Document BR2b08MOn8J7JRbEZEGz4OXRj

FILE NAME: Owens Illinois (OWILL) DATE: 1948 Nov 16 DOC#: OWILL041 DOCUMENT DESCRIPTION: Letter from from Dr. Vorwald, The Saranac Laboratory to OWILL with Attached Report A Hoveaber 16, 1943 Mr, Bowea-- - Ovans-IHiiicis Glass Coarwny : - ' Toledo 1, Ohio" ->* ' . / Dear Mr. Bowes* ' -Btaeloeed you will find three copies of a report on the results of anisal experiments with Kayla dust. As is oar custcn, ve have stcaarixed briefly material previously* presented, including our is-; terla report dated October 30, 1947, end have given detailed dis cussion only .of subsequent developments. Vhen all experiments have been completed, ve expect to prepare a final report which vill in clude details of each phase so that all data vill be available in one place. However, the experimental study of the effects o f inhaled Kayle dust on normal uninfected animals la nov finished and conclusions expressed os that subject are final rather than tentative. In the report issued one year ago, which describes the findings in animals that Inhaled Seylo duct fer periods up to 30 months, the following tentative conclusion was aadej la consequence of the experimental studies with - guinea pigs to determine the biological activity of .. ir ' Kaylo, it nay be tentatively concluded that Ksylo alone " '~ fails to produce significant pnlaonary damage when in i ' h a l e d into the l t ^ During the 30 to 36 months period, however, definite Indio tion of tissue reaction appeared in the lun.-'3 of caixitls Inhaling Kaylo dust and there fore, I regret to say, cur tentative conclusion quoted above aast bo al tered. In all animals sacrificed after acre than 30 souths of exposure to Caylo dust unnistaxable evidence of asbestosis has devalopod, shoving that ioylo on inhalation is capable of producing asbeatosis aad must be regarded a a potentlally-hasardous aaterial. It should bo noted that since neither silicosis nor the diffuse pulaoftary flbroris enured by inhaled diatcrxacccus sartfa vaa observed, the quarts snd dlatcaacecus earth components of the dust apparently do not produce their typical lericna. m order to present sore inforaaticn on the subject asbeatosis, certain vidence derived from our experimental veric with asbestos dust has been die-- seed. As these findings have not yet been released for publication, I re quest that, while using then as required ini formulating a safety progras, rou regard then as confidential. Page 2. Mr. 0.. E. Bowes Ovens-jlllnoia Gig 3a Coaasnr Woventer 16 1948 : The new series of experiments with, respect, to the influence of Kaylo on tuberculous infection are veil under way and are pro gressing satisfactorily. It is, of course, toe early to expect si&dficsnt results on which to base even tentative conclusions At this tine say I review briefly the financial arrangr^nt^'''^ for conducting the investigation with Eaylo? The research program up to this year van carried on under u contract. Initiated in 1915 by vhich the experiaanta vould be subsidised with a grant of $5000 per yaar. As pointed cut in ay letter cf March 3, 1948, the contract terminated officially ca February 15, 1948, but tire investigation vould be continued without charge until June because the original experiments were started late Since a check was received, which took care of the subsidy up to November 15 , 1947 there is due on the old contract the ssan. of $1 ,250* for the final quarter of the contract (from Hovehfcer 15 1947 to February 15 1943). Ye have delayed .sending an invoice for the final quarter until all vork could be finished end a final report subedited. Following the termination of the experiment in. June, It has required several months to do the histological work, study the tissue sections, collate the data and prepare the report vhich accompanies this letter. Ve are including in the report a brief reviev of the nev experi ments in vhich the effect of inhaled Kaylo dust oa tuberculous in fection is being studied* Xcur purchase orderAS-170 authorizing this experiment at $5000. for one yo*r ia dated February 3, 1948, but owing to ft shortage of animals and other unavoidable delays the actual experi mental vork did not get under vay until May. Hence ve have concluded that financial support for this new program should be dated frea May 1 1943 For reasons outlined in ny letter of March 3 I suggested a twoyear contract at $7,000. per year. Tour letter of March 31 acknowledged this but failed to confirm the extra amount of $2,COO* involved. Sever-- theless} ve have proceeded at the old rate and are endeavoring to absorb the increased cost from our Foundation reserve. In a few days our accounting department vlll forward a statement of the payments now due in support of the research program, as follows* Original exparlsgnt. begun February 15, 1945 at rate of $50C0. annually For final quarter (liove.sbor 15, 1947 to February 15, 1948) $1,250. Key experiment, begun May 1, 1948, at rate of 5,000 annually For flrrt quartor (Kay 1, 1948 to August 1, 1948) For second quarter (August 1, 1948 to Hoveaber 1, 1948) $1,250. $1.250. r, V B* Bow .. ' vena-Illlaol* Cinga Conaanr Kovenber 16, 198 X rasila that our findings rgandin? Safio er less fsvombl o&a anticipated* Severer, aloe Safio la cap*bl of produca? a-- atale, it 1 batter to discover it now in. alasi rather than. later i Industrial workers*. Thu* the coajjeny, boia? forevarned, vili be j a bettor position to institut adequate control asasure5 for safe-- ardieg exposed eaploysesF and protedia? Its ova interests* Sincerely your, fiLB (3) : Mr. Dayton Arthur J fervali, MJ3. Director IfiTERBI REPORT RSQARDlHd TSE BIOLOGICAL AC7ITLTI OF KALO WIST . % . . *- * ' to tbs 0VE3S-ILLIS0IS GLASS COMPIEI TOLEDO, OHIO THE SARAHAC LABORATORI SAPKAC LAKE, HEV TOES OCTOBER 30, 194* ilaltted fcy* tbur JL Yorvald, M. D, Director Edvard L. Trudomi Foundation la coopration vithl Philip C. Pratt, H. D. Thomas K. Durian, M E Anthony B. Delahent P .r ` ) > IHTRODDCTIOB . , One year ago, on October 30, 1947, an Interim report vns submitted, overing the progrea* of certain animal experiments vith i&ylo orer e total . eriod of 30 months* It was necessary at that time to recommend further rperloent concerning certain phases of the problem* The present report deals 1th the final phases of the experiment then in progress and vith the early Bserraticns made in. the nev series of experiments* The original experiment has now been coapleted and the conclusions drawn re based upon the results of k full- three years* exposure to an atmospheric pension of Eaylo dust* Previous experience haa shown that this is the re tired period over which exposures to a dust of doubtful biological activity < ist be continued before final conclusions are varranted* This experiment, in tot, constitutes an example of the importance of such prolonged study for, as is to tshown belov, the findings at three years ver* strikingly different from those >two and one-half years and the tentative conclusion reached at that tlae must nov ialtered* Sms, at the tine of the previous report, the evidence indicated that ylo acted as an inert dust in normal rats end guinea pigsf resalting only in . e formation of clumps of dust cells, without fibrosis* Savever, it will be awn belov that &aylo is eapeble, on prolonged Inhalation, of. producing asbestosis the lungs of guinea pigs, and that it should be handled industrially as a ha- rdous dust* . This report will be presented in four sections as follows* A* Final observations, dust Inhalation in normal guinea pigs, B* Discussion*.v : ,, C* Conclusions* - l>* Progress report on nev series of experiments. U final observations* dust Inhalation In normal guinea pigs, Esfrrecc to the Interim Haport of October 30, 1947 vill reveal that two groups of normal guinea pigs vara placed la the dust ro o m one group in febru- 117 194$ and the second in ingust 1945* The animals vere exposed to atmospheric suspensions of JCaylo dust for eight hours daily, flee and one-half days a weak throughout the experiment* the dost concentration, vhlch varied somewhat from tine to tine, haft averaged 116 nil!ion particles per cubic foot of air over the entire coarse of the experiment to date* * -<rr X brief review of tee observations described on page 4 of the previous re- pert vill reveal teat up to thirty souths the reaction in guinea pigs vac Halted to the accumulation of clumps of macrophages, containing dust particles, in groups of adjacent air spaces* While occasional aultinucleated giant cells vers ssaa, there vas bo undue proliferation of tissue histiocytes and fibrosis v&e seat* 4 few unmistakable ashestosis bodies vere identified* In general, the SCCffimlatlon of cells of tee types described above and their persistence as such < * ' ' CTtr a fall three year period, without the development of fibrosis, has been iVl; bead to Indicate that the agent responsible for then is not capable of producing Uresis* Such agents are nov considered to be "biologically inert,* since the b n cellular accumulation has not been shown to affect pulmonary function or resistance to disease* ; However, of nine animals sacrificed eubse<iuent to thirty months in tee pro- - Mot experiment, all have ehovn not only the above lesions but also have developed -:* H ' _ - trsft fibroids of a type characteristic of the response of guinea pigs to asbestos* 5is is a rather diffuse type of fibrosis which forms chiefly about the email air ^Wtir t:_ i te, known as bronchioles, from which tee air spaces, or alveoli, of the lung ' ** ' '*.. - * *d* tee appended photomicrographs shov tee nature of the lesions being dls- ****ed* tele condition is identical with asbeetosis as can be seen by comparing IXfM* 2 with figure 3. . ,, , The lesions in the tracheobronchial lymph codes shoved DO change between iMrfcy months and three years. . .. ; '' Chemical mlynla of the lun^a of guinea pigs that bed inhaled Eaylo dnat Iwr periods up to 36 months yielded the data given In Table 1. It vill be noted c that as the period of exposure beoaaa longer the ash value gradually increased* Indicating an accusalstioa of mineral natter in the lungs. There vaa a pro- Aossced increase in the silica component up to about 30 sooths and then a slight i: ^crease., The reason for this condition, -which has been observed In experiments :tlth other dusts, is not entiraly dsr. Since only tvo animals vers analyzed 'to each exposure period* individual values were occasionally out of line bat ri { "lec.generel trend v&s elewrly indicated. ; V -Tf ;V - ; : - 1 SIseasalon. :\ The final observations in this experiment with Kaylo inhalation in normal b- . -y . gdfie* pigs, reported above and illustrated in the figures, prove that Ecylo is /iAstfi*- ` ' v taxable of producing the characteristic reaction, asbeetosis. It is evident, .`M* . therefore, that & considerable portion of the asbestos component In Eaylo remains .v ... CMh&figed during the senufaoturing process or, if it is changed, that the altered product aaiatains Its capacity to cause fibrosis. "While the lesions up-to 30 tenths shoved no fibrosis, certain aspects of theavere compatible with a prelim- - tsety stage in the development of asbestosis. These aspects wore masked by the r-Ussx - i&rt type of reaction to the materials other than asbestos in the duct. The ftaraeteristlo early stage of the reaction to bsboistoo is the predilection of the ilhvrs to localise in the Inaaa end veil of the small nir ducts, known as teraiaal tfoaehioles This is in contrast to particulate materials, which localise chiefly fs the actual Ir o*es, or alveoli. In the present experiment the greatest portion of the inhaled dust, being particulate, lodged in the alveoli and smoked the peribronchiolar' deposition of cone of the fibrous opponent. la retroapeet, 'it is possible to discern that there- is acre evidence of dust call activity in ;the region of the bronchioles than is characteristic of the reaction to an inert `particulate dust. Little significance as attached to this at the tine of the !previous report because there vss no evidence of the develoaaent of fibrosis. ir-ir* She differences between ths early reaction to Kylo end that to asbestos *say be interpreted as a modification of the lesions by the particulate eoaponenti '11 laylo. Hodific&tloa* of silicosis is veil recognised when lesions of that 'disease develop following inhalation of a aired dust containing quarto together ivith arteriale, of an inert nature, such iron oxide* It is of importance to note that while the peribronchiolar reactions eb- Vfrt$ incriminate K&ylo as eapahie of producing asbestosis, they exclude the V -' ^feasibility that it may cause silicosis, since, over a full three year period,- 'liters is in no animal eny focus of hyaline oodular fibrosis characteristic of *trreaction to quarts. Furthermore, it nay be added that the animale show no :evidence of the type of diffuse fibrosis which has been observed in this labor- 'Uy to follow inhalation of diatoaaceons earth dust. In regard to hydrated tefecaloiua silicate, a najor constituent of Kaylo, it nay be said that while fcteire 1 * no pointed evidence as to its effect on pulaonsry tissue, there is such : V. tt&Sa&ee to show that a variety of silicates, including scese f o m s of eelaium *0101toe, are biologically inert. It geens likely that the celalust silicate ktqfa should canfora vith this previous experience* ' ~ Thus, the possibility expressed by Doctor Gardner in hie early consideration tfthis probiera, that Kaylo might produce ivo pnewssocoxiioees, asbestools end silicosis setjes' the resultant safety hazards, has been adequately studied, and concern over f/latter condition can be diesissod. i ideatosls, however. Farther consideration oust be given to - - " *- rep The 'laboratory has recently completed a large amount of work with asbestos, jrh has been reported to certain other supporting companies, bat not es yet pdllah&de the allowing discussion of the problem is drawn largely from that ** and ve would request that these comments be considered confidential. It ' i*!falt that the following information nay be of aid to the OvenB - H U n o i a health fcgcrtment i n fornalating a safety program, which certainly is necessary in flew .the results of this Xaylo experiment. - je j't.isbestosis, both in man end animals, is a chronic, slowly developing peri- tocchiolar fibrosis, which in late stages extends from the original site of kalisation Into the surrounding alveoli. The bronchiolar localisation is appsr-- ay due to the fibrous nature of the mineral. Experimental studies indicate fat the chief mode of action is by mechanical irritation of tissue by the fibers. U itxucture of these fibers, and the capability of repeated longitudinal divi- to molecular strands,is important in the mechanism of action, since the s*. v B*bl fibers of glass wool are not capable of producing the fibrosis. Chemical i? ' : attends of little or no Importance in causing reaction, since chryeotile rea- particulate by cutting and separation does not initiate fibrosis. * .) rsf Certain investigations have indicated that a seemingly negligible proportion f fibrous asbestos is sufficient to produce the characteristic reaction Thus, \ T : * inhalation experiment was carried out vith bcll-allled asbestos in which en ..... . was made to eliminate all fibers from the material. It was found to be ^esibls to break up all of the fibers and about one per cent of the air sus- . .. "i r.-.s i ... v:,'.. dust consisted of fibers. The characteristic peribronchiolar fibrosis i b. m - . * .'' ... . . . . -- Sloped in the exposed animals after forty months. Thus, it appears that vary A O -5- numbers of fibers art* capable of producing aabeatoais, although the devel- f"* of the lesions is delayed* The present exporiaent vith Xaylo is also an wemfi of this fact. ; t The important natter of progression of reaction after exposure to asbestos ft^eeases has been extensively investigated. The results indicate that in con- truVto silicosis, here progression continues for some time, there is no sign!" * flftaVdegree Of progression in extent of the lesions.' Rather, the size of the V ' hdani'decreases In asbestosis doe to the tendency of the fibrous tissue to tdtriii after the stimulus to its production is removed. The irritation of tissue V "cS iebestos fiber la apparently arrested vithin a few months after it enters filing by the formation of the *sbestosis body* (a coating of the fiber by iron- i. ' < Mowing anterial}, vith the result that the existing fibrous tissue contracts. this contraction exerts a beneficial or deleterious effect on lung fano- a it now under investigation. i - ............... *fefortun&teiy, the studies vith asbestos have not as yet completely clarified t* crohlea of its effect on associated tuberculous infection. It appears that . (S&~. *;ltw y exert a slightly more narked adverse influence on the infection than '*h. . t*-*par* asbestos. The difference may veil be due to the presence of the snail cf quart* in Ksylo or perhaps to other incidental factors. One purpose . .,w - ............... **fie itodies aov under vay la to clarify this problem . .. *.'/?*>'*' ^ ^tislons. ` ... * 1*"f&ylo, because of its content of en appreciable amount of fibrous ^thrysotila, is capable of producing esbsstosis and should be handled as a hazardous industrial dust. 3* Csylo does sot produce silicosis in enio&ls. 3 laylo does not produce the diffuse cellular fibrosis of the lungs now recognized as resulting froa Inhalation of dietoaaeeous earth ' Progress Report on new eeriea of experiments i She three phases of the experiment, as outlined in the report of October 30, U 7 and in a letter dated March 3, 194d, are nov under vny. Vhlle. little of jniflconce has developed thus far, a review of the vcrk is presented here, regress and results to data of these experiments are given below under the tile of each phase (1) The effect of Kaylo inhalation on tuberculous infection initiated at ^ the onset of dust exposure* -- Thirty experlaent&l animals W r e infected vith the attentuated ; strain ( % ) of tubercle bacillus used in this type of experiment and vere placed in the dust room the next day* Thirty-three control animals vere r infected et the ease tine and kept in normal air Of the experimental aalaala, six are nov deed, tvo having been sacrificed at two months, two at four souths and tvo having died "L..... . ^ One death occurred at five veeksp due to intercurrent pneumonie ^ .the other vas so recent that sections have sot yet been prepared. .rvr>; The animala killed at tvo months shoved lesions comparable with ^ those in. the controls, both grossly end jricroacopieally* The aniaala 1; killed at four months have not been studied microscopically, but on gross examination the lesions appear similar in the tvo groups (2) The effeot of Eaylo inhalation on regressing tuberculous lesions in guinea pigs In this phase of the experiment, twenty-five guinea pigs vere Infected, and groups of them vere kept in normal air for two, four and six -7- months before being placed la the dust room. At the present tice the first two groups here been placed in the duet rocaf the third is to go in on 1 Beceaber 15f 1948 f Only tvo animls of the first group have been sacrificed as yet, after tvo aotstha in the dust. Microseopio observations have not been V , 4 M-de, but in the gross, the lesion* vere comparable vith those in control i eninels. ' -i (3 ) The effect of ccttaalated Ksylo In the lunge ca * subsequent tuberculous infection. f Thirty normal guinea pigs vere placed in the dust rooa on Kay 12, i 1948, and on August 12, 1948 vere infected vith the attenuated tubercle bacilli, fire animals vere sacrificed 4at this tine for cheaical analysis % to establish the amount of dust inhaled. % a Control animals vers infected on the ease date, vers sacrificed recently, tvo months after infection, I f grossly, the lesions in tha experiment*1 and control niseis vere comparable, i % bat rgsla sicroscopic observation* here not been stad*. the results to date in this experiment are of little significance, since the htota is & chronic one end any changes due to the inhalation of dust of any nature ilbwva to be alov* However, it can be said that the.experiment is progressing 5y satisfactorily, end that ve anticipate none of the complications which inter* Bfed vith the interpretation of the previous experiaent in regard to the effect ^toylo on experimental tuberculosis.