Document a426b1YBv5X6pn4vmx0ga68XM

PLAINTIFF'S EXHIBIT December 9, 1946 Or. A. J. Lanza, Associate Medical Director, ---------- -------- Metropolitan Life Insurance Comeany, Nev Xorlc 10, M. X. ----------- Dear Doctor Lanza: .............. I shall he reit glad to do vhat service I can in reading Hoy Gardner1 a uncompleted report " on Aaheatoaia and in malting such suggestions as I C may be able. He vas vitJx us Just about this time last year, and I consider hla loaa toaaienae is a major one ^ - ' With best personal regards, I an . SiAoerely yours. XML: hbp C Kenneth M. Lynch, H. D., Dean. U8 !s :3 s I H Ctrudi** by TS2 3ARAXAC LA30RAT08T SJ&JJUC un, BST TOTS Report to tii* JtJSJs.saxrtLLS corpsratios m TORS, SW TORS 3*pt*Bbr 30, 1948 A Z' 2. irtreduction 3. Asbestos VtLncrais ABSTRACT 17. CTSUZSIAL asbestosis Expcrlacntal Methods 6. Spocies Susceptibility ?. Peculiar Characterl?tica of Asbestos 8. Rat of Tissue Reaction to Asbaetoa fibers 5. labeet.-ala Bodies 1. URLUIIOa ECPEcLDOTS n. Ring's floats Aebestcs Dust 12. Dusting Material 13. Dust Ccapositicn lb. Dust Concentration 15. Reaction In Animals 16. Guinea Pigs 17, Rate end Type of Reaction 18. - Progression 1$, Infection Coincident eith Dost Inhalation 20. Infection after Dust Inhalation 21. Asbestosis Bodies 22. Rabbits 23. Rats 2iu Suoaarr and Interpretation u Fas 1 > 3 U s y 6 7 7 8 8 9 8 9 9 9 ID 10 U 12 12 12 13 40. Dusting --tsrtal 27. Dust Caspositian 23. Dust Concentration 2?. Sixe-frequency of Dust 30. Reaction in irtlaa-lj 31. Guinea Pt 32. Hate end Type of Reaction 33. Progression 3b. Aabeatosis Bodies 35. Rate 35. Rate and Type of Reaction 37. Cate 38. Rata and Type of Reaction 39. X-ray- Chances LO. isbaatosta Bodies Ll. Rabbits Id. Rata and type of Reaction U3. Jbsbastoala Bodies Uk. ^Ty and Istarpy station us. 100 Per Canv Ball-eddied iebestos Ifest US. Dustins Usterial 17. Dust Coespoeiticr. US. Dust Concentration u$. Sisa-frsquanqr of Dost ill i-1 Ik 15 15 *XO* 15 15 15 17 17 lfl 18 19 19 19 20 20 20 20 21 21 21 22 22 23 50. Rac-ctlan lr, Animla en _ Guinea Jl^s Rata anc Type of Reaction 53. Progression Lymph Node tnrolrsaent 55. AsbestosLa Bodies 56. Rats and Hies 57. 3unaary and Interpretation 50. Long-fiber Asbeetos Dust 59. Dustins lists -ial 60. Dust Composition 61. Dust Ooncmtration 62. Slxa-CnqQeaey of Dust 63. Reaction in Animals 6iu Guinea Piga 65. Bate and Type o Reaction 66. Progression 67. lymph, feds terolreaent 65. lebestoeis Bodies 6?. Cats TO. Rate and Type of Reaction 71. Z-rajr Changes 72. Rate 73. Eats and Type of Reaction lr ?cra 23 2; 23 2k 2k 21 2k 25 26 26 26 26 27 27 27 27 28 29 29 30 30 30 30 31 Uic* Kate ard T'.'pc oC reaction 76. S^aiary srd -*jtcrp.-3tAt.-oa lyjzn. injection rossir-irs 77. 'otratrac-oai Srperiaact* 77- Conparison of Fibrous and N'on-fibroua Dusts SC. Comparison of rarious Loan-fiber Dusts Cl. Cosparison of Lone-fiber and Short-fiber Eusts 62. Intravenous fa.-perioxnts ir.traperitcnsci rperirar.t3 leqev. <m f_c zr.i.his * 05. Protectire Action of Aliasiasa Cccc'-vsrda 36. Conation of Asbestosia 1idles tvhtkt ipjirrr.iT actxc:< LXSmiZ. COKrUClTIDKS 79. Infection 'X'-t Susceptibility to Tuberculous Infection 71. Susceptibility to Ncn-tuberculous Infection 92. ^plaaei icm. concusicia XCIV. TABLE! XCV. ?2ll2S * T Page 3i 21 31 3? 32 32 33 3b 3b 65 35 35 35 >5 37 37 3ft 33 39 bo U3 - 71 72-75 la a puiacnwT disease eaused by th* inhalation of nsbaatcs ^uart. Xa eninsls it i* character in ad by t peribronchiolar fibresi* which ** to b* the result of fiechsnical, rather than cheedcal, irriUtica of tho tiasun by aabeatos fibers. Only the long fib-era produce e typical reaction} short fibers are relatively inert* 'The filaawnt-od structure of the fibers is an essential factor in the raechanisa of irritation, k character istic tiasu* response can be produced by ncn-eilic*auB aa -well as siliceous fibrous sioerals. Inhal&ticr. of asbestos dust apparently does not alter significantly the course of experimental tuberculosis in guinea pigs. The aabostosis body, which is a specific concomitant of aabeatoels and famd soon after the entrance of the asbestos fiber into the lung, is believed to prereat further damage to the tissue by that fiber end thus to limit pro gression of the reaction whan exposure ceases* Aluxiraa docs not exert a protective action against the tissue irritation of asbestos fibers as it does against that of quarts particles. j: 1T3?.j7C>3I5 .<: Introduction A-sb3tC3is is a. fora of pnsuwvjconicaic resultl_v. ' run "vn3.on.ttc. i-ihcJ.a- | tion of an he sics dust. Tiiu mvao asbestos, literally 'un buyable." is not that of & particular mineral but Is a tern applied .to a rrtuber of different dnerala whose characteristic feature la *- structure ccaposea of Long, par allel, flexible fibers. This structure is unique bscauoo the fibers are capable of repeated longitudinal subdivision to unity of salccular proportions. In length the fibers *nu'7 free a few caevona to six or nora inches. 3omi varieties are stiffer than others but many arc sufficientlr flcritic to ^ ypun Into yam and woven on modified textile taschir.or'/. 3- i3begtos Klrarals The asbestos tcLn-raia are cilicctes of variable composition anc belong to the serpentine and the anphibcle >^roup: Listed fcclrv are the sore cosmor. varieties, lienhibeie Orouo ArfchophyUite O'g, Fa) silicate AaoaiU Inphibcie (Ig, Fa, .113 silicate (Ca, Vg, 1-3f &lr No, K) silicate Treaolito (Ca, its} silicate ActinoUte Crocidoiit* (Ca, Ug, re) silicate (Xar ) silicate Fe silicate Serpentine Group ChiTsatll* U(j sillcata (hydrous) 2 The boUc of tha aubeetcs of comrco is chryo: ; J'C.ZSiC2.2H20, which la aland lr. the Ihxtford rechon of the frcr/wr? cf ^.isbec. CrocLdo- Lite and crcrita are alao csed cocc.vci.-'Jly but ;r. sculler axount*. ChryBotlle occur? cx reins In serpentine, a rair.arai --1 ~i iQ ciinnicd coc- poaiticn to chrysotiic tut r.hich exists in cuts civ* ani in cod* irp of uicrcacoptc fiber? vithoat the parallel orlentAtics coerKCiuristic of chryso- til The seaelve blue block eerpentine, which ia r.ooth -\r.d soapy to tha touch,. Li traversed by nixw of fibrous chrysotiis Tarring in width frosj a barely perceptible line to sir or fours Inches, The fibers run acroe* the reia end not lengthwise Tith the formation. Attention is directed to the sinaral bracite, tyC.F.oO, vrhich 13 often found in the sane formations with serpentine ?nd chryscrtiLo sad aay be fibre113 in structure* It has no cosassrcial value at present tacausa its fibers are not sufficiently flexible to bn used in tortile* but they are cxpablo of repeated lsnsitvd.ir.il rtibiirisicn. Eslite othsr asbestifors minerals, brucite is not a silicate cad for this reason it has been a veluitle tool in an experimental evaluation of the action of fibrous cine rale upon tissue. 17* EZpaaKgrcAi, lsuestosis For cany peers studies hsv* been carried an by the Saranac Laboratory in an Irrvestlssticn of th* csss*, nature md develcpssnt of isb* steals. The present r part is devoted to- SrperiaeatAl isb*?tos.1s In it are described the Miiaai ex periment* with various feted* of srbeetoe duit. Another report, to be pr-pir?d and }sewed later, sdil b-. ccncvmed tril-h Hunan Abe*toi\i.a JJd Till cover the ho* aspects of sorters ortv> here to asbestos dust in an industrial enviroewnt _ - _. wt ours rpciea of an.lr.si character istic tissue chants ptiich nr* stoilsr to the lesions of hunan asbestos La. Sias ths life--srpan or the expsritanMl ar.iasl is relatively short, It is not possible to dffrtdop th* eclataot*Tlytic lesions in aulas 1* undsr the usual industrial eoC. ditica*. CcnsocruczrCly-, to obtiin a easel*Vs evaluation of th tissue response to inhaled particulate and fibrous aaterial. it is Mcassarr to accelerate the reaction 'ey ernplnying high sr concentrations of* dust than would ordinarily be sty countered in industry*. While condltinn* of exposure ere thus different, w* infersatioa yielded by sxpsrinsnte with is icTsloLbla in furnishing a better undsrstending of tbs reaction of the husum crgaa<s to inhaled asbestos dust. 5. Froariaantsl Uethoda . For investljatics tha biological, reectieo of tbs sxperlaeataJL *< i to thr Tarlcus asbestos xinarsla, tw? typo* of technique here been eaploywd, nssely, the label*tloo settled end the infection aethod. In inhalation experiasats, groups of Kn.irs.ls - up to 100 nr sore gain**. pigs and saaetissr* esaller nuxfcsrs of rabbits, oats, dogs, rets or sic* - are kept fer sight beer* 4 d*7 in a cubical dsrt rooa, eight feet ir, dissension, in which a cLoud of asbestos dust is aainteined. , it lsterrals during the experiment, 4. fer niaals art sacrificed end the tissue xenined to dstsrsintf the nature tail extent of tha dust reaction* Sons enlMLls ere exposed for period* up to three rears. The injection experiments, in which th* duet, either dry or vaspsodsj. .la fluidj, is introduced into the ar.lail by the intravenous, intxapstritor*l or irdretrscheel procedure.' are usd to dsteroia* whether or not a particular duet bass *. pertastial capacity to produce tissue reactlea. Long-tsrr. LnhsiaClon *xp*viccnt3 furnish Inf0r2.it,ion upon -wti.it;>. jp-ut raiiunca la placed whan estlxatinc t-h riecrsc *0 v\ich a curt might b*> hazardous to industrial rortcora. ?hatbr cr not atoospharic dust, urea tivju^h potentially dangerous. can be inhaled, pass the natural dofeosp barriere and raach tha pulnxnarr tia^ua in quantities sufficient to cause dinesrs can be dcternir-i only by Lnh.xUticn procedures* Injection erperirxmts ar useful t-srwms* in then contact betvaen f s dust parolelas and tissues is assured and the potential capacity of th* curt to produce reaction cun b ealisated accurately. Whan dealing with fi bre-cs sinerals Ilia asbestos, the intratracheal nethed is r&iuabla tinea it p-raits e'o*erring the effect of tha fibers on pularmory tissue. 6, Species duacgptlblllty Unlike free silica, asbretoe does cot axArt- its specific affect ia *11 orgies of all spociss of An.isal (Table l) Injection of fina quarts into various organs of tha guinea pig, rabbit, rat, cat, deg, chicken and ever, tadpole will produce silicotic nodules. Kc-ayrer, similar injections of long or short fiber asbcrU-.fi h&v* resulted in t fibrous react Ices in tha lung urd, to * lesser extent, in the periUnaus but net ia ether organs. ?, Peculiar Coursetarigtica of isbertoa Experience has deDotsstrst-ed that aot of the perticuiats sailer iniulod into tha lungs of fan end .rL<~o i- 10 taicroas or lass in gjnrima diassrtsr. Larger particles apparently are xiadd by the protect(recMcd ra of tha upper raspixstory tract, la th cjlm of Cibrons saierAftla, hov^ror, this restriction dose mr"ppiy srd fibers 100 srvd $vi POO adcrors In length hare been found in t-hs tir?r>* al air a pec** of huean lags. In well liboratorr an 1,talc expceed to aabesto* dust tha <Hti1 length of fiber fortnd in the lung rarely sxcasds 60 cicrooa. Rot trtrj kind 0? flbrrrcm eatsrial is inhaled vith ecjuil readiness; for exsnple, the synthetic fibers of glass ^ol apparently are too Inflexible to pass easily thrown the nose, pharynx, trachea and brcr.cfci and ."tldon roach tha terminal bronchioles and alveoli. Inhaled particulate natter comet to rest throughout the terminal air spaces (alveolar duct, Atria, alveoli) In all parts -f the luace; inhaled asbestos fiber* are drat retained in the respiratory bronchioles. These very S'oall tubes are !ad lately distal to bronchioles lined by ciliated epithaliva. Their own essen tial lining is lor echoidsi type of epithaliua but, as their name Implies, they actually function in respiration through lateral alreoli given off as pouches along their trails. Either these pouches, or the abrupt change in the character of tha 1 ining epithelium, or the decrease in disaster of the tube, or pertaps the examination of all three factors is responsible for local retention of the inhaled fiber. Only after asbestosis is well established are appreciable numbers of fi bers cnrriffd into the acre peripheral air spaces. Sr Rate of Tissue Reaction to Asbestos Fibers The rate of tissue reaction to asbestos la nuch sore rapid than to an active dust like quart*. Evidences of tissue response appear ac soon aa fibers hare localised in sufficient concentration in specific areas. In rata receiving asbes tos fibers by intratracheal injection this evidence is risible u early aa two week* iLftar ijfjectioeij fee quarts dust. th* Latent period al^it be two rontbc or more. Tha behavior of tha tissue reaction to inhaled dust After tha termination of exposure is not the same in siliccaia as in asbeatosi*. In silicosis, the young nodule* beecos largrr? in asbestosis, young ecar tiasua.th.it cayhare formed,cootracta and becomes asr dens* but the area of inrolTeaent decreases in site. If exposure to asbestos dust la tercLiiated after a brief period, the recently-inhaled fibers in the lung zzr causa v.h^ fibrous fci.crue response to continue for & short tlj, until the fibers hire isan coated. This prosprsision is of ccUy * alight degree and of Little significant*. 9. Aabegtoeis Bodies The peculi.tr structure toon as the asbestosis body or curious body i a specific cortccnitArit of asbestosls. The typical tcly is a goLden-yellcv, beaded or haustrated rod which car be either straight or curved. Often cna sr both ends are bulbous like a dusfc-bsil. Ths bediaa vary ccraaidarabLy in Length, 2nd diasensiane up to 250 citrons hare been recorded* It Is believed, that asbsst-oaia bodies are cue to a deposit of protein and iron pigrwnt upon the surface of Inhaled fibers. In guinea pigs they fora after about 60 4ev ef contact with the tiasroA. They are abundant is raw and the guinea pig (* Table 1} but are such largcrr in the ferser, probably because tha ltrgarsited sir tubes adait fibers 0* greater diesnsloa. In cats, rsbbita and nsire there is an atypical coatlrr of a few of the fiber* after much longer residence in the lungs, In rats arsd d?gs no bodies could be discovered. Although tha aridace is inoorolete, it appears that ths fcnra.tion of the asbcat-osls body parents dsaga tc the tlssus by the fiber. 1. DKiUXICT ESPJSUXEtflS ?our cagyifshsnxlT* Inhalation erpcrirasrrta have been conducted at the Saranac Laboratorr vith rtriou* fersa cf asbestos cuat. In each of these investigations raor? than l60 artftal* rer* ucsd ar<l the exp^risasts carried 00 fer periods ranging frm 2 tc sssr*. than 5 yusra. The four Vnda of sabe-rtos durt ecnplo7==i are identified iaj*8 flcaU. short, fiber, 100 per cant bAHs&llad, aod long-fiber asbestos dcat. 11. Inhalation Erperlrgnt with "Xln^s Flouts1-' Asbestos Curb Tha first Inhalation experiment conducted at the Sarurjac Laboratory with asbestos dust was begun Is l?2o. Astrals inhaled the dust for periods up to aearl}'' three years and seas quuua pigs lived for about four years aftar their first exposure to dust. 1 preliainary report firing obaerratlons after 29 Booths of exposure appeared in the February, 1931 issue of TKS JOCRHAL OP INDU STRIAL KTUIENB.* At tlvat tine observation* covered a period of only 2-l/U years and the conclusions as to the ultimate effects of inhaled asbestos duet were provisional. Results of the completed study show that most of the conclusions drawn In the preliclnarr report were substantiated. A complete review of this experiment follows. 12. The dustlnft saterial was a conoerclal variety of asbestos dust known as Sing's floats and wc* composed of short flbors and particlas of variable size. It was obtained froet tha Thetford, Quebec plant- of the Asbestos Corporation of Aaerica,. 13. I*hs dust coancsitioa Viable 2} reveals that the amount of fibrous chryvc-- tile was only lu per cant, a rathsr leer rslur. 'dowaver, thera was suf ficient fibrous at-erial tc produce a characteristic fibrosis. lit. The duet coocentretlon At first was quite lor aad f<rr impingr easpisi taken eoon after tive tp*riaent wae started, the average light field count - by the standard technique * only 6.0 tilioc particlsa per cubic foot of air. An appreciable atxxber of large ptrticlw (or fibers) also were present, ce STUJXES OH HF^msyZlL FNnacccsiCBG. n, Inhalation of Asbestot Duet., Gardner. L.U., end Cuassingi, D.E. J. Xrd. Ky*., 13* 6$-bl, 97-Uli* 1931. shewn by tn average count of 0.8 nillion far particles greater than 10 nlcrorus. After the inhalation aueperisumt bad been under wey for about two years, the epd of the rotating paddle in the dusting sachtne was increased and for the remainiuig ? or 10 tenths of the erpcrigiast considerably oo?t dust was dispersed into the ataosphere. Average dust counts for imping *r sample* collected after this change were 53.7 million for the acual light-field erthod, and 1.6 nillion for particles larger than 10 edcrcas. 15. Reaction in Mlaals to Inhaled "Sing's floats* Asbestos Duet. Results of the investigation, briefly sasxaarised in Table 3, shoe that inhala tion of King's floats asbestos dust produced a typical peribronchiolar fibrosis in guinea pigs but oot in rabbits or rats. 16. Quicca Pigs, Sevan groups of guinea pigs wre tired. In three groups the effect of a continuous and of aa interrupted dost exposure was studied* in two other groups the relaticcahip between infection and dust closure m investigated. The regaining two groups were infection controls. 17. Rate and Type of abaction, Dciasa. pig? inhaling this dust for period* up to 33 months developed a characteristic fibrosis occurring in conical patches about the respiratory bronchioles. Daring this erpoeuTfi the peripheral alveoli were not itrrolwsd-. The particulate elecer.ts in the dust sen transported to the lycphatlc systen where they caused no signi ficant reaction} the fibrous eleaenta reaainsd fixed at the site of original localisation and wens seldom detected la the Ijncphoid tissus. rTeurlsv and fi brosis in the septa were cbearred only wtaa infection explicated th* procasa. After exposure of opproaijrately a ywr, a jnntli esount of cellular reaction had been produced about n*ry respiratory broncaiolee. la bore dust was Inhaled, * it continued to occuoilat-c in the Sana location and latirr stages of the disease consisted of extensions of the original lesions. Hen ai-oas were not involved. Apparently, the inhaled fibers rere caught in the pocket-like alTeoll that aro given off from the lateral walla of the respiratory bronchioles. There thay imre phsgocytixed and cany of then were carried into the srj.l by aigratory cells. Mononuclear leucocytes attracted to the area caused an appreciable thickening of the bronchial vail. After 16 nonths a delicate fibrosis cade its appearance. The proceae evolved so gradually that nitotic division of fibroblasts could rarely be discovered j nevertheless, the nunber of fine intercellular collagenous fibers (fibrosis) steadily increased. As this fibrosis contracted, it partially closed the alveoli, and with this atelectasis the lining epithelium assured its eesbryonic caboidal fora. The result was the edenoua-liice appearance that Tillis described in guinea pigs inhaling silicon carbide. The longer exposures resulted only in acre thickening of the veils of the air spaces, largely due to an in crease in the amount of fibrosis. The fibrous tissue always remained cellular and never shoved the ftyulinisation characteristic cf silicosis. Ifl. Progression. The reaction produced in exposed guinea pigs did not pre souths vhon the gross significantly during a subsequent period of 37 lived in a nxnxsl ataoephers. Between li sad 11 oonths after exposure ceased, the cellular reaction had been cocpletely replaced by thin strands of fibrous tissue. Observed still longer, the scar tissue decreased in mount but in the last anisal sacrificed, 37 months after discontinuing dust exposure, fcmm fibrosis was still risible. 15. Infection coincident rith port lohalatIon. Of the group of LO guinea pigT infected vith atten uated tubercle bacilli (R^ strain) 31 died or wre sacrificed before two year* of duet exposure and wre reported in the paper b7 Gardner and Cuaaings mentioned above, Seventeen cf these died from intercorrent- pneumonia. Briefly, the re sults wr* as follows* 10 revealed soon evidence ci spread of tha tuberculous process f is 6 of thas* it was eenfinad to the lungs and is the other u Ihs Hbdosdnal rlscer* Also **re inrolrgd. Usually & slight local extension of the tuberculous infection had occurred but subaocnasit healing had resulted in fi brosis of both tha puinenary lesions and the flecor.dxry lesion* in other organs. The heeled pulmonary Lesions snowed core fibrosis than is characteristic of either tuberculosis or asbestosis aIona. The ? anlatls shich ware still olive aftor two pears of dust exposure were sacrificed at intervals durlnc the followinc pear. In lx of then tha prlaery foci of infection had healed with fibrosis and even calcification ?nd there was no evidence cf progression. In tha other 5 the tuberculous foci shored evidence of having previously spraad locally: in U of than it had healed, by tha time of autopsy, with excessive fibrosis j in the othar aninal there raa a genarcliaoc chronic tuberculous pnsuaonla In. one lob* end iso 1ated primary tubercles, edict "were still active but had not spread, in the other lobes. Evidence of extension cf the infection was first sasn after 7 months cf dustinhalation j during the next 20 months vrrrr. than half of the anixsls shewed an actively spreading tubercrulosii and in 3 of thca snail cavities had devaicrped. During the last S aweths no animals exhibited any evidence of active infacticsa although in half of th the. haaled fibrous scars of previous extensions ob vious. Sixty per cant of the guinea pic* vith opr&aiing pniaonary tuberculosis showed tuberculosis of th* spleen and liver. 20. Infection S qperigposed Open &n Satablishad isbertoeis. Twalre guira* pigs, after in haling asbestos dust for nearly 26 sent.he, were infected *ith tubercle bacilli and then reaored to noraal air. The subplsurU. tubercles in the dusted animali wre r.3 ccr rtuaercuj than in non-ductad nont-mls, but & considerably number rsr<< fcunrl in th depth* of tbs lung about .Cool of asbf.*t^aia. The reaction to infec tion shewed only slight local aztensian About the origii-sl aitea in th i>jnm and trixheobronchial lyr^ih nodes. The aMoninal 713cars. nre involved in only one aninal. Caseation was faurd in tubercles 1-1/2 onth? old bat by 5-1/2 nanths it had cnqpletely disappeared. leaving only scru* tissue, The latter still persisted in the last aniaal, which wan VrUind ll -jonthe alter Infection, 21. labestosis Sadies. 'Jbd&rat* ro.tB'bwrs of aatwtftoaia bedioa occurred in the lungs of the guinea pigs, bsccaias aar* mssarou* and core distinctly aeaja*nt*d in later amthe. 22. rabbita. Rabbits exposed to the aebeata* dust for periods up to 19 contha developed a low-grad* foreign-body type of ruction tut no fibrosis, lltheugb their, lung* contained particulate eleamt* of the -Put, fibers were net praserit, indicating tlr-tt t-h* upper respiratory sajehunisa of the _\ rabbit is adequate to exclude Cibrcus foreign bodies. Two rabbits, after inhaling dost far 6 add lb noath?., lived La ncma&l air for ecru than tzo yssra* it autopsy neither aniatl showed any eriesmee of .cellular reaction or fibrosis L tbs .*sorInal bronchicl&s nor ?sn there y fefibeeteffia bodi**. 23. Pat*, ill t-b* *Mte rat* had. acquired to Lr_fscti.onf resulting lr. th* forwiica of pueanarv" ihactasTss, before they cas^ to autopsy;. ipptrcntl/, sc such hecry bicos obstructed their brnrechi that rtrf .Cr* fibers could haw entered bhair lur.gg. In a frn? ov bhf> rit-s, an occasional asc^otas*) body wts discoremd but there *u no fibrosif. 2ii. Svamarr gnd Ictsrtrrtatlon of Inhalation E-rccr-irant rjth Flag1* Floats Dust Tbs findings la the aperl/Kint with King's floats dust can ha susnar- ized under three headings* A. Effect of the Inhaled dust on nomval sniraJu. The Eing's fleata dust caused a charac teristic peribronchiolar fibrosis in guinea pigs bat not in rabbits or rata. r; fibrosis did *.ot propress aft&r the dost wrpoeure was discontinued and the guinea, piga transferred to normal air* 3. Effect of tha Inhaled dust, on ttfoerculoala In trainee xri.es. In guinea. pigs in fected with attenuated tnberclo bacilli ~*d than placed la the dart roce, the results were acre nrlabl# than in usual'In an erperinant of this type, k Sen animals shoved no sign of progression; lr. .roet of them there was oridsnaa of teapertry progression rlth subservient. healing; in one anir-ai there was continuous t progression to daath. In contrast, *tt*n guinea pigs, after being infected, are exposed to quarts instead of asbestos dust, the infectious procsss continues to progress and erwp.tua.lir censes the death of the animals. On the other hand, ex posure of infected anincXs to hamleas dust UVe calciM or gypsua dose not lead. to mr progression of tb infection, Chiinas. pigs Infected with attenuated tuberc.1/? bacilli follcndac th* termination of ehwt two Tears' exposure to asbestos dust did net dsrelop progruaslre disease, The only modification of the infection ns in its Local! nation, a few bacilli Ming retained in the fibrous terminal, bronchioles and forain*; tnbetrcLos there in addition to the urval foci beneath th* pleura. In view of this rarlshilitj, the unusual natur* of the response and the high proportion of deaths fhoa lnfrci.jrrwifc pneusxmia 11 is felt that definite conclu sion* *a to th* inflaenr* cf this dust on the course of tuberculous infection are not Justified. C. Offset of tuber cdoua Infaction on the rw,Mo; ?.<? ^. Infection complicating isboetosis accentuated the tendency of the duet to produce fibrous tissue. This chargo cccuiTsd uhe-her or not the bacteria.1 lesion was in contact with tha area of dust reaction,. o. Inhalation Erpariaent with SHort^flbwr isbostc-a Dust. Since baxai dona dusts LUcs quarts are Boot affective in producing fibrosis den the pertic! s are 3 aicrcoa end l**a in size, an inhalation experiment was carried on to defceroin* whether this condition is true also for asbestos dust. It was thought that by using a ehort-fiber asbestos dust consisting ilaost entirely of fibers end particles smaller than 3 tdcrore an accslorftted tie rue response eigrt be initiated and an adranced reaction obtained in a short vies. The previous inhalation erperiaent eith Xins*e floats asbestos, -ehieh ctmtadoed fibers fresa 1 m- to 1 deren or less in length as -roll as a great deal of particuiste natter and which produced a typical peribronchiolar fibrosis in exposed guinea pigs, oerrod as a basis of comparison. 26. The dustier material for this experiment -ess forv4rdsd from the kumrille plant of the lohn*-44nrrillfi Carpcratica.. It avs tba rcsatajis 01 finer*, collected in dust bins after a carding operation and screened i;o peas 2CO cesii. Since the waterial as roewirsd caat*Lr*ad ranr lor? fitxr-;, it was erourxj lu a eteel bell will to reduce practicall? all the particleg to 3 mere os or leas in size, fhen need slsoe in & rtsaiaerd duating Bschirst, this finfelj-niruiird asbewtee tended to panic in the hopper aro it became nscasisry to niz aits volume of Ibe uu- erovod aaterlal with ttrw volumes of the ground to *nar*-U a satisfactory dost clcod. The addition of the qcant.ity of unsrctmcS a.tbtrtou vza 3vftrtvaa.iMfc because it oonfesed the 1stcrprttalioc of result*. Probably tha aincr cscaat of reaction that developed ' ' 1 ia the Long fibers in ths oJLrttrre although the data of tMf rprlaBt do not prors the point * 27. T% cogpoctlicn of the short,-fib*?r asbestos as raceJ.Tfd Is disclosed bf chaadc1.4pd petrographic analyses given in Tahlo L. Sample* Uksn before madeafter griltfing yielded about th* same raises on analysis, indicating that therm ^ae no cooia-s* inatioo froa the sill cr loss ox* water content . 28, "2y dost isanBatraticr. variod somewhat during - the experiment and light count* Tor atmospheric camples collected inside the animal cages with the hunger appanrtus ranged from 63 million to 182 alllion. The arerage of 4 counts mM 3*30 vsLlUm for the first year of the eoqporinsnt, 13ii million for thi second yes' fad LUO nJlliou for the third ysar. 2$. 53^ft-frosnancr> asaaurtsaenta of air-floated dust fresa Inside tha cages U.4 cagnifixasticsj of 13CCX rerrtied a groat preponderance of fine par ticle* (Tablf 5) Seariy 90 per cent of the particles seen were smaller than 3 microns* . 30. Raytlon In Animals to Inhaled Short-Fiber Aabeatoa Dust. Four epscie3 of animal* - guinea pigs, white rats, cats and rabbits - were vised in e this experiment. The reeult* of the dust exposure, -which are sunaarised in Table 6, will be considered sore in detail below. 31. CM*-- Pitre. Sight? guinea piga were originally placed in the dust room but 21 of tbs were later elIrinatod frea the experiment and 'killed beesnae of eclirged lysph codas.. Of the other 59 animals, L regained in the dust rooo until thay wart sacrificed or died frea natural canss and 13i after being ccpoead to dust for 20 aonths, irere transferred to a narnal atmosphere. 32. Rate and Type of Reaction. The type of tissue reaction to the Inhaled short-fiber asbestos ma essentially the saao as that already c be erred la th* cxperiarot with Xing'e float* Asbestos. The rata c raacti.on also was epproxi- nately the scoe bat the crterrt of involrtunenb uith the short-fiber dust was very much less ssl after 16 to 2h couth:* of exposure coir a very few .<wa^ feel of reaction, whidj generally required nicroacepic exaxLnati on for detection, were produced in the CDCtnaa pigs. Until exposuras had continued for approximately coo rear, thers was littie tendency for duat*<cnt*inirg phagocytes to collect into cluapa. By 16 months phagocytes had begen zc collect about tho walls of * few of the respiratory bron chioles with a little proliforation or infiltration of nemonuclear cells In the** walls. There were-also soae reiltinuciaatsd cells but they were always of the inert foralga-body type. It 20 to 2li tenths the cellular elueps were saaatlaea quite aar)ced and 5oastlacs charges in the epithallvia resulted in the adenasa-like or ?tdenc=atoir appearance previously described in Section 17. In rest of the subsequent nobers of the series, the reaction rocained cellular in type. In a fge, howerer, fibrous elaacnte dccimted the picture. In the latter case, the collagen was jcl3 in color ar.d tenuous with no hoary swollen, hyaiinination. As in the rats described balane, the alveolar wails sight be cade up of a band of collagen Supporting a layer of erdthaliiSE, but with no contained capilltriaa. In the trachecoroocfcis.1 lyspti nodes the reaction was sore pronoanevd in this experi ment than la the prrricqt ctse with King'a .floats asbestos, probably bocaaee of the transportation of an arc ess of fine p&rticl** t-o the nodes in anlrrals inhaling *hcrWlb*r aabeeto.c, 7h reaction was ^s-aentlally an increase in rsticults, rather than a fibrosis, r-tth preserriticri of Ilia original cells between tha thicJcerwsd reticular fiber*. Diffusa chrordc plcu^ Ufcout rridanca of palccnary infection ms praaerrt in a far rrcfywsicv. one ?nr,ns follarrla? ths cessation af 20 &aath3f exposure to duct, urogressinn of disease ires not definitely dmaonntratfrd but nolthar cculd it te absolutely cicprored, owing to the varia bility of the response i_n differant inirw. ` it the end of the dust cxposur* of 20 moths two pigs were-read as and one as 2+. Anong the 13 removed from dust the findings 'ere variable: in 2 the reaction era ; ir h it was *; In 3 it -rae 3*i in 3 it was l**j and in one anlsaJ. it was $. It is quite pooaibla that those with the mat narked changes had alraady dsmlopad more reaction than the reoain- der by the tine exposure ceassd, Since tha mors sa--dr-a roecticna occurred spora dically and bore tc relationship to the Length of tine after cessation of ccpc- rare the differences' were attributed to relation in indiridual susceptibility. This riew received support frea the chaaical analyses (Table ?), which often re reeled coaparable aaxjunts of ash and silica in lungs with wldel? different mounts of tissue change. For example, the ash and silica values were quite tinllxr fer three aninala in dust 20 aonths sad thoo in nortal air 13-3/li nontha, yet the tis sue reaction for one snisal raa h+j for another! *1 and for the third, only i. 3ii. iabestoeis Bodies. Tha formation of asbestos!* bodies was *t first xtreasl? United. After $ nontbs' exposure ool? a vary rare short bod? could. be found, useall? inside of cells. Around the finest intrtcailnlsx particles there were reHot depoeita haring the earse color as the wbeatosis bod?. Srpocrro of or* jeer had panxitl-ad tn acasnlAticn of nan? longer fiber* about which the ttbefftcais-bed? coating devolepod. tost cf these -srere still short enough to be parti&ll? or an tire1? within phagocytic cells. Dy tha 20th tenth and thereafter, they Tiere ccoparativvly auasrous although still rare in ccaparison with the findings in tha King's floata experiaant. -IT 35. Rata. Seventy-three white r&t3 rar exposed to ataospheric aacrtfibcr asbestos duct for periods up to 32 aonths. Sacrl- riclr^s duri-- tho first ID tenths wero made bimonthly and Tor the remainder of tha erperLaen. at less frequent lntarrvls* 3^3* rc-at-s ar-d Tyne of Reaction. Tha dust cells until S months Tars widely scattered sxri sxLsted in foci only sporadi cally. flsactisn was United to occasional alight thickenings of the septa about mall accumulations of dust colls. In & fee rats &t 1C aonths, there tu a sug-- festloo of eerly fibrosis but the change was so alight that it would probably be everlooked wittaut the clasp cf dust cells to attract attention to the area. 0nl7 ID animals sere exposed free 12 to 32 aonths. In each of then the lungs showed minute patches of well-defined fibrosis distributed like that of asbestosis but without asbestosis bodies. Toe lesions, visible only at a oagnification of 150 diameters or more, consisted of patches along alveolar ducts in which the wall* of the air spaces were very thick, due to swollen collagen framework. Comjective tissue and Foot-Bielachowski silver preparations revoalod complete loss of capil lary bed locally. Outside the collagen w? a thin layer of epithelial calls. This did not reaesbl* the 'adeaesatoid'1 chang* characterixtic of guiraa pig as bestosis. Mo pleurisy was present, Soar the lesions the air spaces wars filled with phagocyte* containing grsy to yellow particulate dust and a rare long naked asbestos fiber. Careful search failed to reveal ever. a suggestion of an asbeato- xis body. The trschsobronchisl codas showed compact focal collections of mono cytic calls at 12 month* and, at 20 months, soese diffuse thickening of the rstieulua. In a few rat* there was definite fibroais along the margin* of the node and extending into the codixrtinal areolar tissue. Coopered with the response to active dust* like quarts and chert the reaction to rficrt-fiber asbestos ni negligible. ----- ------- Results of chasicsl analyses race on the white rata are given in Table 3 and the ar-rage have been tabulated in Table 9 for conrarison Tilth ainilar values for rata inhaling other dusts. The concentration of ataospheric partlc laa to which the anicsala ware exposed was approximately the aaae for asbestos and quart*; for the jTpevrs-quart* fixture, it wua about twice aa high and for chart fir# tines u high. It Trill be noted tliat the percentages for asbestos are lower than those far quarts or chart but are similar to those for the gypsun-querta mixture, in which atmospheric agglutination tended to reduce the anount of dust inhaled. It night be inferred that the total.quantity of asbertos dust inhaled su low or that it had been eliainated from or dissolved within the lungs. Ia the present stats of our knowledge evaluation of theee hypotheses is not possible. 37* Cats. Twenty cats were used in this inhalation experiment with the short-fiber asbestos. Eighteen were kept in tha dust roon until daith, the exposure period ranging Iron one conth to nearly b-l/2 years, and two, after a dust exposure nf 31-1/2 months, ware removed to ncrsal air. One of these was sacrificed $ months, and tha other 2li nontha, later. 35, Rate and Type of Reaction. Tha reaction was essentially that to an inert dust, even after more than U years of expo sure. The tissue response in this species was confined to sdcroacopic foci of fibrosis in ths wells of groups of aubplrrrsl alveoli, rather than Lr. the peri bronchiolar arses, la one ardaal the change va* extsai-ive er.cugh to be viru&iixed on gross inspection of the section. 39. I-fUr Changes. Only in the animal with the longest exposure did the I--ray reveal definitely abnormal shadows. After 29-3/1 cootJhs the picture was negative j after iiS oenth* a faint Bottling could be detected tlirougheut both lungs, it autopsy, S son tha later, there was only dcrcscopic ( fibreata ir. the subpiaurai. znn pins he-arr lynphccytic infiltration about, tzsII bronchioles. iiO* A-sbeatosis Sodlaa, On prolonged search a fair yellow atypical c:u bodies, essooth and without vcnatratiorui> *^re foursi In tn ar.ira.Lt exposed for nor* than a Tear. ill* Rabbits* Eight rsbhdts were exposed to dust fer periods axteeding Croc ona to oora than fire years. Tha ia*t saie&l was renewed fr the dust rocss and loft in norm1 air 6 oouths bsfara being sacrificed. k2 Rato and Type of Reaction. Thera was newer enough fibrosis to be de tact ad grossly there sms ao chronic sdhasire plsurir/. liicroacopic evidence of Alreolar wall thickening was first detected after about 3 rears of gr.pcgnrrs and nj seen in all fire animals examinee thereafter. In cno aninal that died of paralysis after nearly four rnars of ex posure ths reaction -was sxtQ3j.r* enough to ba risible on gross inspection of tiaras sections. The possibility of prilsonary infection in tnls arfsal could not be sxclurfM. Kotrsrer> ir. another animsl. dying `tt- years later ths fecal fibrosis ma not nsarlr as atrriou?. or w. adr*need. Areas of irrrolvencnt, which were Largely rlsuall&ed. Vnw of phagocytic reaction within the air spaces, tended oitrxrscopically to biceps aora .fibrem* with ths passage of cine but there was nrrar saich sr.crochamt upeo. the Uissm of air rpactf and ths architecture of ths lung r*M prsserrad* U). Asbegcotis cocCLogc isbertn* bodies wicre not detected Ln rabbits that did early ir( ths xprint but seen in I1 snln&ls that had been exposed to ths durt for core than three years. lii. Simrmrr and Intertxet.itj on. Th* original purpose of the experiment was to /rraluate the chemical theory of the pathogenesis of asbestoais. It was felt that If the tissue reac tion to asbestos were cheatcal in or Inin aa i. iersted cr accentuated response would result frca exposure to finely-divided asbestos, aa Is the case with quarts. This experiment, in which the reaction was slower and less extonaiws than with King's float*, indicates that the reaction probably is not primarily checsicai in nature. Of the four species exposed in this exporinent only the guinea pig aod rat reacted with characteristic peribronchiolar fibrosis. The cat reacted with atypical rub-pleural fibrosis and in the rabbit the fibrosis which occurred could not be positively attributed to the dust because of a strung possibility of pulmonary infection. u. Inhalation gxperiaar.t with 100 Per Ceat Ball-milod Asbestos Dust. In the inhalation ssperiamt with short-fiber asbestos dust a small quantity of unground asaeutos was nixed with ground caterial in order to produce a suitable dust clcud. hen evidence of a dust reaction appeared in the guinea pigs during the experiment, it was sot clear whether this was a tissue response to ths number of Long fiber* in the ungrouod asbestos cr vis a delayed effect of the core abundant fins dust. Consequently, another inhalation experiment was started in which no unground material was usod. ii6. The dusting material tau the ground short-fiber aobeatoa used in the previous inhalation experiment but no unground caterial was clrvd with It. To obtain 4 sufficient amount of atmosphoric durt, the design, of the dusting epperatu* was changed to an open type of hopper and fresh dust was added daily. Grrtrvs to tha terdsncy of the oa^crial to fora small spherules which prevented such of the fibrcue portion ivca floating out of the hopper, the diapeloal of the dust ttws r.ot entireljr satisfactory and after 7 .months of operation, the dust in? irr.ci-.iua *** oceirrorted to its original doalgc. To prevent "pilling" or aho fonsr'.r.ion of rphervlos of asbestos, steel wire brashes ivern attached to the in- . side eurface of tha hopper and to tha rotating paddle. This arrargomevt gave satisfactory resets and ttss used for the remaining 1 months of the experiment. hi* The corgosition of the r.ur notarial (short-fiber asbestos) and of atmos pheric dust liberated froa the baH-odJLLed product in the dusting ma chine is given in Table 10. These values are based upon petrographic study and l-raj diffraction analysis. The atccephnric saa^sle vaa collected r.ith an elec trostatic precipitator after -wire brushes had beets installed In the dusting machine. Previous to this, the chrywotile content of the air-suspended aaterial wss undoubtedly less than the 1$ per cent value given la Table ID. In an IntarIn report, it rae stated that tha air-borne dust contained about $ per cent of chrreotile before is wire brushes trere used cad up to fi per cant ofterrrards, tut these values were probably lew. Quantitative estimates on b all-gill ed asbestos dust oay be sor&ewnat inaccurate because it is difficult to determine bow ouch of a dust aaaple is flbroua cfcrysutile and how mch is non-fibrous serpentine. US. The dust concentration. for the first 7 souths of the axperircut was about IDO trillion particles per cubic foot of air. After the wira brushes had been icstailsd* tha dust counts were a littla higher and tto overall ficrer?^? for tha first year was 1D6 alllion. Tha arerag* of counts far tha second rear was 3.63 aillion and for the third year lU5 million. i_9. The cisa-Occueucr of t!v oreperasts of atxoepherlc dust collect6i ir.side the nniS3.1 esges ri:h the eLsctrccoatic apparatus is reported in Table II. Two oaaples were tilnn. or-i before trsc .Tire oraches rare instilled and or aTtar. It will bo noted that after the irlro bretbes irra Ln uso a greater proportion of rer/ fine pertie lea and also of loader fibers was released into the air. 50. Pugaction in Anliasls to Tended ICO Far Ca;*t hall-milad Acbestoa Dust. Guinea pigs. rata ami siica were used in. the inhalation experiment with the iCO par cent bsll-idlled asbestos dust. The results are surrarised in Tab la 12. 31. Guinea Figs. The experizent ttu started with ICO guinea nigs. is the dust axcosurc proceeded, thorc vert 3? accidental caaths, 32 of pneumonia in an epidemic. ITtcr 23 oaths of dusting the 16 surre-ring guinea pigs intro transferred to norml air. late and Type of Reaction For the firat /oar of exposure practically the only- reaction to the dust wca the pre sence c scattered phagocytes end an occasional nirreta as be 3 to ais be by. At 16 and 20 ccatha no groa* rueponwe was risible on the tissue 3 action but ticrcncopicsi porribronchioLar foci of irvflanKatcirr cells could be s*cn. At 2U sont-h3 there wsj still no chang* ^arj* encupn to be scar, with a hand lens zllhough uicrnacopAc axanination rwrealed cellular accuscilatioas about tomical bronchioles and r.any a*oru asbestoal* bodies, chiefly within calls. Chenical analyses of tha lungs (Table 13) rsre&l that in spits of the United tissue reaction considerable dust had been retained in the lung. 53 Prorreagior,; The lan^a cf .uUnair, exposed for th* lull cruattr~ period (io rontfia) and then livinr in rcmsl air for 2 souths revealed the charges dascribed srove and also very peribronchiolar fibro sis. After 0 months in normal air the findings rare gir-n*- but at )Jl uoathr of U miSili slowed grcasly-Tisibls characteristic peribronchiolar fibrosis with adenomatoid charge. 51w lyaor. abde Irrrolredarrt. Tha tracdioobroMhiai nodes nare essentially nagativa until exposure bad been continued for sere than t year and a half. am mai* sacrificed at 12 swaths sad 15 months revealed a few adenta collection* of phagocytes containing partic las but pricticolly no fliers lar^s enough to be recognised as such. After 20 sooths of srpomrs nany monocyte* filled Kith ycllcnr granules were present* it 30 months there had been a slight increase in reticulum but r.c fibrosis. Ho further changes occurred in the nodes. Isbwtoai* bodies were not sren in the nodes of ary of the guinea pigs- o>. isbcgtogls Bodies, liLnuic *abesto3la fcodisn mre observed as early as 3 months after axposits began, but they did not be- 0X35 saarcus isstil 15 aoni'na rod elapsed. Tho bodice were abort and practically all were intrtdellular, although at 20 month* sees were .Ions trough, to project beyond the coll borders* It i* important to ccta that la the later months of srposure there rss a dis tinct Increase in ths rrsber of' long fibere to 70 ndcrocs in length) in tha iun^a and that after exposure ceased charact-eriztio loeg ssbesto*iu bodies wsre sees. $6. White &xt* and Mice. In this axpariMirt UO rats ware exposed for pariads up to 20 aontha and 2li *dce for periods up to 12 months. Neither speciea developed ct.-,- a sucgosticn cf anbcatot3 and reaction *eL8 Limited to phagecvtoais of lnhalui particles -rj widely-scattered dust calls which remained rcw in. air apaccs or transport'd to the tracheobronchial lynch nodes. Mb asbcoioals bodies trora found in v rats but in the mice there we a very for snail ncm-haustrated farms uithin phagocytes. Xa 21 oouse lungs soctioned thorn ware 3 instances of pulmonary admans 57. Suaaaarr end Interpretation. The tinsue reactions observed in this erperimont vare much lees sxtensira end alower in develapsant than in the previous investigation Tilth ahort-^iber asbestos. Since prestasably there trrrs fstrar fibers longer than 3 microns in tbs material used in this exparimant, the results tend to confirm the interpretation cade 1m Section Lit of tha short-fiber experinont that the reaction probably is not primarily chemical in nature. ` The finding cf long asbeotosis bodies in animals inhaling the balX-adllod material is an eraapla of tha difficulty of completely eliminating long fibers freu an asbestos preparation- In regard to progression of reaction after removal from dust, which was ob served in this experiment but oat in the others, the following interpretation is offered! Hien the reaction is veil-developed at tha tcrdnatlon of xposure,taa contraction of the fibrous ti*rs would obscure any possible progression. In this experiment, hoeever, since only the earliest stage of reaction was presant at the time cf rtaonl froa dwt, its subsequent progress was apparent. It should be noted that the degree of progression ni so slight that it can hare little, if any, practical significance. 53 . Inhalation !lcccrvcar.t with Lon;;-Cl bar Asbestos. Dust. kTtar aniroals inhrJiry: short-fber asbestcs cHurt Tor nor*? than a jesr hid foiled to rforelop sigh* 'V.*.rjrt. rsaction. tho hypothecis that asbcstosia i* pro duced by tho nechardca- Lrritaticm of long fir-arc gifen added support, uixcs thA King's float.-; arbest-o* used. i~. :,ha first- inhalation nrpcrlx-'rr. a rather law content of fibrous chry.scULa and contained considerable serpentina and other irepurit; os, it txls decided to conduct a iusv inhalation ejperixoot ith a purer fora of chrysotiLe -stitch -would be richer in long fibers* 5? The dustlnc* nstoriai saplored La this iETustigition, wac obtained fro* tha UanriUe plant of the Johrs-l^criil* Corporation. Saarple* of *-- Aral rvristlee of an'ooatos duet -sere first subedited to the S*ranac Laboritory for srsnination end cao kind, identified .is Lot Dt i*hinh vaa Los la. caopietite ^ and chroraite and had a. fibrous content smt-ircsted to h* about 75 par cent, wa selected t& cyvrt *\ttt-sbl*; o`c3. -wi.ro bnishoe snare fash*ci*d to the inside $-.jr-- face of the hopper and to ths rotating paddl* if\ order to open up the bundle* of asbestos and liberato sore fibers into the atmosphere. 60. The ootrocaiticn of the long-fiber agbesto* osed in this expurinsnt is Indicated, by thw chssLcal ajvi p?tro graphic analyse* gi-ren in Tania liw It eppsa.rs that this asxarial at? * rj;voh pnpsr form of asbestos! than th* shert- fiber dATSt used in otbsr Thi 5 1-5 bTrw out by ccaparia* the axproi- 1sat* aaslytM o the Icag^fibsr and snort-fllw tdurt in Table 1$. 61. The dust concentration is msrmls.d by inpir^cr' wsrplae taken inside the erJLaal cages cuch 1-rsrcr than th* concsntntion for the axperiaaint* rtth ahort.-fl.har or hall-<d.ll*d For th* first psxr of the expsrinant with lonf-fiber Mbsstna the ersre^s of the ilcht field, cowit? m 52 million; for th* sar-ord 7par, i>6 erf 11.ion; for th* third y-ar, 3? ciilion; md fir th* fourth 7-ar. b3 uiilicn- Srasocaticn of tii* iopir^er sacrpl-o with <i*r*r fi*Id illunin- r.M.rr* rfi.acloa&d f..(Mt avenr fine psrtirl.oo than one rlo'on In sirs iccorpari.M thi largor particles ana dark /laid coi.in.t5 wr, cn the srerage, about < =r 6 tinea .Urgrr than th light field counts. &2. The 3ls-freo;jqgc7 of atzro.rphoric garbles of ths long-fiber ssbeatoe rfiurt an,! of the ball-clUed dust la shewn in Table 16. Beth aicpl& arer- cnLlsct^d with the slaotrostatir. precipitator, It will be noted that there asas far cere fibrous nsteriaJ. in th* Ion?-fiber dust. 63. Reaction in iabnals to Inhaled Long-^lber Asbestos Dust. Guinaa pigs, cats, rate and dee were employed in the Initiation erperisant with long-fiber asbentoso Results af th* expcscirwrit, waatrised in Table 17, ir$ described in pn*4.ter detail below. 6U. Guinea Pigs. The q>erlrnt, was started with 100 guinea pigs. AJTtar crpoeurs had been carried on for a yuar, a. sererc spidaaic of pn*vso.iA arosr. in th* dnst, roor? And *h<mt one-third of the aruxaLLs died cr rare kiilsd. To replace thast, .>3 C*?*1* gnl.n** nig- wrs add ad to tbn aurrivirr ermrp in the dust rocss* 6$. Rate and Trot of Reaction. Histological ecash r.;= Meo r^rsaLsd grossly rtrible Is sirnr in the lungs aftfr.r 3 oonths n.f *rpprir<* to dust, cproirMrig of callular .inflltratiof about th* tarninal bronchi nl*;*,, ly, 12 souths, ther-* i?*n Mervowtold Chengs;, in thr air ipina arid nr the 1.6th rmr.th a dafioi.ti fibrosis ?s prrttmt. in th*** areas in half the The fibrona Isrloa could bn eerm tt*crgcopiciiljr at- 2C couth*. Rroa thl* tio* on the rsection izwr*M*d in extent and In tho saount of collator. cr*A by the 3lith mouth, it had finned out into the parenchyma.. The lesions -were rather sharply localised and the extensions iron different bronchiole* showed no tendency to fuio, even in aninn la exposed for tlia r_*crimxsu ported (3 'ears). Although the intra-puiaonary reaction ooraatimes r-acr.cd the pleura, there was r.o involvement of t!ut ennbrsne. Uo eraphyssrra was visible at any point, ioxa thickining of the lsr"cr bronchi with a chronic infir.-natory iaflltrcticr. war rcvaaied, but it probably was no core than would be produced by a iniLor exposure to any dust. For the first months the phagocytes consisted cf ronocytos or very small giant cells; later, giant cell formation rras sere preninent. After 16 months the giant cells were large, filled with yeMewls h-d roan pigment and senstines vacuolated. An occasional animal shored an .\dnixturs of polymorpho nuclear leukocytes and, in guinea pigs exposed fer a coc.v.doralla period, eosinophilea. Tho reaction was at first antirely cellular but by 16 months fi brous tissue formation was definite. However, it never attained a stage of hyalinitatlon suggestive zi silicosis. A mocerato meiviiuil variation occurred among the exposed : .:nalo. loth in th6 rate of deve loping lasicas and in the stage of dovoloprent atta^red at :'rx end cf exposure. Analyses cf the Izzis (fable 13) disclosed that although the tissu. response was nuch greater in those guinea pigs than in those exposed to either shoit-fiber or tall-mllied asbestos, the aour.t of dnarsl natter in the lung ash was Lee. 66, Progression. Ir> guinea pigs erected to tha dnsl for 20 oontr ? and u \n reecred to normal air, there was a marked tendency for cellular irtTlarmutorv reaction to clear. This effect, accompanied by contraction of the fibrous tissue, resulted in a diminishing siao of the focal lesions. Hone of th*se srics]-*?. !tiUUd at var'.ous p-rinds ;ip to lii rort.'-os after exposure, rmr*4l<H Icnidr-s ** Irrs* s* tfwan ir: tho jroup c.icrv":crj at the :,c ?ws 2CV-cont.h crpoeure pfrn cd or those in .inio>*J.= nuch rc..tf/..d in tl\r, dust rooa for core when ?.0 oonthc, Fourteen mntns after bust c urs ccasiid, the foci. In four of th* rA.r. rrnricir.r judocs. pirj only with 8. hand l<mz. so sr-aj..'. that the;.* rerc risible Raacticin the yrotqa e.vponrd for j7 months arvi tr>rr. transferred to a normal y.vs cp.'ita ei'siliir to t-ha re.cpensft j_cv the 20-oonth exposure Ranttoned abom Rocmver, small foci nre always visible on ^ross inspection cf sections o.f all guinea piss of tho 27-mth aerie:: but Ln no instance ran there aTiceace of extension of the reaction. 67, Lpch Node Iirrciranent, Raaction in the tracheobronchial lynch nodes was first risible at the third sonth of *z- poeirr*!, 7*>t- the 6th srrmth patches of cellular cnnnectirA began to appear in th sratillA &srf bp thn llith month rcost of the node had been replaced bp cellular CJ7rre>TtiTe tissue.. This picture, ntvlch resexoled that in early silicosis, persist**? to th end of the oesperi^ent. inlsz^lz, is t variant, snrn*?d heavy sheets of diffuse jacoocTwes and Itrsc hettm (ftnnt cell? bid; there wy never any necrosis or hyalin* .font* tlcci ?na spindlo-stvcpod new colls wars ysUorLsh la color frog fin* pSP3KSh jraTPilrs th?.t ot.?ined for i ron. Ho fiborr. or ajb&stoeijS bodies *w en. 65. Asbeetoals Ho-llvs, ilt.hav.5t1 A-Wto.-vi f bodies rers seen tr early as cna month liter srxposvrs began, they nrt rare and haa^j to Hod, At ^ rzir&h* rort r--ro Ttr.iblfi. chiefly roiled inside yiant cells; arsd at 6 ocnth many bodies vr?re .free In ronnnetive tissue Thor become fairly abundant. e arrirre prosrssMr. although 1* son** l*ty /miml-fl t.ho e.nbestcs.ia bodice *sjr only noderata ly nusoroug. 6?, Cate. Four cAt.i inhaled the lane-fiber ssbostcj du5t for pariooa of iu, 2$, 33 and ih2 months, respectively, and mere irsr-JKil&ttly sacrificed. Two other catr after being exposed to dust for 16 amthr, hired in a nortnaJL atcoapnero tor an .fditiooai 2i months. 70. Rate and Tyre of Reaction. Ertosure for lL Births Tran ffoTficicri*. to produce cellular accumulations ef phagocytes around terminal bronchial* and peripheral arterioles. together with compact col lections of airdJ u* cell3 in the tracheobronchial lymph nodos. It that tine there wart no typical asbestosis bodies, but smooth, pointed 7*lire fibers were seen very rarely. ith continued exposure, up to 1x2 wraths, reaction in the locations noted progressed to the formation of cellular connective tissue which aade TgH-defSaei sheaths about the respiratory bronchioles and arterioles, narked lympheid hyper plasia and lymphoid infiltration of orouchiolsr rails. The bronchioisr epithsliua was 1st and flattened, giTiag the tubes a smooth contour. Typical aabestoais bailee were not formed although there rtae an occasional yellow, smooth, pointed fiber. Hs pleurisy raa present. The reaction mas similar ir. location to that La the guinoa pigs, but fibrosis ss.it ouch slower ir. deveiopaent and bad net reached the same degree of xaturity, ix. Jt-rtar change*. Roentgenograms of three cats were rede after erpoaur* periods of 2*?, 33 and 1x2 Deaths, but tlsm.vs changes were not dense eacngt to be seen on aa I-r*y SLla. 72* Rata. Although 20 rate were placed in ths dust roett, many died from pneu monia and were net sdUbls for study. Five aaimels, of which ozs was exposed for 19 month* and four for 25 eonthn. were ?** ffte pulaccary infec tion and offer a basis for conclusions. . ?3. Rate and Type of P.gactlcn. All fcur ArJ.jA.Ia sacrificed at 25 eenths showed a wBU-earked peribroncMolar fibrosis. tr the lS-nonth aninal, reaction vac just beginning. isbestests bodies were practically absent at both 13 and 25 months although two small 32100th bodies war* found in the l?-nonth animal alter s long search. Hue, these aniaala exhibited fibrosis without aabestosis bodies. 7U. Mice. Out of 20 white alee used in this experiment, 11 lived a year cr aoro la chist and died or were killed without showing an appre ciable degree of pulmonary infection. 75. Rate and Typo of Reaction, Reaction was United to phagocytosis by dononuclear colls 4 Usually these were wide ly scattered through the air spaces j a Halted mntJar wore grouped about the ter minal bronchioles producing some thickening of their walls. There was no sug gestion of fibrosis. The striking fsature of the experiment was that 9 out of the 11 nice (82 per cant) exposed to dust for a year or acre showed pulaonary turners, usually adenomatous in type'. These lesions did not contain dust or asbe a to a Is bodies, Numerous aebertosle bodiaa wore observed in aninaln killed late in the experi ment, Thus, these srdrwiLf exhibited asbnstosis bodies without fibroma. 76, Svm'arr and Interpretation. The purpose of this experiment was to evaluate the lrsportanc* of long fibers in the tissue response to inhaled asbestos. The results indicate strongly that long fibers are chiefly responsible for the reaction. Thus, in guinea pigs react loo developed earlier and became acre extensive than in previous experiments in spite of a ewalLsr concentration of atmospheric dust and a lower uinaral con tent in the Lungs, Furthermore, a typical peribronchiolar ------------ '-----J in cats althnu^n in a previous curpsrinjsat- with 3her*.--fiber dust it did net develop in this species. Tho cause of the cellular fibr03is in the lynpn nodes cf the guinea pigs ia not clear. It did not occur in other inhalation axperinente with asfceatos. uDCVII. IKJECTlOy EZPZ3E.NTS ' In order to deterrina to what extent the raxious fibrou* timersIs possess the capacity to produce tissue dosage, esaerous injection exper Inants were per formed. In those cqparlaents guinea pigs sad rabbits were used and the mineral dust was injected by the intratrachoal, intrJ.penton*a1 and ir.trsrrerioja tech niques. i'or the purpose of simplification the findings in aacb ssrifns of testa have tear, condensed -3rd report'd in tables, to which reference will bs*cade 75. Eirecrleants Ualng Intratracheal Technique. S Lnce the asbestos .rLnrrala do not cause a typical advanced fibre sis in axtra-pulDonsry tissue, t-ho intratracheal technique is tha perferred vc- of in troducing fibrous dust into the xp^riasn'csl anioel. In this =athod the dust euapeosion is injected by aaans of a special needle or catheter deep into the trachea, Crcm which it flows Int-o toe Inrj;;, 7?. Coeparisori of fibrous and for." Fibrous fusts. To -isaenstrata that the ability cf asbestos to produce HIres Is maidw in its fibrous, char.trier, th* swriw of injection experiDemts reported in Table -1? were performed. ?h* test* mrn sace with unheetod Long-fiber chrysotila end with chrysotil* that had been ignited to destroy its fleccibls strorturo or bcll-rniilcd to reduce >.? ; cr1 ' i-b<?r to 3 microns and less. At t.h same ties centre1 Vet:-, rerf -v;': r-'.-. t..-- ;.;ti.ne, Krtich hu eta sarr chemical composition cS chryro.'ile :/iv 1-: r.cr.-'i'.r. . c review tha rj.Tdi.T53 reveals that only tha unhent-cd long-filer- erry: produced fJ.hrosis. Fibers Tubjactftd to ignition or shor-ired br ir r. rxd lest choir capacity to cause 3erterns tissue iars'je. Ignition prsduced >:._ ci-taut chsngss ir. th chry- sottle fibers, among thes being lose of rater, an citoration frea a flexible to a brittle structure and possibly other changes. 30. Coapirison of 7arious Lopg-fToar Dusts. Sotie very interesting findings * t'c disclosed by ths results of the experiments included U. Tab In TO. First, all. . u lon-\('itu- asbostos minerals tested, with the sreeptian of anthephyllita, produced a typical fibrosis. It is not entirely nicer rhy ar.thophyllitu b6ha7ad dlfferontiy .'mm tha other asbestos minerals. Unfortunately, 5 of 0 nrinr.ls died of rnouxsonia within ths first tiro weeks of tha experiment tnc. ths rrrralnir.g anir-aio worg sacrificed at 1, 3 and 12 months: thus observations T*are non .nude at the ortimun periods cf 2 and U months. Second, with the mirna-al brucitc, stiicd' is not a silicate but i.*< a fibrous fora of cagnesiua hyirmnida, a characteristic fibrosis lias that of the asbestos minerals was obtained. 3free ths brucito uxac contained only C.?0 per cent silica (as tn ispuritgr), it la obriccs that a siliceous component is not an eKsantial factor in the darrsiopment of act-eatosic. Third, no fibrosis resulted fro- ths injection of class wool fibers, seen though glass wool r! 3 fables asbestos in eooc* my*. There are f'usdanental differ ences, hovwver. A gbwe wool fibor 3 microns in disxoetar is a a olid rod and, in ehort lengths, is fairly rigid, while an asbestos fiber of the same diameter is a bundle cf artretaely fine filaments which impart to tho fiber x high degree of flex ibility. It wjuld seem thnt this structure And the associated flcxibilitr sm isportairs factors gcreming the capacity of & dr.aril to produce parlbroncmolar flbrosit. fll. Conotriacfi of lor~ -?lbcr ar.d Short-Fiber Dusts, With qaarti dust it has boon daoonstrated that the the particloe. tho acre intense is the tissue reaction, and that there is little reaction to particles larger than 3 dcrons In disaster. In the case of asbestos, bcrswrecr, the nrrgrse is true and apparently only long fibers hare % any specific effect. 7iis is coniirrd br the data of Table 21, la rhich a series of tests rath fibrous dnersls is reported. fihen the Injected dost consisted of fibers 20 to 9D Bicrons long, ell the ciner&le tasted (except anthophyilite, as noted in Section 60) produced a fibrosisj rhea the naterlal ms prepared by first grinding the fibrous dart until the length of fibers res reduced to 20 microns sni lees (cr, in cone cases, 3 nitrous and less), none of the injected ainsral dusts ceased fibrosis* 62. gxperinents Using Intrarsnoua Technloue. The axperiaeata, described In Table 22, in which the Intrarencue nethod of injection was aepieyed, shew that the asbestos xtnereJL* ere far different froa quarts in their action on tiaaue. It has been repeatedly doBonrtrited that intraresous injection of quarts pertielse 3 tdcrons ard lees In dlsaetar Till cause a typical tissue reaction xith to* darelcpaent of fibresie in extrupolaonary sites, such as ths lirer and spleen. Asbestos minerals, fccmrrwr, on intraTenous injection generally produce ooly an inert type of reaction, *8 Is rcrealad by the result* giTen in the table. The reason for the early death# in the experiaent with chrysotlla pertlclaa is not dear) it nay hare bean caused by dlicic add liberated by tha finely-ground ainaral. 03* rbcrgrlaeatg Using Intraperitoneal rcchniouo-. The rwult# of injectioo errerirents with the intraperttoneal technique * (Siren in Table 23. It. -rill be noted that the long-fiber dusto produced c. fibrous reaction while dust* cospoeed of particles 3 micron* and Lass in else caused only an inert typo of response. Theae erpsrlaeata indicate tlsa that the fibre ale initiated br the irritation of asbestos fiber# la not restricted to the lungs, a# waj formerly asironed, trot can be produced in the periteneta aa veil. U3H7. OTKCT SHRIKEST5 TTETH 1SET.5TOS KEKSUia 1 Busbar of additional expariosats wo conducted to three sore light on specific phase* of the aabestoei# probLao, / 05 Protecting Action of Alnm-i nxm Cfnaponnds. Intratracheal injection of a. ywpen*iott of lenc-fiber chryaotile to which colloids! alnsrtraa hyrirarLclB had been added revealed that the addition of tha lusdnua eccpenad did act prerent tha tissue irritation produced by cfcrysotile. If anything, tha acute inflaraastciy response to the injected fibrous mi atm.1 u aecaiasrated* Ora ssth after tha last injection of the duet euepeusLon tha bronchiolitis ex* bewaring fibren*. 86. fCroatlog of Isbeetosla Bodies, The iron la tha coating of the asbestosis body appear* tc b e derived Cr-cs blood or tissue eleoesjt? ssd not, an has been yaggssted, frees tha aibrril fiber, following rubcutaneous ibjocticn of too Vlada of chryoctila into tha groin of Ctlnaa. pig# - ooa bind containing 2 par cent and the other 0.2 per cant Tv^y tha aabectoaia bodies irore easily macrons at both sited of injection. / / // V/ An attempt to produce s-sb*fitri?i3 boril*>a in rp^jve*''pigs by inpiintation or U\tm 5ilk bars containing fibrous chryuotila was y^succasaful. -------------- / bag planted subcutaneously in the tbdocirol Trail disappeared; the other tw begs, placed in the peritoneal csrityt produce*. little for sign body reaction but no asbeatoais bodies in a year. Intratracheal Injection late guinea pigs of asbestosin bodies rscore red free inrsao lung tissue failed to produce the typical tissue ruction to asbestos fibers. The injected material -was obtained by digesting with sodium hrrochloritg .solution lung tissue removed at autopsy Crca an asbestos worker. The asbestos is \ bodies could be seen in the guinea pigs for at least a yesr after injection. This expsrissnt shows that the asbeatosia body has a rather resistant coxtirg ' which is not destroyed by moderate hypochlorite treatment and nay be nair.tainsd in Tiro for a year or longer. l LXXX7H. TTCORT Of miTJLiT ACTION 0? ISEZSKS ULVSHJLLS b. Two hypothesoa here bees proposed to explain the tissue irritation and rear- ticc oesasd by asbestos fiber?: the cheat!cal and the aachaxiicaL. In ths chemical theory, which is baaed upon srperiero* with quarts, it is assumed that tbs a>- baebog gjaerals dissolve In the body dtddjg and that ia this proceae their bases are leached ewy to leave silica in ?. fora capable of iriititing tissues. Accord ing to this hypothesis r csbestoei.* would be merely an ^ndir^ct ailicosia. Several \s fact* nakn the rhmiciO thtcry untenable 4 (1) intratracheal injection* of bru- cite fibers, which, had a silica, content of only 0.9C par cant, causad a typical fibrcsis liks that produced by the asbestos sinsralij (2) free-ailic* particles increase in potency as tha partial* becomes lest, but asbestos fibers shorter than about ID to 20 edemas are relatively innocoou*i fl) slnerimr* ' hyrircoG.de rcutralirea tha irritatinc effect of quarts but not of asbestos; `Ji't serpentina has the sane c'.ierucii or. it ion -? Img-fibw.r chrysotilc- but doer /-rt. product the sane IdLnri of '-irrue reaction; CD thore is a rice rar.^c . th* c:`.csTucal composition of the oincrals which do cause asbesteaia (see Table Zli). In riax of this cridance it seats nare likely that asbeatosia is 4 caucad by an unusual mechanical irritation Ircra lens asbestos fibers. Probably this irritation is related to the pactiliar rUsxantod structure of the fiber and the associated flexibility, which are poesessed by ra other foreign bodyT Fct"*" * essnale, ig Ution of chrysotile fibers changed their strocturo end made then inert -while the sane fibers, befara being heated, would produce fibrosis (sea Table 1?). Further support for the theory of nachanlcal irritation is that asbestosis occurs in an organ of high nobility - tho lung ~ and that a fibrous reaction can be produced by injection of asbestos flbors into tha peritonoun, nhere chare is also a degree of nobility, but not in' other ertrapulaonary organs. ,, lecviii. carncAiicys The erperisentil lorestigatiou. with asbestos dcecrals was concerned primarily with the effect of the dust as normal tissue but soma attention was ^iren to other phases, such u susceptibility to infection ard occurrence of nalignancy. G9. Infection. The only experiment in which the effect of inhaled aabestos dust os & pul- nonary infection mx studied m the first inhalaties experiment, carried on with "nine's floats" dust. It is, pertupe, unfortunate that infection etcriiaa were not czbde in the other inhalation experiments alio. 90- Susceptibility to Tuberculous Infaci.XQH.. The doTclc'pnant of a txu>6rculcaa process Initiated at the oeginnitu: cf ccpcruro to asbestos dust. srl also e: an i_-fctlon superlrposed upon an established asbostosis, rrae b-scribod la rectiai_. 1? and 20 of thin re port. It will to notec that aabeatos, whan classified according to tha effect of a dust on tuborculoas infection, rould ho placed trlorr an active cunt lila quarts but abov inert duote, such as calcite or.d r,;r?siut- In anirnLs infected with attenuated tubercla bacilli, quarts till cause the infectious p.oceae to progress until the araaal dies of tuberculosis. Inert ducts will hare no effect on the infection and the lesions will usually heal and the disease disappear. Asbestos dust is in a different catogory. <>.an tho fibrous dust was being in haled during tiia evolution cf the infection, there was a spreading of the tuber culous process for a tiao but usually tho stimulus for continued proliferation of the tubercla bacilli was not sustained, the progrosaica vas arrested and healing foilowed. In guinea pigs infected with attempted tubercle bacilli following the cccpletioa of nearly three years 'if exposure to asbestos dust, pregreeaive disease did out develop. Toe only codification of the infection was cue of localisation, a few bacilli being retained la tho fibrous terminal bronchioles and forming tubcrrclae there is addition to tha usual focdL beneath the pleura, Such tubercle* healed in a few aonths tad there was nothing to suggest ary influence on the course of the disease* 7L, Susceptibility to Kon-Tuborculous Infectlor.. Thsrs was no pointed ex periment concerning the effect of inhaled asbestos dust on ru>n-tubcrculoua infoctlon. Inter current pneu monia among anJLsals erpoaed to asbestos dusrt wts rather coanou, the frequency in guirsMi pigs exposed in the four inhalation experiments ranging from 16 to 35 per ' cant, This incidental endcr.cr r s - n cooc. siHty of art ('ffect of &jt'^sCofl dust on ron-tubcrculcus ir.'c"*-icr.. 'h-v.rthcicss, since such apdenies are not. uncosewn In ishALaiicr. sxrcr..-c*rvs -.rich oilier duotc and c^n in the colcry of rorrw.i cmimla, it is fell tie i:ihalatlon of asbestos dust decs net exert a significant effect or me susceptibility to ixm--tuberculous pulr!onrir; infection. 92. -?e<yclas~i. ;$> specific sxperirev.t res conducted to dfitordca win\hr this Inhalation of asbestos furors the ccrc losrr.cnt of neoplastic disease but certain obeer-rations on this subject r.re record'?.", in the outline of tfco proposed atorvipraph on aabeatosis submitted by tha lai<i us. i. <j, Gcrdnor in February lSii3. In :( ha called atten tion ?<o the high incidence sf lung cancer among adca inhaling lcus-flber asbestos. In hi a eTparia&ctal notes, ho-orrer, he referred to these icssonn 13 ad-ccras. There is an important distinction betr/een adcncua and cancer itvich should be njudo clocr. A cancai- is n tvear, or neoclasa, capable of local in vision and de struction of tissue. Thich cm distribute cells through tha lymphatics a:* blood etrenr to produce isolav.eu foci. from ,vhich ner tuners drreiep. The\ phenomenon of dieaerd.re.tj.cn is kserr. as tataatasis and any ttaar which ezhibits it is a malignant growth, of which concar 13 or typo. An nder.orct, cz the o.hfir hand, is a so-callod benign cr Twa-ralijrumt tuner (oecrpl&sz) which ircy.or at; not be capable of local inraaico but -rhich decs not metastasisa. In order tc clarify the cruet ruturs of these lesions tha path '.'.cjicai raater1*1 is being carefully enrzLwd. Since it is folt desirable to ha-', the benefit of Dcctor VorTrald, judpainta rerie* of the <Uta on this subject \a being post poned until, after Wx return fron Europe, Rather than delay the enl're report, further discussion s*Lll be referral for a supplement to bo issued let v. to the vacu Eraunt ci da-*. ire.Vrio-.' ir. .-' it r'*p*,,:n : f. s`-crs .v-'si ccnvcni .-*, to a Wee toe or.ciusiona ;lri\*o;J i.-jr hr.-* irr.'-'oti-ation at. i . *n-.t'.r. r.ceocanry, folios' earl ono sith a bri'l ram:': c-f i!; evidence. A. ''ariocs fena- of csbestos fi!;r-rs pvtf'jrc c. peritt*-.:c"Ac'.-* :i ivesi.*; cl iur.ns o;` pij ;*h pi<jr, rate, cat.': ?_~d rabbits art n<.*t of irf.ee ind <i<?cs. Both InhoXiticr cad injection ::zvlscnt8 prcrri.de mpie rappcit for this nonelesion. ri:;vrcs 5 ard 6 Jhm* the reaction to tro different idr.cir of asbestos rsincrtl. a. 7c* rede of -tetion tppe pvirnril*/' rcehaniccl re*.:ter than chcsdcsl in nature. The eridc.ice is ivcn in scctirn LfTTT.TT* Figures 1, Z, L arc*. ? illustrate the important points. Ibe fibrcris filaaen'.fd - structure of asbestos appears to play aa essential part in the Arritatinp action, rice* the solid fibres si -L'?? rn-i co net produce fibrosis (see ',-L~cre i;. C. Slusrt tabeato# Tiber? do rot produce fi'oro3i3. The oonciieion is larliad ir. the .r-l.or.na ccntitred in pcrc- CTph B doera. Erp-irl7.-4-.t3 Tbish further aup.r.ort this fir.sir.- are reported ir. Tablej ?1 and 2;.. D. Typical fibrosis can be p.--zinced cr an atoocxheric ruspension of asbestos duct contAinir^ only 31 extrcnely snail prorcT-ticn of lens fibers. In the Inhalation erperioe:r-t with ICO pr cent ball-oilled asbestoe dust a typical, though delayed, fibrosis rma obtained 'r.c.c Toil- Ik). c:.. l\ \ er ccrt >." tb* duet nicr.-in^. . - 4 - 1".'i*Tn ..r* L'kiC 1:. ' '. u'.v- irtvc-- -ror -oil 'i..:rtkx*a o/rorlrvr.i -rith lie*- nivs^a r.uct ren tal no nr: ?.ac-: fibers foiled u- prod*..cc- ."v.-roeis. (ueo Ta'rd: "1). u. c: ssbsrrtns rtui.t no; crvr.tI.,- <Jos not niter .si.^ifre o-.tlp course of errcrimentol tubtreuioaic in piir.ei piss. This cone'.unicn is tertatiTa 3ircc the CTidnr.Co nr. irhicr it in bcc'jd docs .net conform irith cur usual experience. kLef*:^- ercc `-e, l/.bio j Till sreor that f.P.co infection v.-'is cnirr.ifcr.t, " th onsc; o>' -hurt crrr.oxj?? inrre tttuj trrporarr p'.'^Teasier, of t!x* disco::* riih 3Ub3eqve.it hcalicr; nbcn lu'ecticr. na after 2t J/V. nucths of cure, crf-ucurc: '.hi covrue e:' V.va tuberculoo.i disease. vcj rot nrcrsc.viblp altered. I:; contrcsi, i*. his beer. eoserrai Li crperLueuts -it*, rtxad roxts con^cirr.r o quarts Vr.it ii i.norx ir. s. slight prnpr'^cion ? cr.i '. ;vsr<-i- losis rl.eu IniVictiou and .fust exposure arc conoid ont, tl*f a offact is ooro marked (instead of laes, as rath asbestos) >r-.oa lnXocti.cn is initiated after a period of duct expc.ivre. This cornel-islov. concemv--. tie aflr.ct ef inhnloa csM-jior dust on Woercuiosio se-.ros justified rec-'cs*. V.' tto ixira sv.*.*:.tire test (infection initiated after a n^ric-d of dust cxpcrirc) thcirt* *-e to rrprcoii-le Increase in ruscoptibilit-T tn the tubercular-! infection. !i'rra7er, since Vr\a findings in the a'oestos I'.i'CT do ret conform wi.h previous ecpurionco, vd ?in t-ho dwtlinf. -.r.V r: ... r. o: *' ' " ' * Turthcr i T.'oat4. *d.l -r c.: ti in ~ -n.'.r. 7C- - c- c*-r.- r fijrar.fLon >;* rir-'.u'.ov.'..- r-.-r." " o:.. t rv.;.I.l ?. .Terrs ~ril in vi' '..V.t7 <> :reJ':c> .Intra.tr-ic.ical In.locMon nd? m r,.J.V:6 tc prcd-ica tie tjpical t-isuix* rc-uc ;irrt vjaa r-:.i"-Lvr. ii). Ti'.z cosaatim of projjpis-v;r r.-ict.tt.n >.> aEtcoton - rern al'icr * *:r Jue to tf.c oi" i'.vrrx ;it l:cci-.n.