Document rp8yvKwVmZg6GnRDQeEb1mxJ0

C - - t. ( /. ` PLAINTIFF'S EXHIBIT een studied in more detail. In general, delay in onset of from 2 to 60 days folwhether the result of a single large dose er doses. s have been observed qualitatively, good i are lacking, particularly in regard to rly obvious that animals can be injured hv segment of the electromagnetic spectrum that humans are similarly affected. Further being done. The important problems arc red evaluation of exposure; limits of exposure and power; continuing studies of humans i hazard is indicated, the question of methods ivestigated. In the meantime it is strongly ; to microwaves, particularly from radar protection is particularly important. Some ade of use of special screen glasses for this any problems involved in their use. b discussion will stimulate sufficient in*ct.. that answers will be found which will it as no problem, or if it is a problem, to ineering and medical--for controlling it. [US] RECENT OBSERVATIONS ON CHRONIC PULMONARY BERYLLIUM DISEASE G. W. H. SCHEPERS. M.D., D.Sc. Oircctor, Ssrsiuc Laboratory and Trudaau Foundation The concept berylliosis has already become so firmly entrenched in the medical literature that it may seem audacious to challenge its validity. The results obtained from research recently conducted at the Saranac Laboratory' impels one. however, to reconsider the criteria of this disease and. more particularly, those pertaining to its chronic manifestations. This research has also brought to light certain interest ing aspects of the fundamental pathology of the pulmonary derange ments provoked by various compounds of beryllium. The observations to be briefly presented in this review of the sub ject are based on the following studies: (a) a systematic histological and physico-chemical review of 31 of the 58 lung specimens constituting the Saranac Laboratory collection assembled since 1943 and on which material remained in the Laboratory for detailed study; (b) a review of the material and results obtained from the comprehensive series of experiments conducted in the Saranac Laboratory with beryllium compounds since 1943 (Table 1); (c) personally conducted long-range experiments on the bio logical action of a variety of beryllium compounds, acknowledgement being hereby made to the Damon Run yon Fund, American Cancer Society, Atomic Energy Commission and the Office of Naval Research for gener ous assistance in connection with this work (Table 2); (d) a detailed study of the pulmonary material from a cur rent series of nine beryllium pulmonary disease cases; acknowledgement is made for the assistance of physi cians who cooperated in furnishing the lung biopsy or autopsy specimens; (e a broad-range investigation of the potential role of beryl lium in the genesis of pulmonary diseases not usually associated with the problem of berylliosis (sarcoidosis, anthracosis, asbestosis. siderosis and silicosis 1. ' -t'-knowiedrement ( made to O. J. Dobro*orkl. M.D.: T. M. DuHton. M.E.: A. B. >elahant: M. Roberts. M.E.. and F. Creedon of the Saranac Laboratory to^tli technical assistance In connection with these proicram*. [139] TAIII.E I. Ile rjrlllu m Com poundii T m trd fo r th e ir ('o p a c ity to (*auac C hronic I.chIoom anil N ciiptaH tic Change. Saranac Laboratory -- 19(4*1953 ROUTE OF IN TR O D U C TIO N SPECIES OF A N IM A L S s3oq auiMg 901J^ ' i : ' OC 00 OO ; iO: sqtqquH oooo'ooo s2t<j eacrmQ ooo.ooo . ; |z 1 i : j2: .ZeoZo 'i1 p^wjuj ! : ! I 1 1 ! ! 1O , i:l{wtaajtnnn i , ! ii o : o i i ii o i a<g8!.1 p9p9.Fi psHMjmufl !1 1o ; 11! |o i 1! || :1!ii! ' ! | |o| snoairrjnoqng 1 1 ; ! 1 1 o 1 : | !o ! prauotuaj ooo o,o. : | | ! o 0 0 o OBtpjBQ 'snooa^ OO OOOOOCOOOOZ Be P h o s p h o r........................ Be S te a ra te .......................... Be S ilic a te .......................... Be G lass............................. Be M e ta l plus B .A .L ......... Bo S u lp h u le ....................... Be P hosphate................... Be O x id e .............................. Be N itr a te ............................ Be H y d ro x id e ................... Be C a rb o n a te ................... Be C a rb id e ........................ B e ry lliu m ........................... B e ry l...................................... B E R Y LLIU M COMPOUND [140] Be Phosphor plus Alum ina 0 -- Negative capacity to cause chronic lesions G --Posiitive capacity to produce granulom aln N P--ositive capacity to induce bone sarcoma Rather obviously it is impossible t data systematically garnered through be made instead to certain highlights have topical significance. That new fac be of interest seems probable, for in n mystery. Furthermore, although a grei been applied to the prevention of bery of new cases have been gratifyingly z would seem that the danger has by no increasing importance of beryllium in t; in metallurgy points to the possibility may yet occur. Chronic Berylliosis versus Chronic P Beryllium Workers This is the first matter which net considered, the issue appears to be tat considered is whether the concept "ber narrowed down to a limited category o from exposures to respirable beryiliun of pulmonary lesions other than the gra regarded as the essential component of question now is whether these non-grant their own be recognized as pathognomon ie form of the beryllium disease. The primary pulmonary manifests nor present as granulomatous processes cheo-bronchitis or a non-specific type of states have wisely been admitted as acu liosis. It would not seem illogical, there! berylliosis manifests itself as chronic va chronic penumonitis. In common practi nosis of the chronic form of the disease the demonstration of granulomata. Thi: 'cr requiring critical examination. Xo nodular chronic lesions. Asbestos and c< tty analogy is it not passible that too tr bo*n placed on the grannloma as the < beryllium disease and too little on t chronic lesions associated with the inhale A review of the Saranac Laborato Traled that granulomata constituted the bout two-thirds of the cases (Figure [141] /'TV-' 'l / o 'o ' oc 1 :UC': oco o o c : O O i O : OC 1ii;; ! i io o o 5ffl I O ! oE o ! Ccc fc) i o l "aouC0Os) : 2; o >> : 12 i o a* 8E i o i W> <3 1 ! j o | `aSo.o aco) JO 0 0 1 1 : ;c : io i ! jO : >* 300 O O : i :o ^ ' ' ; ; ; c ' ; o i 30 00000000002! oac. ll : -- ^o r=r.c= -r x . c^ -- * (3 > -- x .e ~ .5 >UUSZC-k2^ co 5 b i co vh js a o=c. 2 cu tave 2 I O t)Da)4)OiOQ;:i4)D4;otj CSCCGCE XrCQ0C3EC [ HO] Rather obviously it is impossible to present in this paper all the data systematically garnered through these studies. Reference 'will be made instead to certain highlights of our experiences which may have topical significance. That new facts about beryllium disease may be of interest seems probable, for in many ways this entity is still a mystery. Furthermore, although a great deal of engineering skill has been applied to the prevention of beryllium disease and the numbers of new cases have been gratifyinglv and progressively curtailed, it would seem that the danger has by no means been vanquished. The increasing importance of beryllium in the atomic energy industry and in metallurgy points to the possibility that further human exposures may yet occur. Chronic Berylliosis versus Chronic Pulmonary Disease of Beryllium Workers This is the first matter which needs clarification. Semantically considered, the issue appears to be tautological. The question to be considered is whether the concept "berylliosis" has not been unduly narrowed down to a limited category of pathological states resulting from exposures to respirable beryllium compounds to the exclusion of pulmonary lesions other than the granulomatous process commonly regarded as the essential component of the pathological entity. The question now is whether these non-granulmatous lesions should also on their own be recognized as pathognomonic manifestations of the chron ic form of the beryllium disease. The primary pulmonary manifestations of beryllium disease do | not present as granulomatous processes. There may simply be a traJ cheo-bronchitis or a non-specific type of chemical pnenmonitis. These states have wisely been admitted as acute or subacute forms of beryl liosis. It would not seem illogical, therefore, to anticipate that chronic berylliosis manifests itself as chronic varieties of tracheo-bronchitis or chronic penumonitis. In common practice, on the contrary, the diag nosis of the chronic form of the disease has been made dependent on the demonstration of granulomata. This seems illogical and is a mati ter requiring critical examination. Not all dusts necessarily cause nodular chronic lesions. Asbestos and coal dust are notable examples. | By analogy is it not possible that too much emphasis has in the past been placed on the granuloma as the exclusive criterion of chronic beryllium disease and too little on the other non-granulomatous chronic lesions associated with the inhalation of beryllium compoundsf A review of the Saranac Laboratory series of human cases re vealed that granulomata constituted the dominant universal lesion in about two-thirds of the cases (Figure 1). In the remaining third, [1 ] Beryl T A B LE 2. Beryllium Compound* Teeted fo r Their Capeeity to Cause Syntemir Derangement or Fatal or Chronic Leelona or to Provoke Neoplaatic Change*. Period -- 1954 and 1955. Guinea Pigs <3 <1 1 N&G N&G A A Inhalation Monkeys 1 -1- A 1 A , <3 <3 <3 <1 z o o Rats D Q + CT ~s3 Z ; O C z tZ* Db C + ~--r + H--h J + 1 i i ! a ED O <3 < < < <3 < < 1 1 1 i 9ubcutaneoiis R abbits Swine ! 3a a + ^- + + + 1 1 111!1 ! g co *5 w T3 ag w4>> .co2n c ^2 <D *T3 C 3 *U * 2 a S' e E ` Mc 2 a o > >> ,'3 u at S3 11 *53 2 (2 oz BER YLLIU M COMPOUND B e ry lliu m F lu o rid e .................. B e ry lliu m O x id e ....................... B e ry lliu m Phosphate............... B e ry lliu m S u lp h a te .................... Z n -B e -M n -S ilic a te ...................... Zn-Be-M n-Silicate plus A .T.A . Z n -B e -M n -S ilica te nlua C ortisone ......................... Z n -B e -M n -S ilica te plus M g T u n g s ta te ................ BeSOj plus Q u a rtz ..................... BeSO plus F e tO j....................... BeSO plus Asbestos................ BeSO plus F iberglas................. [142] granulomatosis was either* an inconsi In the Laboratory we also have a coi rejected as instances of berylliosis be found. Several of these cases had be* lium-containing aerosols and their lu chronic lesions of the kind that accot ceptable cases." On chemical or spet yielded as much beryllium as was pr diagnosis of berylliosis was accepted b loznata. The question now arises whetl mata should not also be included as in? yoked pulmonary disease, either becau logical phenomena or because of their the series of cases under review, inter infiltration (Figure 2) with or withou reticulosis (Figure 4) constituted a the cases and was absent in less than lialization of the alveolar walls and p of macrophages of the same kind that < lomata occurred with the same free other histological prevalences could he Suffice it to record at this stage common feature in chronic beryllium nificant characteristic of the patholc ultimately prove to be a sign of less panying histo-architectouic changes ii of the latter, perhaps a sign of inad< fortified in coming to the latter coc growing body of experimental evidalmost indistinguishable from those for berylliosis may be provoked by su as well (Figure 6). The granuloma it cific manifestation of the reaction to i To make a diagnosis of beryllium disei additional histopathological diagnostic duction of proof that at least the sp beryllium, is also present Evidence concerning the range of which accompany the granulomatous constitute the chronic beryllium pule possible factors in their genesis, will I this connection reference may be mad' apparent that at least some of the var [143] Ilciyllium Oxirio < <1 0! w ' -3Z . Z <a <1 <1 <3 aa 08 3 < <3 zz 5P ccs a? - -r t -f---- 1- + V ! ! . i - < < < < <3 < I ! --- r + + | ! I I j I w & >v.S |J o E8 3= If Ec j{ > a p8 < .3 3 'c. ji J | 33 3 3l 5X TN ^ bfi f*g.JJJ bue3JJ! m c c c i" S 3 3 3 i 12SS O S 2 a *3. *5. *3. =>bc=%. =>Uot CiscD CcDI C4cD! SCSNN -3> CfS^DSS--.<rdr8<rdn8<d8<or8 t5 CQ CQ CD CD 1.5 55 3 '3 B1. OQ. > w `S & <J +CZ [142] granulomatosis was either an inconstant finding or entirely absent. In the Laboratory we also have a collection of cases which had been rejected as instances of berylliosis because no granulom&ta could be found. Several of these cases had been adequately exposed to beryl lium-containing aerosols and their lungs were the seat of abundant chronic lesions of the kind that accompany the granulomata in*'*ac ceptable cases." On chemical or spectrographic analysis these lungs yielded as much beryllium as was present in those cases in which a diagnosis of berylliosis was accepted because of the presence of granu lomata. The question now arises whether these cases without granulo mata should not also be included as instances of chronic beryllium-pro voked pulmonary disease, either because of the associated histo-pathological phenomena or because of their high beryllium content. Thus, in the series of cases under review, interstitial or alveolar mural cellular infiltration (Figure 2) with or without collagen fibrosis (Figure 3) or reticulosis (Figure 4) constituted a dominant lesion in about half the cases and was absent in less than eight per cent. Likewise epithelialization of the alveolar walls and prevalence in the alveolar spaces of macrophages of the same kind that occupy the centers of the granu lomata occurred with the same frequency (Figure 5). Numerous other histological prevalences could be elicited (Table 3). Suffice it to record at this stage that while the granuloma is a common feature in chronic beryllium disease, it is not the only sig nificant characteristic of the pathological process and may indeed ultimately prove to be a sign of lesser importance than the accom panying histo-architectonic changes in the lung and, in the absence of the latter, perhaps a sign of inadequate diagnostic value. One is fortified in coming to the latter conservative conclusion because a growing body of experimental evidence affirms that granulomata almost indistinguishable from those long considered pathognomonic for berylliosis may be provoked by submicron amorphous silica dusts as well (Figure 6). The granuloma may thus prove to be a non-spe cific manifestation of the reaction to inhaled dusts of a wide variety. To make a diagnosis of beryllium disease would in such a case require additional histopathological diagnostic criteria and perhaps the pro duction of proof that at least the specific etiological agent, i.e. the beryllium, is also present. Evidence concerning the range of dominating histological features which accompany the granulomatous lesions and which collectively constitute the chronic beryllium pulmonary disease process, and the possible factors in their genesis, will be elaborated elsewhere. But in this connection reference may be made to the fact that it is becoming apparent that at least some of the variables in the pathology of beryl- [143] 1 TABLE 3. Dispersion of Dominant Histological Features in 40 Cases of Chronic Pulmonary Beryllium Disease. None S lig h t M o d e ra te Severe Excessive Tissue Reaction C%WG> 'E D Granulomata Macrophage Core... 2 2 15 14 5 2 Plasma Cell Cortex............... 6 20 9 5 2 0 Giant Cells........................... 5 12 12 7 4 0 * Peripheral Collagen.............. 4 11 11 8 4 2 Interstitial Collagen............. 7 15 10 6 2 0 Peripheral Reticulum........... 4 7 14 9 3 0 Central Reticulum 5 14 10 8 3 0 Alveolar Wall Lesions Macrophage Invasion 3 5 13 9 7 3 Collagenosis............................ 4 13 10 7 6 4 Reticulosis.............................. 0 11 14 15 0 0 Elastic Destruction............... 3 5 9 12 7 4 Ischaemia................................ 8 17 11 4 0 0 EDithelialization.................... 10 7 9 8 3 2 Alveolar Space Changes Macrophages.......................... 2 6 13 10 7 2 Foamy Cells........................... 9 18 9 3 2 0 Organizing Exudate............. 28 6 4 2 0 0 Focal Atelectasis................... 4 7 11 10 8 0 Atrophic Emphysema.......... 6 10 12 6 4 2 Foreign Bodies Conchoids............................. . 19 8 5 3 3 3 Crystal Clefts............ ........ 21 8 5 4 2 0 Pigment................................ . 28 6 4 2 0 0 Vascular Damage Peri-arterial Fibrosis.......... 1 4 20 9 6 O Pericapillary Collagen. 5 12 10 5 8 0 __ Bronchial Damage Peribronchial Reaction.... 4 16 15 4 1 u Endobronchial Reaction.. . 17 15 7 1 0 0 The numbers given in the table are the numbers of cases showing various grades of tissue reaction. [144] Hum disease may be ascribable to etio beryllium itself or to differences in tl form in which the beryllium is introdu depend also on the dosage, on the speed occurs, on the presence of associated di enigmatic factors concerned in individu. probable that the granuloma only arises cal factors are present so that the tn disease may be a non-granulomatoos pre On the experimental side we have : that chronic beryllium disease is more Thus we have shown, for instance, tba a primary pulmonary necrosis and diffi Hum sulphate has a marked propensity of alveolar lining cells with an associa epithelialization of atrophic alveoli. I readily leads to the development of diff these substances may also induce the app ure 7). For long the human chronic dis< animal experiments did not yield abunda lomata have since been produced but th appear only after prolonged exposure pounds. The point which has perhaps 1 not altogether overlooked, may be that duplicated rather precisely many of th regularly accompany human beryllium vey of the animal experimentation it wo pounds basically possess the capacity t of macrophages, of plasma cells, and of thelium, to provoke the deposition of col blasts or fibrocytes and to destroy the 1 thelium. Crystal clefts and conchoidal bophenomena and so may giant cells be structure or its altered biochemical com processes may manifest themselves as , as chronic interstitial collagenoses or The actual degree of resemblance betwee in man match rather closely the nuances possible to provoke in animals. Once it be granted that the grantil a sufficient criterion of chronic berylliui additional aforementioned histological f< ence of beryllium in the diseased tissues [145] TABLE 3. ;iu Histological Feature in 40 Cases ulmonary Bery/fium Disease. 2 2 15 14 5 6 20 9 5 2 5 12 12 74 4 11 11 84 7 15 10 6 2 4 7 14 93 5 14 10 83 3 5 13 9 4 13 10 7 0 11 14 15 3 5 9 12 8 17 11 4 10 7 9 8 7 6 0 7 0 3 2 6 13 10 9 18 9 3 28 6 4 2 4 7 11 10 6 10 12 6 7 2 0 8 4 19 8 5 3 3 21 8 5 4 2 28 6 4 2 0 14 5 12 20 10 96 58 2 0 0 2 0 0 0 3 4 0 4 0 2 2 0 0 0 2 0 0 4 16 15 4 1 0 ... 17 15 7 1 00 ihe table are the numbers of cases showing iction. [144] lium disease may be ascribable to etiological agents other than, the beryllium itself or to differences in the physical state or chemical form in which the beryllium is introduced into the lung. Much may depend also on the dosage, on the speed with which the tissue reaction occurs, on the presence of associated disease, as well as on numerous enigmatic factors concerned in individual susceptibility. It is strongly probable that the granuloma only arises when such additional etiologi cal factors are present so that the true chronic form of beryllium disease may be a non-granulomatous process. On the experimental side we have much support for the concept that chronic beryllium disease is more than a mere granulomatosis. Thus we have shown, for instance, that beryllium fluoride provokes a primary pulmonary necrosis and diffuse interstitial fibrosis. Beryl lium sulphate has a marked propensity for stimulating the growth of alveolar lining cells with an associated macrophage catarrh and epithelialization of atrophic alveoli. Exposure to beryllium oxide readily leads to the development of diffuse vesicular emphysema. All these substances may also induce the appearance of granulomata (Fig ure 7). For long the human chronic disease remained suspect because animal experiments did not yield abundant granulomata. Such granu lomata have since been produced but they are admittedly scarce and appear only after prolonged exposure to a limited range of com pounds. The point which has perhaps been insufficiently stressed, if not altogether overlooked, may be that the animal experimentation duplicated rather precisely many of the histological changes which regularly accompany human beryllium granulomatosis. From a sur vey of the animal experimentation it would seem that beryllium com pounds basically possess the capacity to stimulate the proliferation of macrophages, of plasma cells, and of the alveolar wall lining epi thelium, to provoke the deposition of collagen in the absence of fibro blasts or fibrocytes and to destroy the lung elastin and injure endo thelium. Crystal clefts and conchoidal bodies apparently are secondary phenomena and so may giant cells be a reaction to altered tissue structure or its altered biochemical composition. These fundamental processes may manifest themselves as granulomata or may present as chronic interstitial collagenoses or even as an alveolar catarrh. The actual degree of resemblance between the variations of the disease in man match rather closely the nuances of reaction which it has been possible to provoke in animals. Once it be granted that the granuloma may not in isolation be a sufficient criterion of chronic beryllium disease and that either the additional aforementioned histological features or proof of the pres ence of beryllium in the diseased tissues may be required to establish [145] QQ ^S3V 4/ X&GQV "cao -- E=> => t.i |so. .S.S *3 Mo*>*m ^ 9 w j'; 5*5 < '5 * ;5 ceE*d* v.$ 3< co s i.s 5: Jl we =| 3s h Am 'S3 33 CO 4> S x3 0 20 >so3.0E. 3 3 | >. 2 g | i 2 - 30 4 oE 3 . H 20 O 3 0 _ Ctf ^ b. c 2-6 i! s gW z3 !*g5 >X g !b "<D sO o Cl ! CO <0 to CCOl Col rc0s 0) to CO "V ] Cl I 3 <<NC GO lO 05 oi (O to 05 to 0C0l oo 00 CCOl 01 Cl C0*l >ob 0VN0 CI3 3 [146] an acceptable medico-legal diagnosis, the i the latter question becomes critically rele is sufficient? This -question may never be satisfact. of the paucity of cases suitable for stud induction period for chronic beryllium c terval between the clinical diagnosis and t final failure to secure an autopsy. Our c ing to set minimal effective dosage levels of record that chronic berylliosis has be physicians not only in the absence of pro but even after chemical studies tailed t the reasoning being advanced that the I viousiy been present but had since been e the appropriate biological response. Beryl: on the strength of the demonstration of ties of the element in the affected tissues, medical experience that individuals wh lightly- exposed to beryllium compounds c while other plant personnel apparently m exposed failed to react. The inverse sens roked to explain these phenomena. In c however, the degree of pulmonary react is a function of dosage and duration of e able fact that the lungs of human cases lium disease rather frequently contained Not all these tissues had previously bet lium content and perhaps the concept t exist in the absence of demonstrable q from an erroneous assumption that faik beryllium always signified that it had ii not found. This is not so. Beryllium is a natural constituent c (approximately O.OOOly/M*)* so that tl a lung may not perhaps signify a patholo lium is present in amounts above a certa: theoretical possiblity, admittedly remo; Be* and Be1*, either liberated from ato cosmic sources, may find their wav into therefore, arises as to what would const of beryllium in the lung tissue. Reasoni era who had spent decades inhaling ear * SI. Elsentoud - Ptnontl Communication. [147] 6 and less 28 21.4 aq **r CM aq v cd CM : to CM <> GO CM ` to CM ( CM < ao y q q tr CO ad ao CM co [146] an acceptable medico-legal diagnosis, the new information we have on the latter question becomes critically relevant. How much beryllium is sufficient t This question may never be satisfactorily settled in man because of the paucity of cases suitable for study, the often relatively long induction period for chronic beryllium disease, the often longer in terval between the clinical diagnosis and the autopsy, and the frequent final failure to secure an autopsy. Our current experiments are try ing to set minimal effective dosage levels for animals. It is a matter of record that chronic berylliosis has been diagnosed by competent physicians not only in the absence of proof that beryllium is present but even after chemical studies failed to demonstrate its presence, the reasoning being advanced that the beryllium had probably pre viously been present but had since been excreted, i.e.. after provoking the appropriate biological response. Berylliosis has also been diagnosed on the strength of the demonstration of infinitesimally small quanti ties of the element in the affected tissues. It is a well-known industrial medical experience that individuals who had seemingly been only lightly exposed to beryilium compounds developed the chronic disease while other plant personnel apparently much more heavily and longer exposed failed to react. The inverse sensitization theory has been in voked to explain these phenomena. In our experience with animals, however, the degree of pulmonary reaction to beryllium compounds is a function of dosage and duration of exposure. It is also a remark able fact that the lungs of human cases of chronic pulmonary beryl lium disease rather frequently contained large amounts of beryllium. Not all these tissues had previously been analyzed for their beryl lium content and perhaps the concept that the chronic disease may exist in the absence of demonstrable quantities of beryllium arose from an erroneous assumption that failure to report the presence of beryllium always signified that it had in fact been searched for and not found. This is not so. Beryllium is a natural constituent of the earth's surface burden (approximately O.OOOly/M')* so that the discovery of beryllium in a lung may not perhaps signify a pathological process unless the beryl lium is present in amounts above a certain critical level. There is also a theoretical possiblity, admittedly remote, however that stratospheric Be* and Be', either liberated from atomie explosions or there from cosmic sources, may find their way into human lungs. The question, therefore, arises as to what would constitute a negligible background of beryllium in the lung tissue. Reasoning that those industrial work ers who had spent decades inhaling earth dust would be most likely : M. Elscnbud Personal Communication. [147] [US] to show the extreme upper litftits of "na tion in the lung. a review of the aecuruul. the Laboratory was instituted and this ditional material from various coal rich! contains a relatively high amount of ben these cases has brought to light that coal rather regularly contain a small atnoun 0.00 to 0.02y/G dry tissue with an aver of approximately 0.005y/G. We have elude a number of non-industrial cases tuberculosis, hut have failed to demonsi lium in these cases. Though our inquiry warranted to record that we have found in persons with a known beryllium expo; established anthracosis due to coal roinii The tissues of the coal miners with a as 0.02y/G did not contain any lesions c< beryllium industry employees. Berylliosi; tological criteria in the absence of any den the amount of beryllium present was mi current average for coal miners). The alone, therefore, does not, in the judgme constitute an adequate factor in the di phenomenon is familiar to those of us wt lems of silicosis and asbestosis. Thus, in sil which counts, but the proportion of it w of free silica. Similarly the presence of spaces or in the sputum alone does not bestosis: the asbestos fibrils have to gain e where they provoke fibrosis. The asbest epiphenomenon and not the causative fa bestos fibrils which stimulate fibrosis, bein the average asbestos body, are usually in By analogy we need additional informal covered in a case of suspected berylliosi chemical evidence as a diagnostic criterio; tion we have x-ray diffraction apparatus electron microscopy to demonstrate the i cases of beryllium disease it has not yet what form the beryllium compound con in the genesis of chronic disease. Probs pounds are essentially inert as human pai even perhaps only certain crystal pattei [149] [H8 3 j* *t to show the extreme upper limits of "natural" beryllium concentra tion in the lung, a review of the accumulated pneumoconiosis cases of the Laboratory was instituted and this series was augmented by ad ditional material from various coal fields, it being known that coal contains a relatively high amount of beryllium. Preliminary study of these cases has brought to light that coal miners' lungs, in particular, rather regularly contain a small amount of beryllium in the range 0.00 to 0.02y/G dry tissue with an average beryllium concentration of approximately 0.005y/G. "We have extended these studies to in clude a number of non-industrial oases of Boeck's sarcoid and of tuberculosis, but have failed to demonstrate the presence of beryl lium in these cases. Though our inquiry is still in progress it seems warranted to record that we have found beryllium in the lungs only in persons with a known beryllium exposure and in persons with an established anthracosis due to coal mining. The tissues of the coal miners with amounts of beryllium as high as 0.02y/G did not contain any lesions comparable to those found in beryllium industry employees. Berylliosis has been diagnosed on his tological criteria in the absence of any demonstrable beryllium or when the amount of beryllium present was much less than 0.00&y/G (our current average for coal miners). The mere presence of beryllium alone, therefore, does not, in the judgment of competent physicians, constitute an adequate factor in the diagnosis of the lesion. This phenomenon is familiar to those of ns who have dealt with the prob lems of silicosis and asbestosis. Thus, in silicosis it is not the total silica which counts, but the proportion of it which is present in the form of free silica. Similarly the presence of asbestos bodies in alveolar spaces or in the sputum alone does not warrant a diagnosis of as bestosis : the asbestos fibrils have to gain entrance to the alveolar walla, where they provoke fibrosis. The asbestos body is probahly a mere epiphenomenon and not the causative factor in the disease. The as bestos fibrils which stimulate fibrosis, being usually much smaller than the average asbestos body, are usually invisible by direct microscopy. By analogy we need additional information about the beryllium re covered in a case of suspected berylliosis before we can admit such chemical evidence as a diagnostic criterion. For free silica determina tion we have x-ray diffraction apparatus and for asbestosis we have electron microscopy to demonstrate the ultimate causative agent In cases of beryllium disease it has not yet been established in precisely what form the beryllium compound constitutes an etiologieal agent in the genesis of chronic disease. Probably large numbers of com pounds are essentially inert as human pathogens with a few only, and even perhaps only certain crystal patterns among these, having the [149] 2^/-/w /r^ [150] capacity to cause chronic disease. Many o are inert with respect to certain animal s[ Such generalizations may fortify tho immunity for certain beryllium industries therefore, that our Saranac Laboratory examples of the chronic disease from en major industry in the country which h. pounds. Thus we have cases from industrii the extraction of beryllium from ore and t lium copper master alloys: cases fr:m br electrical industries: and even a case arisir The fluorescent tube industry has yielded Lung Cancer Caused by Beryllium Com; One of the more spectacular results with our studies on beryllium concerns the This discovery was presaged by Doctor Ga tion that flnorescent tube powder (zinc be: induced bone sarcoma in rabbits and guii jection. It has now been possible to sho' causes squamous cell carcinomatosis in n the beryllium in the compound mixture monary carcinogen has been confirmed 1 beryllium sulphate (Figure 91. All the cinoma have already been produced and after a relatively prolonged induction pe and 11). Though frequently multifocal in or malignant, metastasize and would eventual' disturbed. The normal control rats have n similar pulmonary tumors. Not only ha planting such tumors to subcutaneous ti.< have succeeded in retransplanting such ( other rats now even to the fifth suceessit planted tumors have retained their capaci conducted studies on the possible co-carci with quartz, iron and asbestos dust. The 1 ress but the earlier studies showed that th or iron in the lungs of animals exposed t* Acknowledgement H made to Dr. O. J. Dodrogc th Saranac Laboratory for their asaittaoce in O [151] / [150] capacity to cause chronic disease. Many of these substances certainly are inert with respect to certain animal species (Table 1). Such generalizations may fortify those who have been claiming immunity for certain beryllium industries. It is necessary to confirm, therefore, that our Saranac Laboratory cases include indisputable examples of the chronic disease from employees of virtually every major industry in the country which has handled beryllium com pounds. Thus we have cases from industries primarily concerned with the extraction of beryllium from ore and the manufacturing of beryl lium copper master alloys: cases from brass foundries; ceramic and electrical industries: and even a case arising in an atomic pile worker. The fluorescent tube industry has yielded the largest number of cases. Lung Cancer Caused by Beryllium Compounds One of the more spectacular results we have recently obtained with our studies on beryllium concerns the production of lung cancer. This discovery was presaged by Doctor Gardner's original demonstra tion that fluorescent tube powder (zinc beryllium manganese silicate) induced bone sarcoma in rabbits and guinea pigs on intravenous in jection. It has now been possible to show that this same substance causes squamous cell carcinomatosis in rats (Figure 81. That it is the beryllium in the compound mixture which constitutes the pul monary carcinogen has been confirmed with repeated success with beryllium sulphate (Figure 9). All the common varieties of car cinoma have already been produced and the yield of tumors is high after a relatively prolonged induction period (Table 4, Figures 10 and 11). Though frequently multifocal in origin the tumors are truly malignant, metastasize and would eventually kill the victims if left un disturbed. The normal control rats have never been observed to yield similar pulmonary tumors. Not only have we succeeded' in trans planting such tumors to subcutaneous tissues of other rats, but we have succeeded in retransplanting such growth subcutaneously into other rats now even to the fifth successive generation.' Even trans planted tumors have retained their capacity to metastasize. We have conducted studies on the possible co-carcinogenesis of the beryllium with quartz, iron and asbestos dust. The latter study is still in prog ress but the earlier studies showed that the presence of either quartz or iron in the lungs of animals exposed to the beryllium sulphate Acknowledgement i* made lo Dr. O. 3. Dobrofonkl and Mr. A. B. Milunt of the Saranac Laboratory for their axvlstance in the program of tumor trmnapi&nts. [151]  I < i-' ( /y i modify the carcinogenic potency of the latter substance perhaps sig. nificantly. These studies pose the grave question whether beryllium may not ultimately prove a factor in the genesis of certain cases of human lung cancer. In this connection the marked proclivity with which the beryllium exposure induces the alveolar lining cells to proliferate may con stitute the precursor for a later neoplastic change. All that may be necessary may be an adequate induction period. A recent biopsy speci men from the fluorescent tube industry quota of pulmonary disease seems to illustrate the exaggerated degree to which the alveolar epi thelium may proliferate. This may constitute a pulmonary variant of carcinoma in situ (Figure 12). (00 EXPERIMENTAL PULMONARY NEO SC CARCINOMATA FOUNO IN 131 RATSIX months exposure at mmala to BERYLLIUM SULPHATE CUMULATIVE TOTALS MONTHS 3 9 12 EXPOSURE TO BSO 1-4------------------------ SURVIV9 Figure 10. 9 EXPERIMENTAL PULMONARY NEO SI RATS WITH ac CARONOMAT. SIX MONTHS EXPOSUtC BY tetALA 4 TO BERYLLIUM SULPHATE PRODUCTION RATES 3 Z- Figure 9. Pulmonary Adeno-Carciaoma -- Rat Lung Experimentally Induced by etx months exposure to beryllium sulphate. (Hematoxlln and Eosln - 300 x) [154] MONTHS 3 B 9 12 EXPOSURE TO B'SCU -4------------------------SURVn Figure 11. [ 155 ] potency of the latter substance perhaps sig- le grave question whether beryllium may not in the genesis of certain cases of human lung i the marked proclivity with which the beryl? alveolar lining cells to proliferate may cona later neoplastic change. All that may be uate induction period. A recent biopsy gpecit tube industry quota of pulmonary disease caggerated degree to which the alveolar epi- This may constitute a pulmonary variant sure 121. #o s ally induced by sis months exposure to beryllium sulphate, latoxlin and Eosin - 300 x) [154] Figure 11. [ 155 ] rr., II SUMMARY 1. The whole problem of elirnuie beryllium disease of the lungs ia reviewed in the light of a re-examination of all the human material assembled in the -Saranac Laboratory and all the experimental data. 2. It is suggested that the granulomatous form of berylliosis is but one of the many histoparliological manifestations of chronic pul. monary beryllium disease. -- 3. The validity of the beryllium content of suspect lung tissue as a diagnostic criterion is re-examined in view of the fact that coal miners' lungs contain small quantities of the element. 4. Pulmonary cancer has been experimentally produced in rats on exposure to beryllium sulphate and beryllium phosphor and this poses the grave question whether human subjects exposed to beryllium compounds may not eventual1.'" develop similar neoplastic pulmonary changes. I-H-F JOINT MEDIC CHEMICAL-TOXR CONFERE MODERATORS: ANNA M. BAETJEF School of Hygiene end Pubi The Johns Hoofcint Unr Chairmen, Chermeel-Touco-ogiCf Industrial Hygiene Foun A. G. KAMMER, Graduate School of Public University of Pittibu* Co*Chai*m*, Medical CcIndustrial Hygiene Four. Figure 12. Proliferating Alveolar Epithelium -- Simulating Carcinoma in Situ Lunr hionsv from a person emplnvxj in (he dis posal of beryllium roniaintnc fluorescent lubes. (Mallory - 1 TOO x> [ 156 ] v `