Document K62korYYxdQdXJR1Za4ErgrgN

A--SBESTOS PNEUMOCONIOSIS Experimental Studies by The Saranac Laboratory .. 4 Report to the Johna-Maxxvllle Corporation _____________January 31, 1949  l Ulafl tH < \ ^at i THE SASAKAC LADCRATCRY sara:;ac lake, .vest yo?.x Roperi; to the JGTEJS-T&HVILLS CORPORATION RE* YOPX, K!3T YORK Jrjiuary 1, 19 43 ;-id by: 'bvc J. TTornalclj # r.'tzzo? Ar. o o n : ;i i s 1 I# Introduction 3, Aabootoo IJinerols I ABSTRACT 17 2XPSHISEU1L AS.BES70SIS Exporisumtal Uethods Species Susceptibility v. Peculiar Characteristics of Asbestoa Rato of Tissue Roaotion to Asbestos Fibers ?. Aebestosis Dodios AT IIJRALATIOR SSPSBI2SH7S XI ZIEG'S FLOATS ASBESTOS TOST Dustins liitcrial \ - Dust Conpositicci Dus-. * Concentration Reuoxion in Aninals Cuinoa Pigs .'a to and Typo of 1`oacticn i > Progrecolon *. -V Infection Coincident with Do.ct Inhalation Infsotion aftor Dust Inhalation Asbeatosis Bodion Rabbits JmwC '.1 J Sumary nd Interpretation . t Pag* 1 2 2 3 4 5 5 6 7 7 8 8 8 Q 0 9 9 10 10 11 12 12 12 13 CO II TESTS " zxv SHORT-FIBER ASBESTOS OTST Dusting Material Dust Comppoition Dust Concentration Siso-frequonoy of Dust Reaotian in Animals Guinea Pigs Bate end Type of Reaction Progression Asbestos!o Bodies Rats Bate end Typo of Reaction Cats Rate and Typo of Reaction - X-ray Changes Asbeetoois Bodies Babbits Rato an<| Typo of Reaction Asbostosic Bodies Suonury and Interpretation' XLV 100 PER CHIT BALL-lcILLDD AS3T3ST0S TOST Dusting Material Cust Composition i-Hxst Cone Titration Si20-frequency of Dust Pago 1* 14 15 1^ *6 15 1^ 1^ 1 15 19 19 19 20 20 20 20 . 21 21 21 22 22 25 C0WT T5 CO. Rsaotion in Anircnlo 51. Guinea Pigs 52. Rate and Typo of Reaction 53. Progression Lyxph Kodo Involvansirt; r>5. Aabestosio Bodies * "v| 56, Rats ana llico r 57, Sunsw.ry and Interpretation LVIII LOITC-r'I !SR ASBESTOS DUST 53, Dusting Patorial nO. Dust Composition 51, Dust Concentration 62. Sisc-frsqusncy of Dunt '3, Hor-::icn ia Animals j-i. Guinea Pigo Kate and Type? of Reaction 55, Progression 37. Lyiaph :!cdo Involveicant -3. Asbcatocia Podios '3. C.nts 70. Rato and Typo of Reaction 71. A-ray Changei * w . * Ha os r* Pnte and Typo of Junction 1*5 26U3 23 23 24 24 24 24 25 26 26 26 26 27 27 27 27 2S 29 29 30 30 30 30 31 ir C 0 3 `r E II T s Si co Rato and 'type of Reaction }> Surmary And Interpretation inJSCTIOH EXPERIMENTS Intratrsohcnl liqjoriinonta i Comparison of (Fibrous end Non-fibrous Dusie 11 C;ccee^)^jariaon cf-^PariouG Long-fiber Dusts Comparison of Xong-fibor end Short-fiber Dusts Iatravonous Zrparinentn titraporitcncal L'zrwrir.cnto LSSEIT OTHER EX? ERIE SETS /rotectirn Action of Muninum Confounds Formation of Acbc3tosis Bodies : :i -n feed on TAXCVII o h y o p t. r r i t a 7 actio n 1 i* UKS7III C 07?LIC AII 0KS / susceptibility to Tuberculous Infection *nsco|jtibi.litr/ to I'on~vubercu1 ous Infection TO II S D :r i* A R 7 XCIH T ABL 3 3 XCP7 P I G II U !? 3 Zisi 31 31 31 32 32 32 33 34 34 35 35 35 35 36 37 37 38 38 40 43 - 71 72-75  !. 3 ST n i\ C T 'arious forms of asbostos fibers produce a poribreaohiolar fibrosis of :ho lungo of guinea pigs, rata, cats rad rabbits but not of mice end aogo, '.hri mods of action of ths asbestos fiber is primarily mechanical rather hhnn ahsrsical in nature. long aebietoa fibers are oaosntial in cho production of peribronchial fibrosis; short fibers Rro incap&blo of producing this roaction. Typical ixporiuent^J. asbastotic fibrosis mis produced by the inhalation of m afciocchoric suspension containing -n average of 138 Trillion particles per cubijKToot of air of which only O.G per cent consisted of fibers longer 10 niorerr. f.v.r duraxioa of oxponuro required to envelop the pulmonary reaction to inhaled asbestos duct is inversely proportional to the concentration of Ions; fibers in the atmosphere. via. as tlie concentration is increased, hi reaction develops in shorter ti:ta fsusbli sheer nxcerisnstal acbeotosicceases to prcjrrecs cn discontinuing suro t: the dust. no formatior. of aabestoHic bedioa reprcconts a coating of the fibers by Mood and tissue elements which rosuits in lor.3 of ability of the fiber 5 ;-rodu::a fibre sis. Irrinun hydroxide failed to neutralise the fibrosing aoticn of the lung r.r ssbo.stol (Section dS)e nlatina'of ashes cos dust did not altor significantly the final outccme experimental tuberculosis in two series of guinea pigs exposed. 2. Antroduottij Aoboato^/a is a form of paouisooonlo3is resulting from prolonged inhala tion of asbestos dust. The name asbestos, literally "unburnable," ia not J that of a particular mineral but is a tern applied to a number of different minerals those characteristic feature is a otruoturo comDOsed of long, par- allsl, flexible-fibers. Tlaio structure is unique boenuse the fibors arc capabio of repeated longitudinal subdivision to units of molecular proportions. I' in length fibers vary from a fear microns to six or more inchos. Some varis:;ics aTe stiffor than othoro but many are sufficiently flexible to be spun into yarn end woven an. modified textile moohinory. 3. Asbestos Itinorala 'Aic asbestos minerals are silicates of variable composition and belong to tho bsrpentino and the amphibolc groups. Listed bolovr are Idle moro common viiriatioa. /.TTVphibolo GronD Anthophylilts Amositc Aisphibols Tremolite Actin oilte Orcciuclito (*C Fa) 0*5, Fs. (Ca, f*a*ir> (Co, r r,.\ (Ca, "vfc (s. Fa) Chrysotile Serpentine Grouo ITg silicato (hydrous) The bulk of the aaboetes of consaerco is chrysotilo, SZIgO^SiOo.SIIeO. which ia mined in the Ihetford region of the Province of <'lueboc. Crocidolite and mo Bite ore also u3od ournmcroinlly but in such smaller amounts. Chrysotile occurs as veins in serpentine, a mineral similar in chemical ocmpoaitlon to chrysotile but vrhioh exists in massive form and is made up of nicroaoopio fiborc without the parallel orientation characteristic of chrysotilo. Ihe massive blue black serpentine, which is rnooth and soapy to the touch, ia traversed by voins of fibroua chrysotile varying in width from a baroly perceptible line to six or more inches. The fibers run across ths * vein -mi not lengthwise with the formation. attention is directed to the siinoral brucito, L'g0.1l20, which is often found in the same formations with serpentine end chrysotile and may be fibrous in structure. It has no ooitnorcial value at present because it3 fibers are not sufficiently flexible to be used in toxtilos but they are capable of repeated -.n-itudinal subdivisicn. Unlilio other aebostiform ininorals, brucito is not e tilicuro sr.d f.r this reason it has been a valuablo tool ia on experimental ov:.iuution of .ho action of fibrous minerals upon lung tissue. IV 2 >. y K R I .v r. N T A L AS3E5T0SJ S or many yrars studios hive.boen carried on by tha Saranac .Laboratory in an uve -igiticn of the cause, nature and development of nBbestonis. Tha present report ia dorotod to Jhcpcrimontal Aobnstosio. In it are described the animal tx-ir ir.cats v.'ith various lands of asbestos dust, .`ci other report, to be prepared --- =sued later, will bo concerned with Human Ashestooie and r/ill cover the ..... 'spccts of worhora who have boon exposed to ''nvircrr.ent. asbes* . dust in an industrial ..1though fisbeatoais in man It a chronic disease '"bich requires years to elcp, it in possible: to reproduce in one or more species-of animal character- S ic tissue charges r.hich are similar to the lesions of human asbestosis- Since life-sr.an of the experimental animal is relatively short, it is not possible .*. r/elcp .^jc chai*r.cteristic lesions ir. animals under the usual industrial c.on{ ,r.s. (Jcncequently, to obtain a complete evaluation of the tissue response inhaled particulate and fibrous material, it is necessary to accelerate the c iion by erploying higher concentrations of dust than would ordinarily be ennured ir. industry% . /hilc ccnditiers of exposure are thus different, the aticn yielded by expsrisents with animals is invaluable in furnishing a :.-sr uni orstanding of the reaction of the human organism to inhaled asbestos -Ynerinenv al Methods or invest!gating the biological reaction of the experimental animal to the is'ir as tic o'oa minerals, tv-x> types of technique have been employed, namely, the . '..ti?r. r. .hr _nr. the injection ms-i-hed. In inhalation experiments, groups r..i:.r.rJ.3 - v.p zo ICO cr more guinea pigs and sometimes smaller numbers of rite, cats, dops, rats or mice - are leapt fer eight hour3 a day in a cubical room, oi.rnt foot in dimension, in which a cloud of asbestos cu3t i3 maintair.sd. ..niervais during the experiment, a few -animals are sacrificed and the tissue "ic ed -.0 d'tcimsir.3 the nature and esrtent of the dust reaction. Sons animals ::r:csr'i -f.-r p?ri-xls up to three years. The injection nxperimsnts, in **hich -`-'r eiti'er dry or suspended in fluid, is introduced into the animal by tho r.ver.cvj, ihtrepariitr.e-ii or intratracheal procedure, are used to determine cr no:. p-arr.cuinv linot ru>s a potential cspacitv to prcduca tissue Lcag-tom Inhalation, experiments furnish information upon Trhich groat roll* nooe is placed when ostimting the degree to which a dust night be hazardous to industrial -.7orhoro, Ihothor ar not ataiosohorie dust, even though potontially dsagsrous, oan be inhaled, pass the natural dor-mas barriers and roach the pulnonary tissue in quantities sufficient to cauco damage can bo dotormined only by inhalation procedures. Injection ospcriEMts are useful because in them contact botwesn the dust nortides and tissues is assured end tho potential capacity of tho dunt to produce reaction can be estimated accurately. When dealing uith fi brous minerals like asbestos, tho intratraohenl method i3 valuable since it per mits ebHerTing tho offcot of tho fibers on pulmonary tiasuo. 3. Species Susoeptibllit;/ Unliho free silica, asbestos does not oxert its specific offset in all organs of all rpocios of animal (Table 1). Injection of fine quartz into various organs cf tho guinea pig, rabbit, rat, mouse, cat, dog, chicken and oven tadpole will protiuco silicotic nodules. Hanover, similar injections of long or short fiber ns?5s?to3 have roF :li:ad in a fibrouu reaction in the lung and, to a lesser extent, in .'a crivonoujj ::t not in other organs of tho guinea pig, rabbit, cat and white rat io dig ana whit mouse failed to rospend. This variation in species is yot to bo accounted for. -cnlin.r Chsrc.ctoristicn of Asbestos cnoricnco has demonstrated that most of the particulate natter inhaled into -- lungs of iiaa und animal i3 10 microno or 103s in maximum dicaotor. Larger par...lcs apparently aro excluded by tho protective meohanism of tho upper roapiratorj tract. Zn the ccsa of fibrous materials, hsnrover, this restriction doss not apply "" !iJ-'r3 IfO and ovon 200 microns in length Imvo boon found in the terminal -ir paces of huaiui lungs. In small laboratory animals exposed to asbestos dust length of fiber found in the lung rarely exceeds GO microns. "t JVOry -ind of fibroue material is inhnlod vfith equal readiness; for examslo. 3 r'nt.:3fibers of "lass trccl apparently too inflenible to pass easily blic nose, pharyri::, trachea and bronchi .uxd seldom reach the terminal cnchicle3 ar-i alveoli. Inhaled perticulate waiter comas to rest ihrorghout the terminal air spaces Lv:o.Lar duct'. atria, alv.rali) ir. all parts of the luivco; inhaled asbestos fibers : irst in the respiratory broncbc.oi.es. Those vary sunli tubes are ccciitel7 diszt sl*#f to bronchicles lined bp ciliated epithelium. Their oun essen1L ILnirv? is a dirr cuboidal type: of epithelium but, as their name implies, they > Jvrcticr. in respiration through lateral alveoli River, off os pouches -.heir trail::. jJither these rjouches, or the abruut change in the character ..vs linir.;,' epiths'.'-iun, or the decrease in diameter nf the tube, or perhaps the ao:.n.it.ion of all three factors is responsible for local retention of the inhaled ter. Inly after antestesis is Trail established are appreciable numbers of fi rs carried into the more peripheral air spaces* v.: of Tisr-re Reaction to Asbestos Mibern .`.s rate cv tissue reaction to asbestos is much more rapid then to an active ot ii:e vuaitz. Evidences cf tissue rer.ponss appear as soon as fleers have ca.izr.d in rufficivnt concentration in specific areas. In rats receiving sebess 'ibers bv ir.trat-achc?.l in.iscr.ion thin avidsnee in -dsiblc as early so tvo i'-.i utar ir .;scticn; fer quarts dust the latent porix* might be tvo morths or TP . -he .'oh?.\ier of the tissue reaction to inhaled dust after the termination ox' rc -s net the jama in silicosis as in acbestosis. In silicosis, the young 3u.es -ecorsc. Isrjerj in isbe.sio.;j.-s, younrr sex* tissue.that may have formed,enn-c cr.d :.-ac ot.vj - jots dense but tho area of involvement (increases in sic.a. If zib-zva dust is teminatsd after a brief period; the recently-inhaled floors in the lung nay oau8 the fibrouo tiosue responoe to continue for a short tise, until the fibors have been coated. This progression is of only a alight degree and of little oignificauoo* 9. Asbaatosia Dodioa 'The poculiar strueturo known as tho isbestoais body or curious body in n specific cor.oonltnnt of a3bostosis. Tho typical body is a golden-yellow, beaded or haustrated rod which may bo either otraight or curved. Often one or both ends are bulbous like a dumb-bell. The bodies very considerably in length, and dlr.cncionfl dp to 250 microns have been recorded. ,`t is bsiisved that aobeotosis bodies are due to a deposit of protsin and iren pij^rsnt upon the surface of inhaled fibers. In guinea pigs they form after -.bout GO days of contact with the tissue. They arc abundant in men oed ths guinea pig (:eo Tabla l) but arc much larger in tho former, probably because the larger- ,, cicec air tubes Gdmit fibers of greater dimension. In cats, rabbits and mice there io cr/picai joaring of a few of the fibers after much longer residence in the lur.-n. ",n ra-.n pir.d dcr;s no bedics could be discovered. Although the evidence is to, it appears that the formation of the asbestosio body prevents damage *-a "hr ".issue by tho fiber. >& i:: halation s : p 2 u i c e n t s cvr ccmprohanoiva inhalation experiments have been conducted at tho Sarnuao cr. tcry v.iuh various forms of asbestos duot. In each of those investigations r->rc *h:n 1G0 uiirnls :ore uned and the experiments waro carriod on for periods ntirr from f. to morr than 5 years. Tho four kinds of nobestoc dust employed tro L-crrifioc :;3 rang s floats, chert-fiber, 100 par cent ball-milled, and *"1*nsbostes dust. XI ISHALA?IO RX?S?JlgST WITH "XiaO'S FLOATS" ASBESTOS HUST '".'ha first inhalation onperimcat conducted at ths Saranac laboratory with acboctos duet, ran begun in 1323, Animals inhaled the dust for poricd3 up to nearly three ysars and some guinea pi ~2 lived for about four yoarn after their first exposure to dust. J. preliminary report giving observations after 23 ucr.tha ex' exposure appeared in the February, 1331, issue of THE JOUFJTAL OF IUDU- 173IAL HIGIEHE.e At that tirno obcorvaticno covered a poriod of only 2-l/*l years *nd tho conclusions as to the ultimato effoots of inhaled asboctos duat T/ero provisional. 2<33ulta of tho completed study oherr that moot of tho ccaolusions irsvn ia tho preliminary report vrsro substantiated. A complete review of this rxr.sr'S'.yax io.'.lovffl: L -G, irr.o dusting material vms a comnsoroial variety of asbestos dust hnerr. as King's floats and nun composed of short fibers and partislo3 of variable 3.uo,, It vrao obtained from tho -lietford, Quebec plcnt of the Asbestos 'r.rforatu-.: of /merlea. -he cuat ccrnaonlticn (Table 2) reveals `chat the amount of fibrous chryaotilc -"us cnly Id nor cent, a rather lcvr value, rlcwover, tharc '.7ao iu: r:ei>3t fibrous -.notorial to preduco a characteristic fibrosis. tear. ,l . 7!;s rivsc r:?-v: atrati sn at first was quits low and for impingcr samples tr.Ven seer after the experiment ivns started, tho average light field vay standard technique was only 6.0 nillion particles por cubic foot of apprec :hlc number of largo particles (or fibers) al3o were preuent, ns rrjj.T7`OCr.:TIO.TI3% VI. Inhalatior of Asboctos Dust. Gardner J. I-d Hyg., 13: `J5-01, D7-J.1-1, 1031. cnovn r-1 ;:p average count of 0.3 niilicn for particle:? greater than 10 microns, ir-er ;::3 inhala-Ion sxcerir.ont hrd been under way for about two years, the speed ?f the r 3 tatin? raddle in the dieting machine was increased and for the reraain- ; r.- r or \o months o:* the experiment rnsiderabiy more dust was dispersed into V;<> fctrnojohere. Average dust counts for impinger samples collected after this . --ren ;J2.7 xillf-on for the usual light-field method, and 1.6 million for clr.j.larg2r than 10 microns. t * > * 1luacOxen h Animals to Inhaled ^King's Floats" Ashaatos Pu3t. Results of the investigation, briefly summai-ised in Table 3, show that inhala- -L.:.-. c.' vin;!s float:; asbestos dust produced a typical peribronchiolar fibrosis lr. -.i '.o.i rigs but n:-t in rabbits or rato. li. Pair.;a ?irr3~. 5o\*en groups of guinea pigs were used. In three groups., the effect of a continuous and of an interrupted dust *xr:.u'c -;as studied: in t~.o other groups the relationship between infection and 7as investigated. The remaining two groups were infection controls. 1'. Hate and T'.-no of R^acbicn. Guinea pigs inhaling thin dust for periods up to 33 months developed a characteristic -roo.o occurring lr. conical patches about the respiratory bronchioles. During " r. r-trpesur.? *;hc peripheral alveoli rsro not involved. The particulate elements '' --e *e tear.spoiled to the lymphatic system where they caused no signirv.c;ic the fibrous elements remained fixed at the nite of original .J=iu..:a-,:.or. aid were seldom detected in the lymphoid tissue. Pleurisy and fl^"s V) '-ilC 'Jcpoa vere obserrnd only when infection complicated the process. v"t,;r -Tuvxre cf approximately a year, a small amount of cellular reaction **" ' ,!n 7r=du-:oc! abeut many respirator;'- bronchioles. As more dust was inhaled, *' 5 <ccu::ulate in the same location and later stages of the disease I '.or.nisiad of extensions of the original lesions. New areas were not involved. erarcntly, the inhaled .fibers Trare caught in the pocket-like alveoli that ire r*i*cn off fron the lateral walla of the respiratory bronchioles. There they ere p.wgocytizcd and many of them were carried into the Trail by migratory cells. "or.-nu'icar leucocytes attracted to the area caused an appreciable thickening of hn mr.c.iial ..-all. After lo months a delicate fibrosis made its appearance. fha -recess evolved so gradually that mitotic division of fibroblasts could nr'lv he discovered; nevertheless, the number of fine intercellular collagenous i_--s vfibrosis) steadily increased. As this fibrosis contracted, it partially :ir.:.*: -.he :ti'*eoli. and with thi3 atelectasis the lining epithelium assumed its rue cuboidal form. The result was the adenoma-like appearance that Hillis eocr.ced in guinea wigs inhaling silicon carbide. The longer exposures resulted \ - : r-.orej thickening of the walls of the air spaces, largely due to an in:r:.ue ir, the amount of fibrosis. The fibrous tissue always remained cellular -':*r? nar.ee the nyalinir.ation characteristic of silicosis. nj-'.r/.i. The reaction produced in exposed guinea pigs did not pro gress significantly during a subsequent period of 37 -r.'.hc men the anir-iis lived in a normal atmosphere. Between 0 and 11 months '***''' '2cr.3surc cense 1, the cellular reaction had been completely replaced by h---. . trends ;f fifcrr.'s tissue. Observed still longer, the 3car tissue decreased -- :rt but ir. the lest ruiiiral sacrificed, 37 months after discontinuing dust -r- rlbro:is was still visib3.s. - -.-.f.-cT.ijn i.-oincidont with flust Inhalation. Of the group of iiO guinea pigs infected with attan- (Hi strain} 31 died or were sacrificed before two years ..r. ^rw.-rc P.nd were reported in the paper by Gardner and Cummings mentioned --7.C - .itcve. Seventeen of these died from inf jrcurrent pneumonia. Briefly, the re sults v/ers as follows: 10 revelled sons evidence of spread of the tuberculous crccsss; in 5 of these it was confined to the lungs and in the other U the ibdcrinal viscera also were involved. Usually a slight local extension of the tuberculous infection had occurred but subsequent healing had resulted in firoci3 cf both the pulmonary lesions and the secondary lesions in other organs. The fisaied puifionary lesions showed more fibrosis than is characteristic of -it.v.:r tuberculosis or ssbestccis alone. The 7 animals which were still alive after two years of dust exposure rere acri-icr.d at intervals during the following year. In h of then the primary foci : infection had healed with fibrosis and oven calcification end there was no 'vijrucs of progression. In the other the tuberculous foci showed evidence of raTir- previously spread locally: in h of them it had healed, by the time of iutorsy, vith excessive fibrosis; in the other animal them was a generalised enronic tuberculous pneumonia in or.o lobe and isolated primary tubercles, which w"r-> _-tj.il active but had not spread in the other lobes. Evidence oi extension of the infection was first soen after 7 months of dust .nha.ation; during the next 2C months more than half of the animals showed an ctvi-.oy aprerding tuberculosis and in 3 of them small cavities had developed, .-ru-.- the last 3 months no animals exhibited any evidence of active infection -~h in half of them the liealed fibrous scars of previous extensions were ob*ic".s. - L'rty r>er cent of the guinea pigs with spreading pulmonary tuberculosis tuberculosis of the sjjluen and liver. ^nsVct-ion STjpsrinposed Bron an Established Asbestosis. Twelve guinea pigs, after in- ---r rsnestca dust for nearly 26 months, were infected with tubercle bacilli and ` Pn rarC7"d normal air. Tho subpleural tubercles in the dusted animals were ::ore numerous than in non-cucted controls., out s. considerable number were u::d in the depths of the lung about foci of asbestosis. The reaction to infecor. shewed only alight local extension about the original sites in the lungs a irachsobrcnchial lynph nodes. The abdominal viscera were involved in only ,e arJjnal. Caseation `tvs found in tubercles 1-1/2 months old but by 5"1/2 . j j.t had completely disappeared, leaving only scar tissue. The latter 3till r.:ictcd in the last aninsl, which was killed 111 jnnths after infection. 11. Asbtsteals Bodies. Itodcrata numbers of csbestosis bodias occurred in the lungs of the guinea pigs, becoming more numerous \r.i -ors distinctly segmented in later months. 22. 7.ebb Its. Rabbits exposed to the asbestos dust for periods up to 19 months developed a lor-graae fereign-body type of reaction but -o .'Lbresis. Although their lungs contained particulate elements of the du3t, Tnrs v are not rrvsent. indicating that tha upper respiratory mechanism of the .tbit i: sdocuatc* to exclude fibrous foreign bodis3. Two rabbits, after inhaling -'or j and Id i-ionths, lived in normal air foi* more than two years. At autopsy - '*.t inimal 3horred any evidence of cellular reaction or fibrosis in the term-- .r.a. bronchioles nor were there ary asbestonis bodies* * * AH the whits rats had acquired an infection, resulting in the formation of pulncnary .Itscesses, before they came-;to autopsy, sc much heavy nucus obstruct 2d iheir bi*onchi that very few fibers .&/* entered their lungs. In a few o.' the rats, an occasional asbestosis -oc.- r ij liscovert~;- but there was no fibrosis. 12- .i"rT' ".r.d Irtor^yn-stinn of Inhalation lypsr/.nent ruth, King *c floats Dust. :/;-r: ..ir.:iir.r,3 in the irreori.rent '.^xth King*3 floats dust can be sunmar- :,hrr:c * readings. ~rr~.cr, of the inhaled .lest on norr.nl anirxals. The King *3 floats duct caused a cliarac- ii-i*.:-orch.ioiar fibrosis ir. guir.c.. ni;.,s but not in rabbits or rats. The Ld not progress after the dust -escresure ras discontinued and the guinea inrrr.d to noraal air .. ~ff .->f the inhaled dust on tuberculosis ir. quires rigs. In guinea pigs in- : .noionnaitcl tubercle bacilli 3nd than placed in the dust noon, the :? .-.vo vr.nabie than is usual i:: an experiment of thin type., A f^w mo no cacn of prc.yrccsicn; in most of then ihore ms evidence of tem- Tcc:ic:; oith subsequent healing; in one animal there ms continuous to .'isc.'.h. In contrast, '-dosn guinea pigs, .after being infected, are r::r-^iA of axcootoc dust, the infectious procsss continues to ~ xiy ^.r.'seo the death of the animals, Cn the other hand, ex- . f-et;.' iri.-uc :-o a hair.lasr duct like calcite or gypsum does not ,*f -.ho i:u`octicn. Guinea pig.-; infected uilth attenuated - - ' ..I'.rL.u' ',;*c to;'.ain-atic a of about tTro years1 exposure to asbestos :: _r. yrcToocsire disease. Tie only modification ox' the induction - lx:.:. ,.'y.v bacilli being retained ia the fibrous tamirufl ; - mi: y c;:c :ror os there in ?jdition to the usual foci fcsneath the . '.r.'.so :.y. i,ro unusmi. r.vtnrs of ~<hc response mid tho liigh fro:-. L-.t:-..current pr.r.uconia it is* felt that definite conclu- - -V.xnc:: ox' asbestos orn, t.hs ujvron of tuhcrculouc infection aro TJX J32ALA.TI0V HrPSRiySHT KITS. goiff-FI3EI? ASBESTOS DUST i* " ~ < Sincb hneardous dustc like quart* we moat effective in producing fibrosis .7hm the particles are 3 microns and loco in else, on inhalation experiment was rcirriod on to determine whether this condition is truo also for asbostos dust. :t -ua thought that by using a short-fibor asbestos dust consisting almost en- ircly f fihars and particles smaller than 3 microns an accelerated tissue rocncnso night bo initiated aud an advanced reaction obtained in a short time, "ha previous inhalation experiment with King8c floats asbestos, v;hich contained fliers from i ran. to 1 micron or loss in length as woll as & great dsal of par- tic-iiato natter and vhich produced a typioal peribronchiolar fibrosis in exposed j.-ir.ca nigs, served r.c a basis of coapcrison. 'S. The ducting material for thio experiment was forwarded from the ``sjivillo plant of the Johns-ijonvillo Corporation. It r;a3 the remains L'i'jQ'.'o collected in duct bins after c. carding operation end careened to pass -- tvs!. fries the material as received contained many long fibers, it was *r- r.J m a stnel ball mill to reduce proctioally all the particlos to 3 microns " '"",= siso. 7.}*en used alone in a standard dusting machine, this finely - '.j'coatos tended to pack in tho hooper end it became necessary to mix one t.-.o unground material with three volumec of tho ground to gonerato a * r.i. .ory duct cloud. The adcliticn cf tho small quantity of unground asbestos ** ruerfrjata heoauao it confunod tho interpretation cf resultn. Probably tho i -r `\ri=i<n-c of reaction that developed mis duo to tho long fibers in tho mixture `'UsJj the dnfci of this experiment do not prove the point. i -14- C7. The ccirxosition of the short-fiber asbestos as received is disclosed by the chemical and petrographic analyses given in Table U. Samples taken cefcr? and after grinding yielded about the same values on analysis, indicating w; there was r.o contamination fron the mall or loss of T7ater content. 23. Tho diiot concentration varied somewhat during.the experiment and light field counts for atmospheric samples collected inside the animal cages ; bopingcr apparatus ranged from 83 million to 182 million. The average of 'tTrr.c as 130 million for the first year of the experiment, 13li million for the . z*c^r.ri 1 rear andj|lli0 million for the third year. . Sisc-rrsn uency measurements of air-floated dust from inside the cages at a magnification of 1300X revealed a great preponderance of fine par- v'able- 3'}. Nearly 90 per cent of the particles seen were smaller than 3 -ic: S. - - ``cact:. ; n in Animals to Inhaled Short-Fiber Asbestos Duet. Four species of *.ninal3 - guinea pigs, white rats, cats and rabbits - were used in l cxt rrarer.t. The results of the cuss exposure, which are summarized in "*blo 3, Tail considered more in detail belonr. `-3. Eighty guinea pigs xero originally placed in the dust room . i. . but. 21 of them rare later eliminated from the e:rpcrinont and '111id ) p-~o of enlarged lymph nodes. Of the other 59 animals, U6 remained . i -* tve :r: tr. until the;*1 rare sacrificed or died fl'oia natural causes ana 13, pf'-.-T.i ir. iust fer 20 months, Tero transferred -.o a normal atmosphere. ) e of ctior. The t/pe of tissue reaction to the inhaled -15- short-liter asbestos was essentially the same as that already observed in the uxoriment -1th King's iloats asbestos. The rata of reaction also wa3 approadL-ately the same but the extent of involvement "with the short-fiber dust was ver:' nuch less and after 16 to 2a months of exposure only a very few small foci *f reaction, which generally required microscopic examination for detection, were rouucod in the guinea pigs. .atil exposures had continued for approximately.one year, thcro was little 'ijrr.cr.cy for cust-containing phagocytes to collect into clumps. By 16 months had begun to collect about the walla of a few of the respiratory hronxl-j;c3 rath a little proliferation or infiltration of mononuclear cells in these -olij. "here were also some multinudeated cells but the;/" were always of the :\roign-body type. At 20 to 2h months the cellular clumps were sometimes rM: * o rar-red and sometimes changes in the epithelium resulted in the adenoma-lil- u .'er.cnatoid" appearance previously described in Section 17. In most of the eeucr.t rerrbers of the series, the reaction remained cellular in type. In a ..jrever.^fibrous elements dominated the picture. In the latter case, the roll-s'er. ra3.j_ala ir. color and tenuous *.ath no heavy swollen hyalinization. As b? rats described tolcrx, the alveolar walls might be made up of a band of `^11--supporting a layer of epithelium, but with no containsd capillaries. In * "n -racheobrcncnial lymph nodes the reaction wa3 more pronounced in this expsrivr.*. '.cr. m tho previous one with Xing's floats asbestos, probably because of crortaticn of an excess of fine particles to the nodes in animals inhaling asbestos. Tho reaction was essentially an increase in reticulum, rather ibrosio, with preservation of the original cells between the thickened " -*3--rs. Diffuse chronic pleurisy without evidence of pulmonary infection a:.rnt in a f*r animals. . -16- I 33. Progression. In the 13-3A months f.`ol3.07dng the cessation of 20 months' exposure to oust, progression of disease was not definitely nstrated "but neither could it be absolutely disproved, owing to the variaXy of the response in different animals* At the end of the dust exposure of months two pigs were read as and one as 2+. Among the 13 removed from dust findings rere variable: in 2 tho reaction was : in h it was ; in 3 it was ` ; 3 it was U+; and in one animal it was 5+. It i3 quite possible that those -h the most marked changes bed already developed core reaction than the remainr by the tire exposure ceased. Since the more severe reactions occurred sporafill/ and bore no relationship to the length of time after cessation of expo rt the differences ware attributed to variation in individual susceptibility, his view received support Iren the chemical analyses (Table 7), which often reaieu comparable amounts of ash and silica in lungs with widely different amounts >f tissue change. For example, the anh and silica values were quite similar for *hr?e arimals in iv.-jt 20 months and then in normal air 13-3/U months, yet the tis sue rraction for : .5 animal ru3 )i+; for another, +: and for the third, only . l3bestosis Socles. The formation of asbestosis bodies was at first ex tremely limited. After *> months' exposure only a Tr~' taro short body could ba found, usually insido of cells. Around the finest -n*.racellular particlss there were yollcw deposits having the same color as the iaofo'.oria body. 'Exposure of one year had permitted sti accumulation of xaany longer *"rrt scut vnich the asfcestcsis-body coating devolopsd. Host of these were *4M .... / -- 3'frt enough to bo partially or entirely witiiin phagocytic cells. By the i V `or.th an-.i thereafter, thoy were cox.p:irativoly nuxsrous although still rare -n : ?**ri3cr. ?/iun .he firdirwfs in the King's floats axpericent. II* ;> iVhite 'Tats. Seventy-three white rat3 rare exposed to atmospheric 3hort~ fibor asbestos dust Tor periods up to 32 months* Sacri- :r:*.r.:n during the first 10 months vrero raado bimonthly and for the remainder of .-xpcrlaant at less frequent intervals. 3^ Hate ?.nu T'tc of ftanctlcn. The oust calls until G months were widely scattered and existed in foci only sporadiReaction mas limited to occasional slight thickenings of the septa about - .ii accumulations of dust cells. In a few rata at 10 months, there vras a sug?svL'r of 'iarl/ fibrosis hut the change was so 3light that it would probably be rlro'rsd wiohcuw the clutro jf dust colls to attract attention to the area. .3 animals wore exposed from 12 to 32 months. In each of then tha lungs .-.c-.-rt. :r.r.uta patches of well-defined fibrosis distributed like that of asbasto3is "r- --.thout as'oos basis bodies. The lesionn, visibl.e only at a magnification of :: meters or more, consisted of patches along alveolar ducts in which the walls a? or '.ce3 wars very thick, cue to .-.-voilen collagen framework. Connective r.d irelschonnki silver preparations revealed complete loss of capil' 'c:i locr_ly. Outside the coilagon was; a thin layer of epithoiial cells. *J ' not resemble tha !,adancnatoid" ciiangs characteristic of guinea pig as- Vo pleurisy ?xao present. Hoar the lesions the air spaces were filled .'.u;o'ra,;3 containing gray to yellow jjarticulate dust end a rare long naked fiber. Carufui search failed to reveal ever, a suggestion of an asbesto: for* i-rechioLror.chiaL rocles shcwjd compact focal collections of rno/*.*: f.ji.s i? vyv.tSis and, at 20 months, some diffusa thickening of the '-xci.;n. in f.rrr race there ras definite fibrosis along the margins of bho >'r' L": :rr..r'dy.-g into tha mediastinal arcolra* tissue. Compared -.rtth the response n -.:o duct3 Mka qrartz end chert the reaction to shcri-fiber asbestos wasi i`.VI -- esults c chemical analyses made on th3 vhite rats are given in Table 0 and erase v.ilue3 have bean tabulated in Table 9 for comparison 7ri.cn similar for rat3 inhaling other dusts. The concentration of atmospheric particles ch the animals rore exposed ira3 approximate]" the same for asbestos and ; for the gypsum-quarts mixture, it eras about trice as high and for chert ov.22 c.e high. It rill be noted that the percentages for asbestos are lower i\csa forSusrts or chert but are similar to these for the gypeumr-quartz s. in rrbfth atmospheric agglutination tended to reduce the amount of dust 1. It light be inferred that the total quantity of asbestos du3t inhaled -t or that it had oa*n e.Urinated from or dissolved within the lungs. In ersent state of our Icncorlcdge evaluation of these hypotheses is not possible. S 7 it"E* Twenty cats --ere usod in this inhalation erepsrimant frith the short-fiber asbestos* Eighteen wsre kept in the dust room until he -exposure period rragirr; from ono month to nearly h-i/2 years, and two, duac. r;: ..urn of M-i/2 months, v/ore removed to normal ;.dr. Cue ef these c.'.*i..\'icr.'i j months, :aid the other 2U months, later. '* ?r-'i "^3 of Reaction. The reaction *#as essentially that to an inert dust, evn after more than L years of expo- S2 tissue response in this species '.vas confined to microscopic foci of in the vail: of -groups of subplsurai alveoli, rather than in the peri- -iIju' .'.rc#*.s. In one animal the change vaa extensive enough to be visualised *3 increction of the section. i~u`:v v'han^oa. Only in the animal with the longest exposure did tho X-ra-/ reveal definitely abnormal shodor/s. After 29-3/U i-i- --- negative; after it5 aenths a faint mottling could bo detected Ai. a .tops-/, d aonth'5 aatcr, there -K13 only microscopic w csi.3 in the sunpleurai eons plus heavy lyrrahocytic infiltration about small xhioLos. i;0. Asbcstcsls doofes. On prolonged search a ibur yellcry atypical asbesto3is bodies, smooth and nithcut haustrations, vrere found -- a.ainals pjcoosed for nor3 t!ian a yvr. 1. .`tabblts. Eight rabbits vers exposad to duct for periods extending from one to more than firs ynars. The last animal *33 romored v.s duet room and left in normal air 6 months before being sacrificed. ` .1 "cate end Tyuo of Reaction. There was never enough fibrosis to be de tected grossly anti there vrac no chronic olsurisy. 'acressopic evidence of alveolar vail thickening T/as first .:.od after about 3 years of excpo3ure and raa seen in ell five animals ercaninaa' '.'cor. In one sniaial that died cf paralysis after nearly four ysars of ex- ..:o r-' -.'.inn rr-s extensive enough to be visible on gross .inspection of 'sauia *. Ike possibility cf pulmonary infection in this animal could not dcvr.xr, in another animal dying tsro years later tie focal fibrosis :: v`-t.arl(y as obvious or as advanced. Areas of involvement, vfcich 7sro ' "iaurflacd because of phorrccytic reaction v.ithin the air spaces, tended vjically to become more fibrous -vith the passage of tins out there vas *" " c>. 0 icreaci.rant upon the umian of air spaces anti the arc.iitscturc of the "ro3;rrad. * gsbsstnsia godies. Asbestos fcodiss rrere not detected in rabbits that A ---------------- i : ' died *e*a! r\Jly in tMhIAe* srcsrixsnt but vrero seen in all i ........"' i1t r.r-en cr1absed to the dust for mmore than throe years. -?C- V4. Summary and Interpretation Tho original purposo of the experiment was to evaluate tho chemical '.'.corj of the pathogenesis of asbostosis. It was folt that if the tissue reacivS to asbestos were chemical in origin an accelerated or aceontuatod response -ov.ld rosult from exposure to finely-divided asbestos, as is the cnee with quartz. -ix^orimont, in which the reaction **ns olo'^or and less extensive than with iu:-.'! floats, indicates that the roaction is not primarily chonical in nature. Of the four epecios exoo3ed is this experiment only the guinea pig i .:r /at reacted with characteristic poribrondhiolnr fibrosis. The cat reacted .t!: .'.vypioal sub-pleural fibrosis and in the rabbit tho fibrosis which occurred not be positively attributed to the duet because of a strong possibility ; ..i.nnuy infection. XLV \'ri*?rsg sxrenjCTT '.viTiT 100 r>?T> c.c::t 3all-hilled asbestos dust .`he '-.halation experiment with chort-fibcr asbestos dust a small quantity ' -r '- ra `-bsr.tos vms mixed with ground material in order to produce a suitable 'loud,. .':hen evidence of a dust reaction appeared in the guinea pigs during c irzori-cn-.j it was not clear whether this was n tissue response to tho small ' ir - f ibers in the ''.aground asbestos or was n delayed effect of the more *-'.rr.:. vine dust. Consequently, another inhalation experiment was started in ` arur.-rund .ntsrisal*. was "used. -t. . . ' * \ * -> ci-.i.- , \ny material was tho ground short-fiber asbestos used in tho =rc-ious inhalation experiment but no unground material was mixed with ? cifcxfc amount of atmospheric dust, tho dosign of the dusting ..`in.red to n open typo of hopper and IVcr.i: .iuat was added daily. -21- V.io tendency of the material to Term small sphorulea which prevented '-.a fibrous portion free floating out of the hopper, ths dispersal of -r not entirely satisfactory and after 7 months of operation, ths dustdo -ms reconverted to its original design. To prevent "pilling" or tho of r.-phcrulea of asbestos, steel wire brushes were attached to the in-.ce of the hopper and to the rotating paddle. T3iie arrangement gave err results and rras used for the remaining 1 months of ths experiment. .''-.s comrosriiior. of the rtrsr material (short-fiber asbestos) ar.d of atnesp.heric dust liberated from the bill-willed product in the dusting na7 Iran *r. Tcbia 1C. Thcae values ara based upon petrographic study and r-'rasticn analysis. The atmospheric sample ns collected vath an elec-rncir.ii.atcr after wire brushes had bean installed in the dusting .r:*urieu3 to this, ths chryeotile content of the air-suspended material .r-rdlr -z-.:s than the lo per cent value given in Table 10. In an inter i vs stated that the air-borne dust contained about $ per cant of :-r.e .Tire brushes were u3c;i and up to 3 per cent afterwards, but .V53 -..ere probably 1err. Quantitative estimates on ball- willed asbeeto3 "orenhat inaccurate because it is difficult to determine how much fibrous chr2-3oti3.e rn;.I hew much is non--fibrous serpentine. r'-~t cor.centrati or, for ths flrrt 7 monthn of the experiment *.ras -3 rillicn particles pr.r cubic foot of air. After the v/iro irtu-hllad, the dust ccratr; -rcre a little higher and the overall year rras IC.'i million. The averaga of counts for ths second ;v*n nnd ior she third yesr lip million. 7V.3 fliaa-lVoseaccv of the components of atmospheric du3t collected :."ida the aairal cages with tha electrostatic apparatus is reported 2.. Two san?le3 were taken, or.e before the wire brushes were installed tsr. It rrill be noted that aftor the wire brushes were in use a oportion of very fine particles and also of longer fibers was released Reaction in Anirrals to Inhaled ICO Per Cent 3aH-Mlllsd Asbestos Dust, turns. pigs, rats and mice were used in the inhalation 3xperini3nt with r cent ball-miHad asbestos dust. Tho results are susaariaed in luima rigs, Tho experiment was started with ICQ guinea pigs. As the dust exposure proceeded, there were 39 accidental deaths, no.vla ar on epiderdc. After 3 irontha of dusting tho 16 surviving veru -V*rforred to nozisal sir. -'at'3 d-.^''f'rT:e of ?.es.ctien. Far the first year of ocnoaure practically ------------------------the only reaction to the dust was the pre- cav-ur'.c ,phi<-jocytss and an occasional minute aabestosis body. At 16 :ths r.o "roe:-: response was visible on the tissue section but rnicroacopically '.icL-r foci of inxlru-anatory cello could bo seen. At 2u souths there was r.n.v-3 !;rrge enough to be seen with a hand lens although ucrcnccpic r. : ove-'ilau cellular accurralations about terminal bronchioles ami many -Otis o-rJiasj chiefly within cells. -l.ij iic:J.` analyses o.C the binge (Table 13) reveal that ir. spite of tha ss::o reaction considerable dust h?d boon retained in the lung. \n rrerraesfon. The lungs of animals exposed for the full dusting period (25 months) and then living in normal air for 2 months r;cal:d the changes descriocd above and also very slight peribronchiolar fibro2.. liter 3 months in normal air tho findings were similar but at 12 months 3 ; 2ni-al3 shdwed grossly-visible characteristic peribronchiolar fibrosis with . ..-.oraicid change. Lynah-Involvement. The tracheobronchial nodes were essentially negative until exposure had been continued -.--re than a year and a half. Animals sacrificed at 12 months and 16 months r.ljd a few minute collections of phagocytes containing particles but prac- . .il'r no fibers large enough to ba recognised as such. /Iftsr 20 months of :r c.-vre many monocytes filled with yellow granules were present. At 30 months v:ro r.sd been a slight increase in reticulum but no fibrosis. Wo further changes `.vrred in the nodes. Isbsstosis bodies were not seen in the nodes of any of .'5- Asbag'v.uis Podias. iinutc asbesicsis bodies ixere observed as early s3 3 months after exposure began, but t?vy did net be- :ur.:.r?U3 until 16 months had elapsed. Tho bodies *.voro short, and practically -1 .?orc intracellular, although at 20 months sons were long enough to project fro coll borders. It is important to nAa fiat in the later months of nrqsosure there was a dis- n-.cr. Increase in the number of long fibers j:p to 70 microns in length)in the lungs 'd ihos after exposure ceased characteristic long csbcoto.-ji3 bodies were seen. "bite and j.'ice. In this experiment ;;0 ato wore exposed fer perieda up to 20 concha and 2U mica Cor periods up to 12  s, Neither species developed even a suggestion of asbestosis and reaction, limited to Phagocytosis of inhaled particles by widely-scattered dust cells h remained free in air spaces or were transported to the tracheobronchial nodes. I.o asbestosis bodies were found in the rats but in the mice there a very few snail non-haustrated fora3 within phagocytes. . L-. 21 rouse lungs sectioned there were 3 instances of pulmonary adenoma (lli$) "Ikrr and Interpretation. ! 710 issue reactions observed in this experiment were much les3 extensive . 'LK . .Ivwer in development than in the proviou3 investigation with short-fiber t ::.o3. Since presumably there were fewer libera longer than 3 microns in the .-.nl used in this experiment, the results tend to confirm the interpretation ,,i .Section Id* of the short-fiber experiment that the reaction is not srilr chemical in nature. -'.s finding of long asbestosis bodies in animals inhaling the ball-milled rial 13 an example of the difficulty of completely eliminating long fibers from it:stc3 preparation. 1; regard to progression of reaction after removal from dust, which was cbed in this experiment but not in the others, the following interpretation is r;ri: Then the reaction is well-developed at the termination of exposure,the ruction of the fibrouo tissue would obscure any possible progression. In this riant, however, since only-the earliest stage of reaction was present at the ez* removal from dust, its subsequent progress vns apparent. It should be <i that the degree of progression was so slight that it can have little, if practical significance. Lvm I73TALATTO!' KXP^.IVUIT " TTH LT.?! G-KIBSP ASBESTOS DU3 ,'irr r.n5..mals inhaling short-fiber isbastos dust for more than a year had .z develop ci/'nifiscnt reaction, the hypothesis that asbestosis is pro- jy Lho mechanical irritation of Ion/; fibers was given addod support. :jv Xing's floats asbestos usod in the first inhalation expcrfcont had *;* lor/ content of fibrous chrysotile ind contained considerable serpentine ;vr isepuritiss, it was decided to conduct a new inhalation experiment with r form ef chrysotile which '.Touid be richer in long fibers. v The duo tin/; material employed in this investigation wns obtained from the Danville plant of the Johns-1`anvllie Corporation. Samples of nev-rioties of asbestos dust were fii*3t submitted to tho Saranac Laboratory crinatic-n and one kind, identified as Lot D, which was low in magnetite remits and had a fibrous content estimated to ba about 75 per cent, was *' cs .scat suitable. Steel wire brushes vroro fastened to the inside aur the he- -jr nnci tc the rotating paddle in order to open up the bundles erasa ar.s '.ibernto more fibara into the atmosphere. 3. The coirpoeition of the long-fiber asbestos need in this experiment is indicated by the chsmical and petrographic analyses given in Table 14. -:1`3 i:h;.t this notorial ".vas a much purer form of asbostco than the enort-vtt U33d in other expa.vir.Mits, This is borne out by comparing the approx- of the long-fiber one short-fibnr oust in Table 15. * duct concentration as revraloi by impingor samples token inside the animal cages tr3 much lower than tho concentration for the experiments r.ort-i'lhor or ball-milled cuet. ?'or tho first year of the experiment with ib.jr '-toe.vccs the aver ago of tho light field counts ;:** 32 million; for isw* /ear, ii3 million; fcr the third /oar, 29 million; and Tor the fourth .... million. Examination of the inpin.'sr samples with dark field illumin- iisclosed that many fine particles 2&.ss than one micron in size accompanied :2 .Lr.-':;zr rarticles and dark field counts 'rare, on the average, about 5 or 6 -j burger than the light field counts. The sits--frequency nf atmospheric sarnples of the long-fiber asbestos dust and of the ball-tr-illad dust is shewn in Table 16. Eoth samples ectrostatic precipitator It will be noted that there --... pore fibrous material in the long-fiber dust. Reaction in Aniicals to Inhaled Lory;-Fiber Asbestos Dust. Guinea pigs, catn, rats and mica "."ere employed in the inhalation experiment with :-fiber asbestos. Results of the experiment, summarised in Tablo 17, are in greater detail below. Pigs. The experiment t.tis started vrith ICO guinea pigs. After exposure had beer, carried on for a /ear, a severe epidemic p.3ir:cnia cro30 in the dust room and iibo.it one-third of the animals died or Milled. To replace them, 33 more guinea pigs were added to the surviving the cust rocn. .Rate and ?rrc of Hnr.cr.joc. lietcloip.cal ecamination revealed grossly visible lesions in tho lungs after C months procure tc du3t, consisting of cellular infiltration about the terminal At 12 aon;,hs, there v.-cre auonciratoid changes in the air spaces and . he J 6th me nth a definite fibrosis was present in these aroaa in half the -'i alj. His fibrous Ic3ion coula bo seen .^troscopically zz`20 months. Prom *fl on the reaction increased in o:ctcnt end in the e.T.-.*,nt of collagen and M* - -ont'a, it had funned out ir.to t!\a parenchyma. Ths lesions were . --.r-t'.v ,* localised ;nd the extensions from different bronchioles showed x,0 fuse, eve:, in aniraln exposed for the macdumuni period (3 years). .. v-v3 .u;tra-pulir/ nary reaction eomotsmc3 reacned the pleura, there was no ::r:nc of that cubrane. o emphysema was visible at any point. Some u. *; of the lacker bronchi with a chronic inflarr.uatory infiltration wa.8 re~ i i;t it properly was no more than would be produced by a similar exposure -..:st. for t) o first $ months the phagocytes consisted of Konocyts3 or Si.! i:icnt cells; later, giant coll formation was more prominent. After . ohs gian. colls were large, filled with yeilowish-trran pigment and v. : *:ucuolav.:d. An occasional animal showed an Admixture of polyr.orpho- MuhocyL.s and, in 3r<onea pigs exposed for a considerable period, ' Lies- The reaction was at firat entirely cellular but by 16 months fi..rsuv formation wa3 definite. However. it never attained a stage of L-v'/on mugger .re of silicosis. /.-irate rjxiiviiuai variation occurred among the exposed a\ Inals, both in < - of dorelcping lesions and in the stage of development attained at the ;\pcauro. u.'.yccs of the lung3 (Table 10) dicclosecl that although the tissue response ch greator in theso guinea pigs than in these exposed to either short-fiber l-iiilr-d asbestos, the amount of Mineral .'oatter in'the lung ash ran leas. fregmssion. In guinea nigs ercnor.od to the cu3t for 20 months and th*n removed to normal air, there was a narhsd tendency Cor 'r inflaxsatoi'T' reaction to clour. This effect, accompanied by contraction fibrous tissue, resulted in a diminishing also of the bcel lesions. I'ono :-/:o animals, Skilled at various periods up to 14 months after oxpocuro, ..-.I. - Ualons as largo as those* in tho group sacrificed at the end of the a..'scocure ooriodjor those in cnimals -which remained in tho dust room r rors thin 20 months. Fourteen months after duct exposure ceesea, the foci ;cvr o' tha six remaining guinea pigs were sc arcoll that Utey were visible ;iv a hand Ions, .`fiction in the group exposed for 2? months and then transferred to a normal tr.c-There was quite similar to the response in the 20-month exposure animals r.i above. However, small foci were always visible en gross inspection of :r:aunr of all guinea pigs of the 27'-month aerioa but in no instance was there ivicc.ico cf extension of the reaction. o7, Lvraoh Mode Involvement. Reaction in tho tracheobronchial lymph nodes trae first visible at tha third month of ex- r.'.'ur-*. At the 8th month patches of cellular connective tiosuo began to appear rredulla c.rvi by the 14t:i centh most cf the node had been replaced by -ilviar conr.uct.rs tissue, Ihic picture, which rssnblcd that in early silicosis, rJfsiatod to ths end of the experiment, 'Some vnimals, sa a variant, chovxnci heavy ".nets of diffuse monocytoa tuid largo active giant culls bit there was nevor eny -Jcroaic or hyaiiro formation. The spir.dle-ahanaa narr cells were yellowish in = :lcr from fine pi^errs granules that stained for iron, Ka libers or aabostosis "zr.f i were a<*unc <0. /abu3to3io lodlsa. Although uebestosis bodies warn seen in tho lung as early aa one month after exposure began, they were `ire anti hard to find, At 0 months more were visible, chiefly coilad inaido giant :ad at 3 months many bodice rere free in connective tir.suc, They boocma *lrly abundant rva^ exposure continued r.ithc.ut*Vi in seme Is -or mimals tho asbsatoais Asdics were only moderately numerous. rZ. Rata end Type of Roactlcn. Ail four animals sacrificed at 25 months showed a './oil-marked peribronchiolar fibrosis. :.vi IC-raonth animal, reaction was just boginning. Asbestosis bodies were .roctically absent at both 19 and 25 months although two small smooth bodies were 'cur.d in the 19-raonth animal after a long search. Thus, these animals exhibited 2 without asbestosis bodies. *A, Mice. Out of 20 white mice used in this experiment, 11 lived a year or more in dust end died or were killed without shewing an appre- lUcia degree of pulmonary infection. 75. Rata and Typo of Reaction. Reaction was limited to phagocytosis by mononuclear cells. Usually these were vdde- lv mattered through the air spacosj a limited number wore grouped about the ter"ir.al bronchioles producing some thickening of their wells. There was no sugyjxttcn of fibrosis. luxerous asbestosis bodies were observed in animals killed late in the experi'pr.c. Thus, these, animals exhibited asbestocis bodias without fibrosis. "8. Summary and Interpretation. The purpose of this experiment was to evaluate the importance of long iters in she tissue response to inhalod asbestos. Tho roaults indicate strongly *-- fibers are chiefly responsible fer the resection. Thus, in guinea pigs 'J&cticn daveloped oarlicr end became more extensive than in previous experiments *a ?pito of a smaller concentration of atmospheric dust and a lower mineral oonient in the lungs. Furthermore, a typical peribronchiolar fibrosis was produced :r* Ca*s although in a previous experiment with short-fiber duct it did not develop k* this speoios. Tho cause of the cellular fibrocia in the lymph nodos ox' the guinea pigs is not clear. It did not occur in ether inhalation experiments with acbectos. -31- LXXVII INJECTION EXPERIMENTS In order to doteraine to what extent tho various fibrous minerals possess :;-.3 capacity to produce tissue damage, numerous injoction experiments were per-* 'Vv.rju. In thess experiments guinea pips and rabbits were used and the mineral -ras injected by the intratrochcal, intraperitoneal and intravenous techFor the purpose of simplification the Findings in each serios of tests -*.vo teen condensed and report ad in tables, to which reference will b9 made Mxngrinontg Usintr Intratrachoal Technique. lince tho asbestos minerals do not cause a typical advanced fibrosis in *x:ra-pvi;nonary tissue, the intratracheal technique is tho preferred way of in.r.-ccirg fibrous dust into tiio experimental animal,, In this method tho dust '"t.vr.siyn i.s injected by naans of a speciol needle or catheter docp into the fr-w : which it flows into the lungs. ''9. Ccmariaon of Fibrous and Non-Ficrous Dusts. To demonstrete that tho ability of asbestos to ,~yz::e fibrosis resides in its fibrous character, tho series of ir.joction expertrcoortod in Table 19 were performed. Tho tests were made jrith unheatod - i'-*jr chrysotilo and with chryeotile that had boen ignitad to destroy its --- structure or ball-milled to reduo the length of fib*r to 3 xicrons and *9ss. *.t the came time control tests ware made with serpentina, which haa the '''icil composition as chrysotils but is non-fibrou3. A review of the . ........ ro'-iiis that only tho unheated long-fibuh chryeotile produced fibrosis. 1 ousjerted to ignition or chorton^d by ball-milling had lost their capacity 0 --jso aorious 'tissuo demege. Ignition produced important changes in tho * a sotila fibers, anons; them being lose of vrafcer, an alteration from a flexible brittle structure and possibly other changes. 0. CcmcarisoR of Various Long-Fiber Ousts. Some very interesting findings are disclosed by the results of C70c>r!<sent3 included in Table 2C First, all the long-fiber asbestos minerals od, with tho sxc3?ticn cf ar.thochyllite, Produced a typical fibrosis. It is entirely clear why anthophyllitc behaved differently from the other asbestos rr.la. Unfortunately, 5 of 0 an intis died of pneumonia within the first two i s of the experiment and the remaining cnir.als were sacrificed at 1, 8 and 12 r.::; thus observations were not made at tho optimum periods of 2 and 4 months, 'scond, -1th the mineral brucito, which is not a silicate but is a fibrous s f magnesium hydroxide, ix characteristic fibrosis like that of the nsbe3to3 ral.; was obtained. Since tho brucite usod contained only 0.90 per cent .-slice -i: impurity), it is obvious that a siliceous component is not an essential ' .. vhe development of asbcctosis. :*o fibrosis resulted from the injection of glass v;ocl fibers, even i-^ss *vccl resembles aobostos in son3 ways, Shore are fundamental differ3. '-.owsvcA glass %vcoi fiber 3 microns in disaster i3 a solid rod and, in ` lengths, is ft.irly rigid, while an a.foostos filor of the camo diaaetor is a - oxtremely firio rilaments whicn impart to the fiber a high degree of flex- It -.-culd -eem that this structure i'nd tho i.ssocial'ad flexibility are ' s.*t factors governing the capacity of r. minoral to produce porib.-oncr.iolar -33* S.l. CeTTurriccn of Lan;~-vfbo- enl Shor:-eioer Cur1:.?, ''-ith quarts duat it has been demonstrated thut aa:-.llsr the particles. tho more intense is the tissue l-osc-ion, and that there is little roaction to particles larger than 3 microns in diameter. In the case ;T .vsboatos, hevrever, th9 i*cver?o is> true and apparently only Ion* fiber.? have r:y .specific effect. This in confirmed by tho date, of Table 21, in v.-hich series r:' lasts r/ith fibrous minsrslc is reported, i'-hors the injected duat consisted of risers 20 to tO miersns Ian?', nil the rrincri-la tosted (onceot anthoohyllite, as -.etoc in Section 20) prcuu-.eu i fibrosis; v/hen the cursorial wao prepared! by first jrir.diiiE tho fib reus duct vntil the ler.qtb of fibers ~t&a reduced to 20 icicrons \:.a ls.is (or, in so.vo cases, 3 microns end loss), rone of the injected ninoral ebar.a cauncid fibrosis. "2. T-'.xnerir.guta Usir.f. ~nere,venous Toohnlovo. '"-*o export-rent;:, described in Tabic 22, in r.hich the ir.trarer.cu3 method of njiclioa 'to.3 employed, show that the asbortoo irdnernlo sro far different from V:?.rts in thoir action on tissue. It he.3 been repeatedly demonstrated that .uv.-r.-.-enoui injection of quarts particles Z wicrons sr.d loos in diojoo'icr -.-ill 'VJa a typic.-.l tisai.o reaction ./ith the dovttlor..T.ont nf hyallnicod fibrotio 1osier.a -i extra-;/ii:s;oiar3* cites, cuon the liver arid spleen. Ashes t-.j minor-la.*ho9ve--cr. inir.vre-icu! injection lenei-aliy produce only an inert typo of reaction, ns is dvrsaXed by tie results ,-ivon in the tabla, Ths reason for the early .'enthn in ^ ^tp-sriaent with chr/sotils particle;; 1.; not clsar : It my have beor esuasd '/ silicic v.cld liberated by the fInolv-^rornd minimi.. ' -iror-lr.or n C ~r'~. us I -Mob r.y.ta o-.' Mr jvciolcn -* V-wrSP *: tv. "ns lxv:r?iUorit:n::d fcciviiq u: : m -r. '.Mi viMi ''7 '>...v f.-? Lr.tf-.fii> or j p/'orlv.ccb r. "ibrcrt: vetipcspc 0:1i' 7.?.: LtliMr.: .* niorcss *-l '.ess in tsiss ciusset cr.l;. inert type o;* rertomce. "hexes 5xc*i rirr.snts i .uinaz-s e.l.-jo that ihJ fibrous ';/ `/is irriiatievi . /'MrS rr'iv' Albers ~?t i-.irr.rir.oed :.o 'oh* i'jxrr-, ;: I's.-r.rr'y accursed. Ijv.t -n or. ;.-*5 in vhe ; if Irc.-ic-unt a-: v:slia lx? : v ii * a *: s. ? o i :: n /> i ' / :vrjjf.r o;' aciltimnu, SMiiorirsnt.; ?;sr3 sanciuctni to thrrv -.tors .li'irh cn Li te ox* tbs usboffciViviK orc-blcm, Action iu? .Ucuir-crs Ccr.oon.irbt, J nor Aural in.`oc\l or. ni* a aveprnaicn of Icny,-Tiber cnrysotlls to uni eh 1.1 r.ix.l ;;Iv: r. ..m hyoro^iMe h.-.u b?;on -\c.doc rw.r.}.cd thn'c tho utMA. tier. of tho a. v:2ir.'jri cr.-p'i ./i Oi.i not oror-urt `bv '.Cfrsv.t:- irr'i'fcrxvic;: urodvscc by ch?/sotil*'. *.* -nj Mi.:;;., :!vs acute .Inr'.'.rjirav.ory 2-.fSoonco t.o oho l*. .jcc tot Aj.b *;>.: j aii^rai " f oc;ci:lo:-r?.t.:rl Oro irrmth .*r*l:er t:S: M?jootf.'m iV- 'horo h.:;;:oho.Loi tb..< : ** c/.ioli'-.ls 'roe 'c-JOf-iTtic;' .''ibretro',. ''ourW.c:-. * Ashe excels V*U*. \0 C'OC *1 T.;-iC ^OAw;:;:; :> .I:-3 otihrsVrf'y ooS'.u>: xc : o: ri-,:.\i Me:.; : c.jcxo olorr.or.t.'! :-.vJ not. :... I Vi.*s ftvi'ipaim, A; wr ; h j ri.\s ,4A ,**.4. \. .. * mtm > oliovlr.fc .j'u'y.-a'caneoi::. Ln.joctlcr. of ti/o ;a ot r.hryc<)i:ii^ }. i';rs cin ci' .Vtiror. i`i jc - bioc:itfcir.t:*.nA A ci** o: ; .uvi'! *Sr* I ai bc-tjt.i fif basi-is rrrm lovably r.x.s:?i cm-: r:; albas ..r / v-:lon. i'.t3.7.o. to ashecnoei.:; ir. in f*'.iinv?s. pif 3 una'-'.io1'. oi* .ii'.c n:**3 wCTit:.ii'jir.' " lbroue rhryset i le \rp.ti unceoccssi'v.J.. :<no :y&i, ulant-id . .?ously in the ibcloniin-l -taII ti jappc'smd; ths other fcr.'O hagn, pi.aijtd in . iLonaal cavity, produced i llhtJ o fcroi:;n body rear tier. bi.r no arhsi tosi3 '. -5 in s year. . vtrvv'jrat.neal i:ijocticn ir.tc :rv\.r.er. pi o:` .vibernocic bed i.-is r?co' 3rv'.i fren . am eg tic rue faiijc" tr produce ti:s tyyicc.i tissv.o re-re tiro' ':r. tubes to:. -r, Tbs ir. jactcd nc.tcria.1 v/.\s 3bwC.ir.0d by (i.T/erlh.ngn-'ith eodiun hypochlorite ...u.i-rn iur.g ciuaua removed r.t auto9ay frar. on nab or. non ;:crkcr. The r.:;bin:to3is ` .? could t3 asea. ir. the yarnor. pigt; i'::r :'. 3cast . yet.? ai'ier injec icr., i ?::?3riTLeri ohev.-n that the ante-atonic`cedy has a ivither .roci::bant cootin.-r ia net bestrcycd by r.cdcrsto hypochiorit0 tree crwnt cad rrny 02 71a .'TUiined :zvo for a yes.? o? Icngur. T IT s 0 a V 0 ? :z::w:z 5. .*? : v .*. r. t iI3 ' i'.vo hypo!'.- :'cs have boon pjeoos-v: to onpluia the Mt.-uo :u*rit"cicn :rd roac- ".cr c.vjcaci bj e.abector, fibs-rc : ihu c^urciical errt tlis noahenicai. dr. the. hinnies! ''ocry. ''hie.`i is nr.sjd upon osporiontu with qv.v.rtx, it iu oxctotc.'. that *h- a*.?- os Tiir.erajc 11ur,;1 vc. ii- oh'.; body .nuiac oavi that in t.'jic v'ceeas oh :ir bsse-c :-r v ?.y to Icr.vo .vllicr In r. born. euyablu 0.' irritat: air tiur/duAccord- :.n- *0 th\* hi oo:;h3-,i, .'.cos.-itosin h* ruroiy an :.TKi.`.r tc1 ccei .*37.rcl r'-c'oj :.;ako t:u chew!col c-nory nr.v. on ".hi0; (1) fntratruohoai ii-ij'.j'toni o.v orr.'..'.to I iVr.r?, vhioh rv.o ; c'.Aun. 0enter.t oi only 0.*.0 j;ar .sent, enusad u tj,~;isai :ih.*oci3 l.iko ih '.t .;r-:c;:c3* hy iho .isls.stos :?:\i*;ro3s; (2J u:r b.cia r. Increase .a petenry ?.s :>.; ;*: it;?. oino boo cat? a lese, '.jut '.chearoc .'lb >??, chertor th:n cent ;;; id . her; tit 1 / U:'viy inn.-)C"'av; (c; r-l;rr-i:vi'-i #  z.-'.r-Cs neutralizes the irritating affect of quartz but not of asbestos; . ontine hr,3 the sane chemical composition as lor.g~f5.bar chry3otiIe but . cot produce the cane l:ind of tissue reaction; (5) there is a wide ranee . chemical composition of the minerals v/hich do cause ashestesis (see .ititf ii)8 In view of this evidence it seems moro likely that a3bestosis :.s by an vnusual mechanical irritation from Iocs asbestos floors; this t,v:ion being related to the peculiar filament ed structure of tha fiber said .... -.socia.tea flexibility, tdtich are possessed by no other foreign body. For ignition of chryaotile fibers changed thair structure and made thorn r.*. *vhile the sains fibers, before being hcatoc, produced fibrosis (seo Table Further support for tho theory of mechanical irritation is that asbootosis icurs in en organ of high rco'oilit;^ - the lung - and that a fibrous reaction can -reduced by injection of asbestos fibers into the peritoneum, whore there is l<5o a degree of mobility, but not in other extra-pulmonary organa. ujj;nz I cor plica tides The experimental investigation "with asbestos minerals '.van concerned primarily "ith tho effect of tho dust cn normal tic bug but acme attention rus giver, to rihor phases, auch 63 susceptibility to infection r.nd cccurrsr.ce of iral.igr.ancy. *0. Infection. The only experiment in v.hich the effect of inhaled asbactos dust cn a pul- nonary infeoticn v/as studied v;e.n tho firrh inhalation experiment, carried on with 'King's floats" dust. It is. perhaps, unfortunate that infccnicn studios r.-ere .lot made in tho other inhalation experiments also. -- i - SO, SraceT>tiblH*y to Tuberculous Infection. The development of a tuber culous process initiated at .-.a beginning of exposure to asbestos dust, and also of an infection superimposed on an established osbostosis, ra3 described in Sections 1? and 20 of this ro-;rt- It will be noted that asbestos, when classified according to the effect a dust on tuberculous infection, would be placed below an active dust like 'rjrr.z but above inert dusts, such as cnlcibe and gypsum. In animals infected :.:h attenuated tubercle jbacilli, quartz will cause the infectious process to o~33S until tfiQ| animal <iic3 of tubcrc-.ilosis. Inert aust3 will have no effect * tiio infection and the lesions will usually heal and the disease disappear. *.cr;3t05 dust is in 3 different category. "-hen tho fibrous dust wa3 being in..::d during the evolution of the infection, x there was a spreading of the tuberci.o-.is process for a time but usually ths stimulus for continued proliferation of e a-barclo bacilli 'rrzs not sustained, the progression was arrested and healing '-Hawed, In guinea pigs infected with attenuated tuborele bacilli follooring the ' relation of nearly tnres years of esepesur-e to asbestos dust, progressive disease nut ucvolcp. Tho only modification of the infection urns ono of localisation, * few bacilli baing retained in the fibrous terminal bronchioles and forming -ccorcles thero in addition to the visual foci beneath the pleura. Such tubercles '.oaied in a few months and there was nothing to suggest any influence on the our.oe of tho cisoaso. 11. Susceptibility to ?k:n-r-.orculor.:: refection. There was no pointed a~cperirant concerning tho -'fact cf inhaled asbestos dust or. non-tuberculous infection. Intercurrent pneu*3nia among aniaals imposed to asbestos dust -.as rather common, the frequency in pigs expor.r.C in the four inhalf.tio:; experiments tungim* from lo to 3? y>sr a This incidental ovidence suggests the possibility of an effect of .fsaston dust on non-tuberculouo infection, Nevertheless, since such epidemics r.j not uncommon in inhalation experiments v/ith other dust3 and oven in the ;ciony of normal anima'13, it is felt that the inhalation of aabeatod dust does -.rt exert a significant affect on the susceptibility to non-tuberculous . .c.'.ronary infection. r ! fc. . y i * * s. -29 XCII 3 U li ii A i r owing to the vast amount of data included in this report it soeir.s most r.venicnt to stato as precisely aa possible tha various points which emerged cm the investigations and, when necessary, follow each with a brief resume the evidence. 'trious foms of asbestos fibers produce a peribronchiolar fibrosis of the lungs of guinea pigs, rats, cats and rabbits but not of alee and dogs. 2oth inhalation and injection experiments provide ampin support for this statement. Figures 5 and 6 shew the reaction to two dif ferent kinds of asbestos mineral in the guinea pig lung. Similar but less extensive fibrosis occurred also in rats, cats end rabbits (Table 1), itice and dogs failed to respond. This variation in re sponse of difforent species to identical dust exposures is still to be accounted for. The mode sf action of the anba3tos fiber is primarily mechanical rather than chemical .n nature. The evidence for this is given in Section LaXXVII. Figures 1, 2, 3, 4 and 7 illustrate ths important points. The fibrous fila mented structure of aabeston plays aa essential part in the irri tating action, sines tha solid fibers of glass wool do not produce fibrosis (soe Figure 8). Long p.sbojtc3 fibers are essential in tho production of peribronchial fibrosis short fibers are incapable of producing this reaction. Experimental -rvidance discloses that fibrosis develops follow ing tho injection of asbestos 1'ibsra between 20 and 50 mi crons in length, but not following injection. o" particles less than 20 microns,(Tables 21 and 23}. This shows that the cactcity to pro duce fibrosis' develops somewhere between 20 anc 50 microns. ;u*sLos i:sve not boon carrise juc to determine the upper I1 i >.*ri:.v?n fcal p.sbertotic fibrouiii ucs produced by the inhalation of sss.oric auouenaioii containing -v.i average of ISb million particles ;ia fact of air of vhic'a onilyy 'O.-l car cent consisted of fibers longer d micron% : t.:*.: inhalation expert went v/ith 110 ysr cent ball-cillad sutos cust containing O.S par ecu*.; of fibers longer then 10 .-r.s (Section t-5 to 57 inclusive) c typical fibrosis was ob;r?d (r.ee Table 12). The wvidsnea presented shows at least that . or sir ia capable of producing experimental csbcstosia, The lever limit of concentration of long fibers necceaar:/ to -reace asbentocis cannon bo established on the evidence available. duration of cxuocur* required to develop the pulmonary reaction to in.:i asbestos dust is inversely proportional to the concentraticn of Ion;; cri ii: the Ltmosphore_. vie. as the concentration is increased, the icvion develops in shortor time. hvidar.oe for tills stascr.ont is presorted in the inhalation `-ttsrinort vritli .lcng-fiber Asbertor lust (Sections 53 to 76 inclusive). Study of the tlse-frconir.cy of the 1eng*-fiber dust :iscloscs that it contained C.7 per cent cf fibers greater than Z nicrcra in length (Table 15). Tho l/ngs of animals exposed to this duct roves led that ths \ju Imcnary rouetion developed in copras-* irately one-half the exposuro tine required for its devolopaent in iinimals rub.jeotec to the ball-millsci duct, hich contained only 0,6 ;.ar cent of long fibers. i '**rxxsrj*&-r,rtyrZ5G V. -'hod erpcricental ssbestosi cer.sas :o progress on discontinuing . ;,, to the du3t. idunce chews in fact that on difcor.tinuing exposure there was oracisble clearing of the mature pulmonary lesions due to fiction of the fibroti^leoction. in contrast, an immature ; .-3 response consistin5; primarily of celi3 with little or no l v'-.is ccntinuod to prepress. It :.3 assumed that following at- .i^ia'c of fibrctic maturity, the same process of contraction -.11 onsun (Section 57). . .ormaxion jt, acbestosis bodies represents a coating of the fibers by .:; ?nd tissue elements wnioh results in loss of utility of the fibor .sauce fibrosis. .-.rcratracheal injection of asbestosis bodies failed to produce typical asbestotic iissva reaction in experimental animals ..cticn 86). The cassation of progressive reaction to inhaled ::cstos dust soon after exposuro torminates r.ay be due to th9 j.rration of asbestosis bodies. u.. inum hydroxide failed to neutralise the fibrosing action of the long .-.zr asbestos (Section 65). .'f.holEiticn of asbestos dust did not a?.tar significantl;/ tho final outcome >f ?xperir.ental tuberculosis in two series of guinea pigs exposed. This interpretation is in Qi3tinct contrast to the stimulating :f:ect of inhaled quarts upen a tuberculous process in tho lung. It trust remain tentative, however, since it is based upon evidence limited to two Goriea of guinea pigs exposed to only one kind of asbestos, nar.sly "King:s floats" (Section 15-20, 90). Reference to Table 3 shows that when infection v*as coinoident with onset of duet exposure, thoro was temporary progression 01 tho infectious process v.ith subsequent healing; when infee tic- initiated after 26-o/4 i".or.ths of cust exposure the course of tuberculosis was not (Continued on ?ngci r2a) - ly altered. This latter rinding is in narked contrast with .uai experience involving quarts dusts or mixed dusts containing : ?.<*orein the adverse influence of quartz upon.a tuberculous .: .icn i3 noat strikingly ranifested where infection is initiated i period of dust exposure, vis. 3uparinposod upon a background of :ichsd silicosis. A3 indicated above, application of this more ; cive test to asbestos dust failed to demonstrate that suoh dust -.1 adverse influence .upon a tuberculous infection. Thus, there .rens: evidence in support of the interpretation. However, it is .ran(led that further investigation bo undertaken to establish . 'oir.t. .1 Aobontori.1. a Bodioa il-** 0 0 gtru > )>WtfcTtflW*o'1 \ w .VTAL7SSS OF SITE'S. FLOATS A332ST0S 1 w .>y^vyw7/* #.37 C<j v?w* 'w W**4' 1.M0%rt rI'#**1 **w*W*}*wW ?trertrv>isio* Oliryaotilo S error* ino Vc'^JTititC Onrbwastes* 2rlo Giaora 1*V?5 40 am is 12 4 ICO "Values jiV'sn are cased oa thtf stmoor c* partis lee, ensrnb chryacriilOj zrcr.il'ir viva 10 laricrr-aft; -cr ehryrtolilj fJ'jero the nanizasn rlin.eaf.ior. *.nas SCO rzloreac* ! 5K 'i.'RbX3 ~j SaSiftKT 0? ,>* ** .k .. , ** iVItli ,s3:i:gs nsATS" .\s3sstos bus? -.Z Ox -.rirrest. ..:c*3ure ccn : through- . ." ; ' 'K'^'ocr of AaivfiaJ.u c4 ^ :;-igo 9 rabbiv.3 13 rats v.rvariuro cq by a i;rc - rosidcnco -.cl air.- .iuiouu in- at start :.j:; eiopoouro. <5 li-. P`j-^3 25 pigs 1 rabbit 1 rabbit <:0 %* pigs to iu-- >.on; ::o duvet iuro srouicro in- '.or.* after /\ non whs of t ixpccuro,.. a veaiuunce 5.n /Air, :rola to inv.ion; ::o east emirs * r,, Z> ?'A23 12 g. gigs 12 g, pigs . TJnriniua Sunt .Sxoesurn . Zb --oritha 19 6 3 ifi.cni.ho 3 'v/r~ /*> 1G-2/3 35 months 0 month Ac >/M*1 0 month liazimss sSvjnrrsal iftar fust . Zjcne3i:ro Recultc 0 months 0 0 'f-rpical peribron chiolar fibrcais. Foreign. body bronchitic. bittlo or no reaction. ` 55 months iTonprogrocsi^o fi~ bronio. 37 fionerogr-onaira fi~ brooic. SO ) iiboorption of forM-l/o } oi@a body reaction. Q months Temporary orogrosnion of infection followed by healing with fibreaia. Healing by ronolution (ono ozcootioa). 14 13-1/2^ I'o appreciable increase in aunoeptibiiicy to `oubcrcuiouo infection,, _ Healing r.-ith fibrosis-. 1 'i Healing by resolution* t I'jv <virul..a ,`t ;> /. f*. 1 infection. v.ir. ox tvbercio baai?.lua . ?.'lbl3 k .^/.YiSLS or SSORT-FID'-?. ASSSSTOS (C2ERT501ZL2) (c,n rccaivod) Chcwj 0i02 r<iou^ -iJ-2^3 ?rSJ CaO -50 ::aoO ::.z6 I?0 } -..nit:, on; i * ^ m C%J 7( z +I 7**/"i*t D..02 I.'IO 0. 14 0-03 0.35 3r>,,ss 0.14 0. -o o.oa m, .* / n .100. Jul Poti'n graphic Tho pafcorirJL ccmtcinc a jrodcninrcico of fibrous chryootilo ond oloty (non-fibrous) . serpentina, Aoccsoory ainoralo aro dolcaito, chrccaita, magao-* tito and a little t-rnraolito nnd aotir.olitc. Eon-unifom niso distribution* Fibrous bursdios vxry frcra about 45 Picrnns to I nicrono -ioro fiberc thro. :ia Zin^'c floats* . 4, X 2 -J icror.d 1-' -O . .'-liilj. ...<J f! --- "VwT.', a r -o ! *1. C r-*-.** 4 .. vJi.-*>\ .-U>m .^AViJ ;:c:" csr.'i* -VU* ,. .1*. Oi-O ;;r crn" '* "* A I/nsvh vail 7>r;r ccfl't 7D.n . S. s 'oo.: ..o 1 I. ./.7. I SCOKT-FISuR Wll'5?T3S (CJ.p'fSWIUj t* *> --C .Oc* oU 1o* 4Oi-:l. UC.nfk2*c vX*i4: ^-c4 tot* J*UD TO 0U is UC >wori<.,4w.v4o^t. 0*>ce----rcrc- c r u ~& am* * ** o ra-. zsi.. 4uOurUu --m4c5roL'* Cu5 *rjt wO *j-}frf* ry; hWu w6*&to- fOw uqi'Jck*. .i a!* .*o> f<14. -Ct*o U& EGtf n2 2u f^3l ci> I ! I ASALVS3E C? 1UITGS OP T.-HXS'S &1T5 THAT ilAD 2IKAL2) Eumtiai of TJxnocuro 0 'ionthe 2 rsontnc 4 Trcr.tlis d renthr 3 I rsortholTO nontha per cone (jcr cent per cent per cent pur cant oar cent .~:3nn t of Rah s *V**/ U r V o.3 O* * 3 3.3 4,9 . '?or cent of dries* Inns) 4.3 9e-.o 3,6 2.4 3.6 4.S 2.9 90 Cr0t/ 3.4 3.7 3,5 5,3 3.3 *?# 4.4 4.7 3*3 3a 7 3eC 3*4 ' ot.il W4Uft0 (car cent of dried lung) 0-00 0.00 0,00 o,co OrOO 0 e 00 0<CQ o.cs On 13 0.03 0cC>5 0,00 0.21 0.07 0.07 0.05 0.04 0.0s 0.13 On 15 0,17 0,15 0,13 0,15 0.15 0.13 . ot.il SiO? { aer cent of ash) 0*0 Wn * A1 ri.v 2.1 *> ? 3,0 0*0 0..0 3,6 w-# #* ** # 9 i/ 0? 1.5 1.1 5,-5 3.3 2.3 0,0 i.r 0.0 0,0 ;..o 4.2 \ 2.3 1 0,0 . "* sioiTjal centreis (no .'Just exposure) Table 10 100 ?23 C C0ICP0SITICIT OF T3/.LL-ZJIL1SD AS32ST0S DUCT r \ jocila -- :-otmo 7:CtltO ' ~nsv;o V.r.craln Short-fibar Asbestos U;grl in Dusting Machines par cent iM r 55 10 2 5 0 J.1 ICO Atmospheric Dust Colloctod with Precipitator parocju 15 60 10 2. 3 0 10 ICO 52- r-blo 11 SIZE-PR^flEIcy CP ATK2ST23RIC DUST COLLECTED TSZITjZ CAGES FOR zz::zs.'zcz ext2F.EiS3? TE3B 100 PER CS1I? 0;-.LL.-V,ILLED ASBESTOS DOST i :-ribvcica of* ( r.oinn, Olusipa ( Particles and clu'ioa . fiber? ( F ibors Cnr.pl o taken before r-iro brushes installed per oent 93.7 1.3 1C0.0 Sarnia taken after rri.ro brushes . installed par cent 93,6 1.4 100.0 iid'froaironov of 'art! cljo [< 5 nicron3 ( 3-10 (> 10 86,1 11.9 2.0 JTCOT 95,0 5.0 0.0 To?5To ;:-Trcpv:cmoy cl . ibarc ' c o microns ^ 0-10 ( ? 10 22 44 24 rco 0 58 4!I J.00 \ AHUYSCt! OF LUSOS OF CUIUEA PI03 I t I I I i 1 /, Cl 'I'r.uJLf: :K X.r.Litt 0? LSiff-nCSX Af.SDSTOS DUS? (na ro.*>ivr>fi) Chemical ao* rcgjj. l-s-cq;- *** ;U0t O.V'i VrO 0,0? C.-.Q 4,0 'G..1C C ,03 :>6 0..CS CC<> C-,5'7 :t *o 14 XD i 39-.76 PotroEmphic ?ho 22vtwr3.nl cor tain a noout ?5 cir cant si' flbroua r-aboacua. probably crir/sctHo* 'vith acno nerncatir nd snail .'.nounto of calcita,, reifnioti.ta and chlorotic cr mica.ccou3 ninemice. Cnly u i'rnco of qvo.rts rrntt cnon6 There vc.rfl nhrctis of non-aeoarated fibora .13 to 33 aicrona long wad 5 to 13 rri.cronn Trtdo, 4 / 4 't .o 1:' r cc:w.?;is^: of .%^v/sss of LO^FIO^!: /JD inFiiJ..IV -.i *i /.causes r-us? A.iCri-v Fiber 1| Original Atneaphorio Itnterial Ownt J1 por cent jor ertivt itilc 75 cO aeia? ;cito 4* ** cite 15 r.o 5 %p*i tr 3-* 2A jktitc ior 0 10* kJ 'V 100 100 Short*Fiber Original -Vtaoanhor;. "Gtorlr.l Subc** par cent war cent 1? 15 55 60 10 10 22 53 00 , 11 10 100 100 ' Centrecinivcioa Fre-rs ether durren* ':> -Vbncspl^ric scenic *rao 100 car cent bell-mUled euth;. l -57- 2cbl* 15 :rslr.s 1'ibsrs CIctpo co*'?:.:i:go:! o? sizs-raKansc? c? aemsphetjc LOUG-FIL"!'* AlffD ICO p::s rvIIT CALL r-.uLLLD ASDSSTOS DUCT collco^ld essids cages 1 uonft-riber Cali-Si 11 ad por orrb nor csnb . < f idorona ( 3-10 f \ ( > 10 G5. 7L 1.1 OoO 90., 6 'i a3 Ov0 ( < 10 ( ( > 10 25,0 6.7 0.3 0,,6 luO lCO.O 100,0 .:~.L'UT OP rrrLVVii'ICW KCPERirailT V.ITH T/JHC-P.T33U Afcr-STOS l : iliitura of .trocrinciit .'Jumbor o? Anir.c.13 I'arimm Duct iiinoouro r-irzir.ua Currinsl /.ftsr IX". it Sapocurc? P.eoult.i 'J.T', W03UTC rcntinucuo ilfa 117 - l3"'jc = cat." 20 rr.tr. *>C> riicrtbo 42 0 months 0 0 ; ,i* r1JoA . 20 .nice i 23 0 Duit onocouro i'oilo.Tod by n pro.l cased re.ij-.loaso in noma! cir 12 g pifj3 20 months 14 months * 27 months o# 2 c av./i 10 L 24 Definite fibrc:::.r. in 16 months- clcrviy dove-j. oping fibroelo .first scan 1.1 24 months. Uarhcd nsribrcnchiolar fibrocia first necn at 24 ivCu C.'.l 5 Limited reaction; no iTbrc3X3* Clooring of inflammatory reaction cnc. definite ccntrr.cf.ica of fibrooin. Clearing of inflarriuvcorv reaction and olirht ccn~ treeticn of fibroei3. Siiailar to continuous ex posure group; auggaation of prcgrocn^cn in one of tli3 tr/o . finals.  - . -- . - r; 4: 2. c,.i t; r X ** ** r.i; *J4. ft G yt s oH ^t* I* l o K- ft iw X 9 6 SR f5 too N ft ft ft ( oo r<f Cp 6 ft o < u c. 66 c> e* U O ft H A pff c rj. o O 92 f; 8 < 8 c> O ft O e? u ft rl Cl N pi ft ft ft '. O GO te ft o Uf) cirt?. O pi o n ri " ! e 'g < r* r: ft SSC t. 6* o<* V i-< v u c- ft ft 1*4 0V? oo rf U> rl aa V ,c. a ft r t e; cl a fcjij o ?!t 4* 0i5 ar &! s 8 o rt <4 irt ft ft o v*u> V 10 ft H U* e o ^ftQofto V tin rl & o to tiiOrt i b ft ft 10 f> Qi SO *> oo as A oa Of CO Vp 4It o ooo 8S ass O to to to ft ft c r ooo P tO p4 PciO aaa ^1 i * A ft n c-: Ctl Q 5d eo e* s p* IO Q Nh h o< S Cl Hpt b on Ci X* s cc 9 b Vi e S 3 (9 n e u OO O>' HA b V? ft ft s. r. 3 S E cc * ft ft t? ow V t: e IO Q 1C o /4 ? M90 o M1 dO<? h c- flfl Ci &oM ft 4V ft t OOO sss' t ev ft *HO SSq ooo HOO NpD NHrt gas 666 t*or* * i HNH cU9 5It4<Vl o- to t OG ss iK b ri ft u C* g^- < 7iSc Sc< o <* > ST.1 H0 Ewo^ o9 H <1 oo b 19 19 I5 & as oo (fOt 4 OO SO3 orl t oo BS 6o *f4t P4 6o t i P c ft M e> to Cb4r e<D*9 es 99 o HIfi (*9* 0J ft ft ______t 4 o V: r. r. u 3r3. w* < 5 C - p# f-3 a r ?s &! c e.1^ 3S r> AT Sfe" u u. ; r.. 1 # -- ;. 1" **: r >. t wO v i Vv * i. ; -c - ' - ?: p n to r- > > * v . r~ u? tao. *0 e ooo ft.p* V* .*V CO 10 t.' ' v , ;; . * ft 4V V O O t.1 O O tv *# pi V** P< *.* p r p <* * iv :- *.. . v^ '<> c cl C ~ '*. oin ~ ^ m, f.1 ; C 1 ! C* rC+O o \4 ! i i i t t ( j Is? ( <b. r ii lr* < n &* : v < M cc c VI tt- o <4 v? > cT C* it* C: U c> * fJt . ft . it. c C.-. h > !; ? \ - ^? c ' . -' C4 r' *-* o -- - r h. - c;* u ' . - I! y. *.v V < V, i. I V ; i ! 11 <* c. i l < -- ; v : V. v , l -blc Ca?AZ&H o? R.V;.*GTI0>! TO -TaaSSDTXlS Ali'y SSSPEITEIS .UIJ20TiJ) HT7 tbi?P.AGllb\LLY C&KSO3 m Hc.ch animal v.*as injected iniratrscheaily v?ith 0.3 co of a b por cone suopension of th-a dust,- Tr/o rseko lator .-mother similar injection troa gwon.- Total amount of cluot injected s. 5C .uncle *I siteUn \ iix'i-cups of 3 ^vir.eo pigs each (one group for each typo o* dust;., rcriricint Foriodn ~ Cno or wo mlnala in sach group at 1, 2, i', 0-1/2 end 12 months after injicti.cn. .'rs-e.rntien of fust CHryaotJ.lc voail-nillGd) unheated: Chrysotilc (ball-milled) ignited ; Chrysptilo (fibrous) unhoated Chryaotilo (fibroua) ignited : Serpentine (ball-milled) vnhonted: Serpentina (bali-iaillad) ignited : Sali-millcd for 1176 hours, driod and roground in agnto mortar* Ball-milied chryootil heated for 2 hours at about 700 Ce, then ground in c.-ats ir.ort.ar ?. or 3 ndnutos. Ground in agate nortar to onas 200 ir.ech. 200-moeh material heated for 2 hour3 at about 700 G. Uo further grinding. Bnll-anilod for 1438 hours, dried and reground in ngato nortar* Sail-milled serpentine hervtod for 2 hours at about 700 C*, then around in r.gaco mortar 2 or 3 ainutoo. Mineral Size of Dust Particles Socults ) Cbrysotilo 3 microns and (tt-li'-.oillcd'i less ! urheated i __ i it 1 1 t1i. | Cfrysotile j (lull milled; ( ignited 3 micrar.s sin*, loss :i_________________ , Grinding dortroypd capacity to cause fibrosis. At 1 r.er.th considerable inflammatory edema rnd collulor proliferation and localisation of dust particles about bronchiolar; at 2 inonths, only a very slirht proliferative reaction; at 6, 3-1/2- aud 12 months* .viasly-scattered email mononuclear phagocytoa. At 12 months, a fan microscopic patches of thin alveolar will thickening with 1 soma adenomatoid change in portion of nir rpuces r.butt:'. -.-: cn thickened bronchi. Ho nebeatoeie 1 hodiorj scon. Rose- . liedted to large foreign-body gioa.: colic . .tr.sut production of fibroua tisane-* (oc-.itmv.sd cn oago 62 ) _ il lernc. di-u of J I fujit P>)^ticXo3 i Results otilo 3U3} .ted -O-iiO rv&ronr. aspr&jt. / 7 > ; ------------------ 1---------------------------- brycotiln iitreus) united 20-S3 `nicrcms appro::-, I \ fibroais. Reaction localised to | couneccive ;i jiq about terminal bronchioles; 1 little within thoao tubes* Contraction caucsd adenomatoid appearance of air spaces given eff cUroetly frees terminal bronchioles. Reaction area became smaller with progress of tine; no now regions involved. No chronic ) pleurisy even at points abutting .uitracubnonj ary change-. At 1 month considerable infism| matesy ede-ra scad foci of cellular prolifera tion? at ? months wall-meritod cellular proli feration rr.d fibrosis occurring focaliy about respiratory bronchioles - This reaction de veloped before achesto3i3 bodies had fcm=d anti mas as advanced an ,that produced by 2 years inhaletier, of asbestos ,xiuat. At S months P roncfcicQ loss oxtenaivo ihrm at 2 months, appar ently duo to contraction of fibrous ticsue; c-sbestoslc bodies wore abundant. At G-l/2 months, reaction still less extensive, confined to tho ircmsuiato vicinity of the ssnull terminal bronchioles, vharo tho near tisnue v.-as otitita dons md was becoming hyaline in character. Sometimec it even obliterated tho bronchiole. Aobeatosic bodies hod beooao scarce. At 12 months, the V7011-developed pori- and intra brcichial adenomatoid arsas of fibrocis had J produced considerable distortion, '.`ore corij chorally \roro patches of pneumonitis v.ltli j eosinophilic infiltrations seme of which i?ac j being transferred into fibrous tissue. Those ! r.oened to be precursors of the localised, j diffuse patches of thin alveolar well fibrocis | soon olporr;hcre. J Reaction li:.vitod t>9 large foreign-body giant colls without proliferation- floating tho fibers, which :rauo thorn ,brittle, destroyed their capacity to produco significant reaction* crpfntiai I o cv.ii-riil leu) r.l:r.r.tod ucrcna loss ad \ "ust relatively Inactive* At 1 and 2 months. I simple phagocytosis without proliferation; .vt I G months, no change except possibly lymphoid j cell infiltration; at 3-1/2 mouths,, a alight j chronic pneumonitis; at 12 months, only a litI tie cnav.r.cnitie without suggestion of fibrosis. ^r-jentine vV.ll - Tail led) ' nitRd lOSS /; 1 fust rv*`'.itivoly inactive Reaction essentially ] -the sri s for unhcacad oerpontinc. `'ith tu nitod - sc rpentine, loos tendency for duct to 1 A Carrie-. *c bronchial nodes. ti labia r.O Jl TD V.KJIOOS I.CICG- TOES CVS! 1 4 ZDV r*flri * ': / a VTr.TMr?Ai:^Af.&TAjLL' :o.->a;3 Jpo Tablo An Inal 3 baeo ?rcr*. 5 to 3 ,7iiu:--i pi,;3 for each dust, fa eri.fi eirl/T Farl-ida ---------daua-ly t~c i, 3 ?nc 12 ::.ont'r.o after injection.. Gi-.a of fust. Partlcloo " ,ior'.ara'soa sc cba'i ricct fibers cr-o fron 20 to 50 nierons -onjo Zino rrl `1h ryootiio '-hatford) ,*V wOw1*,g, [Arizona; Iot iron orntcnt; ` o..:;: P02O3) Anosito | Tosuito ! ,* distinct fib--ocis additional infaiTatica ^iron opposito j 'Jhr7.-noti.l3 (fibrous) uahoated, in Table 19. Dear;tior. virtually identical urith that to '.'hotforci Chryso:ilo0 .loth flbronio and asbactosi3 bedioa produoed rath an icbootos containing reiy little iron. Pibrooio occurred no vrL thin tomir.al bronchioles and as finor doponitn at periphery. riTjroria tlnrolCRod before aofconcoois bedioa :s-n -2'j v:r.c In cellular ctato "roil -forvnod at or.o oonth'Tiv-h .vj-j., fibrous iinrne contracted cad occupied rcallor aroa but ^ar, nora donno0 Adenotsetoid ehancon ainilar to thcoe rit'.i Thetford Cl-rye otilo., "lourisy liroitcd to irr^rdinto oiciniby of early reaction about arcac of pc.osivo .looal .'.satioa, -iCuoatoria bodies fomed but vrerc four in number-. At 1 rr.cnth. eftor in;jocticn0 vunuto fori of r?oicnuc.lacr pro1 ifore.tJ.cn acerb brenohiclen end in r.reao of atolcctaaio; rfc 1-1/2 pcnv.ha,, h-uivy peribronchiolar par-ohoc of fibroc:..." jftsn r.'ith p-ipillary pro.ijctitns partial!'.* ciosxny ivsnsn-of brmchioio; cdtacnatoid appearance tnrksd: connect?,to tie:uo rcection zhzr.-o:i he*.vsy collr-jen but no hyalixii nation; at : -nentho, ninuto foci of 'olj.-rcj.turoa fibroaia about bronch ioles; at o i.'.ontha. itaturvs uabsetoais fibrosis with OTideico .x ccetructioaj nansiclorr'olo chronic pnovc.cnibis vith in-* filtratior. of lyrer-icerr-cca and ctesincohiloo.. At 0 ACivihn, j-all intrnbi-oachieiar fibrous pin,';1* uith foci of -.-.era doll- __:_a\i:o.fit;resi_s___a__t__t_r-_._-_i_rh__o__rv__,______________________________ ___________ yfico?. fibrous cr.. : ti;d roribrcr.chiciitis 'ritlv forrati :a 'tveur.-.x ;'.bcr .bodio?a I'icur/cratiwci of roriae b:.-*-an bo.-h v.;r r.nj-otim.., '-.voi.l--iovolooeu by 8th ` '.Of!' ;.st .-.u'tar 1`ith r.onvli.. -''t,action f't i :v-o.ch heavy -..-ndo . ::.-r?.broachi:;litis already abcjrin.; .r.u.'a r.s *5^.. Iri I v:.m\ -vsiuc ' c cnt' ) i ?r vcif.oiit* dr ;eidoxits f 3- Africa) fvathcahyilits %* '** *?" fivrou.j clv.vr.r-c; rtciouv.v.oi;: tv;c fibreris rith aorvo tm-rosin r.t si ho oi' orvsuiY'i iosaAAaacir.Ti o.v dart- -Vv 'i ninths. I-icnv*,. vidoiy "catiurcd --ndn- and jYrrihronurT.olitis. -.err fibrous, ?;ith .-cirlrcd dsforra. fey of brovioaioiea uri *vith r.;j vJccvor.atoid .-icpsi.rrjics. At 8 ond 10-1/2 rent-ha. rr/Mition in lung SRSontirlly tbs sivao *13 at 4 raaths, At 12 ruMiths, feci sf fibrous oucic- cad peribronchiellhis still Iwj-a with aoro dsnro near tis juc end tier:: Aofor"::lty n' brcncnir.I tybar rut no wtennon into. nr tv'cc?. ectasia or,. puri-hcr.-vl vj-rmchyoua ..donated fibrcuu cn.de- r.nd poribrcnchiolit l:J-. loaded .'.ehestcais 'vrrlioj robed r.t 3 r-voahhct At X month, oar Ay 'iSrour -riUo '..ncl yjribr*cchiolit'vr; nray c;iuz:o coils t-nd j .:cJ.v lyrr/noeyti e reaction,, At. 'V rorths, email 'ireo.o of vir.cirhrn;:.;hioi:itio scattered throvivhcut bho las*; csliular fibrosis.. .if. i; ana 12 rcrithc, trc&g cf boon chic lit is .vruiXir no'cuss cf : ,rtrcctinn of fen so scar ticev*; r.t 12 rc.rclv;,, -.lerAod A;;r.rhocytic irfiltrat-icn and ndencaa'void npporu-nrcca '.'ypr.cal ndvrooed ftbreue oucio- and porA br or-,eh 1 n1 it A n pro duced 'ey 0,,2;j ousvenci'n (1 cc total done); .o.cct enimcAo ould no: .olorato visual /' suspsrvsiono fi.brcoin ->/eli- I'.cocloped before nobotstori?1 bodies seen. At 4 ffionidvs,. e-ell- .laoolcpod fibrous bronchiolitis vo.th ly.r.phccytos end ieat toil'; end rUcnor'itoi'i c'.ror,o. At 0 -months. typical bror.- rhiC'liti:: not q-uito no CRtensire or :\e ho.vrily fibrouc aa *.ith a I;' '.u'-o.-'ccion, otherrn.es Sha sans... 1'an.v deeply- .r.:?.inod fibor. a ^coti pronori-icu of hr.ustratei nshen- :oci.c bciioc. it 12 "eur.hc. heavy fibrous brcnchiolitic., :*.orv ivor. - thm cudobvc:xhi olitAv. -c.th l;/r>phscyten and r.i S3.il,:; very : arJ:od cdoncr-stcid >vpnoareaso,, Ayr./hccytic infiltration and gient cells but no fibvc.?*c. rcry *jTf atypicc.1 ar.bostoni* bedioo At 1 ncuch, suvny oai:tc.rs<' foci of intrabrcnchiclar dust without rvaanivo Iccr-lisaticin; l.vrup.vcs'tio ini'iltrr;tivn of -Tails ar.d a fw . jiant c i.' .lj. At V- and 12 r.outhr. little ovAdcasa of d iov: cU r rea chi. o loa ;vnu b.rt,nchi v.ith :-;iaat -:v..*11j in :Ad;jaceo;t ulvool.'. :.r.d :\.\th .'-^r.hoc.ytin :j::i`'iltratloM cf rails. *r.*.-:-oris .Vocut brcr.shiol.-'c. -ft .1 jenth, .vrea of duat. Iccnl.r.Tf.vicn .-.vfch cellar so of r-.ivcoii r.nd infiltrr.tj.cn .vitb acuta vexii.r.vy sjjIIs. viScvo;i2*.ft;p3 and yUnt cello. -'.vtAxa tha v:cr. frw fact of fibrcua +iocuo .end nv^nsroua ersea K: bysc-rv-rophy of r-Avtoiar upit.hoj.iuia.. liajny brcncMoloa ;>rvv;.:cci -- >.-;h -.'Uvorc, . I * t-'OtLIvs.. vcnoral eppsQranoa of v.iaurr^st'; yi.-vr aiightly thiciitsoc ovur heavy lo'7il:;'tticr3 of dua--- '..a occa'iioao?. !:ojrr.sntod anbestoo.-.o ' .vsc At `J r;- , ri*.Ry focf of fibers in brcwcvp.c.lsa :y. rw-c-'/.v.:- duel * r.hh u-ululur --ractiorv :.c before: vino.. I i r n-vn:::-.- :;v vr? ;:) cd- coutv.r.isa ! Minora.!. ; 7r r.-ioli ta ( ccr.t t t 1 Incite G\.\za Tool ' ; j Sasult 7 ..ome fo?.i shoved distinct- collagen deposition,, -it 12 and ..3 nor.-fis. r?nnticn as boi'oro rrlth fi'oronin about bron chioles iior-i apparent because-of contraction and decrease of inflfvEmation. Giant coils prominent. Pleura markedly involved, G'ypacai fibrous ondc- and coribrcrohiolitir, like reaction to r.nbnitoa minerals,, At 1 month., erreonriro endo- and pori- bronchlolitis vlth- giant cello; dcss fibrous loops within brcnchioloa ?nd ccllul.ir fibrosis about them; adenomatoid change present,, .it 2 months, heavy intrabronchiolar arid pertbrer.ehio.lar fibres! 3 producing Tsr.rkcd deformity with ' difeterticn of tubas ond oblitoratica of surroundin' a*,r rpacer;; fl*renin pale rrithout hyalinisation bu'u rrith few nuclei; no necrosis, i'ypical ccoortosia bodioa soon, .it 1 una 0 ncaths, little change; fibrous tissue contractin';* At IC-1/.2 months, clor co fibrous bronchiolitis with aEbootoais todies, :io pleurisy. Ho extension to surrounding lmr,. "0 fibrosis vrithin a your. At 1 n-.enth, no reaction inoida Vroackiolco; in peripheral air spaces clumps of giant cells racked *.;ith fin9 tipiculos of glass '.rj.th lymphocytic lc.fi 1'.ratioo of adjacent Trails; no r.3bectocia bedieo. at 2 months, reaction less intense than at 1 month; fair-sised clumps of elongated giant phagocytes containing spicules r.nd particles of glass; r.o sndobrcnchitia. At - end 8 reams, reaction still diminishing. At 12 meritsa,, fecal areas of pneumonitis r/ith no fibrosis or cnclobrcnchitin; r.odsrr.to ramsor of cioooth ircr.-stair.ing fibers. .. 5- L .tv' ' D 7.1 r* v --* -- ,J. l -A. &V.CI&AFIMr A *-J 3 \ f:\c.nr. -Vivl^r. ) **ro<:i..-i '\2 Z CztL) ) a. | '-ur. C - ''.T -'-'.C ^ #i *. *v*^VZ^` ` .** *' ' :V.C :Q '.-a.cvcr.r 1 ; L'hori-*ri!.'^r . 2 !-}.fjrr:ir .-.ad .an 2 Cncultc ... .i.ua:..:ot iMurpstn* r.-A.**r to Chi^cor.i.lo i 2X'.2,.' vr-hot-voed :~v "laols 12# ;*o -I'jr rinir... -'ofor to '.irycoMla i.uil;:;nv.eu in 2 ".i),, -nilHod) t 'jC.t;- .'i'5C.r i r.'-,, r'Ji .-P. ereas ? ! j "here-:i.tar ; HO r.j.c:.'or~ v.r.'u ? 'iyn-lftn.1 cwla- and neribrcachio.lA v.ia, ?si'nr vC '.`L'hla V-Oj r.ac.c tod tr i;c? *.G vj.t'.x ].:;'.phocy- ':?.c ini VVirr.tian oi v '-llr., Snert Ti- ' d.vs n.-vataci :h:rlu.j nell-xn vi-a^oaytorj ? 1 anger '"n:>a i:am r.ar-tvd to ?r\`i trniyiai anon to- -tar... .`v. 1 r.oatli ;.v?tor .iroc- !:. ...TjVv'iti *>'>?. r.tr.cd ^rnrv:. *.o.ll2; rr.tr.t nim- i;oc.ruT.'! rar*) vritiiir. Cii* find had not ni# to ".''.ii.j, .t rr,-rathe rco oncrr-aol** t r v'vhrrc v-orl"f;. V.mea.i.oits i.r-to:-- 307.-Vu.j. <r. 'Jxxy .,:nr" way o.TGcncivs nroii. /:r.vai-.\r~i c,2 .\yvriho:.d celJLn and r.iouc:y;:2.*! Ituv. re ri'-Tvirin. :'!t C :..cnoa3, .tarr-.-i'ya i,ct,*r .ro.-iohion 'd.r.U ccno nr.cvnexVfcis, '.o 'ji-ranh.lo.liti.f.. c'aa ::.2h'..': .a.r.-.u hcr.ic;: pre^f-n?. i '-on':-.?'.'car : "iavd;i2 f '.V -iO1.'C'.;TT!.:' T .'uvao*:<$ ?;:hov ~:.v uvAc- .:nCl .y.'r.vrv.*. n:\ol.'. tii!"3* f ! .?.v'.-r :!!.: . ivut . : .'.-nr.3' . n*odorn - :..7.eil t 1 r.cstr.. ''U' ?.-.'cn JO'Tartf:;v.v.. j Villt-.l -:i o'.i at c.vii.i ;:iol:2d \vt..;. . w'.lfi i.nvT.-J.i*, .t./litrntnd | -or.*. r.'/i-nr-o!.'; .'.t -A noath.a. -.. I -;ro ; .::* IrvMtrctxan c.C -nni \n; ! .a v* *.vc Vu ..art .'.rai.?u.\ : i t: rr*-C!v -ilcrc'.c i-x-icshy iliis- i < r-S. sar 7.1 X 2 -- reus ;nt. :o r ft w and V* -i/,2 :".orths, issisoev of f/r-nt c-SaIs, .-.ontaVsir.;- :,in. oral cjjrticias. is --laii '.;rcao;:i but r.jl- in -ruoiratary'fcrcnsui'j.Voa; air-.'.Her co:>3 .ridel:, senStored in terminal sir nowea- ;iv^~ .'rcu.o .\accnv.csia bodies* '-To rsaccico so con-' nce.bi\-o virsur* Mo cndobrcnchi::! uroiifomtxcn. At V5 i-.vrvcirw srsay ccabtorod cr-c.ll -ionosytao 9c.c;:cu T.i L:\ dust, '.'o rr.'iobrrr.o'xi. ".iri- .Io v.oririvj.rni fibrosis* 7.r. lysrh aeds. u slight reticulosis; x no fibrosis-. V . Ly iph^riytxj infiltration and :~i?.nt soils but no 'iruinito fihrossio-. Aafor to imlo <-0. 'o fibres;!.; me r.rr.ctioaily no sr.beator.is bodies, At i r7::.v:.h, iccnl collect;, cue ox* dujt-fiilod Monocyte a usd ?. x'c?7 *yiiT" cells; at -1 souths,, cons c.v.c.uitui.u ooitlioli'-.i ror.stiouj sit 5 nontha, Cinpi: yv.-v^noaitin rvith phn^ecytosi of abortfibers;; \t '.2 r.onthc;,. isolated enu sharply lo~ enlist-/* eoll.-ctions ox dust caiiu inside -xir 'fjv.co.s tovu'.; tcrrslr/d urtari oios. ~oao lion in crsila Aisaitod to iy-suhoid call infiltration. Ko fivX'oui'j-. Tin lynph aouo, reaction limited to slight nx'imiacxxco of reticulum. rrrnoiito ico."-' fiber f-.3-.-A0 : io. ;er. j F!icrt.fiber f:C nic rose ' rd ' 1 as fibre .rlc stent bronchioles. Ilafnr to Ti.blo CO. Sirsnlo i e.vei:~ibo:',y reaction.. '.la ecucs ini'lcas" siaslcn-. '-n s.ycvrnuiaticn of ;h.v;b in or about tomisul bronchioles. to oneobronchitis. At 1 r.iont;-.. aeattored .email ^iunt soils and consi derable imb.itratian of adescent eraclI .riant calls and ccnaidarabio infi Itvstion of adjacent alia T.ith r-nuesytea cr.d lyrvujid awlls* .vt t *ou-:>.oJ little ci.sr.ru oxcoyb :.r.or cellular ini'l.ltre.Ticr. of c rcucetivo tsenua* .It C 'ys-fio.'.d ;n* ll".:mcion sr.d th.iohealr.jt cf -salla s.cout i-cna t :\ot all tarcinai bronchielo.;. ** / 1***1% lor.:; tor -hiv! .iCTOXlS ... /riev i ?:*ct:'. `.;r;u; or.do- and yorlVfcncbiolitir.-'lihc ;q : sbi,:oe i-'inorui.: Hefur ;o 'i'.-.iblj fhorc- ,'itor I ''-uyiJiS, lcr ; Ibcr : - ith mb;; 2 .* -ell: sv.vn) j'rc.vo rsni:civ~* At 1 v.cnth sftor oc- tic--... *sli .vonecy on -Tidaiy iruttarcd r;vou;U *. n ;rt .ecue of c.coioctir.MS vitii ?.;,i:.pjoid ' A.c.'i ex' eu.pronac;;i rir :.raco noils. 1'-. .u:iab. sc.u.i-.l reaction ns r/it:i .-.'lr/cotilo.. .:.t f .*sr.. 'Avian sinil.n' thst nt 1 r.eath; ty;sri- v* bnhioa ncr-n . t 1?. run :hz, ` - *"?. *. * hi* O..X.. v >.' .''o;oii-.*c '.-.ve , filled ',:u*pcvrtc2; iO :-j:-.cvl*va iu iv.vra ;-.c.;c-.-- ft ' .t ; V -i*-' CO c -j'ir.! do'ica (o rc h cuvs ~~ " G no i f a J. p a r ocm'-. ?*ijpc-iaJ.w ) r V . r 'i a r i I I * I l I i i l I j J i . i C* < V. i >t * fI.C..* u O -- i ( 'P U V /% T J. jV i r. ~ V.I *. * f o I3 I ;;. *. MO r r 1 c- Vf C iP Uo 1 ' o u r V; r? V* c- 'i4 v p. il rU. p tj. po4 t** O u r4 r-p 4> o - -> -V : y * i : **V~; . v o ** *. * r i | .. d : r 5* J r* c* ; .V -? * <* 'j v> 4>(-I, c .yc. <> ti . ` .V y * : i. #* * . t' < i i. i. ,, p* *> f-. O .w 1 4.* . : p , 4. y . j( k, t>` L f ' ' 1 ti L . , I Si. <\ . ). O .' r r ^ T. C f-C 4 o t c -r: t h c n.H. t Vr < o t. n c* ^ cti qt: o i wi ** `3 o c:> 0 u !o o ii ,p1* *< ei* to (V n . Z' ?1i:-? *rt3. -io<* 6r j < O .V L a - oh r- r M'1 n c- * tP*V1*1 . o c iV/ ^ ,,'-> S S r. p< i : o r. ^ k> ,r ti xXWJ. ovV w o *. J i, v. * wc V. " r. <* * l i. ; <. ! (; i; i p ..f > . t c j r B. ** r r, r t*. *e f o** .*.^ pj t?/ E (/ tf ti >H .V u V *r- ^ oo i> a. c bo L O U3 e Vi v* > -N J v c; >; V* *i 6 9 x* rs a> o e cun 4.* < CO C -o u ,r TI J3 o r. p' c L c a r r - . A R*3,4* j+s> dob .*JC so ' " }> :S I ro c o i uc c u r~rr ^ - x* o c, &u ;O < u i- ' `V- *> *. 4? " i ii i** t l .? :y t. /. I c r- r r. / u rt p* 4. ... r . Jt o ,* Um p*. 4-. t 'J L. .. c r. 4. i- s l -H <* 4r. M- U ** t. f u r rr I ` ' *- |- i. . 4* n i ; i *' t * ^ .. i c '- If ii ft *. 1 4 .. f 1 ui r. t; i | 4 4- !: j j i! '* I *. ; I * t. f * * : * : o * lu c I !;I . . t m cpc h c.- , > i: 4 i*. ** 4 p. ur. o r- r*- *j* tix. .>0. Hv *I.4 *' 4< 4* U C> "w O (. fc a c,+* ft T* X? O - RS' a xy r tri 4.*i?t in * ;` <; n p L? w r* w r. 4) O o _ r 4. x' . < X 4j ^ > i? t. X. Pt pr;ttf 5 ~~ u P>4l- p> CJ --i C 1 0 o C O n : 4r2j co *> a o .'> p *o '* c cL 4. a 0 p! a o C f5 4* o ii* W tPi 4i4. 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