Document emJBK813VZL74ZLBj6EKN4br4

&*&**& 'WTSROTlAl r'UtU. HEP OBT PLAINTIFF'S EXHIBIT I JM 954 / THE 3 i 0 T O X I C 1 f I V ? PER J, ' `` B to `?hs Perlite Inatituie 10 3aet both Street. Hew fork 16, New York toy The Saranac Laboratory 7 Church Street, Saranac lake. New York March 19, 1955 Submitted by 0-> Wv H* Soiiepcro* MaDo* D*Sc Director .I nKC: n*Vtut i .liiiTWli-fliil'ilrirtiWMt nr / CONTENTS Fbe S. ;* borato'y Perlite .Cnr-tJ Wite Fine..! Jv: ;ort - "?-_9 13 I c INTTCDUCYiCi: II.. MATERIAL III. METHODS A Duet Room D,, Infection of Animals G. Erperiaenial Animal Cr sv.ws 1, Oheiilcnl Analyeie of Ani real Lungs ior Sf.licu IV, RESULTS A, Dust uciicont/ation B. Course of Infection G. Ash end Silica Content of Lungs D. Bates of Accumulation and Excretion of Silica in AnimalB Exposed to Perlite V.DISCUSSION VI., FURTHER RESEARCH VII. SUMMARY . . tables FIGURES i ~i 1 - li i'-- MTC 013942 fee I. INTRODUCTION This final report from The Sai-anac Laboratory to the Perlite Insti tute covers all observations made during the recently completed experiment which was designed as a study of the effect of inhalation of Perlite dust upon the course of tuberculosis in the experimental animal. By means of a previous experiment- it had been shown that the inhala tion of Perlite dust caused no significant pulmonary fibroais in normal animals, but that the presence of the Perlite in the lung tissue atinm^ lated a tuberculous infection. In view of the rarity of such a combination of findings, a further study of the relationsliip between Perlite inhalation and tuberculosis va3 indicated. The experiments which, were designed were intended primarily to reveal whether the buborciiogenic effect of the dust deposited in the lung tissues would continue to be exerted during the months after cessation of exposure. This point was considered to be of practical importance in industry, because, although any dust-exposed laborer who might develop tuberculosis would be removed from exposure for treatment, the outlook for successful treatment would depend in largo measure upon whether or not the stimulatory effect cf dust on a pulmonary tuberculous complication would persist. In human silicosis complicated by tuberculosis, for instance, the prognosis is usually grave. This fact has been demonstrated also in animals, the stimulatory effect of quanta dust on tuberculosis in experimental animals persisting long after dust exposure has stopped. The present study has provided observations which permitted submis sion to the Perlite Institute on December 10, 1954* of the following sum marized statement of the effects of Perlite on animals; 4. Perlite does not provoke any detectable primary lung disease. B. Hie continuous inhalation of Perlite dust stimulates the development of tuberculosis in animals, which therefore develop progressive lesions. C Interruption of Perlite dust exposure after six months and nftar tuberculosis has become established does not modify materially the rate of progression of the tuberculosis during the succeeding S months. D. -About S to 12 months after tbs withdrawal cf the* Perlite dust exposure the tuberculous procsss begins to wane in the sense that a previously progressiva disease commences to show signg of healing through fibrosis. Ultimately the disease is arrested. E. Healing of a tuberculous infective process has never before in the experience of Hie Saranac Laboratory occurred under com parable experimental circumstances in which animals were exposed to quarts dust, and survival for as long as 12 months is ex ceedingly rare. -1- MTC 013943 The- Saranac Laboratory Perlite Institute Final Report - 3-19-55 F. Tne n-.rling process is incomplete in fcuo sense That while the . , cellular components of the- tuberculous lesions disappear, / marked fibrous scar formation tokos its place. The healing requeues of tuberculosis in animals is normally complete with out the formation of such extensive cicatrization, In this T'jspact., therefore, the lung f ibrar.br .mat bs inter prated as a idryuficvnt pathological reeidpijua. The evidence upon vfcich tMs summai'y was based will, be presented- II. ylATEPJ&b The product used for dusting in the prarc-.-t .study vp*- the same as that used In. the erigiefi experiment concerning which a rine.1 report was issued on March IT, lvf-j. This product is ider.tiiiod by The Saranac Lctoratory No. M3) 201, rad its physical end chosical composition as deter mined by us are presented in Table 1. III. METHODS A. Dust boom; The procedure with respect to the dusting of the animals was identical to that in the earlier study. The experi ment was conducted in a specially-constructed cubical duet room 8 feet in each dimension. The dust was generated mechanically by a peddle wheel agi tator rotating in a dust hopper., The dusting apparatus was kept in operation for 6 hours a day, 5-1/2 days a veeK. The sniiMls lived con tinuously in the dust room but the room was ventilated by means of fresh outside air during periods when the dusting apparatus wan not functioning. The dust concentration wa3 controlled at regular intervain by counting the perticles collected by means of the midget implnger.w' A8 in the previous study, the infecting tubercle bacilli were of the attenuated human ftj, strain .;hi eh, &f has bf-.n repor tedly emphasized, is capable of producing in guinea pige s twhrrculcus infection vhicb dev?lope end progresses for sb>;i 2 month?! ,c.h subuepaently, over a period of xeny months, regreecea snd heals.. T>-e 1 tifecticn ,;as accomplished by preparing a dilute suspen sion of the organisms in saline ,-7eXuti.cn and the animals were caused to inhale tor fixed period of tin*? an aio.ntzod 'list of liiie suspension:,. Control enimtls were irfecteri with the r-aoe dose of organisms at the same time as vert the animulr to be exposed to duet, C,, Experiment,si Aairul hrouou: a the purpose of tha present study was to a*certain ','helher or not inhaled Per lite dust, ones deposited in the lung. could stimulate tuberculosis daring a subsequent period of nen-expoeure to the dust, the following protocol of dust exposure and sacrificing intervals of animal groups was designed! i r -2- MTC 013944 The Sai-sHiee. }rf>horr.tory Perlite f-tcn'i'out6 Final Report - 3--19--55 Group A. Infection by inhalation at tne beginnlng of a six-month exposure to Perlite dust. Sacrificings during and after exposure in order to follow the course of the tuberculo sis. Sacrificing periods at 2, 4 and 6 months of exposure, and at 3, 6, 9 and 12 months after the end of exposure making a total observation period of 18 months following infection. Group B. Infection at the end of a six-month exposure to Perlite dust. Sacrificings scheduled after the infection at 2, 4, 6, 8 and 12 months.. The total duration of the study in this group was also 18 months. Group C. Exposure to Perlite dust for six months with sacrificings during exposure at 2, 4 and 6 months, and after expo sure at yt 6, 9 and 12 months. These are non-infected control animals for Groups A and B. Group D. Infection without dust exposure. These are infected con trol animals for Group A and were sacrificed at intervals corresponding to those in Group A. Group E. Infection without dust exposure. These are infected con trol animals for Group B, and were sacrificed at intervals corresponding to those in Group B. Two groups of infected control animals were required because the infecting pro cedure was done separately. Groups A and D being infected at the start of the study while Groups B and E were infec ted six months later. This was to ensure that results did not vary aucn because of 'differences in the culture batches. D. Chemical Analysis of Animal Lungs for Silica: In the Progress Report dated March 12, 1953, it vis pointed out (Page6, Paragraph B) that in certain respects the pro gressive tuberculosis esen in infected animals exposed to Perlite dust was different from that in animals exposed to quartz dust. These peculiarities suggested that there might be excessive accumulation of Perlite in the infected lungs as compared with the normal lungs. Accordingly, the lunge of all animals involved in the present study have been analyzed for their silica content. The technique used permits reporting of the silica in terms of total weight in the lungs, rather than in terms of its concen tration in the lung ash. It is of interest also to record the ash weight of the total lung. . IV. RESULTS A. Dust Concentration: Samples of dust were collected for determination . of atmospheric concentration at approximately weekly intervals throughout the six-month period of exposure of the animal to the Perlite dust. Usually the collecting apparatus was the Snith- -3- MTC 013945 V:.-.' P'fj.cilaboratory re .-1.1 \.a inrV tubs .1.0 -1 ?--55 Zts r-f-iil'-rj `ligfsv r-t'p.r-i/ar i-:.n ows'. C'-:.\tsxAyr II or; ve spacerv*ined Tgr counting tis3 partid1'.* wring a light-field teehrioue.. The average of 8.11 cuuista wr. ~62^1 axl-Ugn particles par cubic foot. At ironthiy intervals t:;s ccacenvPTihoS' of Jcsv was dotermined on a weigh i. basis, using the elertreatstic precipitator. The average of all suer, deivnilnations was 3.C? fAgus* per cubic foot of sir, The range of variation in the levels of duHvdness it summarised in 2ajug 2 and in figures i to 3. It ie ta be noted that the diepereioa iu pirt~<:.ls counts ve*.,, u-nce.-t for ;-:? si.inti troerpeclmd pause,, !>.;nt wltUin ee sat*.rfactory oor.-- t,rcl \t: i-? ? sue/.'ally possible turps r><a&t&X oandittoas, the casifi- cie b of '?..!ti >.i not exceeding ^S,S6 pr.r !r.t average. The siv.e l>sryier,ei.y cj[ f;trlb..licc ,;.f the Kirhcrr-e ;f.':+ ia p;iven 'u f'.ru.-o 4 About, 10 ;-:r vu;!f i thv , 1 /It:- wie . -.-uu t- be .Ltas than 2 microns end #co.;t ?.0 ;>`v c ' y ''i if... '/: f r;f. c .:'or..e, 7u?ae us re the respirable cons'J.fu- face :.> the t?roib oj Perlite, !:* Course o.f ln.iscfci.ee,: The course of tae infection in the experi:iw;ita.1 animals has been presented ir< progress reports daod Orto\wr 19, 19.53, and April 5, 1954. la this riimi report *11 observationa are presented, whether or not they have appeared in earlier reports. The detailed observations in aach individual animal are pre sented in Tsbies 3 and 4 and are graphically portrayed in Jfiguree 12 and ] T}ie points to be particularly noted arej (a) the progressive charac ter cl tue disease became retarded from a tout the 8 months after cessation of bust e-xporuref (h) f fter 12 son'&s had elapsed all animals snowed ntriing lesions vlthoul m\y suggestion of further progression but. with . cor>.c-idt.reb2e scar foxmtico. Thy the numbers in the tables, indicating k..x- extent of direage, reveal that even fcaough healing is veil tdvanced it is menlfeevid by rplacement of the inflammatory process by .'.car tissue rather t wr. h- restoration of toe tissue to normal. 0 .= /ah .-.nu Silica Cor.ten*, of lum^p: In the original experiment shoving progression of tuberrulcria in i. *,t- .u ~ v T : ` : i ,: '... wu Sion was gained that U.ere ''giit f~ f-xcee'b /* ^ cxau.lt tic-' ..urt .-i -i'e lungs of ihleated r.ni'Jela. Tils u.. ursssio-. f c!ri'-ed ft- u . Ir. ;, i..ut less dust was tran.^ferred 'ro*. uaf- l-jiig t-- t;i? ailar ly.'.-h nr: or iu-'setod ani.aels than vt.a trans ferred 5i- uci..-lf5.-cco<i animals, f/i-gce u.;.a phenoaeiion might account for tho i.rogr*>*3on of bus !isense i.< ',;e j->.fecte-J enimsis tui attempt ves made to isuurii-l..u or ' icitn uxcessi vs -' -uuul:/ fcj o-i :f duet by cuemicel analysis cf tue J-./ng vl.-rut; of `x? in hr-is >..tperia*nt for silica. At the same time `.he -.fcif.it. of uhe aru u." tiie 1 lungs was determined. The of d;` chcal!.ral .-ii'alyeea of Um puLaonary tissue ere pTfseoveu ii: figures C,,I0 and Llc. In eecu of these figures, the sloping straignt lines indicate trends ajid the vertlcal lines connecting dots above snd 'r**3v tns t.'.-erid lines (present the actual observed values. As the figures reveal, the an Imal u were e.. posed to Perlite dust for six oontas ii;id were i`ol).ov.jtj for 12 months tJ.^reafiero -1 t j..-: k; MTC 013946 The ?av:<oae Lahorot-ory Perlite Instituta Final import - 3-19-55 Ai '/rri^r: i.;. 'railed particularly to the fr- ;'* tent ih presence of ir. fact Lon does w' alter ths rate of aceumui.-?.Lit.a or elimination of v'-li ca as -co-iyared v$ tft uninfected controls, figui'es 9 uud 11. Thus the leaser quantity of dust seen it; the lymph nodes of infected e.ni.'nals aerely indicates iht duct io mainly eliminated from the lungs vj.a the v-e-spira to/y papsmges, rather than through the lymphatic system. i further point of interest recorded in Figure? 10 end 11 is tb& li2i-3 rnprcsenviag the amount of lung ash vbich remains after subtraction of the silica. flote ter. t this cuantit-y increased after eesssfc*on oi ex posure iu Infected animals Mid decreased In non-infeetea animals* D. Pate* of Accumulation i.;i; Excretion of -31 lira In Animals Exposad to Perlite___ _____ ^________________________________ ______________________ (Supplene.nti ng Final Report of 1953) the time; of issuing fcue final report concerning tne action c.i '.arlite dust i.-por. the lungs c.f normal., non-infecteu animals it had not can possible to complete all unemical analyses of the lung tissueo for silica content. Since these data are now available they are presented herevitfa in Figures 5, 6, 7 ana 8. In each rigure there are tvo pairs of lines, one pair revealing silica in terror, of weight and the other pair representing a percentage of the lung ash. The lungs from Wo animals vere analyzed at each time interval and the upper and lover lines of each pair represent maximum and minimum values. In Figure 7 it is shorn that the percentage of silica rapidly reached about 60 at 8 months of exposure and during the succeeding 16 months rose at a retarded rate to a maximum of only 66 per cent. In contrast the weight of silica increased sfc a uniform rate up to 24 months except for cne pair <> f high values r t 1.3 nonthe, ` J.n Figure 5 the era!ytxcel reaults obtained in animals killed at veriow intervals after toe Zm monte expouure period a: ? presented. There ;e ousi durable variation ir. the .iata obtained but in general there *ppeers fcc be H tile tendency for rapid removal of the deposited dust. , Figure 6 reveals the findings in a brief experiment involving expo sure for a period of 9 lays folic v^d by 9 do.;/ in normal air. Again very little if any of the accumulated .iur iive removed during 9 of the days in normal air. In Figure 3 date sra assembled shoving the rates of silica-accumula tion in the lungs of rats exposed .to terlire dust over ?_n 18 month period. The results with rats are more variable than for guinea pigs concurrently exposed (Fig, 7) but general trends are similar. L !, r ~5" MTC 013947 The Saranac laboratory Perlite Institute Final Report - 3-19-55 V, DISCUSSION The.most important and practical point demonstrated by this study is that, although pulmonary deposition of Perlite dust stimulates pul monary tuberculosis, tne stimulatory action persists for only a relatively . short period of about 8 months after interruption or dust exposures When this fact, is contrasted to the indefinite persistence of the stimulatory effect of quartz dust in the lung under comparable circumstances it becomes clear that Perlite dust, though dangerous, is distinctly less potent than quartz in this respect,. This less pronounced tuberculoge-uic propensity of Perlite should not be underestimated.. While the experimental evidence suggests taat tubercu losis in the presence of Perlite dust doe3 not have the high mortality rate of tuberculosis in the presence of quartz, there i.3 yet a rather prolonged illness and in the animals the extensive residual fibrosis may well be associated with some loss of lung function. It is granted that the course of events in Ri infected guinea pigs does not necessarily indicate precisely what is to occur in industrial workers exposed to Perlite dust who may develop tuberculosis. Thus it is possible that in Man there may be no demonstrable effect of the dust upon infection. On the other hand, the effect may be even more pronounced and prolonged in Man than it is in the guinea pig. However, the good correla tion found in previous studies between the effect of various dust upon Rj tuberculosis in guinea pigs and on tuberculosis in Man indicates that the experimental findings with inhaled Perlite dust should be considered as a warning that some degree of hazard exists but that the dust is by no means as noxious ao quartz. An attempt has been made to present graphically in Figure 14 the correlation we believe aay exist between the guinea pig results and the possible effects to be expected in Man. Vith respect to the application of the experimental results to the estimation of allowable dust concentrations in industry, the observations in tneee experiments with tuberculous guinea pigs seam to require that atmospheric suspensions of Perlite products should be regarded as somewhat more serious than more nuisance dusts. Since the evidence is that at least one of the Perlite dusts can stimulate tuberculous infection, it seems wise to suggest a somewhat lower limit of concentration than the 50 million particles per cubic foot mentioned ebove. Since the influence of Perlite dust upon tuberculous infection is not ao pronounced as the influence of quartz dust, it would appear that concentrations higher than those allowed for quartz dust would be permissible. In the case of atmospheric suspen sions of relatively pure quartz dust, the generally accepted maximum al lowable concentration is 5 million particles per cubic foot of air. On the basis of the considerations Just mentioned, it would seem that a maximum allowable concentration for Perlite dust may be greater than this though appreciably lower than the standard permitted for mere nuisance dusts (50 million particles per cubic foot of air). MTC 013948 The Saranac Laboratory Perlite Institute Pinal Report - 3-19-55 The attainment of such a maximum level of dust concentration in many plants may indeed require strenuous precautions, but such efforts vill surely not be es intense or costly as they would be were it necessary to recommend' a maximum concentration of the order of 5 million particles per cubic foot. Great attention will also have to be given to careful pre-employment selection of personnel who do not have tuberculosis or scars of past tuberculosis. All parsons exposed to Perlite should be subjected to annual radiographic examination and any showing suggestions of tubercu losis forthwith eliminated from further exposure. No persons already suffering from tuberculosis or whose x-rays show signs of past parenchymal tuberculosis should be employed under circum stances where they may be caused to inhale Perlite dust. Personnel exposed to Perlite dust should undergo periodic x-ray examinations for tuberculosis. Vhen tuberculosis is suspected in any worker exposed to Perlite dust, such a person siiould be immediately removed from such an environment and carefully studied. The reason for the stimulatory effect of Perlite dust upon tubercu losis remains obscure.. The identification or the mechanism of such action would constitute an important step tovards its ultimate prevention. It was suggested in the progress report of March 12, 1953j that the mech anism might be related to excessive pulmonary accumulation of Perlite dust. The present study, figures 9 10 and 11, rules out this possibility. Other possibilities exist and ore being examined. The nature of the healing process in these animals is also of inter est, in tliat it is accomplished chiefly by scarring of the lesions rather than by resolution or disappearance. The healing oi tuberculosis in experimental animals is usually by resolution, and involves much less scarring than is customary in healing human tuberculosis. The course of these phases of the disease is summarized in figures 12 to 14. The rather extensive scarring noted in this study may provide a tool with which idle effects of the residual fibrosis could be investigated. How ever, such investigation must await the availability of funds for basic research. A final point of academic interest is apparent in the results of chemical analysis of the lungs. This point pertains to the rising trend of the line representing the pure lung ash, minus silica, in the infected animals after interruption of dust exposure. In uninfected animals this trend is downwards. The difference between the weight of pure ash in each group of infected animals and the weight in uninfected animalB is statis tically significant and may parallel the degree of tissue reaction present. -7- MTC 013949 The Saranac Laboratory Perlite Institute Final Report - 3-19-55 VI. FURTHER RESEARCH la view of the tremendous ir.dustr5.al importance of Perlite and the likelihood of its future use on an extensive scale, further research cn its 'unique tuberciilogenic propensity is to be highly recommended, par ticularly vith reference to the questions! 4. Vfhether animals nearer in the evolutionary scale to Man are likely to react in the same manner as do guinea pigs. Ve reccommend a study in which Monkeys- are to be used, B 1'hcther the progressive tuberculosis observed under experimental conditions is amenable to satisfactory treatment by means of modern bio- and chemotherapy. 0, Vhetber the disabling effects of tne ultimate fibrosis may be prevented or minimir.ed through the administration of substances, such as cortisone, vhicn are Itno'./n to be effect!ve against a 'uriety of fibroiic phenomena in ilan. L1. Whsther the admixture of other- co;merci;il substances with Perlite irs likely to enhance or reduce its harmful effects., E. Whether Perlite in a state of finer subdivision would have effects materially different than loose of the produci ve studied. Throughout this report we have sc far assumed that vast happens to the guinea pig is likely also to happen to Man. This is not necessarily too case. In the case of quarts dust the lesions seen in guinea pigs fare identical vj th thooe seen in unman victims of silicosis. However, in the experience of Tbe Strar-H: Laboratory with an extensive series of sub stances ether tt.cn qaarnz a narked species variability has often been observed. Though va raws thus i'-r aptiidstienliy extrapolated our results directly from guvr.fcn pigs to Mar. (by analogy with quartz) it may yet prove to be the cuxv 'tut Far'.its vill $ rove to he more dangerous to Man than the guinea pig ra salts would seem to irvllct ts. The tuberculous complica tion may, on the contrary, also prove to be either lea,-: or .core serious in Man. To test these possibilities vt. would like to recoraraend a study of the effects of Perlite on a group oi about 10 monkeys. The tuberculous couplicato on vos thovr; to. heal by means cf scarring. This Is tiie result without ehemc-fnerupy, ft la deemed to be a matter of grast practical importance to study the influence of the modem chernoand biotherapeutic agents which have preyed so successful in human tuber culosis. These drags onve, hove ter> consistently teen a failure in cases of tuberculosis complicating or combined '-1th silicosis. Jit the most they hold the diseese temporarily .in check a.ri relapse usually follows soon after the drug therapy is v?r, thdrawn* -a- MTC 013950 The Saranac laboratory Perlite Institute Final Report - 3-19-55 The Sarsnac Laboratory has had experience with one cither substance (aluminum) in which tuberculosis was stimulated by the metallic dust though the latter alone had no primary fibrosing effect on the lung tis sue. In this case the tuberculosis responded rapidly and completely to chemotherapy. It is possible that the tuberculosis provoked by Perlite may show a similarly favorable effect provided therapy be introduced suf ficiently early. It is therefore strongly recommended that experiments be sponsored in which the effect of drug therapy in Perlite induced tuber culosis can be determined. If the disease responds readily and psrraaner.tly the outlook for Perlite will be considerably improved and it would be per haps permissible to relax somewhat in respect of dust precautions. On the other hand, if the tuberculosis were in spite of therapy to follow the same inexorable course as does the tuberculosis provoked by quartz dust, even greater precautions will nave to be observed. The residual fibrosis of the lungs may in itself be a severely crippling terminal result, judg ing by the extensive nature of the lesions in animals. The disability to be anticipated from such fibrosis may be compared with that found in as sociation with advanced silicosis. It has teen shown that a number of the fibrotic complications of pulmonary disease respond well to substtuices 3uch as cortisone and ACTS. It would be of considerable medical interest to determine whether these same results could be expected in the case of the residual fibrosis likely to be Induced by tuberculosis supervening on Perlite exposure. If ACTH or cortisone are likely to prove beneficial, the gravity of the tuberculogenic propensity of Perlite would once more be minimized to some extent. It seems highly probable that workmen will seldom be exposed to Perlite alone. It is even possible that Perlite will be commercially mixed with other substances such as cement, gypsum, talc, asbestos, etc. Tie effect of double exposures of this kind may be either worse or less harmful than the individual substances used in isolation. Cement, for instance, is, except for its influence in causing bronchitis, harmless to the lung tissue itself in spite of its high free silica content. Most of the silicates are similarly relatively innocuous. Quartz combined with tale or with asbestos, however, have an enhanced deleterious effect on lung tissue. Gypsum, on the contrary, tends to neutralize the effects of quartz to a certain extent. It cannot be predicted yet how ny parti cular combination of substances will behave when introduced into hurtan lungs as dust. If it is already the practice to combine Perlite with other substances it is recommended that their combined pathogenicity be experimentally explored. It ie of rurther importance to examine the particle Bize range under which exposures to Perlite are likely to take place. Recent studier? in The Saranac Laboratory have revealed that subBtancee which are inert in the larger particle size range may nevertheless become pathogenic in smaller and especially ultra microscopic particle size range. As shown in Table 1 the median size of the 1,64 per cent of particles in the Perlite MTC 013951 The Saranac Laboratory Perlite Institute Final Report - 3-19-55 vc studied vaa less than 5 microns. However, in the dust clouds raised ia the Perlite chamber ve maintained an average particle size of 82 per cent of the microns. Quartz of a particle size larger than 5 microns is virtually inert and the particle size range exerting maximum pathogenic effects lies below 0.5 microns. In the Perlite experiment fever than 50 per cent of the particles vere less than 2 microns and less than 15 per cent vere under 1 micron in size. It should be pointed out, therefore, that the favorable result thus far obtained with Perlite only applies for products comparable to that represented by Substance MD 201. Should Per lite products be marketed or used in such a way as to yield dust clouds with a particle size range considerably smaller than the median diameter of 7 micron diameters we have studied thus far it will be necessary to re-examine their separate effects individually. The smaller the particle sizes to be encountered the more necessary vill a renewed experimentation become. It must also be pointed out that the present product contained 1 per cent quartz only in the fraction with a particle size smaller than 200 mesh. Any other products with a quartz content substantially higher than 1 per cent will require renewed experimentation. It is particularly to be emphasized also that when quarts is heated to temperatures in the range of 300 F. to 2300 F. it may undergo a change with its isomers tridymite and cristohalite. These substance*: are appreciably mors harm ful to human and animal lungs than is quartz itself. Should Perlite be treated commercially to such temperature ranges it will be necessary to determine the presence or absence of cristobalite and tridymite, and if these are found the whole issue will have- to be reviewed. VII. SOMMARI 1. An experiment, designed to reveal the influence of inhaled Perlite dust upon vbe Rl tuberculosis in guinea pigs during a period after removal cf the animals from dust exposure to normal air, has been completed. 2. The previously observed stimulatory action of Perlite dust upon Ri tuberculosis was a gain demonstrated and was shown to persist for about 8 months after interruption of dust exposure. Beyond 8 months, how ever, the stimulatory action diminished and the disease healed. 3. Healing occurred by means of scar formation, rather than by disap pearance (resolution) of tue tissue reaction and restoration of the lung to normal. 4. An overall evaluation of trie present study and the earlier one pre viously reported, when compared with similar etudieB with quartz dust, warrants the suggestion that the tentative allowable dust con centrations for Perlite of the typ-> studied at The Saranac Laboratory might be somewhat higher than that for qj&rtz. On the other hand, if Perlite products are to be marketed with either a higher free silica content or with a greater proportion cf line particles less than 5 microns in diameter the whole situation will require to be reviewed. -1C- - MTC 013952 The Saranac Laboratory Perlite Institute Final. Report - 3-19-55 Table 1 PHYSICAL AiJD CHEMICAL CHARACTERISTICS OF PERLITE PRODUCT MD 201 I. Screening Teat Percentage of Bulk Sample within Each Range of Sieve Sizes Greater than 20 mesh 20 to 40 mesh 40 to 100 mesh 100 to 200 mesh Smaller than 200 mesh - 32.0# - 38.2$ - . 20.8$ - 7.0$ - 1.64$ II. Median Size Range of Portion Smaller than 200 "esh: 7 microns, . III. Quartz Content of Portion Smaller than 200 Mesh: 1.0$ IV. Chemical Composition of Bulk Sample Si02 Fe203 . Ti02 A1203 CaO MnO MgO Na20 X20 Loss on ignition 75.45 . 0.55 0,05 12.92 0.85 0.07 0.10 3.42 4.81 1.51 99.73 MTC 013953 The Saranac Laboratory P e rlite In s titu te F in a l R eport - 3-19- 55 MTC 013954 r\ O' $ hi 25 co B & 0-5 b xo: H & h .8 $C sCM 3 a) 5 a O rU-4"\ E-> a & O' *< a>4 4P) 0u CL* JBU002 aP 0 CO ! ,'i!t; iiisritube Final Report - 3-19"55 iSbl'i ; COURSE OF Hi TUDERCLiLOSIS IN GUINEA PIGS EXPOSED TO PERLITE DUS? AND IN UNEXFOSED CONTROLS Group A 1 Group D INFECTION PLUS PERLITE INFECTION WITHOUT DUST Infection at Start of Dust Exposura Controls to Group A Animal Duration in Number Months Perlite Normal Duet Air ~ 1 3K 2 0 Status of Disease S-l F-0 Animal Number Duration in .Months Perlite Normal Dust Air Status of Disease 21 K 0 2 S-l AK 2 0 S-2 F-0 22 K 0 2 S-l 7K 4 0 S-l F-0 23 K 0 4 F-0 8R 4 0 P-1 F-0 24 K 0 4 F-0 9K 6 0 P-3 F-l 25 K 0 6 F-0 10 K 6 0 P-2 F-0 26 K 0 6 .. F-0 11 K 6 3 P-4 F-l 27 K 0 9 F-0 12 K 13 K 6 6 3 P-3 F-0 23 K 0 9 F-0 6 P-4 F-3 29 K 0 12 F-0 14 K 15 K 16 K 6 6 6 6 P-3 F-; 30 K 0 12 F-0 9 P-1 F-3 31 R 0 15 F-0 9 P-2 F-3 32 K 0 15 F-0 17 6 12 P-0 F-3 34 K 0 18 F-0 18 6 !2 P-0 F-4 35 K 0 18 F-0 Key: K Killed D * Died S Stabilising P Progressing P " Fibrosis (Collagen deposition) Numbers indicate relative extent of involvement. MTC 013955 The Saranac Laborstory Perlite Institute Final Report - 3-19-55 Table 4 COURSE OF TUBERCULOSIS IN ANIMALS EXPOSER TO PERLITE DUST AND IN INFECTED CONTROLS Croup B Group E INFECTION PLUS PERLITE INFECTION WITHOUT DUST Infection at End of Dust Exposure Controls to Group B Animal Number Duration in Months Perlite Normal Dust Air Status of Disease Animal Number Duration in Months Perlite Normal Dust Air Status of Disease 57 K 6 2 P-2 F-0 76 0 2 S-l 58 K 6 2 P-2 F-0 77 0 2 S-l 60 K 6 4 P-2 F-l 78 0 4 F-0 61 K 6 4 P-2 F-l 79 0 4 F-0 63 K 6 6 P-2 F-2 80 0 6 F-0 64 K 6 6 P-1 F-0 81 0 6 F-0 67 D 6 6 P-4 F-l 68 K 6 8 P-3 F-l 82 0 8 S-l 69 K 6 3 P-2 F-l 33 0 3 F-0 74 D 6 11 P-1 F-3 72 K 6 12 P-1 F-2 85 0 12 F-0 73 K 6 12 P-0 F-2 86 0 12 S-l 75 K 6 12 P-0 F-2 38 0 12 F-0 89 0 12 F-0 Keys l 90 0' K " Killed D Died S - stabilizing P - Progressing F * Fibrosis (Collagen deposition) Numbers indicate relative extent of involvement. 12 F-0 MTC 013956 -PERLITE TRUDEAO Boom 7 Period 9/19/51 - 12/14/51 . The Saranac L a b o ra to ry P e rlite In stitu te F in a l Report 3-19-55 Ij/'liej suornrw MTC 013957 oino On) o O I s iV s.. S> i i is. sspi^je*! uoi'uiw PBRLIfE - TRUDEAfT Room 7 Period l/V /5 2 - 12/17/52 The Saranac L a b o ra to ry- P e rlite In s titu te F in a l Report 3-19-55 -Trudeau Room 7 U n til 3/4/53 -Saranac L a b o ra to ry Room 2 -3 /4 /5 3 10/15/53 PERLITE The Saranac Laboratory P e rlite In s titu te F in a l Report 3-19-55 -Mj sejarq.jed uoiH'W: "f18 3 MTC 013959  5 Ih .3 O2P tr f0fH"J"i a HP ScfoSn3J P5>0 5 4> 8) <S 3 3' a> OG0h) VCG'**!| MEOh 3 MSEOH' s p"\ ry s s-, tMW<J CO 73 a p JCfi' `V- p cP rtHt p c 0> <r13* r*i J--l Ij e 'If <*> f-i $> C It OO toH to c? p fl\ Pffi' > 0 -Pi r^j e> -P -JO g3 pH O :q ?' A-> u r;- *K ,-% l i. > ~ ~ , 5. >.] .1*' . ".. \ S| (8 i t: ^C **$ 12 1a 3feids5In|32i?D *|r # X3 JU-J */i;i.) j 1 jy 1 1 I I I .J I j i I ?*0 ig 01 S> ? wt*W S S e^m aiB J CAT'} BftWKiri 06 06 06 0? '*& 06 8*66 66 66 8 6 ' 66*66 096CK) 01IAI Amount o f S ilic a , per co a t o f Ash Amount o f S ilic a , W eight in M illig ra m s 30 L 24 r 28 < 12 h ; Saranac Laboratory lev'llte Institute Final Report 3-19-55 440 __ 1 Silica, par cent of ash ./I -t400 360 320 Weight of' silica;. milligrams 780 240 200 Total Silica Content of Lungs of Guinea Pigs Than Had Iihaled PERLIY2 for 24 Months and then Were Transferred to Normal Air Exp. #1168 160 120 80 -L_ _L 8 12 16 20 Humber of Dnyc in Normal. Air Figure 5 24 MTC 013961 Th- Saranac Laboratory f .11 te Institute Final Report 3-19-55 22 20 . Total Silica Content c;f Lungs of Guinea Pigs Tbs c Inhaled PERLITE for 9 Days and then Vera Transferred 18 to Clean Ai r / 16 14 12 Silica, per cent of Ash Animals removed to clean air after exposure to dust for 9 days 10 Animals exposed to dust for 9 days' 8 6 Weight of Silica, Milligrams 4 \Animals removed to clean air - "ter exposure to dust for 9 days Animals exposed to dust for 9 days 2 Exp-. #1188 0 16 20 24. Duration of Exposure, Days Figure 6 MTC Figure 7 Amount or S ilic a , per cent o f Ash Amount o f S ilic a , V e ig h t In M illig ra m s The Saranac Laboratory " Perlite Institute MTC 013963 Amount o f S ilic a , per cent o f Ash Amount o f S ilic a , Weight in M illigram s i Pile Saranac Laboratory Perlite Institute 110 100 90 80 TO 60 50 40 30 20 10 Figure 8 MTC 013964 .he -Saranac Laboratory Perlite Institute Finel Report 3-19-55 W eight in M illig ra m s 200 Weight of lung &3h end of s.i li <*.r< in aninals with dust only and dust plus infection.. 180 -Period in dust.-- 160 140 L 120 100 80 L 6c L 40 J- /i " n. !i ,/i I! 'I fi h i l /: // /r !i // / / '/ f p f'/ /' // T 1--L /. . // Weight of a It Weight cf silica > /r . 'jI height of allies 20 oL 7 So.lid lines: Perlite * Ri_ sinu-lt-oneeusly Dotted lines: Perlite dust only L- b 10 .Uf. lb ;b in Momiio iigur.-e 9 MTC 013965 The Saranac Laboratory Perlite Institute Final Report 3-19-55 Weight in M illig ra m s 200 Weight of ash minus silica in animals with dust only and dust plus infection 180 160 HO -Period in dust120 j- <--------vleen ai r 100 9-------------------- *"Ash minus silica < 80 Xec .y.. Ash minus silica AO 20 Solid line: Perlite + Rj simultaneously Dotted line: Perlite dust only JL 8 10 12 Time in Months H J____ 16 18 20 !V i tv F b MTC 013966 (: ' Weight of lung ash and of uili&t in animals with infection at- end of 6 months dust. * 200 180 160 140 ^--Period in. dust-- --*-------Clean air ' Saranac Laboratory Perlite Institute Final Report 3-19-55 j l Weight, of ash r; 1.7 f i 120 j j100 SO. l Veight of silica 60 40! 1 ft 20. 0 2 4~"~ 6 3 ~ 1C 12 14 ' "1j6 Tfmo in Months this line for fh fixJ 'U1X lUfi-filica with the line in Che. t B for ath-ainus- in non-infooted animals. Figure 11 18 20 MTC 013967 MTC 013968 W''- vii tto-i EfZ-<. p4 S o< 3Q J> e Sg S3 SB 0, r C! -H O H-pp Ow- c: O p Wj t oa ,r._ o rt-a1 n; "5 Cl' e.1 _.j zr C* CO & -*p* p to B w d o 0 ;r] ; atr--i ^ Cm O -P u .< -H rP 0j p> OO CO CrJD sC rj .3 `j-* c *1 A-i Vt o u O ID T-l Ph *-* o C H O' k c $ <"Mp jj d 4.) g '1 *r4 H c -i p.' A? fr4 ? C-i* r-`? i r** 2' Blig 4 'T' ! o O'- ; o-. TO CO co fi eo t- :h. c~ J -4 i a- co 00 3 cr4v I MtD' ho ta a 4< P aO ao m j* o ju> a.ho T<ai> f*oH S -p os SQ -1 6HfB P8 (0 o <D d c* d c <3 k a \V :; r( t ii : & ^ !*' C*3 S' ,I o! \ X CS O') iHO vCO'"'1i f- >| P Ui is- ).'> '| -31 O J ;C. O \0 tV f~l _____L. o __ \0 -1_. RKL IVE INFLUENCE Qg PERLITE AMD g.,..f2 OM THE COURSE OF A TUBERCULOUS INEECTIOK MTC 013970