Document 1QwLOG2vzXdLORV7e8VdDmprZ

FILE NAME Corning OC DATE 1948 Oct 30 DOC OC011 DOCUMENT DESCRIPTION Internal Report for Corning from The Saranac Laboratory - Regarding the Biological Activity of Kaylo Dust en . REGARDING THE BIOLOGICAL ACTIVITY OF KAILO DUST . 4s B PLNGAQ ob 2-10-21 2-10-21 2-10-21 Sig 2-10-21 ES to the ILLIEGIS GLASS COMPART COMPART TOLEDO O513 _ ty ; THE SARCHIC LABORATORY LABORATORY BAPAKAC LAKE IN YA OCTOBR 30 1948 subuitted by Arthur Yarmeld M. The RivardTrudean Foundation a 2 IS c abedahant c abedahant ccabedahant ccabedahant ccabedahant In cosperation with K.I. Philip C. Frett Thomas M. Durkan M. I. . , Anthony B. Dichot { PLAINTIFF'S EXHIBIT INTRODUCTICK INTRODUCTICK / / tots 30 7 <29 " ' " nrt " extering the period of 30 progress months of certain animal experiments It was Decessary at that then with Isylo over a tote to recommend further experiments concerning certain phases of the problem The present report de 1 vit ths ' " " tben ' "pvm observations made in the new series of experiments t te er The original experiment has now been completed and the conclusions drawn are based upon the results of a full three years exposure to an stresshetic sussrsion ef ef "" < ar^bs < that y~ quired period over which exposures to dust of doubtful doubtful Mological activity must be continued before final conclusions are verrestol This experiment in fect constitutes constitutes an example of the importance of such prolonged study for ec. is to be shown below the findings at three years vare strikingly different from that et two and hilf years and the tentative conclusion reached at that time t oe. & ' <' " ^... prt te ido Mente et Legic acted at an inert dust in nereal rats and guinee pigs renting any in the formstion of eliumpe of dust Cells, without Mbroete, Bowerer, it vill ^ @hown below that Larlo ts Capebie, ca prolonced sBaslation, of productie asbe-tocts in tie longs of pul sa Pigs, and thet it should be handled indestriaily as 2 a: sardous dust, | This Teport will be presented in four sections as follows * reueston, 4, Fine} observations, dart fnlation is porns; guines piss, 2 M _ C. Conclusions, D. Progress report on new series of experiments 1. Maal observations dust inbelation in normal guinea pigs th ntr Apprt of October 30 7 <19 groups of normal guinea pigs ware placed in the dust room that c one group in Febra- ary 2945 and the secant in dugest 1925. Toe aniasls Vera But pensions of Keylo dust for eigtt hours l<:y, five end exposes toetoorznenic ose-pele 4.52 6 west throughout the experiment The dust concentration which were somewhit somewhit from time particles to time hat sveriged 116 million million per cubic foot of air over the entire course of the experiment to deto i brief zwview of the observations described on page 4 of the previour - port will reveal that up to thirty months the resetion in gaines pigt was l 14 to the accumulation of clumps of meropenges containing dust particles in | groups of adfscent air spaces While occasional maltinucletei girst call ven seen there was Be undze proliferation of tisme histiocyter and fibrosis wit absent A few maistakable asbestosis bodies vare scommulation of cells of the types described above identified In general and their persisteres se the se ore a full three year period without the development of fibrosis has been found to indicate that the agent responsible for them is not expable of producing abrosic. fi Such agents ers poy ccasliered to be "biologieslty inert, sine: _ aire colluler accumilstion hat not bean tliowm to affect puimcascy functics er > resistance to disease sent Eovever of erperinest, nine animals ascrificed ell hive showr pot only vaben cent ' " " o<ath ' th - the above lesions bit eleo bere develoned true fibrosis of a type characteristic of the response of guinea pigs to asbestor This a is rather diffuse type of fibrosis whieh forme chiefly aboct the exail air ; Swete,Taows a breoeblcles, Troa whieh the air epcees, or slvvoll, of the liny arise The azpended photoaleregraphs show the pature of the lestons being die - @ussed. Tate condition is identionl with asbostosis as can be seen by ecnzering Figure 2 with Figure 3 Toe leslans tn the tracheobronchie} dyna nodes gh-va! no Chinze betvecs thirty months enf three yesrs. Qaue Fef et th c for pertods az to 35 montthr yleldot c c pig the Gat: given tht be fn Teble tt : the rid er th lue irtce. ting an atcrelstios of Bin^'ralartter in the dung. : . It Will bs notes ^>vererse here wor ;T nounced inces in the siller caposent up to about 23 months and then e slight decrease The reason for this condition wife bss been observed in experiments experiments with other dusts for each exposure is not entirely clear Stace only two animiansimis vers analysed period individual values were clout clout of list list the general trend was clearly indiente E. Discussion inh The fins] obrervetions in thi; experszent vith Leyle letter an Borel : ' . ra < expable expable of producing the charecteristic ' "te feres gree recction asbestosis Tt therefore that a considerable portion of the asbestos component in " - eride Style remin Wwennged during the memifeeturing process or, 1f 18 1s ecenged, t th tas rlten: product maintains its expacity to cause fibrosis fibrosis months shoved no certain aspects of then While the lesions upup were ocupetible with toto 30 30 30 2 sreline inary iaart rteze in the Cevelement of asbestosis, type of reastion to the mterisle other these aspects were musced than aetestoe in the dust. by tue Tor early abarestaristic stage of the reaction to asbestos is the predilection of the Aart to lotalise 12 the lume end well of the smell air docts known as terzinel awashloles, This 19 {5 scetrast to partleulate meteriale, wh^>chloselise chiefly in the actual air spaces or alveoli In the present experiment the greatest portion of the inhaled dust being partimuinte lodged in the alveoli and masked the peritronchiolar deposition it is possible to discern that of some of the fibrous there is more evidence component In retrospect of dust cell activity retrospect in the region of the bronchioles than is charecteristic of the reaction reaction & an inert particulate dust Little significance was attached to this at the tins of tas previous report beccuss there was no evidence of the development of fitrends The dif erences differences between the early resetion to Laylo and that to Lebester may be interpreted as a modification of the lesions by the particulate conpement of isglo Modification of silicosis is well recognized when lesions of that fistsce develop following inhaletion of it cr n srt ptare , ized dust conteining ' euarts tore ire It is of importance to note that while the peribroschicker rections ob- asbestosis served incriminate Kaylo as expable of producing asbestosis they possibility thet st wey cause gilicosis, eince, overs e full terve exclude the yecr poric., tre : in no '' cf ' no^^... roce<cticroce<ctic .e .e .e .e rbes fi the't te < " evidence of the type of diffuse fibrosis wine has been observed in that t atary to foliow inhsletion cf diztomececus calcium silicct^' 2 major constituent earth Cust. of Teylo, {t Is reper te Gyori te. mey be seid tyst wile thare is no pointed evidence as to its effect on pulmonary tissue thoecsrciues ocscius evidence to show that a variety of silicctes including scae forms e is much siliester are biologically inart It seems likelythat the calcium silientsilieente da Keylo sould Conform with this orsricns experience, the Thus possibility expressed by Doctor Gardner in his early considersti b considersti b ents =. 6 ft Protlea, tdzt Keylo aight produce tye alores asbestosis and silicosis safety with the remttant Rasards, has been atesuately atutiat aed enn nwee the letter condition can be dismissed asbestosis however . . Purther consideration consideration must be gives to The laboratory has which has been reported recently completed a large amount of work with to certain other supporting nies but not arbeater as get published published largely The following discussion of the problem is drawn from that work and we would request request that these comments be ecosidered confi ot. is felt that the following information may be of aid to the Hocic health certainly department in formaleting & safety program which of the results of this Keylo experiment is necessery in view Asbestosia both branchioler fibrosis in man and animals is chronic which in late stages extends from slowly developing developing the original site peel. of lotelisation ently due to into the surrounding siveoli The the fibrous nature of the mineral bronchicher locrtiestion is i Experimental studies indir te that the chief mode of The structure of these setion is by Rechenical irritation irritation of tissue by the fibers and the espability of repeated longitudinal filem diri- sion to melecular strands is important in the mechanism of action since the solid fibers action is of of glaze wool are not expeble of producing the fibrosis Chemical little or no aportance in causing reaction since chrystile chrystile chrystile reus dered particulate by cutting and separation does not initiate fibrosis . Certain investigations have indicted indicted that a seemingly negligible proportion experiment which reaction of fibrous asbestos is sufficient to produce the abaracteristic an inhalation was carried out with bell milled asbestos in That co ded dust consisted of fibers The characteristic paribronchiclar fibruals exceed exceed ze developed in the animals after forty mouths Thus it appears that very smill authers of fibers are expable of producing artestosis although the devel- development of the leziona is delayed The present experiment with Keylo is also at example of this feet The important atter of progression of reaction after exposure to rebeton durt ceases has been extensively invertiented The results inferte ist in esse trast to siliceria where progression continues for rets that the desig desig desig ficent degree of progression in extent of the lesions Rether the size of t lesions decreases in asbestosis due to the tendency of the fibrous tissue to contrect after the etimuins to its production is removed The irritatio - ao . by an asbestos fiber is apparently arrested within a few months after it enters the lung by the formation of the asbostosis body corting of the fiber dense containing material with the result that the existing fibrous tissue contries contries . aa ether this contruction exerts & beneficial or deleterious effect on long fans sion is now under investigation Unfortunately the studies with asbestos have not as yet letely clarific the problem of its effect on associated tuberculous infection It appears that Kyle my exert & slightly more marked adverse influence on the infectie the cock pure asbestos The difference my well be due to the presence of the rat amrunt of quarts in Laylo or perhaps to other incidentel factor of the studier now under way is to clarify this problem One purjet purjet purjet C. Conclusions 1. Layio because of its content of an appreciable amount of fibrous + chrysotile is capable of producing estvetosis and should be handled as hazardous industrial dust s 2. Kaylo does not produce silicosis in animals ee eee, 3. Kaylo does not produce the diffuse cellular fibrosis of the Tongs maceous earth ti ng os ' -ducto D. Progres Report on series of experiment The three phases of the experiment as outlined in the report of October 3 7 r dt Kneii 19S e Mer Mer Mer of cignificance has developed thus fer a review of the work is presented here Progress and results to date of these experiments are given below under the title of each phase ( reffect reffect of tylo ' the onset of dust exposure , rectior " .t Thirty experimental abisals were infected with the attenturie attenturie strain B1 of tubercle bacillus used in this type of experiment und ver^ Plaeec in the Curt reos the next der. Thirty control animals were infected et the same time and rept in normal air Of the experimental animals six are now dead two having been secrificed at two months the et fcir en d h ' . One death cecurred at five weeks due to intercurrent prese The other was so recent that sections have not yet been prepared The animals killed at two months showed lesions comparable with those in the controle both grossly and vicroscopiselly The enimals months killed at four have not been studied microscopically but on gross exeainetion the leslous appecr sinilar in the tac groups. ) ttat or oyo ttat ttat ' ' ' tudercu / ' Zn this phase of the experiment, trenty-five puines pigs were infected, and groupe of then wers kept fa pormal eir for two, four and six 4 44 months before being placed in the dust roox tro groups Lite beer ylis n thc e due st rd oce; cember 15 298 At the present time the first ths third is ts go in on Caly two snimcle of the first group have been sacrificed at yet after two months in the dust MicroscopiMicrocscopic observations observations have it the the rcs t ^rbs#re & ticos cTimeis, not bre cri (3) The effect cf eeenmilated heylo {no the infection lunze ez 6 pubas WEDS tute-cotec Thirty nerecl] gute; cigs ware plsced im the Stat Foct eon Nor tf, , rr qrrt qrrt o w intactd th tc rttm 4 tuereif becilli Arc nti m tc : tb -mt ic et tir < sz1a Contw for :: : : : : : e t c- the M .t esa tr But sg.n aMorcscorie '.ere .ere .ere .ere and ontc ry here act .ere .ere .ere word'word The results to date in this experisant are of little significanes since the asteise 2s 8 ehranie one an andy @isages Gig to the inhointics cf auct Gian Tew. -a20 Knows to be slow, However, it exp be sald Shst the axjerinzest is Testing very satisfactorily ans that w entiel te mone of the cozcliestton: mies intrre fered with the interpretation of the previous experiment in regard to the effect effect of Laylo ec axperisect)1 tuberculosis, << ~\ ~ 4 fs ne ree ee, ere the macrurhares end the giant it is virtually it is cells, dessrite: normal normal as of apparent well of the virtually normal as le apparent on oouserisonbroolneesbieis; Fig. < - Eayio inhaliticn, % acath:, 247 o Te: tronchfcts 25 3 LoLtotothethiebt9hieb9alveolar th con co khi nght of centre Detrvecn 4ts wat and that ef thieb9 vith the brosehloler wa otriats cf fibrous therus eca be 95 extendedto feld where less dense feld where Mbrosis has to adjacent t^,,y th alveolar valir . oe 500114 ERANUS ERANUSERANUS av SENAR SENAR Fig 4 - Xezlo isdctlatios, 3 months, 12001 1201 1201 Tris higher reveals af pert of the field show: in Figure1 reveals a typical form of esbertosis the surved dark elongated structure structure to the body right of seater _2- (Nai . Fig 5 - Normal guiose pig lung 2001 This field shows two bronchiolss one in longitudinal longitudinal the other in cross section The will associated blood Tessal is seen above the former bronchials Compere the thickness of the well of these bronchicles with that of the breaenioles in Figures 1 2 and 3. Note also the exity alveoli and thin alveoler walls Table 1 AKALYSES OF LENGS OF GUINEA PIGS Animal Amber Duration Duration of Exposure mouths EXPOSED TO DUST IN TEHALATION EXPERIMENTS EXPERIMENTS WITH RAYLO DUST Ast Tisus DryDry Tissus Tissus per cent Per of of fisare 8102 Dry Caf fisare per cent per cent per cent PPerer Cent Cent Cent of of LE LE $ 102 102 102 [ &] ket per cent par cent per cort 24 12 mos 24 23 23 27 208 .13 4.98 0.82 0.46 5.00440 5.00440 INTERIM REPORT REGARDING THE BIOLOGICAL ACTIVITY OF KAYLO DUST to the ILLINOIS GLASS COMPANY TOLEDO OHIO by THE SARANAC LABORATORY SARANAC LAKE NEW YORK October 30 1948 Submitted by Arthur J. Vorwald M.D. Director The Edward L. Trudeau Foundation In cooperation with Philip C. Pratt M.D. Thomas M. Durkan M. E. Anthony B. Delahant Figure 2 with Figure 3 The lesions in the tracheobronchial lymph nodes showed no change between thirty months and three years Chemical analysis of the lungs of guinea pigs that had inhaled Kaylo dust for periods up to 36 months yielded the data given in Table 1. It will be noted that as the period of exposure became longer the ash value gradually increased indicating an accumulation of mineral matter in the lungs There was a pro- nounced increase in the silica component up to about 30 months and then a slight decrease The reason for this condition which has been observed in the experiments experiments with other dusts is not entirely clear Since only two animals were analyzed for each exposure period individual values were occasionally out of line but the general trend was clearly indicated D. Discussion The final observations in this experiment with Kaylo inhalation in normal guinea pigs reported above and illustrated in the figures proves that Kaylo is capable of producing the characteristic reaction asbestosis It is evident therefore that a considerable portion of the asbestos component in Kaylo remains unchanged during the manufacturing process or if it is changed that the altered product maintains its capacity to cause fibrosis While the lesions up to 30 months showed no fibrosis certain aspects of them were compatible with a preliminary stage in the development of asbestosis These aspects were masked by the inert type of reaction to the materials other than asbestos in the dust The characteristic early stage of the reaction to asbestos is the predilection of the fibers to localize in the lumen and wall of the small air ducts known as terminal r ~.bronchioles this is in contrast to particulate materials which localize chiefly small numbers opment of the of fibers are capable of lesions is delayed The producing asbestosis although the devel- present experiment with Kaylo is also an example of this fact The important matter of progression of reaction after exposure to asbestos dust ceases has been extensively investigated The results indicate that in contrast to silicosis where progression continues for some time there is non significant degree of progression in extent of the lesions Rather the size of the lesions decreases in asbestosis due to the tendency of the fibrous tissue to contract after the stimulus to its production is removed The irritation of tissue by an asbestos fiber is apparently arrested within a few months after it enters the lung by the formation of the asbestosis body a coating of the fiber by ironcontaining material with the result that the existing fibrous tissue contracts Whether this contraction exerts a beneficial or deleterious effect on lung function is now under investigation Unfortunately the studies with asbestos have not as yet completely clarified the problem of its effect on associated tuberculous infection It appears that Kaylo may exert a slightly more marked adverse influence on the infection than does pure asbestos The difference may well be due to the presence of the small amount of quarts in kaylo or perhaps to other incidental factors One purpose of the studies now under way is to clarify this problem C. Conclusions 1 Kaylo because of its content of an appreciable amount of fibrous chrysotile is capable of producing asbestosis and should be handled as a hazardous industrial dust 2 Kaylo does not produce silicosis in animals the latter condition can be dismissed asbestosis however Further consideration must be given to which The laboratory has recently completed a large amount of work with has been reported to certain other supporting companies but not as asbestos yet published The following discussion of the problem is drawn largely from that work and we would request that those comments be considered confidential It is felt that the following information may be of aid to the Illinois health department in formulating a safety program which certainly is necessary in view of the results of this Kaylo experiment Asbestosis both in man and animals is a chronic slowly developing peribronchiolar fibrosis which in late stages extends from the original site of localization into the surrounding alveoli The bronchiolar localization is appar ently due to the fibrous nature of the mineral Experimental studies indicate that the chief mode of action is by mechanical irritation in tissue of the fibers The structure of these fibers and the capability of repeated longitudinal division to molecular strands is important in the mechanism of action since the solid fibers of glass wool are not capable of producing the fibrosis Chemical action is of little or no importance in causing reaction since chrysotile rendered particulate by cutting and separation does not initiate fibrosis Certain investigations have indicated that a seemingly negligible proportion of fibrous asbestos is sufficient to produce characteristic reaction Thus an inhalation experiment was carried out with milled asbestos in which an attempt was made to eliminate all fibers impossible to break up all of the fibers and material It was found to be about one per cent of the air sus- pended dust consisted of fibers The characteristic peribronchiolar fibrosis developed in the exposed animals after forty months Thus it appears that very INTRODUCTION One year ago on October 30 1947 an interim report was submitted covering the progress of certain animal experiments with Kaylo over a total period of 30 months It was necessary at that time to recommend further experiments concerning certain phases of the problem The present report deals with the final phases of the experiment then in progress and with the early observations made in the series of experiments The original experiment has now been completed and the conclusions drawn are based upon the results of a full three years exposure to an atmospheric suspension of Kaylo dust Previous experience has shown that this is the required period over which exposures to a dust of doubtful biological activity must be continued before final conclusions are warranted This experiment in fact constitutes an example of the importance of such prolonged study for as is to be shown below the findings at three years were strikingly different from those at two and half years and the tentative conclusion reached at that time must now be altered Thus at the time of the previous report the evidence indicated that Kaylo acted as an inert dust in normal rats and guinea pigs resulting only in the formation of clumps of dust cells without fibrosis However it will be shown below that Kaylo is capable on prolonged inhalation of producing asbestosis in the lungs of guinea pigs and that it should be handled industrially as a ha- zardous dust This report will be presented in four sections as follows A. Final observations dust inhalation in normal guinea pigs B. Discussion " D. Conclusions Progress report on New series of experiments