Document Moj4DN9Mzzqq6KBX75xNZz1k9
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K33USI23 ?S2 EJC'XOICii ICTITITI OF KlILO EII2T
to ti OV1I--ILLIEG13 GLiSC CCJCPA2T
TOLEDO, C3X0
the si2;ru LSggttsgKr SiSX3IC UX2, 'E ICES
- OCT3EIE 30, 294*
fcrtttnr J Ysr**ld, H. 5>..l>tretar; T&* Edward L,. Xgsgp-ta. Tocgdatloa, '
Za ^cooperation vTtlu
Philip C. Pratt, . B. Ti*a SL :BurxzvK* 2.
ntheny fl. Osli
CC ; : f. Q
:
____ IBTRCTCTTTIOn
CLAIMED
PRIVILEGED BY OCF
(hi year ago, cm October 30, 1947, an lntorla revert vns outfitted,
ecvering the prepress of certr-ln calssl experiments with. Ltylo over a totel
period of 30 nonths. Zt was necessary ct that Use to recossead further
expcrlcouts concerning certain phases cf the problm. The present rc-rart dc?.is
vlth the final phases of the experiment then In progress and vith the cerly
observations node In the new eorlco cf exporlaents.
fha origins! experiment hae new bean eonpletef end the conclusions dr-vu
ere based open the results of a full throe years* exposure to an ttsccpLsric
cuspens2.cn of Eoylo dust. Previous experience has shown that this is the re
quired ]>riod over vhleh exposures to a dust of doubtful biological activity
east bs continued before final conclusions are vureated. This experiment, in
feet, constltotes an exsxple of the lapcrfccnee of such prolonged study for, cr it to
be shown below, the findings at three years ware strikingly different from thsrs
at tvo end oas-half years end the tentative `eonclosicn reached et that tins =rt ur .-
be altered. Thus, at the tine of the previous report, the evidence indicated ir.t,
Kaylo acted as an Inert dost In rtorucl rats end..guinea pigs; resulting crily in
the famatiou of duaps of dust cells, without fibrosis. Sowar, it will be
shows below that Eaylo is eepeble, oa prolonged inhalation, of producing tube-tosi a
in the lungs of golrsa pigs, end that It should be hsndlwi industrially ss a hs.-
sardaros dart.
Pis report will be presented In four sections an follows!
i. final observations, dust Inhalation in norsal guinea pigs.
B .Mecasslan. C. Ccnelnsioas* D. Progress report oo new esrles of experiaeata.
08 006 Ills
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4. Final observations. dost lftb^Intlnn In pcimal guinea ol-y. ( Cofarcaee to the Xntoria Raport of October 30, 1947, vill ravcal that tv
Eroups of norsal golnsa pigs vara placed in the dust rocxu oso grcrp in Fetrs-
jy 1945 tai th second in iugust 1945. 3b aninals vere carpccod to ctrscphcric
cuspenaioas of Stylo dust for eight hoars daily, fiv* end cse-balf d^s s vecl
throughout the experiment. The dust concentration, which veried ccrsnin.t fron tir
to tine, hat evereged 115 nmion particle* per cnbie foot cf air oTer the entire
course of the oxperiaeat to date*
4 brief mira cf the ebserratien* described ca page 4 of the previous re
port vill reveal that up to thirty sonths the reaction in guinea pigs vac United
to tbs tceuaolatlon of clunps of caozcphKgtts,
n- curt particles, in
groups of adjacent eir spaces. Vhile occeeJen*! nmltinurleeted giant eelle t/cro
Been, there was no uadae proliferation of tissue histiocytes and fibrosis v&s
absent. 4 ftr usaistahable esbentosis bodies vsro identified. In tair.i, the
ecccsalatioa of cells cf the types described above and their persistence sc such
over a full three year period, vthout the darrelopaaat of fibrosis, has been
found to indicate that the agent responsible fer than is not capable cf producing
fibrosis. Such, agents are now considered to be *Mologieally Inert,* since the
are cellular accoanlatlou has not ton shewn to affect pulnaa%xj function or
resistance to diseaee. Eovever, of nine enlaals sacrificed enbe<iant to thirty sooths in the pre
sent experlaext, all hare shows sot only the nbenrs lesions but also have developed
true fibrosis of a type characteristic of the response of guinea pigs to asbestos.
This Is e rather diffuse type of fibrosis vhleh fora* chiefly about the snail air
duets, hsown as bronchiole*, frua vhleh the air spaces, cr alveoli, cf the lung
arise* The appended fhotonicrogrsph* ehsnr the nature of tbs lesions balng dis
cussed. This ooditlcn la identical vith asboetosls aa can be sees by coaparing
. 08 006 1116
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The Lesions la the trsdicohronehlnl lyaph todos ehcved to chinas botvr-sn
thirty ncmths sad three years*
Chealeil cnalyaie of the lack's c*f cuiasn pigs that hr-d inhnlod r.r.yle dur.t
for poricis up to 36 ecatho yielded tho data gives in Tuble 1. It vi 11 bo ertr d
that sa tie period of exposure beemrs lcn-cr tie ach mlae gndually incrrccra,
icdlcxilzg sa eccusalstloa cf slaerol sattor la tin Xus;?. Thera vac e pro-
aosacsd 5acrea.se in the allies ccspaaest np to shout 33 ccstha end then e slight
decrease. The racoon for thin cosditlsn, vhieh hie been observed la er.uirinffnt.-.
vith other duets, la not entirely clear. Since caly tvo tnl*?le vrr ennlrcri
for cedi exposure period, inilTiSrr.l mice a `were ecenniosslly oat of line but
Lu *enaa*1 trend v. clo-rl7 iadicotoi.
B. lieensedan.
The final cberrvztiaas In this experiment with Reylo inhalation in nerxal
fnlnea pljj, reported above end lllsstmted in tho figerer, prove th-.t LLylc in
Cnpohlo of producing the chsxeoteristic roectisn, asbsotcale. It is orldant,
tnareforo, that s considerable portion of the asbestos coopesont la Hrylo reuuim-
unchangvl daring the garcifentering process or. If it is changed, tbit the clterel
prodset aalatalss Its capacity to cause fibrosis. Villa the lesione to JO
cosths shoved no flbroele, certain aspects of the* vere capstibia vith c yrt-lia-
1nary stag* 2a the darelopeant of asboatoai*. These aspects wore scelai by tnc
inert type of reaction to the enteritis other then oabcatos la tha dust. the
charaotaristio early etage xst the reaction to esbcstoa is the predilection cf i:.e
fibers to localize in the
end vail of the ksaU cir ducts, fctnva ns ttrdn.'-l
trcnehlolsa. TMa i in contrast to ycrticnlate mtarials, ehlch localise chiefly
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In the cctual air ipe*, or nlvrcll. In the present J-.tpcriusat the greatest
( portion of thn inhaled dust, being particulate, lodged in the alveoli end tricked
tiie perlbronrhiol&r deposition of cose of the fibrous ccsjcnsnt. la retrcrpcct,
is
it is possible to discern that there ic aero evidence of dost cell actirily in
the region cf the bronchioles than is charecjuristic cf the rwetien to zzi inert
partieclats dust. Little sigaillcr-nce vas attached to thic ct tat tins cl the
previous report because there v&s do evidence of the dorrslopoeat of fibrosis.
She differences betveea the early reaction to &&7I0 end that to apbostes
jtty bo iaterprotod ce t codification of the lesions by the particulate ccspoacnts
of Lsylo. *?iodlficatioaa of silicosis is veil recognised vhen losicns of that
disease develop following inhalation of a nixed dust containing quarts ttgeiher
vith cat*rials of an inert notare, each ns iron cxidc.
' It is of laperlcnce to note that vhile the poribrcnchiciar reactions et--
eerred incriminate Stylo es capable of producing esbestoals, they exclude the
poscibillt7 that It nay cause silicosis, cince, over c full threo year period,
there is in no anlr.t? any focus cf hyaline nodalar fibrosis characters Stic of
the reaction to quarts. furthersore, it sagr 1* added that the cnlm-ls taev no
evidence cf the type of diffuse fibrosis which has been ob*am>d in this labsr-
story to falloy Inhalation cf dintestaceous earth dust. In regard to hydra us-d
ncoo-calclna silicate, e major ccastltmnt of Stylo, it acy bo said that -while
there is no pointed evidence cs to its effect oa pulaosaiy tissue, there is rzuch
evidenoe to ahov that a variety cf silicates, including sons ferns of calcium
silicates, ere biologically inert. It vearu likely that in* celeiaa oiliest-*
in Saylo ehould conform with this previous experience.
Thus, the possibility crpreesed by Eoctor Gardner in his early cca-iidtruticn
of this prohlea, that teylo might prodnee tvo paeusocor.loaee, csbeatosis and rilicoais.
vith the resultant safety haaards, has been adequately studied, and conceit over
08 006 1118
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the latte* wnditlon can be dlsalesed. yorthsr consideration oust bo gi-ren to
( Bi^istosli| hsvmr. The laboratory has recently cearletcd a large amount of vork vith aebssto*, vhieh has been reported to certain other rapportin^ coaprnisc, bet not cd ret published. She following diccucsicn of the problem Is dravn largely from thr.t verb, and ve vculd request that those consents be considered confidential. It la felt tint the following infomnticn say be of aid to the Ovens-Iillcoic health department. In fcrsalatixg a eafety progran, vhieh certainly is nseessciy It viev of the requite of this Esylo experiment. lsbe:)tosls, both In can cad cminals, Is e chronic, elcvly developing peri/ hronchlolur fibrosis, vhieh in late stages extends from the original site cf loctlication Into the surrounding alveoli. The aroneaioixr iocniisalien i r rspar estly dae to the fibrosa nature of the rdnsral. Experimental studies indicate that the rhlef node of notion ie by cechanlc.*.l irritation of tissue by the fiberr. Tbs structure of these fibers, and the capability of repeated longitudinal divi sion. to soleeul&r strands, 1* Important in ths mechanism cf action, aicee the solid fibers of {lass vool are not capable of producing the fibrosis. CbcsicrJ. action la cf little or no importance in causing reaction, since chiycotile ren dered partimints by cutting and separation does not initiate fibrosis. Certain Investigations hove Indicated that a Beamingly negligible proportion of fibrous asbestos la sufficient to produce ths characteristic raaetion. Thun, en Inhalation experiment vaa carriod out vith btll-eiHed asbestos In vhieh an attempt vu Bade to ellainate all flbsrs from ths material. It vas found to be lnposeibla to break up all of the fibers and about one per cent of the air cuspended dust consisted of fibers* The charaetaristic peribronchiolar fibrosis developed in the exposed animals after forty months. Thus, it appears that very
Produced under C ourt O rder In
sr i
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P ro d u c e d u n d o ? C o u rt Ord<
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sll ousters of fiters ere ccpablo of producing tsbestosle, although the drrel-
( psent of the lesions is dolnyod. The present exporlaent vith Ecylo la alr.o go exasple of this fact. The ir.portent natter of progression cf rrtetien after exposure to mtestos dust cesses has teen extensively lcrerti^jr.trd. The results ladler.to that la con trast to silicosis, whore progression continues for ease tins, there is no eijul. float degree of progression in extant of the lesions* Bathsr, the oise cf the lesions decreases in eeteetosis doe to the tendency of the fibrous tierce to ccntrset after tha etisulss to Its production is renoved* The irritation cf tlsouo by an asbestos fiber la apparently arrested vithln a few aoatha nftor It enter* tbs lung ty the foraalien of the *csbestosls body* (e coating of the fiber by ireneontaiaieg nsterlal), with the result th.it the existing fibrous tissue contra eta. Vbsthor this osstnoticn exerts a beneficial or deleterious effort on lung func tion la new under investigation*. Unfortunately, the studies with, cctestos have not as yet eeaplately clarified the prohlcn cf its effect on associated toterculouo infeotion. Zt appears thet Eaylo say exart a slightly sore narked adverse i.nflnenre on the infection than coca pure asbestos* Tha difference uy well be due to the preoence cf the eoouat of ipiorts la Kaylo or perhaps to other Incidental factors. One perpose of ths studies now under way is to clarify this protxLaa.
C. Cocclasloos* 1* Ecylo, because of its content of an appreciable aaount of fitreui; chrynotile, is capable of producing ssbaotosls end fhmiiA be
- as e hassrdona industrial dost* 2* Coylo does not produce silicosis in ssisals*
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CLAIJ^jj -JRIVILEGED
SY OC?
( 3* *; o doss not produea th diffusa cellular fltroeis of tho
laega siev reoopilxad as rccultiag free inhalation of dittoaceoos earth.
0. Progrgfc Escort on r.yg series ef experlacnts. The ttm phases of the oxporincat, sc outlined in the report of October 33,
1947 end lii a letter dated March 3, 194.8, ere &cv uador viy. Vhile little of cigaifictcjM* Lea dtreloped tha* fer, roTiav of tha work is presented here. Progress and resuite to date of these experiments are given belcv under the title of **ch phase.
(l) The effaet of Eaylo inhalation on tuberculous infection initip.tod -.t the cnaet of dost exposure. Thirty experimental eniaals vera i&faeted vith the attentuated
rtnia (Ep) of tubercle bacillus used in this type of experiment nisi vert piecei in the dost roca the next day. Thirty-three control anlaals vers infected ct iha ess* tins and hapt in normal air. Of the experlaantal sniaala, six ere now dead, tvo having been sacrificed at tvo months, tvo at four aoatha end tvo having died.
Qua death cocnmi at flee veekdp due to intercurrent paouacaia. The other vu ao recant that sections bar* not yet been prepared. a
The wn*A. tt tvo taonths shoved lesions coaparahl* vith those la the controls, both crossly end ricroscopicaUy. The enlnals killed at fetor nenths hare cot been studied alcroscoplcally, but on cross exealnatlea the lesions appear alnllar in the tvo groups.
-- SOeB
(2) Zba effect of Eaylo fuinaa pigs*
on regressing tuberculous lesions in
Xa this phase otf the experlsent, tventy-flTa guinea pigs vers
infected, and groups ef then vers kept in noraal tir for tvo, four and cix
OS 006 1121
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by ocf
ncnths before being pieced in the dust roos* it the prcstzt tlsi? the flrrt two greap hm bees placed la the float nxaj the third it to go la on
Seccnber 15, 19X8. Only tvs r.n-Oa cf the first croup hers trees sscrlflsed to
yet, after two sooths in tho dust* Kicroscoplc ebsereatioafl h*vc sot beta Bade, but la ths gross, the lesions vtrs comparable vith those in control
eriado.
(3) The effect of eecuailated fcxyio la the lungs on e Buhsecsuant tuberculous infection*
Thirty Boml guinea pigs were pieced in the dust rooa on Hrj 12,
1918, end on ingest 12, 1943 vere Infected vith the attenuated tubercle
bacilli* Tien anlsale vere sacrificed at this tins for ehenic^l esaljsl?
to establish tho ossant of dust Inhaled* Control eaisalt vere infected on
the can* date*
vere sacrificed recently, tvo oocthr after infection.
Crossly, the lesions in the expariaant*l and control onin*2s vers comparable,
but again niercscopie observations hare not been atde*
Ths results to date in this exjmriaent sxo of little elgalflcaacs, sines th_a disease is a chroale o&e end acy changes dua to the inhalation of dust cf any natcr* . are taerra. to be alov* _ Severer, it Can be said that the esperlcest is progressing vary satisfactorily, end that ve anticipate none of the canplications vhleh inter fered vith. the interpretation of the previous experiment in regard to the effect of Laylo ca erperinentel tuberculosla*
08 006 1122
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SY OCF
(
=ss - s
H n
n^. 1 - layla IsSulattco, J3 scntha. 53CX 1h fboio chocs a. cross gsct.toa cf & Isranchlols Jast.
shore cad eli^hily to the left of eater. The ether spaces ear elreoU. Vote the dsrJj mns vithin ooam cf th* ssnllsr
geydsTIy to the rlsht of the fcreac&Lols. Thess *7 the scerophagss ad altliaiclcatdd giant Mils, described. Is the text. Bote the thimsss of the veil of tbs bronchial; It is eirtnally noracl es is sjraunat ca caapnrtooa with Hfitxre .5* ha aj&s&iesis hedy Is present la this ft aid, sad Is nrrsslsfr la floors 4 at hl*?s*r sognl fleet!os.
08 008 1123
CLAir-SD
"Zr/ILEGEJ BY OCF
71$. 2 - Zajrls Ishxlxilea, JS
23CI
- ' Tho taroachlaia is this phctsalcrv^T^h Is Jnat bora cad ta tho rijit f eesi^r* Sate tip thieisiso ef the tlssca t3t*sau lta Isu ssd that cf th) cdjccast -tlTsoli 2a ecaparlaoa vith the tgrachloipr vails 2a Mgarwi 1 bad 5* 71z* triads cf-fibres* tiascc* era be mos ber*# X>s they era rero cggajreat,teeggB3C leas dense, la the cm at the right of the field %t*T+ fliiwia has ertesdad to *4Jeeet alveolar walls.
08 006 1124 00-
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(
Fig* 3 - AaVto lchsl&tica, 30 acgrtha. 2001 da brocchiola in tils photcaicrosraph la just
a&orva end to th loft of canter* Seta tba tMcViwSag of its vail as In tba ^cylo nnlnal art 36 atetbs. Itrsuir of fibrous tissue era njperoat vltbla tbo anil of this krooe&iel** as vail as in tba adjacent alveolar valla.
08 006 1125 -11-
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CLAIMED PRIVILEGED
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(
a
li
Fig* 5 -- Zorstl. galas* pig lung. 2S0X tbis field eacvs taco trpashlclsc, cae in Ica^Vadli^i,
tba otbar la crcii ssctioa. Bis eanTT associated blood vassal Is ssca abort tbs icxatx broaciilols. Ccspexa Xtm thickasss of tbs rail of Uuu Jwcaebiolss,. vith tbal cf the breacoiolas la Tlgsrss 1, 2 and 3* Sots also tho aroty alvsoll.aad tala alveolar sill**
13-
08 006 1126
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SPOSSB TO DOS? IS
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TK3AL4TI0S EXPESISm DTITH IATL0 DOST
Deration
Ash For Csat of Dry Tlescs
/nlrs.1
of
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SuabsT Exposers Dry Tlstes ClOj
CaD
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Per Cent of /oh
810* e&o
aoatha psr cant par cent psr cent por csat psr cent psr csat per ccr.t
2 2 cot. 6
4.42 4.04
0.24 0.20
0,06 0.06
0.07 0.03
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4.4T 4.42
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4.13
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8 BOS*
4.0 4.54
10 BOS.
4.63 4.61
0.22 0.19
0.25 0.20
0,31 C.26
0.48 0.41
0.09 0.08
0.08 0.10
0.13 0.11
0.14 0.11
0.09 0.08
0.08 0.08
0.03 0.11
0.21 0.14
4.87 4.42
5.63
C.5S
C.C4 6.49
10.12 8.42
1.93 1.59
2. CO 2.C3
2.73 2.45
3.04
.20
1.55 i.eo
.03 2.1S
1.77 2.43
4.20 3.C2
45 12 90S. . 4.66 46 4.99
67 16 BOS. S3
4.S3 4.50
0.63 0.51
0.60 0.84
0.14 0.15.
0.C9 0.10
0.22 0.09
0.26 0.32
10.80 10.25
12.27 17.65
2.80 3.17
1.83 2.C6
4.65 1.C0
5.31 C.5D
105 21 BOS. 103
49 24 BOS. 60
114 27 BOS. 119
72 30 css. 78
121
29 bos.
122
5.12 .23
6.02 4.71
8.13 4.78
8.62 6.S3
8.70 S.M
0.G4 C.64
0.68 0.60
0.89 0.48
1.10 1.12
0.8T 0.S9
0.19 0.15
0.13 0.14
0.14 0.12
0.14 C.12
0.13 0.12
0.11 0.08
0.06 0.06
0.190.13
0.06 0.08
0.21 0.17
12.54 10.30
12.70
12.52
15.93 9.55
19.56 0,26
17.10 11.00 .
2.63 2.90
2.54 2.92
2.57 2.41
2.56 2.23
2.25 2.22
2.Co 1.45
1.20 1.72
3.76
3.C8
0.92 0.S1
3.77
5.25
80 36 bos.
87 8f
8.63
8.38 6.43
0.85 0.67 0.54
0.16 0.11 0.18
0.19 0.17 0.13
15.10 12.45 9.93
2.C3
.U 2,65
3.25 3.17 2.5
U- 08 006 1127