Document NeEo9N0v6a65VELJ31Qyz4O5g

FILE NAME: Texaco (TEX) DATE: 1945 July 2 DOC#: TEX009 DOCUMENT DESCRIPTION: Unpublished Report for Shell Oil Co. Carcinogenic Hydrocarbons and Related Compounds FOR INFORMATION ONLY - NOT FOR PUBLICATION A CONTRIBUTION OF INFORliATION TO MEMBERS OF THE A.1*.I. J ^ I C A L A D V I S O R Y C O n T T T E E ' V ' fiff-FT.T. on, COMPANY. INCORPORATED WOOD RIVER RESEARCH LABORATORIES REPORT NO. M-12^7 JULY 19k5 > SUBJECT: . CARCINOGENIC HYDROCARBONS AND RELATED COMPOUNDS' ' A LITERATURE REVIEW AUTHOR: H* ZUTEEMAl JAM 014818 Exportation of-This Report is Subject to License Under the Rational Defense Act SHELL OIL COMPANY, INCORPORATED WOOD RIVER RESEARCH LABORATORIES V REPORT WO. M-12^7 JULY 2 , 19*5 SUBJECT: CARCINOGENIC HYDROCARBONS AMD RELATED COMPOUNDS A LITERATURE REVIEW AUTHOR: H. H. ZUHJEMA Industrial cancer v&s first recognized In England in'tlje latter part of the eighteenth century, vhen It vas established that chimney sweeps were particularly liable to cancer of the scrotum.5 Ibis 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 end. 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. Ohs 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. Dae- carcino- genlclty of a given compound Is influenced by many factors including the genetic constitution of the animal species end strain, its age . end 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 3 While carcinogenic properties are generally associated with _ certain polynuclear aromatics and their derivatives, there are many substances entirely unrelated to these compounds .Which M v been ref*- ported as birring similar cabCer-pcroducing ability?*' *Affih^ 'idib'fi(b<nilay be mchtlono'd asteit&au-57 , lnarffihiid af^1hS3elH.c and o f aqueous pbtefeslum -t ' ethyl alcohol25, 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 quite different, - _ i.e., physical rathor than chemical. Materials which havo been roported ,, " JAM 014819 Report No. M-12^7 ^as carcinogenic and vhose carcinogenicity la probably due to the presence of polynuclear aromatics include coal tar and pitcb2,i'27 blue shale oil5, mineral oila and asphaltUj, tobacco tar"39, tars - obtained in the destructive distillation of teaU2and coffee*10, diesel fuel52, distillates from Borneo crude petroleum511, combustion gases from fuel oilal, the SOg extract from a spindle oil- produced , . from a paraffinic crude petroleum511, the products obtained by heating acetylene, isoprene, yeast, a non-carcinogenic petroleum fraction, or human skin to 700 - poc^C-'o, and the products obtained b y treating acetylene, xylene, naphthalene, or tetrahydronaphthaleno vith aluminum chloride53. Die carcinogenicity of tars produced by heating .various substances tends to increase vith increasing tempopature.50."s j t is probablo that tho carcinogenic hydrocarbons proacnt in certain coal tar end petroleum fractions vere to a large extent formed during the process steps and vere not present in the coal or crude petroleum from which they vere derived. Hovever, the carcinogenicity bf a given fraction depends upon the source as veil as the method of processing. According to the Manchester Committee on Cancer119, the following order of increasing carcinogenicity prevails: Russian, Pennsylvania, Texas, Mid-Continent, Mexican, California, Persia, Romanian, Borneo, "Venezuela, isl 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 vere carcinogenic, and 23 additional ones produced papillomas but no true 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 tho most detailed study are the throe derivatives of 1 ,2-bonzanthracene: 1 ,2,5,6-dlbenzanthacene, 3,t-bcnzpyreno-, and.20- methylcholanthrono. All throe aro 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,pogoe 5-^0. Structures, complete with numbering systems, are Included, since lack: of uniformity among various In- vestlgators in this field has led to some confusion. There la fortunately less deviation in the current papers than in the case . of those written ten to fifteen years ago. The numbering need In this report corresponds to that used by Hartwell25. It should be understood that the carcinogenicity of the compounds -shown I n Table 1 varies considerably In degree and that the results have bo en verified by several laboratories In oomo cases vhilo in others the results of only one or two experiments are available. Die reader_ . Is referred to Hartwell for more detailed information and for rb- - ' ference to the original experiments. It will bo observed that *T most of the compounds ere either hydrocarbons or their- derivatives containing at least three benzene rings or nitrogen compounds con- tnlning at least two benzene rings. More specifically, the first * of those classes consists, with only three exceptions, of derivatives , JAM 014820 Eeport Ho.. M-12^7 3 of phenanthrene. The exceptions are tetraphenylmethane, tripbenylbenzene, and trlphenylethylone. In Table 1 the hydrocarbons are subclassIfled , further as derivatives of 1 ,2-benzanthracene, 3,4-benzpyrene, cholanthrene, * end other derivatives of phenanthrene. Examination of the structures above 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 oxamplo, 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. Hovevor, a paraffinic or naphthenic hydrocarbon or one containing only one or two benzono rings may..with . a reasonable degree of confidence bo assumed to be non-carcinogeriio. The amount of compound required to produce an experimental cancer on a test animal is surprisingly small. Doses of 1,2,5,6-di benzanthracene and 3/^-benzpyrene os small as 2.5 and U micrograms, respectively, givo positive results when applied to mice .^-Discontinuous application, e.g., once a week, of a given total quantity of material is moro effective than continuous exposure.15 A single application of 20- =s--mothylcholanthrono in 0.656 benzone solution Is capable of producing cancer on the skin of mice. U5 When different carcinogenic hydrocarbons, e.g., methylcholanthrene, benzpyrene, and dibenzanthracene, are applied *' successively the effect is additive-35. The investigators-who made this observation offer the hypothesis that carclnogenlsis Is eBBentlally 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 rather long end tedious process of exposing experimental animals to the substance In question. Fluorescence spectra have received-core study in this regard than any other property^>7 2 8 -s The author of a recent paper made the statement that all known cariinogonic chemicals are fluorescent I*5 However, It is obvious from a glanco 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 ter for physiological tests; It Is conceivable that other Carcinogenic compounds, vhlch ere not fluorescent, exist or could be synthesized. _ . - - . _ . A rough parallelism between the carcinogenicity of pbly- - ' nuclear .aromatics end the dlazo coupling reaction has been observed.2 122 . Attempts have also been made to correlate refractive index, or more specifically, specific refraction, with the carcinogenicity of oils. ` - JAM 014821  Beport No. M-12^7 k The Manchester Committee on Cancer1*9 recommended that sptndls oils > of various ranges of spcifie gravity have specific refraction values below cortaln limits to assuro the absence of carcinogenic properties. However, It is obvious that thoro 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, which would have little effect upon optical properties, affect carclnogenlo properties profoundly; furthermore the presence of a large concentra tion of a non-carclnogenlc aromatic would raise the specific refraction of a mixture much more than would the presence of a small amount of a potent carcinogen. Die 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 carclnogonlc compounds. It Is, of course, very difficult to obtain such an understanding, for so little le known------- about cancer Itself. . Whether or not carclnogenlele 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 of estradiol (see Table 1) which Is closely related to th sex hormone estrone, are carcinogenic. Spontaneous cancer quite often occurs In . the reproductive organs. Furthermore, the very potont carcinogen, 20-methylcholenthreno, can be produced by the degradation o f -des- - - oxychclic acid, cholic acid, or cholesterol, the first two of whlqh are normal constituents of human bile and the last of which Is present In all tissues of the human body.22 ihoso 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 - ' carclnogenlele by methylcholanthrene or ffilated 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 suscoptlblllty 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, which are carcinogenic to m i c e . . However, many of the compounds shown In Table 1 do not occur In any products known to have caused occupational cancers, and It la conceivable that some compounds harmful to mloe are irmocous to man. Until that can be - ' proved, ..the only safe policy la to regard all compounds which ars harmful to mice as dangerous and to avoid exposure by humane. EHZ :YAC 6/23A 5 JAM 014822 Report No. M-12U7 `5 TABLE 1 CARCINOGENIC COMPOUNDS All 'compounds listed by Hartwell25 unless otherwise indicated.. 1 . Derivatlvee of 1,2-benzanthracene .* The following derivatives of 1 ,2-benzanthracene: 3-methyl . 5- methyl 6- methyl ' 9- methyl 5-ethyl 10- jathyl 5-n-propyl ' 5-n-butyl2 5-n-amyl2 5- n-hexyl2 6- 1-propyl 3-hydrooy 10-hydrory f 10-aldehyde, -C - 0 H 0 10-methyleneacetory, --O-C-CH^ H H 0 10-methylenecarbomethory, -CI-C?-O-CB3 - H H 1 10-cyanomethyl, -C-CN H 3-methoay 10-methoxy ' U,9-dlmethyl h,10-dimethyl 5 .6- dimethyl 5 .9-dimethyl 5 ,10-dlmethyl 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-dibenzanthradene31 1 ,2,5,6-dlbenzanthracene JAM 014823 Report No. M-12^7 6 Die following derivatives of 1, 2,5/6-dlbenzanthracene: 9-methoxy 2'-mothyl ' 3'-m6thyl U-methyl 9 -methyl H i f ,9-mothylcnc -jj}- H k 1,10-dlmothylone, H L --C- 3,^' -dimethylene (phonanthra- 8,9-dimethylene acenaphthene) 2 . Dorivativeo of 5 .6- cyclo pcnteno - 6.7-cyclopentcno ' 1 ',2 ',3 ', -tetrohydro Na aalt of 9,10-end , 5-aldehyde k'-methyl . 5-methyl l',2'-dihydro, U'-methyl 3. Derivatives of Choianthracene 1', 2',3', ^-tetrahydro 10-acetyl 3,U,0,9-dlhenzpyrene _ 5,lO-dihydro-3,*-,8,9--dd- benzpyrene 7-methyl ,1 /2,3 ,U-dibenzpyrene Cholanthrene Die following derivatives of -cholanthrene: 20-methyl 20-ethyl 20-isopropyl EO-tert-butyf1" 15 .20- dimethyl .* ~ 1 6 .20-dimethyl -- 15-hydroxy,_ 20-methyl 15-heto,'20-mathyl - JAM 014824 Report No- M-12^7 7 k. Other Derivatives of Phenanthrene Colchicine The'following derivatives of 3 h-henzphenanthrene ' 1-mothyl2 2- methyl`s 2-ethyl2 2-isopropyl2 7- methyl2 8- methyl2 2,9-diethyl 2-methyl, 1,2,3,^dihenzphenanthene Cholesterol oleate CH3 H H-C-(CH2 )3-C-(CH3 )2 1 ,2-dimethyl chrysene2 5-methyl chrysene17 U,5-methylene chrysene17 5,6-dimothyl chrysene17 JAM 014825 Report Jio. M-I2U7 Equilonln bonzoate 8 0 Other Aromatic CompouniQ Tetraphenyimethane 1,3 ,^*tripbenylbenzene Triphenylothyleno 3 3 JAM 014826 Beport No. M-12VT 6. Organic Compounds Containing Nitrogen 2-amino, 1 -naphthol Alpha naphthylamine13 Beta-naphthylamlne . 0 OH Acetylcholine, CBj-Cii-O-CHs-Ni-(CE3)3 o-amino azotoluen< NHs p-dimethyl aminoazobenzene (butter yellov) - n (c h 02 Searle* fed HO Indole H Syyryl k30 0 H CHj-C-N- Benzidinelc H3C O-C-CHj -NH2 JAM 014827 Report No. M-12b7 10 1,2,5,6-dibenzacri dine J 1 ,2,7,8-dfbenzacrldine ' "' ' . " M. 3 , b, 5, -dibenzcarbazole 4 ' 7. Misclleneous Arsenic trloxide Potassium arsenlte Aqueous hydrochloric acid Aqueous potassium hydroxide Zinc chloride Zinc sulfate Ethyl alcohol Fructose Glucose Galactose ' JAM 014828 Report Ho. M-12^7 BIBLIOGRAPHY 1. Auld, S. J. M., J. Inst. Pet. 'tech., 24, 577-83 (1938). .. 2. Badger, G.M., Cook, J.W., Hevett, C.L., Kennavay, E.L. ,Kennavay, N. M., Martin, R.H., end Robinson, A.M., Proc. Boy. Soc., B129#. 439-67.(19^0) 3. Badger, G.M., Cook, J.W., Hevett, C.L., Kennavay, E.L., Kennavay, N.M., and Martin, E.H., Proc. Roy. Soc., B131, 170-82 (19^2). 4. Barry, G . , Cook, J.W., Hoelevood, G.A.D., Hevett, C.L., Hleger, I., and Kennavay, E.L., Ibid, B-117 318-51 (1935)* .' v* 5- Bereriblum, I., and Schoontal, R., Brit. J. Exp. Path., 24, 232-9 09*3). .. 6. Bottomley, A.C., and Twort, C.C., Am- J. Cancer, 21, 781-8 (193*0* 7. Bruce, W.F., and Todd, F., J. Am. Chem. Soc., 6l, 157-81 (1939) 8. Campbell, J.A., Brit. J. Exp. Path., 15, 2&J-9h (1934). 9. Campbell, J.A., ibid, 20, 122-32 (1939)- 10. Cook, J.W., Nature, 145, 335-8 (19**0). ...... - ...... 11. Cook, J.W., Haelevood, G.A.D., Hevott, C.L., Hioger, I.,Kennavay, E.L., and Mayneord, W.V., Am. J. Cancer, 29, 219-59 (1937). 12. Cook, J.W., and Kennavay, E.L., ibid, 33, 50-97 (1938)..- 13. Cook, J.W., and Kennavay, E.L., ibid, 39, 381-428, 521-82 ** > 14. Cook, J.W., Hleger, I., Kennavay, E.L., and Mayneord, W.V*./'Proc. Roy. soc., B ill, 455-84 (1932). (1940). . 15. Cramer, W . , and Stovall, R.E.,Cancer Research, 3 668-81. (1943) 16. Dobrovolskaya-Zavadskaya, N . , Compt. rend, eoc. M o l . , 129:. 1055-7 * (1938). 17 . Dunlap, C.E., and Warren, S., Cancer Research, 3, 606-7 &9^3') 18. Evans, E.E., J. Urol., 3, 212-15 (1937). . . _ 19. Fieser, L-F., "Chemietry of Phenanthrone**, Relnhold Publishing - - Company, N.Y., (1937). -r JAM 014829 Report No. M-12*7 J Bibliography (Continued) ^20. Fleeer, L.F., Am. J. Cancer, 3j, 37-12*- (1938). 21. Fleaer, L.F., and Campbell, W.P., J. Am. Chem. Soc., 60, llh2-5 (1938). -- ' 22. Fleaer, L.F., and Fleaer, M . , "Organic ChemlBtry", pages 8l*-26 Heath and Co., Boaton, Maaa., 19**. * 23. Gottachalk, R.G.,' Proc. Soc. Exp. Biol. Med., J50, 369-73 (I9U2 ). 2*. Haddov, A., and Roblnaon, A.M., Proc. Roy. Soc., B127, 277-87 (1939)- ' * , . % 25. Hartyell, J.L., U.S. Public Health Service, Nat. Inst-- Health, Nat. Cancer Inat., 19*1, "Survey of Compounds vhlch Have Been Tested for Carcinogenic Activity", 371 pp. 26. Heller, I., J. Ind. Hyg., 12, 169-97 (1930). 27- Hnry, S.A., Kennavay, N.M., and Kennavay, E.L., J. Hyg., 31, 125-37 (1931). 28. Hleger, I., Blochem. J., 2k, 5 0 5 - H (1930). 29. Hueper, W.C., J. Ind. Hyg-, l6, 255-79 (193*)- 30. Kennavay, E.L., Brit. Med. J . ,. 1925, H l-1. 31. Kennavay, E.L., Blochem. J., 2*, *97-50* (1930). 32. Kennavay, E.L., and Hleger, I., Brit. Med. J . , 1930, No. 3622,- ' lo**-6. 33. Lavlk, P.S., Moore, P.R., Rusch, H.P., and Baumann, C.Al Research, 2, 189-92 (19*2). Canpr ` . 3*- Llnzbach, A.J., and Wedler, H.W., Arch. Path.- Anat. .(Yirchov's), 307, 387-*Q9 (19*1). 33- Loeb.-I,., Alexander's "Colloid Chemistry", Yol. Y, 995-1050 (19**), Reinhold Publishing Co., N.. 36. Morton, A.A., Clapp, D.B., and Brand, C.F., Science, 82, 13* (1935). r __37- Nordmann, M., Z. Krebaforach., hj, 288-302 (1938). . -~ - JAM 014830 Beport No. M-12U7 Bibliography (Concluded) 38. Bobaon, J.M., and Bonaer, G.M., Nature, 142, 836 (1938)* > 39. Boffo, A.H., Prenaa Med. Argentina, 26, 721-38 (1939)* 40. Boffo, A.H., Bol. Inet. Med. Eip. Estud. Cancer, 15, 741-56 . (1939). 41. Boffo, A.H., Ibid, l6, No. 52/ 1-6 (1939). U2. Boffo, A.H., Ibid, 17, 661-98 (1940). 43. Boffo, A.H., and Boffo, A.E., Jr., Ibid, 20, 143-87 (1943)- 44. Shear, M.J., Leiter, J . , and Perrault, A., J. Nat. Cancer inat., 2, 99-113 (1941). _ ' 45. Simpson, W.L., and Cramer, W., Cancer Beeearch, 3/ 604-5--------- - (1943). 46. Stallybrasa, C.O., J. State Med., 34, 249-68 (1926). 47. Stowell, B.E., and Cramer, W . , Cancer Beeearch, 2, 193-7 (1942).. ' . 48. Twort, C.C., and Fulton, J.D., J. Path. Bact., 33, 119-43 . (1930). '* 49. Twort, C.C., and Lyth, 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., 29, 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, l6l-9 (1939). 55. Woodhouae, B-I., J. Inat. Pet. Tech., 20, 1057-63 (1934). For those "wishing to acquire a more extenslT In this field, a review by Fieser20 la recommended as "a good starring point, followed b y th original papers b y Cook and co-workers. F o r a detailed tabulation of carcinogenic compounds Hartveil's book25 should -be consulted. ' ....r. .... JAM 014831