Document zoEvp3rnX3385ZQqqL4myv3J7

343 Experimental Asbestosis Paul O rtas, M D: R obert T . P- deTreaSle. M D , DSc: E thel B . Tot& er.BS; M arianne K atchak, BS; and M ary A nn Wed&ek, B S, FlH tetioih jr, MD. formerly t the De ' Research, S i X ate^ Ho ...... ........ Paul G n a , MD, 'ft the Hygiene Foundation, M M A helped 7. King, T M JX i Measurement of Functional He- Capacity in the Bat. d Appt P h y M 1233- f l* . '.. ' . 8. |fojit J .. apd Whittenberger. M<"'. i ifiininn t,lltnrH ' ` . Spiration, 7 App* (juoeFim ,` 9. Ctaaby, W.H.; M tau. aud ita , F.W.; " _ a .M atbod tor ....... ...................... m A n ie d FaTeet M ed ' * 6 4 - Vi -V^f'tl^, : 1L tew r,M .G ,, e l a!: Blood Q , Content U ag r % `3he Oagqgn Electrode, J A p p l P hysiol M K W . -V`- a * a*K 12. Dmmfit, IdS- Quantitative Methods to the ' itudy o f M a a a q r M a t t e r , TAomi I7329-333 ' .Dec) 1902. m; HISTORY , n age of transition, the fitst major cultural ... `'. C. H ie changes go on about ua are ao - --x la lifetim e than generations of aurauoes- : to to be alive.--Coon. C.S.: The Story of - ' JureandB eyond,ed% N et- Todc: " D u r in g a Study of experimental asbes M aterials and Metbods tos involving guinea pigs, rats, and hamstem that had inhaled dirysotite dust, ft found th at pulmonary cancer had drooloped in several rats. Spontaneous primary . Canadian chrysotile asbestos was baU-milled and a te q u r a fir hammer-milled, using essen tially toe metood pf H d t et ah* The principle of th techoiqoeis to relax lb s comminuted lung cancers exclusive of lymphdblaatea- chrysotile totoqgh the hiripspeed femmer-mill ta, Is bom exceedingly rare in our rats so to a t m u cM fth ed u st to o f ulttemieroseopic - (we have not seen a single spontaneotis piri- dimensions ( llg l) . y ito to leto tfa^ erne y e , ' mary pulmonary cananoma or fihro8anBaa in about IDyOOf) rats examined). Therefore, a cause-and-effect relationship between the pulmonary deposition of dirysotfledustand tumor development was suspected. Stwpidon tecreased as the number of malignant lung tumors discovered in rats th at died more than 10 months after initiation of % a it became nccessry t6 rqplaoeth^ steel-alloy hammers with new pne* bece of excessive wear. Abo; to maximize the dust concentration in the cluim W , tt output ^ a second ham mer-mitt was added to inhalation chamber. The chamber measured 8 X X 8 ft. Initial ly, it had only one foar-ineh input opening con necting with the outflow duet of a hammer-mill. After 52 weeks, a secendfour-taeh input for the ebryaetfle'exposure increased rapidly. second hammer-min w w iintritech There were There has been increasing evidence, three exhaust opentogstothe chamber. Two of mostly epidemiologic, linking tong-torte ex these were 1.5 inches to diameter each. Both posure to asbestos dust with gm devefop- led to electrostatio preripitato sold then con meid of pulmonary cancer in man.*-* Since nected with a vacuum pump. The flaw of ex the development due to the pulmonary osition of chrysotile asbestos chat of mary lung cancer in an experimental dep pri- a n i haust air through one precipitator was approxi- 1, mately 125 liters per mioute whereas the flow through the other precipitator was adjusted ac curately to 8 liters per minute. The dust to the mal has not been reported, the occurrence latter was carefully weighed at the end of each of malignant lung tumors in our asbeetotic week to detonate to e avtoag dust eneentra- rats is being reported and a hypothesis ex tion to toe chamber dtntog took Week. The plaining this phenomenon is offered. total exhaust <nmng to too chamber, ten inch es to diameter, lOd to a ten-toch tornaoe-type Submitted lor pftlieatKn May 4, 1967; accepted May 24. . -' - , From tbe Industrial Hygiene Foundation, MeHaa taitoto, Pitfaburgh. . * <4 filter and then to an toh*tok t o - `I'fie latter w w ,uaei;la'toihw H #h cum ber rapidly a t the end of each day's exposuto The chamber was actuary m ^ ^ a rikrit, h u t A n 8e, negative SB IS, Sept 1967 Arch Snobon U tO Kh-Vot IB, Sept i m 'wus" op y y i w . 1iu "Jii'gigtonwnpo 1 -la-Afcj 844 E X P E R IM E N T A L A SBESTO S1S-G IO SS E T AL A total of 131 nude w hits rats were exposed to chiysotile dust i s the chamber s hours a day, five days a week for a maximum of 62 weeks. O f these 131 anim als, 70 had had an in tratracheal application of 0.05 m l of 5% aqueous sodium hydroxide, the purpose of which was to impair clearance from the lungs of inhaled d u st (T he 70 rats were the survivors from a total of 81 anim als that had received the caustic applications Intratracheally.) T he in tratracheal caustic applications were accom plished with the nimnl under ether anesthesia and with the aid of a self-retaining illum inated speculum that allowed visualization of the vo cal chords. A kmg lS-gauge needle attached to a m icroliter syringe was used. T he end of the needle wa plugged, rounded off, and two sm all openings made on opposite w alls about 5 mm from the tip. After expelling the contents of the syringe onto the tracheal w all, the needle was withdrawn with sptad m otion to distribute the caustic as widely as possible. The caustic-treated animals were introduced into the Inhalation chamber at different stages of healing of the tracheal lesions. Some were exposed to the dust im m ediately; others, one, two, and three weeks after the caustic applica tion. The 61 rats not treated w ith caustic were also exposed in the chamber to chrysotile dust Fig 1.--Electron photomicrograph of chiysotile dust and were assumed to have normal tracheas. obtained by thermal precipitation from the inhalation D ust exposures were discontinued after 62 chamber. weeks. The survivors were then pastured for the remainder of their lives. _ D u st concentrations in th e cham ber during the first year, w ith on ly one m ill in operation, ranged from 42 to 106 m g /cu m . D uring the second year, w ith both m ills in operation, th e range w as 67 to 146 m g/cu m . T h e overall aver age w as 86 m g/cu m (based on w eekly deter m ination s). A nother group o f 64 rats w as given intratra il. in jection s o f ch rysotile d u st obtained served a s laboratory controls and treated in any manner. They were ] room, remote from the exposure ch were pastured for the remainder of L ~ ---- Another group of 15 rats served as controls for the caustic intratracheal applications. They had survived an intratracheal application o f sodium hydroxide but had not been exposed to asbestos d u st Finally, a group o f ten rats served as con trols for the rats injected intratracheally with t th e electrostatic p red p i- h e sam e in jection Table 1.--Overall Mortality and Lung Cancer incidence _____ _ was used as that used for intratracheal caustic applications except that the 16-Month .Survivors Rat* With Lung Cancer* 18-gauge needle had its open ing in the tip, the edges of Animal Group No. of Rats No %ot * %of Total No. Survivors which were rounded off. T he Chrysotile inhalation with dose injected was 3.5 m g sus intratracheal NaOH 71 ' 31 44 15 pended in 1 ml water. Of the 64 rats, 14 anim als received but one injection; 14 received Chrysotile inhalation with out intratracheal NaOH Chrysotile, intratracheal 61 64 41 19 67 30 10 3 two; 1 received three; 9 , four; Laboratory controls (no treatment) 40 25 63 0 and 26, six. In addition, 30 rata of the NaOH controls (no ehryeotite) IS 14 93 0 same shipment as that of the ' ` ` exposure rats). 48 24 16 0 0 Arch Environ Health-- Voi IS, Sept 1967 I'^iiWirAVit litfAn-r EXPERIM ENTAL. asbestos dust. They had received intratrac injections o f water. The survivors o f the m ultiple intratrac chrysotile injections were killed 21 months er the first h jecfio s. The tangs o f idf <*&.,w w e distended 10% formalin solution under * pressure o cm water. Sections went cot a t 6 s from M of tang mrifedried In paraffin and stained hematoxylin mad esta. A fter photomicrc phy the M ettons were deodorized and imp nated with s6l*W according to the methcx Gordon and Sweets. Som e sections were incinerated in order to obtain information the am ount and distribution of the chrys The earliest lung cancer was found i rat that had died 16 months after initial of chiysotile dust exposure in th e inhalal chamber. Calculations of the prevalency lung. tumors were based on the numbei animals that live 16 months or longer a having been placed in the inhalation ch ber (72 rats) or after they had received first intratracheal injection (19 rats). Of 72 surviving rats front the inhalation ch: tar, 31 had received an intratracheal plication of sodium hydroxide and 41 : not been so treated. (These data are she in Table 3U> Many lung cancers were microscopic size but scans were visible grossly, the : ranging from 1 to 6 mm in diameter. AH mors were peripheral in location and n originated in a bronchus or bronchiole. ' tumors were light gray-tan in color, bul slightly above the surface, and were cove by a shiny, thin, transparent pleura. ' consistency was firm, verging on hardn On section, the tumor presented a d gray, dry, and compact appearance. The surface did not appear to retract or bu The edges of the tumor were smooth : stood out sharply from the surrounding tracted, moist, generally dark-red lung sue. There was no evidence of a caps Distinguishing these tumors grossly fi the lymphoblastomata th at occurred Sp taneously in our aging rats offered difficulty. The latter tumors were loeatec the hilar regions, although some of the lx ones extended to tits periphery. T were infiltrating, hence their edges were Arch Environ Rei u iiiy u y p ! V; 'isyFprrwi O m s s ET AL ^ in l ii a i i f iMiii K'inta^Wi E X P E R IM E N T A L A SBE 8TO SIS--GROSS E T AL asbestos d u st They had received intratracheal injections o f water. The survivors of the m ultiple intratracheal chrysotile injections were killed 21 months aft er the first injection. The lungs of ail rats were distended with 10% formalin solution under a pressure of 12 cm water. Sections were cut at 6p from M s of lung embedded in paraffin and stained with hemataxyfift and eosin. A fter photomicrogra phy the sections were decolorised and impreg nated with silver according to the m ethod of Gordon and Sweets. Some sections were also incinerated in order to obtain information on the amount and distribution of the chrysotile dust. . ! 1.-- Election photomicrograph of chrysolite (test 1 by therm al precipitation front the Inhalation tved as laboratory controls and were not - Sated in any manner. They were housed in a , remote from the exposure chamber, and ' pastured for the remainder of their lives, er group of IS rata served as controls for t caustic iritratracheal applieation3. T hey had l n intratracheal application of sodium i b a i not b te,ew w 8lte, asbestos , a group of ten rats served as conthe rats injected intratraeheally with and Lang Cancer IneWence* SJJ", R ats With tting Cancer* % ot Total *of No. Survivors 71 31 44 15 0 .. wt 61 41 67 10 r ^ t 64. 19 30 3 48 24 lfi 40 25 63 0 0 id IS 14 93 0 0 . fhobtestomas-thnown to occur spontaneously in thssn Jii, j'ljf IS, S ept 1967 il Vf The earliest lung cancer was found in a rat that had died 16 months after initiation of chrysotile dust exposure in the inhalation chamber. Calculations of the prevalence of lung tumors were based on the number of animals that live 16 months or longer after having been placed in the inhalation cham ber (72 rats) or after they had received the first intratracheal injection (19 rats). Of the 72 surviving rats from the inhalation cham ber, 31 had received an intratracheal ap plication erf sodium hydroxide and 41 had not been so treated. (These data are shown . in Table 1.) Many lung cancers were microscopic in size but some were visible grossly, the s te X 40). ranging from 1 to 6 mm in diameter. All tu mors were peripheral in location and none sharply defined. The cot surface was glisoriginated in a-bronchus or bronchiole. The tening -gray, tended to bulge slightly and, tauwra w erelight gray-tan in oolor, bulged . most important, itte n d e d to b e tabulated, slightly above the surface, and were covered e a * lobtoe havtag atto y h o le to tte center, by a shiny, thin, transparent pleura. The The hole was the lumen <rf either a veaeelor consistency was firm, verging on hardness, a bronchus (or bnm diiole), heroes toe On section, the tumor presented a dull, lobule represented adventitial and periadgray, dry, and compact appearance. The cut ventitial tumor Jnfiltmtion. surface did not appear to retract or bulge. Altogether, there wetoi.28 animals with The edges of the tumor were smooth and primary malignant tumors of the lung, exstood out sharply from the surrounding re- elusive of spontaneously occurring pulmotraeted, moist, generally dark-red lung tis- nary lymphoblastoma toft inclusive to one sue. There was no evidence to a capsule, malignant mesothelioma to toe pleura and Distinguishing these tumors grossly from three questionable, but probable, adenocartoe lymphoblastomata th at occurred spaa- ctoamata to toe lung. The overoB prevtaneously to our aging rate offered no aknro v m 3 ^ Itortft en 9 | ftntomls aurdUBctator. The latter tumors w en located to vivtog 16 months o r longer. Of (lie 28 rats the hilar regtans, although some to the larg- wito roallffsadt puhaenaa^ ttmjonh 25 had cr ones extended to the periphery. T ito fahatod dnysotite toto, stog tois grtm a tone infiltrating, hence their edgro were km cancer prevalence to ff% (baect o n e - draft Environ Hanttk-Vol IS, Sept 1967 iniuijipMii`" wraujirawite'ronw,1 !"illtl 'W-'eetou fiW W ^11'""" ""wwy11! T7----^-^-7 w - :V, * % * 346 E X P E R IM E N TA L ASBESTO SIS--GROSS E T A L E X P E R IM E N TA L AS: Fig 3.--Adventitial and perfadventttial Invasion by tum or glands about a pulmonary artery in a rat ex posed to ebryaotilo dust for 62 weeks beginning three weeks after the intratracheal caustic application. It died 15V4 months after removal from the exposure chamber (hematoxylin and eosln, X 150). hort of 72); three had been injected intra tracheally with the dust, a prevalence of 16% (based on a cohort of 19 rats). Of the 25 antealB with primary lung cancer in cluding the mesothelioma in the inhalation group, 15 had received an intratracheal ap plication of lye, giving a cancer prevalence of48% (based on a cohort of 31 rats treated with lye and surviving 16 or more months). The remaining ten animals with lung can cer that had nothad intratracheal lye treat ment, represented a cancer prevalence of 24% based on a cohort of 41 Tats. There were 17 rats with certain adenocarcinomata and three animals with question able but probable adenocarcinoma. Of seven rats with flbrodarqomatous lung tinnors, three are also listed with the ones having naiy squamous cell cancer, one also is fisted wife tbo 20 buying adenocarcinoma. A list of.the animals with Iw ks% their ea$Q08^ survival time, and nature of the tumor is given in Table 2. No lung cancer was seen in any control nnimnl other fban the spontaneously occur ring lymphoblastoma. The of adenocarcinoma is usu ally not difficult since a large nodule com posed of crowded, diminutive and atypical glands makes recognition of this malignant tumor relatively easy (Fig 2). Often, how ever, other foci of altered morphology in the same lung or even In the game fwcfcfan lead to less certain conclusions. The diagnosis of some pulmonary leaiqns is not easy and, in able but probably eonect.* i fairly common, but fascinating lemon inwdvea cegiims of wlhihr, collagenous scarring aSecting tespiratory bronchioles, theiradjoining abwdar duct* and their eraginating alveoli. lb few Tab 2.--Fata With Lung Dust Exposure NO. O f Rat Survive Me. NaOH* 62 Waeks Doses (Mo) a m -- 16 8847 * + -- 16 8742 1 + -- 16 8752 0 -- 16`A 8761 I + -- 16(4 9068 0 + -- 23 8747 3 * -- 25 8781 z -- 26 8340 0 Hh -- 26Vi 883* -- -a 27 8836 + * 27 8782 8863 z -- + -w 27 -- i 27 8767 1 + --* 28 8854 -- rk -- 28 8743 8828 8788 1+ *+ '3 ' ` + - 28 -- 28 -- 28 8768. 8811 '8 8 0 1 -w + * -- 29 -- .3 0 -- 31 8783 10886 10067 11175 2 3 3 -- + .. + * -- -- -w -- 31 32 32 34 9188 4 -- 6 21 k: 9191 -- -- 4 21 K 9204 -- 4 21 K * Applied intratracheally w eeks prior to inhalation e caustic application are designated by 0. Those ( ta t reo t Exclusive of lymphoblastoma, which is a common : carcinoma; 5q. squam ous: Fibre, fibrosarcoma: Maso, i I Killed. All o ther anim als w ere found dead in their c ecarred foci m many lungs, the air spaces are Hi^d by darkly staining ouboidalto columnar i epithelium. The combination of distortion of ! the air spaces with abnormal epithelial lin ing give the impression of neoplasia. Be cause the lining epithelium is uniformly regular, well oriented, and devoid of exces- Tabte 3.--Trace-Metal Content of Chryso and of Worn Part From Hammer Mi Chrysotlle * Element icfcel ''"tomtom lead " P riorto im /im Sample 134.0 8 .8 114.6 Men After Hammer Milling M8/nm Sample 248.5 ' 21.6 153,3 37.9 Incree 96 82 145 34 ... A n h Environ H ealth-Vol IS, Sept I9S7 Arch Environ Health- mmmm mm m m m *m pgpp ) of on* of M many i,,. . ___________ j **fe**WBe * tongs- w ri 'tif*e **a tosrpoaiptesytic csubtoids!aepitrhelisums.JH. a. .... '* w S * * * thick but not eoltogeniiod. The lesta. an adenoma, but more tHtely repM*** 1 mrt*pl*l* end hyperplasia. Fremthe >in Fig3 (hematoxylin and eosin, X 150). bnev and nature of the tumor is .to Table 2. seen in any control , I other ffonn the_ spontaneously occur' '**' ^T he diagnosis of adenocarcinoma is usu- not difficult since a large nodule comof crowded, diminutive and atypical makes recognition of this malignant relatively easy (Fig 2). Often, howother foci of altered morphology in the to--~ lung or even to the same section lead .,VA leas certain conclusions. The diagnosis r' J |f some pulmonary feafensfe not grand, fa km instances, was designated as "cpiestlon` iH ebut iobably correct." A fairly aminon, ................................. involves regions of re- and their evaginating alveoli. In a few mm |fe * , a m ritiirmsiiiialifiii m EXPERIMENTAL ASBESTOSIS--GROSS ET AL 347 Table 2.--Hate With Lung Tumors and Tholr Survival Dust Exposure No. of Primary Lung Cancers! Rat 3.5-rog Survival* ..... .......... No. NaQH* 62 Weeks Doses <Mo) Aden SqCell Fibre Meso Adenoma 8804 8847 8748 8752 -- -- 2 0 + + + -- 16 -- 16 -- 16 -- im 4- 4r 4- 8761 1 + -- 1614 9068 0 4- -- 23 + 8747 3 4- * 2514 + 4* 4* 8781 2 4- -- 26 4- + + 8740 0 4- -- 2616 4* 4- 8834 -- 4- -- 2714 4- 8835 - 4* -- 2714 * 8782 , 2 4- -- 2714 8863 -- 4- - , 2714 + 4* 4- 4- 870'1 3 8854 -- 44- -- 28 -- 2814 + 4* 4- 8743 8826 1 -- 44- -- 2814 -- 2814 44* 8796 3 4* -- 2844 4- 8768 1 4- -- 2914 4- 8811 - 4- -- 3014 4- 8840 - 4- -- 32 4- 8783 2 4- -- 3114 4* 10566 3 + - 32 4- 4- 10567 3 4- -- 324 + 11175 -- 4- -- 34 4- 9188 -- -toe 6 21 Kt 4- 9291 -- -- 4 Z l k 4- 9284 - -- 4 21 K *4' * Applied Intratracheally weak* prior to inhalation epoure. Animals exposed to d u st immediately a lte r the caustic application are designated by O. Those th a t received no caustic application a re designated by -- t Exclusive of fymphobtastoma, which is a common spontaneous tum or in th e se aging animats. Adeno, adeno carcinoma: So. squamous; Fibre, fibrosarcoma: Mesa, mesothelioma, t KiHed. AMother animals were found dead in their cage*. *rred foci in many lungs, the air spaces are sive mitotic activity, these fod, if consid lined by darkly staining cnboidal to columnar ered as tumors, should be designated as be epithelium. The combination of distortion of nign, ie, adenomata. But if they are indeed the air spaces with abnormal epithelial lin to be considered as adenomata, they are ing give the impression of cause the lining epithelium is uniformly nary regular, well oriented, and devoid of exoes- (and rarely in rats and guinea pigs). Al though the usual pulmonary Table 3.--Trace-Matai Content of Chiyaotlta Dust and of Worn Part From Hammer Mill adenoma is not circumscribed when small, the Element Sick Cob Chromium Lead Chrysolite it grows, the more it to compress the sur- Prior to Hammer Milling, After H ammer Mining Worn Hammer Increase, From Mitt, and t^us develop a pseudocap- Mg/gm Sample (ig/m gSarhple % jtgfem Sample . suie of compressed lung tis 134.8 246.9 82 2.338 sue- The adenoma-like foci 8.8 21,8 145 185 to the tangs of 114.6 None 153.3 37.9 34 ... 3.5 to moderate Arch Health--Voi IS. i ! i 348 e x p e r i m e n t a l a s b e s t o s i s --g r o s s e t a l EXPERIMENTAL , i,' thrift, ; V , V : ' V / -<i4 ,, -J v J iV .- Jit,1* Fig 5-- To the right of thi* targe adenocarcinfr matous mesa there ere two sm att foci of peribronchioter adenomatosis. To th e right and below center of the field f t a smaller nodule of adenocarcinoma in which glandular epithelium Is darker than In larger m ass. This is from a rat th at received six intratracheal injec tions, each of 3.5 mg chrysolite dust. It was killed 21 months from tim e of the first Injection (hematoxylin and eosln, X 150) Fig 6.-- Small pleomorphic, cells, many of them more o r less i ing the thick walls of slit-like spec-- ------------ -pregnation the thick wails are recognizable as septal walls. The pleomorphic cells are associated with fine argyrophllie fibers distinct from the thicker septal fi bers. This Is from a rat exposed 62 weeks to chrysotile dost without an intratracheal caustic appHcsHon. It died about 11 months after removal from the Inhalation chamber (hematoxylin and eosln. X ISO)- size, lack even a suggestion of circumscrip tion. Other significant points of difference between adenoma-like foci in asbestotic rat lungs and the usual spontaneous pulmonary adenoma of small laboratory animals are the presence in the latter of crowded glands with minimal intervening stroma, tall columnar epithelial 11b with abundant pale cyto plasm, and papillae with delicate stromal stalks. None of these features are found in the adenoma-like lnnns of asbestotic rat lungs. Yet, there are similar foci in which the lining epithelium of the spaces is so crowd ed as to suggest growth activity beyond that consistent with mere hyperplasia; the epi thelium is larger w ith more abundant cyto intra-acinar papillae are present, and smaller oval or tubular glandular struc tures are found within expanses of acellular collagenous stroma. These foci are mani festly neoplastic. Malignancy is by the presence of numerous irregular small glands and ceU nests witbta broad, densely collagenous scars, forming a picture renfinfaewit of a scirrhous breast cancer. In oth er lungs, foci of malignant neoplastic glands may be characterized by cellular atypia such as piling up of nuclei with poorly defined cell boundaries and loss of cellular polarity. Occasionally the diagnosis of ma lignancy is facilitated by demonstration of epithelial tissue in the adventitia or the periadventitial stroma of larger vessels (Fig 3). Diagnostic problems arise when lesions intermediate between those manifestly neo plastic and those considered as atypical meta plasia are encountered. Sudi intermediate lesions are fairly common (Fig 4) ! In a number of rata, multiple fod of ade- Areh Environ Health--Voi IB, Sept v j& i r ! - > . w .r i - y s & ** Fig, 7.--TWa field represents an undifierentiat large call sarorona involving Subpteurel parenchy and aiso extending over the ptaural surface. The sil preparation indicates an intim ate association of a re pbiBc fibers with these ceils. From a rat exposed weeks to chrysotile d u st beginning two weeks after intratracheal caustic application. The animal died l] months after removal from the inhalation cham (hematoxylin and eosln, X 300). nocardnoma are present in the same at tion, indicating the multicentric nature the tumor (Fig 5). In several animals, a cellular fibrosarc matous tumor was found in the lungs (F 6). On the periphery of such tumors, the e spaces are narrowed, their walls thicken and composed of pleomorphic cells with h Perchromatic nuclei and scanty cytoplasi Coherent masses of these cells partially f the air spaces. They are associated with delicate, argyrophilic supporting stroma. TJ more substantial stroma of the alveolar sep< remains intad. Although supafidally reser bling the lymphoblastoma that occurs spoi tanebualy in aging m t* these fibrosarcom; differ from the latter by the pleomorphia of their cells, their tendency to respect tl alveolar architectureat their periphery, an the presence there of a delicate argyrophil Arch Environ flea I 111. uipiu,iiii!spmipM ifRi! "WS ear , u 'rw*F Jjtm * 0 m h n ) m & m am i EXPERIMENTAL ASBESTOSIS--GROSS E T AL n 349 - 5 . / / . 28* ** Fig 6.--Smalt pleomorphic, darkly-shrining tumor >cells, many of them mote or less spindle-shaped, lin t Ing the thick walls of slit-like spaces. With silver im I pregnation the thick walls are recognizable as septal 1walls. The pteomorphlc cads are associated with fine j argyrophilic fibers distinct from the thicker septal fi- hers. This Is from a rat exposed 68 weeks to ehryso. tUa dust, without sir Intratracheal caustic application. [ It died about 11 months after removal from the l inhalation chamber (hematoxylin and eothi, X 15). ___ ______ Malignancy is evidenced by the presence of numerous irregular small i within broad, densely ' a picture remi , Inath- by cellular atypia such ,, piling up of nuclei with poorly umiiwal cell boundaries and loss of cellular polarity. Occasionally the diagnosis of ma lignancy is facilitated by demonstration of wptrtwdw.1 tissue in the adventitia or the periadverrtitial stroma of larger vessels (Fig 3 ). Diagnostic problems arise when lesions ntamndiate between those manifestly neo- plaria are encountered. Such, lesions are fairly comrnon (Fig 4)1 tw o number of rats, multiple foci of ade- -V a t IS, Sept 1987 --This field represents an undifferentiated, large cell sarcoma involving subpleuraf parenchyma and also extending over the pleural surface. The silver preparation indicates en intim ate association 0* rgyro- plkic fibers with these cells. From a rat exposed 62 weeks to chrysotite d u st beginning-two weeks after an intratracheal caustic application. The animal died U /j Fig 8.--Combination of adenocarcinoma and fibresarcom a of file lung. Both fistua tlem ant* are well diffrentfed. Glandular eolia xacrate mucin whereas strem a) coll* are spindleshaped and resemble those of endometrium. This fie(d is taken from file king of the same rat as in Fig 7 (hematoxylin and eotm . x ISO). months after removal from the inhalation cham ber (hematoxylin and easln, X 300). In contrast, the spontaneous lympho- ompletely destroys the alveolar nocarcinoma are present in the same sec architecture .whether it is of the lymphocyte tion, indicating the multicentric nature of or the reticulum cell type. A second form of the tumor (Fig 5). fibrosarcoma was encountered in a lung, with In several animals, a oellular fibrasarco- an adenocarcinoma in which the stroma is matotn tumor was found in the lungs (Fig composed of crowded, fairly uniform vesicu 6). On the periphery of such tumors, the air lar ovoid nuclei and an unusually dense spaces are narrowed, their walls thickened argyrophitic network. In one animal there and composed of pleomorphic cells with hy were foci in which sarcomatous cells resemble perchromatic nuclei and scanty cytoplasm. decidual cells (Fig 7). Interesting combina Coherent masses of these cells partially fill tions of adenocarcinoma and fibrosarcoma the air spaces. They are associated with a were found in several animals (Fig 8). The delicate, argyrophilic supporting stroma. The fibrosarcoma may be pure or may contain mote substantial stroma of the alveolar septa epithelial components (Fig 9). remains intact. Although superficially resem Perhaps the most interesting of all, be bling the lymphoblastoma that occurs spon cause a t its rarity, whs a pleural mesotheli taneously in aging rats, these fibrosarcomas oma in one rat th at covered portions of both differ from the latter by the pleoroorphism lungs and fhs pericardia Hies a. cuirass. of their cells, their tendency to respect the The tumor consists a t straight and tortuous alveolar architecture a t their periphery, and as w dl as brsBddngfafbular glanis seen In be presence there of a delicate argyrophilic longitudinal and cross sections, A rth Environ Health-- Voi IS, Sept - :j-r - i  '*ti,r.;uMibir+t***,* EXPERIMENTAL ASBESTOSIS--GROSS e t a l . IT ; . . yi ` w aa EXPERIMENTAL A r.,g fl ri x =t>r3LV f - *)vV ss^ Fig 9.--Another combination of nd fibrosarcoma of tile lung showing a small gland i the canter surrounded by well differentiated fibro- srcomatous tissue. This is from a rat exposed to chry- e.amMtiloevaadllufsrmtoumfmo rthh6ea2 SIwMeMekIIsIManodtmduietod f 13Ifr rmaonmtHhinsKlbdaiufMtoedri io intratrechea lematoxylln mid sin, X 3 0 . Fig 10,-- Portion of thick, pleural i composed of irregular glands embe collagenous tissue. Except for a few : . foci, the tum or does not invade lung tissue. This tumor woa nfound In a rat exposed to chrysotile dust for 62 ttiicc aanppcation?Tha anim al died 13% months after re " the Inhalation cham ber (PAS stain. X 40). with a moderately cellular but relatively dense stroma (fig 10). The glands are lined by sharply delimited, cuboidai to low colum nar epithelium with round, uniform-appear ing nuclei (K g 11). The lumen of some of the glands contains PAS-positive materi al, yet the cytoplasm of the lining cells is PAS-negative. Tim density of the stroma is i in toe silver-impregnated section risscrossing thick collagen bundles seem to enclose glandular elements. Tim stromal cells are ovoid in shape and their nuclei of a uniform, moderately dense char- act. Over the greeter portion of dm pleur al surface, toe tumor is sharply confined to the pleura. However, in several foci there is superficial invasion of alveolar tissue. Sev- The smallest consists of stroma only and forms a lentiform pleural thickening. Although toe squamous ceil carcinomata are not difficult to diagnose (K g 12), occa sional foci of intra-alveolar atypical squa mous cell production have some malignant aspects (Fig 13). These have been-catego rized as probable atypical metaplasia. Another interesting tumor is a mucinous adenocarcinoma, forming a subpleural mass about 4 mm in diameter. This tumor, also termed "colloid" ogrclnrwng, consists of ir regular, mucin-filled cystic spaces th at have destroyed and replaced the alveolar archi tecture (K g 14). Very few viable tumor cells lining been spaces can be identified (Fig 15). This type of cancer is more com- isolated foci upon an otherwise pleura. Whether these are W ith multicentric primaries is difficult to say. carcinoma that cett to a Arch Environ Health-Vot 15, Sept 1967 I of the lining <. ...... i PAS-posltlve metertal Is p to sti toe discrete pleural foci of the mesothe denoe of . , no satellite nodes or i otter organs in animals with lung cane failed to deutonstmte the presence of a t morto a t coffid have produced a pulmona These hmg cancers have no apparent r latiim to toe degree of asbestotic invoh menf- Not one tumor-bearing rat hi diffuse asbestoses. In all animals the aste totic involvaner.t was multifocal, wh abundant normal, or near-normal alveo1. tesi between such to d . Lesions were os) te e d in the proximal portions of the pi tor toe fhrysotfle dust to ra "k to Arch Environ Het mm rmmm mmm mmm * * * * * .n l'S iH iii EXPERIM ENTAL A SB B ST 0Sm ~G m SS MT AL m m r 1 0 --flortien a t thick, pteitral roeK>thalil torn e t im fr tm gone ombodded In tense ' BxeepMw e te# ito d jM p S fe 1 or <te a a m m * , to. d w s t t o to* to W tfnnlgM ^ en tatoWmSiMI !- sppUBOttnn. The enlmel died 13% nwith e ft re- (rom ttie inhetetion cham tw <PAS Stain, X 40). smallest: eoasiste erf stroma osly and foot erf faira-aiveolar atypical aqua- , 11production fame seme malignant | (1% 13). these have hem catego -probable atypical metaplasia. Another interesting tumor la a mucinous | . . j a subpleural roses' ! 4 a m in diameter. H d* tumor, ah j ` ' to ^ t i l l 14). Very lid i i f f f H b p i * feting these spaces can be identified feat Fig I I .--Higher magnification of cow rel tubules of the nesoWeliome. Cytootasm o f the fining epithelium is PAS-nagatfv although m s-paeitive m aterial is pro- sent in the lumen (X 300). - -- . R g 12.---Irregular eoids an d n ests o f well-difiarentioted sqiMmous cells shew no keratin formation. Ex- teneh* keratfoiiatfon is p n een t in enter fields of this pufcnoMQf aquamovs ce catdnom t. from rat ex posed to chiysetMe asbesto* for 62 weehe without i.yi.np.h...n...o..d..e...a...n..d.. th.e....p..o...shsO,, uIity m at some Of eeusttetoetetoieot Aolm eidiejl M m onthsaasriecnw ial from exposure ch*mbar <fttmtfoxylin and eosin. the discrete pleural feef of the mesofeeli- X ISO). oma represent secondary nodules^ no evi- ' '' - fence of metastasis has been observed in cause-and-effect relationship between ebry- satdlite nodes or elsewhera Examination of aotile dost e ra su re and h a g cancer. Until other organs fit anim alsw ife lung cancer thisstudy, su ch a cause-and-effect reiation- failed to demonstrate fee presence of a tu- ship m a only surmised epidemiok>gically mor that could have produced a pulmonary by a study of workers exposed to chrjreotile metastasis. dust to the British asbestos textile industry* These hm gcancm havottoapifeH m t r e - , (largely prior to 1933). In the United States tation to the degree of asbestotie involve- an epidemiologic study of members of an ment. N ot one ttim orheattog rat had asbestos workers' union also to d tated in diffuse asbestos. In all animals fee asbes- creased prevalence of lung cancer, bat the totto involvement was multifocal, wife nature to fee dusts to which the workers abundant normal, or pesK-nonnat alveolar had been exposed toss uncertain.8 tissue between such fe d , Lesions were am - The present study, with its 31% prev- tered to fee proximal porfems to fee pti- alence to ptomonaqr sneer, is in striking mary lobule. ' contrast to results reported by Wagner e t ah ` 'n o lung cancer. I t seems >'feafc a d ifferenooto susceptibility . cam to fee strains to rats used The development to lung cancer to rats could account for fee dffiecenote to restota. used by the pubnonaiy deposition to S to m p s., fetes is an enefeeot probability chrysotile dust a to M fi experimentally fee fe d a parttetoar quality to chrysolite dust 1. S ept 1967 Arch Environ Heoltk~-Vol S e p t 1967 :' ;' ^TitirkiiifefrifJnfrTiin EXPERIMENTAL ASBESTOSIS--GROSS E T AL m . 'jsJm'Mmi E X P E R IM E N TAl * et transitional et parti!* us epithelial ceB derived by M > iter Unte pftheBlini. Although tei r potertty sud IM M ai sMsd up on ir are unitem i In appearance and show y. Squamous celte ara contaad withta [ o f OWCOtar n p i . MOR **"< o s w testified as neoplastic. This te from a rat that had itenocareinoma b anothar portim f h- Thtt it bad beenaxposad to chrysotile dust for 62 s sad had <Bed 18% mwdbs eftor.rewwfe* *" "! a chamber. There had --< application (hematoxylin and botbi. X ISO). Fig 14.--Typical mucinous adenocarchwma. commonly primwy in gastrointestinal tract but in tuns of rat exposed for 62 weeks to chrysotBo dust wltfaout a prior Intratracheal eaustie application. Pe- m S ^ l l t e T i f f i l ^ i . m " *i destroyed and cr nouml tpl llledtsehlyf t dfed 19% months altar removal team Inhalation tom ber (hematoxyHn and sosia, X 40)- sponse of lung and pleural tissues to this du st These factors are as follows: 1. The chrysotile dust used in this inves deposited & (He lungs of our rats sms sig tigation has a high trace-metal content, con nificant to producing lung ttunors. siderably higher than it was prior to the longed hammer-milling used to prepare the hammer-mill treatm ent (Table 3). The in chrysotile dust to our investigation was not crease in content of trace metals after mill employed to other long-term studies. Wag ing was nickel, 82%; cobalt 145%; chrome, ner e t al* did not further comminute the 34%. Aanlysis of the worn hammer of the dust they tmd for animal exposures but hammer mill revealed a nickel content of reported obtaining material directly from 2,338p.g/grii of sample. industrial dust collecting apparatus. We. 2. There is a disparity in the published toon!liatldW tood>aP>ato^vreareiiote- prevalence of lung cancer among those who ta in ,fta tth e tra ce in fita l m te n to fth e la t- worked in the British asbestos textile indus r. - nun, m i hiIrean as high as in the try prior to 1933 and th at among Canadian dust to which ainr aalmals were exposed chrysotile asbestos miners who worked from (Table S>. The probability exists (hat fee- 1950 to 1968.* Although toe workers to the ~ ' i Arecrystallro hydrated roag- British asbestos tesffle to tash y had a ten fold greater risk of developing lung cancer >account tor toe than had toe general population, fids to- / , ........... of several s -pH In Fig 14. shows thn _ . I o f there o rto , a feature car p re s e t in th is typ of cone (tiemetoxyVn end : risk of lung cancer was not ---------- j t o toe Canadian d ay /-* Aside from- differences to t tie conditions, ethnic backgrounds, A of dust exposure^ and possibly also to t ing habitsi, ft appears probable that < ito th e d u s tits e lf to which thee ' ' groups had been exposed for the disparity. For examp the mines, chrysotile mineral is sub; to considerable crushing contact with strength steel -alloys to "open" the and remove adherent nonfibrous mi components prior to shipment to mar turors. However, considerably more t rive contact with nickel- and chrome llo^m volving more and more of the carding as well as ......In toe fabric am arm er Arefc Environ HeaUK-Vol 15, Sept 1967 Arch Environ PPP u iy . t e j i g i p - ' <rm 'K- I E X P E R IM E N T A L ASBESTO SIS--GROSS X T AM fo r {be than fosBd inhum an a n j animal citingagent a t the she of neoplasia. I t Is OT1asbeetos non-neoplastic R the aasociatkm of as- 4 U s 14..--Typical mucinous adenocarcinoma, most wnmonly primary k> gastoointsstinsl tmet but found , |k lung of 1 exposed for 62 week* to chrysolite dust * a prior M M M caustic application. Pa- (subpleural) nodule composad of Irrepilar Hadspaces that have destroyed and comptetely 1alveolar tissue. Bat died month* after ... from inhalation chamber (hematoxyBn and 1% 15.--Higher magnification of several of the mucin-filled cyst* seen tn Fig 14, shows the loss of lining epithelium of these eysts. a feature commonly present In this type of cancer (hematoxylin and eosht, X ISO). creased risk of lung cancer was not found sente a S p fi# b W to le{ a s p la a a ti u n _ n )l,M n. m 0PK SlO & IG u the site of dust or several trace X 40). among workers in the Canadian d nysotte mineral dust of lung and pleural tissues to tins tcfors are as follows: industry.* Aside itout differences In cllma- eluted after tic coodRiEUS, ethnic backgrounds, dEn% as* MS* chrvsotile dust need In this invea- ing habits, It appears probable that differ* bein shown to ! , higher tban It was prior to the .raffi treatm ent (Table 8 ). I t In ences In the dost Itself to which these two caaoer _ a l a! population groups had been exposed may found th at rats espoeed to nicfad cahonyi account for the disparity. For example, at developed pulmonary squamous e d t card- the mines, ebrysotile mineral is.subjected noma. t was nickel, to considerable crushing contact with high- The many different types of primary ma- .-7a. Aanlysis of the worn hammer of the ! strength steel alloys to "open" the fibers lignant lung tamora In o a r animate with hwmwtr mill revealed a nickel content of j and remove adherent nonfibrous mineral pobnonaiy deposits o f ebrysotile dost and |,338Mg/gra of sample. 4 components prior to shipm oit to manufac- the different fe p of cells in theee;fm x m i 8. There Is a disparity In the published haerat. However, considerably more extern bring to mind a conceit originated ty Wad- rive contact with nickel* and duome^teel delT1and M ended by work in this laborato- alloys, Involving more and more erf the most ry.8 This theory holds th at the parent cell Pfocessand during carding as well as spin- capable of ning, essential prooesses in the fabrication "f a*estoste*tfles, This, in a maimer simi- :mesothelioma. b r to th e hammer-milled asbestos, may -- J" * -- - - Hat acquire a cpt- ArcA Enairoa H e a lA -V M IS. Sept t m , V l^ y JM. t>B3Ak' 354 E X P E R IM E N T A L ASBESTO SIS--GROSS E T A L EXPERIMENTAL At taa concept In support of which are th perpheral Location of all tumore in question and lailure to tfcmonstrate a bronchial 4gin. The thesis that metaplasia of alveolar epithelium to the columnar type representa a so-called `teronchialization," % a downgrowth of bronchiokr epithelium, has been greatly weakened by Totten's demonstratkm that these metaptastic oolumnar pithelial ceils contata rwmfophilfc inclusions similar to those seen in normal alveolar surface cella, tochudong not found in normal brottchiolar epithelium. The abffity of neoplasie alveolar celta to the importara* of the tract clearance mechanism, particularly in elimtaattag tnncerogenic partides. Attention is also directed to the nature of ti asbestotic inflammatkm in re te D ebite a massive esposare to duat for 62 weeks, the tion was multifocal. rether i characterized by poorly celluLanzed < The presence of the lattar and of alveolar tisane beta* U co ^g ^to ed fed confirma our opinion ato u t healing and nopprogreasion of terysotile asbestosis in the rat.1 chrome, 34%. Analysis of the-worn hanno T t ma*pltogy e f alveolar Inraor oelb found in ateestotln ret- tea* ranged from squamous to columnar, from partially dlfferentiatd squammia (K gl3> to fully differentiated (Fig 14), even with much keratin production; and from darklystaining cuboidal (K g 4) to the highly One hundred and teuty-cne rats were pama to chiysotile asbestos, finely milled, ta an exposure chamber for six hours a day, days a week lor a maximum of 62 weeks. Dust concentrations were very heavy, ranging from 42 to 146 mg/cu m (average ft I . Doll, R.: Mortality From Lung Cancer Amo A sha* Worker, Brit J Indurir Med O AU differentiated mucin-secreting variety (Fig 86 mg/cu m ), About half the animals exposed 8 and 15). The neoplastic connective tissue also had intratracheal application of caustic cell types ranged from undifferentiated (|ye) to reduce lung clearance and maximize small, pleomorphic cells (K g 6) to large, dust retention and pathogenicity. Also, 64 anaplastic cells (K g 7 ); and differentiated types ranged from small spindle cells resembltag those of endometrial stroma (K g 8) to plump, collagen-producing fibroblast-like cells (K g 9). The rapidity (within two hours) with additional animals were given tatratrateeal injections of chrysotile dust, 14 receiving single doses and the remainder multiple in jectionaof 3.5 mg each. Controls oonsistedof 30 untreated, unexposed animals and 15 rats treated with caustic but unexposed to asfces- whteh new argyrophilic fibers become demonstrable on an alveolar wall of a sensitized animal when challenged with tuberculin,w suggests that cells of the alveolar membrane rather than the exceedingly few toe. Designed to study asbestosis, the meet important findings of the investigation related to lung tumor production. Other tavestigators have not been successful ta produc tag lung earner experimentally in rats with and widely scattered interstitial mesenchy- chrysotile. Tumor incidence was hitfr. Of : t mal cells of the alveolar taterstitium are those surviving 16 or more months (te, after responsible for these fibers. appearance of the first tumor) 31% had pri- - '- In a recent study of pulmonary adenomas mary malignant tumors of the lung. Occur- of mice, the apparent ability of alveolar rence ta rata treated with lye was 48%, twice membrane cells to produce argyrophilic the rate of those exposed but not treated with , stromal fibers was described.8 Finally, the caustic. Malignant pulmonary tumors in- When dentists and engineers undertak ever, they find it im possible to stick to qua include too m any other aspects, and in t unitarian concept of the origin of these tu- eluded adetwearcinomas, fibrosarcomas, and im a m beings. A n dao weary cynics lik e 3 more is supported by the observations of squamous cell cancers as well as a mesothdi- previous investigators who noted te a t many oma and a mucinous adenocarcinoma. A mntotase and transplants of mouse adeno- number of pulmonary lymphoblastomas mas w oe sarcomatous.-** w hite occur spontanenudy in rats were not The fact that tee prevalence of lung can- counted. Also, atypical metaplasia, not mam- cm- among tee rate which bad intratracheal festly malignant, was commonly noted. Mtth caustic applications was more than double ticentridty of malignant lesSorewreobserved that ta animals not so treated, underlines ta several animals. Results of tins study sup- A ite JBntfw HevEh--V v i IS, Sept M T An;h Environ Ileafl im m m mm >>-f. ' i r 5--GROSS ET AL the importance of the upper respiratory tract clearance mechanism, particularly in eliminating canceragenic particles. Attention is also directed to the nature of , in rata. Despite ctarysotile for 62 weeks, the aabestotio inflamma_ than diffuse, and cbaritctertmcl harpoorly celhilarized collagen. The presence of the latter and of normal in the One hundred and thirty-one rats were ex posed to chrysotile asbestos, finely milled, in an exposure chamber for six hours a day, five days a week for a maximum of 62 wed. Dust concentrations were very heavy, .ngin^ from 42 to 146 mg/cu m (average 86mg/cu m ). Abouthalf the animals exposed also had intratracheal application of caustk (lye) to reduce lung clearance and maximize dust retention and pathogenicity. Also, 64 eAKHnn] animals were given intratracheal injections of chrysotile dust, 14 receiving single doses and theremafnder multiple in jections of 3.5 mg each. Controls consisted of 30 untreated, unexposed animals and 15 rats if,-.;. treated with caustic but unexposed to asbes tos. Designed to study asbestosis, the most important findings of the investigation re lated to lung tumor production. Other inves tigators have not been successful in produc ing lung earner experimentally in rats with chrysotile. Tumor incidence was high. Of those surviving 16 or more months (ie, after appearance of the first tumor) 31% had pri mary malignant tumors of the lung. Occur rence in rats treated with lye wa46%, twice the rate of those exposed but not treated with caustic. Malignant pulmonary tumors in cluded adenocarcinomas, fibrosarcomas, and squamous cell cancers as well as a mesotheli oma and a mucinous adenocarcinoma. A in rats were not EXPERIMENTAL ASBESTOSIS--GROSS E T AL port th unitarian concept of tumor origin from alveolar cella. Despite extreroe expo- e aabestosis m a not was multifocal, oen- tered in th proximal portion of normal appffliing nfaw. Cancer production-with chxysotiie in of th tent of if vide an $ T t* duoed during hammer milling which in- m ill revealed a nickel conTbis finding, should pro aid to guide industriai of potential health haz- by Public Health New York, through K. W. i m aterials were done at the ` ; Health. their taste to hammer milling. The increase m content of trace metals after milling was as follows: nickel, 82%; cobalt, 145%; chrome, 34%. Analysis of the worn hammer Sy.*FM D* Epidemiology and FfeM stu d ies ot M ___ parUeineted in stages of this" ^ ri L D oll, H.: M ortality From Lung Cancer Among Workers, B rit J Induetr M ed 12*1-86, 2. S d iM t LJ.; Cburg, J.; and The Occurrence o t i in the United States, A n n N Y Acad S ri (-16B, 1966. 3. H olt, JX; M ills, J.; and Young, D.K.: The Earfy Effecta ot ChryaotOe Rat Lung. J P ath Sort 87:15-23, 1964. 4. Wagner, J.C.: Aabestoeia in Experimental Ani mal, B rit J Indurir M ed 20:1-12, 5. Braun. D C ., and Traen, TJD.: An logic 8 tudy o f Lung Qmcer in Arck Indueir H ealth 17*34-653, 1958. 6. Sunderman, F.W., et al: Nickel Poisoning: IX . Carcino^neaia in Rata Expooed to Nickel Carbonyl, Arek In d tu try H yg 20*6-41, 1969. 7. Waddell, W Jt: Oigenoid DiSerentution ot tbe Fatal Long: A H istologie Study ot the DifierentiaU< r i Mainmalien Fatal Lung in Utero and in Transplanta, Arcfc P ath 47027-347, 1949. 8. Groes, P ., and Poel, W.: 1 P olli 77:424-428,1964. . Totten, R & , and Pierre, G.B.: Cortisone and A^ijd^PufanaaM y- ^ iib e E d " Hyperplasia: Fur- Amer J P ath 45*77-090, 1964. 1 Gross, P . ; ........................ JJA : T he Pulmonary : iponae to Tuberculin, Arch XL YH.] Lung Ttanoen Occurring in ; H eolth B ep 54:1519-1524, 1939. 12. Stewart, H.L.; Grady, H.G.; and Andervont, H.B.: Development ot Sarcoma at S ite ot Serial Transplantation r i Pulmooary Tumors in Inbred M ice. * N a t Ornear b u t T207-22S, 1947. 19 O twa, P aad taTreyiUe, R.T.P.: Experimen- aica ravira^ nr tfO....Ba .ft.f w db.p. ..uraiw i to apply Science to practcal problems, how- , they find it i i tostick to quantitative data and rules of logic. The problems parta, and in deafing w ith them they naturally bebave like And so weary cynics like Iawyers and political sdentisia take a oertain in showing that the natural scientiata are led by confidence in thair chniquta to try to make judgments on p^ iitkal valuea or pdBcy ded- iaing aB ha other componente of a nonsd optific taire f lir t go fo to ,, . r ! ... ; i'f he foyw a tmlid and important one,and n t ^ t o he drivan heme to f they do not like for n ^ ^ n ta ta to remitid them of It-P ie T 3 X . i V h ^ ^ ^ Eriate, Cambridge, Masa: Harvard University Presa, 1965, quoted in Amer Sci 53:528 (D ec) 1965. - 4*6* Enwnm Hialfh--Ve 16, Sept A liljWIIW Frtyp MI p p 1 ,,,/?i- i mmmm