Document B5gN8GbDDQoB17dDBdjRmbpoJ

FILE NAME: Metropolitan Life (ML) DATE: 1936-1949 DOC#: ML311 DOCUMENT DESCRIPTION: Suppression of Saranac Cancer Experiment #1 [Part 1 of 2] ftfidgapor t , C o n n . November 10, 19oG Hr. F. II. Echluter, President, Thornoid Kubo^r Co., Trenton, N. J. My cear Hr. Echluter: . The v.rittr m o Hr. Vandiver Brov.n, of Johns-Hanville, hud h conftrance with Lr. Leroy Gardner, of Saranac,* Now Xori-:, and Dr. Lanza and Dr. McConnell, of thu Metropolitan Life Insurance Co., %ith reference to the 'Asbustosis situation in the Asbestos industry* As you no doubt know, Johnn-U&nville and ourselves have bot..n coins considerable wont, in conjunction v.ith the Metropolitan Life .Insurance Co., in the way of eliminating Asbestos Dust in our factories, unci we have made a very satisfactory job of it. \to have now reached the point where v:e can eliminate a large pert of the Dust, but as yet Have no definite information ns , to vhat Asbesiosia will lend into. They claim it leads to Tubercu losis, but t,u clo not find this, to be the case. Still, we cannot go into court end state definitely and specifically that it will not co so. V/e do imov; that Asbestos Fibres can, end do, get into the lungs, anu muy set up a Fibrosis condition, which, for v.v.-nt of a bet tor name, so.no doctors have culled Asbr.stosis. Dr. Gardner has a well equipped Laboratory, and a number of separate Dust Chambers in his Laboratory it Baranr.e, end he r.nc hie associate have been studying various types of Dust for a number of years, in connection with Tuberculosis, bat practically nothing h.*('A*M; been cone v.ith Asbestos. . In order to carry on a systematic lust investigation, it takes from tv.o to three years, and these investigations are general ly pale for by industry, mostly wording as a unit. Dr. G?;rcnc-r's Laboratory charge is i-b, J JO. j.) per year, and any jtacy should be based on a three year period, in order to get re sults that will stand up and bo accepted by trie i.iocical fraternity, and, I boilv'Ve, by tuc courts. . n,, I thiruc t h e Compensation Laws in th e v a r i o u s s t a t e s a l i i ` DceOiic no re x'i g i a i n toe ne/. t fev. ye.ii*; *ne, no d o u b t , A s b e s t o s , on a c c o u n t o f the- stiv er U s i n g i t has had l a t e l y , w i l l become or.e o f t h e / C o a u c n s u t i o n c a s e s , and we should nave a l l t h e i n f o r r m t i o n wo can pon s i b i y get to su b m it t o the* Corapcnnution Co.nmi n s i o n s o f the? v a r i o u s sti.itv.s i.tRn the q u e s t i o n oi Asbet. t.osis comes up Schlter 11/10/23 v.orir-on experimenting'with Asbestos at once, and has suggested to us that the Asbestos Industry take over this lust Chamber and employ him to'carry on the experiments'with guinea pigs and rubbits. The idea of Mr* Brown and myself would be to have four or five (or even more if ve could get them) Asbestos manufacturers take over this study by subscribing an equal amount per year, for three years, and then v.c could determine from time to time after the find ings are made, whether wo wish any publication or not. My own idea is that it would be u good thing to distribute the information among the medical fraternity, providing it is of the right type and would not injure our companies. This would mean, if four of us went in to carry on this work, it would bo;$1,2130.00 a year for each one of us for a period of threo years. If you are interested in this subject, I should like to have a meeting in New York, on Tuesday, November 17, at lit30 o*clock, at The Biltmore, or ,if this is not satisfactory, can make it any place you caro to have it. I am asking the following to attend the mooting, Hr, Vandiver Brown, Johns-Manville, Inc.'7 . Mr. F. H. Schluter, Therraoid Itubber Co / . Mr, A. i>. JiJ.agd.en, keasbey & Mattison.Co. Hr. H. h* L&Mont, Asbestos Manufacturing Co;- . Mr. 0. M. Williams, Russell Manufacturing Co' Mr. fc>. Simpson, Haybcstos-Manhatton, Inc. / \ Is there any one' el3e you would suggest? Very truly yours, SS-G. President  Hovember 20, 1936 LeRoy U. Gardner, M. D., Director, The Saranac Laboratory, Saranac Lake, New York. ii Dear Dr. Gardnoneerr:* . , it -a meeting yefterday ^ tin^crebabler to1 pre8ent mentation wi,,tthn aasboeeastwoas d-u--st-.' - o i l received and i t appears The proposal was wer> w el! cr more, corporations. ItJhUei.lines dis-c-ussed* a fen days ago . Accordingly, you "? tSS^tSteSSitt^MSeSlfcente rusriort^r^psrr sr^tr^sr; 11 answer, <= w - f--o-U-OWlDg-S - - ( 1 ) ' S f r ^ r , f . rrf1Ot S e U g s ^ h L r r s 5reiignOatfdO sU.0e asbestosis. . a<*hestos dust W i l l produce <> 5 S U . ! ? S ^ > i 3 b % ^ ^ d d i f r d ^ e r dh u ^ e ^ o s l * /sn be reproduced j ISlSSle without in fectio n . m Whether the flhroel* produced ^ ^ e s t o ^ l s of the progresslwe *ypjlt has started) efter flhroel* l"=i?"L i t See ceeeed. t? ( i ) whether th e f i b r o s i 3 r e s u ltin g from exposure to asb esto s dust i s occasioned by the s i l ic o n con * te n t o f the a sb esto s or by i t s fib ro u s str u c tu r e . ( 5) Whether the presence o f "asbestos bodies" has any [ diagnostic sign ifican ce. I t i s also our understanding th at th ese as "r , i - " ' . Tt. i _ otlr further understanding th at the r e s u lts \ }] obtained . I l f * considered t h . P r o p e r " " `V X . f E & t X L il i S ^ ^ r ^ S t r ^ e y; s h a l l J e ^ d . ^ b l l c In the - - ^ I t Is "provLl prior to p u b lics- / tio n . ' . H sK Sk ^ s s u s k u r -s iM S .. Any"method you suggest w i l l be s a tis f a c t o r y . . Since the experiments argJ?:n^ 1^ cieasr i t o a tte r o / c ^ n - t i v e l y la rge group, i t has b e e n -I r d in ^ t h e ^ o r i be addressed to me v en ien ce, any communications | he c o n t e n t s thereof to s a . n : s & s h s & 2 " '.k : j t q rata contribution. I . w i l l ad vise you la te r of the names o f the ot tributing parties. .' ' / I s h a ll appreciate your ln ( g" 1^ t l i n e d h e r ein*meets p o s s ib le moment whether the arrangement as ou tlin ed her with your approval. . , Sincerely yours, VB:T luxtn -I Vand lLvveeir Brown General Attorney T h b Sa r a n a c L ab o r a t o r y for t h e St u d y of T uberculosis ' . of . THE EDWARD L. TRUDEAU FOUNDATION ... 7CHURCH *TR.^)^ ViU WrA** Saranac I ^ ke.jJNOf.^ /l?: -4 *r\ November 23, 193 j {3! - %/$ Mr* Vandiver Brown Johns-Manville Corporation 22 East 40th Street New York City ' we$tmu*. ovvtv Dear Mr* Brown: Your .authorization to proceed with the proposed asbestosls experiments at the Saranac Laboratory Is acknowledged with satisfaction. We believe that such experiments can be ex pected to furnish asnwers to the questions which you have outlined. The estimated cost of $5,OO0annually for a period of three years, making a total of $15,000, Is correct. Your suggestion to make advanced quarterly payments of $1,250 will be entirely satisfactory to the Laboratory. If this is not convenient any other arrangement that you may care to make will be acceptable. The Saranac Laboratory agrees that the results of these studies shall become the property of the contritutors and that the manuscripts of any reports shall be submitted fcr approval of the contributors before publication. I would recommend that the experiments be performed with pure Canadian asbeotos fibre containing re- iatively little serpentine rock oust. The "Kings Floats'1 useu in our first experiment was unsatisfactory owing to the fact that it contained such a high concentration of non fibrous rock dust. If this meets with your approval I would suggest that a sample be submitted to the Laboratory for chemical and petrographic analysis. Having mutually satisfied ourselveo as to the material to be used I would request that the companies agree to s u n d y a sufficient quantity or asbestos, ground to the finest state of subdivision possible. 1 am not awure.whother any of the contmoutors have apparatus capable of reducing fibres to inhalable dimensions. If this request should not wr v.^rowa,i'ovc;o,ioe,p.<; prove practical some arrangement for its final reduction will have to he made by the Laboratory. But at least the material received by us should be broken to powder. It is impossible to estimate the amount of material necessary for the experiments at the present time as its behavior in our dusting apparatus has never been determined. With the "Kings Floats" tests approximately 1200 pounds a year were required. It is conceivable thufc a pure fibrous oust might be dissipated into the atmosphere more rapidly and hence even a larger quantity would be necessary. *ie are reedy to start the work at any time and will be pleased to examine samples of oust as soon as they can be procured. ( . Thunking you for your cooporation in arranging this program, I am , With best regards, L U G jCC Mr. Vandiver Brown -2- February 24. 1543 .v ^ t u r a l l y , I s h a l l veloone any o r l t l o l s n t h a t yc-> c*ny of the o th e r o o nt r l b u to r a would care to o f f e r . Should a-v e ' w!TW*ni t ^laouea d e t a i l s , 1-would bo pleased to cee t with :*!- ..ay I take t h i a oppo rtuni ty to thank a l l the oponeoro t h - o u r 1- the support t h a t we have had. -- * Blnoerely yours, t Ll'O: =HK Leroy U. Gardner, M. D. Director t y y -5 ^ t > / The Saranac Laboratory FOR THE STUDY OF TUBERCULOSIS Of THi ICTWAIO L HUOtAU FOUNDATION Saaamac I a u , N.Y. February 24, 1943 1^ Hr. Vandiver Ercwn Johni-Konville Corporation 22 East 40th Street New York, New lorlt ' Dear Mr. Erowr.: f .... - I have at last eucceeded in ar.alytin? cost of cur vo^Alnoue sxperlnental data and assessing the results!} I realize tr.af"this should have been completed before thle, but the ecerrer.cy hao left se short-handed in the Laboratory and also necessitated = doing a good deal of extra traveling'. I hope that the sponsors cf' our study of asbestos!a will be oharitable and realize that the vcr> has far exceeded Its original scope. . We have done over 40 different experiments, cany of then divided Into several parta, vhlch Involved exposure of ar.icals for 1 to 3 years to various du6ta. The buoiness of preparing cicrccccpic sections and oheclcally analytir.g the tlseuee on core than 600 enicals has been a Job ir. Itself. Hy tlse for studying sections and analyzing data has been so H a l t e d that ve are behind our ecr.edule. T have still not had ties to write a j !ull report of this work which will of necessity be conographic. However, for the benefit cf the contributors, 1 as subnlttlng a table of contents and an an notated outline to lndlcato conclusions and the line of argument that will be developed. The latter itself occupies 15 pages, tut I hope they will find it sufficiently Interesting to read. 1 shall verb cr. the final manuscript as I have opportunity. There ere a few expericents still ir. Prcgyeas vh Au csehtohuclids b.eofccduaeptledteetderbcyintahtelotnl,ce Iweoonesreiderreadiympofrotrantth eer.ougAhhe twoarin-cr. elude in the study. The question of cancer suscept lbiii ty now aee r = i core sigr.ifleant than I had previously ir.agir.ed. I tell eve I c&r. obtain support for repeating It free the cancer res earch grouo. Ae it it will take two or three years voul d better be onltted fron to oocplete the present such a report, stuIdfy t I be shcu becoce possible to cake this study, I hope that I a ur.t cr. of your cecbers to supply ne with enough pure, long "f ibr e astes for the purpose. ? P-L-lii  ,i O m i N S OF Pg003g HCN'OQajPU Cl A39Z3Tn.<lTfl ' l a i s j a s a i t e A a t o . wo,.,,-.. Z^RT I HUMAil ASBESTOSia 1 Human Pathology - a atudy 0f 2S autopay aoaae, Illuatratad 2 X-ray Patterns In Aabeatosls, Illustrated 3 Ash and Mineral Values In Hunan Aabeatosls 4 Conpllcatlona of Aabeatosls . (a) Susceptibility to Infection 1 Tuberouloua 11 Non-Tuberculoua 111 Cancer of the lung 5 Disability, causes and cooparlaon with silicosis 6 Diagnosis i.a ) h i s t o r y o f adequate exposure / \ i ' r y f l l o p a t t e r n (c) Physical examination \d / A a b e a to s l s bo d ie s In sputua, their algnlficanc e i ? K L* - 'v 'D- PAPT 11 E s o e r l a w p ^ Aebentoelg ' I Methods . (a) Inhalation oxpooure to plant dusts. 2 Species Susceptibility Han, g-jinea ple a, rabolte, eat., v h u , 0l_e ani ^ 3 Peculiar Charaoterl.tloe of Aabeato.l. a a s s ^ - s s a s s u y .. U,J nOc?c?uproe,nlctelonIn>nd<i1ff"eartehnotda epoefolfeoersatlon " M 'S l i S i . J S i . S ' S i i i ` \ * TM ' 4 Cooperative Effect, of Different A.be.tlforo olneralc. ' (a) Canadian Chrysotlle. (b) Arltona Chrysotlle, low i**ar (c) Crooldolite 1 Bolivian specicen atit+ _, 11 South African . f t ' (d) Anthophylllte *~ex*ole. (e) Aaoslte. . (f) Trsoollte. ' 5 Effeo ts of Control Minerals ' (a) Orannular Serpentine ra , chrysotlle. ' eoical coE/.osition as (b) Glass Wool, a synthetic silicate rfc~- (o) Brualte, a flbrou. caer.ealuc hydronie'alnost free of 6 irrltatlon?D:>08ltl0n f A*fc" `li" l . In Relation to U 1 capacity*0 coapo,1Uon " e l a t e d with relative ~ ^ 4 . (b) Prellolnary acid treatnent ' 1 Hydrochloric aoid 11 Carbonic aold ' (c) Effeota of Aluainua 7 Physioal Properties In Relation to Irritation (a) Length of fibre (b) Effeot of Crushing [o; Heat treatoent 8 Nature and Signifioanco of Aabeatosis Body (a) Foraation ioo); UU1l M.ninaartieV0solubilityPrmeventtlianague further Irritation 9 Theories of Aotlon of Ajjbeatlforn Minerals (b) 7 reaaona for considering Invalid - (b) Meohanical - experimental deaonstfatlon of. 10 Ccapllcationo . (b) c i i e r 1o"'lunfferCUlal? and oth0r varieties pr o l l n 8 '0XParlantal data suggestive but not 11 Disability 12 Essential Features of Haiardoua Exposure '.* " S5as,a i ; `!.,s s } i! a " ' " =>`:"* (c) Duration of Exposure 13. Rceecnotarcaetnldoantsi-oonfeAsfboerstaosHeDwusSttandard of Safe AAttoaooasponhee."'^- '-oV.. ' U > ?e? cu"fi?fflCial otandori r * to 5 alllion portion, (b) Vork upon better oethod of sanpling (c) Necessity for oooparlson of results with X-ray f w < -- in eaployees J 14 Prevention (a) Chenical neana not.practical ,.w w o o o u than Aebeatoaia J >u uuivg * ili C h u r a l ?hrapy InappHaable o m xunga sroro p e i a l . n p h l a l J ' i ^ n " ? ^ ? i S " o S p 01,,nn?.l t h ^ S7;SI3 - c -,;t u ::e i s d i c a TM H;s u l -3 i3I I - HU?!AN A3BE3TQ9I5 1 Husaa Pasholot-Y emj i i l M fMtern. - Deeoriptlon Baaed upon 23 hunan autopaloa 2 Aah ^ Ijlaarfll S a l m i U} Huc^n Lungs. 3 Cooplloatlon f Aabeatoel^ (a) Ju.ceptlblllty to Infeotion upHcated,lnHSrv"S1ofntoerlefnSPlSht8,:perlence not % & "ol o f eel- ii Hon-Tuberouloua- The reaaon babl ill Cancer of Lung eeSnStSeieliSe:o acnhoenogk'a4sbestoJs iwmo.rk1e1r:s?. ab.Ditto, but there are on nSeatoaio t h l l L n ^ r f autPle 4 Disability ; o5?itll,-2;hnir5#re ^ T o V V t ; . susceptible individuals? cancer in uiBawinty. .nere la urgent need for a a,,rr i u . or atuxiy of pulaonary function In ssbe s t o a i ^ ^ 1 ph^aioloS:ical dUinadaobuibltletdyl.y, t.here are cany d U g* J o H b19l eCacaaeas L ^ ^ * n5o aseiVgen^if^ic`ant 3 Diagnosis depends upon three faotors. (a) History of adequate exposure, usually e ta ft tine, longer, .t work where both the c L e r f r ^ - e n r 8' character of the "asbestos" dust are hazardous. d Ale ' 'c l* (.') -a7,-*',*/iv;T.r*AM,* . ,^, r#% ^ ( . M ErldenCe 0f " J f " hrterletlc X-rr pot:ern. ^ (c) ,A physical jxaDlnVtion which reveals certain ,k ?> .lens and oa/ reveal evldencea of dl.abuuy ir prese.nt! ! 1 I Methods , . . ....................................................................................................... * '*e** * * 32 II Experimental, Aabcatoalu * * *4 # * V ' .. .*% ... 1 fISrcala.n lb>) i , ^ _m a i E a l i mt'o trachea^ ' *v;>. ~ " `-- (c) Injection of Suao^njlgng of Puri*;M r**.ai8-/ '*~ ^ ` Fibres dissolved no aaDgaToTTr^^i r 9* .lnt0 ot,`er organ afsibneesdtotso cPahryegtosooyftohsuinaana,n-dsubejneocatpaaSatioA ' Co^-wnorre9?t:hieic^ c: .. 4*. *.?; '.'/.*../'%,, .> II I2cli8 3_u_scentlbll(i;7 # 1 //.; .U^-;0 / Unlike free silicai.'/aabeatoa''doin' . v r:`V'' .. ___ * the lung?of man and those ^ . . . . ribrcel, -- ``':> Cnf'.,^>1>.?-. B _A -3* '/ v WhltaiHottaa-rC ... i*`V**. T*"' Z1 Ltvriop.1 labMtoh bml 1in)' ' 'Doty r ~ r o *'" III Peculiar Charaoterlatio^ f Asbeetoeia .' { W - y .* (a) L-ooooaallll_t_a_t_ion of fibrouo'minerala/in iinr*i` *1 of granular 1) J I. ^ * .r*,f/~L' ev'*Cw *<V.! ''i' J. . V # *.* ' v'-... ..''..ie"Vi**.-'*-,'!Tl-- Vi,-v'/i. * ''- -*. *. .. 1 1 -0- (b) ta ro l" I a ir .pabe^i n an4 la "idely aoattar.S "i"o,,uSti`TMi th1e' to ao active d u l l u C n t0 aobeetoo la ouch -n soon aa 8urfloiii0,, qUarti- Evidence if"?! r?Pld than in apaoifio arena* itn<lantratlon of f i b r c h i ? 8! *?-=ea-" nontha. reaa> wlth -uartt, there l8 "rJ`.baf perlid^r (c) J?.""riuiS e c ^ U c c ^ T Pr ^ ' ` n oaaeatlon or expoaure oeaeea. ' (d) ,)roun ndulea beoooe larger^*ter" pne'laoconioala^^hay "Spiolflb ""'!< of t M r upon the eurfaoa o f ?ue t0 8 depoelt of fora oi nftteirn anbaonutan6d0idSaiyei.ff,,*fJon'ta?ftlbvrl't8h- thIen etulllnjala pdl?8 t?hhafn4-'lorroan lnrjer in th? fL-* a (See pnragrnnh ? nC re abur.d * u i V e ? fiS,"r Pibablf h o e i u . W l a r r ^ e ' *1* =uch atypicol coatlne- fr* Jn cato* rabbits and niff fu d air tube dence in tf l u L f f f fow of he flbreo iftii !* Ihfre 13 *n covered. Froa p f r a g i a c h T n " ? dS8 nbodiea co?idf`f'irefli" y-frt le-uvall adirMed t ! * Jh*C c v e l o p i d N n i u 1?!? laJ*lon several 'i(a artLer"exp.o,sluarie!rceoafeebaodies.ee-I tw "ccrea-aberoaia Co.QQa"f^lL*LEa Efiiou, r (a) Canadian ^ h r v f l o * n . k < i., ' " Qa:9?wl?-g " h l Su / I r r i t a t i n g . S g e^r iiS tintes aais- nuac^hVir^o^n.d f e \ - e ^ `i*;- CTanaa-dEian eprr,odpurcot. ( 1 fibfiffilff 'oil* alinlt*d^C8n bluasb-*otoa ia ~0 non-productlve^ex^' teeta into the ,,1 oeuee of ? t.' -ed c r ! ^ ^ r . `" M r r the I n t e r c C f i , f " , : ;'e *--< In tIon Perhaps bi`c a u ? i % f 1J f t l c than tbe c o t t o n y % u t h j j ; r ? 1e h : a *'. - L- L- G ) (d) Anthoohvll1t -'stiff, (e) Anoqltq - Ditto. , ( f ) Anoh1bo1g - Ditto. . ' (?) Treno],lfrg - Ditto but vory fow aebeatooio bodies - being continued. .. Observation V Control Mineral <8) S S 5 I S f i S zne lunS but T oourae, no "bodies1 devoid (b) O l a eg W o o l ( a synthetlo silicate) fibres alts n o t i n v l u v r - N i 'iu B^ t, : ; ^ s v . : s s ; : 1#5f.iy -- o V & t s i i s 2 J r = nxoocafiiibrreoolIan vhe air att* .rtubesabu-t fatr*e v7iidaeeliv/ flcettored. TTuheyoz oaus a few D-ifaf *riK ter* ,or 4 oontho in oontaot with lunc fluid iiiW^L.'i^rSot (c) gruclte free of of Interest because s i l l o n r* q<\ iji a ifxiobrouas cilneral praotlcalliy c ^ l s t t oht^ p` i n needle^lke00^ 1^?,1"5 M en e t u - The fibres* > are sstil fifo n : "P2 and . v-'i ??;iP"ii?b.So*.i.etbos;?i,ie#;a?0us " ' ? 4 = r 8 or b.*. reaction oic;csuirusi.a-rao*ufn;d.,idI5nrs;the;ard? .osf" iwiit!hri:n;*-tthiteufb?etuusebh';aensd?*tiisusruse VI Chemical Congos It Ion jjj Relation to Irritation (s) Nothing related in the following chemical compositions with variations in capacity to provoke caan ti be cor- 3eus reaction. (See Table NextPag-e) f 2 -(a ~ (s i f (j4^ i t tii___ #* Chryeotlle S i - 2a___ 3 7 ^ 5 * Crooid ollte 34.93* * 2 j$ L - L r :'f o K fi / w - y ^ V n < " ^i<?6*___ :':'3t0g/V r 'v7 . 2 ^ ' ^ ?a< 0 ________ 0 t 2 9 Ka.0 . 0,08 LQ-*3<105 4.30 Aold treatnent of ohryootile fibrj'o >/J . 1 w ! r ? 2 E o1? n & 2 % 2 ? .olvoo an* dl.appe.re' d o not l t ^ U -*''- Juice ;, with liberatlonCof^eiiioa 'm 22Sn e U a " pa")al < ^ aa it does aloluuaffrltizn.a doOensinnoiteetnie-u-tralize tbe 'e*"**f?rC*wnS n** asoes'tt* aluclnua hydrate eolution: f r ^ e i ^ J d ^ i S fl'-ispsr.ded m elop at the usual pate It rinl and aoteatoa bodies der . fibres*beooce ooated wi*h a if 7 ! ^ - 0 econstratc whetr.er tl h*s been proved in the case o / q - a - t aa does not affect their capacity ?o i.-r'itato t u L e ? ' ' ' es` VII Phxiioal 13 Relation S3 h 2 l S i S l 2 3 of 32 Tlaao, -V (a) Lenrth of Fibre . . ' . . . . `:* \ *. 20to 50rnioron%fibr'`Un,Jer 3 Ol:!ron -- practically lrer- Th. .rr.r?i ^ if rei eaui# epical flbroela. ' reael! `f ,lonSr 'Id not b. teated for technical (b) Cpiehins completely deotroya the flbroua atructu-e of "a I^re*: h 1088 f atruotu'-. 11. capacity to Irritate O.(o- Glees') VIII Q . ', ,'. 7V -- --'---* 1.1*TV'*i"r ~ u..t1tA.'yu >f** I*.'. .. = n.rai. or 1, (b) 00 Iron!" bo P3 bodloo would no t>. ? 4..`X (c) lung# Sh o u l d (d) Tho produl diittnoearflno; ex . '/J'.Yv *'* ''* /: '** ' ^ tloauo fluids. . , () a*cause of fibrosis^17 * fortuitous oonoocaitant rather than' " I X . -- q" Cq 21 i H ^ n t Action of Asbeetlfor* Mineral, (a) Cher.lcnl (b) Mechanical Irrltatiog oanifested only m the lun^s b e c ^ ^ s lrrUflr on vhlch * hose nora.il ohyslologlcalfuaa-ioi! , V ri3n 13 th3 "1/ c:*.e nobility. Sxoerlaent d l 2 d " i 2 ! ln,o!!''s kloh ieerea of In`* t-huisa tuissssuue hnave failed forr%toceo^nni^cnail ,,r'*9 -n-e-c-e8,8wl-t">^' r*r =--3' fFor this theory to be a p p l i c a b l e 1 ? lfal,,rea30n3- fibre, be concentrated in the tel SaWlS'tub* *. ^iifaihn^lFlHrHbinV '4 '& * the proper physical hlr^tI r L l l l l ' 5"?TM. "i"! 1 lont' enough before it dissolves In tb * i.,n~ x-0i0 a-all pare, nice rat./doy.. U apr:,ren?!y1Si`?|1J ^ 00i * ? S j t!uitl\ \ iinr pPai rut,n\ ith7el.l ei xl l o f' r fflloarioasll}. ^l,, roarpEia<ni. other than the lung. '. - _ I t * .. - 0-la - b tr`( (r) > eurnoi re"on<'. 9 the 1 XV ^ Ratlin thiberculoua - a T T ^ ' n a t i v f ^ ^ 6nd no:0 ^ 1737* like noa- 0.h cC #,eoti-n8UacePt5illtvA* c'Jar:z w h u ? * ^er cire-e ^ ? r : or * :he .. cln 22 Z SU Lunr ? ' `/ *** alao . / 7 v s^ - s . ^rrt?aXi/f^er6ivaieHna^maVerV'j5^'<,a,i/,r'/nJ/M ` p o in t* 2 Jhen t h ,, .,, ' 0 a t 9 ani1 i0 a lur` tu= 3 Soc strain of whit oioe do develop tumors vithrmt apparent oaua. i^nout 4 duch a strain of threo lnhalatlbh whit nice vao unintentionally experiments with asbestos. uaed In j?*1! loe.lnhfJ-lnS Ighff -fibre aebeotos for 15 to 24 aort^ 0 developed oallgrtant tuaors In their -lungo and 6 of hadjunor. 1 othar organa. T ^ AnotdfP9j u u S U - H i i 6 11?2 nDonnnt?hha2erotn!l'yhn31de8vJe1rloSUp1^ed lung toubnoersst.oa Rfaotr no13t. longer th 7 As oontrols, we have dust experiments. only the experience with nloo In othe llftgrJ 2 *rlortfii there were 51 nice exposed kinds of dust for 10 to 12 months. Incidenoe to of 4 other lung tuno: ^1 long there were 143 mlc exposed to 4 differ- dUOt'1Jol^(line Pur quartz, 23 to 31 months, til 2 f E?10 th ay*r2?e incl(1enco of lung tumor tS fliA ? du5t! h 8 98t rat9 (25*> waa in a subgroup oxposec i12i?enC% 2 f luns canoer in lDS fibre asbestos mio rcfotanpnonrrafbiliei6pe1r1i?o9d!s tahnVd oVv9errage3 tinesitohee Imnahxailmiunmg oftorheranyduosttsherf'orrron- l.lce exposed to the praotloally Inert ohort f i b r e h* * LeWoetherJnIuo"!ri althUgh 7 tl0', 0r^ n . . In'lSSit'^Jolur "e8e ob6ervaCiona ara suggeatlve but not conclualve evidence o' a cancer atiaulntlng aotlon by aebee'.oa duat. They are open to severs* orltlclsns. The strain of nice was not the same In th ?fr=u ,xPerlBent. * Id =any of the othero olted; apparently the the .d?us't? !f!orul?ounog?earU)rthfeinuatoheepU1b5lem.onthNsotapepnaoruegnhtlaynlnnaelcaessaaurryvivtoid in produce many -tumors, W a were no unexpoaed controls o T L e same strain and age ar.d no diailar controls exposed to other dusts It la hoped that this experiment can be repeated under proneriy oa'n c ^ ' p r t h r ^ ^ r 6 t0 d , U r 3 i " ^ ^ ^ 0, M l T f i v o r , XI Disability ffrrnonmthhesflafmeercaauisneesd mlent awnilt3halian- alJ'lheouarccdiudaetntailnhadleaattihosnweerxepericents. \ A.5.1: -laV>'(S).. XI-I . ' Essential Fnctore ojC *Utardai,* Mtokh,re ;' * + , >r*!^rfegv vi:.`-*i' ' . ' , . . '; , . i'T-. .',*V ...*T i , ; ' '* '* .*<*1 4AM. .V. -.. U) Naturi of 2hsI ' - ' ''* J*1^ iI Ahe hWaMrr1d/4at I4nMcArWeAaIksAeAsfl uwi4tt h^ ttWheA proportion o^f'iIntact fibres^ *J In the duet. Granular material and crushed fibre are Inert diluents. n 11 -The long flbreo ouet be thin enough (1-3 Hicrons) and short ` enough (under 50 Microns?) to be Inhaled. ' 111 Very short fibres (under 3 Microns) ore practically inert, (b) Atmospheric Concentration Still-under study. Apparently this factor is lower than In the case of dusts ooaposed of granular minerals but methods of estimation are misleading. . . The average standard Publio ^ealth Servioe lmpinger count In the long fibre asbestos dust roon'was 40 million particles per cu. ft. of air. ^his'concentration-caused fibrosis visible to the naked eye in 20 to 24 months. For comparison the average lmpinger oounto in an experiment with pure quart! was 120 million particles per cu. ft.*and fibrosis developed at about the same rate. : * 11 However, lmpinger oounts are deceptive because by this method of sampling very few fibres, which are the significant elements in the dust sire oollooted...*'i : - ill Sampling with an electrootatio preolpltator Is a much mere efficient means of colleoting fibres from air-borne oua- ' pensions. Samples from our long fibre aobestoo room ohowed that the dust In the air oontair.ed 52.5,* of fibres few of which had been oolleoted or counted In the lmpir.rer sample. The latter sampled largely the Inert granular parti- oles. '. . * ' lv As ordinarily employed precipitator samples are welrhed and the results expressed In mg. per cubio foot of air.' There is no means of oonvertlng such values into numbers of %particles particularly when these vary in sire, shape and s.peclflo gravity. v * ... . r.- # `I . ' * v Simultaneous sampling with precipitator and standard is- pinger yielded the respective values of 0.65 mg and 60 mil lion partioles per oublo foot of air. t: * vl *heoretloally the best Index of hazard would be either the number or weight of fibrous elements In the dust. 3*(p- (p(a(9i) I.'. (c) .Duration of Zxcosu m ' ^ ' Crea3eS lnl * '' '.<(.' ,4* A ' ^oSbieque la'nonth?0" ^ 8 SXyOB'JS-'.g i ^ e f Uye?3P le i K % i r ^ ?" F dt a ,U o a l ;:. ...>; * d r ? ii j s eui r ? " ^ ^ - ri r pf 1 ? y "I"V . .' *fwo^^6uunnaaWce1l!'y; not susceptiblveo-.T. o p ^ e . , ',fl* ors ore u <\*" '! pI*;.'/ > kMI".wv,0^ :J wrearrea. not a'Ioei^Ctoo^^a^l1fi1i1i0o^ne 5o6f? htaheVeobbfjfeecnticvlensl^oafl and t h l e % 0. feV' *: . B i c o z ^ d a t l o n f n p - a NrtW' ' * * feVtV'V of A s b e T t l ^ u ^ f ^ - ^ Standard of 3gfe'At-oonherio Concur-,,., V'U. .<. ,'/*' .*'*,.* .. .` 7<.;1. . ---- ` P*-: [i^r^v v;(a) While there n,, ^>%`T . ^ ,' :Jc' [:*<' r 'l " * . tk : .. vr;*.\.. (c) q4uootred5. Qillion Ppaarrttiicclleess^peratactulbdicrd,roottheo'fteanitratiisver.one or requer.tly `'U J. "r of * ' Ye now tv*,ri'*i-i..fc _ U .iVbaeod upon sosolm- W " ^ * \t: colleotei-wuh ni t l U ^ S u t ' c ^ te t a t i i "?" . =!. -Ot e r . ?lne m 4 1 1 y ,fc. r e i a u v ^ : ^ ^ ,';j ? * " i"" - H I - . &ccoonn'c?enr*t"ra'*ti-ion"s* of dust. A . /:A-1 - ? * 0.;?.;xp?8d '-to -irrerent :;. XIV Frevpr. e* #* '/"#** --* . , ' Vi' *'* */***. ^ i t A s i^ tc .i. ' > . --- *. ^ . -.,v enperlcento hoy, f a U < d '7a-d^ `i M ' 1 V* ' ' - (a t> 0 e) * V. . > '*'ors-re'*%.than*.tvh.e '>f-'4.'*.S'i1; . /*.* : v;1".:; ; > V 1 - fr- t. ?r *v#' .!.**-**% .4*, #?%%,;.. \ , . v,. os s or I < X u 't (o ( u ) LaRay a. Gardner, M. D., Director, Tha 8aranac Laboratory, Saranac Lake, Haw York. Daar *Jr. "Gardner s * aeetlng yesterday attendai by cartaia braxt lining manufacturers, Hr. Slapsan and I were able to present, tp a fairly larga group of intcreated corporationj the proposal that one of your dujtlag chambers ba engaged for further experiaatatlon -with asbestos dust. The proposal was wary wall received and it appears tost not less thaa eight, and perhaps ten or sore, corporations will participate la financing these further experiments along the lines dijcussed enea we net with Or. Lanxa and Dr. HcConaell a few days ago. Accordingly, you easy consider this letter as an authorization to you to commence the contemplated experiments with asbestos dust for the purpose of determining acre definitely the causes and effects of asbestoiiJ. It is ay understanding that, among other questions which it is anticipated these experiaents will anjwer, are the following* (1) hat concentration of dust is necessary to produce . the fibrosis of the lungs which la designated as asbestosls. t (2) Whether exposure to asbestos dust will produce asbestosls without the existence #3^.ewious infection and whether the X-ray changes found in advanced human asbeatosi! can be^rwproduced in minala without infection. . ' ''-iVU'X.Vvft.*5 (3) Whether the fibrosis produced by asbestos is of the progressive type, that is, wili the fibrosis increase (once it has started) after exposure to the dust has ceased. 04037063 -2- (l) Whether the fibrosis resulting from oixposurt to asbestos dust is occasioned by the silicon con . tent of the asbestos or by its fibrous structure. . (5) Whether the presence of asbestos bodies' has any diagnostic significance. It is also our understanding that these e x p e r i m e n t s will require approximately three years, which will mean that they will not be concluded until about the end of the year 1939; and that they will cost $5,000 annually, or a total of $15,000.*I It is our further understanding that the results obtained will be considered the property of those who are advanc ing the required funds, who will determine whether, to what extant and in what manner they shall be made public. In the eTent it is deemed ...desirable that the; results be made public, ..the manuscript .of -your- 3tudy .will .be, submitted-/.to .us /:for approral-'.prior ..to .publics tlon. _____ , I shall appreciate your adTislng at if the foregoing accurately expresses the proposition you had in mind, llso, let me know the manner in which you would like to hare the funds ad vanced to you. Would you, for example, desire to hare $1150 paid quarterly in advance, or Just what arrangeaient would suit you bejt? Any method you suggest will be satisfactory. . Since the experiments art being underwritten by a rela tively large group, it has .been suggested that, as a matter of con venience, any communications regarding the work be addressed to meand I will, where necessary, communicate the contents thereof to kr. Simpson and the other parties. You will be provided with fundi by either Johns-kanville Corporation or Raybestos-kachattan, Incor porated and we or tt.ey will secure from the other parties their pro rata contribution. I will advise you Later of the nsaaea of the other con tributing parties. ^ . I shall appreciate your inforaing me at the earliest possible moment whether the arrangement as outlined herein meets with your approval. ' Y3:T Sincerely yours, * 1 ; V andiver Brown General Attorney 04037064 V U > : ~ -> T he Sarakac L abcratciiy rou the Study o r T uoc.e c u u k b 01' TH2 EDWARD tj TRUDEAU FOUNDATION ' M U ornct rsN 7 cituncii 1 *"" vj:> Mr. Vor. d i v e r Bror.n JOSWE-Kinvilie C o r p o r a te 22 u a t -lech S t r e e t lte*.7 York C i t 7 ' D o o r Mr B r o w n : x u u r a u c r . o r i : ** -'*1 U(J . p r o p o s e d o o t e a t c s i a e x ~ ' r J-~'^v ^n n f '*>, la acicr.C-.71edS s d .wlth aaxi^fictloa, c" `-u Saror.uc Ufccratcr- opuetcltiondedt.o rTohruol'Jh n a i r a S "*. h r t iquuooat?-lMorna"*hiSc?h\Cy!moubhoavo;o`- o r threo K;;~: that you cay cere' to i?--e ?, ? r ? nt Iu'7 othor "rrEngcrnr.t o f tho:io s t u d l c a ^ ' c h u l i b o c o r ^ t h ^ n 1*7 a r o e 3 t h u t tho r o a u l t s ond th a t t b ' r a n u a c r io t, S t h o Pr o Pu r t '/ o f tho c o n t r i b u t o r s approve! or thereon tribu tor , 3abo Toro pub lice tIon? /, *.* * , 3 *^ 'pa.-rorr.od with our~Uf-Ldl3nr,"r - tho t tho eppori.Tonto bo iof.TP,y uttto U j u i i I n o u r i I r a t eriia* ...,i ,, . ffji ;t t h a t I t c o n t a iJn:etdy s u c h fibrcua rock duat. I f ~ J rxuoca u n s a t i s f a c t o r y ovrins to tho h l ^ h ,c o.,n c o r . t r u t i o n . wo *f- 1nen- cc hhoornnrl c"nil thaundd p e rt r o g?r1ap h i c a n a l y s i s . _ * ( - * '" * ^ ^ u u . l l y sit ^ tid hitm 11 v tr.a t o r i o 1 t o b e u s e d I w o u l d r i o u e a r t h a ? ? ? J *rc^ culd , . ?3 to tho to 3U3Dl7 n o u f f lo lo n u ^ w n .itu v o r a s c e s ' e o ^ n- o o f J n o a t a r,Ht o ; o f s u b d i v i s i o n p o s s i b l e - . 1 o - ' s o t C C" j?g r.broo to -ln noleble dlr.onalona. l ^ T u V cT al - : `:a. z ko: I f thta q u ost {iouid'nSt j '; T r . ^ A y/>j.1--/*SC7 - A S - . ^"* ' * \ ''* 'H*.Y*-Sro7rri,M6v.23,193G,p.'2 S i T 8v r . / lCi 1CK1 SOXI 'Q QrrRnG-rr-9r.t f o r i t a r r i u l . h a v e t o bo rnado b y tho Laborator*.-. final red-cBu- a t ^ " on m a t e r i a l r e c e i v e d by ua sh o u ld bo broker. t o ' p o n d l - ? ' tho material in lnoanaible to nocoinary for' the p . r f>3ti-nfn 'i ,, ' n "! of aa ita behavior It, our d u e t l - OBoe--.. bn? ti=o :i determined. With the "Ki.-.ra Floats" e n t ^ n VT S a1P.-C'0u-tp-eunda a year torn reSulr'u"* V1 w ?13a con,cPariTv0uriblfe thi yu t inoro*-a-j*di- Ind E~ " C bo Q l ^ a i p a t a d i n t o tho atr.oa ph e r o nocoasory. J h'*CG a l a r g e r q u a n t i t y would bo W i l l b e p l u a ^ d t o r L : 0 ?d7 t0 3 i-a " th0 * orl< nt "hy time and can bo p ^ i e d . " lr-= 3U!=Plea r CU3t " . o n a a t h e y thie proSrat,,. I haukl:iS ^U t0 r 5roUr -cooperation la arrensir.s With boat regnrda, LTJG :C C r Sinceroly your3, J , tL L /U s ^ J s y ^ i.'U -'jA / L e r o y U.^Gardher, M.D. JrJLrayior c I \ PLAlffT|Fps . n * * V 'f exhibit " 1 < . I t 7* * . - !9 a -s* . wmmm A, 9* Im m 1 V* k t AA. It Bfia--ta*ta-- T, ftM I l V* Ita V -- I n a 1 l i fatta-- 9M, .! tonaMtttaa m itili-- r i Ita B N ttai. ha -- Ita -- U H l i t o riM lta 1 i r A t a O * V U tar'i affla. l i a tt i r i V m y r a m li ti -- Ita f r i - t i r tarla tu a U r i f Ito p u r-- t f taarla a f r i -- V ita ta # Iva-- < Ita ta li iU ta M ta la-- -- i -- NT* a-- avuta Ita m ata to-- t ita a-- vta-- a ritta lai-- m -- l aa ita l i -- lata-- tory. ria Hai-- ll a w riita a -- r i Ita latattlrial taf!-- -- t i -- al U-- a r itta tari taaa aavavri la a y-- Uaa aaalla* m tarila I r , Uaaa la Ira a rtyart r i Ita r i a -- h i r*i A t a tari p i -- ri aa tata -- tri ta Ita fava-- latovai-- . Pr. la tta r-- r i a Ita! avla ria -- ari ria lt r i tari aa-- a la a ll ita aaaava-- -- aataa la ft 1 Ita lata to la*-- ta ta l latta alita -- alU allr -- vftor ih-- to -- aaaa-- r i v ir i Ito ari* - k , ari-- r i i ta l a a-- apatia aaaral-- tari -- aria-- al ria tari i b ri far tata aalr -- varia a ia lr -- jaav tariara ta la, tatia -- -- taalaa r i Ita ito l yaav, ato *U tara r i ha* ftaat tifa avavythlac_ -- I hai -- -- -- ala# r ila la -- vite fraa ita ftiaa rial-- ta l tafanatlaa la itaa alita trita r a-- ria -- a Uh tata-- Bri-- Ir. ilaa avttala aa Aataaatoat Ila rifatta aa atiaalt* ita,affari I aa all aa vaiala raaaavata m t t w i p -- laa -- talaaa ria aarira1 af < la Iffavari tal-- af lato ririal p u t i t aia. la tari -- rii -- I r fiala-- Ita y-- a f feto rapavi aalla ritta Ita aff-- af ta to ri aa I-- a balata a ri tari -- r i tl .-- lag -- ta -- aa -- a-- -- a. k , iM M -- a M Br. laa-- ta lv a to ri Ito -- l tata-- U harlataa. .., taa tari ta-- aa-- U iri riita Ita U ta I r . avtoav -- tatawrif aa a U t r i Ita aavlr aita aa a-- laa aa-- . tofana tata r i taa aia-- a taa -- 1-- u a m u li r i i ta far aa tatto tato la yrarito riattata aaytoa -- aaaanri. to tt tato 11 tari ta-- ama la -- a Ih tota Pr. aitate' aarataiy rito Ita a-- aaaiy aaplae -- fa n -- itaaa. (latto-- tir. Ita ( n r i-- r i Ito -- I -- to r ta -- -- atei-- -- ta ri-- r. u -- 1 affte to. 1-- h a faa r i I t a ta -- I to -- tria l ta tr ite .) US *2*2 7< a- Ir te a k u t t f i m i k , Ifaal tei te ta rla i U l te f i m i t e a tea a aa m 1 te te te m te la rIU te a ay a telte te tete k . M M r 'i t e t e U t e : ate te te raaalrai a te r te te te te te te Irate te teA te pparteal? te nate te ateartel, te te li Aterate tette 1 te yaaattl te ja l i l atete te aateitetela l a * . , te . te a tea te a a rt te te teate atea te irte f fa tm rp * tea Arlate te* Ifa a l tei te U l am ai lf jaaam a ter te artel a te tea te t e n tete tea a, t e d i M ate te n a * tea 1 U l te w m ltete a t e t e a terte ir tea , Ir* te a aate te vaali tea te rate v ite M atea tea. A tea te a te te . teate MM ldM te a A Ite te ateartel. la aaai te ter aa alla a la afateavtel aaA te tea te teata par--te iaalla Ite te affa af Mtaalaa t e l a t e a teu w -e aa a te te te fatrl aaajltea aaA te te lte rte 1 vaali aate a llafaater t e . Mr. V. te a tafairte a tette te . te a tte |M te . Ir * ***U a lla ! a * te aallra nk ararla* "aateatea* Itali te . AarAaar teA te i la atei, ar tette te vaU a a a a tr m a i l r l t e f t e AaUIat ttl a r t f t e f aatealaa tea te a telata: te teak te te a rU lal te AU ate te , a la te . te tte vaali iIAa atea Il U af te te i raw lrvi te atea -- te te aa tetta te U l te 1 aw li te t e lata aaaa aate af tea. te . te a ta fa n a i a te atea v iti aatetea H ai te . Vate*. te te t e m J U te lU Ttimntim a te i ntenrrr* te te Mia aam I aaA aaaaaA te te . Srate alate aN aa af Ite ta fa n a ti ttataai ttm H a aita, la i t e i r t l i i ili la te teak I la tea a aiatete. te . te a a rm i tei li alte te te* affa af a la af Mteataa Aate. aaA te alaat te I la n llla a i. i a ia ftaita J il a Aa la te l a la la r a la ll a __te fiala tei a raya. If te af a v a ria i tei a la a affa Ite te n n i affiata I r t e , Ira! lafa rrla t a te . teate'a atetaa a te . t e a te te n U a If te aatarU I a n i tea nUA te yat tataH atU atetla* fa n , te . te a U lte attaattaa a a al In te l I n U aw anw gaaart U lta , i m m S atenlatf UH y w rliai te ten li te aa fatila af te n a u ta af farla lite n r a n d . ^L e L .t L l t t ! I fL al a te Ite ari f rapar a vnlA te a lai a ter y atllalai, te tepai te . ItmI rUA laalvia a atjaattaatl la rtU ftea w tata af r i , aa, far p i . r j te - iloa te tra Mteataa Aaai A aaaa, arai aa la rrfaraaaa Ila! te . Aariaar te i aia a tila la Ila aaaaiTl la a iia i. te arm te rapar aaatalaai a aatarlal !te t m * aa fa rS S l , fte T n r palU af rU. * ter 1 patialai taaaa af te teaafl a t la te f m te telaa n f te rapar. Ir. te a aartrai Ir. rapar praparai tf te y atllalai Uaartera. te te lai af te ata la fa ta ti aa te p n U fin te a tte n ta i a f ate a te n tila ta fara telar rapar w aataalaa 'ama t teaaaai f la ----------------- , aal U te i te a n a aa fa ri. Mr. Variar r r ----* te I a la ti aaaa tarara, te i am i alla ilffaraaUy, alaaa 1 iaralapai te I Itela in a i la ra lr m n y a rt t ter a Ira tea aaA pattelaclaal alte, !U t te i Mi te faaai te Ila Iter Irte. . 'N ta lli * iUtattrMIta li i m taf* t i n tal i i r a w h ta l* ta ta l f iu m i i f tal ta d itta if ntaH ii a,iittaa,l atttaicwit*irM tattaata fatata t a t a * Ita m p m t a l l i u ntami ai ita l u m i tataitany. ta l i ta l tal l i itaf alia ta i t a t a f n ir a r t a l1 fn jn to . n im m i m i t a tata l i m in i, tal in ta tto * ita Im m i f Ita ulta if M ln li l i t a t a ? t a t a n i nW ta ita H d at a r M r to ta ( m i U ita ta llii ta llii, itavi tal ta n m ita-ai tt ta tanta ( ita ta ta . M i iftav Ita m u ta m i tav tata m i l i t a ti n tol i Ita* t i Ita Ita m Im i m t a llii M i Ita li tm ta i M U lm i fa i m i . t a l i , ita m i Im i f m t a * ftatolictol m i inn ata? ta totavft* fi f i * ! * * M i ita i i*M ikta. ' ftr. tolta fa ti gitali to lta li ta Ir. I . I , totan i, ito l i i n t a t a M anin i f ita Vantaitaa. * m ta l u m i * m nvr mm, u lt i t*itotaal ta 'nana nta ita t a l'* , Ita? ta i k * a nr? n m n n t fattaliin al Im a n 1? ila aaai if lt m li. tarla ita m ta ta i < m lata ita am ica u ta l f in ii? m enai aa tata i f t im r * t u ito t o r , ir . tona Mi i t ii n l ita! ta im ila to m i > t ira n n i -- tar ta ita la tto n i to n a r* to m U . to. Im aU ta i m l i I w m /aaaar? ir ti. M i ma a illl ita ti. Ir. tatari ta f* l i fir m i t a t i m m ila m m itavi v i* a U lto i f ilr n t n t i atatfi i f ita laWrmiw?* Sf ta i m , am et ta l Jito v ili ta i l totali ita te m a im ta tti ai ftatatofiial Mtortol M i to litfn i t i. torl i ar acr m ta i a rrto * to v ita la III U n i t o v i * i t a mm ito i ita ! I r . Im m i to l i * ita ti, M i ta , i l i , to M eta* M Ita M in ia i, ilita a * ita? ta ta a asm at n i* * t o m ta ita ta llito it y to tota I t a m taa lim ita i? t a t ta r to l i ita JiV arr n i ta lm , i t a ito? a ri i t a * Ita lr fato * ita ita t i f ia t* * a * ita? am ta m f in ta r , ta n -n ila a ila tato to ria l to to tali , Sf I r . ta m i i a u a t i to t iMM 111 male, l i *11 a m i Ito * ita i m i m i l a ita ! m ilito l a n i n i la tim ila a aaa aaa. Vrtaaril?, ita f n ilm m r to ma i f citila * m m taa tai to tali * m ta, ato tato la ala to itaa m aalim tola ila a . Ir. tana t if a li* * t*. Imita tartan, ta n ifitalas ataal ita tacila * aalaala, ta n f a m i to Mila tota M in ila, n tota i k l a n n u v ii. Ir. taam aanani Uai .ta anta Hain an n a tarli. la an an ito a to ta ita amm a n i i ai Canaaa to ta ila ln a n n a atta. I r . Im m aali ta h * tim i ih# n ia a la ta . ta r ta n '! laatari,Ila affa rm i? la ta * * f n a n p n i l i Jahaa-ttntolto. Br. laaaa n f to i tato aalartol a * ta n to ! l i alai to ta ila . la m i taa taf?, aa f i u m i sQa lam a ta rm i taa niaa n i m aria * ta. tartan. 1 f i * taal lia n van 11 4tifa m i n r ln i f m a r in ili n m rtat a i l aalaala ala ila laaanna aartat ita n laalto* ttfn la n ia Ita naia n am aarii. aalato* larii aai f i m i aalilM. Italia ila ln a n n a aarii to ITI ia gn n V. fin a f m alltoa vita tornito! to n?itotollto. Sf tarla la fn a n i, ita n la in n tto a to iif t la lii a * nrtoiiiifcto. tafnlanla v ili ita aalata* aarta n a v i* n Vaimi? T, IM ili 100 I*1m i fim tota 0 m n fn ja a i* tota a v ln la afflaM l Ita lafaaailt t n m nata. A fin toalita lia m , ta. tartaar m ito * ita i ita tevatolgaitoM m ali aa* la i l n n istiaclvi tata n ltn U ? n a ta m i* * . jm -- 11-- -- m p m m m p *i-- i m im i iw in iiN q *m , im s -- p ii i tt n iii i *K m f l i p Ml m i m u - p i n Ml I p -- 1 im w H n * m i -- n u * W `M fMMIMln i n i * H I HMHM n Ml-- t ' M l | N I l>MMl#llMM'lM--l IfH 'F-- I -- mIunm Im wmmmm-- In-- --I %M* H --W J*Mt--,, . ___ , HUI Ml P m t l M -- HI M P P -- tR* -- t -- ni W n " n m m n -- u m j m i m mu i *i -- m m h i-- ii w*" I m i R p VM H TMM P I f f -- I t -- Mf II MI -- 4 P *m IM IP I-- M-- P I M 4 I P n i -- M m M M P -- H M M P M NM W M | p | l Ml -- Il J* | P 4 I P P f*M-- -- M *PI-- *tHW 4 P U 4 IP I P m n-- i p i Ml 141 -- JJ 4 I 4 P 4 I 4 P P -- P P Ml IMI IW ' H a* P |-- ttMHW M PIPII U% -- I l P P IIP IP I 4 h -- I-- P I P m -- i p % PP n-- p ip im i P tm i um -- p p t P I n i-- tc p MM p p -- *wi-- m -- ip m -- -- m m tm *p-- m -- P I P P -- P *-- P I M-- P I -- P i *1 wimiC 9|< -- | P p p p p p -- m m p -- m-- P ip iM Q *P ... M P p p PPM M P -- P -- M P. -- MP `PPM -- PM-- um Ml a Mlp M |m < MMP P -- P I PM-- IMPI p p p -- H M p p N 1-- 4 1 m -- P M , m-- vi** | w p %wn%xl m m m m n m n M q tH***tl *411*1 1* rn> i in i iM iip a n !* it Myim>A i ik m im m % MfMf i,iw<n m |i tmmjx m ni n iM M i i m m nm v im n n n i * *tn i m m i n n o n *m i m i i i n i *n *k h m n i k u m i m*;h ^kim wi iimni Mn ntiimnmmi mi mm.iimmimnmmi wn imnacm'mn nnmwmnium n m ni i niiuq ifninM m w m m i u n `m m i i i m " i h i n m * i n i * n -- t n a* * *m ii m < m m n i m n n im j; i m u n vtMft i m i f m | i m i m m m m ama 'n m n l u i u m im i m i k m_ __m._n_m im nm m_n_i_m m m ni tn mn mn i m*minmi nsu'mnniin *m mm mimi1 mun *imi ammn11imm m inf m 1 n ym mn m n m %m a n m mm mhIivyn min a n i a *i MnjyHtaui ai 1 msi* i m m i ima m i i m m w rnitfai n i i im ) * n ani n m im n n n m r m i n__i nmarnini mi ammki m mainimi ma * Ma n i m y m n 'n m m iim m u m ma m m m ani itmimiii mn mmin myi m m ma ama ym m iam i *m i mi mane tuntymmmmammmmmmnmamtnmuammmAa a i mm am ma mmnnmpii ^ m n m n m ma v iw m a i<a m rn rn m ai i n n n a m M n T i!! j ? n i i ! , m _m a m in n a m a fta m nm a aimimmeimmaame<maw nM l m i am aU w in f ja im m am narn n m *VHa|m n m mmy a ,n np* n -m m m n a ama ***** m w u m -- -- . IT m aimn ammymmamami m mm**mmmmmvm*atmm nmtmamma iammymam*mp ijm a tmn mm i * m n m m m m in a a u a m a m p i p ip m m i* 4 m mwi m m m m m m i# vm n * m am m im i mm tf tym S m a nav arnpj ta fIMI im m p p m vm rnpm p i pw y * * * * m m m i mi m i l i m pM lym J p S 8 S S m ^ U p l m n ma m n m k mi atmum m amverni n marna m ma m pma am in v i m amvm m mm ma vm% mm nam ai m wmmpi m vmi am 3222 amami *m aummamna vim iv amai J m l m n'lt ami m m i fm ami n m m amami a Mm m in m im i m p ma m m vm mm a m m m 01 p m j p im **% **m *m %m*% m a p n n m mwawmw nm* ai 01-- ma-- m ma M ai n aia m*mm *n ima ' p m m i rn im i % vm jm m n n m  t t l l M l f i t t (IIU m U* m m te tlh V i Ir hmm ata** i tlk M ^ H l N Wfalaa. Ma I b A M atir iitttIfr .ftta I W tW W faa**tf fe la rt yawln T , * t a ka jw kM y n U viali m t a x M I f ltn U m l a fUaa aa M i a ; " tai u n tt m u kaaa p l W i r afila # B# t a i w /^n 0 lA*ii, ' \S< _ ^V - \ '* -Cb*----` > lW I- PLAINTIFF'S ;-|lii /.fo^HjI^BlT t n m i or n v n > n u f u n u r 3 1 . m r 1 * a m u hux^ i u ^ m i n ^ **as or a t, x. lull n . m lot or ru ia u a o ra u m m n n m o a ra , am la m a u m cor n j n c m n i ? yp n a gjutm c u j a n K g r . P r*ii v,rtt ,. . ' ` * ' i , ; 4 a u * V. I a A* 1* T ith r A. 8 H m W 1 T* Irrtm 0. V* l i t * 7 X* J L n rk m c X* / m Iuaa <T JU Z a a l l l t i J ? , Yol&rd . *r. Ifw U ri u r r k u ehalm a rf tiu m t i ^ , a X*?rl V $ r. j.* i : . ; r,rt i & * t Lama f .Utaa af tha p a r ^ a t. ; * * & * - , ; -- 7 ? i called f* r th puxpo# / h * * riaf S S % iU S 5 * " > n l ~ rrtx. at I * . hlah ta ftr u tlta tAiA ha ha* oatharad o a t i . r ~ .a , tr tp U ^ Ryport Vr Dr, L n t t t l . t S t t a t / 'r v i ; 1* ** *""> 0001190 . . . . n .h. l i t a t . t t t t S E a t a S * * "* " " U tatliatf 2 2 ? S ''a S S f l S S i f t l a t t a i T t ? 11*1" t " * " U U 'U " f *" pratta,. th. a.,t,.i t i . ' i t t C l ";;. S a w Pw flal.had tha part af hi. rapt* daUla i u t S I i t t itli.lt *"* aa h a hala*., aad h U aanatatad.tha ra.t af It,S * l r E ^ l a t . , r. Laaaa nil ta Hr, laanath hjaah at tha Xadloal Sahaal la Charlaataa 9 0 h, hu ..a a*.ootatad vlth tha lata Dr. Oardaar id hla.alf a S m E l r * "`S t f ; " "ii* f ef * "*" *ta h a d w i t a t ^ . ' t . I . far har. uf ta .! St. X & t# S D r* t i l i"***1"",'1,', "* ""nl,d^ C rd b lir^ fl i i n r i t x r r ts V x 4>ir - * hla_IJt a ______ i*. _ had tan arrrf t. X 1 of --p*oo M *Xf as ? p ? ? 2 g % i p e e I oo Io H ' *1 * * t* m I I *- ac xt H O gar M b-- -- oP -- -- Hof q H s ssr? g * 5 n* : r a - a r l*^ p p-*i a 1 5- 5 i * ir5 ^ O* b* K O P - S s . 2** * r & H i : t i 3J 2 W- os* . -- *i? 2 r g r 5. 2Eb -i l<r o*fMHbm--a fA' J b a tbi<A4H : C. 5*_ . - f *f ? * ? 5 s s s s i 2 n r l . 4W SM M5-b'pU.bPah Pa^ P -..* :oo H**dd*tnio*b5w | 3 - b-- bN i* m-- --p* VO* tr f-2 s s ek*O tt ^-- o3 S?bG i 3 . -P n r*3g ft tr 3O*ft ft -t p. -- ^ ET ? - a s * - * i r str r - r 5-sra v b5* P-->o^ g* 2 - - zi - " l " '3 ' * o H"o W fc < i tr o 3 **" 3 R *M K I* b P*--b*H1 b ar n sr* 8 : *> se* a * P w * 5 S-* | : I ? I l E S ,ir Ef ^*3 3 * 3 3 l 4T2-(^ o& . - . -a ^ f l d *w<cCJ e t <* * i S*- t oM- >o-- o tbf L 1} N t* i i i 'Jm m 2 2^ t-_ 3* * -- 5 + tttp A * t k.. . h 3 o PH E%*P oK;rp; Pi arir 6:o *24s <sf n ;r e t r b:> *b K -- o a 'd F ft o - f m - 3 -* *! H aft * * fi ft K H * a S tS *r i l I e E ^ f r * -! n Tp s* rE^fl s' Exhibit ,0o*aflalaW U)*k tur,uo Uu *a*r*tho*n**u"*1th^a* ttItkappthaarsahtni/u t rf **v<n.1ttr^it i urul auaosptibtlHj V# pa*nxa tad 54 (iliM lln 1*4, lx tl* first ~at*, aad w, t. ivii, m i , 47 n i x ,1*, h J died fra. m i m L tttr> J1111 frlTla* 11 with 14 ath* cpaavra, U with 7 u i U u semiti Ih t V# kiyl xa li| u ?ruiLm U j fax a rtitr *f la-- cffaotg. Anar 10 M t ) b czp4nn tha vari affsata af the calelaed earth r. * 4 * ^ ^ ' * fl^rata la the lax*, Wt aa ttnml ferale* bW/ raaatUa with chroalo lafla***tloa aad valik that btalaad from t h a w . T*m oetS4 t/ya m l fij a t elmaphpxetairo. fallita tkl a fiVrtili #f the m - , *Ia fta a u j, IMI, tha hit enoiatntiiu m t l u m i a l without mrr ratable hupi, Thia n i iiu far tt trai tkaitM that tha Ijaxrr af p u a n i a m t w , 0*a kxrdxed aid fitta* art nixaa plfTvar added. laJeoUa* xparlwata lata iwda, that li. latrarla, t*rxe<*iax, latratr*ch*al, aad lata th haart, vara all awpletad asa eaaiiderahla tira 14. l filmi, thajr ahev that tlw m u 4 aataral aarth k i vd Oardaar liti a Pira 4 1*11*4 a* ia tarla vhiah fa ta ab* | j^lrta (trTilrita). 11ta osa^latad vara tha lahalati. zraxtrarit riti. 'la**aCr!fciti#m,va1cUaliM vretrl"a ahfeLv*a*frWa*"th*i*a a*z"^rlvrlaxtt*asmiil*iatt/pcaadafxsrt*tVarrsla. eaata (piai f ila*. ^ . *** o h m r p i a n t i uairf nlilik aarth viti l i t n t m b i l Ixjaetiaa 1* riraa 7I4 *1*4 H/fle. Jf tha r-r*7 refrwtiea rathal4 tkt hart 24> J7i1Wllt. Eli* n i tha erti erlairM vltk rHi aah* im i tilo* pari*arti m i earriad aa vltt *lxaa. ptf trarla* ta ctpanxa ta tikrela lxfwtUt, ale* riti M a n i a tafa*la*. mU . aftar axpacura ta tvbarol# ixfeotioa, Buia z?riletta vili aitine far at latti ara rara p e j ala# lihalttls* azparlaaata vlth Irfla ylthcrt *7 addai iafaotiwu Ih* indicati! ara aa far that Hpfla Uniat a tubarci* tafetiaoL. " It vet f e lt that tha coaeluaioa reached at tha aad,' ta tha affect that tha irlica tlex * ar that fiyflo tiaulat tuberele l*fetloa, vaa rathar iia tu x U n f u d vat tha part of th Tport that ai^ht It # as acre eaaatnu fir* X m a w a * asked far hi* srlaiaa a to hov vuch tla vould ha required hafara a daflalta aaaalaalc eaali ha reached about thl, and ha tatad that it prebablp would taka vat11 tha sad af tha rtf* ha thought tha taohriolaa vho haa sharia of tha dartiif af aalxala vovld hart ta carrr or hi azparlaat fr tha rat af tha r#ar, cad, ty th tlx ha grta thrragh, tha pathologiat v i l l hara har ahla ta oatoh vp vith hi latarprrtatioa af th# alidaa. Ha addad, that vhai ha ta Vaak fra* his trip ta tha Vast 0ut, aVrat tha firat cf . Jura, ha would Ilka ta fo hack ta Saraaao, aa a* aa pasalhla after thait, ta flrd out ut vh*t prtfrasa ha* hea aada. - - . fo aa iaqulry fro* Kr, Zliaahaat aa to whether !tha ladlcatloaa a i v 'that ;^fla : tlarulata tuharola lafaotiom , vai tha l&ta l>r* Oardrar'i aplaioa, Dr, :la a j a ` ; rapliad that i t vaa mat, hut that i t vaa Mr, Dal aha*1a i*pr#sioa, and that "ha 1 * ooatiderad a Try iperitnood raa. Kr. Zlttahari laquirad fuxthar vhathar thara vao aaj arilaaao that Dr. Gardaar had reaohd a rj uah oaaoluiloa hlalf< M - Dr. L a n a ar*vrtd la tha nagatir. -5- hiah h u M l frtB thj < h m i S S ^ l 'lii f u *?1* ^ dhrmahilita, * * viuh had prWxaad !"* fcnad t# *** IthhiiaAhhiiaagf.. L^*rp*a h^u ahippad aatural !x^wrln^ ! V * V K Uf?,'*u*"**** *Dr# a * * * 1 * ? ! f a a t a r la l lx rh ia h U r G arda " r# r i m i Uu p a x tio a la r f# lt it m af l i l u t i i t i ? * > * * h i a i J L ^ i r r ** t a l* j 5r. O tria tr'i M t M . ia t m iju v h a th a r la m ^ o u l r l i ^ , , v 1 f 4 , ' * * ' I l m k * , t ^ " * fra i " 7 ta i t la tha h* a U *tl# JJ** * ***** M *hia wwjOa, ,h* " .4 M W tW pi.. * 1, ^ 1 . W **" J f * J r * n u ? r t i . a d * u H t h a t D r . G a r d a a r had e a r r i W th p la la q T U itia a , Jh a *C*rfeart *P th at a lia , ha had a l t d r ta a t ia l partaataga a f a h r7 ta tilita la it Sa W m / parcaata** *f e h ry rto h lliU , that ha h U ^ ' t W v. " U a * rr?*r i**I t v ith t h j * * " " * * '* U < n r i a g *****^*1 /oad a auh- ^ M t,rU 1 *h i* fhhThaddi hmao atttrtlWr tijW. ^l_ Ti4hh*wva-_TMr r vi*.-t*_ha^t a r th a ? r* a ita x a a f e h r r . t a h ^ f l i , aad f a r t h l a r m u L t . U L aa d a r ix ia a f th a O arh art aam p le. tha . Carhart* ilitri u i* P o ria a t itarial--U ^vhlai 4 "* *~*h t \ t i w i M tn m k r * W n c ra a ta r thaa ia ta t r y ta a r t a U la h th a aavrea " <*. Ukki^, ,, ^ t'11 *1" * M t i i r i L i ^ . w i i f i ^ i i ^ '^ V f l a p ard ar ja t a> ha ra e a ira a i t fr* d rad a ). aad th at it ^ ^ 8araaa-o aad ia ^ u L ra v h a t h t ^ i w L a if o r t had D . aada U xt* L ^ 2?r{f-`- S* *i4M- kUliiii vh at tha a n ra x a p a r tio la a ix a s m i , i,i:r*:s,t^ "i T it ^ * w ,i1f "/*" ^ . . at Saraaao ta h a i tha 1* " T I * * * -- * * Jr<l^ l * f ' h * r * r t r , ta v r i t a to r a c a ir ^ l, a r yfcathar xz 2J r a ftt ia a l/ ia ta rm ia a d . . S r i t S S T ^ S a lie f y&a azprtMad, hovarar/ that tha datam laatiaa af amah fa a t. vmO* v ` ' a ffact..ias ,,chaca.gia*,,t.hka fialld.a .^tr ia l hrriaaa prahla. a T hxT# u a ifa o tia g Loapoo, a i i t vaa f a i t that aa forthar tiaa ti. i* * P^hla* d*'1-1"* - > * * . k. ^ ir:^ ns? * g la a ia r ia f o r t 1 ear la g tha a a a t i a g , Dr. T . . e ffa r < 4 >4 . ..* * 4 . . . 4- . ik. v.,, c*.., ^ i S * * ' . r i k T ^ L T "*r PLAINTIFF'S EXHIBIT onD1 9.nno Ylea *ealie* y* a*le e f 11# lezt Wol rk ia l r i l l I r . /ela**, r f Lee ia t e le *, ie yreeeetlj ****1 ^a*Y / ehaiei r e l l c al draV Ileii veall l i e e u i r *l u r t lb*l re T re rile fe r tle VeeJc txr a d e r ia l te Ve eeeal. deal rill 'lii-UHii1, **1 h ix v r llia c , Dr. k m rtxiL t l d 1 rlll lia, a\ Lee la^alea, lia r**rxi ilrWMdvrU MTll rilik vi b *r . >rv e*C rtei le r. L a n 11*1, *l e * l i 1* 1*t* m b u Ii i te taH r l l l Dr, f * * r l u k i i i f t l i i , 1* xLclt m l 1 l l i e u i r l l l l i a * m a t rrpeTt le 1*1 md* #f * "J * " ri ^ ^ l m i l i i t e e w m i M rtl 1*1 1*1 i l * e ife rt e f r r U r i l **, *r <r i . I le p rH T n . e f txVer^LUaii U * e*r t * ia i i l i r l l a e l v ie , i f le 1*1 Wx g* e r ll**r7 *, r r a l i 1re lied *1 * n * l e *x lie r 1*1# lh** le 1U . *r . le * **11 le 1 *7 * 1 Dr. L a n n l i r l e l l Leepee d xria f li e r i e l l 1* i l * * r t Oeart. . k m u n r d l i a 11*1 le cqpertel le ; t a l i , f i 1e r e a u *e1e i i i *t , b a le r i e i l i i l * yl a i t , 1* eit i m s x l 1*11 m r i k u t r l a l tq rcio i u l l t n p e t m l l r r i l l Xx. Vestmoal, rallier lia * v it ! * crerp e f f i r * *r e ix yerple. Xr, eilm eal, 1* e*i l ^ 1*1 * ar* la lia e le u l 1 1 k a e rle ift c a l x e l*n t **l i * i * f i l * r le le **** viliai k* eali Vetter iapart ia * eerrerM tiea ala* r l l l Dr. k . tw . l e <r * l i i f * l* r c t r grrep r*re 11*1 la. Dr. L**c* **1*1 Kr, H m U i t le ixfera Kr. Veitaeat 11*1 1* p r i k U j m i l r i e i l Leapee rn w tl* dar lac H # U l le r >*rl ef fe lra ju T . . *r . Yeedari u n r k r , Leaia 11*1 Il lle e * p r t a i f e i l eiie r v lir r e i rre r l i e d i t e le 1*1 l m *11# le VU1* frm Dr, O t r i u r 'i f i l e , u r e l l u lie rtp erl le l*d u i i m lie experiaeate la ; re < rtu *1 S&r n u , fe r i l l i t eemed spparczl l l d l i e eeepaaT' r o a li Cet y r a d i M l lr *11 11*1 i l r e a li l *r # gti 1*1 Dr, Gardaer u t lie d , xcepl, ef eo*x *a, l i e er* expert iaterp retatie* of 11* experiaeat. J * 1* Xaailtea f 0 0 0 1 9.nni Unor u.Caronkr,m .d. The Saranac Laboratory OP THE EDWARD L TRUDEAU FOUNDATION Sa r a n a c La k e , N.Y. February 27, 1947 Kenneth M. Lynch, M.D., Dean _ Medical Goliege of State of South Carolina Charleston, South Carolina Dear Dr. Lynch: Dr. Lanza has asked me to get together and send to you all pertinent material in connection with the report Dr. Gardner wdaos preparing for Johns-Manville, and this r have attem*pted to In one folder you will find progress reports that have been made from May 5, 1937, through February, 1943, when Dr. Gardner submitted to Johns-Manville an outline of a proposed monograph on AS3EST0SIS. Attached to the monograph are various data identified with- it. I have cooled from * Dr. Gardners notes his comments on paners on the subject by Dr. Gloyne and Dr. Merewether, also*two outlines which may be of interest to you. There is also enclosed a draft of a paper by Dr. Gardner and Mr. Donald S. Cummings; apparently this was to follow the 1931 preliminary report referred to which was published in The Journal of Industrial Sygiene, Vol. XIII, lio. 2, February, 1931 (reprint enclosed). I have included considerable data on the susceptibility an,^ma^3 to lung tumor, since thi3 has a bearing on the .ASmSTOSIS problem. Dr. Gardner intended to carry on further investigation in this connection, and undouotedly his successor 'will wish to do so. In a second folder are a number of reprints, and in a third folder, the illustrations Dr.. Lanza used in his book. 'Silicosis and Asbestosis.,r A H this material, of course, we would eventually like to have returned to us. There are many gaps, I know, and if you will call on me from time to time as the need arises, I will try to provide any additional data which you may require. ' CC: A. J. Lanza, M.D. Sincerely yours, j t r .' (Mrs.) Lillian a. 31inn Secretary to the late Dr Gardner ?.S. The above is being sent to you by Railway Express, acknowledge receipt. Please Progress Reporta - iiay 5, 1937 April 13, 1933 December 9, 1933 Deceaoor 14, 1939 November 30, 1940 December 4, 1940 Proposed Monograph. - February, 1943 (accompanying data) Dr Gardner's comments on papera by Dr Gloyne and Dr Serewe then Two outlines Draft of a paper by Dr Gardner and Ur Donald S. Cummings. Experimental data February 2G, 1947 Enclosures to Dr. Lynch: UN Public Ho1th. Bulletin 2b* 241 - A. STUDY OP AS3EST0SIS 13 THE ASBESTOS TEXTILE INDUSTRY Special Bulletin Ho* 37, Cooaonwealth oT Pennsylvania, Departnent of Labor and Industry, Harrisburg, Penna., October 1, 1934 - ASBESTOSIS - Part I Special Bulletin Ho* 42,Caaaonvealth or Pennsylvania, Depart~oent or Labor and Industry, Harrisburg, Penna., September 20* 1935 - ASBL3T0SIS - Part II anri part III Beprint Ho. 1665 Cron the Public Health Reports, Yol. 50, Ho. 1, . January* 4, 1935, pp. 1 to 12. - EFFECTS OP TH1 IHHALATIOH OP ASBESTOS DOST OH THE LUHGS OF ASBESTOS 30RSER3 Reprint - THE P0HHATI0H OP THE ASBESTOSIS BODY IB TOE L030 by 3* Roodhouse Qloyne, K*D. (reprinted from Tubercle* June, 1931) Reprint - THE H0H3ID ASATOJCT ALD HISTOLOGY OP ASBESTOS IS by 3. Raodhouse Gloyne, H*D* (reprinted froa Tubercle. Jhlv. August and Septeaber, 1033) Reprint - A BEM0RA3DUK OH ASBESTOS IS by E. R. A. Herewether, M.D. (reprinted froa Tubercle * Hoversber-Deceaber, 1933, January, Booklet - TEE PS0D0CTI0H ASD GRA3DIBG OP ASBISTOS by Johnson's Conpany, Thetford Hines, Quebec, 0anada Reprint - HARTXS3 OPERATION EHPEASIZE IHDOSTHIAL HZ0IES2 PR33I2H3 OP AS3E3I0S IHDOSTRY (reprinted froa The Illinois. Labor Bulletin,. Pebruary 23, 1943 Isaufc) Paper - AIH SAHPLIHO OP ASBESTOS DOST, COMPARISOH OP IHPIBDEH ABD ELECTROS TATIC PRECIPITATOR HETdODS by J. Wau Pehnel (given beTore the Twenty-fourth Annual Use ting of the American Asaociatlon or Industrial Physicians and Surgeons with American Conference on Occupational Disease a and Industrial Hygiene, Cleveland, Ohio, June 5-8, 1939) Illustrations used in book *311100018 and Asbestosis"by A. J. Lanza, M.D. Pebruary 26, 1947 Enclosures to Dr. lynch /l March 10, 1947. Dr. A. J. Lanza, c/o Metropolitan Life Insurance Company, 600 Stockton Street, ~ San Francisco 20, Calif. . Dear Doctor Lanza: I have received the material from Saranac hut have not yet had time to even review It. I shall do- that as soon as possible, la relation to the present very pressing season, and shall then let you know my thoughts on the whole p*roposition. With best personal regards, I am . Sincerely yours, Kenneth M. Lynch, K. D 9 IML:kbp Dean. CC: Mrs. Lillian R. Bllnn Saranac Laboratory, Saranac, N. X. C U m o v U . Gardner, m .D . The Sa r a n a c Laboratory OF THE EDWARD L TRUDEAU FOUNDATION Saranac Lake, N.Y. March 18, 19k7 Kenneth M. lynch, M. D., Dean Medical College of the State of South Carolina Charleston 16, South Carolina Dear Dr* Lynch: Enclosed are copies of an exchange of letters with Mr. Vandiver Brown of the Johns-Manville Corporation, which I believe you will find entirely self-explanatory. have no idea how grateful we are to you for ac ceding to Dr. Lanza's request that you undertake to bring Br. Gardner's notes on aabeatosis into transmittible shape. Sincerely yours, MB: AD enc.. Manfred Bowditch Field Director f The Sa r a n a c La b o r a t o r y OF THE EDWARD L TRUDEAU FOUNDATION Saranac Lake, NsY. Lxr o y U . Ga r d n er . M .D . dircctor Hr* Tandirer Broeo, Secretary Johna-Kanville Corporation 22 East Loth Street See Tbrk 16, ff. f* Doer Ur. Brow : arch 18, 1?L7 . ... Than>lf J W letter of ILrch 1 2 ^ I m r ^ iv .to - ply frith t d u t suggestion and as doles so by jtSnKrj; to a k Lynch copies of your letter sod enclosure, and of this r^piyr The distinction which Dr^ Gai- * discuss -with ae mainly that between fibrous ancT itoe dust, whereas Dr*ing and his colleagues refer"'to long ' ' uustwhat they oaan by those designations is not clear and I. find that we do not have the original, parer* King for an extended stay and I an sure that this was one of ___x w ___ _o_n_w_h_i_c_h_h_e and D_r*# Gar.d.ner pcchanpd notes, though the paper wavroo^Sly aubnttted for"pnblicltion be-* fore -log left England* I as taking stgs to secare a copy of the paper* Dr* Gardner, in Dr* Lynch, Bakes the fo transcribed and sent to 1. The English errneed to aefasStoeT 2* Fibres under structure ngard to tuberculosis among workers^ - duplicated in oar Azicrlcan plants* -- , inert, those botfrn.ua 2C and 93 a L crasned to destroy the fibrous the fibres nust be lour enough so that therr I-- -irr-r- 'phaio^PEBaESsr------------ *" _ 'inhaling long fibre asbestos derelop lanr cancer. jaas average for other dusta* j r a S C g i r J.J -- -- U ^ L ^ ort xibre asbestos ereioo lung cancer,. a seren tip the aarerage for pthar CUBO* ' Itigie results are 'suggestive, rather than cQoaEHver-- --- - - ' _______ * ? rB notations fro* Dr* Gardner* notes re given aerely for the purposes of this correspondence and should not be regarded as anything acre* To what extent they nay be nodifled, in the light of other findings, in the re p o r t f s b I oe to be seen* Sincerely yours, YBiAD anfred Bowditch Field Director At '( M e t r o p o l i t a n L i f e In s u r a n c e C o m p a n y One Madison Avenue, NewYork io.N.Y. Anthony J. Lanza. M.D. A s s o c ia Mx o ic a i. D ir e c t o r B3LALTH A2TD VTSUARS June 25, 194.7 Dr. Kenneth M. Lynch Dean, Medical College of the State of South Carolina Charleston 16, S. C. Dear Dr. Lynchs I hare finally returned from my stay on the West Coast. I am planning to go up to Saranac on July 8th for a couple of days as I am anxious to confer with Dr. Vorwald. Before I go up, I would appreciate it if you would let me know what the going is with respect to the Gardner material. Is it workable and if so, when do you think a report will, be available? With best regards. Sincerely yours, A. J. Lanza, U.D. . Associate Medical Director June 3 0 , 194-7 - Dr. A. J. Lanza, Associate Medical Director, . - Metropolitan Life Insurance Co., 1 Madison Avenue, New York 10, Hew York. Dear Mr. Lanza: . Follawingour previous correspondence I received Gardner's and aa well as I oould, during the extreme pressure of working on a large legislative program here, I examined it in re lation to the expressed desire that some publication should be made of it, possibly even a monograph. I came- to the tentative conclusion that the more ambitious type of publication as a real monograph is questionable, but that toe partially completed manuscript which Gardner left oould properly be published as a final report upon the experimental program which so far as the immediate problem was concerned, had been conpleted. Then I got involved, in finishing up the year* a effort and de cided to delay my deoislon until I could review the question. Your letter came Just as I was turning the matter over in mind again. It appears to me that to use Gardner's material in a monograph in whioh the writer would have to set forth his own views and add material of his own would be neither fish nor flesh and might be foul, to use a bad paraphrase. Although Gardner's material would be used, toe view point would not be his and the writer might not be able to accurately represent him, try as he might. Also the additional material necessary would not be Gardner's. In other words, to collaborate with anyone, posthumously, without that one having even contemplated it. perhaps would not be proper. On the other hand to submit his manuscript for publication practically" as he has it written, with an explanation, would be to properly represent him. He undoubtedly meant to add to the manuscript, but it is worthy as it stands. Dr. A. J. Lanza June 30, I9A7 My present Idea is that it should he sent to the same publication as Gardner*a first report on this study and entitled as a final report Please discuss this with the people in Saranac and let ne know what you think and it any decision is reached. Sincerely yours, Fenneth M. Lynch, M. D., Dean. A. J . Lanza. M. D. Onte Madison Avzntjz New Y ork Dr. Kenneth. M. Lynch Dean, Medicai College State of South Carolina Charleston 16, South Carolina Dear Dr. Lynchs . X am very much obliged to you for 7our thoughtful letter of June 30th and quite in agreement with what you say* I am going up to Saranac on July 8th and will spend a couple of days there during which I will have the opportunity of discussing this subject with Dr* Packard and Dr. Vorwald who has taken over as Dr. Gardner* s successor. I then hope your suggestion that Dr. Gardner* s manuscript be published can be accomplished within the next few months* " There i3 a situation here which has given me and others who are interested in the successful continuance of the Saranac Laboratory, considerable concern* It. is almost ten years since various industries began miHng anmini appropriations to the Saranac Laboatory for research in the effects of asbestos upon human beings who inhaled it. In that time, those of us who have been follow ing what was done at Saranac and who have had the opportunity of first-hand cUninni information, have learned quite a bit, but there has been no authoritative pro nouncement embodying the results of the Saranac research. This state of affairs is nobody's fault, but it is quite unfortunate. During the war period, as you know, Dr. Gardner lost, through death, three of his chief assistants and could find no replacements for them. His efforts to carry on with all the added responsibilities due to these deaths, I think, were largely responsible for his own death. In the meantime, there has been quite a stirring up of activity on the part of State Industrial Commissions and similar bodies in the United States and Canada, with the result that there has been threatened legislative actions or procedures based upon assumptions as to "the effects of asbestos which may or may not be correct. All concerned are looking to Saranac for a reply to their questions and it would be an immense help to both industry and constituted authorities if they could believe that some of the fruits of Dr. Gardner's activities will soon be available. I will write you again as soon as I return from Saranac which will be about July 11th. With best regards, I am, Sincerely yours, X & A. J. Lanza, M. D. M e t r o p o l i t a n L i f e In s u r a n c e C o m p a n y One M adison Avenue,Ne w a r k io.N.Y. A n t h o n y J.La n z a . M.D. A s s o c i a t i Me d ic a i. Der ecto r HEALTH AND YTEUAKE July U f 1947 Dr. Kenneth M. Lynch Dean, Medical College State of South Carolina Charleston, 16, South Carolina v '. ' 7nr Dear Dr. Lynch: . With further reference to ny letter of last reek, X have just returned from a trip to Saranac where I . discussed your letter of June 30th with Dr. Vorwald* I think we are all agreed that it is desirable that as much of Dr. Gardner's material as is workable be presented at an early date. It would be best if you could give.us such excerpts .of material as can be presented in one article dealing with asbestos. Please let me know if this idea meets with your approval. With best regards, I am Sincerely yours, A. J. Lanza, M. D. Associate Medical Director ( f V%\ Ju ly 23, 1947 Dp A J LfiRZfl, Associate Medical Direotor, Metropolitan Life Insurance Company, Sew fork, 10, N. X* Dear Dootor Lanza: X am sending herewith Gardner1s manu scripts as I have arranged* Joined and titled them in a proposed single publication. . The- experimental report is left as it was, except for the heading Please pass Judgment on the title and footnote. Hie monograph outline of human asbestosis contains little IX any significant material No one else oan write what he intended without it becoming the writer's instead oX Gardner's. - On the other hand, the outline on experimental asbestosis is more than that. It la really a summary of Gardner's observations and is valuable and publishable as It stands. I have put a heading on that part, deleted section 1, on "Methods", and renumbered the other sections The whole makes somewhat of a balky publica tion, but I believe that you oan induce the Journal of Industrial Hygiene to take it in this form. If not, let's split it into two. I a m sending the detached Part I of the Out line aide, in order that you may see what I mean. Please consult with such others at Saranac as you should and with the Absestos people, if that is in order. Feel free to rejeot any idea of mine which ~ * does not seem best and criticize freely. With best personal regards, I am Sincerely yours, XKLlkbp. Kenneth M. Lynch, M. D. DP Lanza, Page 2 - July 23, 1947. P. S. I am retaining for the present the other mat erial sent me. Can someone at Saranao reddily supoly the references In. the manuscript? I am a bit short on time Should Cummings be in this? KML. ( f (From Dr. Leroy U. Gardner's OUTLINE SUMMARY OF ASBESTOSIS) 9. Complications ' A. Susceptibility to Infection. i. Tuberculous. Asbestos behaves like most other minersls in this respect not like quartz, which specifically increases native susceptibility to the tubercle bacillus. This infection may spread for a time, but then heals. The resultant fibrosis accentuates that caused by the mineral fiber. ii. Non-tuberculous Of no greater frequency than animals inhaling dusts of other kinds. Occasional epidemics of pneu monia occur in our dust rooms, but these are due to methods of housing rather than to dust; they also oocur in unexposed animals. ill* Cancer of Lungs. No experiments were parti cularly designed to elucidate this point, but certain evidence suggests that asbestosis may actually favor development of tumors in susceptible species. a. In guinea pigs, rabbits, rats, cats and dogs, lung tumors are rare. b. When these species were subjected to 2 to 3 years inhalation of asbestos dust, the incidence of lung tumor was not Increased. o. Some strains of white mice to develop tumors without apparent cause. 4. Such a strain of white mice was unin ' . tentionally used in three inhala tion experiments with asbestos. , e. Of 11 mice inhaling long fibre asbes. tos for 15 to 24 months, 8 developed malignant tumors in their lungs, `and 6 of them had tumors in other organs. The incidence rate. 81.8* is execessive. / (2) f . Of 22 mice inhaling short fiber asbestos for not longer than 12 months, only 3 developed lung tumors. Rate 13.6g. g. As controls, we have only the exper ience with mice in other dust experi ments. For short periods, there wert 51 mice exposed to 4 other kinds of dust for 10 to 12 months. Incidence of lung tumor 1.9#. For long periods, there were 143 mice exposed to 4 different kinds of.dust, including pure quartz, 23 to 31 month; ( For all this troup of mice the aver age incidence- of lung tumor was 18,8# the highest rate (25#) was in a sub group exposed to flint dust. Thus the incidence of lung oancer in the long fiber asbestos mice was over 16 times the average for mice inhaling other dusts for comparable periods, and over 3 times the maximum for any other group. Mice exposed to the pra otically_..^ert_qhor&jCl.er asbestos- showed fewer lung tumors, although 7 times more than liKose in short exposures to other dusts. These observations are suggestive but not conclusive evid ence of a cancer stimulating action by asbestos dust. They are open to several criticisms. The strain of mice was not the 'same in the asbestos experiment as in many of the others cited; apparently the former were unusually susceptible. . Not enough animals survived in the dust for longer than the 15 months ap parently necessary to produce many tumors. There were no un exposed controls of the same strain and age and no similar con trols exposed to other dusts. It is hoped that this experiment can be repeated under properly controlled conditions to*deter mine whether asbestcita actually favors cancer of the lung. The Saranac Laboratory OP THE EDWARD L. TRUDEAU FOUNDATION Sa r a n a c La k e , N.Y. bKIW* W i.grtWHKWi M tO. August I, 1947 Kenneth K. Lynch, M.D., Dean - Medical College of State of South Carolina Charleston, South Carolina Dear Doctor Lynchr As you perhaps know, I have been released to inactive duty after five years and six months with the Navy. During the past two years of that duty I served as Director of the Medical Sciences Division of the Office of Naval Research. In that Rapacity my office enjoyed some correspondence with you.- Now, I have returned to Saranac Lake as Director of Research of the Trudeau Foundation and Director of The Saranac Laboratory in an attempt to discharge many of Dr. Gardner's obligations and commitments and to accomplish much of what he planned and en visioned. That task is indeed a tremendous one, yet my prewar years of association with him afford at least some background for the solution of the problems and issues confronting the Laboratory at this time. One of the problems relates to the collation of clinical and experimental studies of asbestosis accomplished by The Saranac Laboratory* In reviewing these studies and related correspondence, I learn of your kind efforts In editing Dr. Gardner's manuscripts and recorded writings for purposes of a report and publication. This matter has been discussed with-our mutual friend Dr. Lanza, who has kept the Laboratory informed by copies of correspondence pertinent to such publication. In consequence, a copy of your letter of June 30 to Dr. Lanza and his reply thereto have been forwarded to m e . I recognize your concern and appreciate the difficulty in presenting adequately the interpretations and views which Dr. Gardner recorded before his death. The manuscript which he was preparing constitutes a significant contribution. Its publi cation alarms me, however, lest'other evidence accumulated in the past several months might have caused Dr. Gardner to revise some of the statements which he recorded at that time.- In his interests and also because of the Laboratory, which must continue as a lasting memory in his honor, I know you will agree with my alarm. I am sure that Dr. Lanza would concur. Therefore, Dr. Lynch, I would appreciate your comments and views so that our action con cerning the host of studies, reports and publications which we contemplate might be prepared accordingly. Page 2 Kenneth M. Lynch, M.D August 1, 1947 We at the Laboratory would welcome you at any time should you find the opportunity to visit us. Sincerely yours, AJV:LB . CCr Dr. Anthony J. Lanza Arthur J * Vorwald,. M.D. Director of Research The Edward L. Trudeau Foundation f Metropolitan Life Insurance Company FREDERICK H. EckerChairmanofth*Board Le r o y A. Lincoln,M n / One MajdisonAvenue,New York xd;N.YT* . A n t h o n y J . L a n z a , M.D. Associate Medical Director m ntxx ato vnofAM Dr. Kenneth M. Lynch Dean, M edical C ollege o f the S ta te of South C arolina C harleston 16, South Carolina t , " ^ j August A, 19A7 v. *61 9 9nv '/' . * - ' " Dear Dr. Lynchs I am in receip t today o f a copy o f the le t t e r Dr. Vorwald wrote you on August 1 s t . I am not too d e a r about the concern th a t Dr. Vorwald expressed. However, I note th a t a t the end o f h is le t t e r , he hopes th at you might be able to pay him a v i s i t . . I am going up to Saranac m yself on August 16th. Would you consid er making a tr ip to Saranac a t any time soon, p o ssib ly we could meet there on the 15th . Tou can f l y from Hew fork, to Saranac in about an hour and a h a lf, which c e r ta in ly takes the curse o ff that part o f the t r ip . I f you could fin d i t p o ssib le to come, we would be glad to take care Of a l l your expenses and make reservation s fo r you. \ P lea se do not think th a t I am trying to urge you to do anything fo r which you have no in c lin a tio n and i f you f e e l th at you do not have the time to make such a t r ip , or th at i t i s unnecessary, do not h esitate to say so. I have to go to Washington on Thursday so w ill telephone your o ffic e Wednesday afternoon to g e t your reaction to th is le t t e r . . With b e st regards, I am, Sin cerely yours, A. J . Lanza, M. D. A ssociate M edical D irector Charleston, S. C Aug. 7, 1947. TTET.fffMAM - straight message. Dr. A. J. Lanza, Metropolitan Life Ins. Co., New York 10, N. Y. (1 Madison Avenue) ACCOUNT SCHEDULE IMPORTANT MATTERS UNABLE TO LEAVE AT TIME REQUESTED. FOLLOWS. HERE LETTER r (signed) K. H* Lynch KML:kbp. 10:55 A. M. C f tu 'Q August 7 , IP47 Dp. A. J. Lanza, Associate Medical Director, Metropolitan Life Ins. Company* New York 1 0 , N. Y. Dear Doctor Lanza: Following your telephone call Wednes day morning, I received your letter of August 1 and I assume that you also received a letter from me which was then mailed Because of very pressing business here during that time, I do not feel that I can make the , trip to Saranac on o r about August 15. If there should remain a reason for a conference there, It is possible that I might make it sometime in September, or I might at least get to New York City for a confer ence there, ir that may be desirable. Like you, X am not clear as to the reasons for the concern expressed by Dr. Vorwald. However, from the copy of,my letter to him which I sent to you, you may see that I think that the course to be followed should be decided by those on the ground. Without any knowledge of what is in Dr. Vorwald*s mind, I still believe Gardners material is publishable as It stands and that nerhnps revision by anyone else might not truly . represent him. On the other hand, if Dr. Vorwald is to carry on the work, it should be decided whether Dr. Gardner's efforts may be merged, with full credit to him. X offer these suggestions out of a coopera tive interest, and I feel that the decisions should be made by you and him and your colleagues without regard to any other consideration of my participation than that. Incidentally, X wish to offer my congratula tions and best wishes on your new connections which I . have seen announced. Sincerely yours, VJ/V Kenneth M. Lrnch. M. D.. IBW iIJiC*Tim*i M.B. The Saranac Laboratory OP THE HOWARD L TRUDEAU FOUNDATION Sa r a n a c La k e , N.Y. K e n n e t h M. Lynch, M.D., D e a n Medical College of the State of South Carolina Charleston 16, S.C. August a, 1947 ~ Dear Doctor Lynch: I appreciate the expression of your opinion as recorded in your letter of August 4 apropos the work accomplished by Dr, Gardner during his many years of research in the interest of asbestosis . All of us recognize the high degree of relative urgency regarding the correlation of our experimental and clinical studies for the purpose of a report for the sponsoring in dustries and for publication. Every effort will be made toward an early accomplishment in that regard. I will appreciate your continued counsel and advice concerning it, so that in final analysis the contribution will be a creditable and lasting record in the memory of Dr. Gardner.. Tour letter of July 30 and the manuscript which you en closed have been forwarded to me by Dr. Lanza. He will be in Saranac Lake on Saturday, August 16, and I will discuss the matter with him at that time. Please know, Dr. Lynch, that the Laboratory would be honored should you collaborate in the final publication. This point will certainly be considered at the time of discussion with Dr. Lanza. With sincere good wishes, Cordially yours, AJV :LB CC: Anthony J. Lanza, M.D. Arthur J. Vorwal d, M. D. Director of Research The Edward L. Trudeau Foundation FEB-13-95 HON 17:18 r `A J F HUMPHREYS ATTY FAX NO. 3043434186 .U AnoJTR.CT 2 * Introduction 3. A sbestos M ineral 5. Hciperi-ncr/onl J& thods __ . J> ` w S Y ^ . . ,t IV SXFERH3ENTAL VSBSSTOb-tS * | t \ V \ - u C~ *^ T -T A. S p e c ie s S u s c e p t i b i l i t y 7 . P e c u lia r Charac t e r i s t i c s o f A sbestos 8 . Rate of T issu e R eaction to A sbestos F ib ers 9 . A sb esto sis Bodies ' "SE. V C N 6 S flttVs A s t i a i 3>*s-t King *3 F l o a t s Asbccoo tc o -Bust- -,---- --- -- 12. D usting M aterial. 13- D ust Com position lli. Dust C oncentration ' 15. R eaction in in itia ls 16. Guinea. P ig s 17 R ate and Type o f R eaction 18 . P ro g re ssio n In fe c tio n C oincident T/ith D ust In h a la tio n 19 20. In fectio n a fte r D ust Inhalation 21. A sb esto sis Bodies 22. R abbits 23- Rate 2h- SuiSTjary and Interpretation P. 05 rare n Li.A 5 c 6 7 7 8 8 8 Q 9 9 9 10 10 11 12 12 12 13 FEB-13-95 MON 17:18 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 06 reir AbPoGtor Thiii ' 2o - D usting lia ta r is l 2 (- Dust Com position 23 , Dust C oncentration 29 S ize-frequency o f Dust 30. R eactio n in Animals 31- Guinea P ig s 32. R ate and Type o f R eaction 33- P ro g re ssio n 3h. A sb e sto sis Bodies 35. R ats 36. R ate and Type o f R eaction 37. G ats 38. R ate and Type o f R eaction 39- X--r a y Changes UO. A sb asto ais Bodies 111. R abbits 112. Rate and Type o f R eaction 113. A sb e sto sis Bodies UI4. Summary and I n t e r p r e t a t i o n 5r~ 100 P er Cent B a ll-a il U6 . D usting M aterial ' li7. Dust C om position u8. Dust C oncentration 1x9. S ize -fre q u en cy o f Dust Hi Ih -"'I< 15 15 15 15 15 17 17 18 16 19 19 19 20 20 2C 20 21 21 21 22 22 23 FEB-13-95 MON 17:18 J F HUMPHREYS ATTY FAX NO. 3043434186 o u i. j it x -- 50 - R eactio n in Animals 51. , Gui nea. F ig s v 52. R ata and Type o f R eaction 53. P ro g re ssio n 5k , lymph Node Involvem ent 55. A sb e sto si3 Bodies 56. R a ta and lSi.ce 57. Summary and I n t e r p r e t a t i o n nfTwnr U o M G ^ f ^ W - aU jQ-z-- Deng f i Vioi Asbest o s- Duct-- . --------------* "" """ 59. D usting M aterial 60. D ust Com position 61. Dust C oncentration 62. S iz e --f r e q u e n c y o f D u st 63. R eactio n in. Animals 6i u G uinea P igs 65. R ate and Type o f R eaction 66. P ro g re ssio n 67. lymph Rode Involvem ent 68. A sb e sto sis Bodies 69. C ats 70. R ate anci Type o f R e a c tio n 71. X -ray Changes 72. R ats 73- R ate and Type o f R eactio n P. 07 ;-aee o '2 3 23 2li 21i 2 k 2h 25 26 26 26 26 27 27 27 21 28 29 29 30 30 *0 30 31 htb-13-ab HUN 1f:1b J' P HUClPHKtYS ATTY FAX NO. 3043434186 P.'UB Ih. ili.ee 75- ' R r.tr end Ty; 76- - a 'o n n r r / anc. 7Gt llr-rrat r o h ea l Ilcpari:r.o:its 19 Cotjc^risori o f >Mbrous owl .-ro**? 80. C cirparison o f r sj.*1oos i - - r .`is-is 31. Ccsnparison o f I c n r ,-fib e r sn d ': r - . - r o r r r ;-1-s-t' 32. Intravenous Eisperisisrits ;-.*d I iit r a p e r it o n e a l ' r ^ r i n s r i i s ^ LxZXIV. -OTrISn. raT--Tirli~lETH~T<S-1 3 5 . P r o te c tiv e A ctio n cx AT: unLnuir= Ccxpcra-.r-i 36. Poraation of A sbestosis Bcdias . ^ _____ ^ r ' rtl LXJXVIll/THTCORT Of'"IRRITANT ACTION ^ i -- f-- t-- \ N----- -- * bXXXVIjl^I I i C0" ?.r,ICAT ICI.^ 39. I n f e c t i o n 90. S u sc e p tib ility , to Tuberculous in fe ctio n 91 S u s c e p tib ility t c Non-tubercr: leus In fectic^ -- i3 SllCjLfC^A'VJir5 vl^ -^ * --IC-Tp- L TT-aVB-L*S- , aj T` 32 32 33 3L. 3u 35 35 3$ 35 36 37 37 38 38 3? ilO b3 - 71 FEB-13-95 HON 17:19 J'F HUMPHREYS ATTY FAX NO. 3043434186 P. 09 abstract - :1 . . A s b e s t o s i s i s s. p u lm o n ary d i s e a s e c a u se d t h e i n h a l a t i o n o f a s b e s to s d u st. In anim als i t I s - C h aracterize 1 by ^ ^ ^ e rib ro n c h io la r fib ro s is idiich r. Y~ ^ <( seem s t o b5dto, t--h e r--e--s--u--l-t- s f m e c h a n ic a l, a th e r th a n c h e m ic a l, i r r i t a t i o n o f V- ^ ^ > 7^ / , th e tissu e by asbestos fib e rs. th e long fib e rs produce a ty p ic a l 6c */ J r e a c t i o n ; s h o r t f i b e r s (a re r e la b tv e ^ y i n e r t <Y\ T he f ila m e n te d :s t r u c t u r e o f th e ^ f --' ,bu> U>V*1* fib ers is an e sse n tia l facto t h ^mechanism o f i r r i t a t i o i ^ it- c h a r a c te r i s t i c t i s s u e r e s p o n s e c a n b e p ro d u c 3 b y non--s i l i c e o u s / a s - ^ r e ll a s s i l i c e o u s ) / ' h , K *< fib ro u s m in erals. In h ala tio n o f asbestos d u st ^pparentl^r does not a lte r CJN'CVW''-- fy< ; v '. sig n ific a n tly the h * ' of experinu ntalHtuberculosis ixii^gguuiinneeaa ppiiggss . T hec H' s ' a s b e s to s is body, u h ia^ i s a sp e c ific concom itant o f a s b e s to s is and forms so o n a f t e r t h e entnfence o f t h e a s b e s Los f i b e r i n t o t h e l u n g , is-D y llU V etfn E T i * prevent fu rth er /' damage to th e T tissu e by th e fib er ' and th u s --- * W lim it pro- g r e s s i o n o f t h e / r e a c t i o n "when exposu -c c e a s e s . Al u mi n um d o e s n o t e x e r t a p ro tec tiv e actio n ag ain st the tissu e ir r ita tio n o f asbestos fib ers as i t does age 'th a t o f quarts p a rtic le ^ . FEB-13-95 HON 17:19 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 10 2 . --i n t r o d u c t i o n - . . A s b e s to s is ifi s. f o r 7.n o f p n eu m o co n io sis r e s u l t i n g from p r o io r t i o n o f a s b e s to s u s t . Tua name a s b e s to s , l i t e r a l l y "u n b u rn sb le- d inhala is not t h a t o f a p a r t i c u l a r m in e ra l b u t i s a te rm a p p lie d to a iraubei* o f d i f f e r e n t m in e ra ls Tihose c h a r a c t e r i s t i c f e a t u r e i s a s t r u c t u r e composed o f lo n g , p e r a l l e l , fle x ib le f ib e r 3 - This s tru c tu re i s unique because th e fib e rs a re capable o f rep eated lo n g itu d in a l su b d iv isio n to u n its o f m olecular p ro p o rtio n s- I n l e n g t h t h e f i b e r s v a r y from a few m ic ro n s t o s i x o r m ore in c h e s . Scms v a r i e t i e s a re s t i f f o r th a n o th e rs b u t many a r e s u ffic ie n t!-.- f le x i b le to be spun in to y a m and woven on m odified t e x t i l e m achinery. 3- A sbestos M inerals The a s b e s to s m in erals a re s i l i c a t e s o f v a ria b le com position and belong to t h e s e r p e n t i n e an d t h e a m p h ib o le g r o u p s . L i s t e d b e lo w a r e th e m ore common v arie tie s. Amphibole Group A nthophyllite (Lg, ?e) s i l i c a t e Am osite A m p h ib o le Ofe, F e, A l) s i l i c a t e (C a, Kg, F e , Al, Ha, X) s i l i c a t e Trem olite ' (Ca, Kg) s i l i c a t e A ctin o lite C rocidolite (Ca, Kg, F e) s i l i c a t e (Na, F e ) s i l i c a t e - Fe s i l i c a t e Chryso t ile S e rp e n tin e Group Ug S i l i c a t e (h y d ro u s ; FEB-13-95 HON 17:20 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 11 The 1* o f t h . ****> 15 e h io h i , mined i n th e fc e tfo rd reg io n o f th e P ro v in ce o f BfObec. C rocldo- K __ -t ;,- v.*!* i-- | tmicil SEiallor BluOti.'l'w3 u t e an d a a o s i t e a r e a l s o o s s a commar...3- .j y i - t C hryEotile occurs c* jj-,,u ss ee ri yp -- ni t i n e -. a m i n e r a l s i m i l a r i n c h e n i c a i com- p o sitio n to c * * e tM * * * * " E3iTO * " * + * artcroscopic fib e rs vdfeout th e p a ra lle l o rie n ta tio n c b a ra o e ristic f ------- t i l s . The m assive b in e b la c k s e rp e n tin e , v h ic h i s smooth and soapy to th e to u ch , i s tra v e rs e d by v e in s o f fib ro u s c h ry s o tila v a ^ n g In v id th from a * f^hprfl mn iLCXTOSS "t-Iis vsin b a r e ly p e rc e p tib le lin e bo s ix o r mora in c h e s- Ih a f ib e r s ^ ac and n o t le n g th w is e -with th e form ation A t t e n t i o n i s d i r e c t e d t o t h e m in e r a l b r u c l t e , MdO-XlO. v h i d i i s c f t s n fo u n d i n t h e sam e f o r m a tio n s u i t h serpentine and c h r y s o t i l a an d may he f i b r o u s iu s tr u c tu r e . I t has no com m ercial v a in , a t p re s e n t because i t s lib e ra a re not s u f f ic ie n tly f le s ib le to be used in te x tile s b u t th e y a re capable of repeated lo n g itu d in a l su b d iv isio n . U nlike o th e r a sb e stifo rm r d n s ra ls , b r u c it . i s n o t a s i l i c a t e and f o r t h i s re a so n i t has been a v a lu a b le to o l i n am ex p erim en tal e v alu atio n o f th e a c tio n o f fib ro u s m inerals upon lung tis s u e . TV_ EXPERJ^^1TAL A3BSTQ3^IS F or many y e a rs s tu d ie s Ssranac laboratory in an in v e s tig a tio n o f th e cause, n atu re and developm ent o f e s b e s to s is . fh e p re se n t r e p o rt i s devoted to Experim ental A sbesto sis. In i t a re described th e anim al ex p e r im e n ts e i t h v a r i o u s k in d s o f a s b e s to s d u s t . A n o th e r report, t o b e P ^ e a _ and issu ed l a t e r , m i l b . concerned - i t h d a - A sbestosis and m i l * asp ects o f w orkers uho have been exposed to asb esto s d u st in ah in d u s tria l "*" * environm ent. -3- FEB-13-95 MON 17:20 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 12 Although eobost-osic in 'a m i s a chrom e i s ^ e reqm rcs s to d e v e lo p , i t i s p o s s i b le to rep ro d u c e in one o r mors s p e c ie s c f a n M . c u a r a o te r - i a t i c tis s u e c o n g e s * h ich are sim ila r to th e le eicn o f a o b esto sia. Since t h e l i f e - s p a n o f th e e x p e r im e n ta l a n im a l i s r e l a t i v e ! } " ';C r'' i x " J"> n o t 350 to ~ d e v e l6p th e c h ^ a c t ^ i s t i c l e s i o n s i n a n im a ls d m th * u s u a l d i t i o n s . C o n seq u en tly , t o o b ta in a com pxst* ev^_c.c.t,.o.i d . > t o i n h a l e d p a r t i c u l a t e an d f i b r o u s m a t e r i a l , i t i s n e c e s s a r y --o a c ^ e ^ e i a t e r e a c tio n b y em ploying h ig h e r c o n c e n tra tio n s o f d o s t th a n Tronic o r d in a r i ly b e en countered in in d u s try . * h ile co n d itio n s o f e x p o s e s a re th u s c x fie re n t, .he inform ation y ie ld e d by experim ents m th anim als i s in v alu ab le in fu rn ish in g a b e t t e r u n d e rsta n d in g o f th e r e a c tio n o f th e human organism to in h a le d a s b e s to s d u st. 5. E x p e rim e n ta l M ethods For in v estig atin g th e b io lo g ical reaction of th e axperioental annual to th e v ario u s asb esto s In ,ra in , t-o types o f technique have been eaployed, nanely, th e in h a la tio n method and th e in je c tio n m ethod. I n in h a la tio n ex p erim en ts, groups of - up to Iff) o r re gu in ea p ig s and som etim es sm a lle r naebars o f r a b b its , c a ts , do g s, r a t s o r mica - a re k ep t f o r e ig h t horns a day in a cu {just room , e i g h t f e e t i n d im en sio n , i n m iic b a clo u d o,. a s b e s to s duso i s At i n t e r v a l e d u r in g t h e e x p e r im e n t, a f a - a n im a ls ~ -- and th e tis s u e to determ ine th e n atu re and e x te n t o f th e d u st re a c tio n . S o e n se a ls m- 4 "l O il C 'C P O r ^ - j T i ^ i t S * a re exposed to r P erio d s up to th re e y r s . -O. , -- ' W licfcl th e d u st, e ith e r d ry o r suspended in flu id , i s introduced in to th e anim al by th e in trav en o u s, in tra p e rito n e a l o r in tra tra c h e a l procedure, a re used to determ ine eh eth er or not a p a rtic u la r dust has a p o te n tia l cap acity to produce tiss u e r e a c tio n . -U- FEB-13-95 MON 17:21 J F HUMPHREYS ATTY FAX NO. 3043434186 P.13 . ___ -- --aunniii 1-n* --W-- Long-term in h a la tio n e ^ e r ir ie n ts fu rn ish i:iio rraa tio n upon rrtiich g re a t r e l i an c e i s p la c e d v/hen e s tim a tin g th e d e g re e t o -chich a d u s t m ight be hazard o u s tu in d u s tr ia l w orkers, b le th e r c r not atm ospheric d u st, even though p o te n tia lly dangerous, can be in h aled , pass th e n a tu ra l defense b a rrie rs ^ d j ^ h ^ ^ m onary t i s s u e i n q u a n t i t i e s s u f f i c i e n t t o c a u s e dam age c a ^ b e d e te rm in e d o n ly 'ey i n h a l a t i o n p r o c e d u r e s . I n j e c t i o n e x p e rim e n ts a r e u s e f u l b eca u se xn them c o n ta c t b etw ee n t h e d u s t p a r t i c l e s a n d t i s s u e s i s a s s u r e d a n d t h e p o t e n t i a l c a p a c it y o.<. th e d u st to produce re a c tio n can be estim ated a c c u ra te ly , ^hen dealing w ith f i b ro u s m in e ra ls li k e a s b e s to s , th e in tr a tr a c h e a l method i s v a lu a b le sin c e i t p e r m its o b serv in g th e e f f e c t o f th e f ib e r s on pulm onary tis s u e . 6. Species S u s c e p tib ility ttoUVo f r e e s i l i c a , a s b e s to s does n o t e x e r t i t s s p e c if ic e f f e c t i n a l l organs o f a l l sp ecie s o f anim al (Table l ) . In je c tio n o f fin e q u artz in to various organs o f th e guinea p ig , r a b b it, r a ^ J ^ T ,* dog, chicken and even tad p o le -w ill produce s i l i c o t i c n o d u le s. However, s im ila r in je c tio n s o f lo n g o r sh o rt f ib e r a sb esto s have re s u lte d in a fib ro u s re a c tio n in th e lung and, to a le s s e r e x te n t, in th e * * ,. bale 4**^ p erito n e u m b u t n o t i n o th e r o rg a n s W v'tft* T *1 " / . / ' ' I S . -* M ^ ----- > * * * 7 . p ^ iH a r C h a ra c te ristic s o f A sbestos ^ f Tuf !iT*fi ~ . E xperience h as dem onstrated th a t most o f th e p a rtic u la te m atter in h aled in to t h e lu n g s o f man an d a n im a l i s ID m ic ro n s o r l e s s i n maximum d ia m e te r . L a rg e r p a r t i c l e s a p p a re n tly a r e ex clu d ed by th e p r o te c tiv e mechanism o f th e uppar r e s p x r - a t o r y t r a c t . I n t h e c a s e o f ,f i b r o u s m a t e r i a l s , h o w ev er, t h i s r e s t r i c t i o n d o e s nou a p p ly and f i b e r s 100 an d even 200 m icrons i n le n g th have been found in th e te rm in a l a i r sp aces o f human lu n g s . In sm a ll la b o ra to ry an im als exposed to a sb e sto s d u s t t h e maximum l e n g t h o f f i b e r fo u n d i n th e 1 * r a r e l y ex ce ed s 60 m c r o n s . Not e v e r , k in d o f fib ro u s m a te ria l i s in h a led w ith e q u a l re a d in e s s ; fo r exam ple, FEB-13-95 HON 17:21 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 14 the sy n th etic lib e rs =f * w t ^ e : v t : > ir . icc i.n f ^ - b ie to yens eesily through th e nose, p W ry K , tr M i bronchi and *<=> t h e W r a l n a l bronchioles and a lv e o li- __ In h a le d p a r ti c u la te m a tte r comes to r e s t thro u g h o u t th e te rm in a l a a r spaces (alv eo lar d u ct, a tria ,-a lv e o li) in a l l p arts of the i u n ^ in h a le ^ b e e te s-.fiib e rs a re f i r s t re ta in e d In th e re s p ira to ry b ro n ch io les. These very w a l l tubes are Iz a n e d ia te ly d i s t a l t o b r o n c h io l e s l i n e d b y c i l i a t e d e p ith e liu m - T h e i r o-un e s s e n t i l l i n i n g i s a low c u b o id s i ty p e o f ap ith o lim n . b u t, a s t h e i r name im p lie s , th e y a c tu a lly fu n ctio n in re s p ira tio n through la te r a l al^eol.. given o ff a s pouches along th e ir w a lls . E ith e r th ese pouches, or th s abri.pt change an th e ch aracter o f th e n ty in g ep ith eliu m , or th e decrease in diam eter o f th e tubo, o r perhaps th e com bination o f a l l th re e fa c to rs i s resp o n sib le fo r lo c a l re te n tio n o f th e in h aled f ib e r . Only a f t e r a a b e s to s is i s w e ll e s ta b lis h e d a re a p p re c itb lc numbers o f f i b e rs c a r r ie d in to th e more p e r ip h e r a l s i r sp aces. 8 . R a te o f T i s s u e R e a c tio n t o -5b s 3t o s F ib e r s The r a t e o f t i e su e r e a c tio n to a s b e s to s i s much more r a p id th a n to an a c tiv e d u st lik e q u a rt* . Evidences o f tis s u e response appear as soon as fib e rs have lo c a liz e d in s u ffic ie n t concentration in sp ecific a re a s. In r a ts receiving asbes to s f ib e r s by i n t r a t r a c h e a l in j e c t i o n t h i s evidence i s v i s i b l e i s e a r ly a a two w eeks a f t e r I n j e c t i o n ; f o r q u a r tz d u s t th e l a t e n t p e r io d m ig h t be tTO nrr'-.ae o r m ore. The b eh av io r o f th e tis s u e re a c tio n to in h aled d u st a f te r th e term in atio n o f exposure la n o t th e same i n p ilic o a ia a s in a s b e s to s is - -n s i l i c o s i s , th e young n o d u le s become l a r g e r ; i n a s b e s t o s i s , young s c a r t i s s u e , t . , a t may have ..c.-med, v tr a c ts and becomes more dense b u t th e a re a o f involvem ent d ecreases in s iz e . I f exposure to asb esto s d u st is term inated a f t ' a b rie f p erio d , the recen tly -in h aled FEB-13-95 HON 17:22 J F HUHPHREYS ATTY FAX NO. 3043434186 P. 15 f i b e r s i n th e lu n g may c a u s e t h e f i b r o u s t i s s u e r e s p o n s e t o c o n s u m e J.or & sh o rt tim e, u n ti l th e fib e rs have been co ated . This progression i s o f only a s lig h t degree and o f l i t t l e sig n ifican ce- 9. A ab esto sis Bodies _ - - , - The p e c u lia r s tr u c tu r e known a s th e a s b e s to s is body o r cu rio u s body i s s p e c ific concom itant o f a s b e s to s is . The t y p i ^ body i s a golden-yellow , beaded o r h a u s tr a te d ro d w hich may be e i t h e r s t r a i g h t o r cu rb ed . O ften one o r b o th ends a re bulbous lik e a dum b-bell. The bodies v a ry considerably in le n g th , and d i m ensions up to 2^0 m icrons have been re c o rd e d . I t is believed th a t asb esto sis bodies are due to a dep o sit of p ro te in and iro n pigm ent upon th e su rfa c e o f in h a le d fib e r* . In guinea pig* th e y fe rn a f te r ab o u t 60 day* o f c o n ta c t u i t h th e t l e s e e . They e r e abundant i n ra n and th e g u in e a p ig (s e e T able 1) b u t e re much la r g e r i n th e fo rm er, p ro b ab ly b ecaase th e la r g a r eised a i r tu b es adm it fib e rs o f g re a te r dim ension. In o a ts, ra b b its end n ic e th e re i s an a ty p ic a l c o a tin g o f a f e e o f th e f ib e r * a f t e r much lo n g e r re sid e n c e i n th e lu n g s . In r a t s snd dogs no b o d ies co u ld be d isc o v e re d . A lthough th e evidence i s incom plete, i t appear th a t th e fonm rtion o f th e a sb e a to sie body prevent damage^ to th e tissu e by th e fib e r. Z ' ^ . I . P516IAIION EXPERB^TS '-- frx-- ' * j f , your com prehensive in h s la tio n m p e rim an ts have been conducted a t th e Saranac ^ l a b o r a t o r y u ith v ario u s form s o f asb esto s d u s t. In each o f th e se in v e stig a tio n s more th a n 160 anim als m ere used and th e ex perim ents s e r e c a rrie d on fo r p e rio d s ra n g in g from 2 to re th a n 5 y e a rn . The fo n r kind* o f a s b e s to . d u s t employud a re id e n tif ie d as t i n g ', f lo a t s , s h o rt f ib e r , 100 p e r ce n t b a ll- e f U a d , and lo n g -fib er asbestos d u st. HEB-13-96 MON H ` 22 J- F HUflHHKtYS ATTY FAX NO. 3043434186 P. 16 J* asb esto s d u st was begun in 1928. A n i - ^ iu h aled th e d u st fo r periods up to n e a r ly th r e e y& ars and some g u in e a p ig s li v e d fo r about lo u r y e a .s a f t e r t h e i ^ f i r s t e x p o su re t o d u s t.'~ A p r e lim in a r y r e p o r t g iv in g o b s e r v a tio n s a f t e r 29 m onths o f e x p o s u re a p p e a re d i n t h e F e b ru a x y , 1931 i s s u e o f THE JOURNAL OF INDU STRIAL HIGIENE.* A t t h a t tim e o b s e r v a ti o n s c o v e re d a p e r io d o f o n ly 2 - l / h y e a r s and the con clu sio n s as to th e u ltim a te e f f e c ts of Inhaled asb esto s auBt were p ro v isio n a l. R e su lts o f th e com pleted stu d y shop th a t m ost o f th e conclusions d ra m in th e p re lim in a ry re p o rt were s u b s ta n tia te d . A com plete re v ie * o f th is experim ent fo llo w s. 1 2 . The d u s tin g m a te r ia l was a com m ercial v a r ie ty o f a s b e s to s d u s t known aa K in g 's f lo a ts sod was composed o f s h o rt f ib e r s and p a r tic le s o f v a ria b le s i t e . I t was c h a in e d from th e Ih e tf o r d , Quebec p la n t o f th e A sbestos C o r p o r a tio n o f Ame r i c a s VJ3 1 3 . The d u st com position (Table 2) re v e a ls th a t th e amount of fib ro u s cfarysot i l e w a s o n ly H i p e r c e n t, a r a t h e r low v a lu e - However, th e re was s u f fic ie n t fib ro u s m a teria l to produce a c h a ra c te ris tic fib ro s is . 1* . The d u s t c o n c e n tra tio n a t f i r s t was q u ite low and f o r f i n g e r eam ples tak en soon a f te r th e experim ent was s ta rte d , th e average lig h t f ie ld co u n t, by th e e ta n d a rt tech n iq u e was o n ly 6.0 n a t i o n p a r tic le s p e r cubic fo o t of a i r . An a p p r e c i a b l e num ber o f .la r g e p a r t i c l e s ( o r f i b e r s ) a l s o w e re p r e s e n t , as STUDIES ON EXPERIMENTAL PNEUKDCONIOSIS. 7 1 . A sbestos D u st., Gardner, L .U ., and Cumnrings, D .E . J . In d . H y g ., 1 3 * -6S-81, 9 7 -H L , W * - -8- FEB-13-95 HON 17:23 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 17 A fte r th e in h a la tio n experim ent had bean under way fo r about tx o y e a rs , th e speed o f th e r o ta tin g pad d le in th e d u stin g m achine vas in c re a se d and fo r th e rem ain in g 9 o r 10 m o n th s o f t h a e x p e rim e n t c o n s id e r a b ly siore o u s t -eras d i s p e r s e d i n t o th e -a tm o sp h e re . Average- crust co u n ts f o r im pinger s a m p le s 'c o lle c t'< ^ 'g r te f 'th fs change w ere 53-7 m illio n fo r th a u su a l l i g h t - f i e l d m ethod, and 1 -c m illio n fo r p a rtic le s la rg e r th an 10 m icrons. 1 5 , R e a c tio n i n An.iras.ls t o I n h a le d " K in g 's F lo a t s " A sb e sto s D u s t. R e s u lts o f t h e i n v e s t ig a t io n , b r i e f l y sum m arized i n T ab le 3 , ahow t h a t in h a la -- tio n o f K in g 's f lo a ts a sb e sto s d u st produced a ty p ic a l p e rib ro n c h io la r fib ro s is in guinea p ig s b u t not in ra b b its o r r a ts . 1 6 . G uinea P ig s . Seven groups o f g u in ea p ig s w ere u sed . In th re e groups th e e ffe c t o f a continuous and o f an in te rru p te d du st ex p o su re was s tu d ie d ; i n two o th e r groups th e r e l a t i o n s h i p betw een in f e c tio n and d u s t exposure was in v e s tig a te d . The re m a in in g two groups w ere in f e c tio n c o n tr o ls . 17. R ate and Type o f R eac tio n . Guinea p ig s in h a lin g t h i s d u st f o r p erio d s up t o 33 months developed a c h a r a c te r is tic f ib r o s is o c c u rrin g in c o n ic a l p a tc h e s about th e r e s p ir a to r y b ro n c h io le s . During th i s exposure th e p e rip h e ra l a lv e o li were n o t in v o lv ed . The p a r tic u la te elem ents in th e d u st w ere tra n sp o rte d to th e lym phatic system where th e y caused no sig n i f ic a n t re a c tio n ; th e fib ro u s elem ents rem ained fix e d a t th e s i t e o f origj-nal lo c a liz a tio n and w ere seldom d e te c te d in th e lym phoid t i s s u e . P le u risy and f i b ro s is in th e s e p ta w ere observed only when in fe c tio n com plicated th e process- A fter exposure o f approxim ately a y e a r, a sm all amount o f c e llu la r re a c tio n had b een p ro d u ced a b o u t many r e s p i r a t o r y b r o n c h io le s . As more d u s t was in h a le d , i t co n tin u ed to accum ulate in th e same lo c a tio n and l a t e r s ta g e s o f th e d is e a s e FEB-13-95 HON 17:23 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 18 c o n s i s t e d o f t e n s i o n s o f t h s o r i g i n a l l e s i o n s . Karr c r e a s ~ * re n o t in v o lv e d . A p p aren tly , th e in h a le d f ib e r s '-e re cau g h t in th e p o e k e t-li/.s a l r s o l i that, a re given o ff from th e la te r a l n a ils o f th e re s p ira to ry b ro n ch io les. There th sy rroTB p h o g o c y tiz e d and many o f th e m w ere c a r r i e d i n t o t h e n s i ! b y m ig r a to ry ceX ls :.tohonuciear le u c o c y te s 'a ttra c te d to th e a re a caused an p p r^ i^ ie ^ T iic ic e n iB g of th e b ro n c h ia l r a i l . A fte r 16 m onths a d e d ic a te f i b r o s i s made i t s ap p earan ceThe p r o c e s s e v o lv e d s o g r a d u a l l y t h a t m i t o t i c d i v i s i o n o f .--b r o b la o t^ i,ould ra r e ly be d isco v ered ; n e v e rth e le ss, th e number o f fin e in te r c e llu la r collagenous f ib e r s ( f ib r o s is ) s te a d ily in c re a s e d . As t h i s f ib r o s is contracted., i t p a r t i a l l y clo sed th e a lv e o li, and w ith t h i s a te le c ta s is th e lin in g ep ith eliu m assumed i t s em bryonic cu b o id cl form . The r e s u lt was th e adenoma-UJce appearance th a t L i l l i s described in guinea p ig s in h alin g s ilic o n c a rb id e . The longer exposures re su lte d o n ly in more th ic k e n in g o f th e T rails o f th e a i r sp a c e s, la rg e ly due to an in c re a se in th e amount o f f ib r o s is . The fib ro u s tis s u e alw ays rem ained c e llu la r and never showed th e h y a lin iz a tio n c h a r a c te r is tic o f s i l i c o s i s . 18 . P ro g re ssio n . The re a c tio n produced in exposed guinea p ig s d id n o t pro g ro ss s i g n i f i c a n t l y d u rin g a su b seq u en t p e rio d o f. 37 m onths uhan th e enim ala liv e d In a norm al atm osphere. B eteeea 8 and 11 months a f t e r exposure ceased, th e c e llu la r r e a c tio n had beBh com pletely re p la c e d by th in stran d s o f fib ro u s tis s u e . Observed s t i l l lo n g e r, the sc a r tis s u e decreased in amount t a t in th e l a s t enim al s a c r if ic e d , 37 months a f te r d isc o n tin u in g d u st e x p o s u r e , some f i b r o s i s -was s t i l l v i s i b l . - f' 19 . In fe c tio n co in cid en t w ith p o s t In h a la tio n ^ Of t h e g ro u p o f iiO g u in e pigs in fec ted w ith a tten -- u a te a t u u e x .i . b a l l o t j , - t r a i n i 31 d ie d o r e re o a c r ir ic e d b e fo re te c y eere o f d u s t ex p o su re and w ere re p o rte d in th e p a p e r b y G ardner and C-untanes m entioned FEB-13-95 HON 17:24 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 19 a b o v e . S e v e n te e n o f th e s e d: d from in 'te r c u r r e n t. p neum onia. B rie fly -, th e ra s u i t s r e r e a a f o llo w s : 10 re v e a le d some ev id en ce o f s p re a d o f th e tu b e rc u lo u s p r o c e s s ; i n 6 o f th e s e i t was c o n fin e d to th a lu n g s and i n th e o th e r ii th e abdo.Ti.nai v i s c e r a a l s o -were in v o lv e d . U s u a lly a s l i g h t l o c a l e x te n s io n o f *he tu b e r c u lo u s i n f e c t i o n - h o d o c c u rre d b u t s u b s e q u e n t h e a l i n g h a d - r e s iH t'e d 'in ._f I > b r o s is o f b o th th e pulmonary le s io n s and th e secondary le s io n s in o th e r org an s. Th h e a l e d p u lm o n a ry l e s i o n s showed m ore f i b r o s i s th a n i s c h a r a c t e r i s t i c o f e ith e r tu b e rc u lo sis or osbestosis alone. The 9 jm-imalg w hich w ere s t i l l a l i v e a f t e r two y e a rs o f d u s t exposure w ere s a c r if i c e d a t in t e r v a ls d u rin g th e fo llo w in g y e a r- I n li o f them th e p rim ary f o c i o f in f e c tio n had h ealed w ith f ib r o s is and even c a l c i f i c a t i o n and th e re was no ev id en ce o f p ro g re s s io n . In th e o th e r 9 th e tu b e rc u lo u s f o c i showed evidence o f having p re v io u s ly sp read lo c a lly : i n U o f them i t had h e a le d , by th e tim e o f auto p sy , w ith ex cessiv e f ib r o s is ; in th e o th e r anim al th e re was a g en eralized c h ro n ic tu b e rc u lo u s pneumonia i n one lo b e and is o la te d p rim ary tu b e rc le s , which w ere s t i l l a c tiv e b u t had no t spread, in th e o th e r lo b es- Evidence o f e x te n sio n o f th e in f e c tio n was f i r s t seen a f t e r 7 months o f d u st in h a la ti o n ; d u rin g th e n e x t 20 months more th a n h a l f o f th e anim als showed an a c tiv e ly sp re a d in g tu b e rc u lo s is and i n 3 o f them sm a ll c a v i tie s had d ev elo p ed . D uring th e l a s t 8 months no anim als e x h ib ite d any evidence o f a c tiv e in fe c tio n a lth o u g h i n h a l f o f them th e h ealed fib ro u s s c a r s o f p re v io u s ex te n sio n s w ere ob v io u s . S ix ty p e r c e n t o f th e guinea p ig s w ith sp read in g pulm onary tu b e rc u lo s is shoved tu b e rc u lo sis o f th e spleen and liv e r. 2 0 . I n f e c t i o n S u p e rim p o se d Qpon a n E s t a b l i s h e d j t a b q a t o s i s . Tw elve g u in e a pigs, a fte r in h a lin g a s b e s to s d u s t f o r n e a r ly 26 m onth3 , w ere i n f e c te d -with tu b e r c le b a c i l l i and th e n removed to norm al a i r . The su b p le u ra l tu b e rc le s in th e dusted anim als were -11- \ FEB-13-95 HON 17:24 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 20 no nor num erous th a n i n n c iv d u stR d c o n t r o l s ; b . v t a c o n s i d e r a b l e nuT.ccr -were found in th e d ep th s o f th e lung about fo c i o f a s b e s to s is . The re a c tio n to in fe c tio n showed o n ly s lig h t lo c a l e x te n sio n ab o u t th e o r ig in a l s i t e s in th e lungs and tra c h e o b ro n c h ia l lymph nodes. The abdom inal v is c e r a - o r e in v o lv ed in o n ly o n e a n im a l. C a s e a t io n ""was fou n d i n t u b e r c l e s 1 - 1 / 2 m onths o ld b u t .-7 5 - - / 2 months i t had coxaplate?" .. '?.' s r t r .T .ttor p e r s i s t e d i n t h e l a s t a n im a l, which was k i l l e d lb m onths alte?.- i n f e c t i o n . 21. A sb e sto sis B odies. M oderate numbers c f a s b e s to s is bodies occurred in th e lu n g s o f th e g u in e a p ig s , becoming more numerous and more d i s t i n c t l y segm ented in l a t e r m onths. 2 2 . R a b b its . R ab b its exposed to th e a c b e a to 3 d u s t f o r p e rio d s up to 19 month* developed a lo w -g rad e fo re ig n -b o d y type o f r e a c tio n b u t no f ib r o s is . A lthough th e ir lungs con tain ed p a rtic u la te elem ents o f th e d u st, f i b e r s w ere n o t p r e s e n t, in d ic a tin g t h a t th e u p p er r e s p ir a t o r y mechanism of. th e r a b b i t i s a d e q u a te t o e x c lu d e f ib r o u s f o r e i g n b o d i e s . Two r a b b i t s , a f t e r i n h a l i n g d u s t f o r 6 an d 18 m onths, liv e d i n norm al a i r f o r snore th a n two y e a r s . At au to p sy n e i t h e r Tii-mal sh o v e d an y e v id e n c e o f c e l l u l a r r e a c t i o n o r f i b r o s i s i n t h e te rm i n a l b r o n c h i o l e s n o r "were t h e r e a r y a s o e s t e f l i s b o d i e s . 23. R a ts. A ll th e w hite r a ts had acquired an in fe c tio n , re su ltin g in th e fo rm a tio n o f pulm onary a b s c e s s e s , b e f o r s th e y came to a u to p s y . A p p a re n tly , so much heavy mucus o b s tru c te d t h e i r b ro n c h i th a t v ery few f ib e r s co u ld have e n te r e d t h e i r lu n g s . In a few o f th r a t s , an o c c a s io n a l a s b e s to s is body w as d isc o v e re d b u t th e re was no f i b r o s i s . -12- FEB-13-95 HON 17:25 J F HUMPHREYS ATTY FAX NO. 3043434186 P.21 d e fin d in g s in th e ejcnorimcnt w ith King's f lo a t s d u s t pan be summar- ized under th re e headings. -- A. E ffe c t of th e inhaled d u st on normal an im als. " _ The K ing's f lo a ts dust caused a charac t e r i s t i c p e r ib r o n c h io la r f i b r o s i s in g u in e a p ig s b u t n o t i n r a b b i t s o r r a t s . The f i b r o s i s d id n.ot p ro g re s s a f t e r th e d u s t exposure was d isc o n tin u e d and th e guinea p ig s tra n s fe rre d to normal a ir . B. E ffe c t o f th e inhaled d u st on tu b e rc u lo sis in guinea p ig s . In guinea pigs in fe c te d w ith a tte n u a te d tu b e rc le b a c i l l i and th e n p laced in th e d u st room, th e r e s u lt s w ere more v a ria b le th a n i s u s u a l in an experim ent o f th i s ty p e . A few an<naifl showed no s ig n of. ^ p ro g ressio n j in m ost o f them th e re was ev id en ce o f tem p o rary p ro g ressio n w ith subsequent h e a ling; in one anim al th e re was continuous p ro g re ssio n to d e a th . In c o n tra s t, when guinea p ig s , a f te r being in fe c te d , a re exposed to q u arts in ste a d of asbestos d u st, th e in fe c tio u s process continues to p r o g r e s s an d e v e n t u a l l y c a u s e s t h e d e a th o f t h e a n im a ls . On t h e o t h e r h a n d , ex p o su re o f in fe c te d a n im i s to a harm less crust liire c a l c it e o r g/psusa does n o t le a d to any p ro g re ssio n o f th e in fe c tio n . G uinea p ig s in fe c te d w ith a tte n u a te d tu b e rc le b a c i l l i fo llo w in g th e te rm in a tio n o f about two years* exposure to a sb e sto s d u st d id not develop pro g ressiv e d ise a se . The only m o d ificatio n o f th e in fe c tio n was in i t s lo c a lis a tio n , a few b a c illi, being re ta in e d in th e fib ro u s te rm in al b ro n ch io les and form ing tu b e rc le s th e re in ad d itio n to th e u su al fo c i beneath th e p leu ra. In view o f th i s v a r i a b i l i t y , th e un u su al n a tu re o f th e resp o n se and th e h ig h p ro p o rtio n o f d e a th s from in ta r c u r r e n t pneumonia i t i s f e l t t h a t d e f in ite conclu aions as to th e in flu en ce o f th is-d w st on th e course of tuberculous in fe c tio n are not ju stified . FEB-13-95 MON 17:25 J F HUMPHREYS ATTY FAX NO. 3043434186 F. 22 / C- y-r-Tor-V o f tn b e ^ cu x o u g . r - M - W o a t h e C ectio n conpZx-cati Lt>iat.ad t h e p e n d e n c y o f t h e w h e th e r /far n o t t h e / b a c t e r i a l d u st to p ro d u ce f ib r o u s t p s u e - TK 53f' le s io n n a s id c o n ta c t v ix h th e e re a - U A U A -tT*^. ***- T o h . l n t i a n B c p e r ir " "*- ~ t h S h a r t - n b e r `Aab?*V>a. g j g i,- _ l' ' v ' v + c -fTpctl'B'e i n p ro d u c in g f i b r o s i s Since uaaardoua d u sta lik e q u a rts " most e f f P . , ,,/,, ' an in h a la tio n experim ent tras -when t h e p a r t i t a a r e 3 m icro n * a n d l a a a m alm a, a n i n n , , , . . _ ( |rtuc a i go f o r s b c s to s d u s t , i t c a r r ie d on to d e te rm in e w hether t h i s conoa.ti.on - , . -abesbos d u st co n sistin g alm ost e n tire ly TO* th o u g h t t h a t b y u s i n g a s h o r t - f i b e r s b e s c o a gus* o f T ib e r . and p a r t i a l ^ th an 3 * = -- apcnaa ^ h e in it ia t e d an d a n a d ^ n c e d r a a c t i , o b ta in e d in a .h a r t tim e . T h e p r e v ic n s . . . _________ __ 1 * - . C o a t s a s b e s t o s , * i c h c o n ta in e d -b a rs ir o n X . to X - c r o n a r la a a in le n g th a a n e ii a * a s r e a t d a a i a T p - r t ic n ia t a n a t te r ,,* p ro d u ce d a t y p ic a l p e rib ro n c h io la r iib r a a id in p a c e d * p * s , s e rv e d a s a b a s is o f c o m p a riso n * d e n tin e n a t a r la X T a r t h in e m in e n t -a a T a r ^ r d e d T ra n th e -- * o f t h e Ja h n a -U a n rlX X e C o r p o r a t io n . I t a t h a r o in a t ih e r a c o lle c t e d in d u a t b in e a lt e r a c a r d in s o p e ra tio n and a cre e n a d to p a a . 2 0 0 n o s h . S in c e th a m a t e r ia l ae re c e iv e d c o n t a i n e d ^ X a n , lib e r a , i t - * * a t e e l h a l l m i ll to re d u c e p r a c t ic a lly a l l th a p a r t ic le , to 3 n ic ro n a . o r le a . . in a ,, t ^ d u a tin , n a c h in e , th ie f i n e l ^ n n d aabeato a s i z e , "hen u s e d a lo n e i n a s t a n u a r o * te n d e d t o p a c ^ i n t h e hopper - d i t b e ca m e n e c e s s a r y tao _ onrn)eA volu&PB o f t/hfi uiv* * AmL m t h t h r e e volum es o f t h e g ro u n d t o g e n e r a te a s a t i s f a c t o r y u s ground ma e r Q uantity o f unground asb esto s iras un fo rtu n ate clo u d . The a d d itio n o f th e sm all q u a n tity o f ungroun , 4 _ Pr-oVcihl-r t h e m inor am ount ox h i t conTnaad th a in te rp re ta tio n ad re n a l - ^ reaction t h a t d evelo p ed e a s due to t h e Io n T i b e r , i n th e r e t u r n a lth o u g h FEB-13-95 MON 17:26 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 23 d ata o f th is experim ent do not prore th e p o in t. 27. The com position o f th e s h o rt-fib e r asb esto s as received is d isclo sed by th e ch em ical and p e tro g ra p h ic an a ly se s given in T abls h- Semples taken b e fo re and a f t e r g rin d in g y ie ld e d ab o u t th e same v a lu e s analyaSst*. in c i raftin g th a t th e re van no contam ination from th e m ill o r lo s3 o f rater co n ten t. 28, The d u s t c o n c e n tra tio n v a rie d somewhat d u rin g th e experim ent and lig h t f i e l d co unts f o r atm ospheric sam ples c o lle c te d in s id e th e anim al cages w ith th e in tp in g e r a p p a ra tu s ranged from S3 m illio n t o 182 m illio n . The av erag e of co u n ts was 13 0 m i l l i o n f o r t h e f i r s t y e a r o f th e experim snfc, 13U m illio n f o r th e second y e a r and liiO m illio n f o r th e th ir d y e a r- 29. S la e -fre q u e n c y measurements o f a ir - f lo a te d d u st from in s id e th e cages a t & m a g n i f i c a t i o n o f 13C0X r e v e a l e d a g r e a t p re p o n d e ra n c e o f f i n e p a r t i c l e s (T able 5 )- N early 90 p e r ce n t o f th e p a r tic le s seen were sm a lle r than. 3 m icrons. 30. R e a c tio n i n Anim als to Inhaled S h o rt-F ib e r A sbsstoe D ust. Four s p e c ie s o f anim a ls -- guinea p ig s , w h ite r a t s , c a ts and ra b b its - were used in t h i s e x p e rim e n t. The r e s u l t s o f th e d u s t ex p o su re, which a re summarized i n ' T able 6, w i l l bo co n sid e re d more in d e t a i l below . 31. G uinea P ig s . E ig h ty guinea p ig s w ere o r ig in a lly p laced in th e d u st room \ b u t 2 1 o f them w ere l a t e r e lim in a te d from th e experim ent- a n d k i l l e d b e c a u s e o f e n la r g e d lym ph n o d e3 . O f t h e o t h e r 59 a n im a ls , US re m a in e d in th e du st room u n ti l th e y w ere s a c rific e d o r d ied from n a tu ra l causes and 13, a f t e r b ein g ex p o sed t o d u s t f o r 20 m onths, .were tr a n s f e r r e d t o a norm al atm osphere. 32- R ate and Type o f R eaction. he ty p e of tis s u e re a c tio n to th e in h aled FEB-13-95 HON 17:26 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 24 s h c r i --f i b e r a s b e s t o s -.xls Qsss-r.tirO.br 'ha s u a e a s t h a t a l r e a d y o b se rv e d in t h e experim ent w ith K in g 's f l o a t s a sb e sto s. The r a t e o f r e a c tio n a ls o was ap p ro x i m a te ly t h e aazss b u t t h e e x t e n t o f involvem ent- w ith t h e s h o r t --f i b e r d u s t w as v e r y much l e s s an d a f t e r 16 t o 'L m onths o f e x p o s u re o n ly a v e r y few s m a ll f o c i o f r e a c tio n , w hich g e n e ra lly req u ire d m icroscopic exam ination fdr^deio'ctibnj~ w era produced in th e guinea page. U n til exposures had continued fo r approTddcaiely one y e a r, th e re was l i t t l e te n d e n c y f o r d u s t--c o n t a in in g p h a g o c y te s t o c o l l e c t i n t o clu m p s. By 16 m onths phagocytes had begun to c o lle c t about th e w alls o f a few o f th e re s p ira to ry bron c h io le s w ith a l i t t l e p r o lif e r a tio n c r i n f i l t r a t i o n o f m ononuclear c e lls in th e se w a lls . T here w ere a ls o some m u ltin u cleatecl c e l l s b u t th e y w ere alw ays o f th e i n e r t fo re ig n -b o d y ty p e . At 20 to 2h months th e c e l l u l a r clumps w ere som etim es q u i t e m arked an d so m etim e s c h a n g e s i n t h e e p i th e li u m r e s u l t e d i n t h e adenoma--l i k e o r "adenom atoid" appearance p rev io u sly d e sc rib e d in S e c tio n 17. In most o f th e subsequent members o f t h e s e r i e s , th e r e a c tio n rem ained cel l u l a r in ty p e . In a fe w , h o weve r , f i b r o u s e le m e n ts d o m in ated t h e p i c t u r e . I n t h e l a t t e r c a s e , t h e c o lla g e n was p a le i n c o lo r and tenuous w ith no heavy sw o llen hya l i n i a a t io a . As i n th e r a t s d e s c rib e d b elo w , th e a lv e o la r T rails m ig h t b e made up o f a band o f collagen supporting a la y e r of epithelium , b u t w ith no contained c a p illa rie s . In th e tr a c h e o b r o n c h ia l lymph, nodes th e r e a c t i o n was more pronounced i n t h i s e x p e r i ment than in th e p rev io u s one w ith K ing's f lo a ts a s b e s to s , probably because o f th e tra n s p o rta tio n o f an excess o f fin e p a r tic le s to th e node3 in anim als in h a lin g s h o r t --f i b e r a s b e s t o s . T he r e a c t i o n w as e s s e n t i a l l y a n i n c r e a s e i n r e ti c u lu m , r a t h e r th an a f ib r o s is , w ith p re se rv a tio n o f th e o rig in a l c e lls between th e thickened r e ti c u la r f ib e r s . D iffu se ch ro n ic p le u ris y w ith o u t ev id en ce o f pulm onary in fe c tio n was p resen t in a few anim als. -1.6- FEB-13-95 HON 17:27 J F HUMPHREYS ATTY FAX NO. 3043434186 P.25 33- P ro g re s s io n * I n th e 13-3/U m onths fo llo w in g th e c e s s a tio n o f 20 m onths1 exposure to d u st, p ro g ressio n o f d isease tbs r.ot d e fin ite ly dem onstrated b u t n e ith e r could i t be a b s o lu te ly d isp ro v e d , owing to th e v a r ia b i l i t y o f th e response in d iffe re n t anim als At th e end of th e dust exposure of 20 m onths tw o p i g s w e re ' r e a d a s -* and one a s 2-*. Among the" 13 removed 'fro m duet, th e f i n d i n g s w e re v a r i a b l e : i n 2 t h e r e a c t i o n was s j i n it i t w as --j i n 3 i t was 3 *"5 i n 3 i t w as li+ j and i n one a n im a l i t w as *. I t i s q u i t e p o s s i b le t h a t t h o s e w ith th e most marked changes had a lre a d y developed more re a c tio n th a n th e rem ain d e r by th e tim e exposure ceased- S ince th e store se v e re re a c tio n s occurred spora d ic a lly and b o re no re la tio n s h ip to th e le n g th o f tim e a f te r cessatio n o f expo su re th e d iffe re n c e s were a ttrib u te d to v a ria tio n in in d iv id u a l s u s c e p tib ility . T h is view re c e iv e d su p p o rt from th e chem ical a n a ly se s (T able 7 ) , which o fte n r e v e a le d com parable amounts o f a sh an d s i l i c a i n lu n g s w ith w id ely d if f e r e n t am ounts o f tis s u e change. For exam ple, th e ash and s i l i c a v a lu e s were q u ite s im ila r fo r t h r e e a n im a ls i n dust 20 m onths and th e n i n n o rm al a i r 13-3A m onths, y e t t h e t i s sue re a c tio n fo r one anim al was iiv; fo r a n o th e r, and fo r th e th ird , only . 3U. A sb esto ela B odies. The fo rm atio n o f a s b e s to s is bo d ies was a t f i r s t ex tr e m e ly l i m i t e d . A f t e r *> m onths * e x p o su re o n ly a v e ry r a r e s h o r t body c o u ld b e fo u n d , u s u a lly in s id e o f c e l l s . Around th e f i n e s t i n t r a c e l l u l a r p a r t i c l e s th e r e w ere y e llo w d e p o s its h av in g th e same c o lo r a s th e a s b e s to s is body. Exposure o f one y e a r had p e rm itte d an accum ulation o f many lo n g e r f i b e r s ab o u t w hich th e a s b e s to s is -b o d y c o a tin g d e v e lo p e d . Most o f th e s e w ere s t i l l s h o r t enough t o b e p a r t i a l l y o r e n t i r e l y w ith in p h a g o c y tic c e l l s . By th e 20th month and th e r e a f te r , th e y w ere co m p arativ ely numerous although s t i l l r a r e i n com parison w ith th e fin d in g s in th e K in g 's f lo a t s experim ent. FEB-13-95 HON 17:27 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 26 3?* W hite Ttabs- Scvturty-v.bj.'es -shii-e r e t s vrere exposed t o a tm o sp h eric shorfc- fiboi* a sb e sto s d u c t l'or p e rio d s up to 32 months. S a e ri- i i c i n g s d u r in g t h e - f ir s t. 1 0 surnths r /s r o as*jde b im o n th ly au d T or th e re m a in d e r o f the^eacperirient a t le s s fre q u e n t x n ty rv s ls ... , . 36. R ate and Type o f R ea c tio n . The d u s t c e l l s u n t i l 5 months r a r e w id ely s c a tte re d and er-dsted in fo c i only sp o rad i c a l ly - R eac tio n m s lim ite d to o c c a sio n a l s l i g h t th ic k e n in g s o f th e s e p ta about. sna i l accum ulations o f d u st c e l l s . In a fe n r a t s a t 10 m onths, th e re tos a sug g e s t i o n o f e a r l y f i b r o s i s b u t t}io ch an g a w a s s o s l i g h t t h a t i t -would p r o b a b ly b e overlooked "without th e clump o f d u st c e l l s t o a t t r a c t a tte n tio n to th e a re a . Only 10 an im als r a r e exposed from 12 to 32 m onths. I n eac h o f them th e lungs showed m inute p a tc h e s o f -w ell-defined f ib r o s is d is tr ib u te d li k e th a t o f a sb esto s i s b u t w ith o u t a s b e s to s i s b o d ie s . The le s io n s , v i s i b l e o n ly a t a m a g n ific a tio n o f 150 d iam eters o r m ore, c o n siste d o f p atch es along a lv e o la r d u c ts in which th e w a lls of th e a i r spaces w ere very thick:, due to sw ollen co llag en framework. Connective tis s u e and F oot-B ielschow ski s ilv e r p re p a ra tio n s re v e a le d com plete lo s s o f c a p il la ry bed lo c a lly . O utside th e collagen was a th in la y e r o f e p ith e lia l c e lls . T his d id n o t r e s enisle th e "adenom atoid" change c h a r a c te r is tic o f guinea p ig a s-- b e s - to i s . Ma p l e u r i s y w as p r e s e n t . H ear t h e l e s i o n s t h e a i r s p a c e s w era f i l i a d w ith, phagocytes c o n ta in in g g rey to yellow p a r tic u la te d u st and a ra re long naked asbestos f ib e r . C areful search fa lla d to re v e a l even a suggestion of an asb esto s i s b o d y . The tr a c h e o b r o n c h ia l nodes showed com pact f o c a l c o l l e c t i o n s o f mono c y t i c c e l l s a t 1 2 m onths a n d , a t 20 m onths, some d i f f u s e th ic k e n in g o f th e re tic u lu m . In a few r a t s th e re was d e f in i te f ib r o s is along th e m argins o f th e node and a r t ending in to th e m ed iastin al a re o la r tis s u e . Compared w ith th e response t o a c t i v e d u s t s l i k e q u a r t z an d c h e r t t h e r e a c t i o n t o s h o r t --f i b e r a s b e s to s was n eg lig ib le- FEB-13-95 HON 17:28 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 27 R e s u ite Of ch en d cal a n a ly s e r a * ^ t i * r a te a r Siven in Table 3 and th e average v a lu e s have been ta b u la te d in T able ? fo r com parison w ith s im ila r v a l u e s Xtor r a t s i n h a l i n g o t h e r d u s t s . The c o n c e n tr a ti o n o f a t r o a p h e r i c p a r t i c l e s to. -which tfcs a n ira a ln fro re ex p o sed was appror5.iuat.elr tlxa came f o r a s b e s to s and q u a r ts ; f o r th e g y p s u ^ q u a r tz m ix tu re . i t was ab o u t t e l c o ar. hxgtt a h tT fo r c h e r t fiv e tim es as h igh. I t w ill be noted th a t tb * percantagas fo r asbestos are loner th a n th o s e f o r q u a r tz o r c h e r t b u t a r e s i a d l s r t o th o s e l o r th e Ky-paiM-quaro n d x tu re , in. w hich atm o sp h e ric a g g lu tin a tio n te n d e d to red u ce th e aiaount o f d u st in h aled . I t m ight be in fe rre d th a t th e t o t a l q u an tity o f asbestos d u st in h aled was low o r t h a t i t had been e lim in a te d froffl o r d isso lv e d -w ithin th e lu n g s . I n th e p re s e n t s t a t e o f o u r knowledge e v a lu a tio n o f tb a a a h y p o th eses i s n o t p o s s ib le . 37* C a ts. Twenty c a t s -ssr3 used i n t h i s I n h a la tio n experim ent w ith th e s h o r t- f ib e r a s b e s to s . Eighteen, were k e p t in th e d u s t room u n t i l d e a th , th e exposure p e rio d ran g in g from one month to a rty k - l/2 y e a rs , and tw o, a f t e r a d u s t e x p o su re o f 3 1 -1 /2 m onths, w ere removed to norm al a i r . One o f th e s e jtss s a c r if ic e d 5 m onths, and th e o th e r 2ii m onths, la e r . 38. Hate a n d Tyne o f R e a c tio n . The r e a c t i o n -was e s s e n t i a l l y t h a t t o a n i n e r t d u s t , e v e n a f t e r m ore th a n It y e a r s o f e x p o c u re . The tis s u e response in th i s sp ecies was confined to m icroscopic fo c i o f fib ro s is in th e w a lls o f groups o f subpleirral a lv e o li, ra th e r than in th e p erx b ro n ch io ln r a re a s . In one anim al th e change was e x te n siv e enough to be v is u a liz e d on gross in sp ectio n o f th e sectio n . 39. X -Bar Changes. Only i n th e an im al w ith th e lo n g e s t exposure d id th e X -ray re v e a l d e f in ite ly abnorm al shadows- A fte r 2 9 -3 /U m onths t h e p i c t u r e m s n e g a t i v e ; a f t e r US m onths a f a i n t m o t tli n g c o u ld b e d e t e c t e d thro u g h o u t b o th lu n g s . A t a u to p sy , 5 mouths l a t e r , th e r e was only m icroscopic FEB-13-95 HON 17:28 J F HUMPHREYS ATTY FAX NO. 3043434186 P.28 f i b r o s i s in the craDpl^urai 2.0? ly-.TOhocytic - v -* -4 ' 3T.CJ.1 b ro n c h io le s . ' ;,0 . _ A fibaatoela'B odies., . ,, - , p fenc vt1J.o?r a t y p i c a l a p b e s to o ls On rn ro lo n g ad o33Tv>h a lW - - - b e d is s a sm ooth and w ith o u t ::.n tiro am xnais ex p o se d i b r more th a n a y e a r , !il- R a b b its - E ig h t r a b b i t s -were exp o sed t o d u s t f o r p e rio d s one t o uiora th a n fT3 y o aro - The l a s t e r t x a l u a s r a m d t room and l o f t i s a i r 6 months b e fo re being s a c r if ic e d . h2. . t . and to n e o f K eaction. T here *us n ev er nosb f ib r o s is to be de t e c t e d g r o s s l y an d t h e r e n t s 'ho c h ro n ic adhesive p le u ris y . M icroscopic evidence o f a lv e o la r - a l l thickening uas f i r s t d e te c te d a f t e r a b o u t 3 J o f exposure e i s se e n t o a l l f iv e e n to a ls examined t h e r e a f te r , t o one a n to a l t h a t d ie d o f p a r a ly s is a f t e r n e a r ly fo u r y e a rs, o f ex posure th e re a c tio n e a s ex ten siv e enough to he v is ib le on gro ss in sp ectio n o f t i s s u e s e c t i o n s , toe p o s s i b i l i t y o f p u lm o n a ry t o f e c t i o n t o t h i s a n t o a l c e n to n o t be excluded. H ceever. to another a n to a l dying to o y e a rs to tc r th e fe c a l fib ro s is u s s n o t n e a rly a s obvious o r a s advanced, a re a s o f tovaL veaent, u h ich are la rg e ly v isu a lto e d because o f phagocytic re a c tio n e ith to th e a i r spaces, tended m ic ro sc o p ic a lly to become t o r s fib ro u s n t h th e p aesag e o f tt o e b u t th e re u se ,, e v e r su ch encroachm ent upon th e lumen o f a i r sp aces and th e a r c h ite c tu r e o f th e iirrt^ -was p r e s s * y e d - t U3. B odies. A sbestos bodies - e r e n o t d ete c te d to ra b b its th a t died e a rly in th e experim ent but to r s seen in a l l animals th a t had, b, een e_x_pose^d jt.o_ ot-hhje reiruasst'j, fior more than th ro e y e a r s . FEB-13-95 HON 17:29 J F HUMPHREYS ATTY FAX NO. 3043434186 ' P.29 Tlia o x irin & L p u rp o se o r th s ax p a rim e n t w3 t o e v a lu a te th e ch em ical th e o r y o f t h e p a th o g e n e s is o f a s o e s t o s i s . I t -was f e l t t h a t i f t h e t i s s u e r e a c t i o n t o a s b e s t o s ttevg c h e m ic a l i n o r i g i n a n a c c e l e r a t e d o r a c c e n tu a te d re s p o n s e would r e s u lt from exposure to Palely-divided a s b e s to s , a s i s th e case w ith q u a rts . T ills jroorxaient, in which th e re a c tio n v ac c lo s e r and le a s ex ten siv e th a n id tii X in g 's f l o a t s , i n d i c a t e s t h a t th a r e a c t i o n (jrotJSGiy i s n o t p r i m a r i l y c h e i i c a i i n 1/ n a tu re . Of th e fo u r sp e c ie s axpoeed in t h i s experim ent o n ly th e guinea p ig and r a t re a c te d w ith c h a r a c te r is tic p e rib ro n c h io la r f ib r o s is . The c a t re a c te n w ith a t y p i c a l s u b --p l j s a r s l f i b r o s i s an d i n t h e r a b b i t t h e f i b r o s i s w h ich o c c u r r e d c o u ld n o t be p o sitiv e ly a ttrib u te d to th e dust because of a strong p o ssib ility . o f pulm onary in f e c tio n . , T* ' X U V V j ^ H ^ A U 4 T l 2 > M - : --------------------r I n b ^ a t i o n Rxperirrc^nt ^-wi^h IgO P ^ r C e n ^ B a iy -M il^ e d Aa^ o s t o ^ P u s o Tw t h e i n h a l a t i o n e x p a r i n e n t w i t h s h o r t --f i b e r a s b e s to s d u s t a s m a ll q u a n t i t y o f irg**onri a s b e s t o s w as n ix e d w i t h g ro u n d m a t e r i a l i n o r d e r t o p ro d u c e a s u i t a b l e d u s t c l o u d . **1100 e v id e n c e o f a d u s t r e a c t i o n a p p e a re d i n t h e g u in e a p ig s d u r in g t h e e x p e r im e n t, i t w as n o t c l e a r w h e th e r t h i s w as a t i s s u e r e s p o n s e t o t h 9 s ma^ i number o f Tong f i b e r s i n th e ungrerond. a s b e s to s o r was a d elay ed e f f e c t o f th e a c r e abundant fin e d u s t. C onsequently, an o th er in h a la tio n experim ent was started , in w hich no unground m ats e ria l wad u se d . U6 . T he d u c t i n g m a t e r i a l naa t h e g ro u n d s h o r t - f i b e r a s b e s to s u s e d i n th e p re v io u s in h a la tio n experim ent b u t no unground m a te ria l was mixed w ith i t . To o b ta in a s u f f ic ie n t amount o f atm ospheric d u e t, th e d esig n o f th e d u stin g a p p a ra tu s rras changed to an open ty p e o f h o p p er and f r e s h d u s t was added d a ily . FEB-13-95 HON 17:29 J F HUMPHREYS ATTY FAX NO. 3043434186 ........ ... i urnnn i P. 30 Owing t o t h e u en d sn cy o f t;;e ra te r-.* i ;.-c i'oi-rz s n a i l s p h e r u le s 'd-.ich p re v e n te d m e n o f tiie fib ro u s p o rtio n fro:;; iicav.ing out o f the. hopper, th e -d is p e r s a l o f t h e d u s t Trac n o t e n t 3.r a ljr s a t i s f a c t o r y and c u t e r 7 m ouths o f o p e r a t io n , th e d u s t in g m achine was rscoE V ortsu to i t s c rim in a l d e sig n . To p re v e n t " p illin g " or th e form ation o f spherules of eab ssto sj s te e l w ire brunhas re re attach ed to th e in s i d e s u r f a c e o f th e h o p p e r and t o th e r o t a t i n g p a d d l e . T h is c --r?-ngem<=nt gave s a ti s f a c to r y r e s u lt s and was used f o r th e rem aining XI months o f th e experim ent. u 7 . The c o m p o s itio n o f t h e Z'sxr r a t a r i n l i s h o r t - f i b e r a s b e s to s ) and c f atm o s p h e r i c d u s t l i b e r a t e d f r o - t h e f c a l i - r j l l l e d p r o d u c t i n t h e d u s tin g ma ch in e i s given in T able 10 - The3? v alu es a re based upon p etro g ra p h ic study and X -ray d if f r a c tio n a n a ly s is . The atm ospheric sam ple r a c c o lle c te d r d th an e le c tr o s ta tic p re c ip ita to r a fte r w ire brushes had been in s ta lle d in th e dusting m achine. P revious to th is , th e ch ry so tile. co n ten t o f th e air-suspended m a te ria l was u n d o u b te d ly l e s s th a n t h e 15 p e r c e n t v a l u e g iv e n i n T a b le 1 0 . I n a n i n t e r im r e p o r t} i t was s ta te d th a t th e a ir-b o rn e d u s t co n tain ed about 5 par c e n t of c h ry s o tile b efo re th e w ire brushes were used end up to 6 per cent afterw ard s, b u t t h e s e v a l u e s w e re p r o b a b ly lo w . Q u a n t i t a t i v e e s t i m a t e s on b a l l --m ille d a s b e s to s d u s t may b e som ew hat i n a c c u r a t e b e c a u s e i t i s d i f f i c u l t t o d e te r m in e how much o f a d u s t sam ple i s f ib r o u s c h r y s o t i l e and how much i s n o n - f ib r o u s s e r p e n tin e . IiS. The d u s t c o n c e n tra tio n f o r th e f i r s t 7 months o f th e experim ent was about 100 m illio n p a rtic le s per cubic fo o t of a i r . A fter th e w ire b ru s h e s had b een i n s t a l l e d , th e d u s t c o u n ts -were a l i t t l e h ig h e r and th e o v e r a ll a v e ra g e f o r th e f i r s t y e a r was 106 m illio n . The av era g e o f co u n ts fo r th e second y e a r was 16 3 m illio n and f o r th e t h i r d y e a r 1 hS m illio n . FEB-13-95 MON 17:30 J F HUMPHREYS ATTY FAX NO. 3043434186 P.31 m i n T a b le 1 1 . Two sa m p le s w ere ta k e n , one b e f o r e t h e w ir e b r a s h e s w ere i n s t a l l e d and one a f t e r . I t "w ill b e n o te d t h a t a f t e r th e wire b ru s h e s w ere i n u se a g re a te r p ro p o rtio n of Vry fin e p a rtic le s and a lso o lohgar fib e rs'w a s r e l i a s ed in to the a ir . 50. R eac tio n i n Animals to In h ale d 100 P er C ent 3 a ll-4 & ll6 d A sbestos D ust. G uinea pigs? r a te end n ic e were used in th e In h a la tio n experim ent w ith t h e ICO p e r c e n t b a l l - m i l l e d a s b e s to s d u s t . The r e s u l t s a r e s u jn m riz e d i n Table 12. 5 1 . G uinea F lg a . The ex p erim en t was s t a r t e d w ith 100 g u in ea p ig s . As th e d u st exposure proceeded, th e re w ere 39 a c c id e n ta l d eath s, 32 o f pneum onia i n an epidem ic- A fte r 28 months o f d u s tin g th e 16 su rv iv in g guinea p ig s w ere tra n s fe rre d to normal a i r . 52. R ate and Type o f R eaction. F or th e f i r s t y e a r of exposure p ra c tic a lly th e only re a c tio n to th e d u st was th e p re-- Hence o f s c a tte r e d phagocytes and an o c c a sio n a l m inute a s b e s to s is body. At 16 and 20 m onths no g ro ss resp o n se was r i s i b l e on th e ti s s u e s e c tio n b u t m ic ro sc o p ic a lly p e rib ro n c h io la r f o c i o f inflam m atory c e l l s could be s e e n . At 2k months th e re was s t i l l no change la rg e enough to be seen w ith a hand le n s although m icroscopic ex am in atio n r e v e a le d c e l l u l a r a c c u m u la tio n s a b o u t te r m in a l b ro n c h io le s and many i' more a s b e s to s is b o d ie s , c h ie f ly w ith in c e l l s . C hem ical an aly se s o f th e lungs (Table 13} r e v e a l th a t in s p ite o f th e lim ite d tis s u e re a c tio n considerable d u st had been re ta in e d in th e lu n g . FEB-13-95 HON 17:30 J F HUHPHREYS ATTY FAX NO. 3043434186 P. 32 rev ealed th e changes describ ed above and a lso very s lig h t p erib ro n ch io lar fib re -- s i s - A f t e r 0 m ontlis i n n o rm al a i r th e f in d i n g s w are s i m i l a r b u t a t 12 months 3 o f'li anim als showed g ro s3ly - v is ib le c h a r a c te r is tic p e rib ro n c h io la r f ib ro s is w ith adenom atoid change. 5U. Lymph Bode In v o lv e m e n t, The t r a c h e o b r o n c h i a l n o d es w ere e s s e n t i a l l y n eg ativ e u n ti l exposure had been continued f o r more th a n a y e a r and a h a l f . Animala s a c r i f i c e d a t 12 months and 16 months rev ea led a few m inute c o lle c tio n s o f phagocytes co n tain in g p a rtic le s b u t p rac t i c a l l y no f ib e r s la rg e enough to be reco g n ized a s su c h . A fte r 20 months o f exposure many m onocytes f i l l e d w ith y ello w g ra n u le s w ere p re s e n t. A t 30 months t h e r e h a d b e e n a s l i g h t i n c r e a s e i n r e t i c u l u m b u t no f i b r o s i s . No f u r t h e r changes occurred in th e nodes. A sbestosis bodies w ere n o t seen in th e nodes o f any o f th e guinea p ig s. A sb e sto sis B odies. M inute a s b e s to s is b o d ie s w ere observed aa e a r ly as 3 m onths a f t e r exposure began, b u t th e y d id n o t b e - come num erous u n t i l 1 6 m onths h ad e l a p s e d . The b o d ie s w e re s h o r t and p r a c t i c a l l y a l l w ere i n t r a c e l l u l a r , alth o u g h a t 20 m onths some w ere lo n g enough to p ro je c t beyond th e c e ll b o rd ers. I t i s im p o rtan t to n o te th a t in th e l a t e r months o f exposure th e re was a d is t i n c t i n c r e a s e i n t h e number ,o f lo n g f i b e r s (pep t o 70 m ic ro n s i n le n g th ) i n t h e lu n g s and th a t a f t e r exposure ceased c h a r a c te r is tic long a s b e s to s is bodies were seen . 5 6 . W h ite R a ts a n d M ic e . In t h i s e x p e r im e n t hO r a t s w e e x p o se d f o r p e r io d s up t o 20 months and 2k m ice f o r p erio d s up to 12 FEB-13-95 MON 17:31 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 33 m onths. N eith er sp e c ie s developed even a su g g estio n o f asbesto3XS and re a c tio n was lim ite d to p h agocytosis o f in h aled p a r tic le s by -w id ely -scattered d u st c e lls which, re m a in e d f r e e i n a i r s p a c e s o r -were t r a n s p o r t e d t o t h e tr a c h e o b r o n c h ia l lymph n o d e s . No a s b e s to s i- s b o d ie s w ere fo u n d i n t h e r a t s b u t i n t h e j n i c e t h e r e ware a v e r y fe w s m a l l n o n -h a u s t-ra te d fo rm s w i t h i n p h a g o c y te s . * I n 2 1 mouse lu n g s se c tio n e d th e re w ere 3 in s ta n c e s o f pulm onary adenoma (lhlC). 57. Summary und I n t e r p r e t a t i o n . The t i s s u e resu ctio n s o b serv ed i n t h i s ex p erim en t w ere much le s 3 e x te n siv e an d s lo w e r i n d e v e lo p m e n t th a n i n t h e p r e v io u s i n v e s t i g a t i o n w ith s h o r t --f i b e r a sb e sto s. Since presum ably th e re w ere few er fib e rs lo n g e r th an 3 m icrons in th e m a te ria l used in t h i s experim ent, th e r e s u lts ten d to confirm th e in te rp re ta tio n made i n S e c t io n liL o f t h e s h o r t - f i b e r e x p e rim e n t t h a t t h e r e a c t i o n p M M H y i s n o t p rim a rily chem ical in n a tu re . The f i n d i n g o f lo n g a s b e s to s i s b o d ie s i n a n im a ls i n h a l i n g t h e b a l l --s i l l e d , m a te ria l i s an exam ple o f th e d if f i c u lty o f co m p letely e lim in a tin g long f ib e r s from an asbestos p rep aratio n . In re g a rd to p ro g re ssio n o f re a c tio n a f te r rem oval from d u s t, liiic h was ob served in th is experim ent b u t no t in th e o th e rs, th e follow ing in te rp re ta tio n is o ffe re d : Then th e re a c tio n i s w ell-developed a t th e te rm in a tio n o f ex p o su re,th e c o n tra c tio n o f th e fib ro u s t i s s u e would obscure any p o s s ib le p ro g re s s io n . In t h i s experim ent, however, sin c e only th e e a r lie s t stag e o f re a c tio n was p resen t a t th e tim e o f rem oval from d u s t, i t s subsequent p ro g ress was a p p a re n t. I t should be noted th a t th e d egree o f p ro g ressio n was so s lig h t th a t i t can have liw tle , i f any, p ra c tic a l sig n ifican ce . FEB-13-95 MON. 17:31 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 34 "T< Vfft vLU A.U O-T- m . Ir^ la ^ ^ n ^ ^ p o ri.m .a 'Q ^ jEZtb . ^ r ^ ^ ^ r ^ p ' j a s ^ q s . -gt- A fte r a n ln a la in h a lin g e h c r v - iib e r a sb e sto s d u s t Tor more than a y e a r had fa ile d to develop s ig n ific a n t re a c tio n , th e hypothesis th a t asb esto sis is pro duced by t h e m echanical i r r i t a t i o n o f lo n g f ib e r s was given added s u p p o rt. Since th e K in g 's f lo a ts asb esto s used i n th e f i r s t in h a la tio n experim ent had a ra th e r low co n ten t o f fib ro u s clu ry so tila and contained consid erab le serp en tin e and o th e r im p u r itie s , i t was d ecid ed to conduct a new in h a la tio n experim ent w ith a p u re r form o f c h ry s o tile which would be r ic h e r i n long f ib e r s . 29. The d u s tin g m a te ria l employed i n t h i s in v e s tig a tio n was o b ta in e d from th e B a n v ille p la n t o f th e Jo h n s-B a n v ille C o rp o ratio n . Samples o f s e v e ra l v a r ie tie s o f asb esto s du st were f i r s t subm itted to th e Saranac la b o ra to ry f o r ex am in atio n and one k in d , id e n tif i e d a s L ot D, w hich was low i n m ag n etite and ch ro m ite and had a fib ro u s c o n te n t e stim a te d to be about 75 p e r c e n t, was se le c te d os m ost s u ita b le . S te e l w ire brushes were fasten ed to th e xnside su r face o f th e hopper and to th e ro ta tin g paddle in o rd er to open up th e bundles o f a sb e sto s and li b e r a te more f ib e r s in to th e atm osphere- 60. The com position o f th e lo n g -fib e r asb esto s used in th is experim ent i s i n d i c a t e d b y t h e c h e m ic a l a n d p e t r o g r a p h i c a n a l y s e s g iv e n i n T a b le 11*. I t ap p ears t h a t t h i s m a te r ia l was a much p u re r farm o f a s b e s to s th a n th e s h o r tf ib e r d u s t used i n o th e r ex p erim en ts. T his i s borne o u t by com paring th e approx im a te a n a l y s e s o f t h e lo n g --f i b e r an d s h o r t --f i b e r i d u s t i n T a b le 15* f 6 1 . The d u s t co n c e n tra tio n as rev ea led by im pinger sam ples taken in sid e the nnim ni cag e s w3-3 much lo w e r t h a n t h e c o n c e n t r a t i o n f o r t h e e x p e rim e n ts w ith s h o r t- f ib e r o r b a ll-m ille d d u s t. For th e f i r s t y ear o f th e experim ent w ith lo n g --f i b e r a s b e s t o s t h e a v e r a g e o f t h e l i g h t f i e l d c o u n ts was 32 m i lli o n } f o r r/ FEB-13-95 MON 17:32 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 35 t h e se c o n d y e a r , li8 B i l l i o n ; f o r th e t h i r d y e a r , 3!> m i l l i o n ; s m Tor th e f o r r c n y g a r , U3 m i l l i o n - S x s s d a a tio n o f th e im p in g e r s s n p la o w ith d o rk f i e l d i l l u m i n a tio n d is c lo s e d t h a t many f in e p o r t i d e a le s s ttusa oas H i cron in s iz e accompanied th e l a r g e r p a r t i c l e s end d a rk f i e l d co u n ts -were, on th e a v era g e, aboun 5 o r 6 tin e s la rg e r th an th e lig h t fie ld counts. . 62- The sin e -fre q u e n c y o f atm ospheric sam ples of th s Icr.c-fx cer asoesucs d u s t and o f th e b a l l - n i l l o d d u s t i s shown in T sb le Id - B oth sam ples w ere c o lle c te d w ith th e e le c tr o s ta tic p r e c ip ita to r , i t nil.'- ba noued th a t th e re was f a r m ore f i b r o u s m a t e r i a l i n t h e lo n g --f i b e r gus*.. 6 3 . R e a c t i o n i n A n im als t o I n h a le d l o n r - F i b e r A s b e s to s B u s t. Gxvxnea p i g s , c a t s , r a t s en d m ice w ere em ployed i n t h e i n h a l a t i o n experiment w ith lo n g - f ib e r a s b e s to s . R e s u lts o f th e experim ent, summarized i n T able 17, a re described in g re a te r d e ta il below . 6U. G u in e a P i g s . The e x p e rim e n t w as s t a r t e d w i t h 100 g u in e a p i g s . A f te r exposure had been c a rrie d on f o r a y e a r, a sev ere epidem ic o f pneum onia a ro s e i n th e d u s t room and about o n e -th ird o f th e anim als d ie d o r w ere k i l l e d . To re p la c e th a n , 38 more guinaa p ig s w ere added to th e s u rv iv in g g ro u p tt> th e . d u s t r o e d - 6$ . R ate and Type o f R e a c tio n . H is to lo g ic a l e x a m in a tio n r e v e a le d g r o s s ly v is ib l e le s io n s i n th e lungs a f t e r 8 months o f exposure to d u st, co n sistin g o f c e llu la r in f iltr a tio n about th e term in al b ro n c h io le s . A t 12 m onths,' th e re were adenom atoid changes in th e a i r spaces and by th e 16 t h month a d e f in i te f ib r o s is was p re se n t in th e s e area s in h a l f th e a n i m l s - The f ib r o u s le s io n co u ld be seen ja a c ro sc o p ic a lly a t 20 m onths. Pro t h i s tim e on t h e r e a c t i o n in c r e a s e d in - e x t e n t and i n t h e amoxrct o f c o l la g e n and FEB-13-95 MON 17:32 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 36 j-. -iorrt-'.j i t iiao. far.r.r-A our, i n t o t h e p aren ch y m a. The l e s i o n s w ere r a t h e r c h a r p ly l o c a l i s e d and t h e e x te n s io n s from d i f f e r e n t , b r o n c h io le s sho-jred no te n d e n c y t o f u s e , ev en i n a n im a ls e x p o s e d f o r t h e ma x i cum p e i io d (3 y e a r s ) . A lthough .th e in tra-p u lm o n u ry re a c tio n som etim es reached th e p lc m ^ ^ th e re w asjio in v o lv e m e n t o f t i i a i membrane. No emphysema was v i s i b i s a t a n y p o i n t . Some th ick en in g o f th e la rg e r b ro n ch i w ith a ch ro n ic inflam m atory i n f i l t r a t i o n was r e v ealed , c u t i t pro b ab ly was no mors th a n would be produced by a s im ila r exposure to any d u s t. For th e f i r s t ? months th e phagocytes c o n s is te d o f monocytes or v e ry s n a i l g i a n t c e l l s ; l a t e r , g i a n t c e l l fo rm a tio n w as snore p ro m in e n t. A fte r 16 months th e g ia n t c e l l s w ere la r g e , f i l l e d w ith yeilow ish-fcrcrau. pigm ent and som etim es v a c u o la te d . An o c c a s io n a l a n im a l showed a n A dm ixture o f polym orpho n uclear leukocytes and, in guinea p ig s exposed f o r a considerable p erio d , e o s i n o p h i l c s . The r e a c t i o n -was a t f i r s t e n t i r e l y c e l l u l a r b u t b y 16 m onths f i brous tis s u e fo rm atio n was d e f in i te . However, i t n ev er a tta in e d a s ta g e o f h y a lin iz a tio n suggestive of s ilic o s is . a m oderate in d iv id u a l v a r i a t i o n o c c u rre d among t h e exposed a i i n a l s , b o th i n th e r a te o f developing le sio n s and in th e sta g e o f developm ent a tta in e d a t th e end of exposure. A nalyses o f th e lungs (Table 18 ) d isc lo se d th a t alth o u g h th e tiss u e response was much g r e a t e r i n t h e s e g u in e a p ig s t h a n i n t h o s e ex p o se d t o e i t h e r s h o r t--f i b e r o r b a l l- m i lle d a s b e s to s , th e amount o f m in e ra l m a tte r i n th e lung a s h was l . e s . 66. P ro g re ssio n . In guinea p ig s exposed to th e d u s t f o r 20 months and than removed to norm al a i r , th e r e w as a marked ten d ency fo r c e llu la r inflam m atory re a c tio n to c le a r . T his a f f e c t, accompanied by c o n tra c tio n o f th e f ib r o u s t i s s u e , r e s u l t e d i n a d im in is h in g s i z e o f th e f o c a l l e s i o n s . None FEB-13-95 HON 17:33 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 37 of th e se an im als, k ille d a t v a rio u s p erio d s cp to * * < * *r t e r ^ ? ssu re ^ r e v e a le d l e s i o n s a s l a r g e a s th o s e i n t h e g roup c a c rj-fJ-^ e - t l `G 20-m onth e x p o s u re p e r io d o r t h o s e i n a n im a ls T .iiich Ae i.^ n u d i*. dws ` fo r more th a n 20 xncnths- fo u rte e n months a f te r d u st exposure cessed? -he oc~ in fo u r of th e s ix r e m a i n guinea p is s trere so sm all th a t W ^ v is ib le ~ only -nith a hand le n sR e a c tio n l a th e group exposed f o r 27 M a th s end th e n tr a n s f e r r e d t o a norm al atm osphere w as q u ite s im ila r to th e resp o n se i s th e 20-co r.th exposure anim als m entioned above. H o o v er, sm all fo c i e a r s ataay s v is ib le on gross in sp e c tio n of s e c tio n s o f a l l g u in e a p ig s o f th e 27-m onth s e r ie s t o t in no in ste n c e e s s th e re evidence of extension o f th e re a c tio n . 6 7. Lymph Rode In v o lv e m e n t. Reaction i n th e tr a c h e o b r o n c h ia l lymph nodes ivsls f i r s t v i s i b l e a t t h e t h i r d ao n o h o f ex-- p o su re. i t th e 8th month p atch es o f c e llu la r co n n ectiv e tis s u e began to appear in th e m ed u lla and by th e lllth month m ost o f th e node had been re p la c e d b y ----i . . . T a r c o n n e c tiv e t i s s u e . T h is p i c t u r e , sfc ic h re s e m b le d t h a t i n e a r l y s i l i c o s i s , p e r s i s t e d t o t h e end o f t h e e x p e rim e n t. Some a n im a ls , a s a v a r i a n t , s h o d heavy sh e e ts o f d if f u s e m onocytes and la rg e a c tiv e g ia n t c e l ls b u t th e re a s n ev er any n e c ro s is o r h y a lin e fo rm atio n .- The sp in d le-sh ap ed n e s c e lls s e r e y e llo u is h in c o lo r from f in e pigm ent g ran u les th a t s ta in e d fo r ir o n . So fib e rs o r a s b e s to s is bodies T ere seen. 68. ,h o ,to o ls B o d ies, Although a s b e s to s is b o d ies s e r e . e e ^ a a e a rly as one month a f t e r exposure b eg an , th e y s e r e r a r e and b ard to f in d . At 5 months more mere v is i b l e , c h ie fly c o ile d in s id e g ia n t c e l ls , and a t 8 months many b o d ie s m ere fr e e i n connective t i s s u e . They became f a i r l y abundant as exposure a lth o u g h i n some l a t e r an im als th e a s b e s to s is b o d ie s v e ro o nly m oderately numerous. FEB-13-95 MON 17:33 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 38 Cai>s * Four ca.*c-o i n h a l e d th e l o n g --.f ib e r a s b e s t o s d u s t or p e r io d s ox sacrificed . lli y " ^ and 1+2 m o n th s, r e s p e c t i v e l y , and w ere im m e d ia te ly Tro o th er cate , a f te r being exposed to d u st fo r 18 m onths, liv e d in a n o rm al a tm o s p h e re Tor a u a d d i t i o n a l 2l+ m o n th s. 70. R ate and Type o f R eactio n . Exposure f o r Ik months iras s u f f i c i e n t to produce c e llu la r accum ulations o f phagocytes around term in al bronchioles and p e rip h e ra l a r te r io le s to g e th er r a th compact col le c tio n s ox s im ila r c o lls i n th e tr a c h e o b ro n c h ia l lymph n o d es. At t h a t tim e th e re w ere no ty p ic a l a a b s s to s is b o d ie s, b u t sm ooth p o in ted yellow fib e rs were seen v e ry r a r e l y . V /ith c o n tin u e d e x p o s u re , u p t o 1+2 m o n th s, r e a c t i o n i n t h e l o c a t i o n s n o te d p ro g re sse d to th e fo rm atio n o f c e l l u l a r c o n n e c tiv e t i s s u e w hich made w e ll-d e fin e d sh eath s about th e r e s p ir a to r y b ro n c h io le s and a r te r io le s , marked lym phoid hyper p la s ia and lym phoid i n f i l t r a t i o n o f b ro n c h io la r w a lls . The b ro n c h io la r e p ith elium was low and f l a t te n e d , g iv in g th e tu b e s a sm ooth c o n to u r. T y p ic a l a s b e s to s is bodies w ere n o t forrasd although th e re was an o c c a sio n a l yello w , sm ooth, p o in t e d f i b e r . No p l e u r i s y was p r e s e n t . T he r e a c t i o n w as s i m i l a r i n l o c a t i o n t o th a t i n th e g u in e a p ig s , b u t f i b r o s i s was much slo w er i n developm ent and had n o t reached th e same degree o f m a tu rity . - rx. x-H ay C hanges. Roentgenogram s o f t h r e e c a t s w ere made a f t e r ex p o su re p e rio d s o f 2 ? , 33 and li2 m onths, b u t t i s s u e changes w ere n o t d e n s e enough t o b e s e e n e n a n X--r s y .film . - 7 2 . F a t s . A lth o u g h 2 0 r a t s w ere p la c e d in t h e d u s t room , many d ie d fro m pneu m onia and w ere n o t suitable f o r s t u d y . F iv e a n im a ls , o f w h ich one was exposed Tor 19 months and fo u r f o r 25 m onths, w ere f r e e from pulmonaxy in f e c tio n and o ffe r a b a s is fo r co n clu sio n s. FEB-13-95 MON 17:34 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 39 73. m Tm o r f a c t i o n . A H * r aniinals s a c r if ic e d a t 2 $ months shewed a w ell-niarked p e rib ro n c h io la r f ib r o s is . I n t h e 1 9 -m o n th a n x. m a, l, r e a c 4t.i-o n w a s J-'-,,s,,ti, ho Fe gtr^irr amuijnge . A s b e s t o s i s b o d ie s w ere p r a c t ic a lly a b s e n t a t b o th 1 ? and 25 r n n th s a lth o u g h tn o s n a il sn o b th b o d ie s e re fd an d id th e l? -u > o n th a n in a l a f t e r a Io n s s e a rc h . T h u s ,-th e s e ..e n in a l? s f h iS J i 1 f ib r o s is w ith o u t a s b e s to s is b o d ie s . 7U. K ic e . O ut ox 20 w h ite m ice u sa d in t h is ex p erim en t, 11 liv e d a y e a r o r n o re i n d u s t an d d ie d , o r - a re k i l l e d w ith o u t showing an a p p re c ia b le d e g re e o f p u lm o n a ry In f e c t io n . 75. R a te a n d T yp e o f R e a c tio n . R e a c tio n w as lim it e d to p h a g o c y to s is b y m o n o n u cle a r c e l l s . U s u a lly th e s e w e re w id e l y s c a tte re d th ro u g h th e a ir sp a ce s 5 a lim it e d num ber w ere grouped ab o u t th e t e r m in a l b r o n c h io le s p r o d u c in g som e t h ic k e n in g o f t h e i r w a l l s . T h e r e w a s n o 8115 ... ........ g estio n o f fib ro s is . IT hT ^trxkxng o f th e experim ent was th a t 9 o f t o f th e (ce (8^ p e r cen t)] s e n s e d * 4 a 7*** o r ffl r e f lowad ^ o n a ^ T tu m o rs , a l l y adenom atous in / y p e '- T h e se le m o n s d id n o t co n i dust o r a s to s is Numerous a s b e s to s is b o d ie s were o b serv ed i n an im als k il le d l a t e in th e e x p e ri m ent. Thus, th e se anim als ex h ib ited a sb e s to s is bodies w ithout f ib r o s is . 76 . Sunniary and I n t^ 'p x e ta tio n . The purpose o f th is e rp erb ae n t a s bo e se ln e te th e im portance o f long f ib e r s i n th e tis s u e response to in h a le d a s b e s to s . The r e s u its in d ic a te s tro n g ly th a t long fib e rs a re c h ie fly resp o n sib le fo r th e re a c tio n - Thus, in guinea p ig r e a c t i o n d e r e lo p e d e a r l i e r and becan.0 o r e * th a n i n p r e c io u s e r p e r i a e n t s in s p ite o f a s c a lie r co n cen tratio n o f atm ospheric d u st and a l o ~ r t i n s e l con te n t in th e lungs. F u r t h e r s , a ty p ic a l p erib ro n ch io lar fib ro sis as pmducsd r v. . ^ W FEB-13-95 MON 17:34 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 40 in c a t s a lth o u g h in a p r e v io u s e x p e rim e n t/ w ith s h o r t - f ib e r d u s t i t oad n o t d e v e lo p in t h is s p e c ie s - T h e c a u s e o f t h e c e l l u l a r f i b r o s i s , i n th e lym p h n o d e s o f th e g u in e a p ig s i s n o t c l e a r . I t d id n o t o c c u r i n o t h e r i n h a l a t i o n experiments w it h a s b e s t o s lx x v u . I n o rd e r t o d e te rm in e to w h at e x te n t th e v a r io u s f ib r o u s m in e ra ls p o s s e s s ' th e ' c a p a c it y t o p ro d u ce t is s u e d am age, n u m ero u s in f e c t io n e x p e rim e n ts w ere p e r fo rm e d . I n th e s e e x p e rim e n ts g u in e a p ig s an d r a b b it s w e re u se d and th e m in e ra l d u s t w as in je c t e d b y th e in t r a t r a c h e a l, in t r a p e r it o n e a l an d in tra v e n o u s te c h n iq u e s . F o r th e p u rp o se o f s im p lif ic a t io n th e fin d in g s in e ach s e r ie s o f te s ta h a v e b e e n co n d e n se d an d r e p o rte d in t a b le s , to w h ic h r e fe r e n c e w i l l b e made la t e r . 7 8 . E xperim ents U sin g In t r a t r a c h e a l T e c h n iq u e . S in c e th e a s b e s to s m in e ra ls do n o t ca u se a t y p ic a l ad van ced f ib r o s is in e x tra -p u lm o n a ry t is s u e , th e in t r a t r a c h e a l te c h n iq u e i s th e p e r fe r r d w ay o f in t r o d u c in g f ib r o u s d u s t in t o th e e x p e rim e n ta l a n im a l. I n t h is m ethod th d u s t s u s p e n s io n i s in je c t e d b y m eans o f a s p e c ia l n e e d le o r c a th e te r deep in t o th e tr a c h e a , fro m w h ic h i t flo w s in t o th e lu n g s . 7 9 . C o m p a riso n o f F ib r o u s and R o n -F ib ro u s D u s t s . T o d e m o n stra te th a t th e f- a b ilit y o f a sb e sto s to p ro d u ce f ib r o s is r e s id e s in i t s fib r o u s c h a r a c t e r , th e s e r ie s o f in je c t io n e x p e ri- m e a ts r e p o r t e d i n T a b le 15 w e re p e rfo rm e d . T h e t e s t s w e re m ade w it h u n h e a te d lo n g - f ib e r c h r y s o t ile and w ith c h r y s o t ile th a t h ad b e e n ig n it e d w - 32- FEB-13-95 HON 17:35 J F HUMPHREYS ATTY FAX NO. 3043434186 P.41 f l e x i b l e s t r u c t u r e o r b a l l - b i l l e d t o r e d u c e t h e la n g t h c i .-'ib e r v-o ' ic r e n o * i:c l e s s . A t t-h s 3S.ffs tim e io r . t r c i t e s t s w a re m ade w it h s o r p o n t in e - w h ic n - - is v-h-.-? s a n s c h e m ic a l co T n p o o iti-o n . a s c h r y s o t i l s b u t, i s n o n --f ib r o u s > A rovo.ev- o l t a t f i n d i n g s r e v e a ls t h a t o n ly t h e u n h e a te d lo n g --f l i e r ch rysva b .'-.i.e p ro d u c e d f i b r o s i s , f ib e r s s u b je c te d , t o ig n it io n o r s h o rte n e d b y b a l l- w il lin g lin d 'lo s t i h s i r c a p a c it y t o c a u s a s e r i o u s t i s s u e d an a g e - I g n i t i o n p r o d u c e d im p o r t a n t c h a n na<9 ? " V s o t i l . s f i b e r s ) am ong th e m b e in g lo s e o i w a t e r 7 a n s it e r a u x o n fr o _ i ?. f l e x i b l e l-o a b r it t le s t r u c t u r e and p o e s ib ly o th e r ch a n g e s. 80. C o m p a riso n o f Va r io u s L o n g -F ib e r P u n ts . Some v e r y in t e r e s t in g f in d in g s a re d is c lo s e d by th e r e s u lt s c f th e e x p e rim e n ts ' in c lu d e d ir . T a b le 20. F i r s t , a l l th e lo n g - f ib e r a s b e s to s m in e ra ls te s t e d , w ith th e e x c e p tio n o f a n t h o p h y lllt e , p ro d u ce d a ty p ? .c a l f ib r o s is . I t is n o t e n t ir e ly c le a r w hy a n th o p h y llits behaved d if f e r e n t ly fro m th e o th e r a sb e sto s m in e r a ls . U n f o r t u n a t e ly , o f 8 a n im a ls d ie d o f p n e u m o n ia w it h in th e f i r s t tw o w eeks o f t h e e x p e r im e n t a n d t h e r e m a in in g a n imal s w e re s a c r i f i c e d a t 1 , 8 a n d 1 2 m o n th s $ t h u s o b s e r v a t io n s ir s r e n o t m ade a t t h e o p tim u m p e r io d s ol 2 a n d U m o n th s . S e c o n d , w it h th e m in e r a l b r u c it e , w h ich i s n o t a s i l i c a t e b u t i s a f ib r o u s fo rm o f m a g n e siu m h y d r o x id e , a c h a r a c t e r is t i c f i b r o s i s l i k e t h a t o f t h e a s b e s t o s m in e ra ls w as o b ta in e d . S in c e th e b r u c it e u so d c o n ta in e d o n ly 0.90 p e r c e n t s i l i c a (a s an im p u r it y ), i t i s o rn io n s th a t a s ilic e o u s com ponent i s n ot a n e s s e n t ia l f a c t o r in t h e d e v e lo p m e n t o f a s b e s t o s is . T h ir d , no f ib r o s is r e s u lt e d fro m th e in je c t io n f th o u g h g la s s w o o l re s e m b le s a s b e s to s in souse w a y s- o f g la s s w ool fib e r s , even T h e re a r e fu n d a m e n ta l, d i f i G l a n c e s , h o w e v e r. A g la s s w o o l f ib e r 3 m ic ro n s in d ia m e te r in a s o lid ro d a n d , in short lengths, i s f a i r l y rigid, while a n a s b e s t o s f i b e r o f t h e sam e d ia m e t e r i s a b u n d le o f e x tre m e ly f in e fila m e n t s w h ic h im p a rt t o th e f ib e r a h ig h d e g re e o i f le x i b i l i t y - I t would 3esm t h a t t h i s s tr u c tu r e and th e a s s o c ia t e d ile x t h alf-ry- cirs FEB-13-95 MON 17:35 J F HUMPHREYS ATTY FAX NO. 3043434186 ! H I M .............................. .................................................... ............................. > ` " ' i. . . I ' ` P.42 ' ! important factors governing the capacity of a mineral to produce peribronchiolar t ! fibrosis. ' _ ~ 8 1. Comparison of Long-Fiber and Short-Fiber Dusts. With quartz dust it has i . -* be<an;demons brated^th&t i the smaller the particles, the more intense is the tissue reaction, and that there is little reaction to particles larger than 3 mi.crons in diameter. In the case of asbestos, however, the reverse is true and apparently only long fibers have ary specific effect. This is confirmed b y the data o f Table 21, in which a series of tests with fibrous inarals is reported. TVhesn the Injected dust consisted of fibers 20 to $0 microns long, all the minerals tested (except anthopfayllite, as noted in Section 80) produced a fibrosis 3 when the material was prepared b y first i j grinding the fibrous dust until the length of fibers was reduced to 20 microns and less (or, in some cases, 3 microns and less), none of the injected minera l dusts caused fibrosis. 82. Experiments Using Intravenous Technique. . J T he experiments, described in Table 22, in which the intravenous method of Injection was employed, show that th e 'asbestos minerals are far different from quarts in their action on tissue. It has been repeatedly demonstrated that intra venous injection of quarts particles 3 microns and lea3 in diameter will cause & 1 typical tissue reaction with the development of (fibre wC* in extrapulmonary sites, such as the liver and spleen. Asbestos minerals, however, on intravenous injection generally produce only an inert type of reaction, as is revealed by the results given in the table. The reason for the early deaths in the experiment with chryso- tile particles is not clear; it may have been caused by silicic acid liberated by the finely-ground mineral. FEB-13-95 HON 17:36 J F HUMPHREYS ATTY FAX NO. 3043434186 P.43 Q 3. E x p e rim e n ts U s in g In t r a p e r it o n e a l T e c h n iq u e Ih o r e s n lt s o f in je c t io n e x p e rim e n ts - 1 t h th e in t r a p e r it o n e a l te c h n iq u e a re g iv -n in T a b le 23. I t i l l h a t a d th a t th e lo n g -f ib e r d t a p ro d u ced a A b ro a d re a n tio n h ila d u a te com posed o f p a r t ic le . 3 m ic ro n , m d l in s is e c . d o ,, lr an in e r t ty p e o f r s p o s . T h e .. ^ r i n t . in d ic a te a ls o -th a t th e fih ro a ia in it ia t e d b y th e Ir r it a t io n o f aab eo to s ftb e ro la n o t r e s t r ic t e d to th e lo n g s , a . . a . fo r m e r ly a ssu m e d , b u t c a n h e p ro d u ce d in th e p e rito n e u m a a w e ll. mm. - ______ i ' " ' r ^ . . o js ^ T ^ ^ m s m s .y r r m a sb sst o s iH P A g . A num ber o f a d d it io n a l e x p e rim e n ts w a re co n d u cte d t o th ro w m ore l i t f i t on s p e c if ic p h a s e s o f th e a s b e s to o ls p ro b le m . 8$ . P r o t e c t i v e A c t io n o f A ln a d n u m C o m p o u n d s^ In t r a t r a c h e a l in je c t io n o f a s u s p e n s io n o f le n e - C b e r c h r y s o t ile t o w h ic h c o llo id a l . l e d - h y d rc s ld e had b e e n added re v e a le d t h a t th e a d d itio n o f th e atandnom com pound d id n o t p re v e n t th e t is a n e i r r i t a t i o n jro d u c o d b y c h r y e o t u e . ^ I f a n y th in g , th e .c u t * i n f U c t o r y re sp o n se to th e in je c t e d f ib r e m in e r s w aa a c c e le r a t e . 0 m onth f t th e l a r t ia J * io n o f th e d o e t s p e n t th e b r o n c h io lit is a s b e c o m in g f ib r o u s - 86. F o r m a t io n o f A s b e s t o s is B o d ie s ^ T h e ir o n in th e e o a tfn g o f th e s s b e s t o s is b o d y a p p e O T to b e d e riv e d fro m b lo o d o r t i e s e le m e n ts a n d n o t , h b e e n s u g g e s te d , fro m th e m in e r a l f ib e r , fo llo w in g su b cu ta n e o u s in je c t io n o f tw o k in d s o f c h ry e o td le in t o th e g r o in g u in e a p ig s - o K in d c o n c e rn in g * p e r - a t s e d th e o th e r 0 .2 p e r c e n t h y O j- th e a s b e s to a is b o d ie s w ere e q o a lly n u m ro a t b o th s it e s o f In je c t io n . ^ olA 0 ^-^\ V ' f I'*' " . -V FEB-13-95 HON 17:36 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 44 An attempt to produce asbestosis bodies in guinea pigs by implantation of three eilk bags containing fibrous chrysotils as unsuccessful. ,,One bag planted subcutaneously in the abdominal rail disappeared}-the other tiro bags, placed in the peritoneal cavity, produced a little foreign body reaction but no asbestosis bodies in a year. " ' ' Intratracheal injection into guinea pigs of asbestosis bodies recovered from human lung tissue failed to produce the typical tissue reaction to asbestos fibers* The injected material was obtained b y digesting with sodium hypochlorite solution lung tissue removed at autopsy from a n asbestos -worker. The asbestosis bodies could be seen in the guinea pigs far at least a year after injection* This experiment shows that the asbestosis body ha a rather resistant coating which is not destroyed by moderate hypochlorite treatment and may be nnd in vivo far a year or longer. unvn. .iprsEseqrt or -irritant-.acitrion or .asbestos .keneraisn f t l V \ VV. ^I V ----C1--tV V- v.-- Vv:-:- M - v v Two hypotheses have been proposed to explain the tissue Irritation and reac tion ce n se d b y asbestos fibers; the chemical and the mechanical* In the chemical theory, which is based upon experience with quarts, it is assumed that the as-- b e sto a m in e ra ls d is s o lv e In th e bod y f lu id s and t h a t in t h is p ro c e s s t h e ir b a se s a r e le a c h e d a wa y t o le a v e s i l i c a i n a fo r m c a p a b le o f i r l t a t l n g t i s s u e s . A c c o r d in g t o t h is h y p o t h e s is , a s b e s t o s is w o u ld b o m e re ly a n in d ir e c t s i l i c o s i s * S e v e r a l f a c t s m ake t h e c h e m ic a l th e o r y u n te n a b le * ( l ) in t r a t r a c h e a l in je c t io n s o f b r u - c it e f ib e r s , w h ic h h ad a s i l i c a c o n te n t o f o n ly 0*90 p e r c e n t , ca u se d a t y p ic a l f ib r o s is lik e t h a t p ro d u ced b y th e -a sb e sto s m in e ra ls } (2 ) f r e o - e ilic a p a r t ic le s In c re a s e in p o te n cy a s th e p a r t ic le s is e becom es le s s , b u t a sb e sto s fib e rs s h o r t e r th a n a b o u t 1 0 t o 2 0 m ic r o n s a r e r e l a t i v e l y in n o c u o u s ; ( 3 ) a lu m in u m FEB-13-95 HON 17:37 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 45 r~ hydrraa.de neutralizes the irritating; siTaet ox quartz but not of asbestos; (ii) Serpentina has the same chemical composition as long--fiber chrysotile but it does not produce the same kind o f tis.rue reaction; (?) there is a ride range in the chemical composition of the minerals which do cause asbestosis (see Table 2 b ). In view of this evidence it seems more likely that asbestosis is caused by an unusual mechanical irritation from long asbestos fibersT Probably / this irritation `related to the peculiar filamented structure of the fiber and the associated flexibility;, which are possessed by no other foreign body. For example, ignition of chrysotile fibers changed their structure and made them inert while the same fibers, before being heated, would product fibrosis (see Table 1?)* Further support for the theory of mechanical irritation is that asbestosis occurs in an organ of high mobility - the lung - and that a fibrous reaction can be produced b y injection of asbestos fibers into the peritoneum, i&ere there is also a degree of mobility, but not in other extrapulmonary organs. > u o a ra i. The kLK.perxfflen.tal investigation with asbestos mineral. was concerned primarily with the effect of the dust on normal tissue but some attention was given to other phases, such as susceptibility to infection and occurrence of malignancy. 09* Infection. The only experiment in w hich th e effect of inhaled asbestos dust on a pul monary infection was studied was the first inhalation experiment, carried on with ''King's floats" dust. It is, perhaps, unfortunate that infection stulies were not made in the other inhalation experiments also. . FEB-13-95 MON 17:37 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 46 5*0* Susceptibility to Tuberculous Infection. The development of a tuber' culous process'initiated at the beginning of exposure to asbestos dust, and also of an infection superimposed upon an established asbestcsis, was described in Sections 19 and 20_of this report. It will be noted that asbestos, -when classified according to th9 effect of a dust on tuberculous infection, would be placed below an active dust like quartz but acove inert dusts, such as calcite and gypsum. In animals infected with attenuated tubercle bacilli, quartz will cause the infectious process to . progress until the animal dies of tuberculosis. Inert dusts will have no effect on the infection and the lesions m i l usually heal and the disease disappear. Asbestos dust is in a different category, ^hen the fibrous dust was being in haled during the evolution of the infection, there was a spreading of the tuber culous process for a time but usually the stimulus for continued proliferation of the tubercle bacilli was not sustained, the progression was arrested and h oaUng followed. In guinea pigs infected with attenuated tubercle bacilli following the completion of nearly .three years of exposure to asbestos dust, progressive disease did not develop. The only modification of the infection was one of localisation, a few bacilli being retained in the fibrous terminal bronchioles and forming tubercles there in addition to the usual foci beneath the pleura. Such tubercles healed in a few months and there was nothing to suggest any influence on the course o f the disease. 9JL Susceptibility .to Non-Tuberculoua Infection. There was no pointed ex periment concerning the effect of inhaled asbestos dust on non-tubercuLous infection. Intercurrent pneu monia among animals exposed to asbestos dust was rather common, the frequency in guinea pigs exposed in the four inhalation experiments ranging from lo to 39 per FEB-13-95 MON 17:38 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 47 cent. This incidental eriJanoe ru-csts the possibility of an effect of asbestos dust on non-tuberculc'.is infection. Novertheleos,^ since such epidemics are not uncommon in inhalation exparisants Mith other dusts and even in the colony of normal animals, it is felt- that the inhalation of asbestos du3t ^ J lot^ ax ^ a significant effect on the susceptibility to ..non-tuberculous pulmonary infection. i 92m Neoplasm- , . ^ ?-C , 16 spedile esperia* to* W e d to i W j ' asbestos fetors the deselopment/of neoplastic J^epse. but certain obsarmaUons on this subjectlwere r e c o d e d i n / h e outlineof'the W>P sed s=fsreph on eeboetosis submitted by the late Br. L . L O r d n e r J Februar^ 1 5 U V In it he called atten- tion to the hig^ incidence t> 1 ong mica inhaling Iccg-fiber asbestos. In his eaperdmental n o t e s / h o / J , Y e ^ d f e r r e d tb tiese lesions es adenomas. There is en ikportant. distStetion between adenomk and cancer nhieh sbocld be made clear. A canber 4 * r ^ in-aaion and de struction of t i s s u e , W i c h can distribute cells through \ h e lymphatics or blood stream to produce i s X t e d foci, t j L uhich new tumore d e s W o p . Ihi! phenomenon of dissemination Is j & X n aB raiiisstasis and any tumor uhich ibits it is a n g ^ t growth, o f which cancer is one type. An adenoma, o V t h e o.her hand, is a so-called benign/or non-o^l ignant tumor (neoplasm) which m a y p r mer not be capable of local invasion but^tihich does not metastasize. In order to clarify the act nature of these lesions the pathological mater ial is being carefully exanined\ Since it is felt desirable to h ^ V benefit of Doctor V o rv a ld ' s judgment, a review of the data on this subject is b W post poned until after hie return from f c W . Batbar than del^r the ent ra port, i'urther discussion will ba reserved fo\a supplement to be issued lat v. FEB-13-95 HON 17:38 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 48 ;:ui3 C dng to th e v a s t am ount'of d * t ^ n c l u d e d > t h i s re p o rt i t seen* most convenient to s ta te the c o n c l u s i o n s t h e in v e stig a tio n and, vhen n ecessary , fo llo w each one w ith a b r ^ T reauoa of th e evicsnce. _. _r^ _ , -- .... ^ A. Vario u s forms o f asbestos f i b e r s produce a p e rib ro n c h io la r fib ro s is o f the lungs o f guinea p ig s , r a ts ,, c a ts and r a b b its but .ot Oi jiuv-x. and r dogs Both in h a la tio n and in je c tio n experiments provide a :r.p ic s.pporu fo r t h i s conclusion / f i g u r e s !? and 6 ehcrcr th e re a ctio n to ino d ifferen t i: B. The mode o f action^*] of asbestos mineralzs\-~* * * W , rmjp r S Mtt llr ttechtmicttl rather than |w > * chemical in nature * / t* ? * '-* The evidence is given in section IXXXVTT Figures j., 2, _j, U on- 7 illustrate the imijortant points. The fibrous fuJanenv^ ( ^ p c w r a ^ p l x i / a n essential part ia the i r r i t a t i n g action, [ince the solid fibers of glass nool do not produce fihrosis (te e Figure 8 ) . * C S h o r t a s b e s t o s f ib e r s Ido not produce vf i b r o s i s . %h0 is Inplioa in the evidence n t i o n e d in P = ra - graph B above, ^Derimeate ehich farther support this findint B. a r e r^peefced i r . T`ibles 21 and 23T ypical fib ro s is can be produced by an atmospheric suspension of a sb e sto s dust contai d n g only sn extremely small proportion .of long fibers. Txl t h e in h a la t ic T experiment -with 100 per cent bali-nxLlea a s b e s to s dust a lypical, though delayed, fibrosis ras FEB-13-95"HON 17:39 J F HUHPHREYS ATTY FAX NO. 3043434186 P. 49 l--> .n-r.c \ U ;. Ics^ than 1 per cent of u:' e turno-spr-sric oust conoistea o f fib e rs longer than 10 n itr o n s . '5 i s shown in Table 13. In co n tra st, the ic tr s .- trach cal in.:*ction experiment rd th fine asbestos dust coni?.in:,.ng no 3;orig fib e rs fo ile d tc predate f ib r o s is . (see Tablr 51). . Inaalation ol i-sbestos duot -ttppareRtaj dies not alter significantly the iXAf , coi*se of experiii55-rt.?.I .tuberculosis in gplnea pigs/iV*-!^ *hi3 fionc^'.sidTi 33 tentative sin.ee tq evidence on which it i3 based coe3 not conform -with cur u&ual experience- Refer ence to fable i rill 3hoTT that vrhen /infection was coincidert rith onse--- of dust exposure there 7*3 temporary progression of the disease veil* subsequent healinafj when infection was initiated after 2p 3/h months of dust exposure the course of the tuberculous disease was not appreciably altered. In contrast, it has been observed in experiments ^ith mixed du3ts containing quartz th a t i f there is a slig h t >rogression o f the tubercu lo s i s when in fe c tio n and d u st exp >sure are c o in c id e n t, t h i s e f f e c t i s more marked (in stead o le s s , as w ith asb esto s) when im e c tio n i s i n it i a t e d a f t s r a p? rio d o f dust exposure. This conclusion concerning the e 'fe e t o f in h aled asbestos dust- on tu b e rc u lo sis see'.as ju s ii.*iGd because i n th e more s e n s itxve t e s t (infection in itia te d al te r a period of dust exposure) th e re "was no appreciable increas*- in s u s c e p tib ility to the tuberculov.s in fe c tio n , 'iotrsver, since the findings in th s FEB-13-95 HON 17:39 J F HUMPHREYS ATTY FAX NO. 3043434186 P. 50 FEB-13-95 HON 17:17 J F HUMPHREYS ATTY FAX NO. 3043434186 P.02 2 PLAINTIFF'S i EXHIBIT | 4170.1 9 -------------- AFFIDAVIT WASHINGTON ) - ) ss. D IS T R IC T OF COLUMBIA ) BEFORE ME, t h e u n d e r s i g n e d N o ta r y P u b l i c , p e r s o n a l l y cam e a n d a p p e a r e d MICHAEL RHODE, a p e r s o n o f t h e f u l l a g e o f m a j o r i t y , b e i n g o f so u n d m ind an d b o d y , w ho, a f t e r b e in g f i r s t d u ly sw orn by me, d id depose and say: I , MICHAEL RHODE, am a n e m p lo y e e o f t h e A rm ed F o r c e s I n s t i t u t e o f P a t h o l o g y , W a s h in g to n , D .C . I am c u s t o d i a n o f t h e o r i g i n a l a rc h iv e s o f D r. A rth u r J . V o rv ald . P a g e s 1 t h r o u g h *1/ 7L. a t t a c h e d h e r e t o a r e t r u e , c o r r e c t a n d a u th e n tic c o p ie s o f d o cu m en ts from D r. A rth u r v o rw a ld 's a r c h iv e s . T h e p a g e s a t t a c h e d a r e _____ R e v i s e d v e r s i o n -- o f -- A SB ESTO SIS-- E x p e r i m e n t a l s t u d i e s b y T h e S a r a n a c L a b o r a t o r y . ,-- R e p o r t --t o --t h e J o h n s - M a n v i l l e C o r p o r a t i o n , d a t e d J a n u a r y 3 1 . __1 4 9 -------- ---------------------- D r. V orw ald was th e D ire c to r o f th e S a ra n a c L a b o ra to ry o f th e T ru d e a u I n s t i t u t e . Upon h i s d e a th , D r. V o rw a ld 's a r c h iv e s w ere d o n a te d t o t h e Arm ed F o rc e s I n s t i t u t e o f p a th o lo g y b y h i s w idow . D r. V o rw a ld 's a r c h iv e s a r e in su c h c o n d itio n a s to r a i s e no s u s p ic io n c o n ce rn in g t h e i r a u th e n tic ity ; th e y w ere re c e iv e d by th e Arm ed F o r c e s I n s t i t u t e o f P a th o lo g y fro m D r. V o r w a ld 's w idow a f t e r R H O D E A F F ID A V IT - Pe 1 of 2 FEB-13-95 MON 17:17 J F HUMPHREYS ATTY FAX NO. 3043434186 P.03 D r- V o rw a ld 's d e a th ; th e y a r e p r e s e n tl y on f i l e a s a u th o riz e d by la w i n t h e N a tio n a l Museum o f H e a lth & M e d ic in e , A rm ed F o rc e s I n s t i t u t e o f P a th o lo g y , B u ild in g 5 4 , W a lte r R eed Army M e d ic a l C e n t e r , W a s h in g to n , ..D -C. 2 0 3 0 6 .-6 0 0 0 ; a n d t h e a r c h - iv e s have>-been-**v e x is te n c e f o r 20 (tw en ty ) o r m ore y e a r s . SWORN TO AND SUBSCRIBED b e f o r e m e , t h e u n d e r s i g n e d N o t a r y p u b lic , on th is th e c day o f A p ril, 1992. My ^ o n m i i s p l ^ n ^ E x p i r e s : NOTARY PUBLIC p r in t e d Name: a n -iS RHO DE A FFID A V IT - Piiee J of I  A ti ' % M rrR ojouT A ji Lots Ixsctoance Co h p a k y Ow N i m V n m H n i % u M.N.Y. *9c*kf 16, 19U4 Pt . i r U v 7. ToesaJLd TV* T r a r l i i 7 o m 1a U m Tfca k r u u U A orm terr **r,B U *w I n t rlrt4 B tk o rlti la e n t r i l i r 0P " t I t i t l o c la Q u . < U * f f u a * ta* tV . p r ^ la d a i - -- ~ ^ t? * *? ^ P w iU i of l t oro 1 1 * ? ^ d b Tl i i.i.ily holpful i f ^ roport ProMllh Ml mo 4t0o T^r ' I roUT _-- oocordr toado opio* o f tv* ^ "UOW a*fU*l for \tO m l BBI ti roollf irn s u n c t V lth W rt ** W rt oriho f o r t h m w>i x.j. ^ttoooroljr fo o rs , A. J . U m , b w . A**ooloto fccxUool COreoto r o % i