Document Mw6gJY7Ze1m98Ew73nQ7eQnj

FILE NAME: Oil Industry and American Petroleum Institute (API) DATE: 1945 July 2 DOC#: API054 DOCUMENT DESCRIPTION: Unpublished Report from Shell Oil Co. - Carcinogen Hydrocarbons and Related Compounds - A Lit Review FOH INFORMATION ONLY - NOT FOR PUBLICATION A CONTRIBUTION OF INFORMATION TO MEMBERS OF THE A.r.I. I ^ I C A L ADVISORY COHTTTEE SHELL OIL COMPANY. INCORPORATED WOOD RIVER RESEARCH LABORATORIES REPORT NO. M-12^7 JULY 2, I9U5 SUBJECT: CARCINOGENIC HYDROCARBONS AND RELATED COMPOUNDS' A LITERATURE REVIEW AUTHOR: H. H. ZUIDEMA t 911230 BinEulM 01927 Exportation of This Report Is Subject to License Under the National Defense Act SHELL OIL COMPANY, INCORPORATED WOOD RIVER RESEARCH LABORATORIES REPORT NO, M-12U7 JULY 2, 19^5 SUBJECT: CARCINOGENIC HYDROCARBONS AND RELATED COMPOUNDS A LITERATURE REVIEW AUTHOR: H. H. ZUIDEMA Industrial cancer was first recognized in England in the latter part of the eighteenth century, when it was established that chimney sweeps were particularly liable to cancer of the scrotum.10 This was caused by soot. Progress in this field of study was very slow at first, and it was not until 1915 that two Japanese investi gators announced the first case of carcinoma in an experimental animal. They produced first papillomas and then true cancer of the epidermis on the ears of rabbits by painting with tar over long periods of time. 35 During the thirty years that have elapsed since that discovery, a great doal of work has been done with various coal tar and petroleum fractions and pure compounds either occurring in these fractions or prepared synthetically. Numerous species of tost animals, including mice, rats, fowl, rabbits, and dogs have boon used, and many methods of application, including oral administration, intramuscular, intravenous, and subcutaneous injection, and painting on the skin. The method that appears to be the most widely used at present consists of painting.a solution on the skin of a special in bred strain of mice. Mice are preferred over animals having longer life-spans since they respond more rapidly. The special strains are used to increase the precision of the test. Painting is preferred to other methods of application because there is less likelihood of interference by simultaneous spontaneous carcinomata. The carcino genicity of a given compound is influenced by many factors including the genetic constitution of the animal species and strain, its age and sex, the diet, the physical condition of the animal, the purity of the compound, the dose, the physical state of the compound, the solvent used, and the route or site of application.2 5 / While carcinogenic properties are generally associated with certain polynuclear aromatics and their derivatives, there are many substances entirely unrelated to these compounds which have been re ported as having similar cancer-producing ability. Among these may be mentioned asbestos314'37 , inorganic compounds of arsenic and of zinc2 5 , aqueous potassium hydroxide and aqueous hydrochloric acid25, ethyl alcohol2 5 , glucose25, fructose25, and a number of nitrogen compounds, most of which contain one or more benzene rings25. Radio active elements and compounds are not included in this discussion since the mechanism of their producing cancer is probably quito different, i.e., physical rathor than chemical. Materials which have been reported ' 911230 BinEulM 01928 Report No. M-12^7 2 as carcinogenic and whose carcinogenicity is probably due to the presence of polynuclear aromatics include coal tar and pitch26,27 blue shale oil5, mineral oils and asphalt46, tobacco tar39, tars obtained in the destructive distillation of tea42and coffee110, diesel fuel52, distillates from Borneo crude petroleum5'4, combustion gases from fuel oil41, the SOo extract from a spindle oil produced from a paraffinic crude petroleum54, the products obtained by heating acetylene, isoprene, yeast, anon-carcinogenic petroleum fraction, or human skin to 700 - 900C-3o , and the products obtained "by treating acetylene, xylene, naphthalene, or tetrahydronaphthalene with aluminum chloride31. The carcinogenicity of tars produced by heating various substances tends to increase with increasing temperature.30. It is probable that tho carcinogenic hydrocarbons present in certain coal tar and petroleum fractions were to a large extent formed during the process steps and were not present in the coal or crude petroleum from which they were derived. However, the carcinogenicity of a given fraction depends upon the source as well as the method of processing. According to the Manchester Committee on Cancer49, the following order of increasing carcinogenicity prevails: Russian, Pennsylvania, Texas, Mid-Continent, Mexican, California, Persia, Romanian, Borneo, Venezuela, and shale. This corresponds roughly to the order of increasing aromati city. A large number of compounds have been tested for carcino genicity. Hartwell has published a survey25 which includes 696 compounds tested. Of these, lh6 were carcinogenic, and 23 additional ones produced papillomas but no time cancers. While some of these compounds have been tested under only one or two sets of conditions, others have been studied very extensively. The three compounds that have received the most detailed study are the three derivatives of 1 ,2-benzanthracene: 1 ,2,5 ,6-dibenzanthacene, 3 >^-benzpyrene, and 20- methylcholanthrene. All throe arc potent carcinogens. It has been estimated that they have been investigated in 60 different labora tories. 20 A list of most of the known carcinogenic compounds is given in Table l,pagoe 5-30. Structures, complete with numbering systems, are included, since lack of uniformity among various in vestigators in this field has led to some confusion. There is fortunately less deviation in the current papers than in the case of those written ten to fifteen years ago. The numbering used in this report corresponds to that used by Hartwell25. It should be understood that the carcinogenicity of the compounds shown in Table 1 varies considerably in degree and that the results have been verified by several laboratories in some cases whila in others tho results of only one or two experiments are available. The reader Is referred to Hartwell for more detailed information and for re ference to the original experiments. It will be observed that most of the compounds are either hydrocarbons or their derivatives containing at least three benzene rings or nitrogen compounds containing at loast two benzeno rings. More specifically, the first 0192 of these classes consists, with only three exceptions, of derivatives <11230 BinEulM Eeport No.. M-12kj 3 of phenanthrene. The exceptions are tetraphenylmethane, triphenylbenzene, and triphenylethylene. In Table 1 the hydrocarbons are subolassified further as derivatives of 1 ,2-benzanthracene, 3 ,^-benzpyrene, cholanthrene, and other derivatives of phenanthrene. Examination of the structures shows that all of these are derivatives of phenanthrene. While the work that has been done on the production of cancer by exposure to various compounds has made it possible to draw certain conclusions regarding the effect of chemical structure, it Is not as yet possible to predict with any degree of certainty the carcinogenicity of a given compound from its structure. A phenanthrene derivative may or may not, for example, be carcinogenic depending upon such factors as the length of an alkyl side chain, the position of a benzene ring, or the position of an alkyl group. However, a paraffinic or naphthenic hydrocarbon or one containing only one or two bonzeno rings may with a reasonable degree of confidence bo assumed to be non-carcinogenio. The amount of compound required to produce an experimental cancer on a teat animal is surprisingly small. Doses of 1,2,5^6-di- benzanthracene and 3 -benzpyrene as small a3 2.5 and k micrograma, respectively, give-positive results when applied to mice .^-^Discontinuous application, e.g., onco a week, of a given total quantity of material is moro effective than continuous exposure.15 A single application of 20mothylcholanthreno in 0.6$ benzene solution is capable of producing cancer on the skin of mice. U5 When different carcinogenic hydrocarbons, e.g., methylcholanthrene, benzpyrene, and jdibenzanthracene, are applied successively the effect is additive-^. The investigators who made this observation offer the hypothesis that carcinogenisis is essentially an accumulation of abnormal protein within the cell. Since so many compounds have been tested for carcinogenicity it is only natural that several- attempts have been made to correlate this property with other properties, either physical or chemical. Such a correlation would be extremely useful in that the determination of the physical or chemical property would be much simpler than the rattier long and tedious process of exposing experimental animals to the substance in question. Fluorescence spectra have received more study in this regard than any other property.5.7 .2s s The author of a recent paper made the statement that all known cariinogenic chemicals are fluorescent ,U5 However, it is obvious from a glance at Table 1 or Hartwell's tabulation that this is too broad a claim. However, many investigators have used fluoroscenco spectra to good advantage in this field, and there appears to be a definite correlation with carcinogenicity,- at least with certain types of compounds. The correlation may be due in part to the fact that fluorescence spectra have been used as a guide in selecting fractions from coal tar for physiological tests; it is conceivable that other carcinogenic com pounds, which are not fluorescent, exist or could be synthesized. A rough parallelism between the carcinogenicity of poly nuclear aromatics and the diazo coupling reaction has been observed.2 1 *22 Attempts have also been made to correlate refractive index, or mere specifically, specific refraction, with the carcinogenicity of oils. 911230 BinEulM 01930 Eeport No. M-12^7 k The Manchester Committee on Cancer119 recommended that spindle oils of various ranges of specific gravity have specific refraction values below certain limits to assure the absence of carcinogenic properties. However, it is obvious that thore can be no general correlation between a physical property of this nature and carcinogenicity, for slight changes in structure, such as the position of a methyl group, vhich would have little effect upon optical properties, affect carcinogenic properties profoundly; furthermore the presence of a large concentra tion of a non-carcinogenic aromatic would raise the specific refraction of a mixture much more than would the presence of a small amount of a potent carcinogen. The probability of obtaining a general correlation between carcinogenicity and some more easily determined property would be greatly enhanced if there were a clearer understanding of the mechanism of the action of carcinogenic compounds. It is, of course, very difficult to obtain such an understanding, for so little Is known about cancer itself. Whether or not carcinogenisls by hydrocarbons and related compounds is in any way connected with spontaneous cancer is a question that has received much conjecture. That such a relationship does exist is suggested by the fact that certain derivatives oi estradiol (see Table 1) which Is closely related to the sex hormone estrone, are carcinogenic. Spontaneous cancer quite often occurs in the reproductive organs. Furthermore, the very potent carcinogen, 20-methylcholanthrene, can be produced by the degradation of des- oxycholic acid, cholic acid, or cholesterol, the first two of vhich are normal constituents of human bile and the last of which is present in all tissues of the human body.22 These degradation reactions were, however, conducted under drastic conditions which are in no manner related to those prevailing physiologically, and there is no evidence that 20-methylcholanthrene is formed in the body through the degradation of bile acids or cholesterol. The possible connection between cancer produced spontaneously and carcinogenisls by methylcholanthrene or related compounds therefore remains a matter of conjecture, at least for the present. There has, for obvious reasons, been little attempt to induce cancer in human beings through exposure to the various com pounds that are carcinogenic to mice. Thero is, therefore, no direct correlation between the susceptibility of man and the tost animals. There is, of course, an indirect correlation of occupational cancer largely through exposure to coal tar and dye intermediates caused by materials vhich are carcinogenic to mice. However, many of the compounds shown in Table 1 do not occur in any products known to have caused occupational cancers, and it is conceivable that some compounds harmful to mice are innocous to man. Until that can be proved, the only safe policy is to regard all compounds which are harmful to mice as dangerous and to avoid exposure by humans. HHZ:VAC 911230 BinEulM 01931 6/23A5 Report No. M-1247 5 TABLE 1 CARCINOGENIC COMPOUNDS All 'compounds listed by Hartwell25 unless otherwise indicated. 1. The following derivatives of 1 ,2-benzanthracene: 3 -methyl 5- methyl 6- methyl 9- methyl 5-ethyl 10- ethyl 5-n-propyl 5 -n-butyl2 5 -n- amyl2 5- n-hexyl2 6- i-propyl 3-hydroxy 10-hydroxy E 10-aldehyde, -C - 0 10-methyleneacetoxy, H 0 i tt -C-O-C-CH^ H 10-methylenecarbomethoxy, H 0 i > -C-C-O-CH^ H H ' i 10-cyanomethyl, -C-CN H 3-methoxy 10-methoxy 4.9- dimethyl 4.10- dimethyl 5 .6- dimethyl 5 .9- dimethyl 5 ,10-dimethyl 6.7- dimethyl 9.10- dimethyl 6.7- dimethyl 9.10- dimethyl 5-chloro, 10-methyl 7-chloro, 10-methyl 5-cyano, 10-methyl 7-cyano, 10-methyl 1 ,2 ,7,8-dibenzanthracene31 1 ,2 ,5 ,6-dibenzanthracene 911230 BinEulM 01932 Report No. M-12^7 6 The following derivatives of 1 ,2,5 ,6-dibenzanthrac ene: 9-methoxy _ 2' -methyl ' 3'-methyl 4-methyl 9-methyl T' ,9-methylene - k H 10-dimethylene, -<jj-- 3 ,b'-dimethylene (phenanthra- 8,9-dimcthylene acenaphthene) 2. Derivatives of E 5,6-cyclopenteno--L ' 6,7-cyclopcnteno 1 ',2 ',3 % V -tetrahyarp Na salt of 9,10-endo alpha,beta succinic acid: 5-aldehyde k`-methyl 5-methyl 1', 2'-dihydro, ^'-methyl 3. Derivatives of Cliolanthrac ene l',2',3',V -tetrahydro - 10-acetyl 3, 8,9-dibenzpyrene 5,10-dihydro-3, 1-,8,9-i - benzpyrene 7-methyl, 1 , 2 , 3 , dibenzpyrene \ Cholanthrene The following derivatives of cholanthrene: 20-methyl 20-ethyl 20-isopropyl 20-tert-butyluu 1 5 .20- dimethyl 16.20- dimethyl 1 5 -hydroxy, 20-methyl 15 -keto, 20-methyl 911230 BinEulM 01933 Report No. M-12V7 7 4. Other Derivatives of Phenanthrene Colchicine 1,2,5,6-dibenzfluorene 6 The'following derivatives of 3.4-benzphenanthrene 1- methyl2 2- methyl2 2 -ethyl2 2-isopropyl2 7- methyl2 8- methyl2 2,9-diethyl 2-methyl, 1,2,3,4- d ihenzphenanthene Cholesterol oleate 1,2-dimethyl chrysene2 5-methyl chryseno17 4.5- methylene chrysene17 5.6- dimethyl chrysene17 911230 BinEulM 01934 Report No. M-12V7 Equilenin henzoate 8 0 1 ,2-cyclopentcne phenanthrene2 5 Other Aromatic Compounds Tetraphenylme thane 1 ,3,5-triphenylhenzene Trlphonylothyleno 53 911230 BinEuAM 01935 r\ 1 . f 1, C . Report No. M-12^7 9 6. Organic Compounds Containing Nitrogen 2-amino, 1 -naphthol Alpha naphthylamine13 Beta-naphthylamine 0 OH 11 j Acetylcholine, CH3-C-O-CH2-N-(CE33/)3 0-amino azotoluene /--- ^ " 3 _._,c h 3 ( \ 5 /~ ;-N=N \ NH2 p-dimethyl aminoazobenzene (butter yellow) /' / -1FN- \ / - N ( C H -)2 Scarlet red r^ r' Indole EO / \ -N = N- \ \_/ \ _ /\ N1 ' H Syyryl U30 / CH-,-C-N-( \ ) --W- X " \_ / Benzidine1' x. . A E3C ? ? > -C 0 _\ 0-C-CH3 H2N-/ 'V " \ -ME 2 \_A_/ -HH; / 911230 BinEulM 01936 Report No. M-12^7 10 1 1 ,2,7 y8-dtbenzacri dine P J 3 ,4 ,5,6-dihenzcarhazole 7. Miscellaneous Arsenic trioxide Potassium arsenite Aqueous hydrochloric acid Aqueous potassium, hydroxide Zinc chloride Zinc sulfate Ethyl alcohol Fructose Glucose Galactose 911230 BinEulM 01937 Report No. M-1247 BIBLIOGRAPHY 1. Auld, S. J. M., J. m a t . Pet. Tech., 24, 577-83 (1938). 2. Badger, G.M., Cook, J.W., Hewett, C.L., Kennaway, E.L., Kennaway, N. M., Martin, R.H., and Robinson, A.M., Proc. Roy. Soc., B129, 439-67-(1940) 3. Badger, G.M., Cook, J.W., Hewett, C.L., Kennaway, E.L., Kennaway, N.M., and Martin, R.H., Proc. Roy. Soc., B131, 170-82 (1942). 4. Barry, G., Cook, J.W., Haalewood, G.A.D., Hewett, C.L., Hieger, I., and Kennaway, E.L., ibid, B-117, 318-51 (1935). 5. Berenblum, I., and Schoental, R., Brit. J. Exp. Path., 24, 232-9 (1943). ' 6. Bottomley, A.C., and Twort, C.C., Am. J. Cancer, 21, 78I-8 (1934). 7. Bruce, W.F., and Todd, F . , J. Am. Chem. Soc., 6l, 157-61 (1939) 8. Campbell, J.A., Brit. J. Exp. Path., 15, 287-94 (193*0. 9. Campbell, J.A., ibid, 20, 122-32 (1939). 10. Cook, J.W., Nature, 145, 335-8 (1940). 11. Cook, J.W., Haalewood, G.A.D., Hewett, C.L., Hieger, I., Kennaway, E.L., and Mayneord, W.V., Am. J. Cancer.. 29 , 219-59 (1937). 12. Cook, J.W., and Kennaway, E.L., ibid, _33, 50-97 (1938). 13. Cook, J.W., and Kennaway, E.L., ibid, 39, 381-428, 521-82 (1940). Ik. Cook, J.W., Hieger, I., Kennaway, E.L., and Mayneord, W.V.-, Proc. Roy. Soc., Bill, 455-84 (1932). - 15. Cramer, W., and Stowell, R.E.,Cancer Research, 3.. 668-81. (1943) 16. Dobrovolskaya-Zavadskaya, N . , Compt. rend. s6c. blol., 129; 1055-7 (1938). 17* Dunlap, C.E., and Warren, S., Cancer Research, 3, 606-7 (1943). 18. Evans, E.E., J. Urol., 38, 212-15 (1937). 19. Fieser, L.F., "Chemistry of Phenanthrene", Reinhold publishing Company, N.Y., (1937)- 911230 BinEutM 01938 Report No. M-1247 Bibliography (Continued) 20. Fieser, L.F., Aa. J. Cancer, jj4, 37-124 (1938). 21. Fieser, L.F., and Campbell, W.P., J. Am. Chem. Soc., 60, 1142-5 (1938) . 22. Fieser, L.F., and Fieser, M., "Organic Chemistry", pages 814-26, Heath and Co., Boston, Mass., 1944. 23. Gottschalk, R.G., Proc. Soc. Exp. Biol. Med., 50, 369-73 (1942). 24. Haddow, A., and Robinson, A.M., Proc. Roy. Soc., B127, 277-87 (1939). . 25. Hartwell, J.L., U.S. Public Health Service, Nat. Inst. Health, Nat. Cancer Inst., 1941, "Survey of Compounds which Have Been Tested for Carcinogenic Activity", 371 PP- 26. Heller, I., J. Ind. Hyg., 12, 169-97 (1930). 27. Henry, S.A., Kennaway, N.M., and Kennaway, E.L., J. Hyg., 31, 125-37 (1931). 28. Hieger, I., Biochem. J., 24, 5 0 5 - H (1930). 29. Hueper, W.C., J. Ind. Hyg., 16, 255-79 (1934). 30. Kennaway, E.L., Brit. Med. J., 1925, II 1-4. 31. Kennaway, E.L., Biochem. J., 24, 497-504 (1930). 32. Kennaway, E.L., and Hieger, I., Brit. Med. J., 1930, No. 3622, 1044-6. 33 Lavik, P.S., Moore, P.R., Rusch, H.P., and Baumann, C.A., Cancer Research, 2, 189-92 (1942). 34. Linzbach, A.J., and Wedler, H.W., Arch. Path. Anat. (Virchow's), 307, 387-409 (1941). 35 Loeb. L., Alexander's "Colloid Chemistry", Vol. V, 995-1050 (1944), Reinhold Publishing Co., N.Y. , 36. Morton, A.A., Clapp, D.B., and Bran4, C.F., Science, 82, 134 (1935). 37* Nordmann, M., Z. Krebaforach., Vf, 288-302 (1938). 911230 BinEulM 01939 Report No. M-1247 Bibliography (Concluded) 38. Robson, J.M., and Bonser, G.M., Nature, 142, 836 (1938). 39* Roffo, A.H., Prensa Med. Argentina, 26, 721-38 (1939)* 40. Roffo, A.H., Bol. Inst. Med. Exp. Estud. Cancer, 15, 741-56 (1939). 41. Roffo, A.H., ibid, 16, No. 52, 1-6 (1939). 42. Roffo, A.H., ibid, 17, 661-98 (1940). 43. Roffo, A.H., and Roffo, A.E., Jr., ibid, 20, 143-87 (1943). 44. Shear, M.J., Leiter, J., and Perrault, A., J. Nat. Cancer Inst., 2, 99-113 (1941). 45. Simpson, W.L., and Cramer, W., Cancer Research, 3, 604-5 (1943). " 46. Stallybrass, C.O., J. State Med., 34, 249-68 (1926). 47. stowell, R.E., and Cramer, W., Cancer Research, 2, 193-7 (1942). ` " 48. Tvrort, C.C., and Fulton, J.D., J. Path. Bact., 33, 119-43 (1930). " 49. Twort, C.C., andLyth, B., J. Hyg., 33, 464-73 (1933). 50. Twort, C.C., and Twort, J.M., J. Ind. Hyg., 13, 204-26 (1931). ~ 51. Twort, C.C., and Twort, J.M., J. Hyg., 373-9 (1930). 52. Twort, C.C., and Twort, J.M., ibid, 35, 130-49 (1935). 53- Twort, C.C., and Twort, J.M., Lancet, 1935, II, 1226-8. 54. Twort, J.M., and Twort, C.C., J. Hyg., 39, 161-9 (1939). 55- Woodhouse, D.L., J. Inst. Pet. Tech., 20, 1057-63 (1934), For those wishing to acquire a more extensive background in this field, a review by Fieser20 is recommended as a good starting point, followed by the original papers by Cook and co-workers. For a detailed tabulation of carcinogenic compounds Hartwell's book25 should be consulted. 1 911230 BinEulM 01940