Document KJQ60yeqkb8e00Me2oGnEEbb0

P R OPOSAL ASBESTOSIS AND PULMONARY CANCER i A ( x- \ to TheA.AabestoeA*f.AVka<a*o*7oiated ^>/t( (nrO - ( ?/o, cr^o - I (l^b | "T a/LTWlML * o by The Sarenao Laboratory of/M*e- The Eduard L, Trudeau Foundation Sarenao Lake, Bern York Submitted by Arthur J. Vomald, tf.D. Director, The Trudeau Foundation and The Saranao Laboratory September 21, 1950 ufir/s* s A * Scd*TM-TMrr"\- o/a^o* >^-*1^0*-*" &-* PLAINTIFF'S. I "v EXHIBIT; I `ist-\V5- WATJONAL MUSEUM OF HEALTH AND MECXQNE- Ml*MEn FORCES INST1IUIEOF PATHOLOGY ^ PART I IHTRODOCTION 1. THE PROBLEM The speoifio problem ie to aaoertaln whether or not a rela tionship exists between the Inhalation of asbestos dust and primary pulmonary eaaoer. 2. (H51ERAL REMARKS The rapid inorease in the incidence of lung oanoer daring the past thirty years has beeoms the subject of a great deal of erltioal study and speculation. Many investigators oontend that this Inorease is merely apparent and can be oredited to a shift in the age composition of our population in recent deoades, to better diagnostic facilities, and to a keener appreciation by the lay pop ulation and medical profession oonoeraing the importance of early detection and treatment. Others maintain that the inorease is real and caused by the presence of nam oareinogsaio factors in our en vironment, many of which are of industrial origin. This concept of occupational lung cancer receives some indirect support from the fact that the majority of near occupational oanoers involve the respiratory system. Some of these oanoers have been traced to cer tain oheadoal or physical agents. In consequence, there is a grow ing tendency to incriminate many other agents irrespective of the lack of deaz^cut evidenoe to prove their oarolnogenio capabilities. 1- t<UTONAf MUSEUM Of HEALTH AND MEDICINE. JTCMpn COBCES INSTITUTE OF PATHOLOGY Evidence regarding many of them, however, although frequently can4 tested, is sufficiently serious to warrant extensive epidemiological and experimental Investigation. Asbestos dust is in this category (Hueper, Lynoh, Herewether, eto.) and the asbestos industries in Quebeo are in a unique position to pursue these epidemiological in vestigations. PART II EPIDEMIOLOGICAL ISVBSTIOATIOBB S. It is pertinent to point out here that such investigations are indeed complicated and demand the most considered design lest in final snalyals the results obtained will have little significance. For example, the incidence of pulmonary cancer appears to vary geo graphically and racially. A statistical study of a series of indi viduals exposed to asbestos oust be controlled, therefore, by a similar study of individuals of similar geographioal distribution sad racial type, and of the same age and sex, not exposed to asbes tos. Sine# the inoidance of deteoted pulmonary oanoer varies with the degree of effort applied in detection, both groups, the exposed end non-exposed, should bo studied by the seme technique and perhaps even by the same personnel. As it is not possible to examine a large population by exhaustive techniques such as biopsy, sputum examination, and bronchial washings, it seems most praotloal to oarry out the proposed statistical study essentially as an X-ray survey. -2- Olid NATIONAL MUSEUM Of HEALTH AND MEDtONE- INSTITUTE Of PATHOLOGY tthsn the presenoe of neoplasm In an individual is suggested by this teohnique, he should be further studied with the purpose of esta blishing or excluding this diagnosis with certainty. Other fac tors suspected of being oaroinogenic, such as oigarette smoking, may constitute variables within the population to be studied. In formation as to these variables must be obtained as well as infor mation oonoeraing exposure to asbestos. It appears that oigarette smoking is the most prominent variable factor in the epidemiological study proposed. Other suspected factors such os atmospheric hydro carbons would be essentially constant for each group of individuals in the same geographio area where asbestos is being mined. 4. In view of these considerations, it is suggested that only cer tain phases of the epidemiological study be undertaken at this time pending the advioe and recommendations of those with a wide experience in the oonduot of such studies. Agencies with this ex perience ere: the Uedioel Researoh Councils of Canada and the Thkited States, the oanoer societies of both countries, the respec tive tuberculosis societies, the Rational Caneer Institute of the C. S. Publio Health Service, and the Sloan-Esttering Institute of the Caneer Memorial Hospital. 6. The phases of the epidssdologioal study whioh might be under taken Immediately lnolude the elinioal and statistical data al ready available for employees in industries such as those at Thetford and Asbestos, where routine physical exam!nation ohast -5- H KATIONAt MUSEUM Of HEALTH AND MEDK3NE. 1 III III FORCES l^TIM^OfPATHOtOGY^ oir-- -* ? -93MT * X-rays bat* been standard praotioa for years. In essence, this program should Include serutiny of all msdioal records, of chest roentgenograms of all employees, of autopsy protocols, and of death certificates for evldenoe of malignancy. It should be pointed out that statistical calculations relying an clinical records or an death certificates based on clinical diagnosis may contain a elds range of error in the fundamental material and may be unre liable as to the absolute numerical conclusions reached. Simi larly, autopsy protocols may represent only a highly selective sample of the total mortality and may constitute, therefore, a weighted index of the incidence of cancer in subjects exposed to asbestos dust. PART III BXPBRDEKTAL INVESTIGATIONS 6. The Sarsnao Laboratory with its background of study oaaearning ohronio pulmonary disease, especially that resulting fro the inhalation of industrial dusts including asbestos, is uniquely qualified to pursue certain phases dealing with the problem of asbestosis and pulmonary oanoer. 7. For purpose of completeness and general information, oertain brief comments seem justified for guidance in the design of the experimental approach whloh we propose. A number of experimental methods may be employed to test the capacity of asbestos to produce cancer. It is desirable to keep la mind, however, certain facts concerning asbestosia which affeot the selection of the method: (1) Asbestosis is a chronic pulmonary disease resulting from the deposition of asbestos fibers in the lung; therefore, the experimental method employed should direct em phasis an the lung. (2) The weight of evldenoe is that asbestos fibers produoe their irritation by a maohanloal rather than by a ehsnieal mode of action. The meohanioal action is intimately related to the movement of the lung during respiration. Thus, an experimental method whioh negleota movement of the lung and there by excludes the mechanical action in all probability would be highly inconclusive and subject to criticism. (S) Asbestosis is a disease resulting from widespread dissenlnatian of asbestos dust la the lung. Reliable oonolusiens in an experimental investigation with asbestos cannot be drama solely from experiments with the intratracheal injection teohaiqua whereby a high concentration of dart becomes localised in a restricted portion of the lung and stimulates excessive focal irritation. Vhcn tits asbestos dust is introduced into the animal in that manner, the injected dust may miss oertain potentially oaneer-produolng sites in the lung whioh are remote from the 5* NATIONAL MUSEUM Of HEALTH ANO MEDK3NE, apiAPn FORCES INSTITUTE Of PATHOLOGY localized area of implantation of dust. It ie further possible for the excessive foo&l irritation, which is not a oharaoteristio feature of human asbestosis, to induce pulmonary cancer whioh mould not have developed had the dust been uniformly distributed throughout the lung, Thus, the intratracheal injeotien technique alone might lead to unwarranted conclusions. The intratracheal method has been used for oaneer studies by a number of investiga tors, probably because of the relative difficulty and tediousness of methods involving inhalation of the potential oaroinogen. The inhalation method, however, has been employed by eminently recog nised investigators of oaroinogenic agents. 8. In passing, it might be said that lung tuaors can be produoed by ntnerous means in susceptible mioe, i.e., mioe possessing the tendency to develop tumors spontaneously. Some of the methods garnered from the literature aret repeated applications of coal tar to the skin; subcutaneous injection of oaroinogen!o hydrocar bons; intravenous injection of serum and oharooel dispersions of oaroinogenio hydrocarbons; feeding large doses of dibensanthraoene; and introduction of oaroinogenio hydrocarbons into the rectus, vagina, peritoneal oavity, or pleural oavity. For explanation of the occurrences of ltmg oanoer following suoh methods, it has bean suggested that the introduction of oaroinogenio compounds into the body of the mouse alters the body state so that tumors arise at points of incidental irritation. The more plausible explanation advanced by certain investigators ie that the lung tumors are pro- -6- duoed beoause very snail amounts of the caroinogenle agent leave the site of application and come in oontaot elth extremely sus ceptible alveolar epithelium. If this is true, it is unlikely that such methods oould be used for investigation of oanoer end asbestos, a dust which remains within pulmonary tissue, which is not transported systemioally as are soluble ehudoal agents, and which produces its irritating effeot by a maohanioal rather than by a ohemical mode of action. 9. Reference has been made to inbred strains of mice ih which the spontaneous occurrence of tumors of the lung ie a oharaoterlstio feature. Strains are available in whioh the incidence of spontaneous lung tumors is accurately known. In seme strains the incidence is low, so that an increase in the incidence after an experimental pro cedure is easily detectable. Other strains with high incidence of spontaneous tumors are suitable to determine whether the procedure has oaused tumors to appear at an earlier age and whether the number of tumors per mouse has beau increased. The suseeptibllity of the pulmonary tissue in* selected Inbred strains of mloe is such that they serve as excellent teat ani mals for checking an alleged extrinsio oaroinogea such as asbestos. A reasonably delioate assay of the potency of asbestos aa a car cinogen ia possible beoaase of the unique multiplicity of tumors formed. -7- H KATJONaTMUSEUM Of HEALTH AND MEDK3NE. M ARMED FORCES INSTITUTE OF PATHOLOGY PAST IV PROPOSED BSPERIMBHTAL IBVBSTIGATIOII 10. 1GTB0DS TO BE EMPLOYED In view of the considerations mentioned in the preoeedlng paragraphs, the Saranac Laboratory proposes to oondnot an experi mental investigation employing the inhalation method and also, for supportive evidence, the intratracheal injection method. Tcro groups of pure lnbrtid strain ados mill be used, l.e., the low spontaneous lung tumor "strain C 57 blade," and the high lung tumor "strain A" (obtained from the Rosooe B. Jackson Memorial Labor atory). The animals of each group will be divided into subgroups, equivalent as to eex, ago, and weight at the time of inauguration of the actual experiments. After mixing, part of each subgroup mill be exposed to atmospherio suspensions of long-fiber asbestos dust of controlled concentrationsj part mill be injected intra tracheally mlth measured amounts of the dust suspended in sterile normal sallnej part mill bs sat aside in normal air for controls, Eaoh animal mill be ntnbered and a separata record mill be kept. Animals from each subgroup will be saoriflood at intervals, mid the other members mill be permitted to live out their natural Ufa span. After death the lungs mill be fixed by intratracheal injection of Zenker's formal or formalin solution. Sections passing transversely through both lungs and the mediastinal structures mill be prepared for mloroseopio study. 8 HI i&TTONLArMUSEUM OF HEALTH AND MEDONE. 1 l| I III I HBCES INSTITUTE Of PAIHOIOftV ^ ---2 r :-- " - 11. EVALUATION OF EXPERIMENTAL RESULTS Carclnogaalolty Is to be evaluated by comparing the fol lowing live f&otors In all subgroups! (1) The per oent of aloe with lung tumors. (2) The average number of tumors per mouse. (5) The number of tumors arising In the asheatotie areas versus the non-asbeetotic areas of tissue In the ex posed aloe. (4) The Induction time for tumors. (6) Bvideaoe for direet origin of tumor from asbestos, l.e., idle histological appearance of taaor mill be oompared with the nan-cancerous epithelial byporplasiaa that may be present. 12. COMPARATIVE ANALYSIS WITH OTHER INVESTIGATIONS UNDERWAY The studies concerning asbestos mill be Integrated with other Investigations of the Sarenao Laboratory. Those investigations concern the oaroinogenlo properties of inhaled quarts and of nonirritating dusts, suoh as osrbon and iron oxide. The data obtained mill fora e basis for statistical study of the oeeurrenoe of pul monary eanoer in aloe exposed to dusts other than asbestos. 13. BSmtXND DURATION OF IBB EXPERIMENTAL INVESTIGATIONS The Investigations proposed involve disease prooesses nhioh develop very slowly. This applies to asbestosis as well as to pul monary eanoer. Tilth respeot to asbestosis, previous studies indioate that at least sixteen months of continuous exposure to dust are neoessary in order to produce definite fibrosis in a highly susceptible NATIONAL MUSEUM Of HEALTH AND MEDK3N&. ABkAFn toads INSTITUTE OF PATHOinrsv ^ i-x animal such as the guinea pig. In contrast, the souse is more re sistant and develops his reaction even more Bloody under similar conditions of exposure. The development of asbeetosis in mice may be speeded up considerably by increasing ihe concentration of the dust to which they ere exposed. Thus, it Is anticipated that rather definite results can be obtained in not less than too years by the inhalation method, and in not less than one year in mice receiving an intratraoheal injection of the dust. Regarding the latter method, it must be stressed that although the injection ex periment is of shorter duration, the results are inconclusive. An inhalation study of relatively longer duration should be performed to obtain reliable results. With respect to pulmonary cancer, there are many complex problems Inherent in any study of the subject. Ihe very nature of the disease and the experience of other Investigators dictate that at least a two-year, and preferably a five-year program, should be envisaged. This should not diseourage the sponsorship of the pro gram by the companies, as unfortunately there is no other alter native if reliable results are to be obtained. 14. REPORTS OF 8XP&BIHE3TS -- 3^ Progress reports will be issued from time to time during the experiment and a comprehensive report will be submitted act the can- elusion of the Investigation. These reports will be forwarded to the proper authorities identified by the sponsoring agencies. -10- ^TIONaTMUSEUM Of HEALTH AND MEDKM. BARMED FORCES INSTITUTE Of PATHOLOGY ^ - ----------------------_____ ----- ----- " IS. PUBLXOAHORS OP EESOUS OF IHVESTIGATIOBS The Saranac Laboratory reserves the right to publish the results of its investigations in the recognized maimer commonly em ployed by tiie scientific fraternity and in accordance with esta blished practices, whereby the manuscript, prior to its publica tion, is submitted to the sponsoring company for its review and approval. 16, COST ESTIMATE The oonbined project including both the inhalation and the intratradheal techniques requires the services of a number of staff mashers, the use of an exposure chamber or room and special appara tus needed for control, the purchase of a large number of mice of a pure inbred strain, ths use of speolal mouse cages, and a large quantity of expendable materials suoh as chemicals, glassware, miorosoopie elides, and cover slips. The oost for this comprehensive study *111 approximate #16,000.00 for the first year and #10,000.00 for the second year. AJTibar 11