodlag, iabestn* bodies snere not detected in rabbits that dird early irt th* erparinant but vere a ecu in ail tnlrals that had besn rpowd to th* (hurt for aor* than thro* years. UU Svaaaarr and Interpretation. Th* original p^^T03 f the experiment was to evaluate the cheeical thoory of the pathogenesis of asbsstoaia. It-was felt that if tha tissue ruc tion to a-sbj&toa wra cheoical in origin an t. ' berated or accentuated rcapons* would result frca exposure to finely-divided asbestos, as ia the case with quarts. This experiment, in which the reaction was slower and leas extensive than with King's float*, indicates that the reaction probably is not primarily cheeical in natur*. Of the four species exposed in this exporinent only the guinea pig and rat reacted with characteristic peribronchiolar fibrosis. The cat reacted with atypical sub-pleural fibrosis and In the rabbit the fibrosis which occurred could not be positively attributed to the dust because of a strong possibility of pulmonary infection. up. Inhalation Zxperinar.t with 100 Per Ceat Ball-itillod Asbestos Dust. In the inhalation asperiernt frith. ahort-fiber asbestos dust a snail quantity of unground asoeertos was ntrsd with ground material in order to produce a suitable dust clcud. h*n evidence of a dust reaction appeared in tha guinea pigs during th* experiment, it was not clear whether this wus a t la rue response to th* small naotor of long fibers in the uz^round asbesrtoa or was a delayed affect of the sore abundant fin* dust* CotaMqusatly, another inhalation experiment was started in which no unground aaterial was usod. U6 The dusting material was the ground short-fiber asbestos used in the prtTious inhalation experiment but no unground material was taixud with It. To obtain a sufficient MuRt of &taphoric dust, th* design of the dustinc apparatus was changed to an open type of hopper and fresh dust was added daily. Offing to the terdency*; of the material to Com 5=ill spherules which. prevented such of th* fibrous portion f.voa floating out of the hopper, the dispersal of the duet rrr not entirely eatisfactor*/ and after 7 .Tenths of operation, the dustjne irnchinn xss \ cccrrrorted to its original dasapn. To prevent ''pilling" or tho forcv.r.ion of spherules of asbestos, steel wire brushes t/ern attached to the in- , sice eurfacc of tha hopper and to the rotating paddle. This arrarss*orce,"t gave satisfactory results and was used for the remaining `1 months of the experiment. hi* The concosition of the r.nr ratarial (short-fiber axbestcs) and of atecsptieric dust liberated from the ball-cdlled product in the dusting ma chine is given in Tabla 10. These values are based upon petrographic study and i-ray diffraction analysis. The atcasphric sasple vaa collected y-ith an elec trostatic precipitator after wire brushes had been installed in the dusting mtchina. Prorims to this, tha chrywotlle content of the air-auspeuded material ww undoubtedly leas than the 15 per cent value given in Table 10. In an intarin report, it" rze stated that tha air-borne dust contained about $ per cent of chrreotile before ta wire brashes wire used end up to 6 per cont afterwards, tut these values were probably lor. Quantitative estimates on ball-milled asbestos dust nay be somewhat inaccurate because it is difficult to determine how much of a dust asaple ii fibroa cfcrysotilg end hesr ouch is non-fibrous serpentina. JjB. Tha chart conoegtration fen* the first 7 months of the ooqparlrent was about 1DQ dllion particles per cable foot of air. After th* wire brushes had been installed, tha dust counts were a little highar and the overall average for tha fir'st year was ICO ail,lion. The average of counts for tha second year vas 3.63 million and for th# third year lU5 million. 'L9. The giae-frocueacy ct th* occpcreuts of atxoe-pheric dust collected inside the unixai ctrco riih thu electrucailic apparatus is reported in Tablo 11. Tnc uayle& vers fcslnn, one before the '.Tire brachea irc-rc installed anq one aftor. It ili bu noted that cl tor the wira brushes icera in use a greater proportion of very fine particles and also of longer fibers -was vcleaned into the air. Q. Reaction ia anjjaals to Inhaled ICO Par Cert lollbilled Asbestos O-j.yt. Guinea. pigs, rate and nice rare used in the inhalation experisvent with the ICO per cant bsil-iti.iled as'oautou dust. The results are sursaarised In Tail* 12. 51. Guinea Fit?g. The er^srisent tram started tilth ICO guinea pigs, is the dust. 07X0sure proceeded; there tiers 3? accidental caaths 5 32 of pneumonia in cm epidxriLc. After 23 /souths of dusting the 16 sunriring guinea pdgo trera traraferrrd to norm! air.- r'M. late and Typa of Iccactlon. For the first yoar of capoeuro practically tha only- reaction to the dust uas tho pre sence of scattered phagocytes and an cccasional tainute aabestoaie body. At 16 and 20 centha no gross response tsaa risible cm the tissue section but xicrcncopicall; peribronchiolar foci of infln/WAtory c-lls could b seen. At 2U months thers tras a till no changt ^srg* enough to be scan rlth a hand lens sithough rzicrnscople ccaaination rereeled cellular ^curulitloud about torninad bronchioles and nany acre asbeetoai* bodies, chiefly rithin calls. Chemical an.alyaea of the lungs (Table 13) rrreal that in sprits of the Halted tissue reaction considarabLs aunt had been retained in the lung. 53 Progression* The lungs of aiinalc Goosed for th* lull ouatir- period (cl'O r,ont?L3) rind then living in n-cmal air fer 2 eor.th* revealed the changes doccritcd above and also Tory alight peribronchiolar fibro sis* After 0 months in normal air the findings rsre similar but at 12 uoothr of ii micala siowad sreasly-visible eharsctsriotio peribronchiolar fibrosis with adancrcicid change. 5lu lyaoft Soda Inrolreiant. The ta^aohaobroachial nodes rare ea sentlolly najatlvo until exposure bad been cor.Linuod f`?r sere than t year aad & half. Anlaf-Is sacrificed at- 12 swaths and 16 souths revealed a few minute collections of phagocyt-oe conia.in.lng particl*a but prac tically no G.bars large enough to be recognised as such. After 2Q ooatha of exposure oary conocyte# filled with yellor granules tsm present, it 30 months there had: bean a slight increase in reticulum but r.c fibrosis. Ho further changes occurred in the nodes. Asbestaoie bodies wqrg not seen in the nodes of any of the guinea pigs. $5* labegtosls B-edigs. llinute asNr.6to35 bodies rers observed as early aa 3 months after unpogura began, but they did not be* 1 cocoa aaaeuxus until 16 centos red elapsed. Tha bodice vets abort and practically all were intrscellular, although at 20 sonthe sere were lens trough. to project beyond the coll borders. It in lqportsxA to note that in the later months of exposure there css a dis tinct increase in the rrxbar of' long fibers fc? to ?0 eclcroua in length) in the lungs and that after arposure erased chtrfiflteristio long asbestos!* bodies vure aoes. $6* White Sets and Lg.ce* In this axpariJwnt UQ rato -wars exposed for periods up to 20 noaths and 2h sdee for periods up to 12 ncnths. Either species developed cva- a ra^ost.icn of acbcatoeis and reaction uua limited to phage cvtools of Lchalori particles :-r? wdcalv-gcattered dust calls which regainad froe in air apaccs or were transport'd to the tracheobronchial ijnph nodes. No aabestools bodies werra found ia v rats but in the mice there were a Tery few small r/on-haustr&ted ferae uittein phagocytes. In 21 nousa lungs sectioned thorn were 3 instances of pulmonary adenoma. (lM;, 57. Suaaurr and Interpretation. Tha tisana reactions observed in this experiment Tare much less erfcansiva end alower in derelapsant than in the previous investigation with short-fiber asbestos. Since presumably there vrro fawsr fibers longer than 3 microns in the material used in this experiment, the results tend to confirm the interpretation tsda in Section hk of tha short-fiber experiment that the reaction probably is not primarily checic&l in nature. ' * Tha finding of long asbootools bodies in animals inhaling the ball-adllod catorial is an eram&La of the difficulty of coapletdly eliminating long fibers free, an asbestos preparation- In regard to progression of reaction after removal Iron dust, which was ob served in this experiment but oat in the others, ths following interpretation is offered i Wien the reaction is veil-developed at tha termination, of xposure,tha contraction of the fibrous tissue would obscure any possible progreesioru In this experiment, however, since only the earliest stage of reaction was present at the time of removal froa dart, its subseewnt progress was apparent. It should be noted that th* degree of progression was so slight that it can hare little, if mj, practical significance. 53*. Inhalation ^brorixant with Long-fiber Asbestos Dost. ------------w--w---- m ^ i ----------> , 11 ^ m*-- kTtsr aniroals inffOing $hort-.ClHr axbestcs churt for rorr than a yosr had Called to develop sign* <`J.-r.tjrfc reaction, th3 hypothsois that asbcstoais is pro duced by tho nech-anica.. irritation of long fix-arc given added support* Dices the Cline's fixate asbestos vised in the first- Inhalation expertsinrst. -t&d a rather low content of fibrous chrysctile and contained considerable serpentina znd other inpurlives, it t?zls decided to conduct a now inhalation experinaot with a purer fora of chrysotil* which would be richer in long fibers* .5?* the dusting ggterial carloped in this inruot-igitioa tux obtain** Xroa fcho UanviUe plant of the Johra<4tenrille Corporation* Saaple* of se veral ruristiee of acboet-oe duet wars first subeitted to the Saranac Laboratory for esrsninatlon end one kind, identified .a.?. Lot D} which was low in sagnetite r < and chrow.te and had a. fibrous content estimated to be about 75 par cent, ms selected sjs nvewrt switchlei Steel -wire hntshes were fast^oed to the inside sur-- fax<! of the hopper and to ths rotating paddle ih order to open, up the bucdlsi of asbestos and liberate sore fibars into the ataxwphers. 63. The coapcaiti.cn of fchs iong-.Cibttr fixt-e-rtex used in this erpariasnt in indicated by tha chsaicil and potrographic atialyss* given in Taxis lit. It sppsa.r* that this jwiftri*! sa-s % sr-tch p'xznr fora, of asbustca than th* short fiber d\?.?t uasd in ht>vrr nspcrisrntSo TM?i is borr* out, by c-capering the approxisate analyses of th* iong^fiber and srwrt-fibstr idust in fiblx 15. 61* The duxt concentration 4$ rvo-*i*.d by inpinger ' tssplag taken Inside the anin&l. cages r?- such lower than the concentration for the enp*riinta ith short.-fl.bar or bHl*octll*d (tret,, For the first- yr of tha espsrinant with long-fiber Miresto* the of the light field count* n* 32 million; for vhn aencffid 7iry b5 cdlllaR? for the third ys&r, 3? million; and for th* Tsar. b3 sillier?.. Srasiaafcicn of the itspinger swrplsa with derk field iHicinat ion disclosed ^a*.t Ttvtnjr fine p3.rtir.V13 less t-han one rien'on in site accorparia-i the larger particles *na dork field counts w?r> cd the srernga, about < or 6 tines Jarsw than ths light field counts. 62. The 3logo-frequency of aijsosphoric ganp.Iet u ths long-fiber asbestos. du-rt ssvi of the ball-cilied dust is shewn in Table l6* Beth socplos xnr cnlleotad with thn sloctrostat.ir. precipitator. It in.11 be noted that there SB2LS far acre fibrous material la the Ion?"fiber dust. 63. Reaction In Inijnals to Inhaled long-^fflber asbestos Dust. Guinea pi g*, cats, rst-a cod dee wre exployed in the irJialsticn exporiaeat with long-fibar asbrnto^o Results of tha exparirntj rrisatriisd in Tolls 17, are described In gr**.tr detail below. &u Guinea Pigs. The experiment w*.s started with IDO guinea pigs. Alter * crposun had been carried on for a year, z ssrerc epidemic of pnwaon.lA arose in thft duet rocra *\rd About one-third of trie animals died cr gsre- killed. To rsplacA th-. 35 tot* gain** pigs wsru added to the *urrlrli'4' group la the dust rocsu 6. Rate and Type of Reaction. Histological exactnation, r-srsoLsd crossly ricibla Isaiosr in the lungs after 3 oonths f expojpiris t-5 <hjst? ^cralifting of c*3.Iul*.r inliltratiop about tha tarcinal brorr.trtnLftj., It 12 softths? ther* 's*-T's .!d*rvo?Jtoid thongs*. in lhr air apac.** and by thcr 16th tonth a deficit- fibre act# ?s prrtcnt in the?? arens in half the animal*., The fibrone lotion could be eetm .*acxn*capic*21y &t 20 conths . Pros thix tim* on the ruction increesed in sxtant and in tha amount of collagen end by the 3Uth. scnth, it had fanned out into the parenchyma. The Lesions were rather sharply Idealised and the extensions 1'rcsn different hrcrchioles showed no tendency to fato, even In anioals exposed for the rrccissa period (3 rears). Although the intrs-puiainary vcvacticm aosatlaos reacr.ed the pleura, there was r.o invclrenent of that cerJorana. ho eraphyssiia was risible at any point. Soxo thick-ening of tha lor~or bronchi with a chronic ir1i~Lr.nna.tor7 infiltration wan re vealed, but it probably tras no cars than would be produced by a sinilar exposure to any dust. For th* first nonthe the phagocytes consisted of nonocytos or very small giar.t cells; later, giant ceil forsatiou ras sore preednent. after 16 aonths the giant cells were large, flllad with yeilcwlsh-trcrra pigment and sonstine2 vacuolated, An occasional animal shored an Admixture of polymorpho nuclear leukocytes and, in guinea pigs exposed fer & coc.v.doralla period, eosinophilea* Tho reaction was at first entirely cellular but by 15 months fi brous tissue formation was definite. Kmerer, it never attained a stage of sugs'estire of silicosis. L aoceratc meivmiuci variation occurred saong the exposed a loth in the rate of developing lesions and in the stage of dovclopnant attained at the end of exposure. Analysea of the luajs (Tabic 13} disclosed that although the tissue response was ouch greater in thaw guirve* pigs than in those expaeoc to cither she* r-fiber or ball--silled asbestos, tha *aour.l of cdnersl cat tor in tha lung ash tess Lc-c. 65, Progression. In guinea pigs exposed to tha dost for 20 oontr-c and U.\n reocred to normal air, thr* *nLS a marked tendency for cellular inflsnssatory reaction to clear. This effect, accompanied by contraction of the fibrous blague, rwrulied in a diminishing siio of the focal lesions. Hone of these srdcwls. JciUUd at various periods up to lb i.-or-tas after e^posur*, revealed a* Unr? s? *.ho3n i;: tho -proup c.acri"::cr-i at the *?.,< c,r ?.v,5 20-cont.h 'jxpc&txr* prvcd or then i.v .ir.io>a!L= rhich rct.-ti.:ad in thn dust r?oa for core than 20 oonthc* Fourteen ninths after bust urs cessed, the foci In four of tht* t,\x rrrvd-oir.5 guinea pi-r.n tore so start..', that they -wera visible only with a. hand lens. fUsactic.: ip the fcroiip exposed for 57 months and '.`nor. transferred to a noraal atw??pherft Cfttita similar to t-ha re-opcnce in the 20-nonth corpssure a^nAi* escort toned abom, Reproverj scsll .foci vere drays visihlo on gross inspection cf sections of iLX &mo> piss of tha 27-vttth aerisx bnb in. no instance ran there evidence of axtension of the reaction. 67, Lyxsh Hod a luToirenent. RaacUon in tha tracheobrerichi si lynpfc nodes was first visible at the third so nth cf *z~ it the 6th month patches of csllul^r connactiva r-i?su* began to appeur in th swd&lXa. &srf by tha liith month r^,rt of the node had been replaced by cellular connective tissue, This plctvi.ro, rtvich resembled that in early silicosis, persisted to the end of the cesperiscnt. Sose anijcnlc, as a. variant, ronwed heavy sheets of diffuse* aso&ocyw-es and 1-trgo aotivn giant cs01,< hut there was never any necrosis or hyaline foziti<ma The epindlo--shaped nr* ?ll3 vara yuHurlsh in color fron fin* pdLgpjsrrrt graswl*? th?.f stained foe iron, ho fihrs or- 4.3bstciss bodies vfljv *tn. 65,. Asbaeto*lg goilvs, l.Uhovgh *.o!>nftiooi? bodts* rare seen ts ssrly as cua month after sxpo.vurv; began, they rrtr* rare and hard to fiod, At ^ rrrth-T rort rrrro vtsiblfi. chiefly colled insid* yitrrt cells, arxi at Q oonth* pviy hodA** vrrre .Cbee in connactive tissue, Thor bscene fairly abundant *a expozrjr* s.liticugti An son** later suAml* tho sbentoa.ia bodies wra csdy noderateljr numerous. 6?,, Cate. Four cats Inhaled the. lone-fiber asbostes dust far periods of Hi, 2$t 33 and l'-2 months, respectively, ana -rrer* immediately sacrificed, Two other catr alter being expoaed te dust Tor IS months, lired ir. a normal atcospnere for an .ddltiooai 2k months. 70, flatc and Tyre of reaction, Exposure for 1it sceths *ran sufficient to produce cellular accumulations of phagocytes around terminal bronchiole* end peripheral artariolte together with compact col lections of sisriJ ir calls in the tracheobronchial lymph nodes. It that time there war* no typical asbestosis bodies, but ecocth pointed Telle*- fibers *sr seen very rarely. "ith continued exposure. up to U2 months, reaction in the locations noted progressed to the foraation of cellular connective tissue which sade rell-defiaed sheaths about the respiratory bronchioles srd arterioles, marked lynpbcid hyper plasia and lymphoid infiltration of brouchiolsr rails- The bronchiolar epithsliun was icrsr and flattened, giTing the tubes aaooth contour* Typical asbesto&ix bedims were not fenssd although there -rat* an occasional reHow, smooth, pointed fiber. Ho pisurisy tw present, the reaction -was similar in location to that in the guinea pigs, but fibrosis r?, such slcrar in deveiopaeut and had not reached th* same degree of maturity, ' fj.. Ji-har wvangee* Roantgersogrss; of Vtirm cats were cade after expoaur* periods of ?Af 33 end lv2 Deaths, but tisp.vj changes were not dens* enough to be ism on I-r*y 2-lo- 72, Hats* Although 20 rata -were pLtcad in this dust rocss, nany died from pneu monia and rr not suitable for study. five toimals, of which ets was erposad for I? months and four for 25 aonthij, ners r*$ fStts pulmonary infec tion end offer a basis for conclusion*. . ?3. Rate and Type of Ssactlon. All four ar-1 asla sacrificed at 25 nsnths showed a wsll-earked peribronchiolar fibrosis. T.n the 15~onth animal, reaction vas just beginning. Asbeatcsis bodies trrre practically absent at both 15 and 25 norths although two small smooth bodies wer* found in the 15-worrth animal after c long socrch. Thus, these animals exhibited fibrosis without asbeetosis bodies. 7U. Klee. Out of 20 white alee used in Vni3 experiment, 11 lived a year cr ncaro in dust and died or were killed without showing an appre ciable degree of pulmonary infection. 75. Rate and Typo of Sanction. Reaction was Halted to phagocytosis by oonomiclaar call*. Usually these were wide ly scattered through the sir spaces j a United number were grouped about the ter minal bronchioles producing some thickening of their walls. There was no sug gestion of fibrosis. The striking fa&ture of the experiment was that 9 out of the 11 nice (82 per cent) exposed to dust for a year or core showed pulmonary tuners, usually adenoraatous in type. Thees lesions did not contain dust or aabsteals bodies. Numerous asbestosis bodiaa wore observed in an1.ra.ui killed late la the experi ment. Thus, these sjsLb&I* exhibited aabeatoais bodi*3 without fijaroaia. 78. Suanarr and Intararetation, Tb purpose of this experiment was to evaluate the importance of long fibers in the tissue response to Inhaled, asbestos. The results iraiicate strongly that long fibers ars chiefly responsible for th* reaction. Thus, in guinea pigs react ioc developed earlier and bncaae acre extensive than in previous experimenta in spit* of a anwtller concentration of atoospheric dust and a Lower ulnaral con tent In the lungs. Furthermore, a typical peribronchiolar fit*-n<H ------1-----J in cats although in a prtrrious oxpen-inszat with short-fiber bust it did not develop in this species. _ The cause of tha cellular fibro3is in the lyuph nodes of the guinea pigs is not clear. It did not occur in other inhalation experiments with asbestos. !XX7H. xsjECTioy expchhots ' In order to detersina to what extent the wwriou* fibrous clnertLs possess the capacity to prochsca tissue dosage, sxaerou* injection experiments were per formed. In those experiments guinea pigs sod rabbits were used end the srLneral dust was injected by the intratrachealt intrs.peritone-il and intravenous tech niques. for the purpose of sioplifica.ticn the findings in each, series of test* have beer, condensed -aM reported in tables, to which reference will be* cade Later. . ?6. Erccrlsants Using Intratracheal Technique. Since the_ asbestos .uinarfcla do not cause a typical advanced fibrosis in extra-pulmonary tissue, ton inirctrfcchwil techniqus is the perferred wey of in troducing fibrous dust into the exp^riasn'esi anicsel. In this sathod the dust suspension is inject ad by owns of t special naedlc or catheter deep into the trachea, Crcm which it flows into taa lungs ??. Cowparisoti of fibrous and Bonfibrous Cuats. ?<: deaonstr&ts that tha ability cf asbestos to produce fibrosis rnaibM in its fibrous, char&rier, ths serisaf of Injection expert Dents reported in Table IS? were performed. test* sre sane with unheat-od long-fiber chrysotila -wad with chrysotil* that had been ignited to destroy 1U flexibls structura or 'ball-trilled tv reduce ^ <-h r*. 1 Jiber to 3 microns and less. At the same ties control toct:: rorv .' v;t-.*- . -.-.stine, Kitich has the sasic chemical composition es chryro.-.i'Le sw i.-: r.cr.-' '' ' revierr 3f the fj-ndings reveals that only tha undented long-.r<',er- C ~'S' .-.c produced fibrosis, Fibers subjected to ignition or ?ihorvr.cd tpr ''mil -i-r. :uud lest thoir capacity to cause serious tissue dar-age. Ignition produced -.rtaiil. changes in the chry- sotila fibers, among then being loss ox -mater- an ci cre.tioii uxa a flexible to a brittle structure and possibly other changes. 30, Coanxrlson of 7arious Long-Fiber Dusts, So:* very interesting findings * -'re disclosed by the results of the experiments included is. Tab In 2C,, First mil u lon;?*\'`itei- asbestos minerals tested, -with the exception of anthcphyllita. produced a typical fibrosis. It is not entirely clcer irby antloph.ylii.te beiu7ad differontly from tha other asbestos minerals. Unfortunately, 5 of D at-c?.13 died of cnousonia within this first fro vN?eks of tho experiment snc. tha roxaining eniialo 3ac-f'ificed at 1, 3 and 12 months j thus 'observations rare nor, .-t3.de at the optiTun periods cf 2 ard h months. Second, xith the ainaj-al brucitc, nhic]' is not a silicate but i.*i a fibrous fans of magnetites hydroxide, & choractariatic fibrosis like that, of the asbestos miner *ls ra obtained. Since, ths brucito used contained only C.?0 f*zr cent silica (as en iepurity), it la obrlcus that a siliceous component is oat an ansontial factor in tbs derslcprent of aoteatosic. Third, no fibrosis resulted fro- the injection of class wool fibers, oven though glass rocl rsamblso asbestos in eosw ray?. 'There ars fundamental differ ences, henwrar. A jlaxs wool fiber 3 microns in diirastcrr la a solid rod and, in short lengths, is fairly rigid, srhile an asbestos fiber of the same diameter is a bundle cf uxtrewly fins Ci.lanenta xhich impart to tho fiber x high degree of flex ibility. It would *ea thnt this structure and the associated flexibility am isportact facxcrs gcreming the capacity of a sdneral to produce peribronchiolar fibresit. Ol. Comparison of Lor~ -7iber ar.d Short--Fiber Dusts. With quart* dust it has boon dcoonstrated that the .tm 11^ the particles. fcho acre intense ia the tissue reaction, and that there t la little reaction to particles larger than 3 alcrons in diameter4 In tfca case of aabestoe, bora-rar, the rmnerse is true and apparently only long fibers hare 1 any specific effect. This ia confirmed by the data of Table 21, ia -which a aeries of teats with fibrous alnerala ia reported. fihen the injected dust consisted of ^_ fibers 20 to 93 nicrora long, ell the mi nereis tasted (except anthophyllite, as noted in Section 80) produced a fibrosis} when the material -ms prepared by first grinding the fibrous dust until the length of fibere tkm. reduced to 20 aierene and Late (cr, in soae esses, 3 sicrons end lass), none of the injected rd&snd dusts censed fibrosis, 52. Experiments Using Intrarrcnoua Technical. The axperiasats, described ia Tails 22, In which, the lxtrarrencxis nathod of 'injection was eeplcyed, show that the ashesta* adnerwla ere far differect fro* quarts ia thair action on tissus. It has been repeatedly demonstrated that intratwoous injection of quarts perticlaa 3 atcrons and lees 1a diameter rill cause a typical tissus reaction edth the derelopnant of fibre ad* in axtrapol arm ry sites, such as the lirar and spleen, iabeetoa ssinarala, tewwrsr, on intrarsnous injection generally produce only an inert type of nuction, &e is rtmwled by the results gi-ran in the table. The reason for the early deaths ia the experiaent with chrywotile particles is not dear} it nay here been caused by silicic add liberated by the finely-ground alneral. O3* rlcreriaente Using' Iirtraperltonoid TechmouQ, Tha results of Injection experts*nts vith tha intrftperitoneal technique ar* 6Ivan La Table 23. It "will be noted that the long-fiber duste produced c. fibrous reaction vhile dust* cospoaed of particle* 3 tsdcrcaa and laaa la ala* caused only an Inert typ of reepcsnse, Tboae erpartamta indiceta also that tha fibrosis initiated by the Irritation of asbestos fibers la not restricted to tha lungs, as waj fonaarly asstuacd, but can be produced in tha peritonaea as veil. 1X1117. QTCSt SHKlKEgTS 7TCTH 15ESST0S KIMZR-LLS " JL umber of additional expariasata rsro conducted to three taore light on specific phases of the aabestceitf problao, 0$* ProtectIra Action of Almsima Cogoounds. , Intratracheal injection of a suspsaiott of lens-fiber chryaotil* to ahicb colloidal aluglraa hyxlrnitia had been added revealed that the addition of tha aiudnua ccspcirsd did not prevent the tissue irritation produced by cferysotile. If anything, tha acute icflajaaafcorf response to the injected fibrous asinoral mi aooaiara^ed, Ons aosth after the last injectina of ta dust suspension tbs bronchiolitis ni beooalnc fibretk>. 66, yornatioe of isbertcsAj Bodies, The iron is. the coating of tha aabeetoaia body st^sam to be derived fre* blood cr tissue elsnert nd not, as has been -lugsvstod, fra the ainrrei fiber. Fallowing rcbcutsnaou* injvvcticn of tao kinds, of chrysotil* into the groin of guinas. pigs - one kind containing t par cant and the other 0*2 par cant the aebartoeia bodies*- sasro aryiAlly traserous at both ettaa of injection. An attempt to produce &5bfito*i3 bodies in {yuina^'Figs by icnlintfition of three silk b&gs containing fibroma chrraotils -waa pr^uccaaafui. On# bug planted - / mibcutansoualy in the abdominal Trail diaappssred; tha other tw b&gs, placed in the peritoneal carity, prcducec a little forsign body reaction but no isbestoais bodies in a year. Intratracheal Injection into guinea pigs of asbsstosio bodies rucorer&d free, busaa lung tissue failed to produce the typical tissue reaction to asbestos fibers. The injected material tgjsl obtained by digestif irith coding hypochlorite .solution Lung tissue removed at autopsy Cress an beeto* worker. The asbeujtosia N- bodies could be seen in the guinea. pigs for at Least a year after injection. This experiment show? that the asbestosia body has a rather rcslsrUnt coating ` shieh ie not destroyed by moderate hypochlorite treatment and n*y be ca.intalced in Tiro for a yasr or longer. LXXaTII. TH70RT GF miTAXT ACTTOM 0? JLIBSSTCS ICKgUlS Two hypothesas hsrn bees proposed to explain the tiscua irritation and rsan" i in"1 i > *i ticc pcd by aabesvca fibers: the cheadcal arn tbs awcnaiicaU In tbs ebonies! theoryf shich is based upon, erperiero* with quarts, it is **stsd that ths as bestos sLnarslg dig soIts in the body fluids and that in this procoe thair bases are leached oay to Lear* silica .in 3. fora capable of iriiisting tissues. Accord ing to thi* hypothesis,. asbostoei* would be merely an indirect ailicoais. 5e-raral </ facts aaka th- rhecd.ns.'V theory :iut*oablss (!) intratracheal injection* of brucita fibers, Thick had a silica content of only 0.90 par cant, cutssd a typical fibrcsii like that produced by the Mbseto* mineral*; (2) free--ailic-t particlsa increase In potency m the partirl* sit# b#coee lets, but oebento* fibers shorter than about 10 to 20 ricarons are rolatirely innocuous 1 (1) altininrrs ' hytrcgo.de neutralizes the irritating effect cf quarts but not of asbestos; [h) serpanti.no has the 5one C.tenicai .-ottor.ition es> long-fiber chrysotilc- but it does wx- product th ease itLnd of i-irrue reaction; (f) there is a ride rang;; the cMcmical composition of the aincrals v.hicn sio cau.ee asbeatoaia (see Table 2i)* lb Tier of thdLa cridanee it aetata more likely that asbeatoals la 4 cauctid by an unusual mechanical irritation fraa Ions asbestos fibers. Probably this irritation ia related to the peculiar filaaumtcc structure of the fiber er.d r/*sS Vi.1-- - * . I. - the associated flexibility, which are possessed by no otftor foreign body. Fcr example, fg, Ution of chrynotile fibers changed their structure and mads then inert -while the sane fibers, before being hatted, would produce fibrosis (see Table IS)* Further support for the theory of rechcnical irritation ia that asbsstosis occurs in &a organ of high nobility - the lung - and that a fibrous reaction can be produced by injection of asbestos fibors into the peritonaea, rhere there ia also a degree of nobility. but not la* other extrapulaonary organs. _ Ltxr/ni. CfirLlCATICTvS The experimental inroatigatioa. with asbestos edesrais xwa concerned primarily with the effect of the dust os oarssii tissue but soma attention waa giren to other phases, such as susceptibility to infection and occurrence of malignancy. G9. Infection. The only experiment in which the effect of inhaled asbestos dust on a pul monary infection rax studied m the first inhalation experiment, carried on vita "King's floats" dust. It is, perhape, unforturats that Infection stadias were not cade in the other Ixhalatiott experiments also. 90- SviscgrtibiUtT to Tuberculous Infection, "he dorclopicant of a tuber culous process initiated at the beginning cC ccpceura to asbestos cusi, ard also of an in faction superlvpoeed upon an established asboatosls, wa* described In 5cctioi_. 1? and 20 of thin re port. It will to noted that asbestos, rhan classified according to tha effect of a. dust on tubarcuIou3 j.nfcction, could be placed bp.JLor an active dust liha quarts but abov inert cuate, such as caicite and gypsure. In anirals infected with attenuated tubercle bacilli, quarts trill cause the infectious p.-ocoss to progress until tbs* aniaal dies of tuberculosis. Inert ducts crill have no effect on the infection and the lesions Trill usually heal and the disease disappear. Asbestos dust is in a different category. i>.an tho fibrous dust vas being in haled during the evolution of the infection, there us a spreading of the tuber culous process for a tine but usually tho 3ti.aii.U3 for continued proliferation of the tubercle bacilli was not sustained, the prcgrossica vas arrested and healing followed, In guinea pigs infected 7?ith attenuated tubercle bacilli following the coapletica of nearly three years of erpocure to asbestos dust, proqreaaive disease did not develop. Toe only ocdlficatian of the infection r& one of localisation, a few bacilli being retained in tho fibrous tsminal bronchioles and farsing fcuboa-cles there Is sdditica to the usual fad beneath the pleura. Such tubercle* healed In. a few aonths and there was nothing to suggest any influence en the course of the diaeaae. 91. Susceptibility to Kon-Tuborcul.ous Infection. Thsra waa no pointed ex periment concerning tte effect of inhaled asbestos dust on rusrt-tubcrculous infection. Inter current pneu monia among animals exposed to aabojatoa dust. was rather coscon, the frequency in guinea pigs exposed in the four inhalation expertseats ranging froa 16 to 39 pr cent, This incidents-:, evidor.cr t.^ccg'.s th oossibility of art effect of ajbectoa dust on non-tubarculcus infection. hevicrthelcss, cince such epiderrico arc r.ct unccconn In ishalailcn "xterirctr.c -.rich otiicr ducts and even in the colcr.y of rjorsvti animals, it ic felt M:;;t tie lihaLatton of sabesrios dust decs net exert a al^ni-Tf cant effect up the sr.wcc7vtifcili.l7 to uon-tuberculo-is pul-nonary infection* 92* ifeoplasa. iirv specific experiosivt res conducted to detordna ehn'.hor the Inhalation of asbestos furors the coyclop-rcnt of neoplastic disease but certain observations on this subject r/.re recorded in the outline of tha proposed aon.t'yaph on asbeatosis submitted by tho laU*. Dr- i- d. Gardner in February l?ii2. In :t be called atten tion X<o the high incidence of lung cancer among r/dLca inhaling 1:^-fibsr asbestos. In hi a aapariaeutal nota3. hoorrer, ha referred to these iesienn is adenomas. There is an important distinction betAreer*. adencua and cancer t+iich should be made clear. A cancel' is n tumor, cr neoplasm, capable of local in vision and de struction of tissue, -rhich cm distribute cells through the lymphatics or bleed stream to produce isolated foci, from rhich nsr tusors develop. Thi i phenomenon of di3seririati.cn is keesr. as metastasis and any tutor -*hich exhibits it is a malignant growth, of *hich cancer is o typo. An nrier.wc*, cn the o.her hand, is a so-callod beniaji cr nsu-cwlispant turner (neoplasm) -ffhich c'cy.or rer not be capable of local inrasica but enich docs not metastasics-. In order to clariIf the sract nature of these Lasicr.s the path 'logical mater ial is being carefully examined. S\.r\c<s it is fait desirable to bar'.- tho benefit of Doctor Vorrmld'a judspaint f a reriem of the data on this subject is being post poned until after hie return fron Ettrcpe. Rether than do lay the eafre report, further discission -will l* reserrod for a strppljncant to ba issued lot v. to iU'co t.ie conclusion:; ;t?ri'-*od i:x nv-?^v--ation at.-. TiCV.iiZ3?j~f, SalXcv c~c.'\ one rith & brim' raau.i;': of ',\\e, evidence. A. ''urioc.T fora* of asbestos fibers wwjrr c. pcribrancnisizr :iVroo.in c iur.rs o;` i^u: \hh pi<;t, l'cle, cafes c~d ribbifee art n.<fe of idee zsA clogs. Both inhilAtier and injection ere:i-cincuts proride rr.ple ruppcrt for this nonelesion. Fi:;vrcs arl 6 ;ihoi the reaction fea tm different kir.ce of .\sb-nJ.oe nincrei. S. The rc-ia of -Letion appears Vo pYirarily rcchcniccl rather than chccdcal in nature. Tne eridc.ice is (jivon in fccsion IXT1*^- FiC'3r`?s -> m ^ b-r-J? illustrate the important points. The fibrous filan-.n'hd _ structure of asbestos appears to play sa essential part in the -irritatin-; action, sir.cr fehc solid fibres of -Li?? mci co roc produce fibrosis (see '`'inure r*). / Slort asbeato fiber? do rot croducc ribroai3. The oancJ.-rrion. is implied ir. the ;rrjr.cnne ccnticred in pern- grsph S ebers, esperiT.e-.ts 'c-'.inb further 3up:.ort this fir.dirv are roperted ir. Tablci fl and Zj. D. ?7pictl fibrosis con be produced br on atoarpheric r uspension of asbestos duct containins only ai extrenely snail proper'ticn of lens fibers. la the inaulAtion experi-Cf.r-t with 100 per ccr.t bill-oilLed asbestos dust a typical, though delayed, fibrosis ms obtained 'r.cc I--!" if). let." I cr o.* tbe -xvrir.; i.\r'ic -*- :'..-ytcc >!' SL'': - '/.'or M on nitrone, r." i.' .'":i*Tn l.i\ ir',uc I:. icr '-". wlv- xrtrc- ^ror. oi'. U..:r:CtJ.i.-a o/r-ori,-;:/* -- th ff.rr ;:"hvso.<j r.uct :ro.- tainir-; nr fibers fcu Tiivl: 11;. t* pr-od`-.?:- rieroeis. In'.jRjAvian o: sohss-tns rfu&.t does not :.Iter y.i.Tnifi.c.-'r.tlr course o.f errovima-vtal tubtrculoolc in .Toir.ea. piss. This conoluni cr, is terthatiTa 3ircc the evidcr.cz nr. vfticr it in bns-jd dor* not conform rrj.th cur usual trrpcri-Slice. 2eVr*- eriCc `-n Irtbia j ttHL s/.crrr that then infection tias coincident mth o;wc: r>' -irat ccrroour? tnrrc rraj tnnjvorcr/ profT*easier, of the dincx;.:n sith subsequent hoalter; *dicn iufseticr. traa ini.in.und after 2'T i/l. aunt'es of dual crcusure '/rut. course c:' V.-.e tuberculosa diocese, veo rot aperact idly altered. In contrast, it. hnfl beer, coser.vj in crper Luisuts fit.-. nixed ire to convrirlr r quarts V/.at if i.aore is i alii'bt profrrsacion ox th.n '. n:\.- losi/i shcu infaction wad duot exposure arr coincidor.t., thia affect is norn marked (Instead of lass, -as rath asbestos} >r.on infecti.cn .is initiated after a period of duct expc.vore. This couc-tciov. c*nccmv.\* v.'-.o sf'.cct of irhaloo 5SM*.*t*v dust on ittbercuiosii ae-.r/a justified boc-wof. in the uura sv.v'xtd,Te test (Infection initiated After a period of dust p.rpc3U7''.} thort* *-*5 -10 etiprcciai'le Increase in rusceptibiiltr to tha tubercular.,j infection, il'rrsrer, since iiie findings in the Mbestos tt-ycT1 ac zet conform wi.h previous ecpurionc, v.d t-hcr'dvr/Mr..-. \,-x-r ' ' " x: dr-rJLvnr. -.it'*: i. (\ ` r.-.l::o- :i -v:. *. . ' . .. * . . ,, further l.T/outl "r.ti *r, ~i ii in ~ -n-r. sidor-rd. sa $ car. o fornr.Mon o* ntr^.u'.osir, \iinr r-.rr.v- a r0;. *. iTerrs r.roJ rrf'ir.ia ir. vrm ,Intra.trachcal ir.;jcc--ion si rrcJ*;c-> , I J#4 rrfii-:r f'd-lx he prcd'ica tao vrpical tiuuce rone ;3rrt (us3 rv.r.-i v,\ ti). Tin cosa&tim of prssrin.rc; r ;v> vr-sO/.d as-o.jtos dun- r.cm oficr *-:r.o."3-a Uti.'Lrav*:* 'i-r hr due to the C-jvnn .iou of ;io l:cc.i *.r:.