Document JJ73M40ZGod43VJBkg95DOqL6

FILE NAME: Oil Industry and American Petroleum Institute (API) DATE: 1952 June-Aug DOC#: API028 DOCUMENT DESCRIPTION: Letters, Memos, Reports, Financial Reports & Other Relevant Documents from June-Aug, 1952 HewouUME1DSITC.ALMO.IRDEC. TOR THE TEXAS COMPANY 135 EA ST 4 2 nd S TR E E T N E W Y O R K 17. N. Y. Juno 3, 19$2 pobars of tha Rasoaroh ?rojaot Adrisory C tittoo Hoso arch Projast MC-1, Amrloan Patroloua Ins t i tu ta Pir Sirs As pop oup talagraa o f kj 29 tharo 111 b t i o a M ty tin g o f tho Rosoarah P rojost (OC-1) Adrisory Casndtto oa jsly 10 1952 M M la i a t 9i30 A.M. a t tho Kottarlng Laboratei 1b C lnalnaatl. Dr. Xahoo i l l bo unablo to bo peasant, t o t BP, aor ton and otbar mbbars o f tho Kottarlng s t a f f i l l a t toad. Kindly oond oo any auggostlsno th at joo nay hart for la* alusloa on tho aganda hioh Z 111 ooopllo and sutodt to tho aiobBrs In adanoo o f tho mootin e w ill yoa a lso in fa n t o as to vhothsr or not you 111 attand tha m a tin g . fory truly yours, vtiRms 1 w. idasa U C. Board. JT. Ciaffar D arla, ti.D. *. I . takardt, M.D. T. M. frank, l.D. c. K. Hina, M.D. t K. London ! K. U ndar, M.D, * D. laakanslo *. C. M lthoff * I . Shapardsoa Adrisory O am lttoo API 05326 FOR INFORMATION OF MEMBERS AND ASSOCIATES OF MEDICAL ADVISORY COMQTTgE.____________________________ ___ _____________ 6-30-52 UNIVERSITY OF CINCINNATI Department of Preventive Medicine and Induetrial Health flia Kettering Laboratory Coll8e Medicine - Eden Avenue Cincinnati 19, Ohio June 5, 1952 Mr. David V. Stroop Technical Service Director American Petroleum Institute 50 West 50th Street New York 20, New York Dear Mr. Stroop: In going over the last Interim Report to the Medical Advisory Cosmittee an error was found in Table I. On page 19 of the Appendix under API Sample No. 12>6 the description shows this is the distillation residue b.<1065F. This should be the redisue b.>105 F. Please change your copies and the stencils accordingly. Very truly yours, /s/ M. J. Graf Mary Jane Graf, Secretary to Dr. A. W. Horton mjg API 05327 30, 193 Dr* Bobart A. SOho U & loRoltr o f Cincinnati Osa Battarlag Laboratory Collag af Madida Cincinnati 19, Ohi lattar o f Patatar 86 m Baw n v 3 , 1967, ta ara anoloalng tba T a rlitato *a chaek la tha a a a rt a f p t,500 yayabla to tba tadto ra lty a f C la a ls s t l io oar antritntia tonada tba da-valognast of la ftiw tl<w oo flonrtn aat finarla wapowto for tfa tala anntb parlo* anting Jam 30. 1953* aas . X MMO TO . UAXJDKt fM spanditor la to "ha otorgad agalaat tfa Jfedieal Baaaarab Tuai. API 05328 THE TEXAS COMPANY 135 East 42nd Street N e w Y o r k 17, N. Y. J u l y 2, 1 9 5 2 To M e m b e r o f t h e R. P.A. C o m m i t t e e of Subcommittee on Carcinogenicity Gentlemen: As previously advised, there will be a meeting of the Research Project (MC-1) Advisory Committee at the Kettering Laboratory, Cincinnati, 9:30 a.m. to 4:00 p.m. EST, on Thursday, July 10, 1952. For your confidential information an agenda wit h attachments is enclosed. If you will be unable to attend the meeting, kindly let me know. MNN.-JKF ENCS. Very truly yours, in t . j A M. N. N E W Q U I S T k D. I Chairman, Research Project Advisory Committee i ' E. W. A d a m s E. K. Linder, M . D . V L. C. B e a r d , Jr. K. G. M a c k e n z i e KiefJer Davis, M.D. R. C. M i t h o f f R. . E c k a r d t , M.D. R. M. S h e p a r d s o n T. M. Frank, M . D . C. M. H i n e R. M. L a n d o n V Mr. D. V. StroopJ' Dr. Robert A. Kehoe API 05329 AGENDA Research Project (MC-1) Advisory Committee Meeting Kettering Laboratory, Cincinnati, Ohio July 10, 1952, 9:30 a.m. to 4:00 p.m. EST Summary of April 1952 Progress Report Comments on the P r o g r e s s Report progress of studies since A p r i l 1952 and'future plans Effect of v i s c o s i t y on p o t e n c y and the use of e m b o d y i n g agents to m o d i f y vis c o s i t y (a) Need for additional studies on straight-run, uncracked distillates and residua (b) A p p r a i s a l of B r i t i s h l iterature and the m a gnitude of the h a z a r d in Great Britain plans of the Sub-panel on Lubricants and Process Products Hygiene of the API Lubrication Committee Report on mid-year meeting, General Committee, Division of Refining, May, 1952, with respect to the RPA C o m m i t t e e 's report of April 30, 1952, to Mr. T. J. Sullivan Epidemiological Surveys (a) A m o n g e m p l o y e e s of p e t r o l e u m companies (b) A m o n g e m ployees of customers Other business Date and place of next meetings of (a) Subcommittee on C a r c i n o genicity (b) RPA Committee Dr. A. W. Horton Dr. R. E. Eckardt et al Dr. A. W. Horton R. M. Shepardson L. C. Beard L. C. Beard R. M. Landon K. G. Mackenzie L. C. Beard R. f.u Landon Dr. J. J. Phair Dr. E. K. Linder Dr. M. N. N e w quist API 05330 COPT SOCOMY-VACUUM LABORATORIES 26 Broadway, New York 4, I. 7 Juno 5, 1952 g. S. Mewquist, M.D. gsdloal Department fhe Texae Company X35 Bast 42nd Street I York 17, N. T. Dear Or. Hewq-iisti In reply to your latter of June 3, 1952, I advise that I plan to attend the meeting of the subject committee commencing at 9*30 0,a. at the Kettering Laboratory In Cincinnati. You may wish to elarlfy to members whether this be Daylight Saving Time or gastern Standard Time. As an Item for your a-ends, I suggest a reallstle discussion of the haxarda of straight run, uncracked distillates and residua. I feel this is an aspect of our work that must be squarely faced. The large majority of eases of oaneer of the skin from contact with petroleum products that have come to our attention have a history of contact with relatively non-vlseous lubricating oil distillates. To name theat 1) kule skinners cancer In Great Britain - while there was an early history of use of shale oils, yet such have not been used for many years) . 2) Cancers of tho scrotum In wax pressmen - these were confirmed by tosts at Kettering to be due to the pressed distillates) 3) Cutting oils oontalnlng 94)i of 100" pale paraffin oil - experiments at H7U on sueh oil from two different manufacturers both operating on Mid-Continent crude produced eanoere In mlee) 4) An increasing volume of British literature of which the recent paper by Crulckshank and Oourevelteh is an example) 3) Rumors of more ossss of csneer of the akin from outting oil on the Paelfls Coast - our psolfls Coast representatlv# asy be able to elaborate. While * have proven as consents also that high boiling oatalytiaally cracked produete are muoh more eareinogenlo, yet we must face the fast that the oaneers in men we now know of come instead from straight-run products of the character indiested. API 05331 *. Rewquiat, M.D a- I* June 5, 1958 m feel It would bo in order to request lottoring to make a appraisal of tha British literature and advlae ua of JJe magnitude of thia hasard. Plaoa ahould be provided for a I f l r f praaactation of tha plana -f the Sub-Panel on Lubrleanta -ad proeaaa Produota Hygiene of tha AFX Lubrication Committee of ^leh Meaara. London, Maokanaia and X ara member. j foal that eloaer llalaon with tha Britlah workara la In order* ia minute a attached to your letter of nay 17, 1958, are not Tory Ipful. PrIrately X hare learned - "that fraotiona froai Oklahoma bright orulea were teated biologically at Bermlnghaa gniraraity and yielded Intereating results, amongst than tha finding, that the aoat aotire oareinogena are oonoentrated in a fraction whoae initial boiling point la 600 to 686P* The upper limit of diatillatlon waa not ao aharply defined aa the oaroinoganioity fell off gradually. Whether thia effect waa due to a 4eoreaae in apaoifio aetirlty with inoreaae in moleoular weififrt, or to a lower oonoentration of actire hydrocarbon t/pea waa not dear"* fhe quotation abore givea in my opinion aome aubatantiation to a point that has bean stressed by Dra. gckardt and Shepardaon - to the effaot that viaeoalty appeara to leaaen oarolnogenlelty. Over tha years wer hare not load that our aoat violent deraatltia com plaint deal with produota of relatively low vlaooaity but a boiling range higher than conventional solvents* This w o u l d s u r e s t that the product must be sufficiently non volatile to stay on the akin and of sufficiently low viaeoalty to penetrate - and, of course, be irritant or earelnogenlo* X repeat a suggestion made aoae tine a^o that it might be in order to take one of our relatively non-viscoue active earelnogenlo fraotiona and dissolve therein several peresat of a material te inoreaae vlaooaity without materially changing composition and then test this material of increased viaeoalty to determine if ita carcinogenicity la lower* Thought ahould be given to the uam of Vlstanex, Alkylated Poly Styrene and Aorylolda in the order mentionedj also, aluminum atearate or allies flour dispersion (run through a eolloid mill) might well prove effective thickening egenta for thle purpeee* Very truly youra, LCBsHL L* 0. BEARD, JR* eos R. E. gckardt, M.D. I S. E. Linder, M*D. | 0. V. Saunders, M*D* Dr. R. M. Shepardaon API 05332 rw* * y f0ley Horton " [*t-rin IMt)or* fcory Cinn., Ohio M V 20, 1952 rtf. H o rton: #fy aorry that I did not got tho opportunity to diseuso with you your > # ^ 0nt interim Hoport and alao othor information whioh I had for you in Cincinnati. It was my full intention to come to tho Kettering theory on Monday afternoon, but in the meantime, a meeting of all the affiliated industrial hygleniats vaa called on Monday, which laated 0f*!?Lt and I felt that I ahould attend this meeting beoauae it repreaented JJ^rtunity to get together with the induatrlal hygienlata affiliated 'f^tbe company, which rarely preaenta ltaelf. Therefore, I did not get the |*Ltunity to cone out to your laboratorlea and ao I am writing thla letter to 7ou thoughta which I hare had concerning your Interin Report. I of all* 7ou will remember that in February, thla year, we had some dia ge concerning the composition of API 86 and API 89 For your information enclosing a table giving the dlatillation data on theee two aaoplea aa d for me by the Prooeaa Division of thla company. It will be noted Ijfl 99 containa owar 30^ of material boiling ata ve 700F. and, there . could be expected to have a relatively high potenoy. The predioted Uty by the ultraviolet method la 1*2 In our own work we ordinarily con- _ that any samples which hava a predicted potenoy above 30 have a algalint degrae of oarcinoganiolty. API 86. although callad a tar in eery parlanca, aotually representa a u30P / material from the team king of kerosene, and undoubtedly the low boiling oosqxmenta of thla rial account for ita low viaeoalty. It would saem, therefore, that thsre been no mistake in the labeling of thla material. felng now to your report, there are several things that ware apparent to M I went through it. The first of these la that if you take all of tha { uaiples which you hava studied and rate them on whether or not they con la significant quantities of material bolllhg above 700F., it would appear il in moat cases where there la muoh material boiling above 700F. in the I sample the Phc fella below 0.1. It le difficult, of oouree, to make a Anita distinction at 700F. because the distillation data given in your lisa are broken into less than 7500, 750-925 and greatar than 925F. You II remember, however, that we have claimed that 700?. represents a latively critical boiling point for the carcinogenic material contained in Bid eatalytieally cracked oils and has bean found useful by ua in ffsrsntiating oils which hava what we consider to be a significant dagrea arcinogeniolty from thoa# which we consider not to have a significant Apas of carcinogenicity. Ve have tried oarefully not to apply thla 700F. pit to all types of oils, but rather, to confine our remarks specifically tbs FCC oils. You have, on occasion, taken considerable exception to our * of tha 700oF. figure, out in looking over your own data, it appears to that it gives partial support at least to our previous contention that it aa a useful guide when it la remembered that if an oil con tains 10 a material from fluid oatalytlo cracking boiling above 70007, it la in * satinstion significantly carcinogenic) whereas, if it contains leas than l* 10 figure, it does not have a significant degree of oarolnogenloity* *s have indicated, we find this to be a useful guide, although I aa sure `t you are aware of the faot that our own efforts in attempting to develop ^alytloml tool are an Indication that we are not completely aaticfled with * guide. API 05333 f# *l7 H orton * -2- kay 20, 1952 txt of your report you Indicate that little difference seems to exist B ^# f#aulte which ere obtained when 100 mg. of e cample are applied over a of an animal *c back as when 20 mg* of the cample are applied over tree of the animal' back. Thlc presumably vac baccd on the results > Vflid *ith API 2 k 3, cc lictcd in Tabic 2 on page 20 of the tablea of your However, if you look at the rccultc of Table 1 on page 12 of your in ehloh API 8.vac painted on C3H mioe once a veek in one group with over a large area of the back, and in another group, where 20 mg. r*uacd over a snail area of the back, the rccultc do not aeea to bear out f contention. Thus, in the two groupc of animala, the maxima inoidenoe % ^P* lo r* (wTe.eIk.s) indicate a that in the first g ro u p , where 100 mg. were uaad, V* figu*" ia whareaa, in the second group, where 20 mg. were uaed, the t* *re ^9* To ra this means that in the first group, of the eniaals ioped turnon in 2k weeksj whereas, in the second group, only 53 of the LiTbave developed tumors in 37 weeks. The corrected average latent for tumor induction in weeks for the first group was given as llf.3/ '.'V whereas, no figure is given for the second group, but it is difficult j, to see how this oould be much lees then 30 weeks. It thus appears to e considerably greater amount of work must be done to definitely v* the point that the use of 20 mg. on e email area of tha back glvea ** whioh are comparable to those which are obtained when 100 mg, are ^^(jfer a large area of tha baok. 1 with API Semple Ho. 73 two apparently identical ax- '^PJeilUmntae were performed on CC\3KR aloe which were painted once a weak. In the n pit group the maximum lnoldenee of tumors is 8^j wWhaereaa, in tha eaoond the maximum lnoldenee of tumors le :< \r* Tha corrected average latent ffioi for tumor i n d u e tion in weeks ie 18 for the first group and 22.5 for Moond. This represents a difference of only k S weeks in tha average >a knot period, yet the Pyc is 0.1^5 in the first group and 0.27 in tha eaoond mp. This than means thet e k $ weeks difference in average latent periods :#!r represent a 66-2/3^ error in the results. ii' i n i duffareboa of 1*.5 weeks in the average latent period le not a vary - Imi time and would represent about shat I might axpeet aa an error of an ex- risent. In support of this contention, if you look at tha results obtained JJ lit API 203 on page 20, where 0.075 g./lOO ml. of methyeholenthrene in "3 bmqs wee painted on two different groups of alee, the oorreeted average .-U| lint period for tumor indue tion in weeks in the same strain of aloe, namely V is *.2 weeks. This, ee you know, represents, e control sample. Thus, *<! ^muld appear thet from the data which have thus far been presented, there ~-jt likely to be a yt 66-2/3^ error of e - approximately 30% error. This to me j 4 1ot too far off from the results whioh have been obtained previously in ' literature by investigators using subcutaneous inJsotions of e pure oar- end in whioh they indieatad that tha error of quantitative determine- was of tha order of 1004 or - 50% Again, it is my feeling thet these te very strongly suggest that more duplicate experiments on axaotly the concentrations of oarelnogen in a solvent, as wall as duplicate determine on oil samples, be obtained in order thet we can more accurately define J tbs error of the biological axperiTnenta really is. You will remember * the rpa Comittee has stressed within the pest few months the Importance 1 ^^itltatlvs biological test in order for the analytical tool to hava any loanee. Although I believe that tha biologloal test can be eami-quanti se I hava for a long time fait that a truly quantitative test, in tha API 05334 sesley Horton -> I* sy 20, 19S2 0f what a chemist thinks of as a quantitative test, it is lspoaslble %m a present blologleal tasting methods. If an error of 7^ 664 or -33 is 1Js&X ln *** development of an analytical tool, than I believe the bio* tests will be satisfactory; but if such an error is unacceptable, ' eonsiderabls amount of doubt is thrown upon the desirability of ,tlng to develop an analytical tool by correlating results with a bio Met unless it be recognised that this analytical tool will only be untitative tool. I also would like to point out that in the ex on API 73 there were only 12 final effective number of aloe out of ; ^ ^ i n a l s in the first group where the P*c was 0.1*5) whereas, there were wr dcsl effective number of mice out of 20 originals in the second group ^ the Pyc was 0.27. You have indicated throughout your report that the " t ^ of animals throws off the test and tends to make the results less . than if the animals are healthy and surviving. If this is the case, Ms |J: gas eight presume that the actual potency of the first group, here only . fdnal effective aloe remain, would actually be higher than the 0.1*5 in- `',4 in the table end that, tharafore, the error in this duplicate ax- w idgit be even greater than has been pointed out in the above peragrapl ~ further support of what was said above, I think it is import t to look at .faults obtained with duplicate determinations on API 79 listed on page fif your Table 1. In this experiment Cyj mice were painted twice a weak , , maxima incidence of tumors in one^group of 100. and ln the second - , of 53. In the first group only 1* final effactlve number of mioe remain; is 2*u in the second group 15 final effective number of mioe remain, result would probably indicate a difference of more than 1* weeks ln the ited average latent period top tumor induction and, therefore, an error sight bs greater than indicated abort. P4* 19 of Tsbls 1, the aromtlos from Sample Ho. 12 vhloh boll between tad 710?., oorrooted, wane tested m d the aromatics belling between 1010 1065P were alee tsstsd on mica, but apparently the aromaties boiling 710? and 1010p. ere not subjected to biologioal testing. I ly believe this to be unfortunate since it is the aromatioe in this ;t diioh we consider to be the most important from tha carcinogenic ataud- It also occurs to me that the less than sign which is in front of the figure for Sample 12-6 probably should be a more than sign. I believe la is s typographies! error which you night wish to eorreot in future Td bias of your report. r.i Mgs 28 of your report, in Semples 232 and 236, there is apparently a sig .'.w nsant iiffarenas in tha maxi mum incidence of tumors, aven though it is .1- .aH Moult to deslds why there should be such s difference when the conditions cm t ho experiment were so nssrly identical. Do.you believe that it would be C tffkible to conclude from this experiment that dodoeyl bensene, painted befgi s tingle application of a oarclnogenlo oil and then painted following ingle application, has an inhibitory affsot on earelnogsneslsT Peraaoal- 11 do not believe, as I also feel you probably do not believe, that this hs esse, but, rather, that tha difference ln maxi lnoldenoe of tumors ir two experiments is rare likely simply representative of the experimental of technique. I would be very interested ln your explanation of theae Ttasacaa. b-a-v-a-i-n-d-i-c-t-t-a-dto you above, the moat satisfactory may of discussing s J*t of this nature la with a personal discussion between the two indl-- ..if^Is involved, and I am sorry that such a discussion could not be API 05335 u $ l 7 H o rto n u y 20, 1952 in Cincinnati. I did not wish to take up the tin* of the Sub * on Carcinogenicity In discussing theaa things vlth you before tha tLni h#nc* I lat than allda In tha ballaf that I would ba abla than with you latar during tha week; but hawing fallad to have ^fgouaalon with you, I am taking .this opportunity to opan tha discussion 1 ou* 7139 ona point which I would bring up for discussion before tha Loeosnittaa on Carcinogenicity, nansaly, tha validity of applying a slaPfrd slops llna to the biological rasuits in riaw of previous evidence i^Jliterature that tha slope of tha llna will gradually diminish as tha , carcinogen diminishes (in subcutaneous experiments with ;.ura .J ` J% ^.fogens), still has not bean answered completely to my satisfaction. It the application of a standard slope to these experiments places ^emphasis on the initial latent period for tumor induction, which ^?ou* *nTeiti3*tora indicated is not a particularly reliable index <- ri ^ |M^*rI*hi_r*oreT, as I indicated fteon 7v 0n nU iinn ftehHe* course noff ftehVie* SubcommitfetfeeAeA seiantHing, * *igQefrkk*errss iInn tthese l"aboratories originally applied a standard slope to the P of our own experiments but subsequently abandoned this practice when ^ ^f*und that it did not seem to satisfy the majority of the experiments, 1itiiifcluUl**a*rly wluhieoriev ba wieduve ra01n1g5e wo*f relative wcgairwceiMnwo^gweiniiAcw*itwyj is being twoeisted. ore, there Is considerable doubt in ray mind as to the validity of ' .0*3 lying * standard slope line to obtain "corrected" PMC valuos for oxperi- rsaulta. I simply call this to your attention again because I believe frrants s considerable amount of diacusaion before it ia adopted as a ral procedure. -*r'Sfl " fi Iilso have looked rather carefully at the relationship of tumor production to Lt|fat response in the ani-.als and find it extremely difficult to find that Hr i constant relationship between the two. In many experiments where gsiidersble drops In weight have oeeurred, a significant number of tumors -Saq 4 jpurs to have been produced at the time of this weight drop; and even in Iff*rent groups of animals on the same experiment the relationship of tumor - W J. reduction to weight drop is not absolutely apparent to me. This then raises '-s'JA'J** It question of whether or not group weights are important, or whether in- e '-nq ftfldual animal weights may not be the moat significant factor Insofar as `bask uor production is concerned. In my own biological experimental work on the -viosl /ttosins, we used to weigh our animals individually because we found that lire was a rather important difference in when animals would begin to lose -lot wight after they were placed on a vitamin deficient diet, even though they .HP* art presumably of the same age, litter mates, and fed exaetly identical diets 1liwply point this out as a suggestion to be considered in trying to make the 4. a, Wit nor quantitative. > i ..lit tat though the abore comments may sound critical of the work which you arw J 1 ting let me add that I believe that it la Important and significant, and I ue< kink your report was an excellent one on the whole. I have simply offered emit W m criticisms in the hope of stimulating thought and discussion on the sub* Jm of all of these investigations. *- U p Sineerely, S. K. BCKA3DT, M.D. .i Dr. C.fc. Brown Mr. n. g . M. Fischer Mr. r . K. Shepardson - Attn: Kr. I. Priestley Dr. M. w. Swaney - Attn: Dr. !.. T. Ebny API 05336 iahohatww I. o*"0 % UNIVERSITY OF CINCINNATI OWAtTMJfT or PUVENTIVC MUMCIHI MO INDUrnUAL HEALTH CAHLt ADOAIA*. KATLAS. CIMCINHATI TIUWOW: Captol MM July 8, 1952 Id.. D. V. Stroop American Petroleum Institute cq Vest 50th Street jjev York City 20 5ev York pear Mr. Stroop: I am sending you herewith, for your infor nation, statements of expenditures made on behalf of American petroleum Institute during the first quarter of 1952. I believe the statement is self-explanatory, but if you have any questions or comments, Doctor Kehoe w ould appreciate your bringing them to his attention. Very truly yours, IS Enc. loia Sheppard Financial Secretary API 05337 1 * UNIVERSITY OF CINCINNATI KETTERIN G LA B O R A TO R Y A C C O U N T O F flW TRTf! flTJ d t t -ROT^TTM T T IS T ^ T T rT R FO R____1ST Q U A R T E R 1952_______________ jALAR* (Based on Proportion of Time Actually Spent on Project) Direct S ala rie s............................................................................ 34-49 5 & .... Indirect Salaries Histopathologicai Preparation .... 1 0 9 1 .7 3 Other Services............................................................. 5 9 3 7 * 8 7 ....... 1 5 ,4 7 9 .1 3 M ISCELLANEOUS e x p e n s e Purchase of A nim als.................................................................................................... 4 l. 40 Special Laboratory Supplies ........................... ...................................... 6 9 1 24- Travel ........................................................................................................................... 2314o Overhead (Proportion of Heat, Gas, Electricity, Steam, Telephone, General Laboratory Supplies, Postage, Annuities, Pensions, Maintenance, etc................................ ^ 9 2 6 .5 1 T O T A L .......................... 2 0 ,3 6 9 .8 2 Balance Available for Further Work at End o f ...I.951........................................................ 1 3 , 9 9 5 . 0 6 Balance Due Kettering Laboratory at End of...................................................................... Receipts................................................................................ 3 1 ,6 9 2 ^ -4 2 5 0 ,6 8 7 -4 8 Expenditures......................................................................... 2 0 . 3 6 9 . 8 2 Balance Available for Further Work at End of ...1.5t. t o r t . e r . , . 1 9 5 2 ...................... 30, 317.66 Balance Due Kettering Laboratory at End of .................................................................... '** uso. rr. lai., io#. 7-si API 05338 Copy from D. V. Stroop for Information of Doctor Linder and Doetor Sewqulst. ________________________________________ 2d k S cnyxRSZT? op czxcznuTZ Department of Preventive Nedlelne and Industrial Health The Kettering Laboratory College of Nedlelne - Bdsn Avenue Cincinnati 19 Ohio July 8 1952 Nr. D. V. stroop American Petroleum Znatltute 50 Meat 50th Street New York 20 New York Dear Nr* Stroopi I an aendlng you herewith for your informtion atatwenta of expenditures made on behalf of American Petroleua Institute during the first quarter of 1952. I believe the statement is self-explanatory but If you have any questions or commenta Dootor Sehoe would appreciate your bringing thms to his attention. Very truly yours /a/ Xola Sheppard Pinaaslal Secretary IS ApI 05339 UHIVKRSCTY OF CZBCXHKASI Kettering Laboratory ACCOQHT OF AMERICAS PETROLz*u FOR 1ST OPARTSR 1952 Salaries (Baaed on Proportion of Tine Actually Spent on Project) Direct Salaries $8,449.56 Indirect Salaries. Histopathologio&l preparation Other Services 1,091.75 5.937.87 Miscellaneous Expense Purchase of Animals Special Laboratory Supplies Travel Overhead (Properation of Beat gas, electricity, stean, telephone, general laboratory supplies, postage, annuities, pensions, maintenance, etc. TOTAL Balance available for further at end of 1951 13,995.06 Receipts 31,692.4t Expenditures Balance Available for Further Work at end of 1st Quarter 1952 20,369.8 30,317.66 $15,479.18 41.40 691.24 231.49 3*986.51 80.369.88 API 05340 rv ,,M labobatont % UNIVERSITY OF CINCINNATI KPARTMENT OP PMVINTtVI M IC IN I AMO IMOMTMIAL MIALTM CABLA AOOPISA: U T LAB. CINCINNATI TCU PH O H t: CAPITOL U M J u l y 9, 1 9 5 2 jfc*. D. V. S t r o o p , D i r e c t o r pepartaraut of T e c h n i c a l S e r v i c e s American Petroleum Institute* 5O W est 40t h Street jjev Y o r k 20, N e w Y o r k pear Mr. Stroop: I wish, herewith, to acknowledge with thanks the r e c e i p t of t w o c h e c k s , one i n t h e a m o u n t of $ 5000.00 towards the skin physiology project, and the other in the amount of $ 2500.00 t o w a r d s t h e d e v e l o p m e n t of i n f o r m a t i o n o n fluorine, which yo u forwarded to Dr. Kehoe on June 30, 1952. Very truly yours, IS cc: R. A. K e h o e loia Sheppard F i n a n c i a l Secretary API 05341 u Ot*TO w" <9 UNIVERSITY OF CINCINNATI OIFAKTIUNT Or F U V IllT lV t > (01ClMI AMO INDUH U M . HIALTH April 11, 1952 jjj.. Lacey W a l k e r , S e c r e t a r y American Petroleum Institute c>o West 50th Street jiev Y o r k C i t y 20 f pear M r . W_lker : I herewith acknowledge with thanks receipt of American Petroleum Ins t i t u t e 's check in the amount of .2500.0^, covering expenditures to be mad e on their be h a l f on the S k i n P h y s i o l o g y Project. Very truly yours, ef API 05342 30, i958 fir. Robert A. Keboa Qal-mrolty of Ciaclanatl Sie fettering Laboratory Cooflo of U kU sIsi Cincinnati 19, Ohio Soar ficotor lUtott Pr o m t to the uaderitandlng reached by oar letter of Jtoafc 20 and Ajril 3# re -- Bioala the luetitube*a aback la the -- mint of $3/000 payable to the BlTaralty of CiaoInnati as oar ecafelbatlon toward tb akin physiology project for ilia twaine-ncoth period mediae Jana 30, 1923. f 7 truly year fiVSia eat MEMO TO )B. VALORI M i expendtora la to be charged against the Medical Research fund. API 05343 :^r 1252 Er. Robert A. Kfehoe University of Cincinnati The lettering Laboratory Collage c*f ilediclrn - 2den Avenue Cirrinwiti 19, Chic Drap Toctor hret Please eupniae to Doetor Bnaklad ny appreclotion and thanks for the helpful infofgatian he prepared end east to ae with hie letter of torch ox about the skin physiology project. 2a the nteetadlag that ae eball receive eoyleo cf all periodical and special report resulting from this research project, s* ere enclosing the Ihstltete'e check la the w ent of $2,500 ae our contribution for the alx-smth period ending Jane 30 1952 ab of J'.ilj 1 , 1952 ee shall sake a contribution of $?,000 for the 12 wrath period ending Jane 30, 1953* Reporte steel* be sent to ne for distribution to oanittee neater*. te ehoald like to receive 00 copies of each report ehleh sill bo mdm available In gueatlty. te eases vhere that aster vlll not be veilable to on, one espy eill be aeffleleat fir eer eee la reprodaetlen. It s r j truly yours, 018 io oet Sr. X. Ihm Under MEMO TO MB. VALXSBt Tale expenditure Is to be charged against the Medical BeM a rch fund. March 25, 1952 Dr. T. Zara LIodor, Ctelnain API Modlcal AdTlaory Ccaadttoa c/o Ite Atlantic Bollala* Coupany 260 South Brood Stroot FhUadalpMa lt Poi-- yluoala For yor rodo ttero lo onol.owort griginoi lottar and mm rn t**inm tram. Doctor Bayaood 3. Suoirlad test tte Sida Physiology Freuet. If you apprmo no oboli preparo od wad coploa of this to motera aad accod a too for lnforaotioo la adtaaeo of tte April aeotlng. Alte If you appro** 0 abol aoaad $2.500 to tte UniT o r s i ty of Claoloaatl a s our contribution far tte six nootte oadln Ito 30, 1952. Tory truly ycuro, mi API 05345 * UNIVERSITY OF CINCINNATI DSPARTMSJIT OP p u v i x t i v i M U IC IH I AMD moumiAL HIALTN AVARUA CABLA ADORAS*: AATLAS. ClMCIRRATI TALXPMOMBi CAfiroL MM March 20, 1952 Dr. David V. Stroop, Director Department of Technical Services American Petroleum Institute 50 West 50th Street New York 20, New York Dear Doctor Stroops In Dr. Kehoe's absence I am forwarding the memorandum on the Physiology Program which you requested. I trust that it contains all of the information which you need. If there are any questions concerning any portion of the statement which require further elucidation, Dr. Kehoe who will be back in a few days, or I, will be most pleased to answer them. Very sincerely yours, ERS/mg cc: Dr. R. A. Eehoe End. Raymond R. Suskind, M.D. & API 05346  RESEARCH PROGRAM S O PHYSIOLOGY PROJECT KETTERING LABORATORY, UNIVERSITY OF CINCINNATI 1952 X, Background and Purpose The concept of the skin physiology project at the Kettering Laboratory is a natural outgrowth of the increasing demand for information about medical problems, industrial and non-industrial, in which skin function is an important factor. The establishment of this project is an attempt to satisfy a pressing need for well established scientific knowledge about the chemistry and physiology of normal skin as well as skin in abnormal environments. Since the inception of the project, the field of skin chemistry and physiology has been explored to ascertain not only what specific problems might be effectively attacked, but what techniques of study require development to facilitate an orderly approach to these separate problems. During this pejriod^too, the original program of the project has undergone a process of natural maturation which was characterized by expansion and the gradual inclusion of new problems in the investigative program. The latter has been possible only with an increase in trained personnel and research facilities. It has been necessary, therefore, to meet the expanding budgetary requirements of this project. II. Specific Research Problems The following is an outline in brief of skin problems which have been or are under investigation. A. Sebaceous Gland Chemistry 1. The identification and localization of lipids and enzymes API 05347 I * and other chemical constituents of the sebaceous gland and their secretions in normal and diseased states. 2. The quantitative study of pilosebaceous constituents in normal and diseased skin. 3. A Quantitative study of lipids in various levels of the skin. The observations which were made on the lipids and enzymes by histochemical methods are now being verified and enlarged by the study of normal and abnormal sebaceous material employing microchemical techniques. The particular interest of the group is to ascertain the normal chemical constituents of human sebum, the locale of their development and change, and the chemical alterations which occur in diseases of the pilosebaceous apparatus such as acne vulgaris, occupational acne and keratin cysts. A systematic study of the metabolism and function of the sebaceous glands is closely linked with the project's interest in percutaneous absorption since the pilosebaceous unit is probably the most important portal of entry for non-gaseous, noxious substances which pass through or into the intact skin. The following is a list of publications of the group in connection with its sebaceous gland study: 1. Suskind, R. R.: The chemistry of the human sebaceous gland. I. Histochemical observations. J. Invest. Dermat. 17: 37-5U, 1951. 2. Schmidt-Nielsen, K., Suskind, R. R. and Taylor, E.: The chemistry of the human sebaceous gland. II. Analysis of human sebaceous material ftrom individual orifices. J. Invest. Dermat. 17: 281-290, 1951. 3. Schmidt-Nielsen, K. and Taylor, E . : Use of a quartz fiber micro balance for histochemical investigations of skin. J. Invest. Dermat. (in press). API 05348  9 Percutaneous Absolution 1. The study of factors which influence absorption through animal skin. Z. The application of radioisotopes to the study of skin absorption problems. This includes route of penetration as well as the rate of absorption. 3. The knowledge and experience of the group with respect to absorption is employed in a practical fashion in problams of industrial hygiene. It is consulted by industry and other interested groups on such matters as cutaneous protective measures with relation to irritants, sensitizers, acnegenic and carcinogenic materials. Cutaneous Irritation and Sensitization 1. The study of physiological, chemical and biological factors which influence irritation and sensitization. Problems which have been assailed and currently being studied are: (a) The influence of the endocrines on cutaneous irritation and sensitization (b) The influence of percutaneous absorption on irritation and sensitization 2. The development and improvement of techniques to measure the irritant and sensitizing capacity of chemical compounds. This includes both human and animal methods of evaluation (See E below). ' The following are the publications in connection with the cutaneous irritation and sensitization studies: y 1. Nilzen, A.: Some endocrine aspects of skin sensitization and primary irritation. J. Invest. Dermat. IS: 7-35 1952. API 05349 j B Z . Nilzen, A.: Sone aspects of epidermal testing of guinea pigs sensitized and not sensitized to 2,I:-Dinitrochlorbenzene. For Dr. H. Haxthausen's "Festscnrifte" to be issued October 1952. D. Participation in the A. ?. I. Project on Carcinogenicity Several problems which have arisen in the A. ?. I. project require and will continue to recuire the cooperation and advice of the members of the skin physiology group and their participation in the A. ?. I. program. These problems include: 1. The role of percutaneous absorption and primary irritation on experimencal tumor rates Z. The role of cocarcinogenicity in skin painting experiments 3. The effect of barrier creams and washing on experimental tumor induction E. The Use of Cutaneous Techniques in Problems of Industrial Toxicology The personnel of this project in cooperation with the other divisions of the laboratory are frequently called upon to delve into matters of industrial hygiene at a fundamental or testing level when the skin is a potential or prominent factor in the exposure. The group is organized: 1. To evaluate industrial and consumer materials for potential cutaneous irritancy, sensitizing capacity, percutaneous toxicity, acnegenic properties, etc. Z. To investigate clinical industrial problems when they may arise by surveying the plant or industry and studying the problems involved at a laboratory or clinical level. The facilities available are particularly helpful in the study of such practical problems. API 05350 -jT, Personnel In its present form the program's activities are being carried ont under the direction of Dr. Raymond R. Suskind. Dr. Knut Scrmidt-ielsen, a chvsiolorist, is in charge of the rj.crocher.ical and radioisotope oercutaneous absorption studies. 7ne other members of the staff include a cnemical engineer who is in charge of the isotope laboratory, a technician in the isotope laboratory, a full time assistant for microchenical work and a full time technician for histochemical, cutaneous irritation and sensiti sation studies. IV. Facilities The facilities allocated to the work of the project include a well equipped histological and histochemical laboratory, an analytical labora tory especially designed for microchenical work, a constant temperature room in which a wide range of atmospheric conditions may be produced, a radioisotope laboratory, and animal quarters for breeding a hypersensitive strain of guinea pig and for housing animals on cutaneous e:cperinents. The facilities and services of the other departments of the Kettering laboratory have been effectively integrated into the work cf the project as the particular needs have arisen. V. Finances ' The financial sponsorship of the skin physiology project was initially 'undertaker, completely in 19U8 bv the Rristol-Myers Company which allocated funds for a three year period. The sponsor contributed $20,000 per year from 1=L3 - 1??1. Tntil recently the original endowment satisfied the needs of the program, '.vith the normal development and growth of the project, the API 05351 ) * general increase in equipment costs and salaries, the economic recuire- ^ents of the full program are now several times the amount of the project aS oriair.ally planned. As of October 1950 a grant of $10,000 per year was initiated by the Procter and Gamble Company in partial support of the irritation and sensitization studies. This endowment continues. Several months ago the Monsanto Chemical Company contributed i5,000 towards the general suonort of the project during the year 1951. Monsanto has made an additional contribution of $J,CCC for the year 1950. Additional support is available under the terms cf a contract with the United States Air Force for the work on percutaneous absorption of liquid organic compounds. This will probably not exceed the sum of 10,000 in 1952. A further grant of 3,000 has been made for the year 1952 by the Abbott Laboratories. Two other pharmaceutical companies have expressed interest recently in the support of the program. The funds made available so far towards this work have been without strings except in the case of the Air Force in which instance they are earmarked for work in the absorption section of the program.. A tabulation below summarizes the situation with respect to funds now available for 1952 including that represented in the recent recommen dation of the A. ?. I. Medical Advisory Committee. Sponsors Monsanto Chemical Company Abbott Laboratories U. S. Air Force (approximately) Procter and Gamble Company m%. *O _7 Total Amounts $3,000.00 3,000.00 10,000.00 10,000.00 5,000.00 $51,COO.DO API 05352 5 9 The total sum shown above is not sufficient to support the entire oroeram which we have in nind, and it allows nothing for future develop ment, but it is hoped and believed that additional sums can be obtained, yeanwhile the work will be retarded somewhat to fit the funds available. API 05353 Itt n a r y 1* 1958 Or* Betort A. Stto* tottering Laboratory tolteralty of Cincinnati Cincinnati 19, Ohio I m n i l * addantlai la telai lite te tte ran-- mlBtloa of tte tolaal Arlaery C-- ltte* far oatrltotl-- to joor r u m a i ob teal ptjaialagr of M a a aidai t e r a r t a lank ayaalfla laftenatlaa tea arida aooya, jro g oaa, ad jrogrna of tea pnjaot. It tdll te telefax If jaa eaa and at a srayarte atot-- it, twjitter alte tea a-- 0 of jaat aa proaast spanner and tlia amnia of tealr eoactebatleee Z ftel oortaln m 111 te aateerlxod to aand tea rinr-- infini eontrtetK* of $8,500 Itela a tea oato after tte rocolyt of aaste a tete-- it firm 70. bum oot Dr. B* K* Ttalar to* V* B. Tartar API 05354 UiOBATOET 3 3 UNIVERSITY OF CINCINNATI OSM ETEENT o r MEVENTtVE MEDICINE A ID IHOUOTMAL HEALTH July 1k , 1952 CAELE AOMSSE: EETLAE. CIHC1HEATI TELEPHONE: CAMTOL 141 Mr. D. V. Stroop, Director Department of Technical Services American Petroleum Institute 50 West 50th Street New York (20) Hew York Dear Mr. Stroop: We are returning to you four copies of the continuation agreement covering API Medical Research Project M-2 for the fiscal year ending June 30 1953* This agreement has been signed on behalf of the University of Cincinnati by Mr. Frank F. Dlnsmore, Chairman of the Board of Directors and Mr. Ralph C. Bursiek, Clerk of the Board. We would appreciate your sending us two copies of the agreement for our files as soon as they have been signed by the President and Secretary of American Petroleum Institute. Sincerely yours, r Enel. lj. Verna Rahe, Secretary API 05355 o- ) ) i A merican P etroleum Institute SO W EST SOTH STR EET NEW YORK 2 0 . N . Y. Juno 30, 1952 Board of Diroc tccrs University of Cincinnati Cincinnati I9, Ohio Gentlemen: This communication is authority to continue vork on investigation of the toxicity and mode of action of certain petroleum products for the year ending June 30, 1953, according to the terms of the agreement dated January 8, 1 9 ^ , and on the "basia of a maximum budget for operating expenses of $10h,760. Upon receipt of your approval of the continuation of the project with this budget we shall pay you the sum of $20,000. The balance of $2^,760, less the unexpended balance in the fund on June 30, 1952, will be paid on January 1, 1953* It is understood that any balance remaining in the fund on June 30, 1923 vlll be returned to the American Petroleum Institute, and that no excess over the amount of the budget is to be obligated or spent without written authorization. Very truly yours, A M EhCOVEXVAiUHI PXARABXOlVIirXfBOUMn INSTITUTS By_ Accepted and Approved: d o b s i t i op cmcimiATi T h r a s h ita Board j f Directors *7 i -- - w - F. Dinsmore, chairman BT / I R a l p h C. ^ siek, Clerk" Secretary API 05356 J ) Copy from D. V, Stroop for Information of Members and Associates of the Medical Advisory Committee. ______________________________________________ Zlifrsg UNIVERSITY OP CINCINNATI Department of Preventive Medicine and Industrial Health The Kettering Laboratory College of Medicine - Eden Avenue Cincinnati 19, Ohio J u l y 8, 1952 Mr. David V. Stroop, Director Department of Technical Services American Petroleum Institute 50 West 50th Street New York 20, N e w York Dear Mr. Stroops Enclosed are the stencils of additional individual data sheets on carcinogenicity experiments for duplication and distribution to those members and associates of the Medical Advisory Committee who are not members of the Research Project Advisory Committee. Very truly yours, AWH:fe en d s. /s/ A. W. Horton A. Wesley Horton API 05357 > LEGEND FOR DATA SHEETS ON INDIVIDUAL EXPERIMENTS lini,, u s e d I n c o n n e c t i o n w i t h a v e r a g e w e i g h t c u r v e s : ^7 T i m of d e a t h ( f r o m d i s e a s e ) of i t h t u m o r - f r e e m o u s e . I T i m e of d e a t h ( f r o m d i s e a s e ) of i. t h t u m o r - b e a r i n g m o u s e . or T i m e m o u s e k i l l e d . ? Mouse missing from cage. and microscopic p athology; CD Time of appearance of first papilloma in l th mouse. When this symbol is first used for a given mouse after its death, the presence of non-in v a d i n g carcinoma > (intra-epithelial) or small areas of benign neoplasm w a s d e t e r m i n a b l e o n l y by h i s t o p a t h o l o g y . CD Time of appearance of papilloma which regressed later or was not confirmed by histopathology. 0 Time of appearance of gross changes indicative of malignancy in tumor of l th mouse. Diagnosis confirmed except in cases where no tissue section available. W h e n this s y mbol is f i r s t u s e d for a g i v e n m ouse after its death, the invasive malignancy of the tumor was determinable only by histopathology. :ii` Ill or Gross diagnosis of malignancy of tumor not confirmed by histopathology. No tissue section available for histopathology because of extensive post-mortem decomposition or cannibalism. Tumors n o t r e c o r d e d d u r i n g t his week. Cumulative dose-response curves (summation of data from all cages unless otherwise specified): * --- r Experimental curve for benign papillomas. --------------- 0----- ------- q Hypothetical curve for papillomas. This curve furnishes average latent period (time for 50 p e r c e n t t u m o r index) f r o m w h i c h r e l a t i v e p o t e n c y , P jjC i is d e t e r m i n e d ) . Experimental curve for grossly malignant tumors. API 05358 SKIN PA1NTXNQ KXVEHUIENT AP3-8-10, Fraction b. lt|2-175C/0.03 mm. from Distillation of API-S, Solution in Benzene 3^1- Cage 1, 10 Mice Painting of Both Cages STARTING DATE: 9/5/$o\ Discontinued STRAIN OF MICE: C3H 33 NUM3ER OF APPLICATIONS PER WEEK: 2 32 DOSE PER APPLICATION: . 100 mg S 31 3 w>30 R E L A T I V E CARCINOGENIC POTENCY, Pm ^ i/c/.ll.01 29 o > >28 i/i & 8 12 16 20 2lf 28 32 ; i*o 1A " P 2, 10 Mice o 33 V V 32 >31 < 30 29 (D 28 iii & j_I_i_I-- i-- I-- u-J-- '-- i-- V- L--t.--L 4 8 12 16 20 2k 25 32 55 1*0 ' 1*1* 1*8 iz 6 TIME AFTER FIRST PAINTING (weeks) API 05359 aniN ^AINTIMU DJLk'lUtil&tt.tVC API-0-11, F r a c t i o n b. 17-197 C / O .03 m m. from Distillation of Ml-ft, S Q % w o lutlon Vn B a nian# API 05360 31 30 29 01 I 20 b to ~ 27 cO Pi 26 > . B 25 t/i & 21 Cage 1, 10 Mice KIN I'AINTlWO hX^KHlU^NT A P I - 9 9 T .C .C . C r a c k e d R e s i d u u m STARTING DATE: 7/20/1*9 \ STRAIN OP MICE: C3H NUMBER OP APPLICATIONS/WK: 3 DOSE PER APPLICATION: 100 mg. RELATIVE CARCINOGENIC POTENCY, P : 0.0$!.01 1/50 -- 1--- 1--- 1--- 1--- 1-- T '3 6 40 1*4 48 Scale for Carcinomas 1 23 H g 22 w 0 1 21 < 20 19 18 to. % % I 1 4 0 (UlY) 0 g) I I__x-- J _I_I--1-- I-i_-ij- ,, . 1i- ...11--___Ii,.1-i.,-_-__1i--,...i1,, Ii ,.1im- ll jA .!_.*-- L-- ^. 8 12 16 20 2k 28 3 2 jb *0 1*4 1+8 52 5 6o TIME AFTER FIRST PAINTING (weeks) 1 Scale for Papillomas -3i-2----- i____3I6. - , I____ p ip; SKIN FA1NT1NO EXPEHIMEUT API 05363 AVERAGE WEIGHT OF SURVIVORS (grams) 3KIN k'AlMT 1MO ILXViCMIMkMT API-33# Cracked Sidestream from Belayed Coking API 05364 AVERAGE WEIGHT OF SURVIVORS (grams) ) ) SKIN FAINTING lijtk*L,Kll.UifcVL' API-1|6, P.O.C. Cracked iiidestream ) i < / -r ) ) UKLN k'KlHllHd 1MI.IVV API--57 Dewaxed Oil from Preaslng APl-5b AVERAGE WEIGHT OF SURVIVORS (grans) API 05366 l l K l M r A l M 'l'lH U l tAl.lCV * / AVERAGE WEIGHT OF SURVIVORS (grams) API 05367 ) ) ) .1111 l'MN 11 lIAi.Ul- API 05368 API-205, 0.3 KiN 1*J\A.IVI*1UU k'ki-ULWU-U'L' Mo thylclaolantlarene In loo mi. fenzona API 05369 ) L ) k.l'.lll 1/Vi-lVl lllM l'.Hi l'.H I A P I - 2 0 6 , 0 . 6 gm. t/letliylcho3 autlirene in 10O m i . en7.ene API 05370 AVERAGE WEIGHT OF SURVIVORS (grams) liKIN FAINT XNQ KX1`KHXMBHT API-221, Dodecylboniieno (from propylene tetramer and;benzene) i ) AVERAGE WEIGHT OF SURVIVORS (grams) A P I - 2 2 3 -9 D od ecyl b e n z e n e (DDB) pa.i.nteil for flral. s i x vieeVxa^ , - Cage 1, 10 Mice 30 DDB Discontinued 28 API-9 Started^ 26 zh STARTING DATE: STRAIN OF MICE: NUMBER OF APPLICATIONS PER W E E K : DOSE PER APPLICATION: AVERAGE LATENT PERIOD FOR ... ... ... X U M 0 R - I N D U C T I O N : 5/5/50 1 C3H 3 100 mg. 13.212 22 H 90 20 O 18 BlEl @ I i--L ,1 i I a. 3-'4 iCj.ui:je82, 1210 Mli6ce 20 2iv 28 36 I4.0 I4I4. 1^8 80 7 32 / < 0 60 g 50 30 s 28 30 26 20 <s 2lv 22 H 31 tv 10 m a ;?: 0 J_JL--. il 1 1 1 1 l_J_1L J1_u,_1I_1_---1L 1 !. 11-- j__L 1*1 J*_'.j`uf--tL 5 [ 8 12 16 20 2 k 28 32 3o R 0 I4I4 1+8 . 12 20 ,, _ T I M E AFTER F IRST PAINTING W I T H D D B (weeks) T I M E A F T E R F I R S T TAINTING OF A P I -9 (weeks) 1 Dodecylbenzene discontinued at time of slouching of crusts. . API 05372 API- 2 2 5 m QQ1 Km OKI h I'MN'l' INil Mothylcholanthrene \ieIrMiU1VUl'O ml UoAocm Ibonv.ov^ 38 Cage 1 # 10 Mice 8 STARTING DATE: 5 36 STRAIN OF MICE: NUMBER OF APPLICATIONS PER WEEK: DOSE PER APPLICATION: h 2 S30 90 0 ID :V;i2j . I I 1 I 1 .1 I l 1 I l i.1L.ri-! I I >. Il.it I 1.I.J LI i.li.l. i 80 ( 0 12 16 20 1*. 20 32 36 , ij-8 56 60 6I4.6J3 72 Cage 2, 10 Mice W^i' g7 H 60 350 g ito L--4 E-* 30 20 10 iX! J I 1 I l I-- L_l-- I-- I-- i_J-- I-- I-- I-- I-- I.l-rJ-- If1! V ^Z1^ /I 7 n -- Ij. ft 12 16 20 2I4. 28 32 36 1*0 IjV 1*3 52 56 60 V d 8 72 22 30 TIME AFTER FIRST PAINTING (weoka) API 05373 SL aKih ea intimo bxvtiuiiEH'C API-22$, 0.01 g. Methylcholanthrene per 100 ml. hodecyI t o m e n e API 05374 AV'p.RM.G.gi vxGHT Or' b u n d v Jftw {,i`tJHSJ jKli L'AI N'V1UU U.XL'U.HLHiiM'L' API-227 0.10 (ram Mflthylcholanthrene per 100 ml. Benzene API 05375 r UNIVERSITY OF CINCINNATI OtPARTMINT OP PHVINTIVI MUICINI AMD INDUNTMIAL HEALTH CAMLI AOOUSS: U T LAM. CINCINNATI TELEPHON: CAMTOL 1414 J u l y IS, 1952 jjj., D. V . Stroop, D i r e c t o r Department of Technical Services American Petroleum Institute 50 West 40t h Str e e t 5ev York 20, New Y o r k Dear Mr. Stroop: I wish to acknowledge with thanks the receipt of your check in the amount of $50,000.00 for work to he done on b e h a l f of A m e r i c a n P e t r o l e u m Institute for the year ending June 3 0 t 1953. Very truly yours, IS cc Dr. R. A. Kehoe Tola heppard Financial Secretary API 05376 J * t r x r , i 9 5 Ir* ttbert A. Este* af Slaesaestl ** Stotter1 TJbftmtogy ''sr:*36 of iitdlcLae 3m C S a m S a m U 39, Chft Jn m m ttd i* io aofaovloOgp tbot IstSor o? A d y 2fr i th* f our yoaar files A lee toe* parta to 1 aaouet a f $$0,000 1 M ti Ito tlt* * ' e t M t n m i i 9VSs* API 05377 I v York 17, low York August 7 , 1952 1JSL [^O^QREAT BRITAH r# g. *. ewquist Building |tr Sir: I have ju st had an opportunity to road my copy of tho glAUtoa of Mootinc Mo. 10 o f tho above Research Croup. I an IBOting from page 2 at follows* "It vat agrood that a report shouhd bo rondorod, through Rosoaroh Conuittee, to Council who would nako i t availab le, at I t thought f i t , to suoh bodies ad tho tpontort, and Minstry of fu e l and Power at highoat l o r d , and to those lik o ly to help tho finances. I t should not elaah with tho Medical Re search Council and therefore should avoid nodical asp ects. In th is connection Professor Cook emphasised that M.R.C. in v e s ti gations were only in tho early stages and K.K.C. i s adverse to issu in g general publications u n til i t had sonething d efin ite to say. "It was reconaendsd that the roport should cover whet has been done, what tha Group ia proposing to do, and the Croup*s relation sh ip with tha Ministry of Labour and tho M.R.C.,; and i t night contain, in corroat perspective, s b rief sunnary of the work done in Anariaa. "Mr. Stevenson was asked to propers a draft of. about tho length of four pager of tho I .P . journal for aubalMllon to the Roaoareh Qoanittee in Juno. The Reoort sheuld he fa ir ly f u ll for tho Ratoarch Connittea who oould docide on sultablo axtrnota for tho I.P . Journal." Appnroatly froa t h is , the I.P . tonnitteo w ill taka tho following stopst a. prepare a b rief study o f tho work done in Aaorlon b. transmit th is sunnary with a report o f i t s own work to tho Count11 o f tho In stitu to . c . authorise tho Council to nako th is sunnary available to "tho sponsors, and Ministry of Pool and Power at highest le v e l, and to those lik e ly to help the fin eness* API 05378 9ft K. M. Mewquiet - 2 - August 7 , 1952 d. Research Committee to publish if it thought dolirabio la tho I.P. Journal a summary of tho work don* la America Such a stop would prove soot embarrassing not only to guttering Laboratory, but tho wholo American Petroleum Industry. I pad thought that in transmitting our roporto confidanttally to gol> Auld >;* bad sufficiently safeguarded this matter. Apparently 9or "British cousins" are unable to cither understand or to trans late the "American language" into tho "Rnglish language" . I would strongly urge that you immediately communicate rith Col. Auld, pointing out that as yet the Medical Advisory Com* gittee has made no publication, and specifically ask that the work la merica remain confidential within Research Croup No. 2. I would also suggest that your latter be alao tranala~te.d iato French, which I understand is pretty well known by most Englishsen. Very truly yours, i f M t. jafc*a a n E. Q. MACESIZIS IBH-FKL co: Mr. D. ?. Strocp Or. S. E. Linder API 05379 August 13, 1952 Col. S. J. Auld Institute of Petroleum 25 Victoria Street London. 3.V. 1, England Dear Col. Auldi 1 i l d to thank you again for continuing to sand me minutes of tho footings of your rosearch groups and to acknowledge rooolpt of tho minutes of sooting So. 10, Hosoareh Group 2 . 1 noted on pag# 2 of tho above ninutos that your committee *s eontonplatod report among other things "might contain in correct perepeetire, a brief siumnsry of the work done in America" While mention nay bo made feat similar researoh work is going on in America, it seema inadvisable for you to make such a report on the eork being dona at lettering Laboratory, University of Cincinnati, inasmuch as (1 ) their progress reports, of ehich copies mere sent to you, are not for publication, (2) they eere sent to you for your personal and confidential information, (3) the reports are only progress reports, inconclusive in character, and as such they are not suitable for release as a public report and (It) sines lettering Laboratory has not yet published a report it would be emberrasslng for a premature sumaary of their work to bo released elsewhere While Z hare not yet discussed the above natter with Dr. R. A. Kehoe, it seen to me that ear mutual purposes vill be best served by keeping n s interchange of infonetloa on s confi dential basis until either party releases publicly a definite statement am his particular work With kindest regards and beat wishes, Z am _ Very truly yeuru. ennuis eat Dr. Robert A. Kehoe Dr. 1. 1 Linder Mr. D. V. 3tro< BLIND NCTS / I. I. IWWQUISt, V D. DVS: I would appreciate it if you would nineograoh and circula lze amons rdembers "and Associates of tr.e 3ub-Ccnnlttee on Carcino genicity. M.N.3. API 05380 A merican P etroleum Institute SO W EST 50TH STREET N EW Y ORK 2 0 . N. Y. To Members and A - s o d a tes Subcommittee on Carcinogenicity Gentlemen: I am enclosing a copy of the minutes of the meet ing of the Research Project Advisory Committee which was held at K e t t e r i n g Laboratory, Cincinnati, Ohio, July 10, 1352. Will you kindly indicate your approval or disapproval of the actions and decisions of the R.P.A. Com m i t t e e and you r decision on questions 2 , 3 and 4 listed on the enclosed letter ballot and return it to me. Negative votes should be accompa nied by an explanation. I will also appreciate receiving any comments and suggestions you may have concerning the research project at Kettering Laboratory. Very truly yours M N N :RMS enclosures Chairman, Subcommittee on Carcinogenicity me: Members and Associates Medical Advisory Committee Dr. R. A. K e h o e (2) (Without letter ballot) API 05381 AGENDA Research Project (MC-1) Advisory Committee Meeting Kettering Laboratory# Cincinnati# Ohio July 10, 1952, 9^30 a.m. to 4:00p.m. EST - Summary of April 1952 Progress Report 2 - Comments cn the Progress Report 3 - Progress of studies since April 1952 and future plans 4 - Effect of viscosity cn potency and the use of e m bodying agents to modify viscosi ty 5 - (a) N eed for a dditional studies on straight-run, uncracked distillates and residua Dr. A. W. Horton Dr. R; E. E c k hardt et al. Dr. A. V/. Horton R. M. Shepardson L. C. Beard# Jr. (b) A p p r a i s a l of E r i t i s h l i t erture and the magnitude of the hazard in Great Britain 6 - Plans of the Sab-panel on Lubricants and Process Products Hygiene of the API Lubrication Committee L. C. Beard, Jr. R. M. Landon K. G. M a ckenzie L. C. Beard# Jr. 7 - Report on mid-year meeting, General Committee, Division of Refining, May 1952, w i t h respect to the RPA Committee's report of A p r i l 30, 1952, to Mr. T. J. Sullivan R. M. L a n d o n 3 - Epidemiological Surveys (a) A m o n g employes of pet r o l e u m companies Dr. J. J. Phair Dr. E. K. Linder (b) A m o n g employes of customers Dr. M. N. Newquist 9 - Other business 10 - Dat e and place of next meetings of (a) S u b c o m m i t t e e on C a r c i n o g e n i c i t y (b) RPA C o mmittee API 05382 For Information Only - Not For Publication REPORT ON THIRD MEETING Research Project MC-1 Advisory July 10, 1952 Kettering Laboratory Cincinnati, Ohio Committee MEMBERS PRESENT OR REPRESENTED M. N. Newquist, M.D. - C h a i r m a n R. E. Eckardt, M.D. - A c t i n g Sec'y. . L. C. Beard, Jr. Kieffer Davis, M.D. C. M. D o a n e (For E. W. Adams) T. M. Frank, M.D. R. M. La n d o n K. G. Mac k e n z i e R. C. Mithoff R. M. Shepa r d s o n MEMBERS ABSENT AND NOT REPRESENTED C. M. Kine, M.D. E. K. Linder, M.D. OTHERS PRESENT F. F. Heyroth, M.D. - U niversity of Cincinnati A. W. Horton - University of Cincinnati Arthur Pabst {Socony-Vacuum Oil Co., Inc.) J. J. Phair, M.D. Univ e r s i t y of Cincinnati API 05383 2 The attached agenda of the meeting, which had been dis tributed by Dr. N e w qulst p r i o r to the meeting, wa s u s e d as the program. ffrEMS 1 AND 3 ---------Dr. Horton p r e s e n t e d to eac h of the members the attached* Memorandum from the Kettering Laboratory, Third Meeting of the Advisory Committee, API Research Project MC-l". Dr. Horton followed the outline pre s e n t e d in this m e m o r a n d u m w i t h additional comments, as f o l l o w s : a. The yea r 1951 in terms of the he a l t h of the e x p e r i mental animals did not satisfy the laboratory as well as the year 1950 and, therefore, the laboratory has considerable reservations concerning the accuracy of mouse test data determined in 1951. This has led to the adoption of correction factors for the determi n ation of the Pjvjc v a l u e s of the va r i o u s m a terials tested. One source of this difficulty was discovered in infestation of the animals with mites. These mites presumably caused an eye disease in the mice, which was thought to be due to the scratching by the animals in an attempt to rid themselves of the mites. The mites have now been controlled by using a dusting powder consisting of a low concentration of Chlordane plus pyrenones. b. c r i teria u s e d by the l a b o r a t o r y for d e t e rmination of what is considered a good animal test include 85# survival of the animals for at least 6 months, or until 5056 of the animals have tumors. c. E x p e r i m e n t s are d e s i g n e d so that the average latent period will be not less than 100 days or more than 280 days. If the average latent period is less than 100 days or more than 280 days, it is believed that the accuracies of the P^q determination will be considerably reduced. d. The d e s i r a b i l i t y of w e i g h i n g the animals once a w eek is now recognized and attempts to weigh them at this frequency will be made in order that no breaks in the weight curves will be present in the data sheets presented to the group. API 05384 - 3- In the discussion that followed on Dr. Horton's comments was brought out by Dr. Beard that he had heard of some data from E n g l a n d w h i c h i n d icated that in straight run d istillates maximum carc i n o g e n i c i t y is o b s e r v e d in the 300-4C0C. cut. Dr. gorton then emphasized that the nature of the distillation must be fully u n d e r s t o o d be f o r e the significance of this observ a t i o n could tie accepted, since in disti l l a t i o n s in w h i c h poo r fractionation occurs a mater i a l p resumably cut between 300 a n d 4000c. could c o n tain considerable amounts of m a t e r i a l b o i l i n g below 300c. and boiling above 4 0 0 C. Later, Dr. 3eard placed on the board the following 9 variables which may affect the quantitative nature of mouse tests and their extrapolation to human significance : 1. The amount of c arcinogen per unit of area. 2. The dilution of the carcinogen. 3. The f r e quency of application. 4. The effect of the physical state, l.e., viscosity and surface tension. 5. The h e a l t h of the animals. 6. The psychic state of the animals as concerns eating. 7. The eff e c t of area of application. 8 . The persistence of carcinogenesis if applications are stopped. 9 . The variability of susceptibility of human skin, i.e., black versus whites. Mr. Shepardson then brought up the possibility that the work which Dr. Horton has done indicates that there may be several types of response to carcinogenic agents. Thus, with fuel oils and methycholanthrene it would appear that the activity of a given oil does not increase with the increase in dosage. This conclusion was reached as a re s u l t of the experi m e n t s using 20 and 100 mg. of API 05385 - 4- material per application with solutions of methycholanthrene and with API No. 8 . In the la t t e r case activity seemed to increase wj>th dosage. Dr. E c k h a r d t then co m m e n t e d that this v a r i a t i o n in activity might be both a function of the dosage per application and the dosage per w e e k (frequency). A considerable amount of discussion followed, the out growth of which seemed to be that a great deal more additional work will have to be done in o rder to develop all of the various m variables which seem to influence the quantitative nature of the mouse test. There were many who expressed the opinion that to think that we could b e g i n t a p e r i n g off on the amount of effort in this program in 2 y e a r s ' time is an e x t remely o p timistic outlook. Rather, it was their feeling that this type of research will have to continue for a c o n s i derably longer pe r i o d than 2 years at the present level of effort. Dr. Eckardt introduced the concept that perhaps we have the practical answers which we need at the present time to control this problem and that these various refinements of the technique, a l t h o u g h of extreme interest, w o u l d not contribute appreciably to the development of any practical solutions. He compared to a degree the establishment of MAC values in which a considerable safety factor is always allowed, and where the MAC value is e x c e e d e d certain medical s upervision is carried out. P rom the strictly medical standpoint, this is the type of approach which most medical departments and industrial hygiene departments will require. Whether this approach will provide the answers needed by the refiners is a question that can only be answered by the refiners. API 05386 Dr. Beard brought with him a sample of alkylated poly-"rene w h i c h had b e e n shown to increase the vis c o s i t y of a 3 A catalytlcally cracked recycle oil from about 84 to about 1100 when -- of the m a t erial was added to the oil. It was suggested as a possible agent' to use in i n creasing the viscosity of carcinogenic oils with o u t a p p r e c i a b l y changing their chemical composition. Reference was made to a letter submitted by Mr. Shepa r d s o n w h i c h indicated that Vistanex and polypropylenes would apparently not satisfy the requirement of increasing the viscosity sufficiently with a sufficiently small addition of the agent. ACTION Dr. Horton will test on mice some petroleum fractions of known potencies but those viscosities have been altered by the addition of alkylated polystyrenes (using Dr. B e a r d ' s sample) in order to evaluate the effect of viscosity on potency. ITEM 8a Dr. B e a r d indicated that experience thus far has shown that m o s t o c c u p a t i o n a l cancers a l l e g e d l y due to pet r o l e u m products had resulted from prolonged contact with uncracked distillates and residua. For this reason it is his belief that additional studies should be carried out o n this type of mater i a l in order to help us develop the answers to the problems of this type of material. ACTION Dr. Horton feels that the samples he already has on hand including the fractions of the three crudes (Okla homa, Kuwait, La Gunlllaa) presently being studied in Great Britain would suffice for the time being. API 05387 - 6- Dr. B eard suggested that it p r o b a b l y w o u l d be helpful if cr< phair could or w o u l d review crit i c a l l y the literature on cancer as related to p e t r o l e u m w i t h p articular emphasis on keeping r'aQ members of the committee informed of any new articles w h i c h are appearing in the literature on this subject by circulating to the members of the committee a critical abstract of each of these articles. Dr. Phair felt that this could well be done by himself and is presumably p l a n n i n g to u n d e r t a k e such a critical abstra c t i n g of current literature for the committee. ACTION W h i l e Dr. Phair is favorable to such a n u n dertaking he hesitated to commit Kettering Laboratory in the absence of Dr. Kehce. Therefore, this matter awaits official clearance from Kettering Laboratory. ITDM 6 Dr. Beard told the group of the activities of the Sub Panel on Lubricants and Process Products Hygiene of the API Lubrication Committee. A small s u b c o mmittee has b e e n formed to discuss the advisability of labelling petroleum products in order to warn customers of potential hazards. Solvents prepared from petroleum should probably bear labels which are in conformity with those recommended by the Manufacturing Chemists' Association. Other naterials, such as lube and cutting oils, should probably bear a simple label which indicates that the oil may cause skin irritation, that it should be kept off cf the skin and that if it cannot be kept off of the skin, it should be washed off as soon after contact API 05388 - 7 - 5 practicable. Mr. Mackenzie emphasized the need of making such aftinS3 p r a c t i c a b l e so that work e r s would not be spending half *i*r their da y w a s h i n g things off of their hands. ACTION None taken Dr. Landon reported that a verbal summary of the report 0f the RPA C o mmittee was g i v e n to the G e n e r a l Committee, D i v i s i o n 3f Refining, in May of 1952. As a result, the Gene r a l Committee, division of Refining, addressed a letter to the chairman of the Medical A d v i s o r y C o m mittee as k i n g that the Committee recommend ainimum standards for medical care, qualifications of medical directors and minimum standards for adequate medical records. This letter will presumably be presented to the Medical Advisory Committee at its next meeting. It was the feeling of the RPA Com mittee that the General Committee, Division of Refining, recognizes the importance of the carcinogenic p r o b l e m to the p e troleum industry and the g e n e r a l r e c ommendations of Dr. K ehoe that the pe t r o l e u m in dustry must develop the adequate medical and industrial hygiene measures to cont r o l this problem. However, the General Committee, Division of Refining, went further than the simple problem of carcinogenesis and included, presumably, all of the medical problems of the p e t r o l e u m industry in their request. ACTION None taken ITEM 3a Dr. Phair indicated that he has now received about 900 historical records. Appar e n t l y he is receiving very few current API 05389 - 8 - records and a s k e d the c o o p e r a t i o n of the C o mmittee to stimulate the varlous medi c a l d i r e c t o r s to send in their current records of ca&cer c a s e s * He indicated that since April, only 35 or 36 records jjave been sent to him. He stated that up until the p r e s e n t time ere has b e e n no real call on his services in a c o n s ultation capacity. D i s c u s s i o n b y the C o m m i t t e e indicated that Dr. N e w q u i s t would provide the stimulus to the various medical directors to send in their current cancer cases, and that f o l lowing the a c t i o n of the Medical Advisory Committee, on the request of the General Committee, Division of Refining, much of the w o r k of Dr. Phair may be implemented because some of the companies which do not new have adequate medical records may b e g i n to develop them on the recommends* tion of the A P I as to w h a t constitutes adequate m e d i c a l service, adequate medical personnel and adequate medical records. ACTION The Chairman of the Subcommittee on Carcinogenicity will aid the epidemiological studies by stimulating the various medical directors in the petroleum companies to submit the data r e quested by Dr. Phair. ITZM 3b Dr. Newquist mentioned the need for epidemiological studies among the employes of customers of petroleum products since mest of the cases are apparently occurring among users rather than among manufacturers. He indicated, however, that the collection of such data would require great tact. Dr. Phair felt that the Univer sity of Cincinnati could probably make such studies at the proper time and in a proper manner. * API 05390 ACTION It was the consenus of the RPA - 9 - Committee that the University of Cincinnati should undertake . epidemiological studies among customers at an appropriate time. This matt e r is subject to further action by the Subcommittee on Carcinogenicity. Under item 9 on the agenda Mr. Shepardson presented a table of data collected by the Standard Oil D e v e l o p m e n t Company ar.d Ne w Y o r k U n i v e r s i t y w h i c h indicated that there are at present 4 methods w h i c h w i l l predict tumor potency w i t h i n w h a t it is believed to b e a useful range of accuracy. These 4 methods involve: (1) ul t r a v i o l e t a b s o r p t i o n at 360^ of a 650-1000?. cut of the oil, (2) polarographic d e t e r m i n a t i o n s w h i c h depend u p o n the d i f fusion current at two voltages, (3 ) the c a f f e i n number w h i c h depends upo n the u l t r a v i o l e t a b s o r p t i o n at two w a v e lengths of caff e i n extract of the oil, and (4) the h i g h a r omatics c h a r a c t e r i s a t i o n w h i c h is a more complicated method and was not discussed in detail. He in dicated that the D e v e l o p m e n t Comp a n y is in the process of checking these four meth o d s in three d i f f e r e n t laboratories in order to determine their reproducibility from laboratory to-laboratory. He urged that the University of Cincinnati give serious consideration to checking these meth o d s also since they hav e b e e n found to be so useful by the D e v e l o p m e n t Company. He indicated wi l l i n g n e s s to provide to the U n i v e r s i t y of C incinnati the details of each of the methods as soon as it had been determined that they were reproducible from laboratory to laboratory. ACTION Dr. Horton has already been in communica tion wit h Mr. Shepardson on the above subject and he will give it further study in connection w i t h Kettering's effort to develop an analytical tool. API 05391 10 The Com m i t t e e a d j o u r n e d at 4:30 p.m.,' a f t e r a g r eeing v.a t the next RPA C o m m i t t e e m e e t i n g should be held Sep t e m b e r 24th, t the Conrad H i l t o n Hotel in Chicago, one day prior to the meet- of the Medical A d visory Committee w h i c h is to be on September -sth. It was felt by m o s t members of the RPA Committee that a meeting of the Subcommittee on Carcinogenicity prior to the date 0f the Sep t e m b e r Medi c a l A d v i s o r y Com m i t t e e m e e t i n g w o u l d not be necessary if the Subcommittee could handle its interim work by sail. C onsiderable d u p l i c a t i o n cf p r e s e n t a t i o n and d i s c u s s i o n can oe eliminated b y having the S u b c o m m i t t e e m a k e its report, including Dr. Horton's report, to the M e d i c a l A d v i s o r y C o mmittee as a whole on September 25th. NGTS: During the meeting Dr. Horton distributed a sheaf of data sheets (copies mailed to MAC Members 7"16-52) on various mouse experiments w h i c h are to be included in the available data thus far submitted. Dr. Horton indicated that he would present a series of data tables for the consideration cf the full Committee at its meeting in Chicago. M. N. Newquist, M.D., Chari m a n R. E. Eckardt, M.D. Acting Secretary API 05392 MEMORANDUM FROM THE KETTERING LABORATORY THIRD MEETING OF THE ADVISORY COMMITTEE API RESEARCH PROJECT MC-1 July 10, 1952 A. T e s t s to d e t e r m i n e a p p l i c a b i l i t y of s t a n d a r d r e f e r e n c e curves based on methylcholanthrene to determination of relative carcinogenic potency of refinery samples. 1. P r e l i m i n a r y d a t a o n c a t a l y t i c a l l y c r a c k e d r e s i d u u m , API-63: No. of 100 mg. Applications Per Week to C3H Mice Average Latent Period for Tumor Induction Relative Potency,PMC 1 3lj. w e e k s ^0,13 2 22 w e e k s /v 0 .II4. 3 1 5 ,k w e e k s 0lk Further tests under way on Fuel Oil 30 (API-113), previously examined in skin painting and washing experiments. B. F u rther rechecks on reference standards to clarify in fluence of following variables: 1. D o s a g e p e r a p p l i c a t i o n . 2. Change f r o m Jax to Heston sub-line of C3H strain of mice by suppliers (Roscoe Jackson Memorial Laboratory) 3. Purity of methylcholanthrene (all commercially avail able grades found to contain traces of a powerful skin irritant, removable to a large extent by chromatography) API 05393 2 C. R e s u l t s o n A P I - 8 3 - 2 I n d i c a t e t h a t m i l d a i r o x i d a t i o n of catalytically cracked residua not useful for reduction of concentration of carcinogens. D. E f f e c t s on r a t e of t u m o r i n d u c t i o n of d e c r e a s i n g s e v e r i t y of tests by d e cre asing dosage per application. 1. F o r s o l u t i o n s of m e t h y l c h o l a n t h r e n e , same r a t e of t u m o r i n d u c t i o n b y 20 m g . a n d 100 mg. a p p l i c a t i o n s (results to be rechecked on Heston sub-line with purified methylcholanthrene) 2. F o r f u e l o i l b l e n d s ( p r o b a b l y r e l a t i v e l y l o w c o n c e n tration of accelerating constituents), preliminary data indicates rate of tumor induction same for 5 m g . # 20 m g . , or 100 m g . a p p l i c a t i o n s . 3. F o r A P I -8 ( c a t a l y t i c a l l y c r a c k e d r e s i d u u m of h i g h p o t e n c y ) r a t e f o r 20 m g . a p p l i c a t i o n s s i g n i f i c a n t l y s l o w e r t h a n f o r 100 m g . a p p l i c a t i o n s , p o s s i b l y i n dicating a critical dosage level for action of accelerating constituents. E. Correlation of potencies of f i n i s h e d lubricants wi t h their ultraviolet absorption spectra. 1. A P I -99, s p e c t r u m type C (0.5), w e a k l y a c i d t r e a t e d n a p h t h e n i c s t o c k c o n t a i n i n g 0.2 p e r c e n t a n t i oxidant, PMC 0.0? 2. A P I - 1 0 0 , s p e c t r u m type B (0.3), blended, solvent extracted lube containing no additives, yield of p a p i l l o m a s z e r o a f t e r I4.I w e e k s of p a i n t i n g (3 a p p l i c a t i o n s p e r wee k , C 3 H m i c e ) . API 05394 - 3- p. T u m o r y i e l d f r o m w h ite oils, A P I - 8 0 and 95 zero a f t e r one year of painting. G. F r a c t i o n a t i o n s t u d i e s to d e t e r m i n e c l a s s e s of 3 - a n d lj.-ring compounds responsible for carcinogenicity. 1. E x h a u s t i v e D i e l s - A l d e r r e a c t i o n (ma l e i c an h y d r i d e ) o n A P I -8 y i e l d i n g a n t h r a c e n e s , b e n z a n t h r a c e n e s , d i b enzanthracenes (?), naphthacenes, naphthepyrenes (?), and n i t r o g e n bases (?). These classes separated by solubility properties of their succinic acid adducts and adsorption properties (on alumina) of the recovered parent compounds to prepare samples for biological testing. 2. I n d i c a t i o n s f r o m r e s u l t s of b i o l o g i c a l an d a n a l y t i c a l tests on API--8 --19 and 8-20 that pyrenes and anthracenes not contributing to potency of distillate fractions, boiling 700-800F. (vacuum corrected), from A P I -8. 3. F r a c t i o n b o i l i n g l o w e r t h a n chrysene of aromatic compounds from API-12, F.C.C. residuum, being treated to remove pyrenes and anthracenes; fraction thus p r e p a r e d for mouse t e sting to co n t a i n alkylphenanth- renes, al kylbenzfluorenes, b e n z p h e n a n t h r e n e (?), etc. 14.. F u r t h e r c h r o m a t o g r a p h i c f r a c t i o n a t i o n of d i s t i l l a t e fractions of API-3 corresponding to 8-10, 8-11, and 8-12 to s e p a r a t e ij.-ring c o m p o u n d s i n t o c l a s s e s f o r biological tests. API 05395 - k- H, A c c e l e r a t i n g c o n s t i t u e n t s o f c r a c k e d oils. 1. F u r t h e r e v i d e n c e t h a t c o l o r l e s s f r a c t i o n f r o m c h r o m atography of API-Q has accelerating effect on rate of tumor induction. Potency of API-8-21 not signif icantly different from that of API-8, whereas com p a r a b l e 50:50 b l e n d s w i t h s e c - a m y l b e n z e n e (see 8- 16) or w i t h w h i t e o i l a n d r e d u c e d c r u d e (see 8--4.) d e m o n strated marked reduction in potency. 2. R e s i n r e m o v e d f r o m A P I - 7 1 T . C . G . r e s i d u u m , not responsible for high potency of this relatively low boiling catalytically cracked product. Testing and further fractionation of colorless chromatographic fraction of API-71 to be carried out, 3. L o w d o s a g e tests on c r a c k e d s i d e s t r e a m s for f u r t h e r evidence on possible contribution of accelerating con s t i t u e n t s to their m o d e r a t e l y h i g h p o t e n c y when t e s t e d in 100 mg. a p p l i c a t i o n s . API 05396 r Medical LETTER 3 ALLOT Subcommittee on Carcinogenicity Advisory Committee, American Petroleum Institute PLEASE MARK AND RETURN T O : Dr. M. N. Nevquist, Chairman Subcommittee on Carcinogenicity c/o The Texas Company 135 E a s t 4 2 n d St., N e w Y o r k 17, N. Y. 1. Shall the actions and decisions of the Research Project Advisory Committee, as shown in the minutes of the July 10, 1952, M e e t i n g at Kettering Laboratory, Cincinnati, Ohio, be approved by the Subcommittee? .Yes ______ No ______ Not voting ______ 2. Do you recommend that Kettering Laboratory, Uni versity of Cincinnati, make epidemiological studies of cancer among employes of customers? Yes ______ No ______ Not voting_______ If yes, what Is your opinion on the following points? a. R a n d o m selection of plants for survey. Yes ______ N o ______ Not v o t i n g ______ b. L imit surveys to plants where cancer cases are allegedly due to petroleum products. Yes ______ No ______ Not voting ______ c. M a i n t a i n a cancer registry wherein only cancer cases proven to be due to exposure to petroleum products would be recorded. Yes ______ N o ______ Not voting ______ 3. Do you approve of continuing Research Project MC-1 at approximately its present scope and cost ($100,000 per year) for the year beginning J u l y 1, 1953? Yes ______ No ______ Not voting ______ 4. Do you concur with the opinion of the RPA Com mittee that a meeting of the Subcommittee prior to September 2 5 , 19 5 2 , is not necessary? . Yes ______ No _ _ _ _ _ Not voting ______ It is requested that an y negative vote be accompanied by a n explanation. Name Company A v M. N. iiev^ u i s t , m .d . 135 East 42nd Street N e w Y o r k 17, N. Y. \ August 28, 1S52 *0 members and Associates ' Subcommittee on Carcinogenicity jantlemen : You have b y now all received a copy of the minutes of tvje third m e e t i n g of the R e s e a r c h Froject MC-1 Advis o r y Committee .^Xd at Kettering L a b o r a t o r y July 10, 1952, together wit h a getter ballot on w h i c h to indicate your approval and disapproval 0f the actions and decisions of the RPA Committee and your decision on the three other questions listed. I will appreciate receiving your ballot by return -jail so that a report of the Subcommittee on Carcinogenicity can be prepared and sent to all members of the Medical Advis o r y Commit tee on September 11. Very truly yours, yN:JKF Marshall Clinton, M.D. L. S. Curtis, M.D. Kieffer Davis, M.D. Robert E. Eckardt, M.D. ?. '*!. Prank, M.D. C. PI. H m e , M.D. T. J. Kelly, M.D. W. R. Levis, M.D. Clark R. Miller, M.D. James '.V. Osborn, M.D. 3. 8. Reeve, M.D. George M. Saunders, M.D. Leo J. Wade, M.D. ac: E. K. Linder, M.D. D. V. Stroop ~>x>. M . N., NEWQUIST, a--*n W. L. c. C. L. C. R. L. C. R. C. L. 0. A. s. R. M. K. G. R. C. J. R. F. J. R. M. Adams 3eard, Jr. Brown Brown Burroughs Cole Crockett Dooley Landon Mackenzie Mithoff Morrison Sanders Shepardson API 05398 Augnai 28, 1952 Ir. X. b r a Untar ite Atlantic Raflala* Ccapany 260 Soath arcati 8traet Phlllaipirla 1, Pwmaylinels mar Doctor L1urtart Trrlnaat ara tao aapAaa of tha lattar telici nhlch w aoat to tha aartan ani aaaoalntaa of tha Sntecaaittaa oa Camliwoiinltr oa lagnai 22 Stia lattar telici ano attaatel ta ite alata* of tha anatlmr of tha Baaaarch Irojact Artrlaocgr Coaalttaa beld at lattarla* Lateratcry, Jalp 10, 1952. Tory tmly jo a n , API 05399 COPY 5 . J . M AULD 25 VICTORIA STREET LONDON S. 7,. 1 AIR MAIL ?9th August, 1952 Dr. The 135 New M. N. '.'ew-^uist Texas Company E a s t {.2nd S t r e e t Y o r k 17, N. Y. Dear Dr. Newqulst, I hasten on m y r e t u r n from h o l i d a y to reply to your letter of August 13th and to reassure you in respeot of the proposed report. There was no intention to make and there definitely will be no statement made nor excerpt included, regarding any of the work which has been the subject of mutual exchange of information between the Research Group and the Kettering Laooratory. It was my intention m e r e l y to describe in general terms for the benefit of the sponsors, the organization of the correspond ing American activities and refer to any already published work. You are aware there has been some of the latter and there will be more - generally in connection with the work at He w York University as published in the Journal of Industrial and Engineering Chemistry. Now that you have drawn m y attention to the matter, too, I will make a point of sending you a draft of any material which re f e r s to American actlvltlea. coming people I hope there will shortly be an opportunity of your to this country and mee t i n g for d iscussion some of the who are specially concerned in this work. With kind regards, Yours sincerely, (signed) SJVAuld 5JVAVG3M cc: Dr. . L i n d e r MKrS.M D. V. ' S t r o o p ) ) f r o m MlfH - 9 - 5 - 5 2 API 05400