Document YDdGOB6Yvn5x9G6G2qgnv6g0k

? ii o p o c- r. j AS2'S6TOfI3 :-'iO ?U.*J5 'HLV2K 5MSU! !D $(e 7C Quobso Aobsstoa WlaiBj: Association ^'**^1xu**cm*0*" asM^1 Ch* $ci5`&'?'r.o r?*ory of i-l: * Yha St'werd r. '."ra'Scr : Kerens Lah>, i* " Terfc SyboAt'-afi fcyt Arthur 0* Vor.^ld, !`,,D, Eiroctc**, The trudcsu Fooo<Saticm tint? Tho Saranso lAl>oratcxy Copter ir 21, IS 50 PLAINTIFFS h EXHIBIT I WV-05613 PLAINTIFFS EXHIBIT iMsux WV-05613 PART I XmODOCTIOK 1. TSE FSOBIU The specific problem is to ascertain vfcsther or cot 6 rela tionship pyletg betroap thelohalatiOE of* asbestos dust and primary pul?nc&ery_poncer.. 2. GSfcaRAL REMARKS The rapid increase in the incidence of lung caaoor during tjse p&at thirty vaara lisa bscotas tfca subject of a great deal of critical study and speculation, Bony investigators contoed that thia_increaso is merely apparent and cm be credited to a shift Lc the age composition of cur population in recent decodes, to better diagnostic facilities, and to & keener appreciation by the lay pop ulation and medical profession concerning the importance of early detection and treatment. Others maintain that the increase la real and caused by the presence of net? carcinogenic factors is our enYircffimeBt, many of which are of industrial origin, Wits ooneept of occupational lung cancer receives come indirect auppert from the. faot.jgmt thecae3rity ofjamr occupational oacoers involve tho respiratory system. Some of thebo cancers have bees traced to cer tain chemical or physical agents, lo consequence, there la a grow ing tendency t.n incriminate g&cy other agents .irrespective of the lack of clear-out evidence to prove their carcinogenic capabilities. Evidence regarding many of thws, however, although freqoontty ocaioirted, is sufficiently eartout to warrant extensive spidraloi^ioal end experiflentoi iavsstigefrioa, Asbestos dust it la this category {Huper, lynch, Jfereweiher, etc.) and the esbeotos industries in quebeo are In a unique position to pursue these epidemiological in vestigations. ?mt' n T&izstnoLooxcAL uwsmoA'novs 3. It is pertinent; to point out boro that aucft investigations e,re indeed complicated end demand the most considered design 1art t*. s^"N" ^\ is final Analysis the results obtained will hero little significance. v For exaaple, the incidetsaa of pulmonary cancer appears to vary geo* graphically and racially, A statistical study of a aeries of indi- V ^ viduala exposed to asbestos csut be controlled, therefore, by a similar study of individuals of einll&r geographical distribution and racial type, and of the esse age and sax, cot exposed to asbes tos. Since the incidence of detected pulmonary oanoer varies with the degree of effort applied in detection, both groupfl, the exposed and nan-exposed, should be studied by the sane technique and perhaps even by the ease personnel. As it is not possible to examine a large population by exhaustive techniques such as biopsy, eputua exaqdnation, and bronchial washings, it acea* Boat practical to ?>ryy out the proposed statistical study essentially at cm x-ray survey. >>* h V 1 > 4*/ " -2- flhen the preee* of neoplasm in an iadividual la suggested by thl* technique, ha ehould b further etudled with the purpose of esta blishing or excluding this diagnosia with certainty. Other foo ters suspected of being carcinogenic, euch as cigarette anoiitig, aay constitute eorieblee within the population to be studied, fa- fonaaties as to these variables met be obtained as well na infor mation concerning exposure to aBbeatoa. It appears that cigarette enoki&g i a the neat prominent variable factor ia the epidemiological etudy proposed. Other auepeoted factors such os atmosphorio hydro- earbone would be essentially constant For each group of individual* in the sans geographic area whore asbestos le bolag ained. 4, la view of these considerations, It is suggested that only cer tain phases of tho study be undertaken at this time pleading the advice and recoBar.sndatioas of tUcae with a wide ) i i 1V t< i* *i, v 1 F Ni experience ip the conduct of auoh studies. Agencies with this ex X \x *s Vy i perience ares the ifisdieai Research Councils of Canada sad the V United States, the oaaeer societies of both countries, the re spec- | ^ tivn tuberculosis societies, the tfational Cancer Institute of the \ ^ C, S, Public Health Service, and the Sloaa-ftet.tegfeg _ Institute of It X i \ the Cancer Usaaoriel Hospital. 'S S, She phases of the epidemiological study which might be under taken immediately include the clinical end statistical data al ready available for employees In industries eueh ae those at fbet- { ftsrd and Asbestos, where routine physical examination and chert 3- r r-raye hate 'beets standard pracstos for years. In essence, this progrzsn should include seruttqy^ftl^-aAV taodtogl retards, of host roentgenograms^of ell employees, of autopsy prsteed ^ d of... death QftrHflc&toB for eeldonee of molignancy, It diould bo pointed out that statistical calculations relying os olloioei records or os death certificate# based oa clinical diagnosis aay contain 6 wide range of error in the fundamental materiel and may be unre liable as to the absolute numerical coneItwione reached, Sintiiarly, autopsy protocol# aay represent only e highly selective sample of the total mortality end stay constitute, therefore, a weighted index of tha inoldouco of cancer is subjects exposed to asbestos dust. ( PART m BSPSRBSEmb inrsexioAnoNS 8. The Saranac laboratory with its background of study concerning ohxcEQie pulmonary disease, e apeclally that resuiting from the inhalation of industrial duets including asbestos, is uniquely qualified to pursue certain phase# dealing with the problem of asbest#4a and pulmonary easoer. t* 7 For purpose of completeness and general information, certain brief eoascents eoea justified for guidance In the design of the \ experimental approach which we propose. C iVf -4 A number of experimental mothers may be employed to teat the oapecity of asbestos to produce cancer. It is desirable to keep la aind, howeear, certain facte concerntag s3beetoeifl whieb affect the selection of the moiftodx (1) ftabeetoais is a abronlc pulmonary disease resulting from the deposition of asbestos fibers in the lung; therefor, the experimental method...affipiftyyd should direst cmphaai* aa the lusg, (2) The anight of evidonoe is that asbestos fibers pro duce their irritation by a mehaalaai rather than by a hectical mode of action. The mechanical action ie intimately related to the movement of the lung during respiration. Tbua, an experimental method which neglects naromtat of tha lung and thereby excludes the mschnnioal action in all probabillty would bo highly inconclusive and subject to critic! an. (S) Asbestos!e ie a dicesse resulting froo videspread die- garijsatioa of asbestos duat la the lung. Sellable oonoluoioas in on eigeriaegtal Ineesttgatloa *i th agbestog oemot be drerra solely from e^erimootB with the intratracheal injsetiea technique whereby a high concentration of dust becomes localteed ~U I I is a restricted portion of the lung and stimulates excessive focal Irritation, then the asbestos dust Is introduced Into the animal Id that Bonner, the injected dust my mist certain potentially eaccer-producing sites in the lung which ore reacts from the -5 localised ares of implantation of dust. It is further possible for the excessive food Irritation, crhioh it. net a charaoteriatie foetore of human asbestos!s, to induce poisonary eaacer which would net have developed hod the duct bees uniformly distributed throughout the lucg* fhu*, the intratracheal in.lootIon technique^ l alone anight lead to unir&rranted oosolualone. The intratracheal method has been used for cancer studies by a number of investiga tort, probably because of the relation difficulty end tsdleuenee* of method* involving inhalation of tbo potential carcinogen, The inhalation method, however, has been employed by eminently recog nised investigator* of carolaogenie agents. 8. 1b passing, it might be said that lung tumors can be produced by numerous neons in susceptible mice, i.e., aloe possessing i, -- the tendency to develop tumors spontaneously. Boa of the method* garnered from the literature are* repeated applications of coal tar to the akini subcutaneous Injection of _aaroiaoganlo frydrocar- bonsj intravenous tajectioa of serum and cli&rccai dispersions of carcinogenic hydrocarbons* feeding large dosee of dibensanthrocanej and introduction of cftrqlaogecio hydrocarbons Into the rectum, vagina, peritoneal cavity, or pleural cavity. For explanation of the occurrence* of lung cancer follosing such methods, it has been suggested that the introduction of oarclBOgeaio compounds into the body of the mouse alters the body state so that tmara arise at paints of incidental Irritation, the more plausible explanation advanced by certain investigators io that the lung tumors are pro- -6- duood because very email asumate of the carcinogenic agent leave the alto of application and cone in centset with eietroaely eue oeptibie alveolar epitheliua. tf this la true, It Is unlikely that such aetfcods aould he used far investigation of oaacer aad asbestos, a duet which remalna within pulmonary tissue, which is not transported aystatically aa are soluble chemical 0gents, and which produces its irritating effect by a mechanic a1 rather than by o cheraioal mode of action. 9. Reference has been stale to Inbred strains of m.--iciire ih which the pemtanaoua occur?cnee of tutors of the lung is a characterlotto feature. Strains ore available in which the ir.oidenaa of epontaueous ( lung tumors is accurately known. In eoaa strains the incidence is low, so that an increase in the incidence after an. erporiB^ntal grocedare Is easily detectable. Other strains with high tncidonoe of spontaneous tumors 02*0 suitable to determine whether the procedure has caused tumors to appear at ms earlier age and whether the number of tumors per mouse hae been increased. The mioeeptibiliiy of the pulmonary tissue In selected iabrod strains of tales is suoh tiiat they serve as excellent test ani mal# for checking an alleged extrinsic carcinogen such its asbestos. A reasonably delicate assay of the potency of asbestos as a car cinogen i poseibis because of the unique multiplicity of turners formed. -7. PAflJ IV propose;!) igresTittATloa - > 10* MB3S0P8 TO SB STLOTEB Xa view of tito eontldoratioafl mentioned la the preceding 5>argraphc, the Saranac laboratory proposes to conduct an esporl* 1n^fcha Inhalation method sod aleoy for esmtal investigation ecployi supportive vidncb7'''tho intrstrsabeal ipjeqtlon aystJiofi, Two groups of pur inbrtd strain sdoe sill be used, i.e., the low spentancoue lung tumor "strain 0 67 black," sad the high lung tumor "train A" (obtained from the Booooe B. Oaekaoa ttasnorlal taborstory). Tbe animals of each group tfill be divided into subgroups, equivalent as to eex, ego, sad waigfct at the time of inauguration of tbo actual jperiaeats, After mixing, part of each subgroup will be exposed to atmocpfcerio suspensions of Icag'flbsr asbestos dust of controlled eocoeBtratleass part will be lojeeted intratraehwolly with measured aaouate of tbe duet suspended in sterile normal calinej part will be set aside in normal air for controls, Saeh aaisttl will be nuobered sad e separate record will be kept* Anlsole from each subgroup sill be sacrificed at intervals, nd the other members will b pemitted to live out their natural life span* After death the lrnga wiU be fixed by intratracheal iojeotian of leaker's formal or formalin solution. Sectiona passing transversely through noth luags end the mediastinal structures will be prepared for adoroseopie study. iu mmnoH op Rssctrs Carcinogenicity la t be evaluated by comparing the fol lowing five factors la all subffroupsi v'fl) the per eat of mice with luag tumors* y'{Z) The average miaber of tumors per twuee* s`{$) The auaber of toners arising in the aBbestcti areas varsus the non-aebostotle areaa of tissue in the ex posed oiea. S{A) The induction time for tumors, K6) Evidence for direct origin of tumor fro asbestos, i*e,, the histological appearsac* of teaser v&ll ha capered with the non-oanceroufl epithelial hyporpiaaioo that may he present. 12. corPAHAtm ANAirsrs **na o*rasB invssndATioKfi ukdektjax the studies concerning aabastoe trill be luteprated with other, ineeBtlft&tionB of the Saranac laboratory. Those investigations coneera the caroinogeni properties of inhaled cuartt and of coalirltetlng dusts, such as oarbon and iron oxide, the data obtained will form a basis for statistics! study of the occurrence of pulmenary cancer in mice exposed to duets other then asbestos. 13, mrStttBD IWRAflOB OP fKE EXfBRBEKTAL 1HTO3TIOATIOSS Tha tavsBttgatlona proposed involve disease processes ehlch develop very steely, This applies to sebostosia as well as to pul monary cancer. With respect to aebsstaple, previous studies indi cate that at least sixteen mcathe of contiguous exposure to dust are^ necessary in <arder_ to produce definite Jibrosl* in a highly swicaptibls ( animal arefc as the guinea pig, Xtj contrast, the gouge It aare reBlatant sad develops hi# reaction era mere stardy under eisliar onditioao of w^osure, The development of asbestos! s la aloe say be speeded op considerably by inaressiafl the ooneeatroticm of the duet to which they are exposed. Thos, it ia anticipated that b.y__t_h_e__in__h_a_lai t-ii~on method, and ia not lees _th__e_n__o_n_e_y_e_a_r__is__a--loe resetting so intratracheal leisoticn of the dust* Esgardihg the latter asthod, it must ba stressed that although the injection ex periment is of shorter duration, thoresulta are isoapoluslvp . An Inhalation study of relatively longer duration should be perferaod to obtain reliable results. ( tilth respect to pulmonary cancer, there are assy complex problems inherent ta any stuefr of the subject. The very nature of the disease and the experience of other invent!sobers dictate that envisaged. This should not discourage the sponsorship of tho program by the ewepaaies, ss unfortrnately thers is no other alter native If reliable results are to bo obtained. id, R2pmts op mnffisrs Prtgrftat tepert* *111 he issued from ttoe to ttoa durlcg tfee ' _ .......... ........ I I ll~......... ... r - .. espsrtawrt sad a cac^rshensive report trill be atitmitted at the con clusion of tfc# investigation, Those reports vdll be forwards* to the proper authorities identified by the sponsoring agencies. -10- 16, mticincss of hssolts of istbstiqatiojb The Sareaio Laboratory reserves the right to publish tfca result* of its inrsstigatitt&s ie. the reoegaieed warner oopraoply em ployed by the soientifi fraternity and: In acoofdaa* with seta- / bliefced praetioes, hereby the SMa$ript, prior to its publioa- ji tiea, la submitted to the spcnecrixxg ctt^aaay For its review and )j appro*ml. 18. COST BSTZttAlB The Ofie&ined project including both the inhalation end the intratracheal teohaiquee requires the eorrioes of & number of staff assfcers, the &e of an *jq?oeur* ehsabsr or room and spatial agparatut needed for ooatrols the purchase of a large masher of nice of a purs inbred strain, tfc* ass of special moose sages, and a large quantity of expendable materials suoh as hamlesls, glasmre, aiereiwopie slides, end sorer slips. The eest for this ccanprehcmaive study rill $16,000.00 for ths liras year aad $10,000.00 for the second year. UV,*w /s+ JZk.S - 11- 1/ ^ 4* / A