Document 2j2j6KmG5OwEYpJ29Jr8KB2Da

Z PLAINTIFF'S I EXHIBIT | Dnm cD i o) -1 TRANSACTIONS of the McINTYRE-SARANAC CONFERENCE t on OCCUPATIONAL CHEST DISEASE \ Edited by G. W. H. Schepers, M.D.. D.Sc. Town Hall, Saranac Lake, N. Y. Feb. 7, 8, and 9, 1955 AMERICAN MEDICAL ASSOCIATION PRESS Chicago 10, Illinois 1955 5 PLAINTIFFS i EXHIBIT f /70V, 0 Acknowledgments (irateful acknowledgment is made to ali the participants who contributed papers <p this Conference. Appreciation is expressed also to: .American Medical Association for cooperation in * printing the Conference transactions Professor Philip Drinker for editorial advice Thomas M. Dnrkan for preparing index Kdward 1.. Gockeier for photography __ Secretarial Staff of the Saranac Laboratory for preparing manuscripts Start of the Saranac Laboratory for preparing Conference halls and exhibits G. \V. H. Schepers, M.D.. D.Sc.. Editor FOREWORD For many years the Saranac laboratory, of Saranac Uike. \\ \.. and the Mclntvre Research Foundation, of Toronto. Canada, have been conducting research along somewhat parallel lines. For the past live years the McIntyre Research Foundation has held its Annual Meeting on Silicosis and Aluminum Therapy in various cities in the United States and Canada, while The Saranac Laboratory. >ince 1934. has sponsored a series of Symposia on Industrial Pulmonary Diseases at Saranac Lake. .These two organizations pooled their knowledge and resources for this conference, and the proceedings are documented in this volume. Saranac Lake, for many years a center for the study and treatment of pulmonary tuberculosis and other chronic chest diseases and. moreover, a world-renowned recreational resort, provided a unique and attractive setting for the confereno. i he sessions, which were very well attended, .attracted more than 250 person.-*-- including visitors from the United States. Canada. South America. France. Fitgland. Scotland, Wales. India, and the Union of South Africa. The pronouncements in respect of occupational chest diseases, which have been emanating from The Saranac Laboratory and more recently frqni the McIntyre Research Foundation, have in the past influenced medical, engineering, and legal thinking in terms of .these diseases. The views expressed at the preceding con ferences have guided management, labor, compensation courts, physicians, engi neers, lawyers, and educators not only in the United States and Canada but in many other countries. It is hoped that the record of this most recent'conference will in equal measure also prove of benefit to those who seek firsthand information and guidance concerning the problem of occupational chest diseases. The prediction that this will be so is strong, because practically every paper presented at the con ference was based on original research. Anthony J. Lanza, M.D.. Conference Chairman Emeritus Professor of Industrial MedicineNew York Universitv-Uellevue Medical Center MclNTYRE-SARANAC CONFERENCE PROGRAM COMMITTEE 1955 A. |. Lanza. M.D............................................................................................ Chairman C. P. McCord, M.D................................................................ ............Acting Cha;sn:;>.n D. A. Irwin, M.D............................................................................................................. j. W. G. Hannon. M.D............................................................ :.................................... T. L. Shipman, M.D......................................................................................................... G. W. H. Schepers, M.D.. D.Sc.................................................. ;............. Organizer L. R. Br.tNN................................................................................... ...................Secretary V \ i Chairman .......... Acting Chairman Organizer Secretary A'> Conference Program Sessions 1. General Chairman: Carey P. McCord, M.D., Consultant in Industrial Medicine. Institute nt Industrial Health. University of Michigan. Ann Arbor. Mich. 2. Aluminum in Control of Silicosis Moderator: William A. Scneyer, M.D., Medical Consultant, International Association of Machinists. Rochester. S'. Y. Discussant: Paul G. Bovard, M.D., Consulting Roentgenologist, Tarcntum. Pa. .v Epidemiology of Silicosis and Occupational Chest Disease Moderator: Thomas L. Shipman, M.D.. Health Division Leader, Los Alamos Scientific Laboratory, Los Alamos, New Mexico Discussant: Philip Drinker, Sc.D., Professor of Industrial Hygiene. Harvard University School of Public Health, Boston. Mass. i. The Evaluation of Experimental Research on Dust Diseases Moderator: Dudley A. InAn. M.D., Medical Director, Aluminum Company of America. Pittsburgh, Pa. Discussant: Norton Nelson, Ph.D., Chairman. Institute of Industrial Medicine. New York Universitv-Bellevue Medical Center. New York. N.^Y. 5. Medico-Legal and Clinical Aspects of Pulmonary Disability Moderator: /ran Salwurin, Q.C., Counsel to Quebec Asbestos Producers Association, Montreal. Quebec Discussant: Warren A. Cook, B.A., Associate Professor, Industrial Health and Hygiene. University of Michigan School of Public Health, Ann Arbor. Mich. o. Experimental and Engineering Aspects of Occupational Chest Diseases Moderator: Angus D. Campbell, Manager, McIntyre Research Foundation. Schumacher. Ontario Epilogue: Carey P. McCord, M.D. '. Conference Banquet Master of Ceremonies : Manfred Bmeditch. Director of Health and Safety, Lead Industries Association, New York, N. Y. Leroy U. Gardner Memorial Address: Paul S. Richards, M.D., Senior Consultant, Memorial Medical Center, Salt Lake City, Utah Personal Impressions of Edward Livingston Trudeau and Edward R. Baldwin: Huyh M. Kinghorn, M.D., Saranac Lake, N. Y. 1 V 2 PLAINTIFF'S 1 EXHIBIT 1 noH.o * Cb) Contents Foreword...................................................................................................... PACE m Program Committee ....................................................................................................................... iv Conference Program ....................................................................................................................... v Prologue Carey P. McCord, M.O., .dim Arbor, Mich......................................................................... 1 The Objectives and Achievements of the McIntyre Research Foundation Francis B. Trudeau, M.D., Saranac Lake, N. F............................................................... 2 The Contribution of the Saranac Laboratory to Research on Chest Diseases E. D. Fox, M.E., Toronto, Canada...................................................................................... 4 Comparative Vascular Pathology of Occupational Chest Diseases G. IF. H: Schepcrs, M.D., D.Sc., Saranac Lake, .V. Y...................................................... 7 The Value oi Lung Biopsy in the Diagnosis of Occupational Pulmonary Diseases H. S. Van Ordstrand, M.D.; Donald B. Efflcr, M.D.; Lawrence J. McCormack, M D.. and John B. Hazard, M.D., Cleveland...................................... ..................'................. . 26 Occupational Chest Diseases in Gold Miners G. If". H. Schepcrs. M.D., D.Sc., Saranac Lake. .V. 1"........................................................ 3.' Accomplishments in the Epidemiologic Study of Silicosis in the United States H. .V. Doyle, B.S.; Victoria M. Trosko, A.B.; IV. M. Gafafer, D.Sc.. and S. E. Miiler, M.D., Washington, D. C.......................................................................................................... 48 Silicosis in Canada N. F. Parkinson, M.E., Toronto, Canada.................... ........................................................ 56 Commentary on References by N. F. Parkinson Concerning the Silicosis Problem in Ontario Andrew R. Riddell, M.B., D.P.H., Toronto, Canada............................................................ 63 Talc Pneumoconiosis Morris Kleinfcld, M.D.; Jacqueline Messite, M.D., and Irving R. Tabershcnv, M.D.', New York ..................................... ........................................................................................... 66 Pneumoconiosis on the Kolar Gold Field, South India Geoffrey E. Ffrc.nch. M.A., M.D., F.R.C.P. (C), Oakville, Out., Canada........................ 73 The Dust Diseases in Great Britain A. I. G. McLaughlin, M.D., F.R.C.P., London.................................................................... 83 Clearance of Radioactive Dust from the Human Lung Roy E. Albert, M.D., Washington, D. C.. and Lawrence C. Arnett, M.D., Brooklyn.... 99 The Antagonistic Biological Action of Quartz and Potassium Carbonate G. W. H. Schepcrs, M.D., D.Sc., and A. B. Detahan: Saranac Lake, N. Y..................... 107 An Experimental Study of the Effects of Rare Metals on \nimal Lungs Anthony B. Delahant, Saranac Lake, N. Y........................................................................... 114 vr nwft 2 PLAINTIFF'S EXHIBIT no^/.o c?) DL /JloLjuJ Effect** of Cdafcined Cjij.p5um I- An Experimental Study on Animal Lungs jn subsequent papers, liffort has been in; G. W. H. SCHEPERS, M.D., D.Sc. T M DURKAN M E to avoid repetition of what has alreadv b< ,, K ,, . ', placed on record by Gardner, and though and , A. B. DELAHANT, Saranac Lake, N. Y. the sake of completeness and logic refere: has to be made to such matter, most of !l material now presented will appear for ; first time, and the interpretation of expe ................. ... mental records and slides are our own. Studies dealing with the biological effects of calcined gypsum dust on experimental animals were initiated at The Saranac Labo- materials ratory during 1933 by the late Leroy L. ua$ the staildard product o: ,.aster miIls a Gardner, M.D.. Director. Although the in- vestigations were pursued over many subse- quent years, only partial accounts of the results have been'published thus far.* Carn*ed, a,long ,by th, e. momentum ocf a- succession of studies of increasing importance, Dr. Gardner had to divide his time among manv ,.. , , investigations, and his ambitiously planned being a commercial material, d somewhat composition from time to time. Hie following proximate estimate of composition and particle-s ranse refers t0 llK Troduct received during : et.oarrwlyarpdaerdt olaf tt>ehre teh, xepepreimr ecnetnatl ostf,udh, ieems;ihfvodr, ramteatewr higher and of calche. lower: Approximate Particle size monograph on The Saranac Laboratory ex- Per Range, Avers penments with calcined gypsum dust re- Hen,it.ydr.e o.so.-u u,o.. mained unwritten.' Anhydrite Cuso. ................. Caicite CaCOi ..................... In the present paper the results of a com- "Dead-burned gypsum'* ........ preh. ensive series of long-term inhalation ex- QMugaCr'Ot2i iSi0' ...................... periments, with the conduct of which two Fe.o. j.............................. of us (T. M. D. and A. B. Dv) were inti- "Caicim-d gypsum" .............. ;o i 13 3 <' > 100 i-ts i--to 1--20 1--30 s < 9 3 .................. ...... 1--to s mately concerned, will be recorded. Owing to the broad range of the experimental pro- gram, the paper must necessarily be limited to the presentation of an over-all survey of , . ... ' the investigations. More detailed treatment of individual histological aspects will be given The quartz was a commercial product supplied as finely ground powder with an SiO content whir exceeded 99%. The tubercle bacilli used for tl in,e';,ion puhase of the s,u^' wcreL of the R` lov virulence human strain whose tuberculogenic pn ^sities and cultural characteristics have be. well documented.t Recorded for publication July 15, 11>55. SCOPE OK EXPERIMENTS Director (Dr. Schepers), Associate Director The present report will deal with the re ( Mr. Durkan), and Research Associate (Mr. Dein-_Sults obtained in inhalation experiments i hant), The Saranac Laboratory. _______ * References 1 to 4. t References 5 and 6. j-'4 -v^' I'.lfort Ikis been made what lias already been miner, and though for s and logic reference i matter, most of the i will appear tor the .erpretation of experiides are our own. . ;:.ied in the experiments ct of plaster mills and, rial, varied somewhat in time. The following apnposition and particle-size luct received during the utal studies ; for material ent of hemihydrate was r: Approximate Particle Size Per Cent TO I(> 15 3 <i Range, * 1-75 1--40 1--20 1--30 Average, M 5 4 9 S 100 1--40 5 cial product supplied as a V.. h an SiOj content which i rcle bacilli used for the :dy were of the Ri low-. . hose tubcrculogenic prolaractcristics have been PKKI.VENTS ; till deal with the re- .T iation experiments in A" ] '\ niui.ocic.ii. liiTiicr or c.u.cixrn cvrsiru ntw which guinea pigs were exposed to dust mirier various environmental conditions, as I'nllows: Calcined gypsum dust for 24 months. Calcined gypsum dust for 24 months and tlu-n normal air for 22 months. Calcined gypsum dust for 24 mouth.-, and then quartz dust for IS months. Mnartz dust (comparison) for 18 months. Calcined gypsum dust for three weeks and then, alternately, quartz dust for one week and calcined gypsum dust for the next week, with a continuation of this program of alternating weekly exposures for 24 months. Mixed dust composed of equal parts of calcined gypsum dust and quartz dust for 25 months. Mixed dust composed of equal parts oi calcined gypsum dust and quartz dust for 25 months and then normal air for 12 months. Mixed dust composed of two parts of calcined gypsum dust and one part of quartz dust for 29 months. Calcined gypsum dust for 6 months, then infec tion with Ri tubercle bacilli, and then calcined gypsum dust tor 18 months more. Calcined gypsum dust for 25 months, then infec tion with R, tubercle bacilli, and then normal air for 12 months. Mixed dust conqioscd of equal parts of calcined gypsum dust and quartz dust for 3 months, then infection with R, tubercle bacilli, and then the mixed (lust tor 27 months more. Infection control Ri tubercle bacilli for 22 months. EX HER I MENTAL TECH NIQUES The inhalation experiments were conducted in s ft. cubical rooms. The animals, kept in cages along the sides of the room, were exposed to the aerosol tor eight hours a day, five and one-half days a week. During such periods a rotating paddle device created and maintained in the room an atmospheric sus|>cn.sion of the dust under study. For the rest of the time the air in the room was free of any substantial amount of dust. Periodically, in most cases at intervals of a few months, animals were killed for study, so that the progression oi any tissue reaction to the dust or to any infection given to the animals could he closely followed. Chemical analyses to estimate the amount of dust retained in the lungs were carried out on some animals. During each experiment the dust concentration -was checked frequently by the impinger method. Infection by the R, strain of tubercle bacilli was achieved hv means of the intratracheal insufflation technique, perfected in The Saranac Laboratory.' Kacli animal received 6 puffs of the atomizer from a suspension of R, tubercle bacilli containing 15 to 20 single organisms p.er, oil-immersion field. 1. KXI'OSl.'KE T<> l.AUTNKl) (iYI'SI.-M Dt.'ST At.ONE The results of this experiment on 21 nor mal uninfected guinea pigs have been sum marized in Fable I. The guinea pigs were exposed to duly'calcined gypsum dust, loir the entire exposure period the average dust concentration was 448.000.000 particles per cubic foot of air. The guinea pigs were ex posed to the dust for periods up to 24 months, animals being sampled at various intervals. At the end of 24 months the sur viving animals were removed from dust and transferred to a normal atmosphere .to con stitute the second part of this experiment. Some of this group lived as long as 22 months after the termination of the dust ex posure. and samples were taken at 3-month intervals during this period. Twelve of the twenty-one guinea pigs died of pneumonia or other pulmonary leste This mortality trend was widely disper ; over the whole experimental period. LVau.s were slightly commoner in the earlier months hut perhaps not significantly so. It wotdd seem that the death rate or 28.5% per annum was slightly high. The mortality trend in guinea pigs in one of The Saranac Labo ratory experiments with a comparatively inert amorphous silicate dust was about 22% per annum. The fact, however, that all deaths in the experiment with calcined gypsum were from respiratory causes may he meaningful. In spite of these observations no signifi cant gross signs of pulmonary disease mani fested themselves."and no nodular or diffuse pneumoconiosis ensued. In isolated ani mals pigmentation commenced to appear toward the end of 10 months, and minute foci of atelectasis could be seen. After a year of dust exposure a minimal amount of pigmentation became ati almost constant sign, and atelectasis was more frequently observe;' The microscopic counterparts of these features will be described in further ' i -p- ''i r * -JV, Guinea Pip, No. VJ'23 50 53 32 SI Si 49 63 44 42 70 43 61 46 47 93 55 76 43 54 46 Exposure to Dust, Days 54 69 >*< 263 2S4 285 290 300 312 373 374 426 473 610 610 667 688 715 725 732 732 Fate Died Died Killed Died Died Died Killed Died Died Killed Died Killed Died Killed Killed Killed Died Died Died Killed Killed Cause of Death Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pleurisy Pulmonary abscess Pneumonia Pnetimooia Tissue Reaction io Liing* Pulmonury Lymph Nodes Furul Pig- Focal Pig ment titiou A telnet usis mentation Eolarged Nodes +. - + + + f + -r + + 4- + + + + + f ++ ++ + -r .. -- ++ ++ -H-+ + -H- Symbols: -K slight- reaction; +-r, moderate reaction; r udvunwd reaction. detail later, but in summary it may be stated that although a diffuse cellular reaction ulti mately ensued no fibrosis attended this process. The lymph nodes showed irregular en largement of a moderate degree, character ized by growth of the follicles more particu larly. Only rarely could pigmentation be seen. There were no signs of degeneration, necrosis, or fibrosis. Ten guinea pigs were left in normal u:T for periods up to 22 months after they' hac been exposed for 24 months in the calcined gypsum dust chamber. Only four of the animals died naturally, and in only two of them was pneumonia the cause (Table 2). Pigmentation persisted in the majority, but atelectasis soon disappeared though diffuse cellular proliferation could still be seen. In the lymph nodes a low-grade" chronic inflam- Table 2.--Biological Action of Calcined Gypsum Dust Guinea Pigs Were Continuously Exposed by Inhalation to the Dust for Twenty-Four Months and Then Were Transferred to Normal Air Where They Remained Until Death Guinea Pig, Xo. 553-54 46 51 59 86 77 96 78 79 80 Exposure to Dust, Days OO *m 34 44 46 47 588 666 666 666 Fate Killed Killed Died Died Died Died Killed Killed Killed Killed Cause of Death (?) (?) Pneumonia Pneumonia fissue Reunion In Lungs Focal Pigmentation Atelectnsis Pulmonary Lymph Nodes ___________ /N- Focal Pig- Enlarged mentation Nodes T + ++ + + -H- +. . + 4- ,. - ++ ivf + ++ 326 7.PHRS ET AL Death ion. In monary Lymph Nodes Enlr*j Nodes -H- t in normal air ~ after they had ; in the calcined :ly four of the in only two of utse (Table 2). le majority, but though diffuse still be seen. In : chronic inflam- -Four Months 1 Death oa fa nonury Lymph Nod** csl PI*- Enlarged station Nodes ItlOf.OGICAl. EEEIiCT <>!' CAI.CIXED GVI'SCM l.'UST matmv reaction developed during the lirat uvo months the animals were in normal air. hut during subsequent months this sign re cede'I- -Similar observations have, on occa sion, been made on adult guinea pigs never intentionally exposed to dust. Until the pre cise and specific underlying histopathologic mechanism is appreciated in the case of the gvpsum-exposed guinea pigs, the significance of the occurrence of these lymph node changes may be missed. The results of this study are given in Table ,1. It will be observed that only four of the animals died`spontaneously.. I bis rate of 23% for an 18-month period is actually lower than the average mortality trend of 21% per annum in our dusting experiments with an inert amorphous silicate. This virtu ally suggests that the gypsum exerts some measure of protection against the action of quartz, ft must be recalled, though, that these animals represented the hardiest spcci- Tabi.e 3.--Combined llioloaicnl Action oj Calcined Gypsum Dust anil Quart: Dust Guinea Pigs Were Exposed by Inhalation to Calcined Gypsum Dust for Twenty-Four Months and Thereafter to Quartz Dust Until Death Sur vival fa Guinea Quartz Pig. Dust. No. Days Fate 063-00 3* Died 51 63 Killed 52 G3 Killed 06 123 Killed 07 123 Killed 65 134 Died 02 134 oa 210 Killed Killed 70 2 tO Killed 67 sin Died Hi 3CC Killed 6S :>66 Killed 09 30G Killed 71 42S Killed ____ 423 Killed 73 4S7 Died 74 053 Killed Cause of Death ? Pneumooia Pneumonia Microscopic Evidence o PneumoronioHs ftcuctiou in Pulmonary Lymph odes Pigmen tation ' + 4" *i--4 + 4~r f* T-r-r ~4~r -r* -r- --4r-r ---i_ T -t. Atelec tasis T -r. -- -r 4- - Cellulur Degeneration Enlarge Pigmen (ration Fibrottc Necrotir ment tatioo - 4* T 4- -4 4" 4* 4-4-r-r ' 4--r 4-4- -r 4-4- 4*4-4- 4-4r-r 4-4* 4-4++ 4-4- r-r r ------L rr --r -- -r-*- 4++ 4--1-- r-r Degeneration Hynline Necrotic 4*4--r -r 4-4+ 4- Symbols: 4- slight reaction: 4*4-. moderate reaction ; 4-4-4-. advanced rcnctioa. EXPOSURE TO CALCINED UYFSU-M OUST FOR TWENTY-FOLK MONTHS FOLLOWED BY PRO- I.ONUEI) EXPOSURE TO OUAKTZ DUST In order to determine whether a prolonged period of exposure to calcined gypsum dust would modify the usual harmful effects of any quartz dust which might be inhaled later, an inhalation experiment to investigate this question was conducted. A group of 17 guinea pigs, after being exposed to a calcined gypsum aerosol for 24 months, was trans ferred to another room in which they in haled a quartz aerosol for periods up to 18 months. The average value for the numher~of particles per cubic foot of air was 445.000.000 for the calcined gypsum dust and 120.000.000 for the quartz dust. mens that survived the two years of gypsum exposure, and so protection may be only illusory. 'That the gypsum does have a protective influence, however, is revealed by a study of the pulmonary tissue reaction. While pigmentation increased progressively, even tually attaining a geometric pattern and finally producing mustard-colored patches, it. nevertheless, was not as extreme as the pig mentation which occurs in animals exposed to quartz dust only. Atelectasis was present in animals in the earlier phases of the quartz-dusting period and disappeared toward the end of the ex periment. 1 :u- atelectasis thus may have been a perpetuation of that seen in the later 327 ) PLAINTIFFS EXHIBIT 7 lO^L o _ SCHEPERS ET AL. phases ot tlic experiment with calcined gyp sum dust alone. Consolidation, dominantly cellular in type, appeared toward the latter part of the quartz dusting phase. From about 10 months on ward. areas of cellular inliltration could be found. Strands of fibrous tissue appeared among these areas toward tbe rod of the 12th month. Except in the guinea pig killed last of till, this fibrosis remained moderate in degree throughout the period of study. In this animal and in that one preceding it in the series, some abscess formation could be changes and necrosis appeared, first-toward the eighth .month- and became increasingly more prevalent later. Associated with these parenchymal pul monary changes there was a marked catar rhal bronchiolitis . in the quartz-exposed animals which was not seen in those which had first been exposed to calcined gypsum dust. The lymph nodes likewise showed a considerably enhanced and early expansion in the silicotic control guinea pigs, with progressive fibrosis and ultimate hyaiinization. Table 4.--Uinlotiical .Utiou a; Quart: Dust Control Study : Uninfected Guinea Pigs Exposed In Inhalation to Quartz Dust Alone Until Death Gross Evidence ot Silicosis .Microscopic Evidence of Silicosis Guinea Pt*. Xo. 602-14 :t 2 4 <> t> 5 22 Expo sure, Pigmen Days Fate tation 63 K 123 K 1st K 24.0 K ;y* K -t- j-r 306 K 123 K *.r3 K -rr-- -r-r -T + Pleural Adhe sions -r Cellular Degeneration Pleural Uronchio- Inrtl- Plaques lii i> (ration Fibrous Hyaline Necrotic -J- 4- -T ----f- T 7T --v - - t- -r --- -- -i. 4- *r T-r-f- ------- vr -r**- + T- ' r-4-r J-tt -------- -vr+ Tissue Reaction In Pulmonary Lymph Node ------ '---------------------> Macro phage Degeneration Inm(ration Fibrous Hyalfoe + + ++T -r-H- 4.4- 4--*- ft . ~r *f -}--r fr-H-r+-r .. --- -H-+ Symbols: -f*. flight reuctiou; moderate reaction; rr-*r. advanced reaction. seen. Necrosis was. however, conspicuous This comparison suggests that the prior by its absence in earlier phases. Xo hyaline inhalation of calcined gypsum dust not only changes occurred in tbe lungs. retards the onset of the major ellects of The pulmonary lymph nodes showed inhaled quartz dust by at least six months moderate enlargement only, with no tendency hut also materially diminishes the degree to increase in size toward the end of the to which they evolve and modifies the nature experiment. Pigmentation remained minimal, of the reaction to the quartz dust. . hut some hyaline fibrosis occurred toward the 14th month and in some instances was-, preceded by isolated areas of necrosis. J. ALTER.VATIN(J WEEKLY EXPOSURE TO QUARTZ OUST AND TO CALCINED GYPSUM DUST These changes are the more sharply shown In the preceding study the guinea pigs to be indicative of the protective action of inhaled calcined gypsum dust alone for a the gypsum when Tables 3 and 4 are com long period and then quartz dust alone dur pared. In the hitter table, representing the ing the remaining time they resided in the control group exposed to quartz dust only, dust chamber. .Some of the protective action cellular infiltrates are recorded as having of gypsum against quartz could, in theory appeared within two months and were quite perhaps, he explained on the basis of selec marked by the eighth month. Fibrosis could tion. for it must he recalled that quartz dust he discerned within 4 months, and it in ing was iimeiieed only after 24 months creased progressively, reaching a marked of residence" in an environment containing degree toward the 10th month. Hyaline calcined gypsum dust in atmospheric suspen- 328 r.RS F.T AL 1 first toward w increasingly enchymal pulmarked catarliiartz-exposed m those which icined gypsum vise showed a irly expansion ea pigs, with imnte hyalini- JSt -ue Keactloo la nary Lymph Node --s Degeneration Fibrous Hyaline -4 -r-t +--+i- hat the prior dust not only iur effects of 't six months > the degree ries the nature ;st. i'OSCKK TO i.CIXF.D guiiiea pigs alone ior a i;t alone dur'esided in the tective action dd. in theory lasis of sflect quartz dustr 24 months nt containing lieric stispen- IIIOJ.I >G 1CA L EFFECT OF CALCIXF.D GYPSUM DUST sion. and alter the weaker guinea pigs had died off. A group of 10 guinea pigs was therefore exposed to calcined gypsum dust for three weeks and thereafter alternately to quartz dust for one week and to calcined gypsum dust for the next week. During each weekly period the animals were exposed to the dust for about 8 hours per day for five days and about 4 hours on the sixth day. or a total of 44 hours per week. This alternating weekly routine was kept up for two years. the second year of exposure. The pulmonary lymph nodes likewise showed the same pat tern of reaction as that-which occurs in the silicotic guinea pig. Unfortunately, animals were not killed prior to the eighth month ; hence it is possible that a measure of early protection was ex erted by the gypsum. The degree of reaction seen in the animal accidentally killed after three months was, however, less than that found in the quartz-exposed animal at two months, and at the eighth month the animal Table 5.--Combined Biological Action of Calcined Gypsum Dust and Quartz Dust Guinea Pigs Were Exposed by Inhalation to Calcined Gypsum Dust tor Three Weeks and Thereafter Were Exposed Alternately to Calcined Gypsum Dust and to Quartz Dust for a Week at a Time Until Death Expo- sure jiiioeu to Pi*, Dust. No. Days Futc ia3-l3 IK D s 2ti4 K 378 K 14 3*1 D 12 :t>*> D M :n L> 'J D T 403 --10 . 42G \0 7.32 K K K Cause ot Death Trauma Chronic pneumonia Chronic pneuinouiu Chronic pneumonia Chronic pleurisy Microscopic E-v-i-d-e--n-ce- of Pneumoconiosis / Cellular Mronchi- ,-----I-n-f-i-lt-rfation r Deg--en*e--ration Hya Ne* otitis Focal Diffuse Fibrous line orotic 4- ++ +++ ++ ++T + -*- T + .. .. -44- Reaction in Pulmonary --------------L-y--m--p-h Nodes --s Degeneration Cellular----------- ^ inril- Nfr tratioo Fibrous Hyaline erotic ++ . -r-r .44- + -i-H-4-4 - -- --r-- --r -r-t- -r+-r +++ r -4-.4. TT ++ -r-1* --r-r -`r-r-r -4--- -- -- r+ -4 _ f+T ----- -- ----p t--r r-r-r, -r-r-*- +-*-+ H----r -r-r-r -r-r-r +T + -r-r-r -r + ++ -i-r r-r Symbols: -r. slight rcuction; 4--{-, moderate reaction: -- . ;nlvunov*l reaction: -{--r-r-r, very marked reaction. During this period the average concentration of the calcined gypsum dust was. about 445.000. 000 and of the quartz dust about 128.000. 000 particles per cubic foot of air. The results of the experiment are summa rized in Table 5. Four of the ten animals died of pulmonarv causes toward the end of the first year, and the close grouping of these deaths suggests an intercurrent infection. The total pulmo nary reaction was not unlike that seen in the animals exposed to quartz only ( Table 4). Marked bronchiolitis was a prominent feature near the end of the first 12 months. Ueliular infiltrates appeared fncallv and dif fusely, and degenerative changes followed rapidly and reached a marked degree during from the latter group showed a considerably greater degree of pulmonary and hilar node reaction than that observed in animals ex posed to calcined gypsum dust for a com parable period. .The point which has not been settled by ibis study is whether this slight retardation ot the pneumoconiotic response was due to the fact that the animals received a total dust load about half as great as that which the animals inhaled in the control experi ment with quartz dust only. My comparison with the preceding experiment it would >eem too that anv inhibitory action which the gypsum ir.av possess is not so much dependent on the concurrent presence of the gypsum and quartz in the lung tissue .129 Jfr. ) PLAINTIFFS EXHIBIT > lo'-j. o C/3) as mi. the biological responses . induced by tile gypsum. .1. KXI'i ISCKK TO A MIXTUKKOI' hOC AL I'ARTS ill- lAl.l'IXEI) CYPSU.M ntiST AND ni'AKTZ DUST Another aspect of.the possible protective action of calcined gypsum dr..-: was investi gated in an experiment conducted with a mixture of equal parts (by volume) of calcined gypsum dust and quartz dust. A group of 35 guinea pigs was exposed to this mixed dust for periods up to 24 months, and at the end of that time 15 surviving animals were transferred to a normal atmosphere where they lived for periods up to 7 months. The average dust concentration of the mixed dust during the experiment was 318,000,000 particles per cubic foot of air, and the aver age concentration of the quartz particles in the mixture, determined by using dilute acid as a collecting ` fluid in the impinger flasks, was estimated to be about 124.000,000. Although the material in the dusting machine was composed of approximately equal parts of quartz and calcined gypsum, that ratio was somewhat different for the aerosol derived from the mixture. Table 6 shows that the amount of quartz was less and the amount of gypsum greater in the atmospheric dust than in the parent mixture from which the aerosol was derived. For dust that had settled on top of the animal cages, the situation was reversed, and for this settled material the quartz content was higher and the gypsum content lower. This Table 6.--Composition of Aerosol ami of Settled Dust in Comparison with Parent Hopper Mixture Which Was Composed of Equal Volumes of Calcined Gypsum Dust " and Quarts Dust All Samples Were Dried at 110 C Before Analysis Component SiO j ........................... CaSO* ....................... CaCOs l MgCOi j FezOs, AliOi ......... Ignition lo** ......... Torn!................... Hopper Mixture. Per Cent 3.r 0.9 100.0 Settled Aerosol Dust on Top Inside of Cages. Cages, Per Cent Per Cent 53.7 2S.3 37.5 59.4 3.2 2.7 0.9 0.S 5.2 9.4 100.5 100.6 condition was probably due. in part to the larger average size.- and therefore morerapid settling rate, of the quartz particles The results derived from this study summarized in Table 7. Once again it wa$ found that more than one-half i in this study 55$-) of the animals died of pulmonary causes, the majority of these succumbing within the earlier phase of the experiment-In spite of this, there was very little evidence of a pneumoconiotic response before about tbe 15th month. From that stage on the total reaction was that of a dominantly cellular dif* fuse reaction. Atelectasis was a conspicuous feature in one instance, and bronchiolitis oc curred in two later cases. But lioth fibrosis and necrosis were in abeyance until about the 19th month of exposure and even then re mained limited in their extent or intensity. The pulmonary lymph nodes likewise showed but minimal reaction. Though thev exhibited a uniform tendency toward mod erate enlargement, degenerative changes, such as fibrosis, hyalinization, and necr -::. en sued in but a few cases and to a minimal de gree only. The concurrent ex(>osure to gypsum and quartz, therefore, appeared to have retarded and modified the influence of the quartz on the guinea pig lung. When the 15 surviving animals were re stored to normal air after a full 24-month period of residence in the gypsum quartz dust, environment, the high rate of pulmonary deaths continued ( Table 8). Over the nearly eight-month period of survival, SZ'fo of the animals died of pulmonary causes. At the time of their death, the majority suffered from a chronic pneumonia which was partly based on the diffuse cellular quartz-induced infiltrates in the pulmonary parenchyma. At the same time there was a very marked type of fibrodc response, with hyaline changes in some instances. Unlike in the frankly silicotic cases, however, there was but little tendency toward necrosis, though a dust-engendered abscess was found in at least one instance toward the end he experiment. The pulmonary lymph node- were moderately enlarged and the seal 330 arws et Auf. in part to the therefore more aartz particles. i this study are ;.' nee again it was.W ilt (in this study fl of pulmonary T lese succumbing T the experiment. V rv little evidence ise before about tnge on the total rmtly cellular difis a conspicuous bronchiolitis oc- :t both fibrosis until about the ; even then ret or intensity, nodes likewise n. Though they -v toward modve changes, such ul necrosis, en'.<> a minimal de- to gypsum and . o have retarded >f the quartz on nimals were ret full 24-month sum quartz dust of pulmonary Over the nearly al. 53% of the lses. At the time suffered from a partly based on luced infiltrates a. At the same type of fibrotic mges in some y silicotic cases, indency toward ndered abscess mce toward the lnumary lymph ed and the seat khu.ogical ni-rucr nr cai.ci\i:d gvdsch dust PLAINTIFFS EXHIBIT / 704.0. Table 7.--Combined Biological Action of Calcined (iypsnm Dust and Quartz Dust Guinea Pigs Continuously Exposed by Inhalation Until Death to an Aerosol Derived from ii Mixture of Calcined Gypsum Dust and Quartz Dust in Equal Proportions Expo* sure < tiiincu to Pig, Dust. No. Days Furc 560-23 9 Died 31 20 Died 49 187 Died Jti 223 Died 33 229 Died 27 282 Killed 56 442 Died 24 451 Died 25 465 Killed 28 465 Killed 30 4GS Died 43 487 Died 39 493 Killed 47 494 Died 3*2 496 Died 44 51S - Killed 54 543 . Killed 29 374 Killed 35 G90 Killed 22 728 Killed Cuuse of Death Pneuinooiu Pneumonia Pneumonia ? Pneumonia Empyema Pneumouia .... .. Pneutnooia Empyema Empyema Empyema ..... Keactioo In PulmoDarr Microscopic Evidence of Pneumoconiosis Lymph Nodes /------- :----- ;------------- ''--------------------------- ----------------- 'v------------ Cellular Degeneration Macro- Degeneration Infiltration s --^ phage Bronchi A telec- .- Ne Infll- Hya Ne oli r is tnsis Eocai Diffuse Fibrous crotic trntiou Fibrous line crotic ++ + ++ 4- 4--U 4-4- 4-4-4+ 4- 4- 4.4. -T~r " ^ -r-+-r -r -H- 4-4- 4-4- -H- -i--r+ ++ + 4 ++ 4+ -r-r-r - -*-44 4--" + -r-r-r 4 + 4-+-I- -4 .. * ++ H--r 4 -1-+ ++ + + 44 .. 4_4_ 4-4- ++ + 4-4--r i--l--i- 4- 4- 44 ++ -r-r-r 4-4-4- + 4--4 ++ Symbols: -K slight reaction; +-K moderate reaction; 4*4~f, advanced reaction. of moderate to marked diffuse hyalinization in the majority of cases. It would seem, therefore, that the concur rent inhalation of the calcined gypsum and quartz dust, though retarding the mitigating effects of the latter as long as exposure actively continued, ultimately leaves the It;:: tissue diffusely vulnerable to the effects of the quartz dust. Apparently after the exposed animals have resided for a [>erio<l in normal Table 8.--Combined Biological Action of Calcined Gypsum Dust and Quartz Dust Guinea Pigs Were Exposed by Inhalation for Twenty-Four Months to an Aerosol Derived from a Mixture of Calcined Gypsum Dust and Quartz Dust in Equal Parts and Were Thereafter Kept in Normal Air Until Death Sur vival HAafdteorf Dust Guinea Expo- Pig, sure. No. Days Fute 560-36 53 33 Killed 33 Killed 41 48 Died 29 61 Killed 40 73 Died 18 76 Died - 105 Died 37 114 Died 38 118 Died 45 119 Died 42 120 Killed 36 132 Killed _ *6 132 Killed 34 219 Died 60 227 Killed Microscopic Evidence of Pneumoconiosis Reaction in Pulmonary Lymph Nodes Cause of Death Pneumoniu Pleurisy Pneumonia Pneumonia Pulmonary abscess Pneumooia Pneumonia Pneumonia Puhnonary A telec- Abscess tr.sis 4- 4- Cellular lurtltrutioo Focal 4- . +T -i~H4-4-4* 44-4* Diffu>- 4-44-4- 4-4*4- T-r -- 4-4--*44*-r ++ 4- 4- + -L +-H++-r 4-4--r _4 T-r Degeneration Degeneration Fibrous + 4-4++ 4--h-i- 4*4-4+-r +++ Hya Ne line crosis + + ~4 ++ ++ -H- Enlarge Ne ment Hyaline crotic .. ++ 4-4r+ 4-44-4- . 4-4- ++ + ++ ++ +4- -r+ ++-r +++ .. 4-4-44- ++- +-r ++ -- ++ + ++ ++ ++ ++ 4-4- ++ ++-r -+++ +++ ++ + Symbols: slight reaction; 4-4-, moderate reactioo; 4-4-4-. advance 331 I . ' vfy' air, the protective action of the gypsum is mals that died of natural causes, distinct pig. withdrawn and the quartz particles then exert mentation had .developed, and.bronchiolitis of their- usual harmful effect. The quartz and . a moderate degree was in evidence. The latter gypsum also appear to have been carried to condition may have been linked with the the lymph nodes at a differential rate which pneumonic process, as bronchiolitis was less favored the hvalinizing action of the quartz common and less marked in those animals, at these sites. which were killed for sampling (Table 11). 5. F.XFOSURE TO A MIXTURE OF TWO FARTS OK CALCINED C.YFSUM DUST AND ONE FART OF QUARTZ DUST Focal cellular proliferation due to dust could be discerned from about the 10th month onward, and diffuse cellular infiltrations com Since the experiment with a mixture of menced to appear after the 14th month. How equal parts of quartz dust and calcined gyp ever, except in isolated cases, collagen deposi sum dust gave definite evidence of an early- tion. hyalinization. and necrosis rarely were protective action of the gypsum, the observa observed. Such degenerative changes were tions were checked by conducting another ex slightly commoner and more advanced in periment in which a mixture of 2 parts (by- those animals that had died of pneumonia. volume) of the gypsum to 1 part of the The hilar lymph nodes likewise underwent quartz was used. It was found that on a enlargement, mainly from cellular prolifera weight basis the ratio was closer to 2l/>: 1. tion, with but moderate and considerably de In the experiment with the 2: 1 mixture, 64 layed fibrous changes and necrosis in isolated guinea pigs were exposed for periods up to instances only. 29 months, and the average dust concentra tion was 245,000.000 particles per cubic foot of air. As in the preceding experiment, the actual aerosol in the animal cages differed in composition from the hopper mixture, the ratio of calcined gypsum to quartz in the aerosol being approximately 3:1 (Table 9). It appears then that when the amount of quartz dust to which the animals were posed simultaneously with the calcined g ^ sum dust was reduced to about one-third level introduced in the preceding experiment the tibrogeiiic and necrotizing influences of the quartz dust were materially inhibited Table 9.--Composition of Aerosol and of Settled Dust in Comparison with Parent Hopper Mixture Composed of Two -Volumes of Calcined Gypsum Dust and Otic Vol ume of Quartz Dust All Samples Were Dried at 100 C Before Analysis despite prolonged exposure1. Perhaps degen erative changes might have ensued, as in the previous experiment, had the dusting been discontinued. To show that the animals had actuallytrapped quartz dust in their pulmonary tis sues. the lungs of guinea pigs exposed to dust Component? Sil>j ............................. . CaSO. ........................... CaCOj t MgCOj ) ...................... FesOi. AljOj ............. Ignition loss ........... Total...................... Hopper Mixture. Per Cent 31.4 U2.4 _ 5,'.' 0.3 ti. 90.7 Settle** Dust on Top of Cages Per Cent 33.4 53.2 5.6 0.7 3.1 100.0 Aerosol Inside Capes. Per Cent 17.7 54.1 8.7 0.9 18.8 100.2 of the gypsum-quartz mixture and to quartz dust alone were analyzed for their silica content. The results obtained for the gyp. sum-quartz-exposed animals are contrasted with the findings for-the quartz control series t Table 12). It will be observed that, although considerably less dust was retained in the lungs of the gypsum-quartz animals than was trapped in the tissues of the control animals, Of the 64 guinea pigs, 42% died of respi sufficient quartz accumulated in the lungs f ratory disease, in most cases of chronic pneu have had some fibrogenic influence. It should monia. These deaths were, however, evenly be noted, however, that at the 24th month distributed over the full 29-month period and there was but little more quartz in the lung may therefore be of reduced statistical sig ash of the animals exposed to the mixed dust nificance (Table 10). In the majority of ani- than there was at X months. At the 22-month .1.12 il-PLKS HT .ML luses, distinct pig., nd bronchiolitis oi vidence. The latter linked with the uchiolitis was less in those animals ing (Table 11). ::on due to dust ut the 10th month infiltrations comi4th month. Hows. collagen deposirosis rarely were e changes were re advanced in I f pneumonia, wise underwent rilular proliferaconsiderably deicrosis in isolated n the amount oi nimals were ex he calcined gyp)ut one-third the ding experiment ng influences of erially inhibited Perhaps degennsued. as in the he dusting been Is had actually pulmonary tis- ; exposed to dust e and to quartz j for their silica | d for the gyp- j are contrasted j :z control series I -.1 that, although ! etained in the :imals than was ontroi animals, in the lungs n ence. It should le 24th month rtz in the lung the mixed dust i the 22-month 1 innf.Oi.IC.li. T <>l: C.II.CIMil) Ci l'SIM IH'ST Taiii.u 10.--Combined Biolmjical Aitiuri oi LaUincd (iyfsum Dust and Quarts Dust. Guinea I'iijs Were Exposed by Inhalation to an Aerosol Derived front a Mixture of Two Volumes of Calcined Gypsum Dust and fine Volume of Quartz Dust; Exposure Was Continuous Until Death tabulation of Animals Which Died of Pneumonia or Other Natural Cause During Course oi Exposure iuineit PiK, No. Expo sureto Dust. Days Cause of Death '.si ji; K*; ;,7 . 147 Pnieumouiu PnntmoniA Tuberculosis 47 t 'hronic pneumonia 2$9, Chronic .pneumonia 2S 37ii Chronic pneumonia o9 :lril Chronic pneumoniu ( 299 Chrome pneumonia :<9 4OS Chronic pneumonia V* 409 Chronic pneumonia . :t*. 411 Chronic pneumonia : 412 Chronic pneumonia :.l 414 Chronicpneumonia 41;* Chronic pneumonia 1*2 417 Chronic pneumonia Jf 4t7 t 'hronic pneumonie 19 420 Chronic pneumonia - 41 120 Chronic pneumonia :*i 423 Chronic pneumooin IS 129 Chronic pneumonia rtl i;fy Chronic pneumonia tif* 4:t! Abscess 24 1.V2 Chronic pneumonia 49 4l!S Abscess 21 4*7 Abscess IS fI3 Chronic pneumonin :4 fi.il Chronic pneumonia S62 / Piemen tation Microscopic Evidence of Pneumoconiosis Itronchinlili* Cellular Infiltration Degeneration .------------'------------^ .----------------v-----------------\ weler- Dll- Ilya- Ne- tads Focal' fU6e Fibrous line erotic Reaction In Pulmonary . Lymph Nodes Degeneration: Enlarge- Hya-- Ne- mcni Fibrous line erotic y + T -r -- *--r *r -- T' T -- T - ---- ---- ---- V---- TT --- -1-- ' -- T- +-- U--1- ----- " -t--- ---- --r -- r-r -r-r - . x_i. 4-- ---- X-- -f-r XX -t-t* -*.x ++ -r +++ XXX Jr-r -- T- + -r -r -- -T -r -r - T +. r T T *r - + -!-+ -E+ ++ XX ++ + -r T ++ + -r-r r-r -4- ++ + + -r + + + -T -r TTT X ' 't^ -h-r-r + ++ 4_u -r-r -f4-- - ++ ++ . .. X .+ TX X+ +++ -H-E +-H- -r+-r ++ j_u_ -r-r + -T -r- XX -r-r -r-- +-r ++ X -r -r-r XX XX -r- ' .. r + ++ ++ -f--r -H- -r -r + + Symbols: x . slight reaction:: -r+. moderate reaction: _xx. mlvanctal rc action. period the animals which had breathed quartz dust only had nearly three times as much SiOj in their lung ash as had the animals exposed to the mixed gypsum and quartz dust for the same period. We may, therefore, nut he dealing after all with any specific inhibiting action against the effect of quartz dust on tissue hut merely with a reduction or dilution of the quartz component. i.. EXPOSURE Til CALCINED i.YFSUM DUST. THEN INFECTION WITH TUBERCLE BACILLI. AND EITHER CONTINUATION OF THE DUST EXPOSURE OR REMOVAL TO. NORMAL. AIK In this experiment, which was divided into twy parts, the effect of inhaled calcined gyp sum dust a tuberculous infection was studied. In ;iie lirst part, 20 guinea pigs, after having been ex posed to the dust for 6 months 3J.I ' I Table 11.--Combined Biological .Action of Calcined Gypsum Dust and. Quorti Dust Guinea Pigs Exposed by Inhalation to an Aerosol Derived, from, a Mixture of Two Volumes : ' ... of Calcined Gypsum Dust and-One Volume of Quartz. Study of Animals Killed for Sampling . Guinea PIS, .NO. Reaction In Pulmonary Expo- Microscopic Evidence of Pneumoconjoela Lymph Node* /--------------------------- -s--------------------------- ---- ------- ----- ;--------- ---t . sure ' Cellular Degeneration - Degeneration to Infiltration ,---------------- V------ :--------- ,-- -------- *-------------- -y Duct. Plj(meo* Bronchi Hr*- Ne Enlarge Hya- N. . Days faltOQ olitis . Focal Diffuse Flbrotlc Hoe crotic' ment Flhrotic Hoc erode wa-58 , 1*7 + . . ^. 1, 2 244 ++ 3, 4 6 :.s, 9,32 15, 43, 60. 37, 44, 38, 62 10 . 11,12, 14, IT, IS, 23 27, 54, 30, 63 21,22,23.30 34, 40, 53 304 335 372 402 420 480 555 665 730 870 ++ f ++ -h .+ ++ 44- +-K +++ +++ 4-0. 4-4++ + -+ 4- - .. .. ++ 4'+ ' ,0_ ... .+ . ,, + +++ 4-4- . .. + ., ++ . 4-4- + o- + +- +++ +4- 4-4- + : . +++ 4-4- 4-4- A4-M-. +4-4- + '+ + .+++ 4~f +++ ++ .. . +++ . + + .+ - + -r + + :. + ++ ++ ++ ++ .... .. '. +' . .* + + ,, . Symbols: 4-, alight rcaetlon; -i--4, moderate reaction; ++4-, advanced reaction; A, ateleetaaia.. were infected with attenuated Ri tubercle on the course of experimental tuberculosis bacilli and thereafter immediately returned can be interpreted,, the effect of R; tubercle to the dust room for additional exposure, up bacilli on the guinea pig lung should to 18 months more. For the second part of briefly reviewed (Table 15): the experiment, the preinfection period of It will be noted that, of the 12 animals in exposure to the dust was longer, namely, 25 the control experiment (Table 15 ), 6 died months instead of 6 months. After being in within a 22-month period of observation. In fected. the 15 animals used were not returned all cases the deaths were due to pulmonary :o the dust room. Instead, they were trans causes, and in at least one instance the cause ferred to a normal environment and allowed was spreading cavitary tuberculosis. How I- cn live there for periods as long as 18 mouths. ever, only in this one case was there spread As a control experiment. 12 guinea pigs ing tuberculosis. In all other instances there were infected by Rt bacilli but were not ex were either no signs of tuberculosis or but posed to dust. one to three small tubercles. In only four The results of these studies are summarized instances did these tubercles show any activ in Tables 13 and 14. Before the influence of ity. Tuberculosis was detectable in the pul inhaled calcined gypsum dust or quartz dust monary lymph nodes in one instance, but it Table 12.--Ash and Silica Content of Lungs of Guinea Pigs After Exposure to Aerosols Composed, Respectively, of Calcined Gypsum Dust and Quart: Dust in o Ratio of 2:1 and of Quarts Dust Alone V- mm 1 XCIt EPEfiS ET al. nd Quartz Dust re of Two Volumes Reaction In Pulmonary Ljnjpb Nodes ' alarse-- Hya- neat Flbrotlc line .-.ctaaij. rimental tuberculosis effect of Ri tubercle mg lung should be 15). of the 12 animals in (Table 15), 6 died d of observation. In e due to pulmonary ;c instance the cause tuberculosis. How ie was there spreadther instances there tuberculosis or but rcles. In only four ties show any activtectable in the pulone instance, but it sure to Aerosols sst in a ntrol Silica ---- a-------------- -----r r,, of Dried Luo? % of Ash 2.73 53.53 5.57 (5.13 -7.50 45.77 4.94 41.73 3.80 32.75 3.66 33.90 3.42 33.41 4.22 39.39 2 PLAINTIFFS I EXHIBIT ' . . BIOLOGICAL EFFECT OF CALCIXED gvi-scm nusi | /w.o 1Table 13.--Influence' oj. Calcined -Gypsum Dust on the Course, of Experimental Tuberculosis ' Guinea Pigs Were Exposed by Inhalation to Cab ined Gypsum Dust for Six M|on_thst, /Wsered Then Infected with K, Tubercle Bacilli, and Were . Immediately Returned to-thc Dust Room,for Continuation yi Their Exposure to Dust Until Death (itiinea PitC.' .No. 553-36 37 1G 17 32 33 38 19 23 30 24 39 34 27 41 18 22 31 3.7 10 Sur vival Alter Infection. . Days . yo 144 230 230 258 275 275 307. 386 333 446 474 <M 182 :VU7 520 :.? 5.73 561 .Vl Fa te f> D K K D K K K 1) D D K D n K K K D K K Dissemination Cause of. Death Pneumonia Pneumonia Tuberculosis Pneumonia V Pneumonia ' Pneumonia t V'ulcittlieu leu cation -- -r-r-r r - --44* .;J -- --44 . -r-r-r --i. --r T Tuberculosis Pulmo- --------- a------------------------------------------- nary Casea- . Lymph- Fibrosis Spread tion Cavity Nodes Liver 4 .4 -LJ- -i--h -j-' ' 44 -F+ .. C-r F+ F+++ F++4- F-r +4- T* "i--r . 44 44 *-- +++ FT-1-' C4-+ F-r-t- 4 F-f- + FT+'-r FT++ FT++ rr+H- ++ , + -S-O. F+-E T 44 4-- 44 ++ + TT -i----i- 4. + FT4 FT+ . FX4 FN-r ++ HF HF FT-f . Spice F+ + 044 FT FT FCT F-r F4 .......... HF FT FT Symbols: C. vuscatiun; F. fibrosis:'FN, flhrou* nodules: FT. flbrtm.- tiiiicmilosi.*: FCT, flhrocascous tube-cMosis: HF, hyaline change; X. necroM,-.; -K slight reaction; moderate reaction: 4-4-*-, atlvanceil reaction. was inactive. In the guinea pig with spread ing pulmonary tuberculosis, .active tuber culosis could be found not only in the hilar nodes hut also in the spleen and liver. When the guinea pigs in one of the dusted, groups (Table 15) had been exposed to calcined gypsum dust for t> months, inn.-ted. and then further exposed to the gypsum dust for .an .additional 18 iuoitth>. only of the 20 animals died, spontaneously. Of these deaths, only six were ascribed`to pulmonary causes. While signs of healing were in evidence in Table 14.--Influence of Calcined Gypsum Dust on the Course of Experimental TuberculosisGuinea Pigs Were Exposed by Inhalation to Calcined Gypsum Dust for Twenty-Five Months, Infected with Ri .Tubercle Bacilli, and Transferred to Xormal Air Dteseminatioc Cuineu Pie. No. Survival A Iter Infection. Days 553-6 s 83 9 97 10 S4 27 85 61 87 122 S8 18.7 59 18.) no 241 92 244 94 386 95 368 98 308 99 541 100 541 ---- Fate Died Diet! Killed Died Killed Killed Killed Killed Killed Killed Killed Killed Killed Killed Killed Cause of Death Pneumonia Pneumonia Pneumonia Pulmonary Tuberculosis Healing CulciflTubercle* eation Fibrosi* Spread Casea tion Pulmo nary Lymph Nolle* Liver _ 4 3 4 C4- 25 44 4 C+-r C+ 17 --r TT PT~ 2" ++ 1 4- + F-i- 0 i\ 4- 4 j- -r-r 1 3 4* 25 4 -- !:: ___ ++ F-f- F+ Spleen <;+ Symbol*: ('. mention; F, fibrosis; PT. proliferative tub.-rrlc; advance*) reaction. -ucht rend ion: J~r, moderate reaction: 4-44*. "T v* T Table 15.--Fate of Guinea hiu\ taf with A', 'f'uhrr^tt'Iio'i.Hli Control Study :: No Dust 'Exposure. ' -"- Guinea Survival. Pif. No. Days ,v*3* i 2 89 ; It 98 7 ns 1 174 2 202 5 255 . ' `3 438 i 6- 445 9 585 10 . oot 4 854 5 654 Kate Died Died Died Died Killed Killed Died Killed Died Killed. Killed Killed . Cuuse of Death. ... Pulmonary infarct Pneumonia Acutecouiiesiiou Pneumonia Pulmonary al>nis Tuberculosis . Pulmonary Tuberculosis' * Disseminated Tuberculosis .. Arrested Tubercle 1 ' 2' u. .... i 'iispuiion ++ 4. -r . Continent Pulmonary Tnherni- , Lymph . losis Node. Liver. Spleen 1 :l. i:: 2 ( .+++ +++ +++/ it- SymhoU: -f. slight reaction; -f-f-,' moderate reaction; -r---- advnnred reaction. most instances, in a few cases with asso ciated calcification, spreads occurred in six instances; two cases developed cavitary tuberculosis and one died.from this disease. Fibrosis was a prominent feature in a major ity of instances, but caseation persisted in eight cases. The tuberculous process had. however, spread to the pulmonary lymph nodes. liver, and spleen but in most instances was [tartly healed. Caseation occurred in iso lated instances, and tibrocaseous tuberculosis in one case. There was a higher proportion of nodules in the animals surviving longer, and in these there was also associated. hyaline fibrosis. The occurrence of 34% spreads in the gvpsum-dusted guinea pigs indicates a dis tinct excess over, that which occurred in the control series (8.3%). However, it should be recalled that the control group was rela- lively small. Added to this tendency to spread, there were in the dusted animals the signs of caseation, cavitation and fibrosis,; and metastatic dissemination to the hilar nodes and abdominal organs. All these-change ra dicate some stimulatory effect of the caic . rdC gypsum. dust on the tuberculous process. There was no indication, however, that the tuberculosis promoted any pneumoconiotic process. When the infection by means of the Ri tubercle bacilli was initiated at the end of a 25-month period of exposure to the calcined gypsum dust (Table 14). the influence of Table 16.--Influence of Calcined Gypsum and Quartz Dust on the Course oj Experimental Tuberculosis Guinea Pigs Were Exposed by Inhalation to Calcined Gypsum Dust for Three Weeks and Thereafter Alternately to Quartz Dust and to Calcined Gypsum Dust for a Week at a Time; After 171 Days Pigs Were Infected with Ri Tubercle Bacilli,' and Then Alternating Dust Exposure Continued . Survival After In Guinea fection. PI*. No. Days 553-4 rt ioi 2.S5 1 308 Fate Died Killed Died .) 393 Killed 3 405 Killed Cause of Death Tuberculosis Chronic pneumonia Dissemination Pulmonary Tuberculosis Pulmonary Lymph Nodes Spread -r+-t+-r~ + Tubereulo- Calcifl- Tubercu Cavity silicosis cation losis Silleosls + -!"+ + +++ + ++ -H+ ++ ++ Liver TS+ T+ - - *-*- + -r ++- + +++ +++ T++ -T + +++ +++ T-H- Spleen 3++ .. Symbols: TS. tubercolosilieosis; T, tuberculosis; 9, silicosis; -r. slich: reaction; -i--K moderate reaction: 4~HK advanced reaction. ----- ---------mteaTubtrcuip,), Liver Spleen + " -curred in the ver, it should roup was relaenev to spread, nals the signs fibrosis,. and te hilar nodes se changes in:>f the calcined :ious process, ever, that the neumoconiotic .ns ot the Rt the end of a o the calcined : influence of of V'eeks and .'eek atloa Liver Splfea TS+ 3++ T+ T++ r++ -vaetton; I t -K -.VSfifc- the dust on. the course of the infection via? In the second part oi this experiment. 21'. eittirc'lc licni.i;n. Hut 3 of the 15 animals died guinea pigs were iniected with Ki tubercle. Pi' pneumonia within the first -month after' bacilli after 3 months c/t exposure to an aero- infection and none thereafter. Mild spreads sol derived from a mixture oi equal parts of were found in six of the animats killed before calcined gypsum and quartz., ihc dusting pro - the sixth month and none in the .later stages, cethire being continued lor-27 months alter Caseation was.found twice only.in the lungs the infection was initiated.. Half-of the ;mi- an?! twice also in pulmonary lymph nodes, mals died Irom pneumonia during this pro- I'nimonarv fibrosis was quite common in the traded period, the spontaneous deaths oc* healing tubercles.. No pneumoconiosis- oc- curring- slightly more-frequently towartl the curred. - end of the experiment t Table 17). This study therefore indicates that the prior two-year period of inhalation of calcined gyp sum dust modified the native susceptibility-of the guinea pigs to the tubercle, bacillus adversely; though not materially so. The localization of the lesions was affected, and for their normal tendency to heal by resolu tion there was substituted a process of healing by fibrosis, with calcification in a few in stances. Signs of-pneumoconiosis were slow to de velop, but from the 13th month after infection (10 months from the start of the dusting j marked and diffuse cellular infiltration super vened. with hyaline changes in many of these lungs. Pulmonary.tuberculosis of a confluent type and of moderate extent made an earlv appearance and persisted throughout the long period of the study. Caseation, cavitation, or calcification, however, was limited to isolated ;. ALTERNATE WEEKLY EXPOSURES TO CALLINED f.Yl'SUM DUST AND TO OUART7. DUST AND I.NI-ECTION WITH Hr TUBERCLE BACILLI In the first part of the third phase of the infection experiment, five guinea pigs were exposed alternately to quartz dust and to instances, especially in the latter months of the study. The pulmonary lymph nodes showed . early temienev toward fibrosis and tuberculosilicosis. Necrosis became a rather constant finding at a later stage. Necrotic foci occurred calcined gypsum dust for weekly sessions uter a preliminary course of gypsum in halation tor three weeks. At the end of about 6 months they were infected with Rj tubercle bacilli, and the alternating quartz-and-gypsum regimen was continued for an additional period of 13}4 months. The results of this study are summarized in Table 16." Spreading and cavitary tuberculosis was rapidly induced in three specimens within the first year after infection, while tuberculosiiicosis within the- pulmonary tissues dominated the scene, particularly in the later phases of the study. Foci of tuberculosis could lie discerned in the liver, and silicotic nodules occurred in the hilar lymph nodes in all cases and once in the spleen. These results and their relatively prompt occurrence leave no doubt that alternating gypsum and quartz exposures influence the also in the liver, occasionally with tubercu losis. Rather more commonly, tuberculous metastases were found in the spleen, and in a number of cases tuberculosilicosis likewise occurred in that organ. Once more, therefore, the concurrent exjxjsure to quartz dust and calcined gypsum dust in equal proportions promotes the d<velopment oi tuberculosis in the infected guinea pigs. However, the disease does not reach a destructive and fatal stage like that seen when the dust exposure'is to quartz dust alone fTable 4). Irwill be observed from this record that exposure to quartz dust con verts the infection with Ri tubercle bacilli into a spreading tuberculous process asso ciated with tuherculosilicosis and a high and early mortality rate. COMMENT course of tuberculosis adversely. The result Since in previous exjierimecits the intraper- is greatly modified, however, bv the degree itoneal injection of even an excessive quan to which silicosis develops concurrently. tity of calcine-i gypsum particles did not pro- .W7 .> \ Table 17.--Influence of Calcined Gypsum Dust and Quart': Dust on the Course of : : Experimental Tuberculosis' Guinea Pigs Were Exposed, by Inhalation for Three Months to an Aerosol Derived from a Mixture of Equal . Volumes-of Calcined. Gypsum Dust and Quartz Dust and .. Were Then Infected with Ri Tubercle Bacilli; After Infection the ; Animals Were Immediately Returned-to the Dust Room . \ A'.- ''''here Their Dust Exposure Was Continued Until Death V- Survival After Guinea Infer- PI*. tioo, . No. Days Fate 560-9 .172 K 17 239 K n 277 D is `297 D i 359 K 2 359 K 15 368 D 13 399 K h 401 K 10 406 K 3 428 K 21 482 D 16 482 D C 508 K 19 510 D 7 549 14 555 12 570 8 618 4 651 20 soo D D K D K D Cuusc of Death Pneumonia Pneumonia Pneumonia ............ Pneumonia Pneumonia Pneumonia Pneutnoain Pneumonia Pneumonia Pneumonia Pulmooary Tuberculosis . Dissemination. r--------------------------------Degeneration z Pulmo- ... Con- Case a* ---------- * Pneumoconiosis nary -------- a--------------1 Lymph lluencc tlou Hyaline Necrosis . Focal Diffuse Node- Liver -Spleen T 4-4*- ++-r 4*4-4- 4- C L+- +. + 4- 4* ' .. ' ' F44 . 4- 4 ' TF4 F+ .. 4- ' *H- , 4 ++ '. N+ ST4 - .. ' .. '' T+ +++ ++.->4-4-4' 44-4'++ ++ ++ +++ 4-4- ++ ++T "44-4*4+++ +++ 4- CL+ 4- +++ CL+ CL-j-4*4" CA++ CL4--r 4-4* CA4-4+++ ++ CL+ + ++ ++ 4*4~4++ -H-b ++ +4-4* +4*4* +-H- 4. ++ 4 44 ST44 ST44 + +++ : N+ 444 .X+-I- X+ .. . F44 444 N'44 - .++ N44 ++ . N+ +4*4- N4- ++4 N-r 4-4*4* . H + 4 +++ F44 444 N++ F+ N+ NT~ T+ N+ N+ .. T+ T+ .. ' F+ F+ T+ F+ 17+ TF+ -' TP+ .. T+ T+ T+ Symbols: 4% slight reaction; 4-4-f moderate reaction; 4-4-4-, advanced reaction: CA, cavitation; CL, calcification; F, fibrosis; H. hyaline change; N, oecrosis; ST, sillcotuberculosis; T, tuberculosis: TF, tuberculous, fibrosis. duce progressive fibrosis, it was anticipated that the inhalation of those particles would have no serious effect upon the lungs. That assumption has been verified by the studies reported in this paper. It has been demon strated that the small increments of fine cal cined gypsum particles inhaled into the lungs largely disappear, apparently as a result of solution in the tissues. Very little anatomic evidence of their presence can be discovered. Evidences of reaction in the fixed tissues of the lung are minimal, even after exposures to high concentrations for a period of two years. In the hilar lymph nodes, which must have received the greater part of the gypsum that was spirited away from the lung parenchyma in this series of guinea pigs, there is an almost specific pattern of reaction comprising medullarv hyperplasia in the nodes and -their fol licles which is unaccompanied by any increase in the lymphoid tissue. Fibrosis was, however, conspicuous by its absence. It is .to be hoped that this interesting find ing may mean that it would be inconceivable that the inhalation of calcined gypsum dust will produce significant reactions in otherwise healthy lungs of industrial personnel, perhaps even regardless of atmospheric concentra tions. This circumstance would therefore con clusively eliminate calcined gypsum per se as the cause of the pulmonary lesions which have already been reported in respect of deceased gypsum-industry employes.s It is difficult to evaluate the high pneu monia rate in these guinea pigs. By compari son with other studies conducted in The Saranac Laboratory, it is excessive (Table 18) However, these latter investigations have been conducted in more recent years \yhen it has been possible to control epizootics more effectively hv ultraviolet-light radiation 3.W SUPERS ET AL Course of Derived from a 'ust and Dissemination ilmo* iary inpb ode '~r~h 'F-J- , Liver F+ N+ Spleen T+ - -*r * --!- T+ - F+ r+ r+ --a. T+ N-r F+ -V+ T7+ -r-h N+ T7+ t-t T+ T7+ T+ T7+ X+ l-r N+ --J- .. ---f* T+ T+ T+ T+ ** .Hod; CL, calcification; jus fibrosis. osis was, however, s interesting findi be inconceivable ned gypsum dust :tions in otherwise ersonnel, perhaps pheric concentrauld therefore con1 gypsum per se arv lesions which id in respect of -mployes.5 e the high pneu>igs. By compari'nducted in The excessive. (Table er investigations ore recent years control epizootics iet-light radiation HIOLOGICAL EFFECT OP CALCINED GYPSUM DUST Table 18.--Comparison of Number of Spontaneous Deaths of Guinea Pins in Inhalation Experiments with Carious Dusts Several possible explanations for this con dition should be entertained. The first con cerns the possibility of chemical or physical Kind of Dust Quartz ............................. Silica fume .................... Amorphous Silica A.... Amorphous Silica B.... Amorphous Silica C.... Amorphous Silica D____ Volcanic glass ................ Animals Exposed to Dust, No. 34 268 305 192 209 " 235 91 Auimals Found Dead. No. 19 86 48 64 44 64 6 Mortality Rate, Per Cent 23 32 16 33 21 22 7 interaction between the gypsum and the quartz, either in the hopper mixture or even after deposition in the guinea pig tissues. Next should be considered the factor of bio logical antagonism to quartz which may be induced by the gypsum. To these observa tions should be added, the fact that the dose of quartz was actually decreased through dilu tion with the gypsum and that the quartz was and antibiotics. Perhaps no further attention administered to older guinea pigs and to the need be given to the matter. However, the hardiest survivors of earlier phases of the high pneumonia rates and the emphasis of experiment. It is even possible, though un this phenomenon on certain phases of the likely, that the quartz dust itself may have study suggest.that the matter is at least worth "aged" with the passage of time, thus not further investigation. being quite as potent as at earlier phases of The experiments demonstrated that guinea the experiment. pigs are protected against ordinarily danger The latter question cannot receive an ous concentrations of quartz dust bv the con answer until we have, more information con current presence of calcined gypsum dust in cerning the influence of aging of powdered the same atmosphere. Under the conditions quartz on its biological properties. The prob of the experiments, in which the ratio of lem whether quartz has a greater or a e^s quartz to gypsum^ was relatively high, the propensity for damaging the tissues of ci-.er protection was not absolute or uniform for laboratory animals compared with its effects all the exposed animals. The protective action on the younger specimens usually selected for of the calcined gypsum completely prevented study has never been properly examined. the development of fibrosis in the majority of -Linked with this question is the possibility cases and retarded or modified the character that mere survival against all the forces which of the dust reaction in the. remainder. The naturally or artificially may tend to decimate degree of protection was not defined wholly the ranks of laboratory animals may signify by the length of exposure but was affected to a hardy stock perhaps also more resistant to some extent by other factors not clearly quartz dust. There is no answer to this, but understood. Sporadic cases of nodular fibrosis it should be entertained as one of the possible developed; in some animals exposed for mechanisms which influenced the results in shorter periods than in other animals which this investigation. failed to manifest this type of reaction. Pos The fact that the quartz dose was actually sibly host factors involving "individual suscep decreased through dilution may have rele tibility were involved. vance. Over the * years, experiments with The protection was most evident in respect quartz dust have been carried out in The to the degree to which the prevalence or Saranac Laboratory in a great diversity of severity of bronchiolitis was reduced in the dosage levels. Except iri extreme ranges of animals exposed to both gypsum and quartz : particle concentration, the tissue reaction to to the retardation of the pulmonary cellular quartz does not vary too obviously. To be reaction and the diminution of its extent: to precise, however, no systematic body of jhe limited amount of fibrosis, hvalinization. knowledge exists to enable one to make com or necrosis which ensued, and to the inhibi parisons with complete assurance. The great tion of dissemination of the dust to abdominal differences,observed in the present series of organs and even to the regional Ivmph nodes. experiments suggest decidedly that the ex- 339 J]y ) Z PLAINTIFFS I EXHIBIT | n&J. o i Czs) SCUliPV.HS r.T; ,1L. Table .19.-- liffcct of- I'aryiny the' Amount oj Cypsum on the Solubility of Particulotc Quartz Stispem/ciJ in a Puffer Solution Quartz Particle Size: Im to 3m TiutTcr Solution: HiBOa-N'aOH pH 0.90 . fncubation : 37 C for Twenty Hours Gypsum Suspension, Soluble SiOi, Me. Mp/ioo Cc. 0 0.55 20 0.70 50 0.70 100 o.&o 500 750 . 1.25 1.2$ .. 1,000 1.33 . . 2,000 1,30. 3,000 i:30 5,000 1.23 Control: N*o quartz :.,onu o.J2 lu:r*n* in Soluble Sii,).. Per-Cent ' 22.6 - " 02.4 122.7 127.0 144.4 135.7 116.8 111.3 ' pU at End 20. Hr. 6.70 6.75 . 6.75 6.75 6.75 6.87 .0.05 7.03 7.05 7.16 7JjO planation does not rest tjierely with the ques tion of dilution. In The Saranac Laboratory, experience has also been gained with dilution as a factor in relation to "inert" substances, such as iron oxide, and the results of these studies serve as further confirmation that the inhibition achieved by the calcined gypsum dust is real and not merely a function of quartz dosage. That the quartz dust actually did enter into the lung tissues in a dosage . ratio bearing some relation to that according to which it was administered was adequatelv shown by the chemical analyses of guinea pig lungs recorded in Table 12. That the influence of the gypsum on the quartz may have been due to -some form of physicochemical interaction is suggested by Tables 19 and 20 and the known fact that gypsum particles have a positive electrical charge, while the charge of-quartz particles is negative. In Table 19 it is shown that the presence of gypsum in a .buffered solution increases the solubility of suspended quart/, particles considerably without substantially changing the pH. Table 20 confirms the latter observation and shows that the presence of gypsum raises the pH of the solution mark edly when 1% gypsum and \fo quartz are incubated together in a buffered solution at .17 C for 24 hours. If the theory of Holt9 that silica exerts its necrotizing and fibrogenic action bv virtue of silicic acid polymer';. which can .form1 only in. an acid pH.Tange, be acceptable, the reduction in the influence of the quartz in the presence of -gypsum .may'-' find an explanation. Such a chemical theory receives further confirmation from the obser .-cation that when quartz and -gypsum were administered in alternating weekly doses the resultant ..pneumoconiosis was'much worse than when an equivalent amount of calcined gypsum- dust was introduced into the guinea pig lungs simultaneously with the. quartz dust. Owing to the apparently rapid elimina tion of the gypsum and the tardiness with which koniophores make an appearance in response to its introduction, this would mean perhaps that in the alternating exposure ex periment the gypsum had practically been eliminated at the end of each week end. so that the quartz had an uninqteded oppor tunity to act on the tissues in focal and later diffuse regions where a low. pH prevailed. The elimination experiment in which t!..-.'.nimals were left in fresh air after a pro. -iged. period of exposure to quartz dust and calcined' gypsum dust also indicates the same chemical explanation. By the progressive loss of gyp sum from the lungs, the local tissue pH could have been progressively1, reduced, thus liber ating the full action of the accumulated, quartz; The answer to these enigmata can come only through further research. That the total result may have been simply one of biologically antagonistic effects of gypsum and quartz and even perhaps merely Table 20.--Effect of Varying pH Values on the Solubility of Particulate Quartz When Sus pended with Calcined Gypsum in a Buffer Solution Quartz Particle Size: 1m to 3m Buffer Solution: H,BOa-NaOH Incubation: 37 C for Twenty-Four Hour- Buffer Solu tion, PH 6.1 7.1 7.4 9.0 9.0 10.2 Suspension 1% Quartz -r iKo Gypsum Suspension 1% Quartz + Soluble SIO>. Mg/100 Cc. 1.16 0.23 0.54 --0.86 1.62 2.45 pH After 24 Hr. 6.65 6.94 7.42 3.70 9.U Soluble 8IO,. Mg/100 Ce. 1.25 1.50 3.75 2.51 2.10 1.14 pH After 24 Hr. 6.65 6.60 7.45 8.32 9.50 340 nnrnvs n.r al. an acid pH range, :on in the influence nee of gypsum may i a chemical theory ion from the ohserand gypsum were g weekly doses the was much, worse amount of calcined ed into the guinea with the quartz ntly rapid elimina- . iie tardiness with an appearance in . this would mean ng exposure expractically been ! :n week end, so ; nimpeded opporin focal and later ' w pH prevailed. in which the anij after a prolonged dust and calcined j :ie same chemical 1 -ive loss of gyptissue pH could need, thus liberI'.e accumulated j e enigmata can i :search. ave been simply dstic effects of j perhaps merely !{ Values oh the t; IVhen Sttsp.vnn in o m to 3m ,-NaOH rour Hours Suspeasioa 1% Quartz + i*o Gypsum lubla :0*, 100 Cc. a 50 .75 ` 51 10 M pH After 24 Hr. .... 6.05 6.60 7.45 8.52 9.50 hiolqgical nin:ncT or- calc!xan -gypsi'm, oust 2 PLAINTIFF'S I EXHIBIT ! 110^.0 I z-?y) .a matter of tissue or cellular competition can A final point of direct practical application not he dismissed as a possibility without due might be stressed here, namely, that where a consideration. The paucity of koniopltores in" seriesof pulmonary reactions do result when the gypsum-drenched lung may mean not calcined gypsum and quartz are administered' (inly that calcined gypsum does not exert a either together (successively, simultaneously, chemotropism for these cells, such ns quartz fir altcrnatingly) or in conjunction-with a . exerts markedly,10 hut even that the presence tuberculous infection, the final .histopathq- of gypsum repels these cells. Silicosis doe- logicni result achieved is not a mere quanti not ensue until quartz particles have been tative expression of the relative coiiqoonent phagoevtosed by the alveolar macrophages action of each of these three etiological agent and transported to sites where their cumula but actually, in a sense, is a new type of lesion, tive action can provoke local lesions. If gyp a form of holistic synthesis. This is the prob sum blocks the approach of. these cells, the lem of the mixed pneumoconioses which arc quartz particles will simply not be picked up. being encountered'in increasing numbers :n It is possible too that the absence of alveo industry today. Their-precise nature cannot lar macrophages in the early phase fit the be simply predicted by reference to the known exposure to calcined gypsum dust may sig properties of-the separate component miner:* ' nify merely that they do not need to enter substances. More research is needed alum: the alveoli to ingest the gypsum. The latter, all these matters. being somewhat soluble, could be picked up after penetration of the alveolar walls. As the gypsum is not likely to prove immediately toxic to the macrophages, there would be no barrier to their transportation to distant parts and disappearance from the lungs. In such circumstances they would not he available tn pick up the quartz particles. The influence of flocculation on the aecessiliity of the quartz should also be examined fft was shown by Gardner 4 that when calcined gypsum dust and quartz dust ar.e suspended in the dust room simultaneously there is a marked tendency to flocculation. Gardner suspected that this might prevent the actual inhalation of many of the suspended particles. However, his tabulation shows that more than 52% of the clumps measured less than 5/t in diameter. These would be respirable. What was not settled .was whether these clumps of particles remained as aggregates even within the cells of the lung or lymph SUMMARY In a series of long-term inhalation experi ments. guinea pigs were exposed to calcine*' gypsum dust alone and to mixtures of quar dust and calcined gypsum dust; in addition, the influence of the gypsum and of the gyp sum mixed with quartz on the course oi ex oerimental tuberculosis was studied. The effect of calcined gypsum dust on the lungs of guinea pigs exposed to the dust lor two years was too insignificant to lie classified as a pneumoconiosis. The presence of calcined gypsum dust in atmospheric suspensions with" quartz dust offered to exposed guinea pigs a substantial flcgree of protection against the usual harm ful effects of the quartz dust. The protection, however, was lost when the exposures ceased, enabling the gypsum to be removed from tin lung tissue and liberating the full effect of tinaccumulated quartz. nodes. The inhalation of calcined gypsum dust Biological antagonism naturally goes fur alone influenced the course of experimental ther than these simple mechanistic specula tuberculous infection in guinea pigs to a mod tions. Until we know more about all these erately disadvantageous degree only, mani issues, we must keep an open mind about the fested chiefly bv interference with the proces- possible antagonistic influences and even, par- of healing after initial spread of the infection. haps. specific synergisms between calcined The course of a tuberculous process in gypsum and quartz in terms of tissue and guinea pigs infected with R| tubercle bacilli cellular enzyme and energy transfer systems. was adverse! / affected to a slighter degree 341 L. * m by exposure'to' a mixture of quartz dust and calcined gypsum dust than by exposure to quartz dust alone;. .. Chemical analysis of lung tissues of guinea pigs that had been exposed, to a mixture of quartz dust and calcined gypsum.dust shows that the quartz is actually retained in the lung tissue but in less than half the concentration, which may be achieved when the exposure has been to quartz dust only. . The most likely explanation for. the in hibitory effect of calcined gypsum on quartz appears to be in the realm of physical chem istry. though biochemical factors and bio logical antagonism have not been excluded. 3. Fourth' Symposium. on Silicosis':. Transcript of. the Fourth- Silicosis Symposium held vat The ' 'Saranac Laboratory June 19 to 23,' 1939.. 4. Silicosis' and Asbestosis, edited by A. J. Lanza, New York and London, Oxford University Press. 1938. . 5. Gardner, L. U. : History of the R, Strain of .Tubercle Bacillus, Am. Rev. Tuberc. 25:577, 1932. , . - 6. Dowd. G. R,: Cultural-Characteristics of the Ri. Strain of Tubercle Bacillus with Particular Reference to Dissociation. Am. Rev. Tuberc. 32:50, ; 1935. . 7. Gardner, L. U., and Cummings, D. E.: Studies on Experimental Pneumonokoniosis: IV. Inhalation of Asbestos Dust: Its Effect upon Prir marv Tuberculous Infection,'/, bidust. Iiyg. 13:65, 1931. . . Acknowledgement is made to Stanislaw P. Kaszer, M.E., E.E.. Biostatistician, for tabulating and analyzing the data front which Table 18 was constructed. REFERENCES 1. Annual Report of The Saranac Laboratory-- 1933, 1934, 1935, 1936, 1939. 8. Schepers, G. \V. H., ;and Durkan, T. M.: Pathological Study of the Effects of Inhaled Gypsum Dust on Human Lungs, A. M. A.. Arch. Indust. Health 12:209, 1955. 9. Holt, P. F., .and Yates, D. M.: Studies on the Nature of Silicosis: The Polymerization of . Silicic Acid Sols in Vivo, Brit. J. Elxper. Path. 35:52, 1954. 2. Third Symposium on Silicosis: Transcript of the Third Silicosis Symposium held at The Saranac Laboratory June 21 to 25, 1937. 10. Schepers, G. W. H.: Cytobiological Mani festations of the Surface Propertie: f Quartz, A. M. A. Arch. Indust. Health 12:266-_*75, 1955. t i i r i V - n'-'-V- :