Document YDZN3vQ8XK93BBoRJXaqkLaNk

FILE NAME Quebec Asbestos Mining Association QAMA DATE 1950 Aug 31 DOC QAMA076 DOCUMENT DESCRIPTION Dr. Lanza Research Proposal for Study on Asbestosis & Pulmonary Cancer with Cover Memo from Dr. Smith COPT CONFIDENTIAL . C. M. McGaw -- ----,---- --" ------ last par . _ Hospital August 31 1950 Pulmonary Malignancy I am enclosing copies of a letter and contract received from Dr. Lanza It will be noted that Dr. Lanza has agreed with Dr. Cartier and I that the program should consist of two parts 1 - An epidemiological or statistical study 2 - Animal experiments consisting of a Inhalation experiments b Implantation or injection I still believe that the statistical study can be carried out by a Canadian authority and thus be more acceptable to various groups in this Province Also I believe that the best results from inhalation studies will be obtain- ed through the Saranac Laboratory , Concerning the Implantation Experiment Program proposed by Dr. Lanza I believe that their methods are sound and the results will be scientifcally interesting I would prefer to make no decision until the Saranac proposal is received The contract appears to leave little choice to the Donor if the results of the study are unfavorable to Company interests and are submitted for publication However I fail to see how they can find anything more unfavorable than that which already has been published by Merewether and Heuper / h.n CC - K. V. Lindell G. K. Foster- Montreal Kenneth W. Smith M.D. PROPOSAL ASBESTOSIS AND PULMONARY CANCER JMEA 5569 5569 exped exped exped exped Quebec Asbestos Mining Association by The The Saranno LaboratoryLaboratory Laboratory of the the Edward L. Trudeen Foundation Saranas Lake Nw York Submitted by Arthur J. Director Vorwald H.D. The Trudesu Foundation The Saranes Laboratory and PART I INTRODUCTION 1. THE PROBLEM rela- The specific problem is to ascertain whether or not a tionship exists between theinhalation primary of asbestos dust and 7 weminemowes amamse somnery ee - eee primary pulmonary cancer 2. GETERAL REMARKS The rapid increase in the incidence of lung cancer during lung a the past thirty years has become the subject of a great deal of critical study and speculation Many investigators contend that Oe a this increase is merely apparent and can be credited to a shift in the age composition of our population in recent decades to better diagnostic facilities and to a keener appreciation by the lay pop- ulation and medical profession concerning the importance of early detection and treatment Others maintain that the increase is real and caused by the presence of new carcinogenic factors in our en- vironment many of which are of industrial origin This concept of occupational lung cancer receives some indirect support the lung some ee ree factthatthtehe majority ooff nnewewoccupational cancers involve the c respiratory system Some of these cancers have been traced to cer- tain chemical or physical agents In consequence there is a grow- ing tendency to incriminate many other agents irrespective of tthehe lack of clear evidence to prove their carcinogenic capabilities ee en ene -1- EEvviiddeencnece regarding many of them however although frequently con- sufficiently sufficiently tested is epidemiological serious extensive to warrant at serious warrant epidemiological . epidemiological and experimental investigation experimental investigation investigation Asbestos Asbestos dust is in this category category Hueper Lynch Herewether etc. and the asbestos industries in Quebeo are in a unique position to pursue these epidemiological investigations vestigations PART II EPIIENTOLOGICAL INVESTIGATIONS a ? S. It is pertinent to point out here that such investigations are indeed complicated and demand the most considered design lest in final analysis the results obtained will have little significance only only , 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 must be controlled therefore by a similar study of individuals of similar geographical distribution and racial type and of the same age and sex not exposed to asbentos Since the incidence of detected pulmonary cancer varies with the degree of effort applied in detection both groups the exposed and exposed should be studied by the same technique and perhaps - even by the same persamel As it is not possible to examine a SleaergT e e popa uo lationbyexhaustive techniques m such as biopsy sputum ray ray X all all s examination and bronchial washings it seems practical to carry Stu^' out the proposed statistical study essentially as an ray survey Stu^' Stu^' 020 When the presence of neoplasm in en individual is suggested by this technique he should be further studied with the purpose of esta- blishing or excluding this diagnosis with certainty Other ao- tors suspected of being carcinogenic 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 concerning exposure to asbestos It appears that cigarette smoking is the most prominent variablefactorfactor in the epidemiological factor in Ot epidemiological study proposed Other suspected factors such as atmospheric hydro- carbons would be essentially constant for each group of individuals % in the same geographic area where asbestos is being mined i recomndati make 4 In view of these considorations it is suggested that only cer. tain phases of the epidemiological study be undertaken at this time pending the advice and recommendations of those with a vide studystudy then recomendati study recomendati stsutdyudy in experiencethe conduct of such studies Agencies with this ex- Meee os perience are the Medical Research Councils of Canada and the | United States the cancer societies of both countries the respec- tive tuberculosis societies the National Cancer Institute of the | T advice atined first apropiateappropriate apropriate apropriate ap raporoprpiateriate apropriate U. S. Public Health Service and the Sloan the Cancer Memorial Hospital eee Sug est Kettering Institute of Institute i / first be onj ewe 5. The phases of the epidemiological study which might be under- taken immediately include the clinical and statistical data al- ready available for employees in industries such as those at Thetford and Asbestos where routine physical examination and cheat age rays have been standard practice for years In essence this program should include scru of t mei din cay l records of chest roentgenograms of all employees of autopsy protocols of death certificates certificates for evidences of malignancy It should be pointed out that statistical calculations relying on clinical records or on death certificates based on clinical diagnosis may contain a wide 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 duat PART III EXPERIMENTAL INVESTIGATIONS 6 The Saranac Laboratory with its background of study concerning chronic pulmonary disease especially that resulting from the inhalation of industrial dusts including asbestos is uniquely qualified to pursue certain phases dealing with the problem of asbestosis and pulmonary cancer 7. For purpose of completeness and general information certain brief comments seem justified for guidance in the design of the experimental approach which we propose ee en at e SuscentionSuscention we " A number of experimental mothods may be employed to test the capacity of asbestos to produce cancer It is desirable to keep in mind however certain facts concerning asbestosis which affect 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 mathod employed should direct em- phasis on the lung 2 The weight of evidence is that asbestos fibers pro- duce their irritation by a mechanical rather than by a chemical mode of action The mechanical action is intimately related to the movement of the lung during respiration Thus an experimental method which neglects movement of the lung and there- by in probabilitywould be all excludes the mechanical action meas ree ECU me oe ee oe highly inconclusive and subject to criticism 3 Asbestosis is a disease resulting from widespread dis- semination of asbestos dust in the lung Reliable conclusions in an experimental investigation with asbestos carot from experiments be drawn solely drawnrem te with the intratracheal injection ee injection technique whereby a high concentration of dust becomes localized ee in a restricted portion of the lung and stimulates excessive focal irritation When the asbestos dust is introduced into the animal in that manner the injected dust may miss certain potentially producing sites in the lung which are remote from the localized area of implantation of dust It is further possible for the excessive focal irritation which is not a characteristic feature of human asbestosis to induce pulmonary cancer which would not have developed had the dust been uniformly distributed throughout the lung Thus the intratracheal injection technique ; alone might lead to unwarranted conclusions The intratracheal method has been used for cancer studies by a number of investigators probably because of the relative difficulty and tedioumesS of methods involving inhalation of the potential carcinogen The | inhalation method however has been employed by eminently recog| nised investigators of carcinogenic agents 8 In passing it might be said that lung tumors can be produced by numerous means in susceptible mice i.e. mios possessing the tendency to develop tumors spontaneously Some of the methods garnered from the literature are repeated applications of coal tar to the skin subcutaneous injection ofcarcinogenic hydrocarbons intravenous injection of serum and charcoal dispersions of carcinogenic hydrocarbons feeding large doses of dibenzanthracene and introduction of carcinogenic hydrocarbons into the rectum vagina peritoneal cavity or pleural cavity For explanation of the occurrences of lung cancer following such methods it has been suggested that the introduction of carcinogenic 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 is that the lung tumors are pro- duced because very small amounts of the carcinogenic agent leave the site of applicationapplication and come in contact with extremely sus- ceptible alveolar epithelium If this is true it is unlikely that such methods could be used for investigation of cancer and asbestos a dust which remains within pulmonary tissue which is not transported systemically as are soluble chemical ws -- ee chemical ee eo. its irritating which produces = erent Se wen irritating effect by a mechanical - ee ee we by a chemical mode of action tee oe - _ oem BO agents and mmr than rather 7 ee =. 9. Reference has been made to inbred strains of mice in which the spontaneous occurrence of tumors of the lung is a characteristic feature Strains are available in which the incidence of spontaneous lung tumors is accurately known In some strains the incidence is low so that an increase in the incidence after an experimental procedure is easily detectable Other strains with high incidence of spontaneous tumors are suitable to determine whether the procedure has caused tumors to appear at an earlier age and whether the number of tumors per mouse has been increased The susceptibility of the pulmonary tissue in selected in- bred strains of mice is such that they serve as excellent test ani- male for checking an alleged extrinsic carcinogen such as asbestos A A reasonably delicate assay of the potency of asbestos as a car- cinogen is possible because of the unique multiplicity of tumors my we. oe. formed Cee 0 en vee, PART IV + PROPOSED EXPERIMENTAL INVESTIGATION - > 10. METHODS TO BE EMPLOYED In view of the considerations considerations mentioned in the proceeding paragraphs the Saranac Laboratory proposes to conduct an experi- mental investigation employing the inhalation method and also for supportive evidence the intratracheal injection method Two groups of pure inbred strain mice will be used 1.0 the low spontaneous lung tumor strain C 57 black and the high lung tumor strain A obtained from the Roscoe B. Jackson Memorial Labor- atory The animals of each group will be divided into subgroups equivalent as to sex age and weight at the time of inauguration of the actual experiments After mixing part of each subgroup will be exposed to atmospherio suspensions of fiber asbestos dust of controlled concentrations part will be injected intra- tracheally with measured amounts of the dust suspended in sterile normal saline part will be set aside in normal air for controls Each animal will be numbered and a separate record will be kept Animals from each subgroup will be sacrificed at intervals and the other members will be permitted to live out their natural life span After death the lungs will be fixed by intratracheal injection of Zenker's formal or formalin solution Sections passing transversely through both lungs and the mediastinal structures will be prepared for microscopio study 11. EVALUATION OF EXPERIMENTAL RESULTS ~~ Carcinogenicity is to be evaluated by comparing the following five factors in all subgroups The per cent of mice with lung tumors 2 The average number of tumors per mouse ( 3 The number of tumors arising in the asbestotic areas versus the azbestotic areas of tissue in the exposed mice The induction time for tumors ( Evidence for direct origin of tumor from asbestos 1.e. the histological appearance of tumor will be compared with the cancerous epithelial hyperplasias that may be present 12. COMPARATIVE ANALYSIS WITH OTHER INVESTIGATIONS UNDERWAY The studies concerning asbestos will be integrated with other investigations of the Saranac Laboratory Those investigations concern the carcinogenic properties of inhaled quartz and of non- irritating dusts such as carbon and iron oxide The data obtained will form a basis for statistical study of the occurrenos of pulmonary cancer in mice exposed to dusts other than asbestos 13. ESTIMATED DURATION OF THE EXPERIMENTAL INVESTIGATIONS The investigations proposed involve disease processoswhich develop very slowly This applies to asbestosis as well as to pul- monary cancer With respect to asbestosis previous studies indi- cate that at least sixtson months of continuous continuous exposure to dust aro necessary in order to produce definite fibrosis in a highly susceptible animal such as the guinea pig In contrast the mouse is more re- sistant and develops his reaction even more slowly under similar conditions of exposure The development of asbestosis in mice may be speeded up considerably by increasing the concentration of the dust to which they are exposed Thus it is anticipated that rather definiteresults.combo oobtbaitneadobitnaienedd iinn not less than two years by method the inhalation oe, V and in not less than one year in mice receiving an intratracheal 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 The very nature of the disease and the experience of other investigators dictate that a year at least a year and preferably least ae program should be= program mvisaged This should not discourage the sponsorship of the pro- gran by the companies as unfortunately there is no other alter- native if reliable results are to be obtained 14. REPORTS OF EXPERIMENTS Progress reports will be issued from time to time during the experiment and a comprehensive report will be submitted at the conclusion of the investigation These reports will be forwarded to the proper authorities identified by the sponsoring agencies -10- 15. PUBLICATIONS OF RESULTS OF IEVESTIGATIONS The Saranac Laboratory reserves the right to publish the : results of its investigations in the recognized manner commonly em- ployed by the 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 book book bo k book for wv Ss 18. COST ESTIMATE The combined project including both the inhalation and the intratracheal techniques requires the sorvices of a number of staff members 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 the use of special mouse cages and a large quantity of expendable materials such as chemicals glassware microscopic slides and cover slips The cost for this comprehensive study will approximate ; 16,000.00 for the first year and 10,000.00 for the second year / 1st 16,000 AJVibw 2nd - 10 com Cont of GA Program Program 3nd - 5000 for The 5000 Z 5.- 5.- 5000