Document o4Nr5axJ5q90kNJrV18pbX0X

PLAINTIFF'S EXHTOIT Y MET-339 March 15, 124.3 Dr. Ludvig Hehtoen, Chairman Committee or. Cancer Research National Cancer Institute Bethesda, Maryland. Dear Dr..Hektoen: . In analythe results of a recently completed inhalation experiment on asbestosis, I vas startled to discover that a 9nal! group of 12. white nice that had been inhaling asbes tos duct from 15 .`to 24 months shewed an excessive incidence (31.3.a) of -pulmonary cancer. Thi3 experience was quite at variance with the results in.all our previous long-tern duct exposures which were summarised and published by Vorvald and Karr in the American Journal of Pathology, January 1933. I would have attached little significance to this reaent finding becauee of the snail number o animals involved, but for the fact that the literature new ccr.tai ns ccne 10 reports of pulmonary "bancer in cases of human asbestosis. 3v5.n these I have heretofore attributed to selection of material we have found no cases of pulmonary tumor in surveys of employed asbestos v/orhsrs. However, Cloyne, Merevether and other English observers contend that asbestos has a specific carcinogenic actio on the lungs. The question, is.of considerable importance in iadu strial medicine because of the associated compensation aspects ar.d from a scientific view point, It interests me a great deal. In view of this recent finding I have rear.aI --aed the results of a large number of du3t inhalation experiments w n * *./o have carried on during the past 25 years. Ths incidence of nonary tumors is shown, in the appended table. It would a??e. erxept in mice, tumors have been generally unoommon in the e of different species that we had used. Guinea pig3 have shown occasional adsr.ocaa of the lung whose incidence 13 not influer. ced by dust exposure or by the type of dust involved. However, in white mice that 3urvived for 15 or core months in our du3t rooms, various forma of lung tumors were much more frequent. The average i nc lder.ee of such tumors In a group of 143 mice exposed to 4 different quart acontaining dusts was 13.8^ but this appears saall in contras t to thlo Incidence of 81.S' In the asbestos nice. In 51 younger mice that died or were killed after exposures of 10 or 11 months W` ai r* a vas only one instance of pulmonary tumor. Therefore, either ige o: duration of dust exposure must be important. i* PLAINTIFF'S 1i exhibit Jl2gM 00012350 010255 I Dr. DudwIn Hex to sn ;hone o: these exceriuents was planned to stu: caseinorenic effects. 'lies were only used as there vaa opaca lr. the dust rccu3 and cany of these sninals that died after short exposures were discarded without autopsy as they could not have csvelopea a sufficient amount of dust reaction to be of interest. The strain cf nice kept in the laboratory has charged fret: tine to tine by importation of new stood. At cae tine we did procure from Dr. >laud Sly sone'cancer susceptible steed but as these anl3.nl3 failed to react to inhaled? quarto we lost interest in the subject.- Obviously under such conditions, the results with aso = etcs neoao r^. ^ ~ tt-hw iin~nr* but lr. view of the considerations which x have cited, .1 believe they should be checked. decisive answer to question would. be of real practical value. Froa what we have learned about the action of asbestlform nir.erals in the living becy, I would not be surcriaed to discover that their carcinogenic effects are dif- >rsnt fren those o- ocher minerals. Their crystaiicrracnic structure is unicue. a:t as mechanical irritants rather than chenicall7 as is the case.with quarts and other forms o: Cn crushing cr grinding, asbestos fibres loose carcticall7 all their irritating capacity; quarto cn the other hand, beecnes none irritating ao the particle sloe decreases. Asbestos provokes fibrosis only in th: lungs of certain species; quarto excites such reaction in any organ of any species of ar.innl that we havs tested. Asbestos seers to have no specif1c action upon pulronary epithelium but in sons species, it caus: an unusual type of diffuse fibrosis which ccr.prssses and distorts the epithelial-lined respiratory bronchioles but often fails to obliterate then. However, this ucchon!cn would not a no ear to be the nr. a ra aeons!'. for the nouse tunor3 fo*--r rth* i1s is one of the species which develops no fibre.:! c on exto sure. Possibly, the lack of reaction is due to sup erior upper respiratory protection against inhaled foreign cedies. Th. lungs of nice, exposed to asbestos dust for two years reveal relative!; few fibre and all of these are short and coated to fern that peculiar.- structure known as the asbestos body. In order to verify cur accidental discovery of cos-- : sible carcinogenic action of fibrous asbestos, I would like to repeat! the rcouse inhalation exr.eriuent under properly controlled conditions.. I would breed a large number of cancer susceptible nice, splitting -p ach litter into three groups and keep a record of the ages cf each.Cne third of the offspring would be kept in a normal atnesphere as--acontrol; another third veuid be exposed to quartz du3t as a second control and the other third would be exposed to asbestos du3t. v>'e . 00012351 cm2 / 1 Ludvig -sitcer. O ft obtain SCO dee for each -roue. ?h .*.: parent ly\ have to be continued for 15 to 1-1 netr.tr.j. Cur routine In cuch er.perinentD provides --n a d_a , - days a veed. ''e ha. v e all t h e necessary ecu lone r.t for In ei t r,;r.::er. t3 .-oratory wcrscnr.s*1 * >--rxii -o however. Cur previous study of asbestosl3 which continued for period of ? years vas financed by th-*: Aabestca Association. 31.._c Lie roup of nanufacturere has already Invested vCC,CCO, I cannot sh then for further contributions. I dlocucoed the natter with Dr. F.hodco at the Hecoriul Hospital who favored and -as cf the opinion that it '..us worthy of consideration bp your ccurlltce. I : therefore applying-for 3. Errant of ;5,0C0 to cover the cost cf the first year's expense. I had tcld Dr. -"-hedes that I would be willlrjp to do the entire enrerinent for this arourt and ordinarily I should. How ever, on C7 return freon 'lev forit, I found two proposals for investiga tions of other industrial dusts each of which yield the Laboratory 15,010 a year. As 1 have only two dust roots at the present tine free for new word, I cannot .afford to tla up one cf then for two years for half the arcurt. Should you be favorably Increased with this proposal I -./ould appreciate a.-.7 critiolsn3 or surjesllcns. Sincerely yours, Leroy U. Car Dlrecto 00012352 N .. 010255 Dr. Ludvig Hektoen, Chairman Committee on Cancer Research. Rational Caricer Institute Bethesda, Maryland. Dear Dr. Hektoen: . In analyzing the results of a recently'con inhalation experiment on asbestosls, I vaa startled to disc that a snail group of 11 white nice that had been inhaling ;-tos .dust ..from .15 .'to 24 months showed an excessive incidence .of .nulncnary cancer- '-.This experience was quite at variance the results in.all our* previous long-tern dust exposures vh were summarised and published by Vorvald and iarr in the Am Journal of Pathology, January 1933. I would have attached significance to .this recent finding because of the snail nu animals Involved, but for the fact that the literature new come 10.reports of pulmonary "dancer in cases of human as'oes Zve.n these I have heretofore attributed to selection of mat ve have found no cases of pulmonary tumor in surveys of emp asbestos workers. However, Gloyne, Merewether and other la observers contend that asbestos has a apecific carcinogenic on the lungs. The 'question, is . of considerable importance i trial medicine because of tha associated compensation aspec from a scientific view point, it interests me a great deal. dus c.- In view of this recent finding I have reanalyzed the results of a large cumber of dust inhalation experiments that have carried on during the past 25 years. The incidence of pul monary tumors is shown in the appended table. It would appear tha except in nice, tumors have been generally uncommon in the strains of different Gpecias that we had used. Guinea pigs have shewn oc casional adenomas of the lung whose incidence 13 not influenced by dust exposure or by the type, of dust involved. However, in white mice that survived for 15 or core months in our dust rooms, varicu forms of lung tumors were much core frequent. The average ladder, of such tumors In a group of 143 nice exposed to 4 different quart containing dusts vaa IS.8^ but this appears scall in contrast to thi3 incidence of 61.6^ in the asbestos cice. In 51 younger mice ;\ that died or were killed after exposures of 10 or 11 months there vaa only one instance of pulmonary tumor. Therefore, either age o 1 duration of dust exposure must be important. OOOJ2350 0102 o ij I &d r.eitc er. :i:one of these e/.pericents vaa planned to study cascir.ogenic eff*ct3. kies were only used aa there was opace in the dust rccca and cany of these onicala that died after short exposures were discarded without autopsy as they could not have developed a :our. > 'ust reaction to be of interest. The strain nice keot in the laboratory has charged from tine to tine by in-- donation of new stood. At one tine we did procure from Dr. Kaud -- j _ none cancer susceptible stock, but as these anianls failed to react to inhaled "quarto ve lost interest in the subject.- '' Obviously under such conditions, the results vith a:o?3tc: rear, no Chinn tut in view of the considerations which I have cited, :.-I believe they should be checked. A decisive ansver to this question we n Id'.be 'of Teal practical value, From what v/e have learned about the action < asbestlfcrm nir.erals in the living body, I would not be surprised to discover that their carcinogenic effects-are dif ferent frca those of other nineralo. Their crystallographic structure s unique. They apparently act as mechanical irritants rather than ch=rieall7 as is the case vith. quarto and other foms cf free silica. Cn crushing cr grinding, asbestos fibres lco3s parctioall7 sll their irritating capacity; quarto cn the other hand, bsccnes nors irritating as the particle size decreases. Asbestos provokes fibrosis only in ths lungs of certain species; quarto e.vcltes such reaction in ar.7 organ cf any species of ar.inal that we have tested. Asbestos seenn to have .no Bpeciflc action upon pulnonary epithelium but in cons species, it cans; an unusual type of diffuse flbrosia which ccrprssses and distorts the epithelial-lined respiratory bronchioles but often fails to obliterate than. However, this mechanise would not appear to be the c.os respcnsl': 1 or t reuse tumora for this is cn: the species which develops r.o fibrosis on ex sure. Possibly, the lack of reaction is due to sup erior upper respiratory protection against inhaled foreign cccies. Th: lungs of rice, exposed to asbestos dust for two yearn reveal relatival; few fibre and all of these are short and coated to form tha; structure known as the asbestos body. In order to verify cur accidental discovery cf cos---(.v aible carcinogenic action of fibrou3 asbestoa, I -would like to repeat.^: the .couse inhalation ea:pericent under properly controlled conditions il '--ould breed a large number of cancer susceptible mice, splitting !/. |each litter into three groups and keep a record of the ages cf each. C1--* o" u-.M. --.s-*. O *.^ ^i.c control; another Or\i***+ ~ third w-**r*oC> -->ul.d. .:obueid be keot eases ed In to a normal atcoschere as--ah--' quartz duct as a second [ control and the other third would be exoosed to asbestc3 du3t. Vi'e 3 00012351 March. 15, 19^3 Dr. Ludvig nshtoen, Chairman Committee or. Cancer Research MutionsI Cancer Institute Hethesaa, Maryland Dear Dr. Heltoen: . In analyzing the results of a recently ccmple ted inhalation experiment cn asbestosls, I vaa startled to discove that a small group of 11 white mice that had been inhaling as'c 50- tos duct free 15 .'to 21 contha showed an excessive incidence (2 1-2.5} of 'pulmonary cancer- Thi3 experience was quite at variance vi the results la.all our previous long-tern, dust exposures which were summarised and published by Vorwald and Harr in the Aaerl Journal of Pathology, January 1933. I would have attached lit significance to this reoent finding because of the small numbe animals Involved, but for the fact that the literature new cor. s some Even 10 reports of pulmonary these I have heretofore "bar.cer in cases of human asbestos attributed to selection of mater! -- - o n <23 we have found no cases of pulmonary tumor in surveys of employ ed asbestos vorhers- However, Gloyne, Msrevether and other Tngll sd observers contend that asbestos has a apeolfic carcinogenic ac on the lungs- The question, is.of considerable importance in i nc- s -- trial medicine because of the associated compensation aspects ar.d from a scientific view point. It Interests me a great deal. In view of this recent finding I have reanalyzed the results of a large number of du3t inhalation experiments that we hive carried on during the past 25 years. The Incidence of pul monary tumors Is shown. In the appended table. It would appear that, except in mice, tumors have been generally uncommon In the strains of different species that we had used. Guinea plg3 have shown oc casional adenomas of the lung whose incidence i3 not Influenced by dust exposure or by the type of dust involved. However, in white mice that survived for 15 or core months In our dust room9, various forms of lur.g tumors were much more frequent. The average incidence of such tumors in a group of 143 mice exposed to 4 different quartacor.tair.ing dusts was 13.8^ but this appears small in contrast to this Incidence of 61.Sw in the asbestos Dice. In 51 younger mice .*i that died or vere hilled after exposures of 10 or 11 months there vaa only cr.e instance of pulmonary rumor. Therefore, either age or duration of dust exposure must be important. 00012350 0102 *- Ludvig Helices iOuI- nttenct '0 nice for each ^ ^ ea T." C 2 1' 6 9 I,'- .-. :pnr or.tly\ have to be continued for 15 to l-i o:r.:r.3. Cur routine in cuoh er.perirer.ia provides for dustier; G hours a da/, 6 day3 a veel. ''a have all tie necessary ecuinncr.t for such er. _ i si* a trained lot oratory personnel.' reran are laclir.r however. Cur previous study of asfcestosl3 which continued for a period-of 7 years was financed by tit*; Asbestos Association. 31r.ee this crc-? of nanufaoturere has already invested >5C,CC0, I cor.r.ot ash then for further contributions. I discussed the natter '..'ith Ur. F.hodco at the nccorial Hospital vhr ^'s vcrec ar.d -..-as cf ti ooir.io: :hnt it uas v/orthy of consideration by therefore applying for a grant of }5,0C0 to cover the cost of the first year's e.tpensa. I bad told Dr. r-hedes that I veuid be v:illl.-jj to do the er.tlr3 ezperiner.t for this anourt ar.d ordinarily I should. How ever, on c7 return fret :Iev forh, I found tvo proposals for ir.vestlr tlor.s of other Industrial dusts each of which yield the Laboratory 15,030 a year. As I have only tvo dust roots at the present tine fr for new v/orh, I cannot, afford to tia up or.a of then for tvo years fo. half the oncur.t. Should you be favorably increased with this propose. I vould appreciata ar.7 critic Inna or suggestions. Sincerely ycurn, LUC: .13 H Leroy U. Gardner, X. D, Director 00012352 010253 I /-nr * ~ -- w , -- ^ o .Ov. - . l-Sr^ ;C0 nl: :cr each prett. a :pnrer.tly\ have to he continued, for lay2 a veen. '.a e n o c' u 1* e e ur.ar.o . Cur a day, '-'9 have all the necessary ecultnent for c\ T ^ ^ ^ c r* T-. -- ----S * I ^ ^ ^ r; -.-ci. *^ c. V -- -- --1 - '-- ,1 .,1 W Ck ^ s* * J g-- . --a. however. Cur previous study of asbestoala vhlch continued period of- 7 years vaa finanesd by the Aabestoo Association, this croup cf nanufacturers has already invested vuC,CCO, I ash then for further contributions. I discussed the natter Dr. Abodes at the Mecorial Hosnltai v; to faverse ar.d v.-as cf opinion ..that it '..us vorth.7 of consideration by your ccoait: ,thereforo'.applyins'.-for. a./grant. of. ?5,0C0 to cover the cost first year's expanse. -v lu I had told Dr. Rhodes that I could be vili the entire ezperirent for this anount and ordinarily 1 shou ever, 0 a 0C7 return fron -lev Yorh, I-found tvo proposals for tior.s of other Indusfri ;s,o:o a year. .As I ha Tot* p*3\-f *.'orb, I cannot half the ancur.t. Should you be favorably increased cith thi I v/ouid appreciata ar.7 criticises or suggestions. 2i"cerel/ n/o'-rc , LUG: ?.2r. Leroy U. Gardner, .. 'J. Director 00012352 010255