Document 9L0LDGV78RpV3dyEbBzKzve9V

FILE NAME: Phenolic Resins (PHR) DATE: 1945 DOC#: PHR034 DOCUMENT DESCRIPTION: Unpublished Report-API History of the Subcommittee on Carcinogenicity with Two Attached Literature Reviews UNUM* ,, tMKlCAh fMRUltUM iNS-TitTI API 04607 i ! I API HISTORY OF THE subcommittee ON CARCINOGENICITY 19U5-1950 -a 'er ""1 * - . fof 'A*contributton of i n f e c t i o n to Kenbers - API Uedical Advisory C - g - ; Technical Memo_No. 45-214 Chemical Division Socony-Vacuum Oil Co., Inc, Research and Development Laboratories Paulsboro, New Jersey April 27, 1945 t t e n t i o n Mr. P. V. Keyser, Jr. Dr. A. A. O'Kelly Dr. W. P. Hawthorne A brief literature survey of Carcinogenic Hydrocarbons, M t.prnture Survey ... (flfEVladay/ Carcinogenic activity tas including hydrocarbons, confined to the hydrocarbons and S S S L S f S S i - i identified a, carcinogenic. _ Uost of the carcinogenic b y d ^ c a r t O T s ^ r ^ o r i B i ^ l yJn 30m0 caaee S ^ ! S b r r '^b^anthracenes. T W . m . d Caret-- T " *^- Hydrocarbons (7),(22).(45),(24) (12),(10i,(5),(28), Benzopyrenes 1,2-benzopyrene 3,4-benzopyrene 1,2,3,4 dibenzopyrene IX, cholanthrenes cholanthrene 20-methyl cholanthrene 16 20-dimethyl cholanthrene 20-ethyl cholanthrene IS i 6-benzdehydrocholanthrene 04609 -2- 20-isopropyl cholanthrene 3- methyl cholanthrene meso-dihydro cholanthrene 4- raethyl cholanthrene 5- methyl cholanthrene meso-dihydro 3"methyl cholanthrene 1-k etoch oianthrene III. Benzanthracenes 1 2-benzanthrac ene 10-methyl-l,2-benzanthracene 9-methyl-l,2-benzanthrac ene 5 10-dimethyl-l,2-benzanthracene 5 9-dimethyl 1 ,2-benzanthracene 8.9- dimethyl 1 ,2-benzanthracene 4.10- ace 1 ,2-benzanthracene 9.10- dimethyl 1 ,2-benzanthracene 8.10- ace 1 ,2-benzanthracene 10 ethyl 1 ,2-benzanthracene 5 methyl 1 ,2-benzanthracene 5 n-propyl 1 ,2-benzanthracene 6 methyl 1 ,2-benzanthracene 5.6 dimethyl 1 ,2-benzanthrr.cene 6 isopropyl 1 ,2-benzanthracene 6.7 c?clopenteno-l,2 benzanthracene 3 hydroxy-1,2-benzanthracene 0 methoxv--1 ,2--benzanthracene 5 propyl-9,1 dimethyl-1,2 benzanthracene 5 ethyl-9,10 dimethyl -1,2 benzanthracene 5 methyl-7,8 dihydro-1,2 benzanthracene 1 2,5,6 dibenzanthracene li ,9 methylene-1,2,5,6 ^ a n t h r a c e n e 1' 2 ' 3*,4* tetrahydro-1,2 benzanthracene 5,6 cyclopenteno-1,2 benzanthracene Miscellaneous sym. triphenyl benzene tetra-phenyl methane o-amino-azotoluene 9.10 dimethyl anthracene 1,2 cyclopenteno-510-aceanthrene t The Mature of Petroled Carcinogens The probability that bTTM" 270-300C, and 300-330 C, produced ^ the absorption spectra of to whose skin these fr^c^ as these fractions were simiiar to thoew - cancer-producing compounds, tested showsci the Spectrographic analysis of S and Fulton (59) .tat. presence of the same class ^ ^ n - n f f i n s have relatively little that oils with a preponderance of paraffins nave r API 04610 -> carcinogenic activity, but that carcinogenesis is high in oils with a preponderance of isocyclic compounds. r . SrifL'^nroup % S Z , t= the i l n of rabbits, produced alignant tutors. " A substance containing the bento () ^ r e n e nucleus, with decidedly cancorogenic properties, has been isolated (32) from tar s c ia used in paving roads. Ihe prevalence of (63) to be due to The pure par--fiin l^24 5(j cancer among ..tSd a found to be paraffin wax. non-carcinogenic. The Most Carcinogenic Petroleum fractions Carcinogenic hydrocarbons have been shown ^ b e m o r j ^ concentrated in certain tin/oil bar, etc.) contain more boiling fractions (fuel oil, 1 ^ *tionSt ^ petroleum oils carcinogenic hydrocarbons than the lower fractions 31 times as used in cotton spinning carcinogenic as the low boiling ^ o S s are said to be less potent ctJ;n3 Jr L fhe heavier grade lubricating oils (54). shalo oil was oils; the found (56) to be about 12 ^ flh"J * af S ^ f i n i 8hed lubricating oil from most potent shale oil J" * h a s t e n removed but which has not been treat- which most of the paraffin wax v00& found that while mineral ed with sulfuric acid or filtered (54). carcinogenic, heavy lubricating oil of the type used therapeutic 7 d tar showed the same property to a oils did show some carcinogenicity, cUid tar snow, larger degree. _ # Twort and Lyth (60) ^ v e s t i g a t e d a t ^ g e o ^ c o m e r c i a l ^ d ^ activity of a topped Borneo crude oil. Th^ v i s c o s i t y ^ 200-225 centipoises was associated with the fraction having a activity. This at 25C, and that the whole rang f ^ n a t i o n of the physical properties theirU9eas when likely to eome into contact with the user. 3 _ Evidence of the presence of c^cinogens SonT noted (56) in an investigation of ^ S&-ccntpiession, internal-combustion che soot of the engine. This material was hig y ,'f general, the carcinogenic potency of cru the skin of rruce. In 0jj_3 decreased as the ent at 400Centigrade. cracking temperature wab These investigators also lower' found that a " heavy -rrade grade o0f 1 Diesel Ji fuel oil was carcinogenic but that a light grade oil was uot. Effect of Treatment of Oil" on narcino.renicitz Yioodhouse (64) found and the S02 extract of spandle were carcinogenic. Lyt*" ^parafSn-base crude fractionation of => API 04611 x&'-Sr  -4- i Scottish 3hide oil and a Persian oil, that all samples of petroleum oil which were treated with ethanol provided residues of lower ca" lno^ ^ 1^ d^ ton h i ^ e r refractive index and density than the original oil. *siiica (\q ) found th't saturation by oxidation and reduction cr treatment by silica or S a y reduced the cancerogenic activity of their mineral oils probably $ sdsc^tion and polymaristtion. Alcehol traction and sulfurtc acid tre-tment reduced the carcinogenicity of the oils by extracting the carcinogens. The same authors also found that the active agents could be concentrated by extraction with methyl sulfite or methyl sullate and pi . acid. They suggested the process for treating oil for industrial use. Relation of Carcinogenicity to Fluorescence and Chemical and Physical Properties _ Tvrort and Twcrt (54) found that the cancer-producing properties of mineral oils appeared to. be related to their flueroscence; oils having a blue fluorescence seemed more active than those having Weiss (61) noted that strong fluorescence was almost confined to conjugd.t , rin* systems which possessed highly mobile electrons. Only t h e m o r svmmetrically conjugated systems or those which do net ? ^ e r i s . t o str y innic structures show fluorescence. The author compared the mobile electrons with metallic electrons and stated that carcinogenic hydrocarbons belong to i f y f r ^ X o n s . .Hiesr (26) found that tha n u o r t ^ c . apuatra rt' m-nv carcinogenic substances show bands at wave lengths cf 4000 , 4180, and 4toOAc! These tends are similar to those cf the spectra of 1 ,2-benzanthracene, a known carcinogen of high potency. A relationship between physical properties and carcinogenicity was observed b) 5 S (35) 5ho stated that oil. with a l 5500 were non-toxic while oils with an index exceeding 1.5600 were "Pennsylvania oil. and certain mildly treated oils ere an o p t i o n . The sameP author noted a relationship between ths iodine value f '" treat S i s " 5 carcinogenicity. Toxicity Increased in the same order as the iodine value, Pennsylvania oils again excepted. Fieser and Hershberg (21) found that the behavior of polynuclear hydrocarbons in lead acetate oxidation, aldehyde reac^ n indicated that the most carcinogenic hydrocarbons of the s e n e s tested possessed special susceptibility to substitution. Schmidt (48) discussed the theory of the box model of aromatic compounds L d r t a t e d that the theory is e s p e c i a i i y s u c c e s s f ^ i ^ h a r ^ c t izing the cancer-producing hydrocarbons as compounds with abnormally m =h electrogen density and low excitation energy. Other references relating structure and physical and c^ 4 aaland properties to carcinogenicity include Bradley (8); Clar ( )# Warren (18); Fieser (19) and (20 ; Fieaer and Campbell 22), IballP (28): ngljgt3 Kennaway et al., (29); Lundgren (34); Shear et al., (51), and Truhaut . More general references to known carcinogens, including reviews of the literature up to the date of the reference, nre Addinall W , Andervont (2); Barry (3); Blanc (4); S al ' (16); Bruce and Kahn (10); Butenandt (11); Cook (13) rjid (14) Cook etal., ^ * Cook and Kennnway (15) and (17); Hartwell (24); hewett (25), Kerna l )> API 04612 -5- * *i / . Rnffo (4 2 ); Rondoni (44) Sampey (45)* Shabad (50), > S'-* ^ and Sibcna (52). ^ _ M' schrch (w)i ,,ore ^ vailable *,,d The greater part of the origin For these references the w 'ssx&srtt f f i s s s - -- - -- reference in the bibliography. ' /aJ L. J. Hillenbrand L. J. Hillenbrand LJH-.RMW r BTLIOGRAPKY , - H - I l C K., Merck Report Al, 16-18(1935) (C.A.22,62037 ) I: Andervont, H. B., niv. Wisoonsin, Symposium on Cancer Sept. 19j6, 54-66 (C.A*32,3612 ) -si 1935) (C.A.29,5187^) tig;} B S ^ 1 1 ? - ^ 5 B S # ^SSSSsiSa^ (c-a^,8057> (C.A.32,A979 ) g- r r a, ion 74-91(1938) (C.A.^2,7372) i systeme'65'73' a 1-13(1838, (C.a.22,2a9) & SS:5::;i^5^ ^ ^97C1,38) 1167.. C o o k " '. 1-, >t !. * J '-C"" r 'j21c"Jli, 35 Cook, J. W., and Kermawa:", E. 1., Am. J. Cancer r, 3B - i S '/ S - 32(1940) - 18 ^ 'c^ E - ! and Warren, S ,, Car.cer Research 1, 953-1(191 . - a.22. Fioser, 23. Haddow, H ! L. F a n d Campbell, W. Pj, JA., and Robinson, h . M., Proc. c Koy. o : - 3127, 227-87(1939) ---- (C.A.33,6428 ) . j. q Public Health Service (1941) 26. Hieger, I., Biochem. J. 2, 5 0 578and 810(1932) on uipst. H. R., and King, A. T., N a t u r e b d : 3. 28. Iball, J., Z. Krist. 9^, 7-21(193 ) ( . a J 0 ( C . a .35,32502 ) 29. Kennaw, E. L., et al., Cancer^ ^ ^ 33) (0.4.27,425^) t v s ss f - s s s . s : s s a i f f i u * TM gs.'sr& r 37. Lyth, E., and Inort, C.C., J. /q .a . 29, 6612*! , 38. Morton, A. A., * . 755-60 (1936) (C.A. jO, 5291' ) 39. Merton, ,,., et al., m. 7932) (C.A. 27 , 29932 ) 10. Nyrcp, J. E., Protoplasma ^ , 2 9 1 - 3 0 0 (1932) IC - 0_u (c.A. , 677e ) U . Passano, J. 2., Semema Med. (^e n o s ^ r ) J 4 i _ _ 12. Buffo, A. H., Noplasmes g , 7! ^ Cane^ 17 , 385-111 (1910) 43. Rcffo, H., Bel. Inst. Me-. Expti. w * * -- , (C.A. 5, 1499 ) , /--. - \ mn 148-54 (1935) (C.A. 29j 5176 ) 44. Rondoni; P., Chimica e Industria (Italy) 17, 148-54 ( W < ~ API 04614 T (BIBLIOGRAPHY - CONTINUED) & S X ; C. ; ^ t S ! F r ,, e etude Cancer a , 6-37 47. S a S i / l i f ^ 'l S S d i , I., Bull. sscc. Franc etude Cancer 24 , 534-8' (1935) (C.A. 30, 52904 ) i t schSci; l::M f c K !1 ! * * 1 . &,TM (> 50. Shabairi- M., .'-TCh. SCi. B i d . (USSR) 9, 147-68 (1935) (& g , J . S , i t M . * induct^ 2 , U9-32 2, I. Twcrt, C. C., and Twort, J. U., J. Ind. Hyg. 1, 20^ 26 <1931) C5! ? ^ Twcrt, Lancet *M(C.A- f 56. Twcrt, C. C., and Twcrt, J. a., Lancet 1915 II, l226" ( 2 ^ .5 (1938) 57 ^ c r t C. C,, and Twort, J. U., Oil Colcur Tradeg J. 94, 251 5 U938) 5S. "Twort,""c! C.,2and Ing. H. R., Z. Krebsfcrsch 27, 308-51 (1928) 59. ^ o r t f c ! c!! L d Fulton, J. D., Z Krcbsforsch 5, 543-73 (1932) 60'. 2!!51 Lyth, R-, J. Hyg. 9, 161-9 (1939) (C.A. 12, 506l9) 61. '"eiss, J-, Nature 145, 744-5 (1940) A? Weed. F. C., J. Am. Med. h s s c c . 94, 1641-3 U 93u; ti & u 24,48672 ) --> *, **'> .wsaarir* API 04615 of API )liiel Advisory Conmttse. 'contribution of information to Members THE CARCINOGENICITY OF bituminous compounds Literature Review April 30, 1945 Library of the cal k Research Di1 The Texas Company New York City N0TE In view cf the immense amount of published information on various phcses cf the cancer problem, it should be emphasized that this literature review gives only a rapid survey cf developments in the field of cancer research as applied directly tc the petroleum, coal tar, oil shale and -allied industries. While it is far from being complete, yet it is believed that most of the important work in this particular field has been covered, either in the report itself or'in one cf the bibliographical references given in the appendix and referred tc at the bottom of page 1 . P. Doss T THE CARCINOGENICITY OF BITUMINOUS COMPOUNDS It has long been recognized that the incidence of skin cancer is greater among workers in certain industries and occupations than among the population as a whole. Attention was first directed in 1787 to the very high death rate result ing from scrotal cancer of chimney sweeps; it is eight times more common in these workers than in the general public in England, and in the United States the ratio ' ' . 78 cf cancer cases in chimney sweeps is double that cf the general pep a ion . in practically all eases it is the scrotum that is attacked; this is also the Site in mule spinners cancer discussed later, Barkers in ether industries coming into direct contact with tars, pitches, shale oils, etc. likewise show a high mcidenoe of skin eaneer, for example, laborers in plants making briquettes, tar roofing, wood preservatives, artificial gas, insulating compounds, shale products, etc. However, in spite cf the recognition of the fact that bituminous com pounds were apparently the cause of skin cancer, it was not until relatively recently that skin cancer was produced in laboratory animals by direct application of tar. This was accomplished by the Japanese investigators Tamigawa and Ichikawal22 in 1915. Since then a great deal cf very careful work has been dene in synthesising and testing various organic compounds, particularly p o l y e y c U e cydrocarbons and derivative,. For lengthy r e v i e of this w o * , see References 8-12, 14, 17 , 20, 22, 23, 26-29, 32-34, 74, and 37; particularly the review by J. L. Hartwell cf the National Cancer Institute covering 696 chemical substances, of which 169 are reported to be carcinogenic. L. F. Fieser summarises cur knowledge in this field as follows^: "As iudired bv all available data for the production cf skin and subcutaneous tumors in rats and mice, methylohoianthreneprobably is the most potent cf the known chemical carcmcgens. Syste^t studies cf synthetic model compounds have shown that the me 7 fzrouD is cf nc importance tc the functioning cf the compound, I h a ^ c h U n i T a S cf the efficacy of eh in the analogous hydrocarbon 5,IC^dimethyl-l,2-benzanthracene, that the most significant structural feature cf ch^ ; ^ r"th methylcholanthrene is the 1 ,2-benzanthracene n n g -y cirbon substituent at the meso position 10. 10-Methyl-l, 2-benzanthracene evokes sarcomas in mice nearly as rapidly methylcholanthrene, and, though it is distinctly less.ef in the production of skin cancer, the substance constitutes the nearest approach in a simple model compound to a simulation of the biological properties of the hydrocarbon of more complicated structure, ",11 twelve possible monomethyl derivatives of the inactive 1 , 2-benzanthracene have been synthesized and tested for ca^ ~ 7onic activity, and of these the 10-isomer is the ! of The meso-substituted 9-methyl compound stands next in order of potency, followed closely by the 5-methyl _der^v^ ^ ,t^ e ha3 produced sarcomas in mice with a latent period a u long as that observed with 10-methyl-l,2-benzanthracene. Methylcholanthrene and benzpyrene can be regarded as 2-benzanthracenes substituted at the meso positions 10 and 9, respectively, and in model compounds the combination ^ t h types of substitution is particularly favorable. 9 , 1 ^ ^ ^ 1 2-benzanthracene produced skin tumors m mice with remark-Di " is test surpasses methylcholenbhrene ta sposd Cf action, though it is less effective when administered by subcutaneous injection. The thiophene isologue oi the hydr carbon has comparable properties." Numerous attempts have been made to isolate the definite carcinogenic ,, p o u n d s in cool t.r by sans of distillation, solvent extraction, eto.73, but * ile very potent fractions have been obtained, the individual compounds have been difficult to separate. Kennaway and Hieger 16 proved the carcinogenicity cf 1 ,2,5,6-dibenzanthracene, the first pure carcinogenic hydrocarbon known. Cock, Hieger and Hewitt ^ in 1933 isolated 1,2-benzpyrene, 4,5-benzpyrene and 1 2-benzanthracene and estimated that the original coal tar pitch contained not 1,8s than 0.003% of the potent 1 ,2-benzpyrene. Several investigators 22, 24, 25 have attempted to correlate carcino genesis with fluorescence. For example, the cancer-producing material formed by the action of AlCl-j on tetrahydronaphthalene shows a blue-violet fluorescence, shewing three bands, 4000, 4180 and 4400 .U., which are similar to the fluorescence spectrum of 1 ,2-benzanthracene Kennaway and Hieger 62 suggest the possibility of the use of the fluorescence spectrum for-the preliminary amination of materials suspected of being carcinogenic. -3- An important fact brought out by several investigators is that the temperature to which a tar, shale oil or petroleum oil has been subjected determines its carcinogenic activity. In general, it would seem that temperatures up to 500C. are without effect 52 but above that temperature carcinogens are formed, the maximum yield lying between 80C and 900C. 53 59, Tar and 2- frTM gas works are far more active than that from coke ovens 58, accounting for 70* of all cases of tar cancer in the United States while the coke oven product causes only 5* Vihile petroleum residues resulting from moderate heat treatment are inactive 12, yet by passing an inactive California petroleum through a tubs at 880C. Kennaway and Leitch obtained a very active carcinogen 59, Even an inactive medicinal paraffin oil heated to 330C. under 50 atms. pressure acquired some carcinogenic activity Kennaway 56 likewise obtained an active material by passing isoprene through a tube filled ith U2 and heated to 820C. Wateon U 5 achieved similar results with turpentine at 850C. Acetylene yields an active product on being passed through a red hot tube 59 but it must be pointed out that treatment with AICI3 at room temperature also produces an active compound On the other hand, synthetic lubricating oils produced by AICI3 polymerization at temperatures up to 150C. were entirely inactive . It suggested that the condensation products of acetylene are of a more complicated nature and probably acre unsaturated than those obtained from ethylene. The carcinogenic activity of tars depends apparently not only on the temperatures of their fonnation but also on the chemical compound used as the base stock 10. For example, a tar made from pinene at 850C. was far more active than one from turpentine made similarly, the relative potencies being 100:19. Pinene tars made at 500, 600, 750, 850 and 950C. had relative potencies A.PI 04620 -Ur cf 0, 12, 21, 100 and 61. Oxidation of a synthetic tar at 100C. reduced its potency from 100 to 63, and at 150-l60C. its potency fell to 0. Oxidation with on acetone solution of KMnC4 reduced the potency to 21; with pyridine as a solvent, --lnrst to 0. The active constituents of synthetic tars form crystalline picrutes, the remaining filtrate being almost inactive, and the picrate extremely patent. Shale oil is carcinogenic, probably as a result of the high temperatures to which oil shale is subjected 10Z*. However, temperatures below 100cC. give a relatively inactive product, 500cC. and above being required 101. In England where high temperature tar is used in briquette manufacture, there are many cases cf skin cancer among the workmen, which is not the case in France where the low temperature product is used. The greatest amount of investigation cf any type of occupational cancer has been carried out on mule spinners cancer in the cotton mills cf Lancashire, England. Scutham and Wilson 88 in 1922 first called attention the excessive occurrence of cancer in mule spinners. Women workers are not affected and about 70* cf all cancer among mule spinners is cf the scrotum 8ZS apparently due to the fact that a mule spinner at work walks to and fro in front of his machine, leaning over the moving frame from time to time to join up broken ends of the yarn The base cf the frame is on a level with the groin and the spindles on the frame as they rapidly revolve throw off oil from their bearings onto the clothes. In the hot mills the men perspire freely and so wash off the natural grease cf th~ skin, thus allowing the oil closer contact 1 5 . Irritation by the trousers -end overalls also helps the process. It is interesting to note that no trouble of this sort was noticed in England until mineral oil replaced animal and vegetable oils as a lubricant 1 6 . Henry W estimates that 0.25* of all cotton mule spinners in England suffer from scr,otal cancer. On the other hand in the United States during 1926, for example, there were only 33 deaths from cancer of the -5- scrctura, cf which only three cf the victims were textile workers and three were mule spinners; four cf the six were b o m in England and the other two in Canola *5, which tends to show that mule spinner cancer is rarely contracted in tiie United States. In a woolen mill in the United States employing about 200 mule spinners no cases of scrotal cancer were found 8U. Since the method of operating this equipment is the same in both countries this striking contrast is attributed by Hamilton u0 to the fact that Scottish shale oil is used in the Lancashire mills. However, the literature is net entirely clear as to the origin ana type cf t.ie oil used in Lancashire in mule spinning ' Leitch 70 brings out a fact of possible significance, to the effect that cancer is net known in woolen spinning mills, even though the same machines are u3od ,, in the cotton factories, but points out that the room temperatures in the cotton mills are much higher, possibly resulting in mere relaxation cf the tissues cf the scrotum and permitting entry of oil into the sebaceous follicles. Brockbank l6, however, states that in the woolen iniustry piecing cf broken ends Cf y a m is dene with both hands with a forward level bending movement of the body and thus there is not the same friction of the clothes on the scrotum as in the ccttcn mills. He admits, however, that the same oil is used in both types cf mills. ,,s a result cf the preliminary investigation cf Sc.attain and '.ilson mentioned above, the Manchester Cancer Ccmnassicn, ccnsisting cf mere than fifty members, was organised in 1925 under the direction cf Dr. C. C. Twort tc investigate the mineral oils used in Manchester ccttcn sails. Lubricating cils fr-.n the various field, threughout the world .ere found to have widely varying degrees cf activity. A sample cf Venesuela oil was very petent while 1 2 end Pennsylvanian samples were cn an average less than cne-tenth as active. Purified medicinal cil had nc circl'd:genic properties and several saponifiable cils. such as sperm, Clive, rape, cottonseed -and neatsfoct cil, failed tc produce API 04622 -6- turners when applied to ,,dee, even under the most severe experimental conditions, m general terns, the more saturated ere the constituent hydrocarbon, of the lubricating oil, the less capable were they of inducing cancer in experimental animals, the physical characteristics being the same 101. This preliminary report as criticised severely in an editorial in the ,,petroleum limes of London \ in that - d i e various oil companies (Anglo-American, Anglo-Persian and Shell-**) had contributed U , 0 0 0 for to years for the support of this investigation, yet the Manchester Cancer Commission had not availed itself of the services and advice of expert, from the oil industry relative to the characteristics and methods of treatment of petroleum oils. The Institute of petroleum Technologists, - d i e making no definite criticisms at this time of the e.+ese. -vP i+. own to follow closely the work work of the conmission, formed a committee of in progress 63. In 1934 Dr. A. E. Dunstan, Dr. P. H. G a m e r and Mr. James Keley cf ths institute of Petroleum Technologists are shon as members of the Manchester Commi. ssi. on 21*. in 1933, Twort and Lyth 1" of the Manchester Cancer Conndttee reported that by means of solvents, extracts ere obtained of high refractivaty and -meir recommendations for the selection of correspondingly high carcinogenicity. Their recommend an oil of low carcinogenicity were as follows: ,,hen selecting from several mineral oils ith similar gravity, specify that with the lowest refractive index! hen selecting from those ith similar refractive index, specify that ith the highest gravity; when selecting from those with similar ref ractivity, specify that with the highest viscosity; and when selecting from origin alone, choose in the following order, . Russian, Pennsylvanian, Texas, Mid-continent, Mexican, Californian, Persian, . Rumania, Borneo, Venezuelan,shale. However, it should be emphasized at this point that these authors state definitely that -adequate refining of any of the oils handled, of no matter what origin, results in a product ...............possessing only a very low API 04623 -71 carcinogenicity" K *. Also, that a single traction of an unrefined distillate ,,ith SC, may profoundly loer the activity of a previously very dangerous oil, ,,nil. a second extraction may render it almost inert. They state that "at is ,,robp,ly commercially feasible to treat oils of any origin, or oils of any degree of carcinogenic activity, so that they may be less dangerous than even the Very b=st of the straight oils used today". They evidently assume that untreated textile oils are used in the Lancashire mills. ' Lyth of the c o h e s i o n further stated 71 that hen the r e f r a c t ! ^ of oil as less than 0.5500 it as found to be non-toxic, hile hen the value greater than 0.5600, the oil as highly toxic. Pe^sylvanian oils and c-rtain sdldly treatod oils ere an exception. The i o d i ^ - - oil seems t0 afford an indication of its toxioity, providing the oil has not been treated end again the higher the value, the nxre potent the oil. The toxicity increases in the some order as iodine value, except for Pennsylvanian oils haoh again occupy too high a position. The permanganate values are not regarded as of any value in connection ith estimating the toxioity of oils. Lyth adds that extraction ith alcohols, acetone, e t c , clay and aci treatment, leads to a reduction in the potency, especially in the case of tta .ore potent oils but a corresponding reduction in the r e a c t i v i t y does not ^ occur. Where a marked reduction in the refractivity does occur, there as, a - exceotion, a marked decrease in carcinogenicity, ith a marked increase an r-.:'ractivity, a corresponding increase in potency. e r e the refractivity is nc + ka ffpeted. snd furtner tests re .much altered, the potency may or may not be affected -n necessary. In spite of the apparent definite findings and recommendations of the^ Manchester Cancer Commission, the Cancer Research Committee of the Institute^ Petroleum Technologists 51 was not convinced that "the so-called incid * (c.n .. .. Refractive Index - 1 n * (.Refractivityz -- --- DZKS'TY------- API 04624 -8- cancer is in any shape or form connected with the use of spindle oils". No elaboration of this statement was given, but was possibly based on refined oils ,rsly being used as textile lubricants. An editorial in the "Petroleum Times" of London in 1937 once again attacked the conclusions of the Manchester Committee, pointing out that only on' 0il from each of a number of countries was examined 5. in 1937 the Federation of Master Cotton Spinners Association sent out a letter to its members .recomending that when purchasing spindle oils a guarantee should be obtained that the oil conforms to the specifications of the Manchester Canctfr commission, and that tests had shown that many of the oils in use at that time conformed to the specification. m i l e throughout the reported ork of the Itoncheeter Cancer Conniecion it i. stated repeatedly that acid or solvent treatment of a potent oil greatly reduces ,,r eliminates its activity 97, * . * * . , yet in 1939 T r t and Lyth 107 investigated acid and clay treated distillates fro. a Borneo oil and found the. to be active, the maximum potency being at a viscosity of 200-250 cp -t 25 C. Molecular distillation gave a greater concentration of the carcinogenic uteris! than as obtained by ordinary distillation at fro. 3 - 10 m . In oonfimation of previous findings the iddle fractions of this Borneo oil ere .ostly responsible for pathological changes in the organs. A carcinogenic shale oil as separated by olecular distillation into fractions hich ere subjected to chrcatographic adsorption. Two apparently 2 109 pure hydrocarbons have been isolated and are being investigated > . A recent report (1941) by C. C. Twort of the Manchester Cancer Cotmission 109 states that tests are variable, lengthy and costly and that a acre reliable estimate of the carcinogenicity of oils can be obtained from the refractive index and viscosity. (Yet the data on which selection of these two properties was based were obtained by means of this variable skin test.) -97 Vioodhouse or the ^ * Research Laboratory also states thet M U ,, tests to determine carcinogenicity are dirricult to correlate t h I tendencies to cancer urless these animal tests are strongly e,tive 121. For examplej t . oils ere tested (a) rrom a s p i - n g mall " C2ses 0r mule spinners cancer had been recorded, and (b, rrom a mill here sax - I had r_ l y been reported. Mouee tests indicated slight ca c i n o ^ properties in the case f the to oils hut a greater action on mace or (a) the (b>' Dr. E- M. Brockbank, chairman or the Manchester Cancer C e s s i o n , has ^ bri6lly summarized the investigations or the C o - s s i o n in a recent publac- aon . . Be lists the hygaenac precau ao to be exorcised in mule spinning and urges the rt. He ,,iso makes this a on of the oil speciTication given previously by ad0pV- . . oil that is strongly dermatitis 1nteresting generalisation: "As a general rule n oil interesting 0 mentioned by s U l ,,ot be strongly c a r t i n g - ' *" " extraMly K -nnaway 61 ho states that cyclohexene (hich is non-carcinogenac Kcnnavfay . irritation were an irritating to the skin and should produce cancer aT =h -- 1 ractor in carcinogenesis. ^ ^ ^ ^ ^^ A3 mentioned previously, ---- -- _ Q ,# per annum w incidence of skin cancer is about 0.1% P Scottish shsle industry th. case incidence or a _ g the nil orkers but 0. a m e * the pararrin orkers (tbas is ^ 28 year cord). M s activity of jarafrih i restricted by Schars an 28 jear recoru,. . v/hich view is supported by to the crude product, the ref , , ^ n, statee that the active con.nte ere preeent only m the paraffin oils. tath regard to the ' 1 ,, wood 120 made an -< netroleum oils, on ^ investigation or rerineriee in Pennsylvania end round no scrotal cancer, hie ' sms conTlnned by H e U e r Hoever, Heller round evidence or carcinogenic compounds in Mid-Continent oils as rerined in plants in Ohio and Indiana. c U b o i l s are iairly = ~ = n a * in some case, lead to ekin cancer. In one case A P I 04626 I -10, prnffin pressman in the Middle V,est was treated for ax boila for three ,,ears when a cancerous growth developed on the right forearm and was removed, but iight years later a second similar growth in the same place had to be removed. H,ller also found records of cases of skin cancer in another refinery, using crude f K B the lima field; case, had occurred in this refinery and one was fatal. a l of these cancers were preceded by warts. The length of exposure before malignancy appeared varied from four to thirty four years. The part mos affected was the scrotum and all but one man worked in the paraffin department. Ttese cases were caused by unrefined oils and Hamilton W states that so far there is no proof of the occurrence of skin cancer in the U.S. from the s refined lubricating and spindle oils which have been acid-treated. Heller believes that the relative freedom from occupational cancer in the ,, 5 is due to the mechanisation of i n i t i a l processes, preventing direct contact with the pitch and tar; the extensive employment of negroes, who are apparently less subject to ekin irritants than whites; the use of refined lubricants from crudes which are poor in carcinogenic properties, and the use of tar from c o n v e n e instead of from gas works. Phillips 77 p o r t s the particulars of s study carried out by the U.S. pntlic Health Service as to the incidence of occupational cancer in Texas. The records of 1190 individuals hmving microscopically verified ekin cancers were analysed, covering the period 1920 to 1940. The occupation of the largest group cf these patient, was outdoor wort, ( f a ring and ranching), the wort, of housewives comes next in order, followed by various activities r e a r i n g moderate outdoor life. The professions were next, followed by laborers and carpenters. The railroad and petroleum industries furnished few cutaneous cancers. ^ lafafer and sitgreaves in a U.S. Public Health report issued analyse 70 cases of cancer recorded for the male members of the sick benefit plan of an oil refining company during the period 1933-36, there were 46 death,. The death rate was 0.78 per 1000 and a frequency of 1.2 per 1000 (all U.S. death API 04627 -11- ,.-96 per 1000). Almost 70* of the deaths ere related to the di3estive system ,,,,d the rate for this site as higher than in the total population. Deaths from cutter of the genito-urinary system as 6.5* of the total, compared to 15.0* in the case of the total population. in 1934 Campbell-20. 21 made laboratory tests on mice ith dust obtained trom tarred roads. This dust caused arts and cancer of the skin and an sum months 24 out of 59 mice sho.ed typical tar arts, half of which developed malignancy. This finding as confirmed by Kling, Samsono. and Keros, - ho also separated a substance containing the bensopyrene nucleus from the tar. However, Hogouneg is doubtful of the danger from road tar since it usually takes years of direct contact of coal tar to the skin to produce skin cancer. (Teutschlaender calls attention to the fact that almost all industrial cancers require an exposure of about ten years before growth appears, although a few oases may arise much later., Valade U 1 likerdse is of the opinion that while primary lung t - r . *. -- * ^ ** " " " t inhalation of dust from tar roads, yet these results cannot be transferred to humans. Animals other than mice should be employed in experiments and an inquiry Should be carried out on workers exposed daily to such dusts. _ tmile the manufacture of briquettes in England is attended by a high cancer rate, 5 since high-temperature tar is used, yet in the few plants in the 0.S. making b r i ^ t t e . cancer ie entirely abeent, partly due tc the lack o a ** entirely mechanized and partly contact with the binder since the procese here is entirely due to the us. of petroleum aephalt a, a binder, . This funding as co by ood > in his investigation of briquette manufacture in Pennsylvania. The addition of p r i d e s * r e c c e s the c a r c i n o g e n potency of mineral oils hut not to as great an extent ee lanolin. Speakman and Chamberlain state that - d l . alcohols have not been used for this purpose there can he U t t U cou that such pclar compounds will reduce the risk of cancer formation by promo, ng emulsification, since en oil .hich is easily and completely removed from the C a n - 12- ,,ust carry less risk than one which is difficult tc emulsify. These investigators LSC believe that polar compounds in a mixture with mineral oil may, however, function in yet another way. It is known that the carcinogenic agents of mineral oil when associated with unsaturated compounds are free to concentrate at any surface tc which the oil is applied, the non-pclar paraffin molecules off.r g u t t l o or no resistance. However, when oil-soluble polar compounds, such as cleyl alcohol or wool-fat ether, are mixed with mineral oil they concentrate at the surface, excluding the less polar carcinogenic hydrocarbons. Sequeira 86 stresses the necessity of absolute cleanliness of body and clothing, the application of castoroil to exposed surfaces and medical inspection every three months. Brcckbank 15 suggests a mixture of lanolyLand clive cil be applied to the skin. ' Duckham advocates the use of an oil-eolvent cleanser similar tc the i rf thp lubricant from the ether scap used in hospitals in order to remove all of th 3 pores In view cf the suggested use cf lanclin the fcllowing should be of particular interest: Dr. E. V. Ccwdry, cf the -fashingten Diversity Schccl cf Medicine, St. leuis, has 3ust a m o unted CN.T. Herald Tribune April 29, 1945) that calls can be sensitized to become cancer cells by treating then with a substance ^ *411 even nrevent powerful cancel-producing which dees not cause cancer and which will P chemicals from exhibiting that property. . ' Fcr example, when the powerful carcinogen methylchclanthrene is mixed with lanclin it is without action when applied to the skin cf mice, although alone it always r.eults in cancer. However, when these mice were then treated t h methylchclanthrene in benzene they developed cancers more quickly and tumors c .renter virility than mice which had net received the cancer-preventing treatment. MPD-VL DVJS B3TE53NC3S Anon. , Cancer from Spindle Oil. Oil and Color J*! A letter sent out by the General Committee of the Federation Master Cotton Spinners' Association recommends that when purchasing suindle oilmembers should obtain a guarantee, that the oil conforms aP specification of the Manchester Cancer Committee which a fof aila claimed to minimize the so-called cancer-producing mineral oil . Tests showed that many of the oils i n a B y. ^ 888 form to this specification and are obtained at regular prices. to J Anon Cancer and Mineral Oils. Oil and Color Trades J., 102* 695 *' The report of the Manchester Committee on Cancer, issued for t e year ,, U l o f r , 1 * 1 . .tat., that in .ffort. to i.ole r ani ^ n - acterize individual carcinogenic hydrocarbons from shale oil, recently annreciable quantities of crystalline material have been obtained, but U PC too e a ? ^ t o discuss Z suits in detail. As far as can be til frictions obtained from Venezuelan Oil by chromatographic adsorption are active. Proprietary colloids have varying effects, depending on the " I d U i of the experiment. A colloid containing a c h l o r - c o n p o ^ d was f o S d less efficacious than an olive oil-lanollne mixture as protection the c L i h O S h h i c action of .hal. oil, Philo the - , . r c oppecrod to be the case when the carcinogenic agent used waB benzpyrene. Anon., The (Pa.r)oblTehme offolClaonwcienrg. apPpeetarroedleuimn Taimreesc,ent23,is5s9u.e JoJf0th(e193Br)itish s s a M m lco.: sr= tz r \ " t" y rc. ^ S T S S S i i i i S Pe.or of " SVE S f S - to t S ^ i S e untreated oil have said that its lubricating power is uninpaired^aad the Manchester Committee is therefore able to hold out toe hem* that before long it may be possible to put on the market an oi which^fulfills the needs of industry without being a source of danger t the workers." Assuming that the use of spindle oils be such a souree of danger, it almost necessarily follows that other lubricating oils which come into closer physical contact with the worker must be sources of higher potential danger than any of the light lubricating oils used in the looms of the Lancashire cotton industry. It night be proved u p o a 'weetlgation that little difficulties wo^lA present themselves in tne production of a spindle oil which is noa-earcinogenie, and l*t the present attack widens itself to include the whole range of nlneral lubricating oils, it would be advisable to make an investigation of the most embracing character. - 14- * M W . -- Report on Lubricants 1 . Pot. Times. 27. 3U-320 ' `^Irltlclt.. the report of the the Comltte. hask^^lo^PeMtLi m l the Shell hex but has not availed Anglo-American, t..e to&lo Pe oxnarts frrn th* nil industry t ^ " ^ `t" - * -thol. of treatment of petrol., .oils. s. "" t r ^ w s i i p - . ^ f T h r ^ r . i i pier. than.by the application of the sample to the .Id. It is pointed . . ; S r ^ l "e'.te" ere admlttel. m l that In the 193^-1935 report the jutinal testa were reverted to. It is also pointed out that the abort conclusion m e based > " esamlmtion o? miy on. oil from each of a number of countries. 6. occupational Cancer of the Shin, ^ual Report, Chief Inspector of Peateries industry for each of the years 933 93 ig^ # Tar nstilling and American Journal of aer* 2-' . increased 1937 fieur08 r o r r a r ^ l u n i S c a i f u aUrlbutobl. to voluntary periodical emnin- ation in some plants. 7 Alapy. H. Cancer Prophylaxis by Prellmlaa,ry 7' ^^polycycHo Hydrocarbons. t.rr.bsor.ch W4eA *r\4 r&ts W6W Wlvii J earoln,,eenlc fffl.r'- h y d r ^ ( i j s n i i py* tuctlQn 8&inst th8 implantation later of thracene a. a method of Protection ^ ^ ^ c u t S e o u s injection was highly virulent tumor.. oil. The most effi- naie of the carcinogenic {****" ^at favorable time UO-70 days, cient dose in mice was 1 * W 7 *,_or ejmilsior.. Dibensanthracene was . before the implantation of th _roteCtion in nice was only slight, somewhat the most effective. P * . ani f0r (j_6 iays was slow. Development of the tumor was 5 ylgth ^ y after implantation Growth then became rapid and on the 17th W with treat ed the tumor the tumors were tunoi growth was obtained ment and the control animals . V * li^O-lSOy doses 3-k-80 days in rats given l-100y doses .5C" 8iT S i^ S i f e protection cLnot before implantation of toe tumor. A definite active pro** be obtained by this method. ' !. SacbDBDi,, I. I. et al. Production of Cancer by Pure Hydrocarbon.. Proc. Boy Soc. 3153, 3^3-68 (x937) . rjotency nethylchclanthrene is iltS re.pect to 1. almost equaled not surpassed by any compound yet tes favorei w introduction of by cholanthreae. Produloa of carcinoma l | _ ^ ^ S c . a . 1.1 substituents into the 5 position of to , -15- 3, -'benzopyrene. , Badger, 0. M. .t al. Production of Cancer hy Par. Hydrocarbon.. Proo. Hoy. SOe- f g ^ f n i T L meet eff.ctua:1 " `" 0^ * " " 'not any particular trnor (painting, declsive; In the 0 Utter ""*?'*! ^ tion and .wallowing cannot be contaminated, and lnhala- S the method.. The 3. properties, and U-benzopbenanthrene compounds P benzanthracene. in the production apparently are more active than ^ ^ * 3 ^ lisi the 1, 2-sub- of multiple tumors, cholangioma, respect to gastric tumors, stituted compounds are m0" 2 14e are oiaually more carcinogenic than Compounds substituted on the " j^ong tbe lf 2-benzanthracenes, those substituted, on the 6, 7, .gamble t h-benzophenanthrenes r t ^ e ^ n ^ t h n t S i r ^ n o f o f U adenoma. - * - * - ple tumor., and s deflol.ncy lm .areoma prodnc.lon. ' ,0 Badger, 0. U. et nl. Production of Cancer hy Pur. Hydrooarhene. Proo. Hoy. Soc. B131. 170"82 (iff) ^hthe e.rle.of 5 - W Pr, leo-Pr, Bu, cfll, . ..^.e 0f i 2-hen.anthracene (He, Bt, high.^ t" 4 on the .Kin! member with more than ? r . 2 2 M #S ? * t^ 1s ^ i0`5 S S -gS i M S S " on: .i pound.'were deflolent la ty to proiuc. .Kin . methylphenanthrene hmi a *llht action on the akin and there- tumora. 3. f 5.^bantefluoraa. had no ^ il>2j 7, S-conpouad.. by differed from the 1, 2 5* gltgbt tendency to produce 1. 2. 5. 6-Dlb.n.oomrtMOl. tlblted a ^ ,,,,ibed with s s L S ^ m r s s s i s s ^ " - *. n. Barry, d. at al. P o t i o n ef -- by Pur. Hydrooarbou.. Proo. Hoy Soo. BUT. (^935) Vtiufly tetracyclic and pentacyclie -- L'd Urge uuber of " ^ ^ ' ^ ^ i u n l n g tion, with aromatic hydroomrbona, conaiieroblo cancer-produnlng power wae alee as experimental animal. . coal-tar pitch), methylcholanthrene ..... el by 1. 2-beKPTT' < . -Sn o^enLthren.. Id Z derlw. of deoxychollc moll of =uat ooutaln order to be carcinogenic, derive, oi x, c w sab.tituent. in position. 5 " 4 b * ' 12. Bergmann, 7* of Tutor Production by Chemical Agwnte. C Baeaarch, 2, 660. ^ The following principle, for ^ production hy ohomloal agent. ^ sise of a carcinogenic are hypothetically ejtablitfaei. hydrocarbon ani of activity. Every which parent .trueture reeemble. it also m llc compound* datemine it. more or le.. clo.ely a given blaitonatogenic action, API 04632 16- 2 In the living cell, the carcinogens are adsorbed by an acceptor nessessing a definite adsorption area. This sets an upper limit for the dimensions of the active compounds. A lower limit is given y a in adsorbability with decreasing size of the molecule. conceived as parts of an "ideal carcinogenic gtructur.. 5 A carcinogen oan be Inactivated by additions which prevent its proper adsorption. The eohani.n of this hindering effect is dleonssed. Bonser, 0. V. Tumor, of the Shin Products by Blast-Furnace Tar. lancet 1, ^ ^ r e l u l t . obtained with four samples were remarkably similar to product and is disposed of without further handling# . Borland, E. and Bruee. A. U. Carcinogenic Action of Dlbenscarbasoles. lU. ' P" 0,c M r S t ^ U M ^ i e <S i l y frequent among chemical worker,, feTMd-durtag ^ " t i l g 0. skin of nio. and on. P" TM * " " " U " 0,1 mouse skin) also by subcutaneous injection into r ta. The produced ^"Lt most active wa. 3:U,5:6-iibenscartasole but malignen 'o D b L i e f ^ b l J .0. The dlnaphthylnminee thl.*** `" f d 1 ,2.7 = O-ntoMotolule, k n TM n to produce hepatoma, and d i ^ u o - " I ^ S S e U l o o ^ t a , n.ji.A to ureduce tumors on the skin ox mice PlIU . sole. ' ` Brockbenk, E.U. I t a l e ^ p d n n e r O a a o e r , Brit. Med. J . . 622-3 (U.26.l) 15. 16. Brockbenk. X. M. Male .pinner. Canr. ** Spinner . H. K^Lww lc,,tal cenoer la a mule eplnner wa. re- p o r t e f i a i ^ o h " t" In 1SS7. 37 7 t u t the } f i t l a n of S n e r a l lubricating oil? before that tine sperm oil and neatsfoot oi bed been the principal lubricant.. It l. now ^ " ^ . ' " ^ c ^ e e d SSSHSvis:- mineral oils are more carcinogenic than others, that ieri i E S T n - S i L l i r i y dangerous, and it ha. been learned by experience>hat c t T J U m ^ r S e l T t o *e caused if the same lubricant is us e d c o n tinuously, than if the kind of oil employed is 0cca8^0" 1^ I t h a s been found also that by mixing a n i m l or vegetable oil with mineral oil the carcinogenic potency of the lubricant may e a a . API 04633 -17- * T ,,,,j v.nnawav v L. Experiments in Carcinogenesis: " " "* 2 r h s ~ s K "r . - L " r ; r ' S ' a . 1+19-26 (1936) 18. Campbell, J. A. Experimental Production of Cancer by D t Obtained from Tarred Hoads. Brit. Bed. J . , * 0 0 . X> n f b 1m wlth Thia du.t " 6 L a t h . 2b ret of 59 1= tl" . . 4 ^ U r 'S S T - S S \ f -a-- r. 19. Cambell, 4. A. Th. Iffocto of Rood W Incidence of Primary Lung Tumors of Mice. Brit. WP* * 215"2i t (ias7been shown that dust from tarred roads causes cancer of the skin of ol * ofE ^ o f ^ i c e t ru " t S t e s ^ t h ? p r o d ^ t i o n 8of lung ^ r s ^ m i c e ! but not to so g r a t extent as when the tar is also present. . 20. Campbell, J. A. Carcinogenic A g e n t s ( A p r i l , 1939) induce lung tumops. He employed c h ^ e y aoot ^ ^ e r e ^ ^ s e d to these exhaust pipes of engines dusts for 10 min* an hour ^ 6 hrs. J TM ? TM ^ r. The death 5 lays * ^ t t o a / f o / t h e . c o n t r o l s rate o f both groups was well within the limits or exp08ed to S L S t p T p ^ o M U w S ^ "^ / J / H a r r lf Jfa lso S ^ n " iiS Cr S ^ CI i l i * l M 4p S t a d * w i t h tar from these substances. 21. Clark, H. Y. Cancer from Lubricating Oils. Oil-Color Trades J.. 11.9.3*, 1278-9 22. c o b , J. H.w.tt, 0. >4 Hlagar. I. Coal-Tar Conetituret. red Cancer. '" " l i J i t a L i c a r W - r . i.olat.d from coal tar .hid. t l TM several nyuruu! . . th typical fluorescence spectrum of . in producing arerer. aad M o b J"4 " L i r e c a r t o n Uolat.i .a. 1 , 2- nannlnogreioj^tlore. O ^ . tlB6 rwulred bp 1, 2. 5. S S S K ^ S t r t S i T L d U. 5-benzopyrene ..r. al.o I.olat.d. 23. Cook, J. *. .t al. Production of Creoer bp Pur. Bgrocarbone. (a) Proc. Boy. Soc. (London), B i n , U g j h (1932), (l) ^ ' ^ ^ / ^ d i . >. ^ r ' r e l r e u , rei i .tudy . -- * action Of 22 difference ^cyclic " "" dC re^Tur'rl -a. in their resp. ools. and applied in ,0An* . 2 wekly. Of these pure compds. only 1, 5e of-i-ad.1i0benza.n- S ^ . * 2 r 3 clo..ly r.lao.dr rpi.; p r ^ :d oreoer: TM s r * ^ r r -- a-- including 77 epitheliomas and 21 papillomas. . c -18- (Td) The investigation has been extended to include 52 aidnl. poly cyclic aromatic conpds . Tumors were produced by 6-isopropy1-1, 2benzanthracene, 5, 6-cyclopenteno-l,2-benzanthracene, phenanthroacenaph- thene, and 5 derivs. of 1,2,5,6-iibenzaathracene: 2 -lie, 3'-Ue, 9-HH2 , 9-iieO, 9,10 (C6H^K2)2 . Cook, J. W., Kewett, C. 1, and Kieger, I. The Isolation of Cancer-Producing Hydrocarbons from Coal Tar J. Chen Soc., 3 9 5 ^ 0 5 (1933) The preparations derived from coal tar pitch by a variety o* solvent extraction nethois, the fractions separated by formation of picrates, distillation and crystallization, and the hydrocarbons, 1 :2-benzpyrene, and U ;5-benzpyrene, perylene and 1 ,2-benzanthracene, have geaic and have given the sane fluorescence spectrum (bands at J000; and UbOQA0). The original coal tar pitch contained not less than 0.0039b of 1 , 2-benzpyrene. 25. Cook, J. W. Synthesis and Biological Effects of Carcinogenic Hydrocarbons. Chen, and Ind., +, 1022-3 (1935) ,, + , Certain forns of skin cancer due to occupation causes in industries where shale oil, coal tar and lubricating oil are employed, have been shown to be due to the benzanthracene group of hydrocarbons which also impart fluorescence to the oils. The exact nature of cancer formation in the human body has not been explained although a similar benzanthra cene hydrocarbon has been found to be produced by body changes .rom substances normally present in the human body. 26. Cook, J. W. Carcinogenic Hydrocarbons and Their Helationahip to the Sterols. Chea. fleekblai, 32, 563" 6 (1935) a .. ... Review of historical development of recognition of the cancer- producing constituents of coal tar and earlier investigations; the development of fluorescence spectroscopy and the systematic study of synthetic carcinogenic hydrocarbons including a summary of the results obtained from the examination of a complete series of tetra- and penta cyclic hydrocarbons and a moderately wide range of benzanthracene derivatives. The speculation is advanced that a mesc H atom in a completely aronatio structure plays sone role in the carcinogenic process. The isolation of 1 ,2-bensopyrene from coal Jar and sia are recounted a a i an account is given of the cyclization of bile acid derivatives, and the eventual synthesis of ^ ^ o l a n t h r e n e , ^carcino genic hydrocarbon related to the sterols. It is inferred that there is one enzymic factor present in the animal body which is W f l j J * effecting dehydrogenation of the sterol ring system and that excessive activity of this factor may conceivably contribute to the production i vivo of carcinogenic compounds. 27. Cook, J. ff., et al. Chemical compounds as Carcinogenic Agents. An. J. Cancer,^ i ^ g i l e n of the carcinogenic chemicals, dealing both with their chemical relationships and their biologic effects, bringing together, under'well chosen headings, all the material published up to the end of 1936. They include not only the hydrocarbons of the benzan thracene type, but also the azo compounds, estric, the styryl quinoline derivative discovered by Browning et al., and the inorganic compounds zinc chloride and arsenic. A bibliography of 19*+ references is appended. API 04635 s - 19- . Cook, J. . and K.nne..y, E. L. Chemical O o ^ . ' a . O a r c i n o ^ t c tgente. 28 First Supplementary Report: Literature of 1937. Am. J. Cancer, 50" 97^ o r ). present an erfnmetlye rerte. o f t h l . m b j e c l . h i c h . h o u U be of Interest to all lndu.tr1 .1 phyelelane. 1 continue. the ' l l " review and the two reports together have bibliographies totaling 37 referencese Darts. E. Chemical C.rclaogen..l., Dregs. Dye., lemedle. and Coemetle. 1th 29. * a yViamieal carcinogenic agents which may be introduced into rvSi-^ posure to what are probably extremely small daily doses. The theory is advanced that there may be many other agent, a. yet uakaoen blob n r e " ^ d ^ s p 2 .nTMedl- sri1 t e S l i n k y . . used In the coloring of food etnff..and fabric.. *** 30. -- V r i r t . ; . ; 5SSttZOXSr pr1 31, Feil.'A. 2 (5 , : ,t: mineral oils, including treatment and prophylaxis. -ary Fieser, L. T. Carcinogenic Activity. Structure, ^ ? emical ^activity^of 32. Polynuclear I 'a.critical'equation and compari d long review which includes j ** _ i tt informa-- eon ot thfmethod. for e^ t l S o n - i tS'cclrcial tion concerning thepreparationrii-rbone- III, * summary of the work on sources of the carcinogenic hydrocarbons, ill, a ,, j iv, a correlation of chemical structureaa . various active hydro- Buvaary of investigations on the metabolic fate ox varx carbons'. Thera is a very extensive bibliography. Fleeer 1. I Promotion of Oncer by Polynccl.er Hylro-'hon.. Dnlr. Penna. 33- genic hydrocarbons ntre of a t)OBBibie reaction leading to ture and chem. reactivity, nature P -oTrino^enic hydro carcinogenesis and of the "^ ^ [ "" r b o d y ^ y steroid metabolism,'their carbons can be produced at times in the ^ 8TM e adrenal cortex. The S i JSSrJS T 3 ". p ---- a API 04636 -201 * 1=TM M etabolic elim in atio n o f a carcinogen probably is a d e to x i- conversion into ie r iv s , of oercapturic acid. . M ,, . r . L. 7. and 7l e . . r , U. C a rciao g .n lo Hydrooarhon.. " O rfanlc O h an i.try", 3U ^ ' o f S a n l c n a t i v it y and atru o tu ra; c o r r e la tio n . 1 t h chemical reactivity;m ethod. of ,y n th ..itln g carcinogenic hydrooartons. . . T * woU B r M A P itc h Cancer bb an O ccupational D isease. 35- Medeclne S o ciale 18 126 workers in the province o f S e5 PB, y . Kenry made a were found two ep ith ylio m ata o n ly , " J a8 ^ t h e i r content in 1.2 hen- chemical examination ?f J (thw two most e f f e c t iv e cancerogenic zeneanthracene.and 3*^ benzopyre , 1 itc ll 1-3% of the f i r s t , work- W -- * o f , 0- 500. Therefore It . ^ - ^ o o r t l n * t . " r r '^ a r n a m a l o n . In th . . opinion of the a b s tra c to r.). 37. S a fa fa r , f . U. "d S lt g r M v a ., ^ " s i r S d li i.S i 7 r 9 3 3 - 3 S .d n c lu .lv ,. U.S. Put. Health Septa. ffi. 1517-1526 8.23.*)) ` ` w 38. O u g lie n la e t t l, M. Bn M - a d - Bead. Produc. M h B u ll. A c*i. Mad.. ! . 89- 9M 1939) the li t e r a t u r e . He questioned variou s The author f i r s t review s , re^ardini: the am ber of h o s p ita ls in some o f Germany s r T reo o rts to the managers o f the observed ca ses o f cancer an d ." c i t i e s In crease o f cancer was affirm ed road b u ild in g system in these c i t i e s . *nc*ew but without r e la tio n to macadam roads. "Industrial Poisons of U.S.", 39. Hamilton, A lic e . Cancer from Tar tod Petroleum , Uio-7 (1925) uo. H anllton, A llo a . / I n d u a t r l e l U.S. th . only pub- u a h ^ m 1 s r - i* 3 3 - ~-- a t tha p a ra ffin prooeaa In a petroleum re fin e ry . - - X T In KBS t h . H ealth Committee o f the League o f S a tlo n . ra o u ea ta i i t . -- ^ 1 In a . 0 ^ 1 . * * * * " i S i S r ' i h M i S S p o n n d a S n nan t*de 1 . poa.lU. * 1 API 04637 -21- Heller to make an Intensive investigation in this country, and his report was published in 1930. Heller confirmed the impression held by American ^ i t l on cancer, that thee, of occ^ationaloriglnare rare in the United States. He found in the records of the two Jew York Vioonitals specialisingtainr cancer only 37 caseB and tar product., 26 of of skin cancer that could th... occurring L n handling gae-hene. tar or pit*, cnly *"> ** S e r g a ^ ir .r n ir ^ o ^ : s l u " ^ ^ ta" ud 5 S H n i M f u c f s j s ^ u- = s s r r H H , and these were not considered V the physician in charge 0 e n caeee. Hartwell, J. 1. Surrey of Compound, which hare been le.ted for Carcinogenic Activity. U. S. Public JiiirJi chemical carcino- ' This bulletin represents a survey of the rieia oi wie i_ tv higher animalst the action of carcinogens on isolated ttssu*: 1 iie cSt^r" . plants, protosoa, and bacteria is not consid-. results of the testing of 6l of these compounds ^ ^ L ^ t h e work while U5 are new to the whole cancer literature. Aitogetherthe work ( W * 1 " g^i0.1 c c ^ e f " i S p S t U 06), II, Polycyclic [nogli* cyclic (59)! VI Uhalaaeified (77)* Within this arrangement, compounds are ^"tlbl^give then grouped according to prototypes and alphabetically. The S The tor. ccnditlon. ehc. th. ESSSKSS author &? =. sites. ` aaller- iS^u: and blast-furnace tars and pitch are briefly outlined wit)V \ *he - d health record API 04638 - 23- . . examns., gas-works tar and pitch were responsible for 70.2# of the cases while coke-oven tar and pitch were held responsible for only 5*11#. Coke oven tar is much the less injurious especially when cognizance is taken of the fact that coke-oven tar is used much more extensively. The presence of olefins in gaB-works tar seems to be of particular importance and may be a cause of oil cancer. Occupational cancer does not occur in the briquet mfg. industry . Mineral oils vary in carcinogenic activity according to their olefin or uneatd. hydrocarbon content. There is no method for.the detn. of the amt. of olefins in the various erode oils; if such a method existed, it would be possible to measure the cancer- producing power of mineral oils. Cancer is not attributable to the occu- pagion of mule spinner in the U.S., possibly because of the carefully refined lubricating oils used on the machines, thus ensuring relative freedom from olefins or unsatd. hydrocarbons. . . . m Henry, S. A, Study of Tatal Cases of Cancer of the Scrotum. J. Am, Med. Assn., 102. l667 (1937) Ul* Hieger, I., Spectra of Cancer-producing Tars and Oils and of Related Sub stances. Biochem. J., 2U, 505"'H (1930) Hoffman, F. L. Mule Spinners Cancer. Monthly labor Rev, of U.S., 7, *+57" * U75 (1928) . kf, Hoffman, W. J. Industrial Cancer. Prevent. Med., 6, 7-3u (193&) ' One of the seven types of industrial cancer discussed is cancer of skin in workers exposed to coal, tar, pitch, soot, shale, petroleum and arsenic. They may cause an epitheliomatous form of cancer. In, Hogouneng, L. The Cancerigenic Hydrocarbons from Tar and the Tarring of Roads. Ann. Hyg, Publ. Seciale, 22., 1-7 (1939) The cancerigenic hydrocarbons found in coal tar produce skin cancer in exposed workers usually only after direct contact with the skin for long periods of time It is believed that man is much more resistant to the action of these materials than lab, animals. ... Ug. Hueper, V, C. Cancer in Halation te Occupation and Environment, Bull. Am. Soc. Control Cancer, 25, Ho, 6 (June, 19^3) Owing to induetrial development, the general population and factory workers in particular, are exposed t o m a r y new environmental factors, many of which are disease producing. Occupational cancers are caused by numerous chemical and physical agents. Among then are the heavy metals, nitrates, aromatic y"**>o compounds, bansol, asbestos, mineral oil, soot, radio--active substances, ultraviolet radiation and X--rays. The author citeB statistics taken mainly from the records of industrial concerns, but points out their shortcomings. Cancer of the urinary tract due to coal-tar is the most recent addi tion to the list of occupational cancers. It is most frequent in the aniline dye and related industries,. ^9. Hone Office, Rept. of Departmental Comm, to Consider Evidence eo to Occurrence of Epitheliomatous Ulceration Among Mule-Spinners, (London, 1926) Contains a bibliography on cancer among petroleum refiners. API 04639 -23' cn v ? An Investigation into the Incidence of Cancerous or Precancerous ^ * 'skin Lesions Among Tar Workers in New South Wales. Wed. J. Australia, 8 '26'Thi conclusion 1. ttat ter used In No South . 1 for l o c i road-work is not a serious danger. 51. I.P.T. Cancer Research Committee. Carcinogenicity of Spindle Oils. J. Inst. p6t' Committee^has not been convinced that the so-called incidence of cancer is in any Bhape or form connected with the use spindle oils. . International Lahcur Office. Carcinogenicity of Oils. Ind. and Labour Informa52. ^ v a r y i n g temperatures have been prepared to determine at what temperature carcinogenic compounds are formed, from which experimentait w o 3 appear that such compounds begin to be formed between 500 J * * - . the maximum yield lying between 800 and 900 C. Attempt 19 made to determine the constitution of a few apparently pure or almost pure compounds isolated from such tars. Applying their standard test for determination of carcinogenicity, the staff found that olive oil :aeatsfoot oil, sperm oil were non-cancer producing and they have reason to suppose that natural skin fat is an important factor in the prevention o cancer. . International LabourOffice. "Occupation and Health", I, 5^7 (193u) : 11 837, 53. 1156 Before mineral oils came into vogue the practice in textile was to use sperm, lard and neat's-foot oils and to some extent castor oil a S colza oil. Henry states that shale oil was introduced about IS50 and American petroleum oil about 1S6U, and that, towards 1872, these were being used as components of spindle oil; also that Russian oil as first imported about 1880, Rumanian oil about 1900 and iqoq and all these were used for this class of lubricating oil before the war. During the war Scottish shale oils naturally came more into use for lubricating^purposes. Oil refiners have their own private formulae til m i x S , * t t t r e is no doubt that the bulk of the oil sold for lubricating spindles, during the past forty years has been principally made up of natural mineral oil. . JLeeorllo. to th. 1929 TM p o r , the Uanchs.ter ttoc.r J l the distillation of tars, the carcinogenic products begin to at a Rnn ..jLT-atnrti ranging from 500 to 600 C. and reach a maximum at between 800 ? * C. The addition of sulfuric acid at the time of use to make the oils harmless without injuring or modifying their lubricating power. . 5U. International LabourOffice, Occupational Tumors. Suppl. to Occupation and Health, I.L.O., Geneva, (Oct, 1939) .. , .. ,, Carcinogenic substances are discussed under the headings of byiro carbons, nen-radioaetive inorganic compounis, radioactive radiation, and parasites and microbes. Attention is called t t " sence of any c o m o n physical or chemical characteristics shared by these various cancer-producing agents. API 04640 --24-- It ie suggested that the cancer problem 1b essentially biochemical ,, j tV._t lta solution will come with the discovery of the nature and cause of the intra-cellular chemical changes which follow the application of a carcinogenic agent. ' Jordan, H. Ikperloental .tali., on tha Production of O n c e r by 0.-.ork. Tar. 55? * 2 ? 2 * of Char., in .hit. ale. treated , 1th tar^for four ^oSS^TST S a n e . in about 1 th. tin. required with tbe hole tar. Ho prolifiatloSrouli be produced 1th onthraeen. oil. Different " `oo 'howei difference in the rapidity with which they developed proliferation of l n S by the tar. Apparently the .ork .a. not o d t7 1 " fet to d i i f j S t ho. nany of th. aloe .ith preoanceroue changes would have developed actual carcinoma. 56. Kennaeay, I. 1. Th. fomatlon of a Oanc.r-proluolng Sub.tanc. fron I.oprene. 5 J. Path. Boot. 21, 233-8 (192" ) ' 56a . Ka.ahata,K. Lung Cancer Among Oenerator-Ow Worker. In th. Stool Mill. <te" 'D l i n J 6the5piit3$>y.ar., 21 on... of prlnary few oarolnona ..re ' s k 7 :7 ^ : s r I . W - U r 5.7^ . T h . n e t a . ^ . . n ^ appear very early in the brain, spinal cord and lymph nodes. The du tion of lung caaoer is very short, about 7 months. . 5 7 . Kennaway, E. L. Cancer-Producing Constituents of Coal Tar. Brit. Med.J., 5&l" 7c i i w r >formation by tar products was investigated by ithor. Only higher fractions boiling at 250*500 C. were found active in inducing cancer (creosote, green oil, crude anthracene and pitch). . 56. KennaHy, 3. 1. Caneer-Producln Tar. eal Tar Praotlon.. J. Ind. Hygiene , ^ ' 5S TM f f e i n t . on H t . n l thoue.nl I c e and analy.1. of a great n u . ZStSft Z T A l - r i S jraotlon S T o n 50? S i? i.i S f f i S i . ' S i . 'S i a EirTr.'the s r s s v & s r S u S . ^ ^ ! f ^ r ; . r 7 l S I U r 7 r S ^ ^ t Sp r = e " Loer. The briquetting industry has reported more than,half of the known eases ^ tar o S o e r f Tar naii by dl.tlllln* ceal at a lo. tenperatur. (bale. Kcno) produces cancer very slowly or not at all. 04641 fcPl  25- cq Kennaway, E. L. Experiments on Cancer-Producing Substances. Brit. Med. J . , II 1-ii (1925) ' Cancer has been produced in mice by substances obtained by heating CoH?. isoprene, yeast, human Bkin to temps, ranging from 700 to 920. A petroleum which produced no tumore of any kind in nice in a prolonged experiment showed vary active cancer-producing properties after exposure ' to 880. 60 Kennaway, E. L. and Leitch , A. The Anatomical Distribution of the Occupational ' Cancer. J. Ini. Hygiene, J. 69 (1925) 61 Kennaway, E. J. Further Experiments on Cancer-Producing Substances. Biochen. * j 2^ U 97--50^ (1930) * "Carcinogenic substances were obtained by the action at roomtempera- ture of AICI-j on acetylene, xylene, naphthalene, naphthalene and brono- benzene and letrahyironaphthalene, the last two being the most active. Two cancers were also obtained in a series of 10 mice painted with a sola, of 1 ,2 ,7 ,8-dibenzanthracene. a-Phenylnaphthalene was prepared by action of AICI3 on CgH^Er and CirH,. The distillates up to 3^2 C. containing the hydrocarbon were inactive but the residue in the flask was highly carcinogenic. Cyclohexane, cyclohexane, styrene, hydrophenanthrene, hydrochrysene, hydroretene, perylene, naphthalene and various naphthalene derivatives all gave negative results. .62 Kennaway, 1. L. and Hieger, I. Carcinogenic Substances and Their Fluorescence Spectra. Brit. Med. J . , Ho. 3622, 10W+-- 6 (1930) . . This paper is a review of a large amount of work by the authors in an attempt to correlate fluorescence with carcinogenesis. Tar oils, spinile and shale oils, which show carcinogenic properties are also strongly fluorescent. . 63. ewley, J. Cooperation. J. Inst. Pet. Tech., 18, 2U2 (1932) Mention of the formation of a committee by the Institute of Petro leum Technologists to follow the work of the Manchester Cancer Committee, 9t. iling, A., Samssonor, H. and Beros, M. The Tarring of Highways as a Possible Agent in the Causation of Pulmonary Cancer. Bull. Acad. Med. 120, 130" U3 (1958) Xxpts. in mice showed that the tar, as used on roads, produces cutaneous tumors and malignancy in the lungs. A substance contg. the benre (a) pyrene nucleus of decidedly cancerogenic properties has been sepd. from the tar, . . 65. Kling, A. Samssonov, N. and Heroe, M. Possible Relationship between Tarring of Highways and the Increase of Incidence of Pulmonary Primary Cancer. Bull. Acad. Med., 121, 78^-91 (1939) , ,, 4. Since tar contains benzopyrene, a recognized cancerigenic agent, it cannot be considered as inoffensive. Experiments on mice definitely con firm this assumption. API 04642 - 26- 66. Koelsch, F. Cancer and Occupation. Monatschr. Krebsbekampf. 7 (1937) The author, In the form of an abstract, presents a survey of the relation between cancer occupation. He includes bone cancer caused by radioactive substances, skin cancer from soot, tar, parafiin and lubricating oils (of which those boiling between 250-500* are of especial importance), skin cancer'from arsenic as well as cancer and sarcoma from ultraviolet and sunlight. . . . Kunae, C. Mineral Oil and Cancer. Ghent. Ztg., 52* U07-8 (1935) 67. A study of the of Germany indicated that the number of deaths from cancer was always greatest in regions where mineral oil was .found, refined or used. While no definite relation is established, the author suggests the possibility of the existence of such a relationship. Further research, on this problem is indicated. It.is pointed out that mineral oil by itself does not cause cancer. It may, however, become one of the contributing factors, together with others. . . 68. Lane, (Ci.ghlG). Occupational Dermatitis. Arch. Dermatol, and Sy.phil. 1SU Describes the case of a 68 yr. old machinist who for 3 yrs. had a dermatitis of the face, arms, axillae and lower abdomen. There wore scattered areas of tan-brown hyperkoratotic follicles and follicular, plugs. Keratoses were presont on the scrotum and thero were keratotic areas on the arms. Autopsy revealed carcinoma of the esophagus. Dr. Lane believes the skin changes to be due to oil to which the man was exposed in his Uo yrs. as a machinist, and that the condition is that described by White among machinists, oil.workers and mule spinners in England. It apparently is rarely seen in this country, possibly because oils employed here are less carcinogenic. Lsuber, H. J., Hildebrand, X. and Schocko, H. Possible Therapeutic Action of 69. Carcinogenic Hydrocarbons in Treatment of Cancer. Z. Ges. Exptl. Med., 105, 370-- 9U (1939) Xssentially less harmful therapeutic measures are available. The dangers are dmcnatratod on mice treated with methylpholanthrene. 70. Leitch, A. Mul Spinners1 Cancer and Mineral Oils. Brit, Med. J., 2, 9I+I-3 (192U)Bandered an inert Californ.ia. oil very active by heating it. (No details as to temperature, etc.). Crudo oJls from Assam, Borneo, Egypt, Burma and Badarpur produce malignant growth. Q*lician, Bussian, Californian and Persian samples were negative. Lyth, R. The Eolation of Carcinogenicity of Minerai Oils to Certain Physical and Chemical Characteristics of These Oils. J. of Ind. Hyg. 1 5 , 22^-37 (1933) 72. Lyth, H. Molecular Distillation of Lubricating .Oil. Naturo, 139* 371* U937) A brief report is giver, of the distillation of a Scottish shale oil, using a specially designed molecular still. The most striking result is the inversion in the change in the physical properties going up the tem perature scale, i.e., the first fractions show higher refractive indices and densities than the original oil, with gradually descending values^ from fraction four as the temperature is raised. Lata on the properties API 04643 f of the shale oil distillates are tabulated. These experiments are part of an investigation.of the interrelation of refractive index and viscosity to activity on injection, and thereby carcinogenicity ' when applied to the skin. . 73. Mioscher, G.,.Almasy, F, and Zehender, Z. Is Thero a Connection Between the Benzpyrene Contont and the Carcinogenic Effect of Tar? Schweiz. Med. Wchnschr. ]1, 1002-7 (1^1) , . Tho authors have xaminod the benzpyrene content of gas tar In various towns in Switzerland, using a method dovisod by Alnasy. Then the tars were purified and their carcinogenic effect determined by painting on mice. The investigators tried to evaluate the re sults by means of a statistical method in order to ovorcome tho difficulty offored by the fact that many mice die in the long period needed for the experiments. They find a simple, regular relationship botweon the benzpyrene content and the carcinogenicity of.the tarf 7*. Murray, J, A . , et al. Discussion on Experimental Production of Malignant Tunops. Proc. Hoy. Soc. (London) B113. 268-92 (1933). A symposium in which some attention is paid to carcinogenic chon. compounds, -and to tho ianunochemistry of cancer. 75. O 'Brien, H. P. The Problem of Cancer and Oil. Petroleum Times, 2J., U62 (1932) An open letter to the editor of tho Petroleum Tines (London) in answer to an editorial in the issue of March 19th. The writer points out tho humanitarian nnd scientific values derived from the cancer research of tho Manchostor Committee and criticizes the technological viewpoint of the editorial. . 76. O'Donovan, W, J. Cancer from Handling Anthracene Coke in tho Dye Industry. Br. J. Dorset, and ^^ph., Throe cases of cancer in a factory employing only 25 men. 77. Phillips, C. Relationship between Skin Cancer and Occupation in Texas: Review of 1569 Teriflod Lesions Occurring in 1190 Patients. Texas State J. Med., ^ 6, 613-16 (19^1) 78. Prosser-White, R. "The DeTnatorgoees" 195-238 (193*0 Dermatitis and cancor from petroleum products, shale and tars. Excellent review. 80. . Hoffo, A. H. Experimental Research on tho Production of Pulmonary Tumors by the Distillates of Pool Oil. Presee Med., 538 (19^0) The author demonstrated pa oil, taken from tho streots of Buenos Aires, identical to that from motor car exhaust, which con tains carcinogonip substances. Roffo had rats Inhale the combustion gasos of fuel oil and later found a number of pulmonary cancers among the animals. By injecting a distillate 'of the fuel oil into .the auricle of rabbits, he produced turners in 80^. 81. Houssy, G. and Oberling, C. Can Tarring of Roads be Considered as a Cause of Pulmonary Cancer? Bull, Acad. Med. 120, 181-90 (1938) Tho danger is not considered to be of significance although the possibility is admitted. API 04644 -28- " T W923L h o r inve.ti*ated the pel.< ^ . f " " / n e ? ^ " ^ f t t a of constituents Toy painting mice * C 1 tar readily develops malignancy was r'nSS; X. ^ e ^ n^tar from coal oil 1 . tort effective ae a tumor inducer. ' 83. Schwartz L. Skin Diecasee I n ^ E ^ ' ^ n pfrUtoa^ J It has heon found that workers in oil reii An above the average for ta oa tho hands, foroarms and logs of provalonoe ^ ano^ machinists in contact with oil and greas^was Sso noSdf I b S 10* 1 f such workers were found to have thoso growths. The CSC of totally encloeod nanufacturln* oyetenm Chi of protective ointments is suggested. Schwartz, 1. and Tulipan, 1. "Occnpaticaal Di.caeo. of the Skin. 1935 . 5 ^ . Scott, d. Occupational = TM t o s c | cf the Paraffin Berkere in Scottieh Shale ^ 85. Oils. Brit. Med. J., 8.28.22, 3S1" 5 . j H 'Cancer and other Diseases of the Skin Caused by Mineral Oils. 86. S0!!" ^ a ' i . S " L T i c d . J., . 1 3 (1929) . ,, ,, - - s-rtew cf literature fir 1926-lSS>t. !' *Prt f 0o"miMe'3 on 87. S W t t i j 4 e t r i a ? S n Irrttcrta to to. Public Seal, toe,. . ,8 8 Southa m and Wilson. Oaaoer ef the Scrotm. .Brit. Bed. J,, 2, 971-3 (1922) S3. Spenknto, J. B. tod ^ ^ ^ f S t o t o i ' o ^ . ^ ' a r t ' f . 5' t o o ^ i h i t ' S f ^ i S t o ^ ^ ^ d e f r ^ - their potency. e i t h e r no oil furpaesos lanolin in this respect. . .. folo!t., l. occupational Cancer, tota d. Internet. Ver. f. irobebeknopfurc, 90. * ^Several^ieolated an... of.Inn* boon reported and among works oxpoaod to coal dus , to/itoSem- latos, but tho number is snail. 91. Touteehlacmdor, 0. Indnatrdal *" OetooDnyi.scto1.oof.nro-rrWarroebnrnfeoerre cehn.n^eHejr o f t -lcnn^ workers, zralo epiraere' spob* cancer, which has not appearod in oernany, a-a par tho so who work in the petroleum industry. ~ s s s s , = s ; x v . n K . r r : = S " a i `" (13^1-5 (1937) danger of development of cancor ore Occupations ir. which there is fvreiE.oeor.ic, reviewed; aacy data aro given regarding substances considered carcxnogo . API 04645 - 29- the location of malignant tuners, their latont period, protective measure Jfai%ndustrial-hygienic typo, quostions of insuranco, otc. There ia no e p . ^ g e S connon to all carcinogenic substances as a pronoter of cancer growth. . Ton.ehl3.ilor, 0, ooo Tar Boqnlro Ultra Tlolot Llsht to Prolneo Ski. Oonoort 93- Klin. Wchnschr., 16, 128U-5 (1937) . . t , tho White nico wore paintod with tar. Cancers developed not o .ly i.. the irradiatod snimhls hut also in thoso kopt in a dark chanber so that not only a preparatory but also an independent cancorogenic effoct oust be ascribod to $ar. . Toutschlaender, 0. Light and Skin Cancer. Ztschr. f. ZrobBforsch. 0, Sl-92 % U 9 U The author investigates tho problen of pother'or not a photodynanic influence is necessary in tho genesis of tar cancer. Ho conductedexnerino^ts on tarred nico kept ip a dark roon. Since skin cancer developed tho**naintod n * it is ovidont that ultra-violet light is not a S q S S i i f l a f c ^ c e r genesis, .he sane is shown by the devolopnent of spontaneous cancors in two wild groy house nice that lived - briquet factory. Nevertheless there is a widespread boliof that both cancer of radiant source and tar cancer of the skin are caused by bona. According to Boffo, both typos are originated by oxidation and deconpositicn Sf cholesterol *n the tissues which nay be caused by radia tion ae well as by influonco-- cancer-provoking cyclic hydro- I^ftLSylScrM.d. fwp*li. on.*, therefor., g * r l tho of on? or both factors. Touraino, A. and Bout, H. Cancer iron lubricating Oils. Hev. Mod. Franc. 20, 95. 2S5-92 ^ ^ ^ O0^ lete j^Yio 0f caacor fron lubricating oils, its occur renceclinical synptons and tho medico-legal aspects of such,cases. 96. Twort, C. C. and Zog, H.E* Mulo Spinners* Caacor and Mineral Oils. Lancet 1, 752 (1928). . 97. Twort, C. C. and Ifaltoa, J. . Sxporiionts on toe N a t u r e o f t h e C a r c i ^ g o n i c igents in Minoral. Oils. J. Path, and Bacteriol., 2, lh9-lbl (1929) Tron a consideration of the ehonical reactions ipvolvod, tho authors are of the opinion that it is to bonezonoid hydrocarbons that cortain mineral oils owe their carcinogenic properties. Trcatnont of tho oils with sulfuric acid lod to almost total abolition of their car cinogenic properties, and similar rosults were obtained by the adoption of ne*thods of oxidation, and redaction. . . . 98. Twort, C. C. and'Twort, J. M. Studios on tho Origin of Cancer. Ztschr. f. Krebsforsch., 2, U9I (1930) . . . This is a genersd survey of the work of the Tworts, and is based on eaperiaents oa ^5,000 ice, & n a i l e r number of rats, guinea-pigs, and rabbits, and on the use of some hundreds of varieties of tars and. oils or various capacities to cause cancer. There is but little probability that an acquired physiological immunity against cancer-producing aubstancoa oxlsts. Tho authors* various substances are divided according to their API 04646  *30- cancer-forming capacity in mice, so that every group has about ton times the power of the preceding ono. 99. Twort, C. C. and Twort, J. M. Classification of Four Thousand Experimental Cil and Tar Skd,n Tumours of Mice. The study from which this classification was made was based upon _ 29,10 0 .animals. , 100. Twort, C. C. and Fulton, J. D. Further Experiments on the Carcinogenicity of Synthetic Tars and Thoir Fractions. J. Path. Bact. 119-43 (193). 101. Twort, Ci C. and Twort, J. M. Tho Carcinogonic Potency of Mineral Oils. J. Ind. Byg. , 2CU-2 2 6 (193D ... Painting nice with refined shalo oil induces cancer more roadily tV'or painting with refinod potroleum well oil. The most potent fraction from shalo oil is unfinished lubricating oil from which most of tho paraffin wax has boon removed but which had not been treated with BgSOij. flitrod. Tho *heavier grade oils arc lost potent than spindle oils* The Cancer-producing property of oils appears to be relatod to fluores cence. Oils having a bluo fluorescence soem more active than thoso having a groon fluoresconce. Chrysone dissolved in oleic acid possesses carcinogenic properties 102. Twort, C. `c. and Twort, J. M. The Rolative Potoncy of Carcinogenic Tars and Oils. J. Hyg., 29, 373-9 (193D , , _, , 1 mothod haaboon devised whoreby the potoncy of any given carcino gonic agent can bo compared with that of a standard agent. A unit of carcinogenicity- U X. - has been oetahliehed, and a concentration of 500 units por cubic centimeter is considerod to induco the mn-Hrrvin rolativo rosponse in a niaals whon tho agent is applied twico a week. The carcinogenic powors of oils rate as follows, in descending orders Shale, Tonesuelan, Bomoo, Rumanian,Persian, Californian, Mexican, Midi-Continental, Texan, Pennsylvanian, and Russian. Hypothetical standard agent Penn* Odl Cal. pet. oil Oil Bo. 3 Shale Oil Pitch Gas tar Pinepe synthetic tar Effect of refining Ponn. oil Mothyl sulfite oxtract Oil Bo. 3 Distillate 300-380<>C./I2nn Methyl sulfite oxtract Shale oil Oxidized at I5O-I6O0C. Pinono synthetic tar concontrate Oxdlizod at 100C. Cxidizod at 150-l60C. 100,0 0.1 3..0 0..6 ks.o 25.0 9U .0 706.0 oil 22.0 0,6 12.0 53t us.o 0,3 37^5 ..0 2369.0 58.0 API 04647 -31- - rwcrt, C. C. and Pulton, j. D. Concentration of the Carcinogenic Principle 1 in Oils and Tars. J. fuor Krebsforsch. 25. 5U3-73 (1932) In tho attenpt to o s b o b s U.C, by physical and chemical characteris tics, the specific gravity# refractive index and iodine number appeared noBt promising, though other features nay also ultimately prove to ho of value., . -u iwort. C. C. and Lyth, E, The Selection of N0n-carcinogonic iron Carcinogenic X Oils. J. Hyg., 21. ^ 7 3 (1933) , , All the aninal and vegetable oils tested by tho authors on aninals have proved to be incapable of inducing tunor formation during the life of their aninals On the other hand, oleic acid and linoloic acid, unsaturatod fatty acids which nay be present in connercial saponifiable oils, have frequently induced tunor formation; observations which in thoir opinion are of the h i p e s t importance in relation to many cancers other those of tho skin, and possibly even of those of the skin it self. It has been found that tho carcinogenic constituents of a given crude are not equally distributed in the various products of distillation obtadned from this crude. The activity of the first products to cone over in tho still, the motor spirits, etc., is negligible, and that of the lamp oils, burning oilB, light fuel, ?tc., is also of little account, but when we reach the boiling rango of tho lubricating oils a definite carcinogenic activity nay bocone manifest, Among the latter the most active grades are, on the whole, tho spindle grades, closely followed by oils of a Eedwood viscosity of 00 to 1500 at 70 P . , with a gradual docroase In activity as one approaches the internal combustion engine (motor car) grades. The crude oils themselves, as a rule, aro somewhat loss potont than the motor car oils, but of course, it will necessarily depend upon tho amount of refining to which the latter have been subjected # bofore.being marketed. . ' . 105. Tnort, C. C. and Twort, J. M. Carcinogenicity of Spindle Oils. Oil and Colour Trades J . , 2, 1193-^ (1937) A physical anl an a ^m*T. test for oarcinogenicity and a physical and an .winni tyst for dermatieity of nineral textile oils are described. The average results of these tests on 66 oils (excluding shale oils) collect ed 9-10 yrs. ago ad on 66 oils collected recently a n tabulated. (The animal test for carcinogenicity is not yet completed for the recent oils.) These results Indicate that the original oils are definitely worse than the recent oils in both the dermatitis tests, while in the cancer physical test there is no significaht difference. It ie expected that tho figures for the recent oils in the tost of carcinogenicity will be lower than these of the original oils. It is concluded, however, that little is being dono to improve mule spindle oils fron the biological standpoint. There aro also indications that the average oil used in some of the cotton-spinning towns is more , dangerous than that used.in others. , 106. Twort, C, C. and Twort, J, M. Notes on Sone of the Procedures Adopted for Assessing the Biological Activity of Mineral Oils. Oil Colour Trades J., 251-5 (1938) . . Mineral oils nay induce dermatitis or cancer of tho skin. In dotg. tho carcinogenic aspect 3 essential detns. are made: d . , n and kinetic 04648 API r 107. viscosity COT). The data collected are based on the utilization of. formulas for'assessing the biol. activity, especially from its carcino genic aspect. In Formula A, R = (n-l)/d where R = sp. refractivity, n = refractive index aad.d * density. In Formula B, R Formula 1 is used in obtaining the cancer refractivity CR from Formula C which is CR = Re 3 U-O.9OO)/20. In Formula D the refined cancer re fractivity RCR = CR - (KV/50). Results, where thpso mineral oils havo boon employod, are shown in tables in which mineral oils are groped according to toxicity and according to tho n drop. Tho significance f d. in rolation to tho n drop among oils of similar toxicity and the significance of viscosity in relation to tho n drop among oils of apparently similar toxicity aro Bhown. Tho real Jif i^fa" Jvln at tho truo biol. activity with greater accuracy is the lack of uni formity of tho inert fully hydrogenated constituents. There is quite good correlation betweon caroinogonicity, refractivity, n drop and toxicity. . Twort, J. M. and Lyth, R. The Concentration of Carcinogenic Materials in Mineral Oils by Distillation Prccessos. J, Hyg. 2, lbl"y . Twolvo acid-trootod lubricating cuts of a crude, Borneo mineral oil, wore testod for carcinogenic activity. Tho wholo range was bio logically active, which activity had boon foreseen from an examination of tho physical eharaotoristies. Tho pook activity was a r o ^ a ViS" cosity of 200-250 Centipoisos at 25 C. Molecular distillation gave a groater concentration of the carcinogenic material than ordinary dis tillation at from 3-1G am. In confirmation of provious findings, the middle fractions of a Borneo crudo.oil were mostly responsible for pathological ohanges in tho organs-- fatty infiltration f hyaline dogonaration of tho spleon. long tumors wore more proyalont la usuai when this type of agent is usod for testing carcinogenity for tho skin. Their incidence was rathor higier in the more viscous fractions 1 this inoidonoe was apparently not correlated with carcino gen! ty. for the skin Twort, J. M. and lyth, R. ` Skin Cwicor due Tars Usoi for Preservation of Fiyhing Bets. Nature, WU, W 6 (1939) Several fishermen oontraoted cancer of tho tisla a i t w .handling the tars. Mouse eapts. showed that different coal tats differed in their ca rcinogenie activity, although all produeod some cancers. Creosote oil anthracene oil wore also carcinogenic. Only coal tar made in vertical low-tesg. retorts should bo used on nets. . Twort. C* 6 Mule-Spinnors 1 Cancer: Bio Rood for Using the Correct Oils. Oil-00 lourTrados J., S.29.U1, fhe eancer-prodicing powers of ninoral oils used in the cotton industry from difforont fields of origin, in tho crude and refined statos, wero thorougily examined and tho resul ts showod that .there is a dangor of any one producing cancer of tho skin if appliol long onough but tho oils from oortaia fields are tho noro likoly to do so. Special attoation was paid to the examination of the physical characteristics of various mineral oils, and it was proved that a Imowlodgo of their refractive index ^ viscosity provides a more reliable estimate of their cancer-producing powers than the application of tho samplo to the skin. This test is accurate, rapid and inexpensive, while that with tho Bkin is variable, lengthy and costly. API 04649 33- m e chiof lino of investigation has boon a continuation of the work on tho nolocular distillation of mineral oils with the ohjoct of isolat ing the substancos rosponsihlo for thoir carcinogenic activities. Aninal oSorinonts with fractional iistillatos fron a Venezuelan oil aro in progross. Fractions obtained by nolocular distillation of a carcinogonic shale oil have boon subjoctei to qhronatographic absorption and two apparently puro hydrocarbons havo boon isolated in snail quantity; those aro being investigated chonically. Painting experiments with fractions obtainod by this nathod havo shown that nany of then aro highly toxic for nico. None of the substancos so far tostod has beon shown to possess a high carcinogonic activity. A few spindle grade oils and threo oils intended as vohicles for insocticides havo beon tosted for carcinogenicity. A colloidal material intendod as a protective against carcinogenic oils hsu boon tosted. Thero aro indications that it has sono protective action. Tho carcinogonic activity of two products fornod during the purifi cation of carbonisation has boon tosted, and found to bo loss than that of the avorago gas tar. . 110. Ullnann, K . , Opponhoin, M. and Eille, J. E. J. Ind. Hygiene, 8, 288, 3 ^ Tho lesions caused by crude petroleum are the sane as thoso caused by crude coal tar, showing the analogous substancos must bo present in >oth. The final products of distillation aro tho most active, especially paraffin oil. The carcinogenic agent is presont in fractions iron 200 0. to U5O 0 C., but it is not cortain that tho sane substance CBusos both deraatitis and opitheIlona. . > 111. . Yalado", P. Cancer of tho Hiaaan Dung fron Dust iron Tarred HoadB. 2.1.39, 161 . . . . ' Presso Mod., i 112. _ Van Thonischo, M. 1. Chooical Cancer. Ing. Chin., 20 , 30-5 (1936) Moro **'nr' twioo as nany eases of cancer duo to soot were found among swoopers th *yi raong any, other occupation* Personal cloanllnoss and clothing that fits tightiy'around the oxtrenitios and around tho nock aro the bee* pweventiwoe. Similar care will do nuch toward preventing cancer due to exposure to gasoline and its derivatives, paraffins, oils, nnA gyoaaes. Such precautions are ovon nore nocossary in eases exposed to tar, pitch, rosin or . n i dyos. Strict nodical sup ervision and tho uso of processes which ovoid contact of tho workers with tho product will furthor-reduce the danger. . . 113. Wampler, P. J. Occupational Diseases of the Skin (by L* Schwarz). "Indus trial Medicine" , 19^3. 327-9 ,,, ,, , .. Cliinm7 sweeps1 cancer has l)een reported in Sagland core frequently than in any other country. It is said that the incidence of cancer among chimney sweeps is eight tines more common than among the general population. Ca ncer of tho scrotum of chimney swoops, however, is on tho deeline in v-wgi wh and. It is reported, as being practically aon-esdstoat in othor countries, except for an isolated cas? or two in Germany. Tho local irritation and. rubbing in of the soot as the swoop is cramped in dosconding tho chimney is said to be tho cause. API 04650 "it" lar is usod in "building roads, in making roofing paper and folt. Pitch is used for making conduits, lacquers, insulating matorial, groasos, and mlnatal cements, and workers at thoso occupations aro affoctod with comodonos, tumors, worts, koratosos, and opitholioma, mostly of tho scrotum, lip, face and hands* l No cases of mulo spinners' cancer havo boon roported from Franco, Germany, Russia, or Poland. Tho author node examinations of thousands of nulo spinnors employed in tho Unitod States and did not find any casos of scrotal cancor, althou^i thoro wore maiy casos of folliculitis and fcoratosos of tho thighs caused by oil-soaked trousors. . . llU. Waniok, H. Molanodoraa and Keratoses iron the Action of Asphalt. Arztl. Sachverst. Ztg., 66, ^9 (19I+O). In th? preparation of cork plates (heat-insulation plateB of asphalt and cork) raysh dust develops under very unfavorable working conditions. Two wprkors, who had boon working for threo months, suffored from pigmentation, inflammatory changes and hyperkeratoses of tho face, foreams hands* Tho hypeiplastic procossos wore.intensified in the older workers* The symptoms wore aggravated by light. The intonsive action ?f asphalt dust is considered to bo tho cause* 115. Watson. A. F. Tar Cancor la Mice, III, An Apparatus for tho Preparation undor Standard Conditions of a Bigily Potent Carcinogenic Agent of low Toxicity. Brit. Jour. Sapor. Path., 12, 1&L-7 (1931) . With an ada ptation of the apparatus of Hague and Wheoler tho author h**# succeeded in making from purified terpentine, at 850 C. a relatively aoa-toxio tar whidfolicited tumors after 210 days in 9<# of tho survivors from a group of 37 icJ nost of these growths were malignant* . . . Wolwart. Cancer from Paraffin fax and Mineral Oils* Soifons* Ztg., 62, 792-- 3 (1935) Most chemists and dermatologists boliovo that workors in paraffin factories got cancor from the paraffin itsolf whilo Schorbor and Toutsch- laender claim that cancer does not cono from paraffin but from mineral oils*. . TTindaus, A* Bennhak, 3* Some Derivatives of 3 Benzopyrene. Z* Riysiol. Chom. 2U 9, 256-66 (1937) By analogy to arrays(*-rays produco and x-rays euro cancer") , carcinogenic hydrocarbons should bo tested for possible thorapoutic values. Suggos tive rosul ts have boen obtained with 3 ,U-bonzopyrnet(I). Wood, P. C. The Hon-Carclaogonic Nature of Purifiod Mineral Oils. J. An. Mod. Assn., l6Ul (1930) ' Tho gonoral clinical ovidenco that thoye exists no rolation botwoen tho therapeutic use of refinod potroleun products and the oceurronco of cancer is confirmed by eaperinental studies. , Wood, H. B. Paraffin Not Productive of Cancer. J. Cancor Bos., 1^, 97-102 (1929) . . I ~ool H. B. Skin Losions Anopg Tar Workors. J. Cancor Bos., 1^, 5 ^ 9 (1929) Different typos and composition of tars are discussed. Only tar obtained from tho distn. of coal at high temps, contains a substance API 04651 - 35- carcinogenic to certain lab. animals. Workmen handling coal tar showed . tar warts as a result, hut no other effect. So irritant action on the human skin was found from low temp, distillate tar or from.petroleum, tar. i?l ^ ' Woodhouse, D. 1 Carcinogenicity of Synthetic Lubricating Oils. Pet. Tech., 20, 1057-63 (193*0 ' J. Inst. 12? * Yamagiwa and Ichikawa. Experimental Study of the Pathogenesis of Carcinoma. J. Cancer Res., Ill, 1-21 (191?) In 1915 produced cancer by the experimental application of tar to tho ear of a laboratory animal. API 04652 .4 FOR INFORMATION ONLY - NOT FOR PUBLICATION A CONTRIBUTION OF INFORMATION TO IT ! BINS OF TUB A . p . I . JUDICAL ADVITORy COHTTTZE SHELL OIL COMPANY, INCORPORATED WOOD RIVER RESEARCH LABORATORIES REPORT NO. M-12^7 JULY 2, 19^5 SUBJECT: CABCTKXZHIC HYDROCARBONS AND RELATED COMPOUHDS A LTHRATUEE REVIEW AUTHOR: H . H . ZUHRMA Exportation of This Report Is Subject to License Uhder the National Defense Act gpRT.T. OIL COMPANY, INCORPORATED WOOD RIVER RESEARCH LABORATORIES REPORT NO. M-12^7 JULY 2, 19*0 SUBJECT: CARCINOGENIC HYDROCARBONS AND RELATED COMPOUNDS A LITERATURE REVLEtf AUIBOR: E. E. Z U H E M A Industrial cancer vOs 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.3 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. JS During the thirty years that have elapsed since that discovery, a great deal 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, irvrJ'^ n g mice, rata, fowl, rabbits, and dogs have been used, and many methods of application, including oral administration, intramuscular, intravenous, and subcutaneous injection, and painting on the akin. Hie 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-apans 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 beoause there Is less likelihood of Interference by simultaneous spontaneous carcinomata. Die carcino genicity of a given compound Is Influenced by many factors including the genetlo constitution of the animal species and strain, Its age and sex, the diet, the physical condition of the animal, the purity of compound, dose, the physical state of the compound, the solvent used, and the route or site of application.*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 asbestosJU'37 , inorganic compounds of arsenic and of zinc2 -, aqueous potassium hydroxide and aqueous hydrochloric acid2 ethyl alcohol*5, glucose3 5 , fructose25, and a aber of nitrogen compounds, most of which contain one or more benzene rings 2 Radio active elements compounds are not included in this discussion since the mechanism of their producing cancer is probably quite different, i.e., physical rather than chemical. Materials which havo been reported API 04654 Beport No. M-12^7 2 as carcinogenic and whose carcinogenicity is probably due to the prejence or polynuclear aromatics include coal tar and pitch2* '27 blue shale oil5, mineral oils and asphaltu~, tobacco tar39, tars obtained in the destructive distillation of teaUcond coffee110, diesel fuel52, distillates from Borneo crude petroleum5-1, combustion gases from fuel oil"1, the SOo extract from a spindle oil produced from a paraffinic crude petroleum5", the products obtained by heating acetylene, isoprene, yeast, a non-careinogenic petroleum fraction, or human shin to' 700 - 900C*>, and the products obtained by treating acetylene, xylene, naphthalene, or tetrahydronaphthaleno with aluminum chloride3 . The carcinogenicity of tars produced by heating various substances tends to increase with increasing temperature. 30.us it is probable that the carcinogenic hydrocarbons present in certain coal tar and petroleum fractions were to a large extent formed during the process Bteps and were not present in the cool 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, ccording to the Manchester Committee on Cancer"9, the following order of increasing carcinogenicity prevails: Russian, Pennsylvania, Texas, Mid-Continent, Mexican, California, Persia, Romanian, Borneo, Venezuela, and shale. Diis 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, 1U6 were 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 the most detailed study are the three derivatives of 1 , 2 -benzanthracene: 1 ,2,9 ,6-dibeosaathaoene, 3;^-benzpyrene, and 20- methylcholanthrene. i*fti three arc potent carcinogens. It has been estimated that they have been investigated in 60 different labora tories. 20 A llet of nest of the known carcinogenic compounds Is given la Table l,pcgce 5-J. Structure, complete with numbering systems, ara 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 tan to fifteen years ago. lfce 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 whilo in others the results of only one or two experiments are available. Ifte reader Is referred to Hartwell for mere 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 con taining at least two benzene rings. More specifically, the first of these classes consists, with only throe exceptions, of derivatives API 04655 Report No. M-12hJ 3 of phenanthrene. Hie exceptions are tetraphenylmethane, trlphenylbenzene. and trlphenylethylene. In Table 1 the hydrocarbons are subclassLfled 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, ^he position of a benzene ring, or tho position of an alkyl group. However, a paraffinic or naphthenic hydrocarbon or one containing only one or two bonzono rings may with a reasonable degree of confidence bo assumed to be non-carcinogenic. Hie amount of compound required to produce an experimental cancer on a test animal is surprisingly small. Coses of 1,2,5^6-dibenzanthracens and 3,^--benzpyrene as small as 2.5 and U micrograms, respectively, give positive results when applied to mice.^-'Discontinuous application, e.g., once a weok, of a given total quantity of material is Bro effective thou continuous exposure.15 A single application of 20methylcholanthrono in 0.6jl bonzono solution is capable of producing cancer on the akin of mice. W5 Ifeen different carcinogenic hydrocarbons, e.g., methylcholanthrene, benzpyrene, and diben*anthracene, are applied successively the effeot is additive33. The investigators who made this observation offer the hypothesis that carcinogenisis is essentially an acciznulation of abnormal protein within the cell. Since so many compounds have been tested for carcinogenicity it is only natural that eeveral 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 physioal or chemical property would be much simpler than the rather long and tedious prooess of exposing experimental animals to the substanoe in question. Tluoresoenoe spectra have received more study in this regard than m y other property?>7 >8 8 .*Hie author of a reoent paper m rf* the statement that all known oariinogenic chemicals are fluorescent.U3 However, it is obvious from a glance at Table 1 or Hartwell's tabulation that this la too broad a olaim. However, many investigators have used fluorescence spectra to good advantage in this field, there appears to be a definite correlation with carcinogenicity, at least with certain types of compounds. Hie 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.21.22 Attempts have also been made to correlate refractive index, or more specifically, specific refraction, with the carcinogenicity of oils. API 04656 Report No. M-12^7 k The Manchester Committee on Cancer"*9 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, which 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 wnfl 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 lmown about cancer itself. Whether or not carcinogenisis 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 the sex hormone estrone, are carcinogenic. Spontaneous cancer quite often occurs in the reproductive organs. Furthermore, the very potent carcinogen, pq.Tn+*yTwhni rrhhTf>nfi} can be produced by the degradation of deaoxychclio acid, cholic acid, or cholesterol, the first two of which 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-methyloholanthrene Is formed in the body through the degradation of bile acids or cholesterol. The possible connection between eanoer produced spontaneously and carcinogenisis by sethylcholaathrene or related compounds therefore remains a matter of conjecture, at least for the present. There has, for obvious reasons, been little attempt to induce oamoer in human beings through exposure to the various com pounds that .are carcinogenic to mloe There is, therefore, no direct correlation between the susceptibility of man and the test 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 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 lnnocous to man. Until that can be proved, the only safe policy is to regard all compounds which are harmful to mice aa dangerous and to avoid exposure by humans. EEZ VAC /i _ API 04657 Report No. M-12^7 5 table I OARCTNOGENIC COMPOUNDS All compounds listed by Hartwell25 unless otherwise indicated. 1 . Derivatives of 1 ,2-benzanthracene The following derivatives of 1,2-benzanthracone: 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 f 10-aldehyde, -C 0 10-methyleneaoetoxy, l-C-O-*C-CH^ I ' H 0 i .i 10-methylenecarbomethoxy, -C-C- 1>-c h 3 H H I 10-cyanomethyl, -C-CN H 3-methoxy 10-methoxy 1+,9-dimethyl 1+,10-dimethyl 5 .6- dimethyl 5.9- dimethyl 5 ,10-dimethyl 6.7-dimethyl 9,lo-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-dibenzanthracene5* 1 ,2,5,6-dibenzanthrac ene API 04658 Report Ho. M-12U7 6 The following derivatives of 1 2 ,5,6-dibcnzanthracene : 9-methoxy 2'-methyl 3' -methyl k-methyl 9-methyl H - l" ,9-mcthylcne -6- E k.lO-dimethylone, -6-6 ' H E 3 k'-dlmethylene (phenanthra- M-dlmathj-La acendphthene) Derivatives of 3,h-benzpyrene 3,k-benzpyrene Ite following derivatives of 3,^-benzpyrene : 5-aldehyde V -methyl 5-methyl 1 ',2''-dihydro, 1+7-methyl E H H 5.6- cyclopenteno -6-C-(j- 1E 6.7- cyclopontone 1 ',2',3 V-tetrahydro- Na salt of 9,10-endo alpha,tota succinic acid: l' ,2',3',k'-tetrahydro 10-acetyl 3,k,8,9-dibenzpyrene 5,lO-dlhydro-3,4,8,9-ilbenzpyrene 7-methyl,1,2,3,k-dibenzpyrene 3. Derivative of Cholanthrscene Cholanthrene The following derivatives of cholanthrene: 20-methyl 20-ethyl 20-isopropyl 20-tert-butylJ u 15.20- dimethyl 16.20- dimethyl 15-hydroxy, 20-methyl 15-keto, 20-methyl API 04659 Report No. M-12U7 7 4. Other Derivatives of Phenanthrene Colchicine The following derivatives of 3,^-benzphenanthrene 1- methyl2 2- methyl2 2-ethyl2 2-isopropyl2 7 -methyl2 -methyl2 2,9-diethyl 2-methyl, 1,2,Se ditene phennnthene Cholesterol oleate CHj H ^ H-C-(CH2)3-C-(CH3)2 1,2-dimethyl chrysene2 5-methyl chrysene17 U,5-BBthylene chrysene17 5,6-dimethyl chrysene17 API 04660 Beport No. M-12U7 8 CE Estradoil caprylate 0 CBj-(CHs )fi"C"0' 1 ,2-cyolopentene phenanthreno2 5 . Other Aromatic Compounds Te traphenyime thane 1 ,3 ,5 -triphenylhenzene Triphenylothyleno 30 API 04661 Report No. M-12Vf 9 5 . organic Compounds Containing Nitrogen 2-amino, 1 -naphthol Alpha naphthylamine13 Eeta-naohthylanine 0 OH Acetylcholine, CH3-C-O-CH2-N-(CH*); o-amimo azotoluene /-- CH, ( ;'-_RW==NW- ' A-TBVEi \_/ V-/ p-dimethyl aminoazobenzene (butter yellow) \ / -N=N'\ O ;--N (CH.); Scarlet red CH3 \_J** Indole -CH3 EOf -- -N = N- \ ___ J v_/ / \ \_/ Syyryl ^30 ii / CH,-C-N-( 91 \ ; -C-N- \_/ -NH: Benzidine i z HsN N-NH; /\_/ .API 04662 Report No. M-12^7 10 1,2,5,6-dibenzacri dine 1,2,7,8-dibenzacridine 3,^,5,6-dlbenzcarbazole 7. Miscellaneous Arsenic trloxlde Potassium araenlte Aqueous hydrochloric acid Aqueous potassium hydroxide Zinc chloride Zinc sulfate Ethyl alcohol Fructose Glucose Galactose API 04663 Beport No. M-12^7 BIBLIOGRAPHY 1 . Auld, S. J. M., J. Hist. Pet. Tech., 24, 577-33 (1936). 2. Badger. G.M., Cook, J.W., Hevett, C.L., Kennavay, E.L., Kennavay, * N. M., Martin, R.H., and Rotlnson, A.M., Proc. Roy. Soc., B129, 439-67.( 1 9 ^ ) 3 Badger, G.M., Cook, J.W., Hevett, C.L., Kennaway, E.L., Kennaway, N.M., and Martin, R.H., Proc. Roy. Soc., B131. 170-82 (1942). U* ; G j Cook j J W ^ Hslevood ^ G A D y Hevett ^ C *X*f Hleer j I j - and Kennaway, E.L., Ibid, B-117, 313-51 (1935)* 5. Berenhlum, I., and Schoental, R., Brit. J. Exp. Path., 24, 232-9 (19^3). 4 6. Bottomley, A.C., and Tvort, C.C., Am. J. Cancer, 21, 781-3 (1931*). 7. Bruce, W.F., and Todd, F . , J. Am. Chem. Soc., 6l, 157-81 (1939) 8. Campbell, J.A., Brit. J. Exp. Path., 15, 287-94 (1931*)- 9. Campbell, J.A., Ibid, 20, 122-32 (1939) 10. Cook, J.W., Nature, 14^, 335-8 (19**0). 11. Cook, J.W., Haslevood, G.A.D., levett, C.L., Hleger, I., Kennaway, I.L., and Mayneord, W.V., Am. J. Cancer; 2g, 219-59 (1937). 12. Cook, J.V., and Kennaway, E.L., Ibid, 50-97 (1938). . 13. Cook, J.W., and Kennaway, E.L., Ibid, 39, 381-428, 521-82 (19l*0). 14. Oook, J.W., Hleger, I., Kennaway, E.L., and Mayneord, W.Y., Proc. Boy. soc., Bill, 455-84 (1932). 15. Cramer, V . , and Stovell, R.E.,Cancer Research, 3. 668-81. (1943) 16. Dobrowolskaya-Zavadakaya, N., Compt. rend. soc. blol., 129', 1055-7 (1938). 17. Daalap, C.E., and Warren, S., Cancer Research, 3, 606-7 (1943). 18. Evans, E.E., J. Urol., 38, 212-15 (1937). ' 19. Fieaer, L.F., "Chemistry of Phonanthrone", Reinhold Publishing Company, N.Y., (1937). API 04664 R eport Ho. M-12U7 1 Bibliography (Continued) 20. Fieser, L.F., Am. J. Cancer, 4, 37-124 (1938). 21. Fieser, L.F., and Campbell, W.P., J. Am. Cbem. 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. Erp. Biol. Med., 0, 369-73 (1942). 24. Haddov, A.#, and Robinson, A.M., Proc. Roy. Soc., B127, 277-87 (1939) . 25. Hertvell, 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. Hsnry, S.A., Kennavay, N.M., and Kennavay, E.L., J. Hyg., 31, 125-37 (1931). 28. Hieger, I., Bioehem. J., 24, 5 0 5 - H (1930). 29. Hueper, W.C., J. Ind. Hyg., 16, 255-79 (1934). 30. Kennavay, I.L., Brit. Med. J., 1925, H 1-4. 31. Kennavay, E.L., Blochsn. J., 24, 497-504 (1930). 32. Kennavay, E.L., and Siege, 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 Vedler, 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.7. 36. Morton, A.A., Clapp, D.B., and Brand, C.F., Science, 82, 134 (1935). 37* Normann, M., Z. Bfebaforach., 47, 288-302 (1938). API 04665 Report Ho. M-12*7 amioaraphy (Concluded) 38. Robson, J.M., andfBonaer, G.M., Nature, 1*2, 836 (1936). 39. Roffo, A.H., Prensa Med. Argentina, 26, 721-38 (1939). Roffo, A.I., Bol. Inst. Med. Exp. Estud. Cancer, 1, 7*1-56 ' (1939). in. Roffo, A.H., ibid, 16, Ho. 52, 1-6 (1939). *2 . Roffo, A.H., Ibid, 2, 661-98 (19*0). 43. Roffo, A.&., and Roffo, A.E., Jr., Ibid, 20, 1*3-87 (19*3). It*, Shear, M.J., Letter, J., and Perrault, A., J. Hat. Cancer mat . , 2, 99-113 (19*1). 45. Simpson, W.L., and Cramar, W., Cancer Research, 3, 6o*-5 (19*3). ' " *6. Stallybrass, C.O., J. State Med., *, 2*9-68 (1926). *7 . Stovell, R.E., and Cmner, V., Canoer Research, 2, 193-7 (19*2). It8 . Twort, C.C., and Pulton, J.D., J. Path. Bact., (1930) . 119-*3 *9. Twort, C.C., M d Lyth, B., J. Hyg., *6*-73 (1933). 50. Twort, C.C., d Twort, J.M., J. Ind. Hyg., (1931) . 20*-26 51. Twort, C.C., and Twort, J.M., J. Hyg., 22, 373-9 (1930). 52. Twort, C.C., and Twort, J.M., Ibid, 2, 130-*9 (1935). 53- Twort, C.C.,nd Twort, J.M.,Lancet, 1935, II, 1226-8. 5*. Twort, J.M.,andTwort, C.C.,J. Hyg., 39, 161-9 (1939). 55. Woodhouse, D.L., J. Inst. Pet. Tech., 20, 1057-63 (193*)- 9 For those wishing to acquire a more extenslre background In this field, a review by Fleser20 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. API 04666