Document 82M3D9G8kOg7ZLnGoZJkLan5m

t SC-API-2125 A W RESEARCH PROJECT ADVISORY COMMITTEE 1951 - c ( ( 4 ESSO LABORATORIES STANDARD OIL DEVELOPMENT COMPANY P. O. BOX 51, LINDEN, N.J. MEDICAL RESEARCH DIVISION ROBERT E. ECKAROT. PH.D.% M.D. OlftECTOR HORACE W. GERARDE. PH.O.. M.D. HEAD TOXICOLOGIST Kerch 26, 195k INDUSTRIAL HYGIENE SECTION NATHAN V. HENDRICKS* CH.E. HEAD OF SECTION FRANKLIN W. CHURCH. M.S.* GEORGE M. WILKENING. M.8. INDUSTRIAL HYGIENISTS St, Qeorge K. Saunders Soeoay-Teesua Oil Cowpangr, Ins. 26 Broadway Hew lark U* Maw lark Hear Or. 3condor*i I an wax7 happy to oubalt te pen the progreM report of the Sub- eoanittee on Cardnoganieity. Zt hee hem agreed ty the neabere of thic Subeosnlttee that there Is no longer am need for the RP(BC-l) Advisory Condttee end with peer approval, this Advisory Coaalttee la new being abolished. The total Sabooweittee on Carcinogenicity will La the itatwre eerre the fonotlona that the RP(lC-l) Advleory Ooaadttee need te partam, Including perledle eatings with the Battering laboratory group to learn of the progreee of the work a. t th5-e' . Kettering ^' * Laboratory* . Zt le wy suggestion that pen way wish to svfcnlt thle report of tho Subcotedttee on Carodnegenioity t* tho Kadleal end Eealth Coneittee of the Board at the tine of lta Meting In Hew Orleans on April Slat* R. S'. SOKIRSf, M. 0. Enel. m with entiL Mr* 0, Y,Stroop / Or* A* Healey Barton ^ PE0QBZS3 HEPGRT OP RP(W-l) ADTOCEI QOMQXXB . TO TBS SmOdfOTtS* CAhOPOOWDlS January 22-22, 3$>IThis report mtiu aa * tapplinant to the BKA'Cowdttoo report dated . Snptoflfcer, 1953* 1. Tho Kettering Laboratory has anbnitted namsorlpt entitled "in Analytical Method for Dotominatian of Benia (a) Pjtvbm in Caspian Mixtaras". Zt is tho plan of tho Eattaring Laboratory to scfenlt this nanosoript far publica tion in tho Journal of Analytical ChoadLatrr on or aboot April 1, l$$k, Tho Goaadttoo rotiomd tho namaeript and haliOTsa it anitahla for publication. it is being foroardod to tho appropriate authorities la tho API for aaitshlo action. Too farther ntnascrlpte are In tho proooos of preparation ontltlod "Carelaocenaals of tho Shin z and IP# dea3tng nlth biological standardisation techniques far earoinocealo totting*- It is tha plan to ssCadt thasa to a journal similar to Canoar Research. Tho Caeolttee is praparod to rovlov tbaaa artialaa and *** its raooB--nditiacia oonoaming publication after they are received. 2. The awaenrtpt reeiesod daeerlhae a nethod for detaralniag bansa (a) pyrene in re^tisr nUctaras such aa prtrelstin oils* Zn tha data given* various fair oarralatiaa between bans# (jp pyrene sentant and biolagis eetivity has been -2- 3* In persuing ether factor* which way influence tbo oarelnoganlalty aa oil to ale*, tht following load* ara boiag pursued by the Kettering laboratory*^ _ * . a) Heat pstraleun hydrocarbon* boiling la th* range $Q0-6$D*7 aro probably accelerator*. Shis includes paraffins Araa nonul deeaaa to hex*- or heptedocsns sad naphthalenes which has* at least a butyl chala attached. . b) Materials boiling between TOQT2$*f prabably eeetala ph*nasthr*n#-lik* eardnogans atnllar to bansa (a) phanan throne. . e) Materials balling between 72^*800*7 probably ""**** anthracana-CLika carcinogens, poaalbly eyclcpenteno bansothraeazM* - ' d) Materials boiling above 800*7 probably oantaln th* basso (e) pprano. . ' . ' U. Fahllo Isteraet has recently bean stiaOstad in patrolan prodaeta aai/or their eeabttotiou ercaddaiioto ptrodnet* banana* of their peaaibls ralatian- afaip to pulnanary eancer lnddang*. Tho patrolem Industry afaeuU bo mare of ,.a . ' . . . *. ' ' *;.* `v * tJ^'interojrt ** Itself gst/ti' the preheat uriteriable position that'the V A ' & * f V' ~ * - V t- : ; * * ; tobacea Industry find*1 itself. Soarvar, suitable expariasntal aathods aro sat available far the,.ff&r af. thia problea, ether than apjdasdalogioal stadias, the . ' ' f ^` i ' ? *;* ?-^ - .V. r ' inportaaaoa of the spidanlsioglcal studies near being sponsored by the IPX is therefore 4* TOPICS ON EXPERIMENTAL PROGRAM FOR DISCUSSION, JANUARY 21, 1954 API RESEARCH PROJECT MC-1 1* Manuscript, "Analytical Method for Determination of Benzofaj- pyrene" in Complex Materials", 2, Progress in identification of carcinogens which are extracted by maleic anhydride. - 3* Progress in identification of carcinogens responsible for potency of cracked sidestreams, 4. Manuscripts on biological tests on standards of reference, "Carcinogenesis of the Skin, I and II.", 5 Biological tests involving limited numbers of applications of ( carcinogenic oils, 6. Accelerating activity of paraffins and alkylnaphthalenes, 7. Comparative effects of hygiene on susceptibility to carcino genicity of straight run paraffin distillate versus cracked fuel oil. ( Dr. R. A. Kehoo The Kettering Laboratory Cniveroity of Cincinnati Collage of Medicine Ansae Cincinnati 19, Ohio * Saar Be, Kehoet I wrote yea previously concerning the dotea of January Slat and 22nd for a noetlng of the BPA Coanlttee at the Kettering Laboratory in Cincinnati* I an now si^>ly writing to reccnflm thaae dotea and to Indicate that the Coonittee would to neat with the Kettering Laboratory beginning at 1 p.a. on January 21at and eon- I . tinning until noon on January 22nd, if this oan be arranged with your grovp. We oould either interrupt the meting at $iOO or 530 on January 21at and reconvene --------about 9 a.a. an January 22nd, or at your convenience oould the neetlng into the evening of January 21at in an atteapt to finish up oil buainoao in one v day, if that is aero oosvonisst to you* In any event, Z do not believe it a* be aeeeoeary to decide thie prior to our arrival in Cincinnati. However, it la the plan of the Co--lttss to met together prior to eealng to the Laboratory ao that wa nay have a little greater unaniadty of opinion before wo convene with your - group that ia why wo would like to start the mating at 1 p.a. on January 21st* - j '' : , ''s . 1 1s t tentative agendo for the westing with your group we would suggest the follow ing* - (1) Minutes of tbs last noetlng. ~ (2) Report by Sr. iortoa. - :. (3) Report by ST. Phairv (M leport by St, Xahee on budgetary natters. ($) Feints for dlseusaloa whieh have been agreed vpon by the aeabers ef the Ccmrittoo. (6) Sate and plane of the next meting. * Zt would be very greatly ^preeisted if Bt, Horton mt, Be, Fhair oould have their reports, if they are going to have reports, in the hands ef the mabers ef the SPA Coaadttoo well in advanae of the January 21at data so that wo night all have the opportunity to review the reporta oonatruetively prior to our mitlii sod, / thorsforo, bo ia a moh bettor petition to laid our dlseuaaloas with your group. -2 - - ;' . January fc, 1hi represents a alight departure froa previous nestings of the Bfi Condtts tat baa been brought about by sone dissatisfaction an the part af the Beaters af th Co--rlttcerulth the progress of previous nestings of the Coanittee, and ia being triad to aea if this plan vUl aeeoaplish worm than ear previous nestings nere able to. ' ,, . Slneeroly fsart, . BBEtilk.. . - ca* Or. A. ifcaley Horton Br. ?. B. Hsyreth b. x. muasa, h. b. ' Copies -'Dr. Horton Dr. Heyroth Dr. Phair . ESSO LABORATORIES Standard Oil Development Company P. O. Box 51, Linden, N. J. Dr. R. A. Kehoe Dr. C. H. Hine Dr, E. K. Linder Dr. N. M. Newquist Mr. E. W. Adams Mr. L. C. Beard, Jr. Mr. L. M. Henderson Mr. R. C. Mithoff December 31, 1953 , - Gentlemen: Majority opinion seems t o indicate January 21st and 22nd as the most desirable date for the meeting of the RPA Committee. At present it is planned that the RPA Committee will meet in a down town Cincinnati hotel room the morning of the 21st, will convene at the Kettering Laboratory that afternoon, will continue the discussion the morning of the 22nd if necessary, and hold a meet ing in a downtown hotel the afternoon of the 22nd if this seems necessary. A more detailed letter will be sent to each of you next week out lining a proposed agenda for the coming meeting. Sincerely yours, /s/ R. E. Eckardt R. E. Eckardt, M. D. REEjilk December 15, 1953 Dr, R. E. Eckardt Esso Laboratories Standard Oil Development Company /pNP. O. Bo* 51 U Linden. New Jersey Dear Doctor Eckardt: Dr. Keboe has asked me to write to you to confirm the date of January 7 for the meeting of the RPA Committee at the Kettering Laboratory. f~1 j If, however, you should find that January 8 is preferable, I believe that that date will be satisfactory also. . 1 presume that you will advise us shortly of the Committee's choice. Very truly yours f C.C. *6r. A. W. Horton Dr. J. J. Fhair Dr. F.-F. Heyroth E. R. Fortlage, Secretary to Dr. Kehoe ( ESSO LABORATORIES STANDARD OIL DEVELOPMENT COMPANY P. O. BOX 51, LINDEN, N.J. MEDICAL RESEARCH division ROBERT E. ECKARDT. PH.D.. M.O. DIRECTOR HORACE W. GERARDE. PH.D.. M.D. HEAD TOXICOLOGIST Messrs. C. H; Hine K. tinder M. N. Newqulst E. W. Adams L. C. Beard, Jr. L. M. Henderson R. C. Mithoff Novenfcer 30 1953 * ** INDUSTRIAL HYGIENE SECTION NATHAN V. HENDRICKS. CH.E. HEAD OF SECTION FRANKLIN W. CHURCH. M.S. GEORGE M. WILKENING. M.S. INDUSTRIAL HYGIENISTS Gentlemens Since we have not had a meeting of the Research Project MS-1 Advisory Committee for some time, I am writing to suggest that we plan for such a meeting the first week in January, 195k* In order to permit weekend travel for those who have to come a long distance, I would suggest that the meeting be held on Friday and, therefore, would tentatively at this time suggest January 8th, the meeting to be held as usual in the Kettering Laboratory and to start at about 9:30 a.m. I would furthermore suggest, as a result of our last meeting, that you may wish to give consideration to having the meeting with the Kettering group on the . 7th of January, leaving the 8th of January open for a meeting of the RPA Committee itself at one of the Cincinnati hotels and still having the weekend free for those who have a long distance to travel to get back home. In the meantime, I would appreciate receiving from each of you suggestions for the agenda of this meeting and an expression as to. whether or not you wish to hold the two-day meeting the 7th and 8th, or a one day meeting confined to the 8th. By carbon copy of this letter to the investigators at Kettering Laboratory, I am also asking for their suggestions as to the best meeting time for them. As soon as I have heard from all of you, I will Inform you of the definite meeting time and place and a tentative agenda far the meeting. Sincerely yours. REE:12k cc: Br. R. A. Kehoe Dr. A. V. Horton nr. J. J. Phair Dr. F. F. Heyroth Mr. D. 7. Stroop R. E. ECKARDT, K. D. Copy from D. V. Stroop for Information of All Members and Associates of the Medical Advisory Committee October 13, 1953 "U o-vrj* ESSO LABORATORIES Standard Oil Development Conpany - P, 0, Box 511 Linden, N.J. ' Medical Research Division Industrial Hygiene Section October 8, 1953 Mr. D. V. Stroep American Petroleum Institute 50 West 50th Street New York 20, New York Dear Mr. Stroep: I am enclosing a revised copy of the report of the RP (M3-1) Advisory Committee submitted on September 29, 1953 to the Subcommittee on Carcinogenicity of the API Medical Advisory Commit tee. By verbal arrangement with Dr. Davis it is my suggestion that you lave this report duplicated and distributed to all mes&ers and associates of the Medical Advisory Committee. Sincerely yours, /s/ R. E. Ickardt E. I. ICKARDT, M. D. RES:ilk Enclosure REPORT OF HP (M>l) ADVISORY COMMITTEE SUBMITTED ON SEPTEMBER 29, 1953, TO SUBCOMMITTEE ON CARCINOffiNECIT^API MEDICAL ADVISORY COMMITTEE SUMMARY OF THE API PROJECT ON CARCINOGENICITY AT. NETTERINS LABORATORY The original program of carcinogenic work at Kettering Laboratory grew out of the results obtained from testing a series of 8 oils. The con clusion of this work, reported on November 5, 1?48, was that all 8 oils affected the skin. Two of them produced mild Irritation, two produced a few verrucous papillomata, one produced papillomas and two questionable cancers, two produced a definite cancer each, and one was highly carcinogenic. As a result of these preliminary studies, the Kettering Laboratory undertook a more extensive research program under the'auspices of the API Medical Asvlsory Committee designed to l) survey refining processes and materials which might represent potential hazards from the cancer standpoint, 2)biological testing of indicated oils and tars, 3) chemical research to determine the nature of the carcinogenic components and to develop analytical techniques for their determination, and k) an epidemiological program to develop sound information regarding the actual incidence of cancer among employees of the petroleum industry and to determine the efficacy over a period of years of the various safety programs which have been or are being set up by individual oil companies. To implement this program, it was suggested that materials from a number of process be studied, in accordance with the outline on pages 2 and 3 of the Kettering report dated October 27, 1950. Non-Accelerating Solvents In order to have a reference standard to which the results of tests of these oils could be referred, the laboratory undertook a study of the carcinogenicity of solutions of methylcholanthrene in benzene. For reasons related to well known dose-response phenomena it was decided to use the > average latent period for tumor production as a measure of carcinogenicity, the average latent period being defined as the length of time required to reach 50$ tumor indices. In the course of this work with reference standards, it soon became apparent that C3H mice gave fairly reproducible results, whereas CFW mice gave less reproducible results. It was therefore decided to standardize the mouse strain and to use only C3B mice in subsequent tests, even though a considerable number of tests on oils with CFW mice had already been started or completed. In addlton, it became apparent that if too strong a solution of methylcholanthrene is painted on the C3H mice too frequently, the health of the mice, as determined by non-tumor mortality and weight curves, is impaired, and, apparently, their ability to produce tumors is impaired at the same time. In addition, other factors which influence the health of the mice, such as infections, infestations with lice, etc., also reflected in non-tumor mortality and growth rates, and will seriously affect tumor production. Thus, unhealthy animals frequently do not produce tumors aB readily as healthy animals, and the 4* average latent period la prolonged In the unhealthy animals. Since the average latent period is taken as a measure of carcinogenicity. It is obvious that the apparent carcinogenicity of a meterlal could be profoundly Influenced by the health of the animals, and misleading results thereby obtained* The above observations led to the necessity of painting mice once, twice or three times per week, depending on the strength of solution being used, and to the establishment of three or more separate standard curves, depending on the frequency of painting. The most recent report from the Kettering Laboratory, however, has shown that these three curves can be united into a single curve when they are expressed in terms of the dose of carcinogen applied per unit area of skin per week. This has necessitated measuring the area of skin covered by a solution of methylcholanthrene in a solvent. Within limits this has been found to be constant for each solvent tested. The solvents thus far tested have been benzene, hydro-peroxide-free amyl benzene, cotton seed oil, technical white oil and fractions of refinery streams. The effect of these solvents is their effect on the spreading of the solution. Thus, if the same amount of the same concentration of methylcholanthrene in two different solvents were to be painted on the skin 3 times a week, the dose per unit area need not be the same. If one solvent caused the solution to spread over twice the area of the other solvent, the dose per unit area in the first case would be half that in the second case, and the average latent period for the two solutions would be different, leading to different values for the two solutions. The PTM value refers only to concentration of methylcholanthrene in benzene, and serves only as a reference standard. What this work implies is that it will be necessary in carcinogenic work to determine not only the frequency of application and the amount applied per application, but also the area covered by this amount. Accelerating Solvents J' What has been said above applies only to solutions of pure cardtoogens in non-accelerating solvents. In the course of the work at the Kettering Laboratory it was observed that certain solvents, in addition to having an effect on the area of spread of the solution, also have a specific effect on the carcinogenicity of the solution. Thus it was found that different Concen trations of methylcholanthrene in some solvents, even though they spread over the same area, have essentially the same average latent period. According to the above, this should not be the case since the dose per unit area should be different^ In this case the area remains constant, the amount applied per application remains constant; but the concentration varies, and hence dose per unit area varies. Theoretically, therefore, the average latent period should vary, but actually this was not found to be the case. The explanation for this effect is that the solvent exerts some specific accelerating action on carcinogenesis. To summarize these two concepts, it may be well to give some equations. Thus, dose per unit area, per week may be defined as follows: d = nga x c x f a where mgm mgo of solution applied per application c = concentration f * number of applications per week a area covered ( C -3- In the first case of 2 non-accelerating solvents with different spreading, mgm, c, and f were constant, tut a varied, thereby influencing d. In the second case, mgm, f, and a were constant, but c varied, and.hence, d also was variable; but this did -not influence average latent period* 'Hence two situations exist,-one in which the rate of tumor formation is related directly to d, the other in which it is not. To date, dodecyl benzene, normal hexadeeane, methyl naphthalene, cyclohexyl decane, phenyl dodecane, cetane and phenyl decane have been found to be accelerating solvents, although gasoline-is not. ' An Interesting observation recently made is that if dodecyl benzene is applied once to the skin, and then serial biopsies taken, holes in the epithelium can be observed microscopically but not grossly. It has been postulated by the Kettering Laboratory that these holes provide foci of rapidly regenerating epithelium which may be responsible for the accelerating action observed. Refinery Streams As a result of the above information of a fundamental nature developed over the past several years, the Kettering Laboratory now believes that carcinogenic refinery streams may be divided into two main classes: 1). Those streams or materials in which Pj^ is related to d. 2). Those streams or materials in which P^, is not related to d. In the first group fall those materials such as catalytically cracked residua in which carcinogen concentration is so high or accelerators relatively so low that the carcinogen concentration becomes of first importance as a measure of tumor activity in mice. In the second group, characterized by medium distillates, the carcinogen concentration is so low and the accelerator concentration relatively so high that the accelerators are more important in the rate of tumor production of the mouse skin than the carcinogens. ; The laboratory has developed information which indicates that the accelerators are present in those refinery streams boiling from k50-650F., while carcinogens are present in those streams boiling above 650-700F. Thus in mixtures which have a wide boiling range, say from ^50-1000F., the carcino genicity of the mixture may not be dependent alone on the amount of 700F.+ material present, but also on the amount and nature of the 450-650F. fraction. In partial support of this concept, the laboratory has analyzed a series of refinery streams for their benzpyrene content, in accordance with a method developed by the laboratory, and have related the determined benz pyrene content to the Pj^ (appendix.II of JanuaryvSeptember, 1953 Progress.. Report). These determinations indicate that the $ BP/Pj^n ratio essentially divides into two groups, those that run from 0.30 and higher, and those that run from 0.10 and lower. The first group of materials falls in the first class of refinery materials, and the second group into the second class. ( 4* c Tables of In the newly distributed tables of values distributed on September 1, 1953, essentially three types of results are given: 1). "" Those in which both the average latent period and the PMC values are given in parentheses. It is the feeling of the laboratory that these results are open to serious errors in their'accuracy dad to uncdhtrollfible variables id the'biologies! experiments sueh 'as-poor.health, toxicity of- applied materials, etc. 2). Those in which the average latent period is enclosed in parentheses but the P^ value is not. ftiese are pretty good experiments from a biological standpoint, but the laboratory still has some reservations about the accuracy. 3) Those in which neither the average latent period nor the Fj^ values are enclosed in parentheses. These experiments are believed to be as good a biological experiment as it is possible to obtain. Of the samples in these tables for which a Pjg. value is given, 57 fall into the first group, 93 fall into the second group, and 27 fall into the third group. It is the feeling that the 57 samples which fall into type 1 results should be examined critically and some of them repeated and brought into a type 2 or 3 experiment. Since much of the validation of the theories of the laboratory is dependent upon accurate P,_, values, it .is highly desirable that these PjjC values-be.made as atSursetR .as.biological experimentation wlIL permit. Another serious defect of these tables is that in some experiments, animals have been eliminated from the experiment because the laboratory believed that biologically it was unsound to include them. In several cases the results are based on as few as 6 animals. It is to be desired that no results will be finally reported unless a minumum number of 20 animals sure included in the experiment. The Committee recognizes the validity of throwing out some animals, but feels that where this has been done, the experiment should be repeated to Include at least 20 animals. Other Observations - The laboratory has determined that washing is an effective way of reducing the carcinogenicity of an oil to the shin of the mouse. In general., the sooner the oil is washed off, the better. limited experiments with barrier creams are difficult to interpret but the laboratory feels the use of barrier creams in accordance with recognized practice followed by washing may offer advantages greater than washing alone. . Epidemiology The epidemiological data is accumulating in the laboratory, with some 1200 cases now having been reported. No definite trends are as yet -5- discernible but it was not anticipated that any such trends would be discernible prior to at least 5 years experience. It is hoped that the support which the General Committee, Division of Refining has given to the epidemiological study will stimulate renewed reporting of the cases with sufficient medical and occupational histories to permit some early correlations to be made about 1956. Summary -' 1. The BP (MC-l) Advisory Committee believes that the Kettering I laboratory is performing important work in the field of carcinogenesis of \ refinery streams and materials. They believe that although a great many \ practical answers have already been obtained, the work should be pursued \ because the work of the laboratory .promises to_provide-many fundamental" j answers to-questions wMch'now exist concerning industrial and occupational cafcno'fSnesiB7------------- - - ` ......... ' ' 2. It is believed that the work with non-accelerating solvents which relates the carcinogenic responses of a solution of pure carcinogen to the dose applied per unit area per week to the skin is of extreme fundamental importance. The Committee urges that additional work be conducted to establish firmly the curve which egresses this relationship. 5 . 3. It is also believed that the work with accelerating solvents is also of extreme fundamental importance and that this should be pursued vigorously in_an attempt to_ develop. a. conple_tejjnderstanding of the relative role of carcinogens' and accelerators in refinery streams and~materials'.'..... * 4. Since much of the correlation of chemical analyses with - biological potency is dependent upon the accuracy of Pj^j values, the Com mittee laments the fact that many of the Pj^ values thus far reported are based on data which the laboratory recognizes as not having been obtained from the best biological experiment possible. The Committee suggests, there fore, that the laboratory devote considerable effort to repeating those experiments in an effort to develop Pjj values that are based on the soundest possible biological experiment. ; 5. The Committee believes that the work with washing techniques and protective creams may provide intensely practical guides to refinery hygiene practice and suggests that this work be pursued as new approaches appear to the laboratory. 6. The Committee recognizes that the epidemiological studies cannot be expected to produce significant results until at least 1956, and, therefore, urges that renewed efforts at adequate case and occupational history reporting be made during the next several years. It believes that adequate medical staffs can do most to insure the success of this program, and in this connection it acknowledges the stimulus that the General Committee, Division of Refining has given to the attainment of this objective. 7. The laboratory has already determined that a number of refinery streams and materials have a relatively high degree of carcinogenicity. Although data obtained with mice cannot be directly transposed to humans, there is sufficient data in occupational cancer experience to indicate that the -6- petroleum industry cannot take lightly the observations of the laboratory on the carcinogenicity of these refinery streams and materials. 8. The Committee recognizes that the laboratory at best can determine from its biological and chemical work only the relative carcino genicity of various refinery streams and materials. The determination of the hazard is dependent upon factors of extent, frequency, duration, and length of exposure. As recognized by the laboratory in Dr. Kehoe's talk to the members of the General Committee, Division of Refining the determina tion of the hazard is at present a function of the individual petroleum com panies. -Adequate medical and industrial hygiene staffs are essential in these individual companies if they are adequately to appraise the hazard. The Committee supports Dr. Kehoe's plea that petroleum company managements recognize this truism and make plans for the development of such adequate medical and industrial hygiene staffs. 9< It is apparent that the laboratory has accumulated sufficient data that publication of results will be deemed desirable in the near future. The Committee recognizes the right of the laboratory to publish, and urges that the mechanism be established so that these publications can be reviewed in a finite period of time. As a suggestion, it is proposed that this mechanism be so established that review by API management and suggestions and criticisms for the laboratory from API management be made available within sixty (60) days. If no criticisms or suggestions are obtained by the laboratory at the expiration of this time, the laboratory can assume that none are forthcoming and proceed with publication. It should be recognized that this review is for the purpose of helpful criticisms and suggestions, and not for the determination of whether or not there will be publication, since the contract with the laboratory clearly states that the laboratory determines if and when publication occurs. --00O00-- October 7, 1953 7. ( - ESSO LABORATORIES STANDARD OIL DEVELOPMENT COMPANY P. O. BOX 51, LINDEN, N.J. MEDICAL RESEARCH DIVISION ROBERT E. ECKARDT. FH.D.-. M.O. DIRECTOR HORACE W. OERAROE. PH.D.. M.O. HEAD TOXICOLOOIST September 22, 1953 INDUSTRIAL HYGIENE SECTION NATHAN V. HENDRICKS. CH.E. HEAD OF SECTION FRANKLIN W. CHURCH. M.S. OEORSE M. WILKENINO. M.S. INDUSTRIAL HYOIENISTS Dr. 'Cieffer Davis Phillips Petroleum Company Bartlesville: Oklahoma Dear Dr. Davis As new Chairman of the HPA Committee, I have prepared the attached report summaris ing the activities of the Kettering Laboratory aa I aee then to the present tine. It would be ry intention to present this to the Subcommittee on Carclnocenicity nesting in Houston as a formal report of our RPA Coradttee to the Subcommittee. Escause of the uno.vailabij.ity of time to obtain approval from each of the RPA Committee members. I as unable to claim this as a full RPA Committee report. ' However, I plan to arrive in Houston at about two o'clock lionday afternoon, September 28th. end have a reservation at the Shamrock Hotel beginning ia the evening. I would be happy to go over this report with any and/or all members of the RPA Committee that evening in order to introduce any corrections or sugges tions that might seem warranted, or, if the Cosmittee so decides, to abandon this tf report altogether. For any members of the RPA Committee who will net be in Houston Monday evening.. I would suggest that they writ me their criticisms and suggestions at the Shamrock Hotel and they will be taken into consideration at the discussions 'hich the rest of the Committee will hold that evening. I am sending three copiss of this report to Dr. Horton with the suggestion that if he has ary comments which hs feels I should have included in this report, or if ho disagrees with our interpretation of the work of the Kettering Laboratory, he will be in a position to advise me of the opinion of the Laboratory Monday evening in Houston. Txis tve- cXtrs cop3.es ciT the report being cent to Dp. Horton are for Dr. Kohoo end Dr. PLsir,I I realise that this report cannot be a complete summary of all cf the work done by the Kettering Laboratory, otherwise it would have to bo too long, but I do fcr-I that it represents, at least ir. my mind, the important observations which hive been made thus 'for by the- Kettering Laboratory, and in the summary emphasizes the important points that should be pursued ir. the work cf the Laboratory. It is my hope that our RPA CcrrdLttsa.. if not winning to accept thi3 rspert, will deem it advisable tc prepare c report somewhat similar to this one which can be sub mitted to the Subcommittee on Carcinogenesis at the Houston meeting. If it is agreeable with this Committee and with you, it would be ny plan to read this report ( Dr. Xieffer Davis -2- September 22, 1953 before the Subcoradttee e:a Tuesday corning and then to Jiave copies Bade avail able to osch of the members of the Subcommittee on Ccrc:jiogsnesis following the Houston meeting. Furthermore, it would be my suggestion that the Subcommittee nay wish to consider sending a report similar to this to the Iledical Advisory Ccanri.ttce_.vith the suggestion that it be forwarded to the Safety Committee cf the Board of Directors of the API. As I have indicated above, the report which I an sending to you now should be considered only as ry own rough draft of such a report, representing only my ideas: and subject to the approval of the other members.of the RPA Committee. I trust that our EPA Committee will be able to ccne to some agreement on this report Konday evening in Houston prior to the meeting of the Subcommittee on Carcinogenesis. ' Sincerely; E. E. SCKAEDT, 1!. D. Attachment cc 'with attachment Dr. M. B. Ue-ATOiot lir. E. Acsm D. V. Stroop REPORT OF RPA COMMITTEE SUBMITTED OH SEPTEMBER 29, 1953, TO SUBCOMMITTEE OH CARCINOGENESIS, API MEDICAL ADVISOR! COMMITTEE SUMMARY OF THE API PROJECT ON CARCINOGENESIS AT KETTERING LABORATORY The original program of carcinogenic work at Kettering Laboratory grew ou.t of the rgsults obtained from testing a eerie* of 8 oil*. The conclusion of thi* work, reported on November 5, 19^8, was that all 8 oils affected the skin. Two of them produced mild irritation, two produced a few verrucous papillomata, one produced papillomas and two cue6tlonable cancer*, two produced a definite cancer each, and one was highly carcinogenic, . Ab a result of theBe preliminary studies, the Kettering Laboratory under took e more extensive research program under the auspices of the API Medical Advisory Committee designed to 1) survey refining processes and materials which might represent potential hazards from the cancer standpoint, 2} biological testing of indicated oils and tars, 3) chemical research to determine the nature of the carcinogenic components end to develop analytical techniques for their determination, and, k) an epide/niol.ogical program to develop Bound information regarding the actual incidence of cancer among employees of the petroleum industry and to dotermlne the efficacy over a period of yearo of "I the various safety programs which have been or are being set up by individual oil companies. To imulement this program, it was suggested that materials from a number of processes he studied, in accordance with the outline on pages 2 and 3 of the Kettering report dated October 27, 1950. Hon-accelerating Solvents Zn order to hare a reference standard to which the results of tests of these oils could he referred, the laboratory undertook a study of the carcino genicity of solutions of methyl cholanthrene in benzene. For reasons related to veil known dose-response phenomena it was decided to use the averags latent period~for tumor production as a measure of carcinogenicity, the arerrge latent period being defined as the length of time required to reach 50$ tumor indices. In the course of thie work with reference standards, it soon became apparent that C3H mice gave fairly reproducible results, whereas CFW sice gave lens reproducible result. It was, therefore, decided to standardize the mouse strain and to use only C^H mice In subsequent tests, even though a considerable number of tests on oils with CFW mice had already bsen started or completed. In addition, it became apparent that if too strong a solution of methyl cholanthrene is painted on the C3H mice too frequently, the -health of the mice,, as determined by non-tumor mortality end weight curves, is impaired, and, apparently, their ability to aroduce tumors is impaired at the same time. In addition, other factors which influence the health of the mice, such as infections, infestations with lice, etc., are also reflected in non-tumor mortality;and growth rates, ar.d yill seriously affect uomor production. Thus unhealthy animals 44 . a do not produce tumors as readily as healthy animals, and ths average latent period is prolonged in the unhealthy animals. Since the avenge latent period is taken a* a measure of carcinogenicity, it is obvious that the apparent carcinogenicity of a material could be profoundly influenced by the health of the animals, and misleading results thereby obtained. 3 The above observations led to ths nsceseity of painting nice once, twice, or three timee per week depending on the strength of solution being used, and to the establishment of three or more separate standard corvee depending on the frequency of painting. The most recent report from the Kettering Laboratory, however, has ehown that these three curves can be united into a single curve when t&ey are expressed in terms of the dose of carcinogen applied per unit area of skin per week. This has necessitated measuring the area of skin covered by a eoiution of methyl cholanthrene in a solvent. Within limits this hac been found to he constant for each Bolvent tested. The solvents thus far tested have been benzene, hydro-perosldeg-frce amyl bensene, cotton seed oil, technical white oil add fractions of refinery streams. The effect of these solvents is their effect on the spreading of the solution. Thus if the same amount of the same concentration of methyl cholanthrene in two different solvents were to be painted on the skin J times a week, the dose per unit area need not be the same. If one solvent caused the solution to spread over twice the area of the other solvent, the dose per unit area in the first case vou?-d bo half that in the second case, and the average latent period for the two solutions would be different, leading to different values for the two solutions. The P^q value refers only to concentration cf methyl cholanthrene in bsnzene, and serves only as a reference standard. What this work implies is that, it will be necessary in carcinogenic work to dstermine not only the fre quency of application and the amount applied per application, bat also the area covered by this amount. Accelerating Solvents What has been said above applies only to solutions of pure carcinogens in non-accelerating solvents. In the course of the work at the Kettering Laboratory it was observed that certain solvents, in addition to having an effect on the area of spread of the solution also have a specific effect on the carcinogenicity of the solution. Thus it was found that different concentrations of aethyl cholrnthrens in some solvents, even though they spread over the sane area, have essentially the eane average latent period. According to the above, this should not be the case since the doBe per unit area should be different. In this case the area remains constant, the anount applied per application remains constant, but the concentration varies, and hence dose per wit area varies. Theoretically, therefore, the averege latent period should vary, but actually this was not found to be the case. The explanation for this effect is that the solvent exerts some epeciflc accelerating action on carcinogenesis. To summarise these two esneepte, it may be vail to give some equations. Thus dose per unit area per week may be defined as follows: nan a c x f where icgji = mgm of solution applied per application = nunber of applications par week a = area covered In the first case of 2 non-accelerrting solvents with different spreading. mgr,, c, and f were constant but a varied, thereby influencing d. In the second case, mgm, f, and a were constant but c varied and hence d also was variable, but this did not influence average latent period. Bence two situations exist, one in which the rate of tumor formation is related directly t>> d, the other in which it is not. To date dodecyl benzene and normal hexadecsne have been found to be accelerating solvents, although gasoline is not. An interesting observation recently made is that if dodecyl benzene is - applied once to the shin; and then serial biopsies taken, holes in the epithelium can be observed microscopically but not grossly. It has been postulated by the Kettering Laboratory that these holes provide foci of rapidly regenerating epithelium which may be responsible for the accelerating action observed. Refinery Streams As a result of the above information of a fundamental nature developed over the past several years, the Kettering Laboratory now believes that carcinogenic refinery streams may be divided into two main classes: 1) . Those streams or materials in which is related to &. 2) . Those streams or materials in which F^g is not related to d. In the first group fall those materials such as catalytically cracked residua in which carcinogen concentration is so high or accelerators relatively so low that the carcinogen concentration becomes of first Importance ae a measure of tumor activity in mice. In the second grouD, characterized by medium dI istillates the carcinogen concentration is so low and the accelerator c " relatively so high that the accelerators are more important of the mouse skin than the carcinogens. The laboratory has developed information which indicates that the acceleratore are present in those refinery streams boiling from 450-650!'., while carcinogens are present in those streams boiling above 650-7000!'. Thus in mixtures which 6- c have a vide toiling range, say from 4501000*7* * the carcinogenicity of the mixture may not he dependent alone on the amount of 700*7* + material present* but also on the amount and nature of the 450-650*7. fraction* In partial support of this concept, the laboratory has analyzed a series of l refinery Istrea_ms for their benzpyrene content, in acco)rdance with a method developed*4 and have related the determined benzpyrene content to the PMq (appendix II of January - September, 1953* Progress Beport). these determinations indicate that the $ BP/PMC ratio essentially divides into' two groups, those that run from 0*30 and higher, and those that run from o.lo and. lover. The first group of materials falls in the first class of refinery materials, and the second group into the second class. In three instances (API^, 71 and 91) this ratio lay betveen 0.1 end 0*3, sad these three oils may Tables cf P^q . In the newly distributed tables of PKQ values distributed' on September 1, 1953, essentially three types of results are given; 1). Those in which both the average latent period and the PHq values are given in parentheses. It is the feeling of the laboratory that these results ere open to serious errors in their accuracy due to uncontrollable variables in the biological experiments such as poor health, toxicity of applied materials, etc. 2). Those in which the average latent period is enclosed in parentheses but the Pjjq value is not. These are pretty good experiments from a biological standpoint, but the laboratory still has some reservations about the accuracy. ( - 7- 3). Those in which neither the average latent period nor the PMC value ere enclosed in parentheses. These experiments are believed to he as good a biological experiment as it is possible to obtain. Of the samples in these tables for which a P^, value is given, 57 fall into the first group, 93 fall into the second group, and 27 fall into the third group. Zt is the feeling of this writer (and I hope the remaining members 5*7 of the KPA Committee) that the samples which fall into type 1 and* results 2/V" - can be repeated and brought into a type 3 experiment. Since much of the val idation of the theories of the labor;tor? is dependent upon accurate Pgg values, it is highly desirable that these P^ values be made as accurate as biological experimentation will permit. Another serious defect of these tables is that in some experiments, animals have been eliminated from the experiment because the laboratory believed that biologically it was unsound to include them. Zn several cases the. results are based or. as few as 6 animals. It is to be desired that no results will be reported unless a minimum number of 20 animals are included in the experiment. The Committee recognised the validity of throwing out, some animals, but feels that where this has been done the experiment should be repeated to incluo'p at least 2C animals. Other Observations The laboratory has determined that washing is an effective way of reducing the carcinogenicity of an oil to the shin of the mouse. Zn general, the sooner the oil is washed off the better. Limited experiments with white oil wash and barrier creams ar9 difficult to interpret. or the use of barrier creams in association with washing, may offer advantages greater than with washing alone. J* -8- Epidemiology Hie epidemiological data ie accumulating in the laboratory* with some 1200 caeee now haying been reported. No definite trends are as yet discernible but it was not anticipated th:t any such trends would be discernible prior to at least 5 years exoerience. It is hoped that the support which the General Committee, Division of Defining has given to the epidemiological study will stimulate renewed reporting of cases with sufficient medical and occupational histories to permit some early correlations to be made about 1956. Summery ' 1. Tha SPA Committee believes that the Kettering Laboratory is performing important work in the field of carcinogenesis of refinery streams and materials. They believe that although a great many practical answers have already been obtained, the work should be pursued because the work of the laboratory promises to provide many fundamental answers to questions which now exist concerning industrial and occupational carcinogenesis.- ' 2. It is believed that the work with non-accelerating solvents which relatsa the carcinogenic response of a solution of pure carcinogen to the dose applied per unit area per week to the skin is of extreme fundamental importance. The '_ Comnittes urges that additional work be conducted to establish firmly the.curve which expresses this relationship. 3. It is also believed that the work with accelerating solvents is also of extreme fundamental importance and that this should be pursued vigorously in an attempt to develop a complete understanding of the relative role of carcinogens and accelerators in refinery streams and materials. h. Since much of the correlation of chemical analyse* with biological potency is dependent upon the accuracy of values, the Committee laments the fact that many of the PHq values thus far reported are based on data which the laboratory reco&iizes as not having been obtained from the best biological experiment possible. The Committee suggests, therefore, that the laboratory devote considerable effort to repeating those experiments in an effort to develop PMQ values that are based on the soundest possible biological experiment. 5. The Committee believes that the work with washing techniques and protective creams may provide intensely practical guides to refinery hygiene practice and suggests that this work be pursued ee new approaches appear to the laboratory. 6. The Committee recognizes that the epidemiological studies cannot bs expected to produce significant results until at least 1956. and, therefore, urges that renewed efforts at adequate case and occupational history reporting be made during the next several years. Zt believes that adequate medical staffs can do most to insure the succees of this program, and in this connection it acknowledges the stimulus that the General Committee, Division of Befining has given to the attainment of this objective. ?. The laboratory has already determined that a number of refinery streams and materials have a relatively high degree of carcinogenicity. Althougi It data obtained with mice cannot be directly transposed to humans, there is sufficient data in occupational cancer experience to indicate that the petroleum industry cannot take lightly the observations of the laboratory on the carcinogenicity of these refinery streams and materials. 8. The Committee recognizes that the laboratory at best can determine from its biological end chemical work only the relative carcinogenicity of various refinery streams and materials. The determination of the hazard is - 10 dependent upon factor* of extent, frequency, duration, and length of exposure* As recognised by the laboratory in Or. Xehoe*s talk to the members of the General Committee, Division of Refining the determination of the hazard is at present a function of the individual petroleum companies. Adequate medical end Industrial hygiene staffs are essential in these individual companies if - they are adequately to appraise the hazard. She Committee supports Dr. Xehoa*s plea that petroleum company managements recognise this truism and make plans for the development of euch adequate medical and industrial hygiene staffs. 9. It is apparent that the laboratory has accumulated sufficient data that publication of results will be deemed desirable in the near future. She Committee recognises the rigit of the Laboratory to publish, and urges that the mechanism be established so that these publications can be reviewed in a finite period of time. As a suggestion, it is proposed that this mechanism be so established that review by API management and suggestions and criticisms for the laboratory from A?7. management be made available within Blxty (60) days. If no criticisms or suggestions are obtained by the laboratory at the expiration of this time, the laboratory can assume that none are forthcoming and proceed with publication* It should be recognized that this review is for the purpose of helpful criticisms ( and suggestions, and not for the determination of whether or not there will be publication, since the contract with the 1:boratory clearly states that the laboratory determines if and when publication occurs. ESSO LABORATORIES STANDARD OIL DEVELOPMENT COMPANY P.O. BOX 51, LINDEN, N.J. MEDICAL RESEARCH DIVISION ROBERT E. ECKARDT. RH.D.% M.D. DIRECTOR HORACE W. OERAROE. BW.D., M.D. head toxicologist August 20, 19$3 ^ * INDUSTRIAL HYGIENE SECTION NATHAN V. HENDRICKS, CH.E. HEAD OF SECTION FRANKLIN W. CHURCH. M.S. OEORCE M. WILKENINO, M.S. INDUSTRIAL HYOIEN1STS Sr. H. C. Hlthoff California Research Corporation 200 Bush Street San Francisco k, California Sear Sr. Mithoffs In response to your letter of August 17, 1953* I as listing tbs seven points which Sr. Beard outlined in his letter to ne of April 22, 1953* In vieta of the feet that you have expressed interest in these seven points prior to the meeting, I am also sending a copy of Sr. Beard9 questions to all of the other members of our committee. I shall look forward to seeing you in Cincinnati. . Sincerely yours. R. E. ECKARSF, H. D. REEsilk Attach. ce with attach. - Kaasrs. C. H. Hies E. E. Linder 14. K. Uewquiet E. W. Adams L. C. Beard, Jr, L. 14. Henderson R. A. Kefcoe A. W. Horten^ J. J. Phair F. F. Heyroth K, Daria D. 7. Stroop (Taken from letter to Hr. R. E. Eckardt from Dr. L. C. Beard, Jr*, li/22/53) 1) Establish by mouse tests on successive raffinates the efficacy of T~y-^ J&juCL-Iu multiple extractions with furfural to remove carcinogens from a L'-ly ((t--, t ccrdnogenic lubricating oil fractionj say from a 100" paraffin oil ] from Hid-Continent crude. 2) Continue to coapletion work to determine if viscosity has a physical*'"1^ effect in delaying the appearance of papilloma. It 4 *u~4 11*M 3) Determine if asphalts from catalytic cracked residua have carcinogenic properties. Refer Dr. Kieffer Davis* letter Kerch 9, 1953* Roes their . solid nature prevent skin absorption and subsequent cancer?~Y^^JMM^>^\K^ 4 fc) Kr. llackensie at one time urged to paint a cage of mice with a carcinogenic' * petroleum fraction until the appearsacs of the first papilloma in any one mouse and then to stop painting and just observe. These data are requisite i4J tc answer the question as to whether :ve may have latent eases which can *** bloom forth later. I know that with beta naphthylaadns this can occur. Can it occur with petroleum aromatics? 1 5) What ere the comparative carcinogenic effects of concentration x on 2y square centimeters versus concentration 2x on y square eastinters? In other words, what are the relative, effects of concentration and surface . . area painted? &'>U. *d-*- cU-*-,.. & a*>*i*v ^*1 6) Doing a relative weak carcinogen such as Kid-Continent 100" paraffin oil, what lengthening of the latent period is obtained in cycles comparable to cutting-oil operators washing for lunch and at the end of an 8-hour shift? 7) Should we implement a critical survey of the epidemiologic literature to determine the relative incidence of cancer of the skin in metal workers (cutting oils), garage mechanics (motor oils)? , ..i ,^ V.V kLVsM ifci x ^ . o*U J? ( ESSO LABORATORIES STANDARD OIL DEVELOPMENT COMPANY P.O. BOX 51, LINDEN, N.J. MEDICAL RESEARCH DIaV/IiSqIiOoNn ROBERT E. ECKARDT. PH.D., M.D. DIRECTOR HORACE W. OERARDE. PH.D,. M.D. HEAO TOXICOLOGIST C S, Hlne, If. I), S. K._I>inder, K. D. ' M. H. Uevqulst, M. D. . V. Adams L. C. Beard. Jr. L. K. Henderson E. C. Mithoff August 6* 1953 IINndDuUsSTRIAL HYGIENE SECTION NATHAN V. HENDRICKS. CH.E. HEAD OF SECTION PRANKUN W. CHURCH. M.S. GEORGE M. WILKENINO. M.S. INDUSTRIAL HTOIENISTS - Gentlemenj Having Just returned from a pleasant three weeks is Hew Hampshire, I as now in a position to tally your suggestions as to the meeting at the Kettering laboratory in Cincinnati* Orus far, six Beaters of the Committee and Dr. Kehoe have folt that a Besting somewhat in advance of the Houston meetings would he advisable and all have agreed that Friday, September 11 would be a satisfactory date. Key 1 offer aj apologies to all of you for having-stated that this Friday was September 10 in sy first correspondence with you all. Xfcoh of you carefully pointed out that Triday is September 11, and on checking ay calendar, I find that you are all quite correct. Oierefore, 1 would suggest that our Committee plan to meet in the Kettering laboratory at about-9 a.B. on the morning of TVlday, September 11, 1953* At the moment, X would suggest the following as a tentative agenda; (1) Approval of the minutes of the last meeting. (2) Progress report and outline of future weak by Dr. Horton. (3) Progress report and outline of future work by Dr. Phair. (it) Budgetary discussion by IT. Kehoe. > (5) Summary of Dr. Horton's visit to Europs this summer. (6) Sevon proposals by Dr, Beard which should receive diecuesion by the Committee. (7) Any new items by members of the Committee. (8) She time and place of the next meeting of the Committee. (Presumably to be held at the Shamrock Hotel in Houston in conjunction of the meeting of the full Subcommittee on Carcinogenicity on September 29, 1953.)I I shall look forward to seeing you all at the meeting in Cincinnati and to receiving from any of you additional suggestions for items to be included on the agenda of our September 11th meeting. Sincerely yours BEE:gch cc: Dr. B. A. Kehoe Dr. A. V. Horton Dr. J. J. Phair Dr. ?. Tt. Hcyroth ` Dr. K. Davis K? p, V. Stroop H. E. XCZA2DT, K. D. ESSO LABORATORIES STANDARD OIL DEVELOPMENT COMPANY P.O. BOX 51, LINDEN, N.J. MEDICAL RESEARCH DIVISION ROBERT E. ECKAROT, PM.D.-, M.D. DIRECTOR HORACE W. OERARDE, PH.O.. M.O. HEAD TOXICOkOOIST Jhae 26, 1953 INDUSTRIAL HYGIENE SECTION NATHAN V. HENDRICKS, CH.E. HEAD OS SECTION FRANKUN W. CHURCH. M.S. OEOROE M. WILKENINO. M.S. INDUSTRIAL HVDIINISTS 0. E. Bias, X._9._ 1. E. Linder, X* i>. X. V. Sewquist, X. 9. X. V. Maas 9, 6. Beard, Jr. L. X. Benderoon B. e. Xithoff * - Oentlemenl . It has been suggested by several of ths members of tbs Besearch Project X0-1 Mrisory Committee that ear coaaittee should aset la Cincinnati seaotlaa prior to the scheduled, meeting In Houston on September 29th. You will reaeaber that - the September 29th meeting is being planned as a Joint meeting of oar Sesearch Project K0-1 Committee with the whole Sabeoaaittee on Carcinogenicity and several members of the smaller coaaittee have felt that It would make it la- poseibis to aeeoapllah ear beit effectively In each a large aeetlng. Zherefore, a preliminary meeting at Cincinnati has been suggested In order to dispose of some of the details of the Kettering Laboratory work which coaid not so easily be presented to the total Sabeoaaittee on Carcinogenicity. Such things as budget and detailed discussion of soae of the results could be accoaplished In the smaller aeetlng. I am writing therefore to suggest that our BPKG-1 Coaaittee meet in Cincinnati on Triday, September 10, 1953* * am suggesting this date la order that those, who have far to travel will be able to return on the weekend without less of tins from work and because X will be in attendance at the Oordon Sesearch Conference on Cancer until September 4th. I. I would appreciate hearing from each of you whether this date is satisfactory and whether I should proceed with plans with the Kettering Laboratory to arrange such a nesting. Sincerely yours. cc: Dr. B. A. Kehoe 9r. A. V. Horton Dr. J. J. Fhalr Dr. T. T. Eeyroth S. X. BCKABDT, X. 9. ESSO LABORATORIES STANDARD OIL DEVELOPMENT COMPANY MEDICAL RESEARCH DIVISION ROBERT E. ECKAROT. PH. D., M.O. DIRECTOR N. V. HENDRICKS. B. E.. CH. E. DIRECTOR. INDUSTRIAL HVOIENE SECTION pq LINDEN, N. J. To i M K. lTe;7qu.ist, M. D. 3. 3. Linder, H, B, C, H. Eine, 15. 'B. L. C. Boards Jr, April 7. 1953 X. &. Mackenzie E. H, Landoa E. C. Mithoff 3. V, Macs 3, M, Shepaxdson Gentleman: ^tentatively, the Sixth Heating of the SP (MC-1) Advisory Committee is being scheduled as & joint meeting with the Subcommittee on Carcinogenicity for September 29, 1953 &t the Shamrock Hotel, Eaustcu, Steznc.I I would very greatly appreciate it if each of you would send to me suggested topics for inclusion in the agenda of this joint meeting prior to September 1, 1953* his vili permit ns to circularize the agenda of the meeting to you and to the members of tho Subcommittee on Carcinogenicity prior to the tins of this meeting. Very truly yours. cc: Eisffer Davis, M. B, E, A. Eehce, K. B. J, J. Phair, H. B. A. y. Ebrtcn / J. V, Hcyrctii. !5. B. E. 3. 3CKA2BT, M, D. DVSsJb me: Members and Associates ' Medical Advisory Committee Drs. A. Wesley Hortonx Robert A. Kehoe John J. Phalr ( m.iMsmimutm HOf.FOR PUBLICATION AGENDA AND MINUSES OP SHE FIFTH MEETING RP(MC-l) ADVISOR? COMMITTEE KETTERING LABORATORY, UNIVERSITY OF CINCINNATI January 16, 1953 9:30 A.M. E.S.T. 1. Approval of minutes of Fourth Meeting held 9/24/52 2. Progress report - Be,. A. . Horton^H*P* 3. progress report on Epidemiological Survey - Dr. J, J. Phair 4. Research activities for the year beginning T/l/53 Chemical and biological - B*. A. . Horton Epidemiological - Dr. J. J. Phair ' Budgetary allocations - Dr. R. A. Kehoe 5. Report of the Committee on the Carcinogenic action of Mineral Oils to the Medical Research Council ' (Great Britain) on their "First Three Years' Work" 6. Communications with Dr, Paul Kotin, University of Southern California ' ` 7. Other 8. Time and place of next meeting (MAC meets Hotel Shamrock - Houston 9/30/53) Mama The Fifth Meeting of the RP(MC-l) Advisory Committee was convened in Dr, Kehoe's office at the Kettering Laboratory of the University of Cincinnati at 9:30 A.M., January 16, 1953, in attendance were the following: M. N. Nevquist, M.D. R. E, Eckhardt, M.D.,?k-Vv E. K. Linder, M.D. Kieffer Davis, M.D. C. H. Hlne, M.D.^CU. R. A. Kehoe, M.D. F. F. Heyroth, M.D.f.V* J. J. Phair, M.D. A. . Horton, L. C. Beard/Jr. K. G. Mackenzie R. M. Landon^b&v' R. C. Mithoff ,fk-S E. , Adams, fk-T) R. M. Shepards on \ The minutes of the Fourth Meeting of the RF(MC-l) Advisory Committee were approved. Subsequently the meeting followed the agenda which had been prepared by Dr. Newqulst prior to the meeting with alight modification in that the progress report and the research activities for the year beginning 7/1/53 were combined in both Dr. Horton's and Dr. Phair's reports. ITEMS 2 AND A..-..D.R^-HORTON LS-REPiHS As the basis for his discussions. Dr. Horton used the attached "Memorandum from the Kettering Laboratory"Fifth Meeting of the Advisory Committee API Research Project MC-1" dated January 16, 1953. Considerable discussion was given to the opening two paragraphs which justified the use of mice in appraising the hazards of skin cancer in workmen. In response to a specific question from Dr. Adams, Dr, Horton stated that washing is more effective in reducing carcinogenic potency than a reduction in the dosage of carcinogen applied. As evidence he presented the experimental evidence which was obtained with washing experiments with API-8 and API-113. It was then suggested that consideration be given to a washing experiment with API-113 and API-57 In which these oils would be painted on at a level of 100 mg. two times a week and washed off after 9 hours In contact with the skin. Perhaps the greatest Interests in Dr. Horton's report are his observations or theories that the potency of a particular material is dependent less on the amount of carcinogen than on its concentration] whereas, the effect of accelerators is dependent less on the concentration than on the total amount applied at each appli cation. Although this is an Interesting thou$it, it appears somewhat difficult to'understand how tills could be the situation and how the proper definitive experiments could be conducted in order to con clusively establish these observations. She concept that acceler ators may act because of their similarity in structural configura tion with the carcinogenic agents is an interesting one insofar as it applies to benzo(c) phenanthrene and highly branched dodecylbenzene. It is difficult, however, to see how this concept could apply to compounds like 3,4-benzpyrene or to.dodecylbenzene in which the side chain is not highly branched. The foxmmla presented by Dr. Horton on page 9 of his report is an extremely interesting formula from a theoretical standpoint, but whether it will ever have any practical application seems highly problemmatlcal since the determination of the effective concentration of accelerator in an oil may be extremely difficult, particularly if there is more than one accelerator.present in such an oil. Similarly, such a formula allows for the presence of only two carcinogens, namely, benzpyrene and one C4 aromatic. It seems highly unlikely that there would be only two carcinogens present in as complex a mixture as slurry oil, and this is partially;borne out by the observations reported by the Standard Oil Development Company in which 6-isopropyl benzanthracene was determined In a relative state of purity from one of these oils. It therefore seems likely that this formula will be exceedingly complicated by a great number of accelerators and inhibitors, such that the effective con centration of accelerator will have to be determined for each individual oil, and also by the presence of a large number of carcinogenic compounds, which will highly complicate the usefulness of any such"equation. Another interesting observation made by Dr. Horton during his discussion was that the average latent period decreases more rapidly for papillomas, depending upon the amount of accelerator, than the average latent period for carcinomas, this may he graphically expressed somewhat as follows* ITEMS, 2 AND 4 _ - DB PHAIBVS_ .REP.ORt Dr. Phalr used as a basis of his report the attached memorandum, which is essentially a tabular summary of the number of cases which he has thus far collected from the various companies It appears that an increasing number of companies are participating in reporting cases to Dr. Phalr but that there is a heavy imponderance of cases being reported from companies along the eastern seaboard as compared with companies in southwestern United States. It was agreed that Dr. Phair would outline-, briefly and send to the Chairman of the Subcommittee on Carcinogenicity his latest thoughts on pertinent data which he wishes to have included in the current reporting of cancer cases among employes in the petroleum industry, and that the Chairman of the Subcommittee on Carcinogenicity would then reattempt to stimulate all medical directors to report current cases to Dr. Phair. ITEM 4 - DR._KgHQElB..REPORT Dr. Kehoe discussed the budgetary .allocations of funds and indicated that It vould be possible for the Kettering Labora tory to live vithin the presently assigned budget of $?9>000, but that it must be remembered that- this will result in approximately one-quarter less vork being done during the year July 1, 1953" June 30, 1954. Dr. Kehoe vished to reserve the right to allocate funds under any of the headings given, depending upon the Kettering Laboratory's estimation of hov the funds should be allocated. Thus, for instance, if full cooperation vith Dr. Phair is not obtained,' it may veil be that the $17,500 allocated for epidemiological vork may be re-allocated into other phases of the Research Project. There seems to be a general agreement among the members of the committee that Dr, Kehoe should have freedom in allocating the total funds to any of the four phases of the project that he feels the. funds should be allocated to. Dr. Kehoe also made a plea that if there is a determined effort to have a gradual reduction in the budget of this project during the coming years, he vould like to be informed of this as far in advance as possible so that he might make his plans accordingly. Thus, if the budget is to be cut one- ' half in the Year July 1, 1954-June 30, 1955, and to a quarter of its present figure in the succeeding years. Dr. Kehoe vould like to knov of this as soon as possible. JML5 | Dr. Horton discussed the report from the British on the . carcinogenicity of the mineral oils. He felt that their tests had been performed vith applications of oil vhlch vere so small that they are not getting tumors in the mice, yet they vere observing tumors In the rabbits due to the effects of accelerators* He seemed to feel that the fractionation of their oils left much to be desired, and that same fractionation of oils in his laboratories, vhich vere then applied on his own animals by his own techniques, had re sulted in the appearance of a considerable number of tumors, par ticularly in the K-4, L-4 and 0-4 fractions. He felt that this was probably the result principally of accelerators, and that the carcinogens would be found in the highest concentrations in the K-5, L-5 and 0-5 residues. It was suggested at the meeting that the workers at the Kettering Laboratory feel free to communicate on a professional basis with the workers in England in discussing their mutual work, and furthermore, it was felt that if the Kettering Laboratory felt they would like to keep this communication in the established channels, this could be done by having Dr. Horton prepare a critique of the British work and then having Dr. Newquist forward this to the British workers through Colonel Auld. It is evident that it is too early to draw conclusions with respect to the British work which has been reported thus far. ITEM. .6. '. Dr. Kehoe indicated that he has written a supplemental letter to Dr. Kotin suggesting that Dr. Kotin more definitely out line what information he would like to receive in order that the Kettering Laboratory might be able to provide it to him. Dr. Kehoe did not feel that any of the Kettering Laboratory reports should be sent to Dr. Kotin or anyone else since they are at the present time so tentative. It was also suggested that a possible' means of handling this situation would be to have Dr. Kotin come in to the Kettering Laboratory and discuss their mutual problems verbally. and that such a discussion could get to Dr. Kotin all the information which he might need and yet not jeopardize the position of the Kettering Laboratory. . ITEM-? . Dr. Eekardt reported to the committee that 5 additional cases of skin cancer resulting from cutting oils have recently come to his attention. One of these cases vas a scrotal cancer and none of the cases had previously been reported to the group, fhis simply served to emphasize the growing importance of cutting oils as a possible carcinogenic agent in industry. HEM-8 Some discussion was given to the possibility of holding the next meeting of the Advisory Committee at the Hotel Shamrock on the 29th of September, 1953* and that at this time it would be a Joint meeting with the Subcommittee on Carcinogenicity. Decision on this matter was left to the Chairman of the Subcommittee, with Idle recommendation that if the meeting is to be held on that date, members should be notified and hotel reservations should be made well in advance. ` M. N. Hewquist, M. D., Chairman B. 1. Eekhardt, M. D. Acting Secretary \ -- MEMORANDUM FROM THE KETTERINP LABORATORY FIFTH MESTINg OP THE ADVISORY OOMMITOgg API RESEARCH PROJECT MS-1 January 16* 1953 . A* The use of nice In the experimental appraisal of the relative hazards of cancer of the skin of workmen from exposure to various petroleum produces* % 1. Materials which in Industrial experience have caused cancer of the skin of workmen have been shown to be carcinogenic to mice. 2. The correlation of the responses of men and mice is partic ularly close in the ease of straight run wax distillates* cancers having resulted in both species from intermittent* severe exposure <100 mg. doses applied three times per week on the skin of the mice)* when the carcinogenic material was not removed by washing. Data reported by the New York University group indicate that mice develop very few tumors when low dosages (15 mg. per application) of wax distillates are applied. The mouse* like man, seems to be affected adversely by these oils only when exposure is severe. A confirmatory test at low dosage will be carried out on C3H mice with the Midcontinent paraffin distillate, API-56 (PMC 0.1 at the 100 mg, level of dosage), B. Relationships between potency of oils and the level of dosage applied upon the skin per application. 1, Variation of the relative potency, P^, with the level of dosage (oyer certain ranges of dosage) is just what one would expect on the basis of human experience with such alleged carcinogens as coal tar, shale oil or the distil lates which have been handled in wax presses in the petroleum industry, i.e., the higher the level of exposure, the greater the chance of skin cancer* The results of the tests on mice at different levels of dosage which have been reported for the catalytically cracked residua, API-8 and 71, are therefore neither surprising nor dis tressing when considered from the overall aspect of the program* Really unexpected results are coming from the tests on standard solutions and refinery streams containing either very low or very high levels of concentration of accelerating constituents. Certain materials demonstrate a constant potency over a broad range of dosage: e- ; r> '* A J (1) Solutions of methylcholanthrene or benzpyrene in benzene - ' (2) Some blended industrial fuel oils, e*g., API-113 (3) Some thermal tars from virgin feeds, e*g*, API-108 (4) Solutions of methylcholanthrene or benzpyrene in dodecylbenzene (5) Some catalytically cracked gas oils, e.g,, API-102. Types (1), (2), and (3) probably contain, at the most, very low concentrations of accelerating constituents. types (4) and (5) relatively high concentrations. The types of oils discussed in section B.l. apparently have a critical level of concentration of such components. The situation may best be pictured graphically (see Figure l)s Thus, if no accelerators are present in an oil (A), it will exhibit only the potency due to its carcinogen content. Similarly, oils containing accelerators will show only their base level of potency if the dosage per application is kept sufficiently low so that the amount of the --' . Ij. -- accelerator applied to the akin of the mouse each time does not exceed B* What dosage this will he for any given oil obviously depends on the concentration of accelerators in the oil. If the dosage per application of such oils is Increased until the amount of the accelerating constituent actually being applied each time reaches the critical range between B and C, the relative potency, ?jC, as measured by a shortened latent period for tumor induction, will rise. This effect will then Increase as higher levels of dosage are tested until the maximum response for a given concen tration of carcinogen is obtained (upper plateau in Figure 1), Proceeding in the reverse direction (from D towards C) it will be apparent that the higher the level of the con- . centration of accelerators in an oil, the more the dosage per application may be reduced before a significant reduction in potency will be observed. Ibis category probably Includes a large number of the current distillate gas oils with End Boiling Points >700F. from fractionators of catalytic cracking units. Because of the obvious importance of these relation- . ships between the amount of accelerator applied and the -rate at which an oil containing carcinogens will Induce cancer in exposed animals, steps are being taken to - establish: (1) the exact magnitude of levels B and C (with blends of synthetic hydrocarbons), (2) the classes and boiling ranges of the hydro carbons in catalytlcally cracked gas oils and residua responsible for the acceleration observed, and (3) the levels of concentration of such hydrocarbons in various refinery streams. C. The nature of the compounds contributing to the carcinogenic potencies of refinery streams. 1, Polycyclic carcinogenic compounds. A direct method of analysis for the 5-ringed.carein- f ogen, 3,lj.-benzpyrene, has been developed. Its reliability has been tested and confirmed with four of the major types of refinery streams under consideration, including cycle gas oils and bottoms products from catalytic cracking, tars from thermal cracking of catalytic feeds, and straight run distillates. By application of this method, it has been shown that about 70% of the base potency exhibited by the FCC decanted oil, API-8, at 5*20 mg. levels of dosage is ( 4* C -6 - contributed by benzpyrene. Approximately of the . constant value of the No. k fuel oil blend, API-113, Is due to benzpyrene.. b. '' - As might be expected. In view of the reported boiling point of 3,i4.-benzpyrene (860F.), It has been found that the distillate refinery streams analyzed thus far, with true end boiling points less than 860% contain relatively small amounts of this 5-ringed carcinogen. The available data from biological tests on fractions prepared from catalytically cracked oils suggest strongly that the Important carcinogen In such cycle gas oils is a fringed derivative of phenanthrene Since the results further Indicate that simple alkyl derivatives of pyrene ahd 1,2-benzanthracene ( Pyrene 1,2-Benzanthracene are not contributing significantly to the carcinogenicity of these oils, attention Is being centered upon benzo(c)- phenanthrene. Shis is the hydrocarbon of lowest molecular, weight which has been shown to be carcinogenic without the benefit of methylatlon. Pure samples of benzphenanthrene and of each of its six monomethyl derivatives have been obtained. Their chemical and physical properties are being examined in the development of a direct method of analysis applicable to refinery streams. Accelerating constituents. It is of considerable Interest that the number of carbon atoms (16) in the accelerator, dodecylbenzene, Is the same as the number in the carcinogen, benzo(c)- phenanthrene. The known carcinogenic hydrocarbons have Carbon Numbers from 16 to 25* The approximate boiling range of branched-chaln alkyIbenzene s with 16-25 carbon atoms is 2|.?5"700oP., which is the very range that has been suspected of having accelerating activity from the results of biological tests on refinery streams and fractions thereof. It seems likely that we have here something more than just coincidence. The problem of the identification of the important accelerators in refinery streams is being approached in two ways: 0 (1) Biological testing of certain synthetic liquid hydrocarbons as solvents for benzpyrene, to determine which types have accelerating properties, The results obtained in the prosecution of this phase of the program will furnish a definite outline of the range of molecular weights and of the structural types of possible importance. (2) Biological testing of fractions of certain eatalytieally cracked oils which have demonstrated * (in tests at the 100 mg, level of dosage) potencies three to ten times as high as were expected on the basis of their content of four to six ringed aromatic hydrocarbons These efforts are being concentrated on the components boiling below 700F. which contain not more than two fused aromatic rings. The foregoing phase (2) of this program has already led to the concentration of a colorless, liquid fraction from the TCC bottoms product, API-71, which possesses the specific irritant properties of dodecylbenzene. This fraction is being redistilled through an 80-plate column to prepare a number of well-defined cuts to be tested as possible accel erators of the carcinogenic action of benzpyrene. In general, it is a much simpler matter to separate saturated hydrocarbons and monocyclic aro matics from oils and from each other than it is to fractionate any single class of polycyclic compounds from an oil. Furthermore, in the separation of compounds boiling in the range $00-650 at 760 mm,. : -9 - . highly efficient distillations may be carried out at reduced pressure without fear of eracklng, lenoe there Is little reason to doubt that systematic application of available techniques will lead to an adequate knowledge of tile structural types of the accelerating constituents of refinery streams in a reasonable period of time. The step from that knowledge to a direct method of analysis for their effective concentration In any given stream should present no great difficulties. Physicochemical methods for predicting the relative potencies of refinery streams. During the last six months, the completion of the picture (Figure 1) of the interrelations, between concen tration of carcinogen, concentration of accelerator, dosage per application, and relative potency, PMC, has brought with It a firm confidence that a reliable ana lytical tool will result from the further extension of this fundamental approach to the problem. The equation ' for which parameters are being determined is of the fol lowing type: where f(ca*d) is a function of the amount of the accel erator component applied in each application of the whole oil, cft being the effective concentration of accelerator * in the oil, and d the total dosage of oil per application; 4* Cg and Cj^ are the concentrations of the 5-ringed benzpyrene and of the ^-ringed carcinogen respectively* while Kg and are the respective potencies of benzpyrene and the ^-ringed compound based on methyleholanthrene Since the values for half of the factors in the equation for calculating FMC are already known (d* Kg and Cg), the remaining job is the determination of caV and the breakpoints at B and C in the curve of Figure 1. Sheae phases have been discussed in Sections B2, C fltbt and C2* ( ' ESTIMATED BUDGET OP THE KETTERING LABORATORY FOR THE INVESTIGATION OP POTENTIAL HEALTH PROBLEMS ' OP TIE PETROLEUM INDUSTRY ASSOCIATED TOTH THE PRESENCE OF CARCINOGENIC COMPOUNDS IN CERTAIN MATERIALS AND PRODUCTS ~ API RESEARCH PROJECT MC-1 July 1, 1953 - Jn 30* 1954 Salaries Direct Salaries $ 30,000*00 Indirect Salaries Histopathological Preparation $ 2,000*00 Other Services $ 22,000*00 $ 54*000.00 Miscellaneous Expense Purchase of Animals $ 1,500.00 Special Laboratory Supplies $ 5*500,00 Travel 4,000,00 Overhead (Proportion of heat, gas, electricity, steam, telephone, general laboratory supplies, postage, annuities, pensions,- maintenance,- etc*) $ 14,000.00 $ 25,000.00 Total $ 79,000.00 ESTIMATED BUDGET OF THE KETTERING} LABORATORY FOR THE INVESTIGATION OF POTENTIAL HEALTH PROBLEMS OF THE PETROLEUM INDUSTRY ASSOCIATED WITH THE PRESENCE OF CARCINOGENIC COMPOUNDS IN CERTAIN MATERIALS AND PRODUCTS ' API RESEARCH PROJECT MC-1 . July 1, 1953 - June 30, 1954 I. Further development of semi-quantitative biological testing methods for measuring the relative carcinogenic potencies of petroleum products and fractions thereof f 12,000.00 II, Determination of the relationships between the rapidity of induction of benign and malignant tumors in experimental animals and various exposure factors such as frequency of appliestlon, dosage per application, area of exposure, number of applications,, special irritant or toxic properties of the oil applied, etc. $ 14,500,00 . III. Development of rapid analytical methods for estimating the relative carcinogenic potency of any given refinery intermediate or product A* Isolation and identification of compounds responsible for observed potency of various types of oils and determination of pertinent physical and chemical properties of these compounds $ 30,500,00 < . B, Development of semi-empirical methods of $ 4,500.00 estimation of carcinogenic potencies of oils based on the chemical or physical properties of known or suspected carcinogens and acceleratorsIV. IV. Epidemiological Program Collection and correlation of data on eases of ' cancer among employees of the petroleum industry including any special investigations in particular plants of tfie industry $ 17,500,00 ______________ Total 79,000.00 FIGURE 1 - 1007* CASE REPORTS FROM 13 COMPANIES RECEIVED BY THE CENTRAL REGISTRY ACCORDING TO SEX, RACE AND MALIGNANCY SEX RACE MALIGNANT MALE White Colored Not Given TOTAL FEMALE White Not Given TOTAL 745 26 114 885 33 9 42 NOT GIVEhr .4 TOTAL BOTH SEXES 931 BENIGN 23 38 61 1 5 6 67 TOTAL 768 26 152 . 946 34 14 48 1 4 998 * Nine reports could not be used. Six were not tumors; one of these was Boeck's Sarcoid. Three gave only the occupational history. FIGURE 2 - MALIGNANT TUMORS IN MALES AS REPORTED ACCORDING TO TYPE OF TUMOR AND PRIMARY SITE Type of Tumor Site Buccal Cavity 00-09 Digest. Sye. and Perit. 10-19 Gland. Epith. 00-09 11 247 Respiratory System 20-29 28 Non Gland. Epith. 10-19 64 24 91 Breast 30-39 Genital Organs 40-49 Urinary System 50-59 Skin and Soft Tissue 60-69 1 42 21 1 16 21 170 Bones 70-75 6 3 Leuke- Lympho Nervous Vascular mias mas Tissues Tissues Muscle 20-29 30-39 40-49 50-59 60-69 Non- Embry. Epith. - Mixed Tissues Tissues 70-79 80-89 Tumors Not Class. 90-- Total 1 1 . 77 4 7 3 285 1 2 3 125 2 11 69 11 44 2 ,4 2 3 181 1 21 13 Brain 76-79 2 Lymph, and Hem, System 80-89 12 17 Other Sites 90--- 8 27 1 Total 364 419 12 24 3 5 1 1 13 19 29 1 4 41 17 17 26 885 Type of Tumor Site Buccal Cavity 00-09 Gland. Epith. 00-09 Digest. Sys. and Perit. 10-19 Respiratory System 20-29 8 1 FIGURE 3 - MALIGNANT TUMORS IN FEMALES AS REPORTED ACCORDING TO TYPE OF TUMOR Non Gland. Epith. 10-19 Leukemias 20-29 AND PRIMARY SITE Lympho Nervous Vascular mas Tissues Tissues Muscle 30-39 40-49 50-59 60-69 I Non- Embry. Epith. - Mixed Tissues Tissues 70-79 80-89 Tumors Not Class. 90-- 1 .Total 1 -8 1 ,2 Breast 30-39 Genital Organs 40-49 Urinary System 50-59 Skin and Soft Tissue 60-69 14 2 1 1 3 1 6 15 5 1 7 Bones 70-75 11 Brain 76-79 Lymph, and Hem. System 80-89 Other Sites 90--- Total 26 1 14 1 1 2 1 42 FIGURE 4 - MALIGNANT TUMORS AS REPORTED BY SEX AND PRIMARY SITE COMPARED WITH U.S.A. MORBIDITY AND MORTALITY ESTIMATES SEX Site Number Reported MALES Per U.S.A.* U.S.A,** Cent Per Cent Per Cent of Cancer Cancer Total Cases Deaths Number Reported FEMALES ! BOTH SEXES Per Cent of Total U.S.A.* U.S.A.** Per Cent Per Cent Cancer Cancer Cases Deaths Number Reported Per Cent of Total U.S.A.** Per Cent .Cancer Deaths Buccal Cavity 77 8.7 10.0 Digestive System and Peritoneum 285 32.2 36.0 Respiratory System 125 14.1 8.0 Breast 2 0.2 Genital Organs 69 7.8 12.0 4.7 47.7 15.4 0.2 13.0 1 2.4 2.0 1.2 8 19.0 23.0 38.7 2 4.8 2.0 3.9 15 35.7 19.1 5 11.9 } 51.0 23.5 78 8.4 2.9 293 31.6 43.2 127 13.7 9.6 17 1.8 9.7 74 ao 18.3 Urinary System Skin and Soft Tissue Bones 44 5.0 181 20.5 13 1.5 7.0 17.0 6.6 2.2 1.3 Brain 19 2.1 2.4 Lymph, and Hema topoietic System Other Sites 29 41 3.3 4.6 ) 10.0 6.5 J TOTAL 885 100.0 100.0 100.0 1 2.4 3.0 3.4 7 16.7 11.0 1 2.4 > 1.5 1.1 1.5 ) )2 4.8 ) 8.0 6.2 42 100.0 100.0 100.0 45 4.9 5.0 188 20.3 1.8 14 1.5 0.1 19 2.0 2.0 29 3.1 43 4.6 7.4 927 100.0 100.0 * Primary site of development of cancer- among white males and females according to Dorn, Harold F.: Illness from cancer.in the United States. Reprint No. 2537, Public Health Reports. (Based upon morbidity records collected from ten large cities in the United States between 1937 and 1939.) ** Cancer deaths by site in the United States for 1948 as prepared by the Statistical Research Section, American Cancer Society, utilizing statistics from the National Office of Vital Statistics. I . ' t Research Project Advisory Committee Meeting January 16, 1953 '> r Straight run naphthas from Oklahoma City and Kuwait Just like benzene as diluents - reduoe potency of L-4 by just 50JC (at 20 mg. dosage) - as solvents for Methylcholanthrene gave latent periods essentially same as benzene. 2. Oklahoma 0-3 showed two early papillomas which regressed accelerator? 3. Summary of British work .- Sec. 1 Industry and raw materials Lube oils for cotton spinning * Slack wax * Cutting oils in light engineering industry Solvent extracts as plasticizers during war * Cancer in workmen Sec. 2 Chemistry Isolated perylene from solvent extract No luck with cold cone. HS04 on extract Bolling ranges of K-4# L-4, and 0-4 suggest that most of the carcinogens of the crudes were left in the residuum Does I.B.P. method IP 28/4-2 compare with ASTM distillation? Sec. 3 Biology , Rabbit equals mouse at high dosage - rabbit would be a way out if toxicity prevented use of high dose on mice ' Reduced crudes gave no tumors -- Rabbit more sensitive than mouse (note API-80 and boiling ranges of distillates) Using 0.2 and 0.0$ Methylcholanthrene and 9,10-Dimethylbenzanthracene in white oil as reference standards in new series of experiments. 4. Ask Mr. Landon about trip through Cleves Refinery 5* Ask.Drs. Hine and Mithoff about San Francisco visit (March 11th to 15th.) \ j J yvu~l.lt - FIFTH MEETING RP(MC-l) ADVISORY COMMITTEE KETTERING LABORATORY, UNIVERSITY OF CINCINNATI January 16, 1953 9*30 A.M. E.S.T. AGENDA 1. Approval of minutes of Fourth Meeting held 9/2lj./52 2. Progress report - Dr. A. W. Horton 3. Progress report on Epidemiological Survey- Dr. J. J. Phair I4.. Research activities for the yearbeginning 7/1/53 Chemical and biological - Dr. A. W* Horton Epidemiological - Dr. J. J. Phair Budgetary allocations - Dr. R, A. Kehoe 5. Report of the Committee on the Carcinogenic action of Mineral Oils to the Medical Research Council (Great Britain) on their "First Three Years' Work" 6. Communications with Dr. Paul Kotin, University of Southern California 7. Other " 8. Time and place of next meeting (MAC meets Hotel Shamrock - Houston 9/30/53) M. N. NEWQUIST, M.D., CHAIRMAN E. W, Adams L. C. Beard, Jr. Kieffer Davis, M.D. R. E. Eckardt, M.D. T. M. Frank, M.D. C. H. Hine, M.D. D. V. Stroop (2) R. A. Kehoe, M.D. (3) R. M. Landon E. K. Linder, M.D. K. G. Mackenzie R. C. Mithoff R. M. Shepardson American Petroleum Institute 80 WEST BOTH STREET NEW YORK ZO, N. Y. December 19,1952 To Members, Research Project Advisory Committee E * V# Adams L. C. Beard, Jr. Kieffer Davis, M.D. R. E. Eckardt, M.D. T. M. Prank, M.D. C. H. Hine, M.D. R. My Landon E. K. Linder, M.D, K. G.- Mackenzie R. C. Mlthoff R. M. Shepardson Gentlemen: I am attaching the minutes of the Fourth meeting of the Research Project (MC-l) Advisory Committee which was, . held in Chicago, September 24, 1952. The Research Project Advisory Committee will hold it8 next meeting at the Kettering Laboratory in Cincinnati, Friday, January 16, 1953, commencing at 9*30 A.M. Eastern Standard Time. -- I would greatly appreciate receiving promptly from the members suggested items to be included on the agenda which will be circularized prior to the meeting. Very truly yours, . `TYI.D.TIjuv M. N. NEWQUIST, MW). ** Chairman, Research Project Advisory Committee . MNN:RMS Enclosure me: Members and Associates Subcommittee on Carcinogenicity Members and Associates Medical Advisory Committee Dr. Robert A. Kehoe Dr. A. V. Horton Dr. J. J. Phair Mr. D. V. Stroop Fourth Meeting R. P. A. COMMITTEE (MC-l) Chicago, Illinois - Sept. 24, 1952, 10:00 a.m. D.S.T Conrad Hilton Hotel Room 523 AGENDA 1. Consideration of the various items listed in the report to be made on 9-25~52 by the Subcommittee on Carcinogen icity to the Medical Advisory Committee,-including pro gress reports by Dr. R. A. Kehoe, Dr. A. W. Horton, and Dr. J. J. Phair. (Copies of the reports have been circularised by Mr. Stroop.) 2. For information and any action that may be indicated. (a) Letter of August 26, 1952, from Mr. G. G. Rumberger to Mr. Elmer 0. Mattocks. (b) Letter of August 13, 1952, to Col. S.J. M. Auld from Dr. M, N. Newquist. (c) Letter of September 10, 1952, from Dr. R. E. Eckardt to Dr. M. N. Newquist. 3 Other 4. Time and place of next meeting. Respectfully submitted E. W. Adams L. C. Beard, Jr. Kieffer Davis, M.D. R. E. Eckardt, M.D. T. M. Frank, M.D. C. H. Hine, M.D. D. V. Stroop (2) R. A. Kehoe, M.D. (3) M. N. NEWQUIST, Chairman R. M. Landon E. K, Linder, M.D K. G. Mackenzie R. C. Mithoff R. M. Shepardson For Information Only - Not Por Publication REPORT ON FOURTH MEETING Research Project MO-1 Advisory Committee September 24, 1952 Conrad Hilton Hotel Chicago, Illinois MEMBERS PRESENT M. N. Nevquist, M.D. - Chairman R. E. Eckardt, M.D. - Acting Sec'y. E. V. Adams L. C. Beard, Jr. Kieffer Davis, M.D. T. M. Frank, M.D. R. M. Landon E. K. Linder, M.D. K. G. Mackenzie R. C. Mithoff R; M. Shepardson MEMBERS ABSENT AND HOT REPRESENTED C. M. Hine, M.D. OTHERS PRESENT R. D. Bent R. C. Cole H. W. Gerarde, M.D A. W. Horton R. A. Kehoe, M.D. E. 0. Mattocks A. C. Pabst J. J. Phair, M.D. Atlantic Refining Company Phillips Petroleum Company Standard Oil Development Company University of Cincinnati University of Cincinnati American Petroleum Institute Socony-Vacuum Oil Company, Inc. University of Cincinnati The attached agenda of the meeting, which had been dis tributed by Dr. Nevquist prior to the meeting, was used as the program. ITEM 1 The report.of the Subcommittee on Carcinogenicity to be presented to the Medical Advisory Committee on September 5, 1952# was reviewed. This report, which bad been sent to members of the subcommittee on September 11, 1952, had received approval by the subcommittee. The final tabulation of the voting oh. epidemiological studies of cancer among employes of customers was as follows; Do you recommend that Kettering Laboratory, University of Cincinnati, make epidemiological studies of cancer among employes of customers? Yes 12 No 12 Not voting 1 If yes, what is your opinion of the following points? a. Random selection of plants for survey. Yes No_6_ Not voting . b. Limit surveys to plants where cancer cases are allegedly due to petroleum products. Yes _6_ No _0_ Not voting _6_ c. Maintain a cancer registry wherein only cancer cases proven to be due to exposure to petroleum products would be recorded. Yes 5 No2 Not voting 5 DR. HORTON1S REPORT Dr. Horton used as the basis for his discussion the memorandum from Kettering Laboratory, dated September 24, 1952, which had been distributed to members of the Medical Advisory Committee. Perhaps the most important feature stressed by Dr, Horton was the observation that there are non-carcinogenic oils which are not white oils; that is to say that apparently it is not necessary to carry out such an extreme degree of refining as to produce a white oil in order to eliminate the carcinogenicity of an oil. In support. Dr. Horton stressed the results obtained with API-100 and API-99 There was considerable discussion by the associates on just what the nature of API-100 and API-99 might be since many of them did not feel that the specific gravity and viscosity indicated that these represented a type of oil which - 3- might ordinarily be found on the market. It was emphasised, how ever, by Dr. Horton that these oils were taken out of cans and were used presumably in certain test engines. Dr. Horton suggested that because of the negative results obtained vhen white oils are painted on mice, it might be advisable to test such materials on rabbits since the English are placing so much emphasis on the Importance of rabbits in skin cancer testing work. There was next a considerable amount of discussion on the experiments which have Indicated that dodecyl benzene has a specific irritant action on the skin of the mouse which seems to enhance the carcinogenicity of truly carcinogenic compounds.. These experiments were summarized on page 29 of the tabular summary of current and completed biological experiments dated September 1, 1952. They indicate that dodecyl benzene can sensitize the skin to carcinogens even if it is applied prior to the application of the carcinogen. These results are indicated in experiments designated 221, 9, 9, 221-9, 221-9 (the first 5 samples listed in Table III, page 29). These experiments indicate that if the skin is sensitized with dodecyl benzene prior to the application of API-9, the average latent period of tumor induction is approximately 1/2 of what it is when this sensitization process is not carried out. It is from an accumulating body of data of this nature that Dr* Horton is developing the concept that certain materials contain acceler ators to the carcinogens. It is believed by Dr. Horton that these accelerators are particularly important in what he designates as side streams and are of considerably less importance in residua. Thus he has found that an oil which has been prepared by distil lation which has no benzpyrene, or essentially none, still has a considerable activity. The laboratory is attempting to find out the class or classes of compounds which are responsible for this activity. Dr. Horton's laboratory has developed a very rapid method for quantitatively determining the amount of benzpyrene in an oil sample. This discussion led to the suggestion that Dr. Horton should consider performing an experiment in which a batchwise solvent extraction of a typical lube stock base (for instance API-56, API-79, or API-105) with subsequent testing of the ex tract^) and raffinate(s) would be performed. It is felt that such an experiment might essentially remove 4 and 5 ring aromatic compounds, leaving the 1, 2,and 3 ring materials for testing. Experiments are now underway to determine the effect on PMC of painting once, twice or three times a week. In addition, experiments on the effects of varying the amount of material ap plied at a given application (i.e. from 5-100 mg.) are also being conducted. Preliminary, it is beginning to appear that the amount of material applied each time may be significant in materials which have a considerable amount of the accelerators in them but probably is not important in those materials in which these accel erators are minimal or absent. Thus, when the potency of a material seems to correlate with Its benzpyrene content, the amount of mate rial applied per application seems not to have any effect on this potency determination; but when a material seems to have a higher potency than its benzpyrene content vould suggest It should have, the mount of material applied at each application may have a con siderable effect on the potency determined. In addition to the presence of accelerators. Dr. Horton has some.evidence to indicate that there may be Inhibitors in certain petroleum products, and that these Inhibitors are present in the residua of distillation processes but are absent in the side streams. This fact, correlated with certain other observa tions, has given some suggestive evidence, although certainly not conclusively demonstrated, that the inhibitors may be heavy metals or may be compounds associated with the heavy metals. Dr. Horton believes that these inhibitors probably account for the reason why crude oils are essentially non-carcinogenic, while gas oils pre pared from such crudes may exhibit some carcinogenicity. It is Dr. Horton's belief that crude oils contain sufficient benzpyrene and other related carcinogens to demonstrate a significant degree of carcinogenicity, vhereas, animal and human data indicate that they do not. It was Dr, Horton's intent not to pursue inhibitors very strenuously. Certain members of the committee, however, believe that the pursuit of suoh inhibitors might have veryimportant practical considerations to the petroleum industry and suggested that they not be abandoned lightly. Because of the great complexity of carcinogenesis in petroleum products, which now appears to be a summation of the concentration of carcinogens, the presence of accelerators, and the presence of inhibitors, many of the members of the committee felt that the development of a simple analytical tool to test for carcinogenicity would be considerably more difficult, if not im possible, than originally believed. Thus, it was felt that car cinogenicity is not the result of a single class of compounds but rather the summation of three separate and distinct types of ` activity, and that, therefore, the development of an analytical tool has been considerably complicated. DR. PHAIR'S REPORT Dr. Phair discussed the memorandum from the Kettering Laboratory API Research Project on Carcinogenicity Epidemiological Studies, dated September 24, 1952. This memorandum had been pre viously distributed to members of the Medical Advisory Committee. There was some discussion of the significance of the figures pre sented in Figure 4, page 6 of this memorandum. Dr. Phair empha sized the importance of not drawing any conclusions from this table at the present time since the number of cases is so small. He emphasized again the necessity of collecting a large number of cases for analysis before any statistically significant differences can be demonstrated. Premature conclusions from data of this type ( will be detrimental and should not be done. Dr. Phair asked for - 5 ** the criticisms of each of the members of this committee and of the Medical Advisory Committee of the coding system which he is using on the cas record cards* Dr* Kehoe and Dr* Phair reported that the lettering Laboratory would be willing to undertake a critical review with abstracts of the literature on cancer as related to petroleum and that the annual coat of such bibliographic service would be $4,^30.* The Chairman of the RPA Committee then further emphasized the necessity of medical directors of petroleum com panies, /ijhp have membership on the Medical Advisory Committee, submitting their cancer cases to Dr, Phair if his work is to have any significance. If they are unwilling to submit their records, then this should be brought out in the open and the epidemiological side of these studies dropped now rather than attempting to continue when the lack of sufficient oases doom the project to failure before it starts. ITEM 2a The inquiry from Mr. 0. G. Rumberger, Marathon Corpora tion, dated August 26, 1952, to Mr. I. 0. Mattocks concerning possible carcinogenicity of petroleum waxes and Mr. D. V. Stroop's reply were presented for information with the verbal comment that contributors to the API Fundamental Research Project are not thereby entitled to reports on other API research projects. Copies of this correspondence were sent to members of the Medical Advisory Committee. ITEM 2b- Dr. Newquist's letter of August 13, 1952, to Col. S. J. M. Auld concerning possible reporting in England of the research work at Kettering Laboratory was presented for information. A copy of this letter was sent to each member of the Medical Advisory Copiittee. ITEM 2c Dr. R. E. Eckardts letter of September 10, 1952, to Dr. Newquist commenting on the research activities of Dr. Paul Kotin of the University of Southern California on the matter of cancer and smog was discussed. It was the consensus of the R.P.A. Committee that Dr. Eckardt and any other interested members of the committee might, as individuals, meet informally with Dr. Kotin at the time of the Industrial Health Conference in Los Angeles in April 1953 if they so desired. , ITEM 3 - BUDGET FOR YEAR JULY 1. 1953 - JUNE 30. 1954 Dr. R. A. Kehoe submitted a proposed budget totalling $104,073 for support of research project MC-1 for the next fiscal year, a copy of which is attached. In executive session, the R.P.A. Committee recommended a reduction of $25,790, making a proposed budget of $78,283 for fiscal 1953"195*. The following recommendations were made with respect to Dr. Kehoe*s budget: I - Delete II and III to be combined $25,720 IV - Reduce the total amount by $10,000 and apply the balance to items A & B ' as deemed best. 33,130 V - Delete items B & C and increase item A by $6,263.00. 19,33 78,253 Any change in research activities necessitated by this reduction in the budget would be discussed by the R.P.A. Committee with Dr. Kehoe and Dr. Horton at the next R.P.A, Committee meeting. ITEM 4 The next meeting of the R.P.A. Committee was set', tentatively for January 16, 1953 at the Kettering laboratory in Cincinnati. *' M. N. Newqulst, M. D., Chairman R. E. Eckardt, M, D., Acting Secretary BUDGET OP THE KETTERING LABORATORY FOR THE INVESTIGATION OP THE POTENTIAL CANCER HAZARD OP THE PETROLEUM INDUSTRY SPONSORED BY THE MEDICAL ADVISORY COMMITTEE of the -- AMERICAN PETROLEUM INSTITUTE July 1, 1953 - June 30, 1954 I. Determination of the location and extent of the cancer hazard from refinery Intermediate and product streams Direct Salaries 4 4,000.00 Indirect Salaries 3,500.00 Miscellaneous Expense 2,000.00 Ove rhead 1,860.00 $ 11,360.00 II. Development of semi-quantitative biological testing methods for measuring the relative carcinogenic potencies of petroleum products Direct salaries $ 3,500.00- Indlrect Salaries 4,200.00 Miscellaneous Expense 2,300.00 Overhead 1,630.00 | 11,630.00 III. Determination of the relationships between the rapidity of Induction of benign and malignant tumors in experimental animals and various exposure factors such as frequency of application, dosage per application, area of exposure, number of ' applications, special irritant or toxic properties of the oil applied, etc. ' Direct salaries $ 4,500.00 Indirect Salaries 5,200.00 Miscellaneous Expense 2,300.00 Overhead 2,090.00 $ 14,090.00 Indirect Salaries include Histopathological Preparation and other services. Miscellaneous Expense Includes purchase of animals, special laboratory supplies, and travel. -2- IV . Development of rapid analytical methods for estimating the relative carcinogenic potency of any given refinery intermediate or product A. _ Isolation and identification of compounds responsible for observed potency of various types of oils and determination of physical and chemical properties of these compounds which could be used in the development of a widely applicable analytical tool (Including associated animal testing) Direct Salaries ` $12,000.00 , Indirect Salaries 10,200.00 Miscellaneous Expense 3,050.00 Overhead 5,500.00 . $ 30,750.00 B. Semi-empirical correlations with carcinogenic potencies based on the chemical or physical properties of known or suspected carcinogens in the oils (Including associated aniamal testing) Direct Salaries $ 5,000.00 . Indirect Salaries 3,700.00 Miscellaneous Expense 1,350.00 Overhead 2,330.00 $ 12,380.00 V. Epidemiological Program A. Collection and correlation of data on cases of cancer among employees of the petroleum industry Direct Salaries $ 5,000.00 Indirect Salaries 3,500.00 Miscellaneous Expense 2,350.00 Overhead 2,320.00 $ 13,170.00 B. Special investigations of cases of cancer in particular plants in the industry or among customers of the industry Direct Salaries $ 2,500.00 Indirect Salaries 1,750.00 Miscellaneous Expense 85O.OO Overhead 1,163.00 $ 6,263.00 C. Survey of pertinent literature on cases of . cancer occurring among workers exposed to tar or oil in their occupation Direct Salaries $ 2,000.00 Indirect salaries 1,400.00 Miscellaneous Expense 100.00 . Overhead 930.00 $ 4,430.00 American Petroleum Institute 80 WEST BOTH STREET NEW YORK SO. N. Y. 4* C-fottz2u>*J 7 August 22, 1952 To Members and Associates 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 Kettering laboratory, Cincinnati, Ohio, July 10, 1952. Will you kindly indicate your approval or disapproval of the actions and decisions of the R.P.A. Committee and your 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, 7)1, M. N. NEWQUIST,m. D.* . Chairman, Subcommittee on Careinogenicity MNNsRMS Enclosures me: Members and Associates Medical Advisory Committee Dr. R. A. Kehoe (2) (Without letter ballot) AGENDA Research Project (MC-l) Advisory Committee Meeting Kettering Laboratory, Cincinnati, Ohio July 10, 1952, 9:30 a.in. to 4;00p.m. 1ST ' 1 - Summary of April 1952 Progress Report Dr. A. W. -Horton 2 - Comments on the Progress Report 3 - Progress of studies since April 1952 and future plans Dr. R. E. Eckhardt et al. Dr. A. If. Horton 4 - Effect of viscosity on potency and the use of embodying agents to modify viscosity R. M. Shepardson L. C. Beard, Jr. 5 - (a) Need for additional studies on straight-run, uncracked distillates and residua (b) Appraisal of British literture and the magnitude of the hazard in Great Britain L. C. Beard, Jr. 6 - Plans of the Sub-panel on Lubricants and Process Products Hygiene of the API Lubrication Committee R. M. Landon K. G. Mackenzie L, C. Beard, Jr. 7 - Report on mid-year meeting. General Committee, Division of Refining, May 1952, with respect to the RPA Committee's report of April 30, 1952, to Mr. T. J. Sullivan R. M. Landon 8 - Epidemiological Surveys (a) Among employes of petroleum companies Dr. J. J. Fhsir Dr. E, K. Linder (b) Among employes of customers 9 - Other business Dr. M, N. Newquist 10 - Date and place of next meetings of (a) Subcommittee on Carcinogenicity (b) RPA Committee ^^Information.Only -..Rot For Publication flgfiBLPP Research Project MC-1 Advisory Committee July 10, 1952 Kettering Laboratory Cincinnati, Ohio MEMBERS PRESENT OR REPRESSMas M, N. Newquist, M.D. - Chairman R. E. Eclcardt, M.D, - Acting Sec'y. L. C. Beard, Jr. Kieffer Davis, M.D. C. M. Doane (For E. W. Adams) . T. M. Frank, M.D. R. M. Landon K. G. Mackenzie R. C'. Mithoff . R. M. Shepardson members.absebblabd wot represented C. M. Hine, M.D. 1. K. Linder, M.D. - OTHERS PRESENT F. F. Heyroth, M.D. - University of Cincinnati A. W. Horton - University of Cincinnati Arthur Pahst (Socony-Vacuua Oil Co., Inc.) J J. Phair, M.D, University of Cincinnati - 2- The attached agenda of the meeting, which had been dis tributed by Dr. Newqulst prior to the meeting, was used as the program. ITEMS 1 AND 3 Dr. Horton presented to each of the members the attached "Memorandum from the Kettering Laboratory, Third Meeting of the Advisory Committee, API Research Project MC-l'i. Dr. Horton followed the outline presented in this memorandum with additional comments, as follows: a. The year 1951 in terms of the health of the experi 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 nation of the Pjhc values of the various materials 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. Criteria used by the laboratory for determination of' what is considered a good animal test include 85# survival of the animals for at least 6 months, or until 50 of the animals have tumors. c. Experiments are designed 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 PMC determination will be considerably reduced. d. The desirability of weighing .the animals once a week 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. - 3- ITEM 2 In the discussion that followed on Dr. Horton's comments it was brought out by Dr. Beard that he had heard of some data from England which indicated that in straight run distillates maximum-carcinogenicity is observed in the 300-1W)0oC'. cut. Dr. Horton then emphasized that the nature of the distillation must be fully understood before the significance of this observation could be accepted, since in distillations in which poor fractionation occurs a material presumably cut between 300 and 400c. could con tain considerable amounts of material boiling below 300C. and boiling above 400C. Later, Dr. Beard 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 carcinogen per unit of area. 2. The dilution of the carcinogen. 3. The frequency of application. 4. The effect of the physical state, i.e., viscosity and surface tension. 5. The health of the animals. 6. The psychic state of the animals as concerns eating. 7. The effect 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 result of the experiments, using 20 and 100 mg. of material per application with solutions of methycholanthrene and with API No. 8. in the latter case activity seemed to increase with dosage. Dr. Eckhardt then commented that this variation in activity might be both a function of the dosage per application and the dosage per week (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 order to develop all of the various 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 begin tapering off on the amount of effort in this program in 2 years' time is an extremely optimistic outlook. Rather, it was their feeling that this type of research will have to continue for a considerably longer period 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, although of extreme interest, would 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 exceeded certain medical supervision is carried out. Prom 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. Dr. Beard brought with him a sample of alkylated poly styrene which had been shown to increase the viscosity of a catalytically cracked recycle oil from about 84 to about 1100 when 5# of the material was added to the oil. It was suggested as a possible agent to use in increasing the viscosity of carcinogenic oils without appreciably changing their chemical composition. Reference was made to a letter submitted by Mr. Shepardson which 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. Beard's sample) in order to evaluate the effect of viscosity on potency. ITEM 5a Dr. Beard indicated that experience thus far has shown f that most occupational cancers allegedly due to petroleum 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 on this type of material 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 Gunillas) presently being studied in Great Britain would suffice for the time being. 4* - 6- ITEM 5b Dr. Beard suggested that it probably would be helpful if Dr. Phair could or would review critically the literature on cancer as related to petroleum with particular emphasis on keeping the members of the committee informed of any new articles which 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 planning to undertake such a critical abstracting of current literature for the committee. ACTION While Dr. Phair is favorable to such an undertaking he hesitated to commit Kettering Laboratory in the absence of Dr. Kehoe. Therefore, this matter awaits official clearance from Kettering Laboratory. . 1M-6 Dr. Beard told the group of the activities of the Sub Panel on Lubricants and Process Products Hygiene of the API I Lubrication Committee. A small subcommittee has been 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 materials, 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 of the skin and that if it cannot be kept off of the skin, it should be washed off as soon after contact -7- as practicable. Mr. Mackenzie emphasized the need of making such washings practicable so that workers would not be spending half of their day washing things off of their hands. Ag_TjoN Hone taken ITEM 7 Dr. Landon reported that a verbal summary of the report of the BPA Committee was given to the General Committee, Division of Refining, in May of 1952. As a result, the General Committee, Division of Refining, addressed a letter to the chairman of the Medical Advisory Committee asking that the Committee recommend minimum 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 problem to the petroleum industry and the general recommendations of Dr. Kehoe that the petroleum in dustry must develop the adequate medical and industrial hygiehe measures to control 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 petroleum industry in their request. ACTION Hone taken ITEM 8a Dr. Phair indicated that he has now received about 900 historical records. Apparently he is receiving very few current * 8 records and asked the cooperation of the Committee to stimulate the various .medical directors to send 'in--their current Records of cancer cases, fie indicated that since April, only 35 or 36 records have been sent to him. fie stated that up until the present time there has been no real call on his services in a consultation capacity. Discussion by the Committee indicated that Dr. Newquist would provide the stimulus to the various medical directors to send in their current cancer cases, and that following the action of the Medical Advisory Committee, on the request of the General Committee, Division of Refining, much of the work of Dr. Phair may be Implemented because some of the companies which do not now have adequate medical records may begin to develop them on the recommends: tion of the API as to what constitutes adequate medical 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 director3in the petroleum companies to submit the data re quested by Dr. Phair. < ITEM 8b . Dr. Newquist mentioned the need for epidemiological studies among the employes of customers of petroleum products since most of the cases are apparently occurring among users rather than among manufacturers, fie 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. 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 matter is subject to further r.ction by the Subcommittee on Careinogenlc1ty. ITEM 9 _ Under item 9 on the agenda Mr. Shepardson presented a table of data collected by the Standard Oil Development Company and New York University which indicated that there are at present 4 methods which will predict tumor.potency within what it is believed to be a useful range of accuracy. These 4 methods involve: (1) ultraviolet absorption at a 650-1000P. cut of the oil, (2) polarographic determinations which depend .upon the diffusion current at two voltages, (3) the caffein number which depends upon the ultraviolet absorption at two wave lengths of caffein extract of the oil, and (4) the high aromatics characterization which is a more complicated method and was not discussed in detail. He in dicated that the Development Company is in the process of checking these four methods in three different laboratories in order to determine their reproducibility from laboratory to laboratory'. He urged that the University of Cincinnati give serious consideration to checking these methods also since they have been found to be so useful by the Development Company. He indicated willingness to provide to the University of Cincinnati 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 with Mr. Shepardson on the above subject and he will give it further study in connection with Kettering's effort to develop an analytical tool. - 10 jraf-ia fhe Committee adjourned at 4?30 p.m.,-.after agreeing that the next RPA Committee meeting should be held September 24th, at the Conrad Hilton Hotel in Chicago, one day prior to the meet ing of the Medical Advisory Committee which is to be on September 25th. It was felt by most members of the RPA Committee that a meeting of the Subcommittee on Carcinogenicity prior to the date of the September Medical Advisory Committee meeting would not be necessary if the Subcommittee could handle its interim work by mail. Considerable duplication of presentation and discussion can be eliminated by having the Subcommittee make its report, including Dr. Horton's report, to the Medical Advisory Committee as a whole on September 25th. ROTE: During the meeting Dr, Horton distributed a sheaf of data sheets (copies mailed to MAC Members 7"16-52) on various mouse experiments which are to be included in the available data thus far submitted. Dr. Horton . , t indicated that he would present a series of data tables for the consideration of the full Committee at its meeting in Chicago. M. N. Newquist, M.D., Chariman - R. E. Ickardt, M.D. Acting Secretary COPT Dear c**, Bewquiat* In reply to your letter of Juno 3, 1952, Z advise that Z plan to attond tha noting of the subjoct committee commencing at 9)30 a.a. at the Kettering Laboratory in Cioolnnati* You nay wish to clarify to Beaters whether this be Daylight Saving Sim or Baatern standard Tlaa* , As an item for your agenda, Z auggeat a realiatie discussion of the hasarda of straight run, uncracked distillates and residua* Z fool this is an aspect of our wotk that must be squarely faoed. ( The large majority of eases of cancer of the akin from contact with petroleum products that have come to our attention have a history of contact with relatively non-visooua lubricating oil distillates* To name them) . 1) Hula skinners oancer in Great Britain - while there was an early history of use of shal oils, yet. such have not been used for smnjr 7earsf 2) Cancers of the scrotum in wax pressmen - these were confirmed by tests at Kettering to be due to the . pressed distillates} . 3) Cutting oils containing 94jC of 100* pals paraffin oil experiments at SYU on suoh oil from two different manufacturers both operating on Hid/"cootleant crude prodaoed oanoers in mioel - 4) An increasing volume of British literature at which the. recent paper by Cxulokshank and Ooureveitoh la an example} ) Roaors of more eases of oaneer ot cutting oil on the Pacific Coast - JMifio Coast representative may b# able to elaborate*, . While we have provan aa concerns aloe that ^ilioj} ' ally cracked products are much more carcinS*~* ye tL \tMA$ ( the fact that the cancers in man wa jag* straight-run products of the character indicated, .v y < i\ -2- 1 . Analytical techniques to estimate the order of potency of any given stream from any of the processes listed above. 2. Epidemiological appraisal of the incidence of cancer among employees of the petroleum industry, 3. Hygienic measures to reduce hazard to employees of the petroleum industry, 4. Dilution of carcinogenic oils as a means of reducing potential hazards to employees of industrial consumers of various petroleum products containing these oils. Plans for Investigative ffork for 1952 A. Process Samples for Animal Tests, '[ 1, Cracked residua from thermal cracking of virgin gas ' oils (samples to be collected). 2 /.o. 2. Sidestreams and residua from other cracking processes to be tested on a limited basis to improve analytical methods of estimating potency and further to test the validity of these methods (these samples already col lected, analyzed spectrophotometrically, and held in reserve in the laboratories of twenty-one of the par ticipating companies ), Untreated lube stocks from straight run distillation now being screened by analytical methods. Samples to be selected for animal testing on the basis of a com parison of their physical properties (including ab sorption spectra) with those of virgin distillates already tested. 1;. Scottish shale oil and fractions thereof. To gain further analogies between potencies to mice and (/'''^"potential hazards to exposed humans, two or three . fractions of shale oil comparable to those employed as spindle lubricants in the British cotton industry to be tested. (Samples already collected and held at Kettering Laboratory) Reference Standards. For control purposes and improvement of biological methods it is contemplated that tests on known concen trations of standard carcinogens in standard solvents will be carried out with about 9 percent of the animals received. Analytical Techniques for Estimating Carcinogenic Potencies of Petroleum Products. Chemical research will continue on the two main approaches to this goal, the empirical and the fundamental. Animal testing of fractions which can furnish useful information for this purpose will, as in the past, be given priority over tests on process samples. At the same time, it is recognized that an analytical tool has very limited sig nificance when based on an inadequate number of biological tests of samples of materials to which it is to be applied. Tests on non-carcinogenic fractions of various oils will be conducted to determine the effects of variations in the composition of these fractions upon the total effective potency of the oils. It is obvious that if fractions which do not contain polycyclic carcinogens are markedly affecting ( -k the rate of induction of tumors in the test animals, then any tool based purely on the concentration of polycyclics will be seriously limited in general applicability. D. Epidemiological Studies. Efforts to expedite the collection of case records and other pertinent Information on an Industry-wide basis will be continued. At the present rate of reporting, there should be sufficient accumulation of information by the time of the spring meeting in 1952 to permit a preliminary tabulation of the data. E. Experimental Study of Efficacy of Various Cleansing Agents and Skin Creams. As soon as the current tests which employ rinsing with white oil and washing with detergent solution have been completed, new experiments will be started to compare hydrocarbon solvents, such as technical white oil, with the viscous medicinal white oil currently employed as. a rinsing material. ' Further tests with other skin creams will be designed on the basis of the results of the current tests with Verex. F. Dilution of Carcinogenic Oils. Sixteen of the participating companies have already started or completed collection of representative production ^ blends containing carcinogenic streams from catalytic y'rv cracking or recycle coking, together with data on the com- ( osition of these blends. The majority of the members -5of the committee have evidenced their desire for an analytical tool applicable to these complex mixtures. Since it is obvious that no such tool could be developed without knowing the biological potency of at least a few of the blends, a selected group of these materials, on which detailed information is available, should be suojected to animal testing. November 26, 1951 ~y jy- Esso Research and Engineering Company fPOMMMMLT STAHDA*D OIL MmOfKr OOMPANTJ r, o, iti si, lisxn, *, j. MEDICAL NESEAftCH DIVISION M.ft. IMTMAM V. MVMO*tCC. CM t ` MCA* lMH*T1AL HTMfMT MCMACC . Mm. IM ft.. .. fWTMM C MMMlCOM. .. MC CUMCM. MMCAMCI Hortaber 2, 1955 Nr. 0. V. Stroop Aatrlc&n Petroleum Industry 50 V. 50th Street Hsv York 20, H. 1. Dear Mr. Stroop: I am attaching same information recently received from Sr. Bewquist who received it from our British associates in the field of petroleum cancer studies. I believe that the mnbers at the Medical Advisory Ccnolttee as well as those at the Kettering laboratory would be interested in reviewing the Progress Report by Sr. Carruthers and Sr. Cook, and also Progress Report by Sr. Woodhouse and Sr. Squire. I would appreciate it if you would have these reports duplicated for these individuals. I do not believe that the rest of the attached information would be worth-' while duplicating since it concerns only the agenda and minor changes in the nomenclature. Very truly yours. BXt:evn Sncs. MRC.55/830 C.55/815 MRC.55/814 KRC.55/804 R. X. SCKARST, N. S. Copy From D. V. Stroop For Information of Members of Medical Advisory Coemittee 11/4/55 MEDICAL RESEARCH COUNCIL "tteelaoulfioa* Pgr Snccifiod Circulation (liombors (rf Coanittoe) tC.55/830 C1M0. Ag.15 Casmlttoo on the Carotnogenle Action of Mineral Oils xsmai. for tho Nlnetccnth Mooting to to Raid at 25, Old Quean Streot, ?as*tinstor, London, S.W.I., on Tuesday, 25th October, 1955, at 11.15 1. Minutes of the provtous meeting (MRC .55/510, CUSO. ttin.18 - already 2. Amendments to nomenclature of oil fractions. A moaorandan (lC.5f/815> Cul!0.5J/6) fenclostirc A) 3. Sxponsos grant to Or, William S. Smith for testing oil fractions (Minute 155) A. Progress Reports ' (i) Chemical - by . Carruthors and J.J. Cook (im.SS/QUt., C1K0.55/9 (Enclosure B) (ii) Biologioal - by D.X.. foodhousa and J.R. Squire, Progress Report No. XV (MBD.55/0OA* CiMO.55/7 -(Bnclcroro c) 5. Future Plans 6. Any other business , 7. Ifcte of next mooting . MEDICAL RESEARCH COUNCIL "Unclassified" ?or Specified Circulation (itombors of Comnittoo) 'i Coranittoo on the Caroitioganic Action of tliuaiul Oils Nor.oncl.'.tnr- of ull Prictions It will bo rocalied that, at tho Bightuonth Moating of tho Caamitteo, tho standardisation of tao mwonclaturo of tho various oil fractions i discussad (ilinuto 152) and it was agrood that Professor Squiro and Professor Morton should considor this in tli*j light of ending symbols already ngrood (iilnuto 156). Profossor Squiro and Prefaasor Uorton now propose tho following anondoont to Uinuto 136. paragraph 4 lino 7: DBIUTB SUBSTITUTE wura split into aromatic (L) and ruffinato (R) portions* " wuro split into aromatic (A.) and paraffin xnffinato (P) portions." This amondnont and tho previous confusion of symbols call for anondmonts in tho following documents as 3hown: CXQ.55/2 and G1M0 55/6: for R road P GuM0.5it/l6; GU.55/3 and CW.0.55/4; for M, P and R road n, p and r. MEDICAL RESEARCH COUNCIL t "Unclassified" For Specified Circulation (ilembers of Ccmmittoe) Connlttoe on tho Carcinogenic Action of Mineral Oils Progress Report by ff. Carruthers and J.J7. Coolc The 1955-56 serios of animal experiments with the JCtmft.lt fractions are to bo carried out vrith fractions obtainad from tha actlvo non-piorute-forming material by chromatography and fractional distillation. For this purpose, tho five aon- piorato-forraing fractions K^SgdLr, K^S^mir, K^Kr, K^SgOlr, and K^Sgbdr have boon sopaxuted luto three main fractions by chromatography on altnlna by the general method outlined in tho last Report* The oil fractions, in batches of about 200 g,, were adsorbed on 2 Kg. of freshly activated alunina and successively elutod with petroloun ether, bonseno and methanol. Klutlan with os.ah solvent was continued until no more material was recovered, and three fairly well defined fractions obtained. Corresponding eluates from all the chromatograms were combined, and tho three canposito fractions sent to Professor Horton for fractional distillation. The total quantities of these fractions obtained wero us follows:- (l) putrolou.1 other oluato; 1977 g. (77/') yellow oil, (li) bonseno eluatoj 349 g. (13.5^) orango-yollov oil, (ill) mothonol oluato; 244 g. (9.5') blacx viscous gum with a strong unpleasant snoll. ' Tho ultra-violet absorption spectra of tho chromatogram fractions K^S^e.r 1, 11 and ill, and K^Syblr 1, 11 and ill, indlcato that fractions 1 and 11 are still complex mixtures of diffarant ring systems. In each o&se there la gon-l absorption -.7ith a fall of intensity toward tho long vnvolongth. The spectra of tr.o potroloun other oluatos (l) however, show two well defined at 234 aid 32b my. which p03~ibly indioate tho presenco of considerable amounts of dibensothiophon -orivativos in these fractions. Bxperlmonts are In progress thioh may lead to a 'ocisicn on tills point. In contrast to these, the spectra of the methanol eluatos Jill) exhibited wo11 dofined maxima at 243 , 292 and 318-355 mu./loir B^m; 4*9 4.3> 3-9, and 5.0, 4.5, 4.^7attributable to the presence of oorbasole derivatives. This is quite in seeping with tho difficulty of removing this matorial from tho chraaatogram. It is of intcrost in this connection that at loast one oarbosole ncmolo ;uo Imh b"<iu Isolated from a corresponding fraction In tha piuratu-formlng surLus. ' Wo are continuing our work vdth tho ploxnto-farming fraction* (|i). Thooo have al mo boon aubdlvldud by large-ocala chm>toflraphy, and m have Indiatod two other compounds frun th<t.n Ouo or thouo, front K^SjcApCl) had m.p, 64"06 and ms shown by itn elementary analyst r- and ultra-violet absorption spectrum to bo a trS.inuthyldlbonsothiophnu ^i^L> or ttn oqtilvnlen;., Attempts to denulpliuriso this oar.ipound with I'atiey r.iivul in boiling utfianul wire unnuoosesful* In tntihhyOrufurfutyl olochol dusulph urination mao achieved but naa oooonpnnlod by hydrogenation with foimtlcn of a. moro or loos completely hydrogenated diphenyl derivative which has not yob boot; Idontlflod. Tho socond compound, Isolated fran K^S^oAp(l) had m,p. 100 and waa shown to bo a derivative of phenanthrana by It# ultm-vlolot absorption npoctnmi. Elementary analyeoa of tho aubatnnoo and Ita s-trlnitrihousomi complex (m.p* 205-206) Indicated tho inolaottlar formula Cjgltjg for the parent hydrooarbon. Tha molting points of those two compounds, however, do not corrospend to those recorded for any known g pUonanthrone hydrocarbon or Its trinltrobonsono complex* In mnponao to n request by the Committee tho following Table has boon drawn up delineating tho compounds vhlch have so far bati isolated from tho Kunralt oil. Semnmfl liolfltga Kutootlo of 2:6- and 2:7- dlrao thylanthraoeno 2:6-Dime thylanthraoeno 2:7-Olraethylanthro cone 1 tO-Ditnothylphenmnlbrone Unknown trlmethyldlbonjcthiophen (or oquivalent) (m.p, 8if-86). Unknown tetra- or pento-ito thylfluorcnc (or equivalent) (rup. 198-199) 2:3:6-Tritao thyl anthruceno Molecular -Formula.. c16Hh. C16H1V C15V 0. C'A> 0ieV. 17i6 Molecular Tfclrht... 206 206 206 206 226 222 or 236 220 Urtrovn tri- or totramthyl anthraoeno (o.p. 108-110). Unknown tri- or totmocthylanthraoono (pup. 22V"225^) or %hi8 C17^ or ^ Unknown tri- or totra-Kothylanthraoono (nup. 169-170) . - or Cl^ " Cl^iB . 220 or 23V 220 or 23V 220 2% Structural --formilfl. *! o?a') m,<ixjoF>j 013 OOG?'3 fficS*"3 ^3-CH3 Fraction free phifh iyilAtyl K^SicAq, K^bAa, K^SLjAn* V2wpK^SghAp. GHjCOOb!13 \32wp- K^Sg&An, K^S^bAa* OOC5)^34 ^bAo. SCO jIS/ \SghfciB, J^bAn. 1i% hAn Cormonni lyolatod Holocular . Formula. 1!2:8-Trlrothylphun&nthrcno Unknown trlmothyl6 s 7-bonzothionaphthon C^6 C15HU3 1 >3:5:7-Totranothylanthraoono 1: J:6:7"To tranothylanthrn ocnc 2:3:6 * 7-To trtvsc thyl anthrr. oo no Unknorm tutrr.nothyl.nnlhreicoisc (nup. 67-69) iaPia ciaR.a 3l8Pt3 Unkncra tetiwacthylphenanthrono (rc.p. 103) C1618 1 -llothylpyreno C1712 Unknown totra- or pento - c1617h nothyloarbazolo (n.p. 1 fll#.--105'*^ or w Holocular __HsicSS. 220 226 234 234 234 234 234 216 223 or 237 Structural .gamma- Fraction from ctlioh iaolr-ty^. Wip* K436W`p* \37oAb V7ttn* l^SgoAn, K^3QbA.T. VaaAn* W*ru K^S^bfcn, K^S^nAa. \3jaAp. \S/Ap* lOtb Ootobor, 1955' ( MEDICAL RESEARCH COUNCIL "Unclassified" For Specified Circulation (Kenbers of Conaittee) ' OOUgTIEB ON THE CAHCINPC3NI0 ACTION OF MINERAL OILS Progress Report Wo.XV (Sept. 1955) Fran D.L. TTeodhouse and JSquire, Cancer Research Laboratories, and Department of Pathology, University of Birmingham, ;.!cdisaJ School. Testa carried out by D.L. Woodhouae (1954-55) The fractions have been oppliod to the rabbits for 45 nodes and to the mice for 40 weeks. The rabbit tumours arc given in Table I. tabu: i Fraction Wm w. Wo* W>" Habbit tumours at A5 weeks tumours Fraction tumours Fraction 0) 0 Wb (t) i Wr. (n) 0 WP (a) 2 Wp (f) 0 (m) 1 Wa* (a) 8 K4sgAb? (c) 1 VeV tunours (?) 4 (r) 2 00 5 (c) 7 W Wm (o) 1 (a) 0 Wp K4; 3pCAp 00 2 (9) 2 VA Wr 00 4 , () 3 Total V9 (1) 2 8 D(2) 16 (u) 15 S<4) 25 (i) 7 Mouse tusoura have appeared in the following mineral oil fractions, b (1); o (l)j k (1); 1 (2); m (1); p (l): Kioo treated with the weaker standard B(j) had 100# incidence of tumours by the 28th week. The stronger standard D( 2) had produced 100# of tinours at the end of 15 weeks. A complete return of all tuncurs with sites will be given on ( completion of tho experiments, i.e. after 52 weeks. r* n r r ^ r r ; t . / '"f f l V or;(O rrW 'r t%ffW'<>Tn v . I I IU>!l- t - i- T o -- - o r o m n - b o o r v r . 'n-- ----1i----------------------------r . . , , .------ . XP a'O L.7V . ULiZ----------------_____________'____'_______________ P . - :.-. v-"--.: '.'. ; .:r ' ' ' * . ' . *' '. : *.- . .. . Ii 'j V^Vr .'. "v,i = ' " *.: C i: S !l m k s, r'ri S 9.6 99.1 *9.9 99.99\ $9.f *. Copy Prom D. V. Strocp For Information Of Member* of Medical Advisory Committee and Staff Members at Kettering Laboratory February 7, 1955 ESSO RESEARCH AND ENGINEERING COMPANY F. 0. Box $1, Linden, H. J. February 3, 1955 Mr. D. V. Stroop American Petroleum Institute 50 West 50th Street New York: 20, New York Pear Mr. Stroop: I am attacking recent minutes of the Committee on the Carcinogenic Action of Mineral Oil of the Medical Research Council of Great Britain. I believe that these minutes vould be of general Interest to the members of the Medical Advisory Committee of the API and vould appreciate it if you vould have them duplicated for such distribution, and also to the members of the Kettering Laboratory. Sincerely yours, /s/ R. E. Eckardt R. E. ECKARDT, M. D. REE:ilk Enel. - MRC.55/53 CAM0.Min.17 For Specified Circulation (Committee Members) MEDICAL RESEARCH COUNCIL HRC.55/ 52 CAMO.55/1 Committee on the Carcinogenic Action of Mineral Oils The meeting of the above committee vlU be held at 2.30 p*m. on Monday, 2nd May, 1955, at 38, Old Queen Street, Weatmlnater, London, S.V.l. The Agenda will be circulated in due course. J.C.R. Hudson, Secretary 20th January, 1955. c MEDICAL RESEARCH COUNCIL For Specified Circulation (Committee members) MRC.55/53 CAMO .Min.17 COMMITTEE ON THE CARCINOGENIC ACTION OF MINERAL OILS Minutes of the Seventeenth Meeting, held at 38 Old Queen Street, London, S.V.l, on Friday, 17th December, 1954, at 2.30 p.a. Present: Professor T. Ferguson (Chairman), Colonel S.J.M.Auld, Professor H. N. Green, Dr. T. Helger, Dr. J.O. Irwin, Professor J.R. Squire, Dr. D.L. Voodhouae, and Mr. J.C.R. Hudson (Secretary). Attended: Dr. V. Carruthers, (representing Dr. J.V. Cook) and Professor D. Hey. Apologies for absence were received from: Dr. J.V. Cook and Professor F. Morton. 1. Minutes. ' The minutes of the previous meeting were approved and signed. 2. Progress Reports A. Progress Report No.XII by Dr. D. L. Voodhouae (MRC.54/854, CAM0.5V12). It was pointed out that the standards, D and D^, were usually of about the same potency on rabbits as the fractions being tested, whereas they were more potent on mice than the oil fractions. It was therefore agreed that, in order that the standards should have approximately the same potency as the fractions under test, the standards used in future mice experiments should be d and a more dilute solution, say, Dl/20. B. Progress Report by Dr, V, Carruthers and Dr. J.V, Cook " (MRC.54/875* CAM0.5V16) Dr. Carruthers pointed out that the Di-methyl, tri-methyl and tetra-methyl anthracenes were being isolated from the lower medium and higher boiling fractions. This tended to confirm the effectiveness of the original distillations. Many of the compounds which were being isolated from the varlo\as fractions were found in only milligram quantities. If, at a later stege, it was desired to test their carcinogenicity, it might be necessary to synthesise some of them in greater quantities. Professor Hey said that be already had comparatively large stocks of many of the synthetic methylated anthracenes and he would be willing to make these available if they were required. It was pointed out that the percentage extraction of the M.P.R. subfraction given in Table I did not add up to 100$. This was due to losses in the process of separation and allowances for this had been made in calculating the blends given in Table II. 1 Colonel Auld asked tf, in view of the spread of results amongst the fractions tested biologically, the chemists vere satisfied that the methods being used could give sufficiently discreet separations. In this respect Professor Eey suggested that molecular distillation might give a better separation of small quantities. C. Dr. Irvins Report (MRC.54/887, CAMO.54/19). Dr. Irvin pointed out that comparison of statistical results from year to year and between Birmingham and Leeds showed a reassuring reproducibility. D. Professor Morton's Report. It was noted that lagunlllaa fractions vere being prepared and would probably be available for biological testing to Professor Green when he was ready. 3* Possible Carcinogenicity of Diesel Exhaust Fumes (Minute 138). The review of Research Group Ho.2 of the Institute of Petroleum was circu lated (CAMO. 54/13). The Secretary read a letter from Mr. E.T. Priddle offering the assistance of C.A.V. Limited in any investigation relating to Diesel exhaust fumes. In addition. Professor ley said that a Diesel engine in the Engineering Department of King's College, London, could be made available similarly. The Committee agreed: (i) that in view of their own research commitments, which could be expected to last another 2 or 3 years, they could not undertake any research on this subject. - (li) to recommend to the Council that, as the exaust fumes from internal combustion engines are particular components of atmospheric pollution, their study might be referred by the Council to the Committee concerned with that subject, or to an ad hoc Committee; the members of this Committee specially interested in Diesel fumes would be glad to cooperate in the work so far as possible. The Chairman undertook to write to the Secretary of the Council along these lines. . 4. Future Work. Professor Green said that his biological experiments on mice and rabbits would have run for 52 weeks at the end of a further 4 weeks and 6 weeks respectively. (Professor Green left). Dr. Woodhouse said that his biological experiments on mice H rabbits been running for 6 weeks end 9 weeks respectively. It was noted (see Minute 2, D above) that Lagunlllaa fractions, which Pro fessor Morton had prepared, vere ready for testing by Professor Green. It was pointed out, however, that the preliminary experiments had shown that the Lagunlllaa fractions vere most potent above 390C., which was beyond the limit of the Stedman still. Professor Squire undertook to ask Professor Morton to include in the batches which he sent to Professor Green a fraction or residue boiling above 390C. 2 (Subsequent note: Professor Horton proposes to obtain a Fraction 9, boiling above 390*C. by laboratory distillation of the Lagunlllas residue. Ibis vill provide Professor Green with eight Lagunillas Stedman fractions and one more (L^ Sl-fiA and 14^.9), another nine aromatic extracts of these Sl-8 and Lj. 9A), and the pooled rsfinates (L4. S.R.). With the two standard solutions of 9:10 dimethyl 1:2 benzanth racene, Professor Green will thus have 21 materials for his animal tests.) 5. Possible Carcinogenicity of Anti-Foaming Agents. The memorandum (CAM0.5^A5) vas received and the Secretary added that further enquiries had elicited the following additional information from Shell Chemicals Limited: (1) that the anti-foaming agent was to be added to the sewage in the pro portion of 3 parts per million; (11) that there was no evidence of an oil film on the surface of the settling tanks and it was therefore thought that the majority of the anti-foaming agent was carried down with the sludge. The Committee therefore agreed: a) that those employed at sewage works might be exposed to some hazard in handling the anti-foaming agent and that this aspect of the question might be referred to the Occupational Health Committee; and b) that it represented a negligible hazard as far as the general population was concerned. 6. Exhaust Filters on Internal Combustion Engines. Professor Squire mentioned that in a television programme called "Panorama" a Mr. William Wyness had demonstrated a filter for attachment to the exhausts of internal combustion engines which, it was claimed, removed particulate matter from the exhaust. The Committee agreed that this fell outside their terms of reference. 7. Conference on Atmospheric Pollution. l Colonel Auld reported that the Institute of Fuel was proposing to hold a conference on Atmospheric Pollution at the Institute of Civil Engineering on the 20th January, 195? under the Chairmanship of Dr. Foxwell. Professor Ferguson said that he would try to attend that Conference and it was suggested that representatives of other Committees, for example the Atmospheric Pollution Committee, might also wish to attend. 8. Date of Next Meeting. In the absence of Professors Cook, Green and Morton, it was suggested that the next meeting might be held on Monday, l8th April, Thursday, 21st or Friday, 22nd April, 1955 at 12.30 p.m. The Secretary was to ask the absent members to Indicate which dates they preferred. -3- Esso research and Engineering Company I^OIMiltr MTANOABD Oft DCVCLOPMCNT COMPANY! |. O. KOI II, LlNORN. N. J. IfCOf&U JtCSEAJtCH DIVISION MW1 % IOlMor H.O. 4MCTOH ItATMAM NtNDt.dl, CH.C MCAD IMOUmnAI. NVflWIlf rox(CocofrmcaoHtHIACC m AtMAMCHt. PM.O., MtfTOASfO m. MNNIMN. M.D CMItr C^iWlCAC MIIAICN PHTAJCISN November 1$, 1955 Mr. 0. V. Stroop American Petroleum Institute 50 Vest 50th Street Hew lork 20, Hew Tork Deer Mr. Stroop: Enclosed is copy of the Minutes of the Meeting of Research Ho. 2 Committee of the Institute of Petroleum, end copy of the Progress Report of the Committee on the Carcinogenic Action of Mineral Oils of the Medical Research Council. Please hare these duplicated for distribution to members of the Subcommittee on Carcinogenicity of the API, and to the interested individuals at the Kettering Laboratory. Very truly yours. RZBtnak Enos. 2 R. E. BCKARDf, M. D. Copy From D. V. Stroop For Information Of Members Of Medical Advisory Committee 11/17/55 ( MEDICAL RESEARCH COUNCIL "Unclassified" For Spoclflad Circulation (Usmbar* of Cocnalttoa} " ifflC.55/BlfO CiUO.55/10 Sangit.ttj.o._on tho Carclnogenlo Aotlon of Blnera! 011 Progress Report HJJ, Croon and K.J. Rodollffo Dopartmont of Experimental Pathology and Canoor Hesse,rch School of lisdioins, Loads. Moubo Experiment. Fractions usedt- *a ** Lj'S.jA * o o.oI'/jD.u.b. - a(Vio) LjS^ o O.O&.1D.H.B. d(-j) f L^SR - g . ' \slf " h W-l LjSj/L - 3 - L4S0^ " k Tho experiment ms begun on 7*6.55 Tumours have boon prodaged as follow*:- I b (L^S^l) 3 tuaours, at 9,13 and 18 weeks, c (l^A) 2 tumours, at 13 and Ilf weeks d(Vlo) (O.Ol;jD.H.B.) 1 tumour at lif weeks f (O.OSiD.U.B.) 9 tumour.*:, 1 at 1-1 weeks, 2 at 14 weeks, 2 at 16 weeks and 4. at 18 weeks 1 (L^SyL) 3 tuaours, 1 at 17 weeks and 2 at 16 weeks k (L^Sgl.) 1 tumour at 18 weeks. Survivors at 18 weeks are as follow*: - a 45 b 32 o 39 dd 3355 e 20 f 44 e 29 h 29 l1 2211 3.139.19 k 17 ( .1 Thia *i bagim on 25*6.55* Jbo baginaiaf <* ** ojq>arl*ai*t i dalayad owing to a apidacsto of paatnoel* aaicnjat tba sabbita, Flra zabbita hava died alnoa tha aapariaant baguu So far bo twoura haw* boon produoad. (Tha dilution# of DJI.S. tor mbbtta an 03-> and O.QSi). ( INSTITUTE OP PETROLEUM BES-2-16 RESEARCH NO St COMMITTEE Minutes of Meeting No*15 hold at 26 Portland Plaoe On TuoJdflY.20-9-5S . ' ATTENDANCE ' - - IN THE CHAIR: QUEST! MEMBERS! APOLOGIES FOR ABSENCE! SECRETARY: Ft Marton. . P.H.3. Trasler '7.S i Ault J.N. Hareanapo R.B. Killingsworth pohi K.W. Stevenson E.J. Boorman X.W. Cook E*J* Dunstan A* MeLoan E. Herbert 1. MINUTES OF MEETING HO.18 ( These were signed as\correct, oubjeet to the addition of "Shell Patrolour^jpo.," at the beginning of line 3 of the last paragraph-of Minute 3 - I (Page 2) 2. MEMBERSHIP The neeting aocopbed the resignation of Hr. W. Pohl with regret and desired to reoord its thanks to him for hl3 valuable services. The nomination of Hr. H.W. St ovens on was approved by tlte Committee, who were glad to welcome hir. baok as a Member. . I 3. WORK AT BIRMINGHAM UNIVERSITY The Chairman reported on the progress of work at Birmingham University and drew attention to the paper The Constitution of Petroleum Fractions! Structural Group Analysis of a Kuwait Heavy Gas Oil" whlo'1: was presented at the recent World Petroleum Congress, and to various documents circulated by the MRC, in particular MRC 65/510 CAMO Minute 18 and CAMO 65/5 The Chairman distributed tables (dated September 20th 1955) of Analytical Data on Kuwait, Lagunillas and Oklahoma Crude Oils and mentioned that work in connection with Table 5, Sub-fractions from aromatic extracts, was now being carried out at Glasgow. The results indicated a very considerable potency concentrated in residues. There were small quantities of Kuwait Qrude left overt it was proposed to blend fractions K4S2Aa/K4S5Ab and K4S6Aa/K438Ab and then redistil the blends for further test. ( 2 Thera would also be available some samples prepared from a Commercial Extract supplied by the Isle Grain Refinery. The Chairman mentioned that the Langunillas teats were a year behind owing to the with drawal of the Chester Beatty Indltute. This work was being carried on by Professor Green of Sheffield/Leeds University, but no medical school had been found to take an interest In the Oklahoma Crudes, whioh were therefore, being stored in their fractionated state. Professor Morton added that he would prepare for publication in the IP journal a further paper in continuation of that presented at the World Petroleum Congress. 4.DIESEL GASES FUMES The Chairman thanked Dr. Jdlilngaworth for the material whioh he had provided for the report to the MRC and referred to a letter dated the 14th December 1954 from Mr. A. Pogg of MIRA, in which,on behalf of the Diesel Engine Manufacturers, the IP were asked to draw attention of the major petroleum companies to the necessity to carry out investigations with the objeot of eliminating any exhaust smoke which might be attributable to fuel variations. It was agreed that a general interest In the problem, which was separate from the nedioal aspect of smoke, was indicated but that It was a matter more for the Research Committee. Mr. Ault who promised to raise the subject at the meeting of MIRA which he was attending the next day was invited by Professor Morten to the next meeting of the Research Committee* ' 5. ABY OTHER BUSINESS The Chairman intimated .that he vould kiortly provide for. circulation a copy of Mr. A.7/.E. Poll's Thesis. 6. DATE OF NEXT MEETING To be arrangod by the Chairman.