Document B5NR3qz4LwV5rJbmO8dg8J1XJ

MINUTES OF THE MEETING OF THE SUBCOfflUTTEB ON CARCINOGENICITY Held at the Blackstone Hotel, Chicago , Friday, September 27, 1957 A meeting of thd Subcommittee on Carcinogenicity of the Medical Advisory Committee of the American Petroleum Institute was convened in Dr. R. E. Eckardt's suite at the Blackstone Hotel at 9*30 a.m. on September 27, 1957. The full. Subcommittee wns in attendance, plus Mr. Paul Halley of the Standard Oil Company (Indiana) as a guest. * The Subcommittee discussed preliminarily the work at the^ lettering Laboratory and wishes to point out that work now being performed by Dr. Horton is far more fundamental in nature than was originally anticipated by the Subcommittee. For this reason the Subcommittee believes that its decision to discontinue sponsoring this research under its direction has been a correct one, and the Subcommittee plans to continue with the recommendation that this work be discontinued as of July 1, 1959. However, the Subcommittee does wish to point out that there are fundamental aspects in the petroleum chemistry now being conducted by Dr. Horton, which might warrant a continuation of this type of research, either at Kettering Laboratory or some other laboratory, under the sponsorship of the Committee for Fundamental Research of the API. The method ology now being pursued by Dr. Horton is primarily chemical in nature rather than biological and might therefore well be considered by the Committee for Fundamental Research. In addition, the Subcommittee discussed in a preliminary fashion, the possibility of suggesting to the MAC that Dr. Kehoe be put on a retainer fee at the conclusion of the work at the Kettering Laboratory on July 1, 1959, in order that Dr. Kehoe might attend all meetings of the MAC and offer us his advice and guidance in some of the problems which the petroleum industry is facing new and might face in the future. It is the Subcommittee's belief that Dr. Drinker's attendance at and participation in the affairs of the MAC have been highly worthwhile and if Dr. Kehoe were willing to accept such a retainer agreement, Ms participation In the affairs of the MAC would also be worthwhile. At 11 a.m. the group was joined by Dr. R. A. Kehoe, Dr. A. W. Horton and Dr. J. J. Phalr of the Kettering Laboratory. Dr. Horton began by presenting a progress report of the work at the Kettering Laboratory during the past five months. He indicated that all the experimental work for the past five months has been in the field of analytical methods. He divided this work into two sections r that work done on carcinogens and that work done on accelerators. Carcinogens To date the work of the Kettering Laboratory suggests that the most significant carcinogens in petroleum oils are polycyclic aromatic compounds, most hydrocarbons. ApI 06389 SC-API-2940 f -2- He emphasized the difference in concept between the basic carcinogenic potency of an oil, which is that due to the presence of carcinogens vs, the actual carcinogenic potential of the oil, which is the carcinogenic activity resulting from both the presence of carcinogens and of accelerators and inhibitors. He indicated that certain data developed at the Kettering Laboratory have suggested that some sulfur compounds may act aa accelerators but that they only do so in the presence of other accelerators. Thus, if there are sulfur-containing accelerators they would not be active as accelerators in the absence of hydro carbon accelerators. Present data at the Kettering Laboratory indicated that the accelerators are probably long*ehained hydrocarbons. Suggestive evidence at the Kettering Laboratory indicates that there may be Inhibitors present in petroleum oils. These inhibitors do not inhibit the carcinogens, but rather inhibit only the accelerators. This evidence has arisen from some work done by the Kettering Laboratory with two different white mineral oils which were used as diluents of accelerators. It Is important to enphasize that these Inhibitors are inhibitors of the accelerating action, rather than Inhibitors of the basic carcinogenic activity due to the carcinogens. In the past five months almost all of the work dene by the Kettering Laboratory on carcinogens has been done on what they have previously Identified In the April 1957 report, as 3 l/2-riag aromatics. These consist of pyrenes, fluoranthrenes, cyclopentanophenanthrenes, and benzfluorenes. Dr. Horton believes that these 3 l/2-ring aromatics are probably the most important class of car cinogens in most petroleum oils. The work has been done principally on API-8 and fractions of API-8, as diagramatioaHy indicated in the attached diagram, Deseriptivly, API-8 was subjected to a theoretical 80 plate distillation. Examination of the 660*F fraction suggested that only 0.001# of carcinogens was present in this fraction but that it contained a very high concentration of accelerators. This evidence is supported in part by the fact that tumors appear rapidly but only at a vexy low total incidence of tumors. Following the work on this fraotion. Dr. Horton next concentrated his attention on three fractions which boiled in the range of 730"F to 760*F. These fractions contain vexy little accelerators. These three fractions were subjected to maleic anhydride treatment in order to remove the anthracenes and their derivatives. Testing suggested that ,03 out of .21 of the carcinogens present In this fraction was due to carcinogens of this type. Roughly, therefore, 1/7 of the basic carcinogenic activity of these three fractions is due to anthracenes and their derivatives. The raffinate from the maleic anhydride treatment of these three fractions was next combined and chromatographed, and two fractions were obtained, one of which contained the benzfluorenes and experimental work has suggested API 06390 -3 - that these are unimportant in the total carcinogenicity of these three fractions. The other fraction contains the remaining three classes of carcinogens, namely, pyrenes (and their methyl and dimethyl derivatives) qrclopentanophenantl'renes, and fluoranthrenes(principally the dimethyl derivatives). At the present time. Dp. Horton is working on the separation of these three types of aromatic hydrocarbons in the raffinate from the maleic anhydride treatment of the 730*5" to T60*7 cuts of API--8. This is being done by liquid-liquid partition between 99% sulfuric acid and iso-octane at -30*7, Dr. Horton says that this treatment will separate the pyrenes from the other two classes of compounds. The raffinite of this extraction then is chromato graphed and treated with picric acid which m^y-lead to the separation of the cyclopentanophenanthrenes from the fluoranthrenis* ' Dr. Horton did indicate that of seven oils carried through the maleic anhydride extraction step, only one was found to have much benzanthracene which contributed to carcinogenic activity. This one oil was from a coker gas oil (API-33) In which 7/11 of the basic carcinogenicity was due to benzanthracene-type compounds. This contrasted with other types of oils In which only 1/7 of the basic carcinogenicity is due to this type of compound. In work which Dr. Horton did with a thermally cracked, cat cracked, oil he found that the benzpyrene and li-rlng carcinogens almost doubled in concentration*' but the activity of the oil decreased. This result might be due to the destruction of accelerators or to the destruction of the 3 l/2-ring carcinogens. It is Dr. Horton's belief that possibly this reduction in activity is most likely due to the destruction of the accelerators rather than to the destruction of the 3 l/2-ring carcinogens. Accelerators At the present time. Dr. Horton is following dues which have been provided for the presence of inhibition of accelerators in petroleum oils. He believes that these inhibitors probably fall into a class of compounds referred to as polycycloparaffins. These have essentially the same structure as the aromatic carcinogens except that they are saturated compounds. In partial support of this, Dr. Horton pointed out that Zechmeister and Kotin reported about a year ago in SCIENCE, that hydrogenated aromatics inhibit sarcoma production when injected subcutaneously. However, they used etlyl laurate as a solvent for their carcinogens and ethyl laurate would be expected to be a highly accelerating solvent. Therefore it was not clear from their work whether they were inhibiting carcinogens or inhibiting accelerators. It is Dr. Horton's belief that the Inhibition they observed is most likely the inhibition of the ethyl laurate as an accelerator rather than true inhibition of the carcinogens. API 06391 "s -u- In'discussing the so-called preconditioning of an animal by accelerators, it is Dr. Horton's belief that this occurs through an accelerator "setting up" the animal for other accelerators. In other words, preconditioning does not .precondition the animal for carcinogenic activity but only for accelerating , activity. Support for this belief is contained in the fact that if the ' animal is painted with an oil essentially free of accelerators following ' preconditioning it is not possible to demonstrate the preconditioning effects, but if an oil high in accelerators is used after the preconditioning treatemebt, the preconditioning effect can be demonstrated. The whits oils being studied by Dr. Horton for so-called inhibiting effects (principally API-80) are free of n-parafflhe. They contain some iso-paraffins and condensed cycloalkanes which represent the greatest amount of material present. The suggestion at the moment, therefore, is that these condensed cycloalkanes are inhibitors of accelerators. In an attempt to separate these Inhibitors from other compounds present in the white oils. Dr. Horton is going to use distillation, thiourea separation, and liquid thermal diffusion. In addition, he may possibly consider the use of molecular sieves. Dr. Horton submitted his Interim Report on his work dated September 26, 1957 which was distributed to the Subcommittee at this meeting. Epidemiology Next, Dr. J. J. Phair gave a progress report on the epidemiological work. Dr. Phair indicated that he had completed the coding and punching of the cases. In this process he felt it necessary to discard some cases since the information contained on the report was inadequate. Hence, the total number of cases reported in his final report will not be the same as in previous reports from Dr. Phair. At the moment, the status of this final report is that the intro duction, the objectives, and so forth have already been written up and the data tables are now being prepared and the comparisons and correlations will be made. It is hoped by both I*. Phair and Dr. Kehoe that this final report can be made available to the Sibcoradttee by the first of the year. In Dr. Phair* s work he pointed out that in the cases occurring after 1950, 28% of the tumors have been found to be skin tumors, whereas, only 15*3% of the cases prior to 1950 were skin tumors. In general population figures available, l6.6 tumors are skin tumors. Whether this Increase in the relative number of skin tumors in the post-1950 group of cases is significant, is not now known. Dr. Phair is at present making age, geographic location, primary site and occ upational-group breakdowns of the cases which he analyzed. API 06392 Following Dr. Fhair's presentation, the Subcommittee discussed in private with Dr. Kehoe certain phases of the relationships between the Subcommittee and the Kettering Laboratory and it was concluded that these relationships remain on a friendly, amiable, and professional level. The Subcommittee meeting broke up at approximately U p.m. on September 27, 1957 without having set a date for its next meeting. v. 4 R. E. ECKAHDT, M.D./cJh Chairman, Subcomlttee on Carcinogenicity October 1, 1957 Attachment API 06393 API-3 80 Plate Distillation Nr 660 fraction ,001j carcinogen. Mach accelerators Tumors appear rapidly bat at low incidence 730-760 (3 fractions) little accelerators Maleic* Anhydride of the 3 cuts----------- > anthracenes \ and their derivatives -- .03 out of .21, i.e., 1/7 Raffinate i Chromatographed------------ > benafluorenes (uninportant) Pyrenes - methyl & dimethyl Cyclopentanophenanthrenes Fluoranthrenes - dimethyl derivatives Now working on separation of these 3 hydrocarbons l Liquid-liquid Partition between 99% sulfuric acid and iso-octane at -30* separates pyrenes from other 2 v Raffinate 'V Chromatography & picric acid API 06394 MINUTES OF THE MEETING OF COMMITTED ON CARCINOGENICITY Held In the Conrad Hilton Hotel in Chicago' '.... " Wednesday, November 13, 1957 The Subcomraittee on Carcinogenicity held a meeting at the Conrad Hilton Hotel in Chicago at 9 a.m. on Wednesday, November 13, 1957. The following members were in attendance: E. W. Adams C. H. Hine, M. 0. E. K. Linder, M. D. M. N. Newquist, M. D. A. C. Pabst *\ R. E. Eckardt, M. D, - Chairman . In addition, the following individuals attended the meeting as guests: R. D, Bent Lamson Blaney, M. D. t. F. Boys, M. D. C. T. Brown R. C. Cole L. E. Curtis, M. D. T. M. Frank, M. D. H. W, Gerarde, M. D. N. J. Gothard J. H. Hege, M. D. R. M. Landon B. B. Reeve, M. D. F. J. Sanders L. J. Wade, M. D. . The purpose of the meeting was to discuss the report of the Subcommittee to the MAC that afternoon. In addition to the three points mentioned in the Chairman*s letter to the Subcamnittee, it was decided to add a fourth point) namely, that the Subconmlttee solicit comments and criticisms from all members and advisors of the MAC about the outline of the final report of the work at Kettering Laboratory which was attached to Dr. Horton* a Interim Report dated September 26, 1957. The Chairman of the Subcommittee then sumnarlzed for those in attendance the present status of the wax situation. Briefly, the situation is that a Mr. Kellogg of the Milk Industry Foundation in Washington had collected liO wax samples from dairies which he had forwarded to Dr. Hueper. Twenty-four of these were forwarded to Dr. Shubik and TJV absorption data on these 2l samples obtained by Ik*. Shubik's chemist indicated that the UV absorption at 290 millimicrons varied from O.OU to infinity. From one sample, in which the total absorption at 290 had been greater than 3.0, he chromatographed and isolated k micrograma of 1,2,5,6-dibenzanthracene API 06395 -2- per gram of wax. It was the considered opinion of Dr. Shubik that he believed this quantity of the known carcinogen, 1,2,5,6-dibenzanthracene, in n&lk carton wax is undesirable and that the petroleum industry should establish an immediate standard which does not permit this much carcinogen in the finished product. Long range work then would attempt to establish a standard based upon biological testing. ' ' In discussions which the Chairman had with Dr. Hueper at the recent Lung Cancer Workshop at the American Cancer Society, Dr. Hueper indicated that he was willing to sit still as long as the industry was willing to approach this problem with a reasonable, rational attitude, and 'as long as he was kept informed of the results of any work which was done. The Chairmanvindicated to the Subcommittee that the Three-Man Wax Cosmittee appointed by the Medical and Health Committee of the Board, had met in Chicago on October 2U and unanimously recommended to the Medical and Health Coimdttee, that work be done on waxes to the extent of approximately $100,000 a year for the next three to five years in Dr. 3iubik's laboratory. Copies of the report of the Three-Man Wax Committee will be made available to the members of the MAC through Mr. E. 0. Mattocks' office of the API. The meeting was adjourned at approximately 101 30 a.m. , i / R. E. ECKARUT, M. D./cjh Chairman, Subcommittee on Carcinogenicity November lU, 1957 API 06396