Document DGoaX8GD890y8nbN7yDL4z4Jn

FILE NAME: Oil Industry and American Petroleum Institute (API) DATE: 1955 DOC#: API050 DOCUMENT DESCRIPTION: Letters, Meeting Minutes, Reports, Journal Articles & Other Relevant Documents from 1955 i COT! FROM D. V. S. FOR PERSONAL INFORMATION OF MEMBERS OF MEDICAL ADVISORY COMMITTEE AND ITS SUBCOMMITTEE ON CARCINOGENICITY_______________ ESSO LABORATORIES Standard Oil Development Company P. 0. Box 51, Linden, N. J. January 11, 1955 Mr. D. V. Stroop American Petroleum Institute 50 West 50th Street Nev York 20, Nev York Dear Mr. Stroop: I am attaching recent minutes of the Committee on the Carcinogenic Action of Mineral Oils received In this office from Dr. Nevquist. I believe that the agenda of this meeting, that the first page of attachment A, that attachment B and attachment C would be worth while duplicating and forwarding to the members of the Medical Advisory Committee and the Kettering Laboratory group. Also, I believe the report entitled MRC.54/880, CAMD.54/17 as well as MRC.54/875* CAMD.54/16 would be worthwhile duplicating and dis tributing to the members of the Medical Advisory Committee and the Kettering Laboratory group. I was particularly interested in report MRC.54/880, CAMO.54/17 since it is stated In that report that the relative potency of D-1953"54 compared with that of D-1952-53 is 1.9 This I would interpret to mean that the standard carcinogen solution used by this group is almost twice as active this year as last year. It Is because of data of this nature that I feel the group at Kettering must periodically redetermine their standard curve for methylcholanthrene. Very truly yours, fa/ R. E. Eckardt REE:ilk R. E. ECKARDT, M. D. Attachments API 06032 MEDICAL RESEARCH COUNCIL vor Specified Circulation ([Members of Committee) MRC.54/870 CAM>.Ag.l7 C O m i m E ON TEE CARCINOGENIC ACTION OF MINERAL OILS AGENDA for the Seventeenth Meeting to be held at 2.30 p.m. on Friday, the 17th December, 1954 at 38, Old Queen Street, Westminster, London, S.W.l 1. Minutes of the previous meeting (MlC.54/6o6 - already circulated) 2. Progress Reports Progress Report No. XII by Dr. D. L. Woodhouse (MRC.54/854 CAM) 54/12) - Enclosure A 3. Plans for future research 4. Possible Carcinogenicity of Diesel Exhaust Fumes (Minute 138) (a) A review by Research Group No. 2 of the Institute of Petroleum (CAMS 54/13) - to be circulated (b) A copy of a paper to be published in "Chemistry and Industry" by Professor G. R. Cierno - (MRC.54/856 - CAMD 54/14) - Enclosure B 5. Possible Carcinogenicity of Anti-fpawing Agents Copies of sene recent correspondence are circulated for information and discussion - (MRC.54/857 - CAM) 54/15) - Enclosure C 6. Any other business. 7. Date of next meeting. API 06033 > For Specified Circulation (Committee members only)"" MIC.5^/85^ CAMO.5^/12 Committee on the carcinogenic action of mineral oils PROGRESS REPORT NO. XII (December, 195*0 by D. L. Woodhouse The experiments previously reported at weeks were terminated at 52 weeks. The complete results are given In the tables, copies of which have been submitted to Dr. Irwin. These suggest that In the Rabbit Test the A series show greater activity with the exception of K^SgA which had 5 tumours compared with 7 tumours for I0+S2* Kj^SgA produced the highest final number (16) cf. with 17 for the stronger standard. There seems to be a marked spread of activity over the fractions and Ki^SP showed a slight activity. No fraction showed very great activity to the mice, ^SgA. being the most active according to the actual number of tumours produced. The experiments on fractions produced from the picrate, and maleic anhydride treatment, and the residue materials, have now been commenced, comprising 20 fractions provided by Dr. Crulckshank and (K^S^) from Professor Morton. API 06034 ^ specified Circulation Tcomittee members only) /> MRC.5^/856 CAMD. 5^/11 COMMITTEE OH THE CARCINOGENIC ACTIOH OF MINERAL OILS A paper by Professor G.R. Clemo, recently published in "Chemistry and Industry", is circulated for information. CARCINOGENIC ACTION OP CITY SMOKE At Liverpool I described the isolation of fractions A, B, and C (each a mixture) from city smoke. These have nov been tested for carcinogenic action as veil as 2 fractions isolated similarly from Diesel bus fumes. Fractions B and C produced malignant tumours in 12 of the 29 effective mice treated, the earliest tumour was after 6 months painting (1# - CgHg) but the average vas 9 months. Pure 3.4 benzpyrene is recorded as producing tumours from 4 - 6 months in 50$ of the mice treated. Further 13 of the mice shoved skin papilloma and 5 of them lung nodules (3.4, 3.3 and 1 nodules resp.). Fraction 'A1 produced some lung nodules but otherwise has not shovn the activity of B and C. The Diesel fractions on the other hand have so far given negative results apart from one mouse developing lung nodules. It is clear city smoke has a marked carcinogenic action and that Diesel bus fumes do not appear to be an important factor in this action. API 06035 T- R i f l e d Circulation ^ o r n ^ ttec nenperB only) MRC.5^/657 CAM3.5VI5 COMMITTEE OK THE CARCINOGENIC ACTION OF MINERAL PELS . n-f a. letter from J.C.R. Hudson, Medical Research Council to G.H.W. Cullinan. Shgii p ^ c a l s Lta., dated 21st October, 1954. Re: Ministry of Bousing Cosxnlttee on Synthetic Detergents. "We have heard from Professor Crulckshank, vho as you knov represents the Medical Research Council on this Conmlttee, that an anti-foaming agent called 'Foamrex W may he used in future for the prevention of foam in sewage disposal works. Professor Crulckshank tells us that this anti-foaming agent consists of spindle oil and is supplied hy your Coqpany, and hs has asked if one of the Council's expert committees could advise on the possible dangers that might arise from the widespread use of this substance. Accordingly X am writing to ask if you would be kind enough to let us have a detailed description of the position of 'Foamrex W '. If at a later stage it is thought desirable to carry out some experiments on it, would it be possible for you to provide samples?" 2. Copy of reply from G.H.W. Cullinan, Shell Chemicals Ltd., dated 29th October, 1954. "With reference to your letter of the 21st October, Foamrex W is a material imported from the States. We are, however, making available on an experimental basis at present a similar material, the composition of which is as follows Spindle Oil ... Oleic A d d ... Estax 37 se see Diethylene Triamine We believe that Estax 37 is a polyoxy-alicalene fatty acid ester. It is marketed by the Watford Chemical Co. vho may be prepared to disclose to you the exact composition. It is thought that the American material, Foamrex W, is of similar constitution but using a product, Nonisol 210, in place of the Estax 37, the Nonisol being marketed by the A1 Rose Chemical Co. We shall be glad to make samples of our product available to you although we would stress that experiments now in hand may suggest modification to this formula before any product is put into larger-scale use. In particular, we are experimenting with an alternative petroleum fraction to replace the Spindle Oil." 3* Copy of Specification from Watford Chemical Co. Ltd,, dated 18th November, 1954 Main Constituent Form ESTAX 37 I A.V. Average Melting Point or Setting Point S.G. at 20C. E ffe c t o f Water, 5 gms in 45 c .c . Solubility (Minimum %) at 15^C. in: Vegetable o il Kerosene Tech. White O il 'SI Type of Emulsion Other Properties Hexa-glycol oleate Cleei yellow oily liquid C 5 1.01 Forms stable creamy _____ emulsion _____ 5 10 5 Water-ln Oil Non-ionic API 06036 t MEDICAL RESEARCH COUNCIL Por gnucifjed Circulation {gSSiTttee members only) \ MRC.54/880 CAMD .54/17 Congnlttee on the Carcinogenic Action of Mineral Oils The 1953-4 Experimenta vlth Mice Table 1 shove the results The Standard The responses to D2 vere close to those obtained in the previous year; the responses to D() vere significantly greater than in the previous year. Ptor 1952-3 the figures vere:- Standard or Fraction E.T.L. (52 weeks) 10$ Date Total Number of Tumours D2 13.9 t 0.4 11.4 t 0.8 38 D (i) 24.8 t 1.6 17.1 * 0.6 25 The relative potency of D in 1953-4 to that of D in 1952-3/ using Expectation of Tumourless Life as a response, is estimated to be 1.9 vlth fiducial limits (P 0.95) of 1.4 -2.8. The 10$ dates give a result consistent vlth this but a great deal less accurate. The departure from unity is due of course to mouse variation; the result is of some interest as shoving the degree of accuracy obtainable. Fractions and In 1953-4, Kjt'it yielded two tumours and K ^ (4(l) none. In 1953-3 neither fraction gave any tumours. * Fractions fyS, IC^SA and fySP The residue K^SP yielded no tumours. The aromatic fractions vere more carcinogenic than the non-aromatic; this shows up clearly in Kj,Sg and K^SgA. In the other seven pairs the differences are small, but vlth one exception always in the same direction. The mean difference in Expectation of Tumourless Life for the seven is 1.00 t 0.39, which is significantly different from zero. -1 - API 06037 Table 1 Experiments with mice at Birmingham in 1953-1951* Standard or Fraction d2 D (i) **.l* KkMi) K4Si K 4 SxA K4S2 K^SgA k ^s 3 KjjS^A fySj* K^S^A V5 K i|S 5 A K^S6 K4S6A K^S<jr Kj^S'jA KiS8 Kl*SeA KliSP Expectation of Tumourless Life (limited to 52 weeks) 12.9 t 0.6 18.1 i 1.0 50.6 t 0.8 52 52 50.1 i 0.6 51.9 t 0.2 52 52 51.2 i 0.6 51.2 i 0.6 1*9.6 i 1.3 51.2 t 0.8 51.2 i 0.6 51.9 i 0.1 50.7 i 1.0 52 50.1* i 1.0 51.6 i o.i* 1*7.3 1 1.6 52 Date when lOjt of survivors had tumours Total number of tumours 8.7 * 0.1* 1*0 10.3 t 0.6 1*5 not reached 2 tf ft 0 M IV 0 ft ft 2 tf ft 1 ft tf 0 ft VI 0 ft tf 3 ft ft 2 It ft k Tl tl 1 V It 2 II ft 1 1*6.3 t 1*.0 2 not reached 0 1*3.9 i 0.6 3 not reached 1 28.6 i 2.3 . 8 not reached 0 - 2 - API 06038 , MEDICAL RESEARCH COUNCIL ^ For -- ^ ed cireulatl?g fCcmuittec meuiDers onijJ MRC.54/875 CMC 54/l6 Ccanlttee on the Carcinogenic Action of Mineral Oils Progress Report by W. Carruthers and J, W. Cook We have received from Professor Morton aromatic extracts of all the sixteen 2 k distillation fractions prepared from the Kuwait crude. The top ten of these (jQ.Sj.Aa to KjjSgAh, covering the boiling range 365 - 390C) have been subdivided into maleic anhydride extracts (M), picrate-forming parts (P) and residues (R), and suitable blends of these made up as described in CAMS 54/10 and sent to pr, Woodhouse for the next series of biological tests. The relative amounts of the subfractions obtained from each aromatic extract, and the quantities used in preparing the blends for testing are recorded in Tables I and H . Table I also shows the amounts of maleic anhydride extracts (M) obtained from the six fractions in the boiling range 350-365 (K^S^Aa - K^S^Ab). These fractions have not yet been separated into the P and R subfractions. Table I Subfractions from Aromatic Extracts of Kuwait Dist'tv'*' M Maleic anhydride extract, P picrate-forming part, R Residue ! ' i f ; 1;. *1> b.p. of Volume Su\>fractions obtained Distillate of i Fraction\ "extract" M P R C received gms. i gms. * * 1 : 1 JKQi^^SiAAab > 335502* m 335552* 654300 42..69 ii O0..9805 iI .- .m 11 -- i*i mm K^SgAa ! 355 m 357* 410 3.1 i 0.84 1 - - j- ! m KjiSijAb i 357* - 360 , 9^0 3.8 i 0.45 1281 33 1495 i 59 1 K^SoAa 360 - 362* 1100 9.3 1 0.93 - :- } K^S^Ab ; 3f2* - 365, ; 1160 16.8 * 1.6 ! - 1 t ; K^S^Aa i 365 m 367* : 570 k.k j 0.86 j 200 39 1180 : 34 , K^S^Ab , 367* m 370 j 1130 9.7 ! 0.95 I302 30 550 54 1 Kj^S^Aa ; 370 m 372* ! 790 6.4 0.90 `194 27 467 1 66 ' ^ ? 5 Ab : 372* - 375 1150 5.5 ! 0.53 i 225 22 806 ! 78 1 fySgAa 375 - 377* ! 210 1.5 j 0.80 ; 98 52 . 83 44 1 K^SgAb : 377* m 380 ; 1^30 11.0 ; 0.87 1243 19 1942 ; 73 ! W 1 380 - 382* i 1000 9.4 1 1.0 ! 280 31 420 , 47 fySlAb - 385 1 1100 10.8 1.1 ! 280 28 1640 1 64 . V e * * : 385 - 387* ; 1050 8.4 ! 0.89 |207 22 1546 ; 57 Kl^SQAb | 387* 390 1 735 9.1 1 1.37 194 30 ;438 1 67 API 06039 Table II Bien* of Kuwait Subfractions for Biological Testa Ail are to be diluted to 250 c.c. in liquid paraffin except K^SgAa M, P and R, vhlch are to be diluted to 200 c.c. i- ' fyS]*Ab fySjAa K^b "fySgAb Kh&iAa KhS^Ab 'A.SaAa ; ^S0fcb Weight (gm.) of Subfractions in Blends -------------------- , N p R i I 1 0.5 28 21 : 53 96 ; ! 1,5 _______________ i 0.6 : 0.7 l 21 56 , 30 112 !! ! l -5 i.9 o o H ri : 1.2 1.3 96 63 i *3 164 ! ; -------------------- - 31 46 i 36 82 i t 26 | 75 1 63 These M, P and R subfractions vere prepared as outlined in previous Reports. The aromatic extract was treated vlth maleic anhydride at 100 for several hours, giving an acidic adduct from which after distillation over sodium hydroxide, the a l e l c anhydride extract (M) was recovered. The oil which had not reacted with the maleic anhydride was subsequently treated with picric a d d in ethanol, when part of it separated in the fora of a crystalline plcrate. Decomposition of this vlth regenerated the picrate-forming part of the oil (P). The remaining part (R) was recovered from the mother liquors of the picrate crystallisation. We are now engaged in a detailed chemical examination of these subfractions. Three new anthracene hydrocarbons have been obtained from the maleic anhydride extracts. Fractions K^S^Aa N, fySyAb M and K^SgAa M yielded the same colourless hydrocarbons, m.p. 223-227, when their solutions in petroleum ether vere kept at -10. Elementary analysis of this compound indicated the molecular formula cl6lU> the ultra-violet absorption spectrum shoved that it was a derivative of anthracene. Oxidation with chromic acid in acetic acid, followed by fractional crystallisation of the product afforded a quinone m.p. 241-243, which has been identified as 2:6 dlmethylanthraquinone by mixed melting point with an authentic specimen. The melting point of 2:6 - dimethylanthracene is recorded in the literature as 250. The hydrocarbon isolated from the oil fractions is not 2:6-dimethylanthracene but is evidently the well-known eutectic of the 2:6- and 2:7*isomers whose melting point has been given as 221-222 and 225-226. Oxida tion of the autectle produces a mixture of the corresponding dimethylanthraqulnones fras which in this case the 2:6-lsomer was obtained. Be'teuse of the small amount of material available ve were unable to isolate 2:7-dimethylanthraquinone from the oxidation product. The evidence obtained proves conclusively the presence of 2:6-dlmethylanthracene in the three maleic anhydride extracts, and very strongly indicates the presence of the 2:7- isomer as veil. 2:7-dimethylanthracene was previously found in the fraction K^S^Ab M. Two other anthracene hydrocarbons were obtained from K^SgAa M and K^SgAb M. One of these was a yellow hydrocarbon cl8l8> m -P- 293. The ultra-violet spectrum shoved that it va6 an anthracene derivative, and oxidation with chromic acid yielded a quinone, m.p. 317-320 It 2 API 06040 has been identified as 2:3:6:7-tetramethylanthracene by mixed melting points of the hydrocarbon and of the quinone vlth authentic specimens. The other hydrocarbon obtained from these tvo fractions had m.p. 131 and also analysed for the molecular formula C].gHi8* Its ultra-violet absorption spectrum again confirmed the anthra cene structure. She quinone C^gH^gC^, obtained in the usual way, had m.p. 194 2.96. The melting point of this hydrocarbon does not correspond to that recorded for any known C^gH^g anthracene derivative. Further work with it is in progress. 2:3:6-trimethylanthracene, which was previously isolated from fySgAb M, has now also been found in K^S^Aa M, K^S^Ab M and K^SjAb M. By fractional crystallisation of the picrate from K^SgAb P, we have isolated a hydrocarbon CjjH^g, m.p. 143, which has been identified as l:2:8-trimethyl- phenanthrene by mixed melting point vlth an authentic specimen. The benzthionaph- thene derivative from the same fraction, mentioned in the last Report, has been desulphurised with Raney nickel in boiling ethanol, thereby affording a liquid naphthalene hydrocarbon C ^ H ^ g . The naphthalene structure is supported by the ultra-violet absorption spectrum which, in combination with the infra-red spectrum, suggests that it is a tri-, or possibly a tetra-, substituted naphthalene. The present position of the chemical work might be briefly sumnarised as follows. There are sixteen "aromatic extracts" from all of which maleic anhydride extracts (M) and from the top ten of which picrate-forming fractions (F) and residues (R) have been prepared by the methods described above. Detailed chemical investigation has so far been largely confined to the maleic anhydride extracts (M) and even these have not yet been completely covered. Seven pure anthracene hydrocarbons have been isolated from them. The eutectic mixture of 2:6- and 2:7- dimethyl-anthracenes was found in K^SjAa M, K^S^Ab M and K^&2Aa M, and 2:7- dlmethylanthracene itself in the next higher fraction K^S^Ab M. 2:3:6-trimethylan- thracene was isolated from K^S^Aa M, K^SjjAb M, KlSeAb M and Kj^SgAb M; the last of these fractions has also yielded tvo anthracene derivatives of unknown structure. The first of these has m.p. 169-170, and gives a quinone m.p. 169-170; the other hydrocarbon melts at 224-5 and its quinone at 225-226. Finally, as described above, 2:3:6:7-tetramethylanthracene and another C^gE^g anthracene derivative, m.p. 131, quinone m.p. 195-196, have been obtained from K^SgAa M and K^SgAb M. The tvo picrate-forming fractions K^SjjAb P and K^SgAb F have yielded four homogenous compounds. From the former 1:8-dimethylphenanthrene and an unknown compound which appears from its elementary analysis and ultra-violet absorption spectrum to be a tetramethylfluorene, have been isolated. The ocher fraction, K^SgAb P, has yielded 1:2:8-trimethylphenanthrene and. a sulphur-containing com pound Cj^H^S, known to be a derivative of 6:7-benzthionaphthene. 3 9th December, 1954. API 06041 ESSO LA B O R A T O R IE S S T A N D A R D OIL D E V E L O P M E N T C O M P A N Y P . O . B O X SI, L I N D E N . N.J. m e d ic a l r e s e a r c h d i v i s i o n .,, B E R T E. E C K A R D T . P H .D .. M .D ROBEK' D IR E C T O R w u n R A C E H O R A U fc G E R A R D E . R H .O .. M .D . HEAD TO XICO LOG IST IN D U S T R IA L H Y G IE N E SE C TIO N N A T H A N V . H E N D R IC K S . C H .E . HEAD OR SECTION F R A N K L IN W . C H U R C H . M .S . G E O R G E M . W IL K E N IN G . M .S . INDUSTRIAL HVO IEN ISTS n is w * p t * ham m ................... m i -- k 9t jm * M a w k la I fea to p te T T te ^ a S u M la Um IX I f atfi * iw a tti* to t a i Mm* * a lto to tona * ` a . X. A a* x . m u r , i a. API 06042 CHICAGO DAILY HEWS, Monday, Jan. 2k, '55 ROADS TO DEATH? CABCER NAY BB CAUSED BY ASPHALT, SAYS BRAZIL EXPERT B Y EEHDRIK J. BERKS Dally Hava Foreign Service SAO PAULO, Brazil -- The upsurge in lung cancer nay be due nore to asphalt and oil than to cigaret smoking. That Is the theory advanced b y Prof. Antonio Prudente, Brazil's Internationally fanous cancer expert. In an exclusive Interview at his cancer hospital here, Prudente, who is a pioneer In cancer surgery and hormone treatment, praised Aaerica as the leading nation In cancer research. Be also cited cortisone as one of the nost effective drugs in the battle against cancer. Be Is now experimenting with it in leukemia cases. PRUTSHIE was one of the first to use the hormone testerone in cases of breast cancer. He experimented with it from 1939 to 19*6, whan the results of his studies were published in the United 8tates. Be is also one of tbs few physicians in the world familiar with the adrenal operation, a type of surgery invented at the University of Chicago medical school by Dr. Charles Huggins. HERB'S WHY HE SUSPECTS ASPHALT Discussing the American controversy about lung cancer and cigaret smoking, Prudente told me: -- Smoking is an age-old habit, the increase of lung cancer is rather recent. -- Smoking is also a habit of people in uncivilized as well as civilized areas of the world. Yet lung cancer has increased only in the civilized areas. -- Beyond that it has increased more in countries with asphalt roads than those with concrete roads. -- Finally, it has not increased in those rural districts of the civilized world which still lack asphalt roads. Prudente believes strongly that here lies one of the clues to the increase of lung cancer. nevertheless, he does not deny that tar, and thus smoking as such, nay have some cancer-inducing effects. However, he believes with German scientists, by the way - that it is not only the tobacco which may be harmful but also cigaret paper. API 06043 CHICAGO EALY HEWS, Monday, Jan. 25, 1955 Page 2 OHS CURE FOR ALL REID UMLIKELY As president of the sixth International Cancer Congress held here a few months ago, he has teen and continues to be In touch with nearly every cancer expert In every part of the world. Yet outside of minor surgical methods and a new promising Japanese drug, nltrooln, he sees no Indication for a quick cure for the disease. He believes that cancer-consciousness of the public is a major tool for the cure. It is due to this increasing consciousness that doctors today can cure most breast, stomach and skin cancers, be says. Beyond that, he believes that science will have to find as many cancer cures as there are cancer types. There will never be an all-embracing cancer preventive such as the Salk vaccine, which may well be the sure-fire polio preventive, be told me. ORE CF HIS principal hopes lies in the future use of isotopes which be studies closely at the U.S. Army's atomic center in Oak Ridge, Tenn. But be also feels that, early detection is as important, if not more so, as scientific advance. "If every doctor gave every patient that type of cancer examination that he can give in his office, we could save at least years of lives, if not the lives," he says.. API 06044 E sso R e se a r c h a n d E n g in e e r in g (POSMERLY STANDARD OIL DEVELOPMENT COMPANY) P- O. B o x si. L i n d i n . N. J . Co m pa n y medical research division omceron C K iU lO T. P H .D .. .D . W TH A N V N1MDW CIC. CH.K. HCAO IN D U rm iA L M T O lIN irr ,,omACZ w . K A A A O . PH D . M .D . HBAD roxtcouairr U ffTIIA N O N N lD O N , M .D . CMICF C L IN IC A L R M C A R C H P H Y S IC IA N February 3, 1955 Mr. 0. V. Stroop American Petroleum Institute 50 West 50th Street Nov Tork 20, lev lark Dear Mr. Stroopi I m attaching recant ninutea of tha Ccaaittee on tha Carcinogenic Action of Mineral Oil of tha Medical Research Council of Qreat Britain. I believe that these ninates would be of general interest to the mestoers of the Medical Advisory C o m i t t e e of the API and would appreciate it if you would have then duplicated for such distribution, and also to the nenfcers of the Kettering Laboratory. Sincerely yours, HUtilk R. s. ECKARRI, M. D. el. - ICC.55/53 CAMD. Min.17 API 06045 MEDICAL RESEARCH CO U N CIL For Specified Circulation (Committee Members} MRC.55/ 52 CAMO.55/1 Committee on the Carcinogenic Action of Mineral Oils The meeting of the above committee will be held at 2.30 p.m. on Monday, 2nd May, 1955, at 38 Old Queen Street, Westminster, London, S.W.1. The Agenda will be circulated in due course. J.C.R. Hudson, Secretary. 20th January, 1955. MEDICAL RESEARCH COUNCIL pnr. Specified Circulation ^ConrrJ.ttee ersj S C . =5/53 CAMO.Min. 17 COMMITTEE CIT THE CARCINOGENIC ACTION 0? MINERAL OILS Minutes of the Seventeenth Meeting, held at 38 Old Queen Street, London, S.W.l, on Friday, 17th December, 195U, at 2.30 p.m. Present: Professor T. Ferguson (Chairman), Colonel S.J.M.Auld, Professor H.N. Green, Dr. T. Keiger, Dr. J.O. Irwin, Professor J.R. Squire, Dr. D.L. Wocdhouse, and Mr. J.C.R. Hudson (Secretary). Attended: Dr. W. Carruthers, (representing Dr. J.N. Cook) and Professor D. Hey. Apologies for absence were received from: Dr. JV.V. Cook and Professor F. Morton. 1. Minutes. The minutes of the previous meeting were approved and signed. 2. Progress Reports A. Progress Renort No.XII by Dr. D.L. Woodhouse (MRC.5U/85U, " --- -------- ------------- --------- ---------- CAM0.5V12). It was pointed out that the standards, D and D?, were usually of about the same potency on rabbits as the fractions being tested, whereas they were more potent on mice than the oil fractions. It was therefore agreed that, in order that the standards should have approximately the same potency as the fractions under test, the standards used in future mice experiments should be D? and a more dilute solution, say, Dl/20. B. Progress Report by Dr. W. Carruthers and Dr. J.W. Cook ~ (MRC.5V675, CAM0.5V16). Dr. Carruthers pointed out that the Di-methyl, tri-methyl and tetra-methyl anthracenes were being isolated from the lower medium and higher boiling fractions. This tended to confirm the effective ness of the original distillations. Many of the compounds which were being isolated from the various fractions were found in only milligram quantities. If, at a later stage, it was desired to test their carcinogenicity, it might be necessary to synthesise some of them in greater quantities. Professor Hey said that he already had comparatively large stocks of many of the synthetic methylated anthracenes and he would be willing to make these available if they were required. It was pointed out that the percentage extraction of the M,P.R, subfraction given in Table I did not add up to 1009o. This was due to losses in the process of separation and allowances for this had been made in calculating the blends given lr. Table II. - i API 06047 -q Colonel Auld asked if, in view of the spread of results amongst the fractions tested biologically, the chemists were satisfied that -.he r.eth.ds being used could give sufficiently discreet separations. In this respect Professor Hey suggested that molecular distillation might give a better separation of small quantities. C. Dr. Irwin* s R cnort (lIRC.5i4/887, CAK0.5V19). Dr. Irwin pointed out that comparison of statistical results from year to year and between Birmingham and leeds showed a re assuring reproducibility. D. Professor Morton's Report. It was noted that lagunillas fractions were being prepared and would probably be available for biological testing to Professor Green when he was ready. 3 Possible Carcinogenicity of Diesel ExhaustvFumes (Minute 138). The review of Research Group No.2 of the Institute of Petroleum was circulated (CAMO. 5Vl3). The Secretary read a letter from Mr. E.T. Priddle offering the assistance of C.A.V. Limited in any investigation relating to Diesel exhaust fumes. In addition, Professor Hey said that a Diesel engine in the Engineering Department of King's College, London, could be made available similarly. The Committee agreed: (l) that in view of their own research ccaanitraents, which could be expected to last another 2 or 3 years, they could not undertake any research on this subject. (ii) to recommend to the Council that, as the exhaust fumes from internal combustion engines are particular components of atmospheric pollution, their study might be referred by the Council to the Committee concerned with that subject, or to an ad hoc Committee; the members of this Committee specially interested in Diesel fumes would be glad to co operate in the work so far as possible. The Chairman undertook to write to the Secretary of the Council along these lines. U. Future Work. and and Professor Green said that his biological rabbits would have run for 52 weeks at the 6 weeks respectively. (Professor Green left). experiments on mice end of a further L weeki API 06048 Dr. Woodhouse said that his biological experiments on mice and rabbits had been running for 6 weeks and 9 weeks respectively. It was noted (see Minute 2, D above) that Lagunillas fractions, which Professor Morton had prepared, were ready for testing by Professor Green. It was pointed out, however, that the preliminary experiments had shown that the lagunillas fractions were most potent < above 390C., which was beyond the limit of the 8tedman still. Professor Squire undertook to ask Professor Morton to include in the batches which he sent to Professor Green a fraction or residue boiling above 390C. (Subsequent Note:.Professor Morton proposes to ohtoin a Fraction 9, boiling above 390C. by laboratory distillation of the Lagunillas residue. This will provide Prcfessor^Green with eight Lagunillas Stedman fractions and one mere (Lt^ 81--8 and Lh>9), another nine aro matic extracts cf these (L^ SI-6A and Li*.9A), hd the pooled rafinete^ a v ). With the two standard solutions of 9:10 dimethyl (L4 brzathracene, Professor Green will thus have 21 materials for H i animal tests.) Dr.csi'ble Carcinogenicity of Anti-Fbaming Ag_ents. 5* ------ The memorandum (CAMO.54/15) was received and the Secretary , d that further enquiries had elicited the following additional information from Shell Chemicals Limited: (i) that the anti-foaming agent was to he added to the sewage in the proportion of 3 parts per million; (ii) that there was no evidence of an oil film on the surface of the settling tanks and it was therefore thought that the majority of the anti-foaming agent was carried down with the sludge. The Committee therefore agreed: a) that those employed at sewage works might he exposed to some hazard in handling the anti-foaming agent and that this aspect of the question might he referred to the Occupational Health Committee; and h) that it represented a negligible hazard as far as the general population was concerned. 6. Exhaust Filters on Internal Combustin Engines. Professor Squire mentioned that in a television programme called Panorama" a Mr. William Wyness had demonstrated a filter for attach ment to the exhausts of internal combustion engines which, it was claimed, removed particulate matter from the exhaust. The Committee agreed that this fell outside their terms of reference. 7. Conference on Atmospheric Pollution. Colonel A.uld reported that the Institute of Fuel was proposing to hold a conference on Atmospheric Pollution at the Institute of Civil Engineering on the 20th January, 1955 under the Chairmanship of Dr. Foxwell Professor Ferguson said that he would try to attend that Conference and it was suggested that representatives of other Com mittees, for example the Atmospheric Pollution Committee, might also wish to attend. 6. Date of Next Meeting. k^ In the absence of Professors Cook, Green and Morton, it was uggested that the next meeting might be held on Monday, 18th April, Thursday, 21st or Friday, 22nd April, 1955, at 12.30 p.m. The ^cretary was to ask the absent members to indicate which dates they preferred. API 0604 9 Mr. Frank M. President The American 50 last 50th New York 20, Porter Petiole* Street N. I. Institute Dear Mr. Porter: Recently I called to jour attention artielea point ing the finger of suspicion at various petrole* products as possible causes of lung cancer. Supplementing that letter, I m transmitting herewith copies of press stories pertaining to the sane subject. Very truly yours, JXB/h Xno. 2 # API 06050 / J / Expert Suspects Asphalt M ajo r Cause |/n R/$e of Lung Cancer r i r m n d b k j. m m s Im M ta TM CMmm aa* aai a U M k f M I m Paula, iw H Jan. K -- 1ha Lha dua a n ts -- halt uA^afi thaa M . That i tba tEaSriMeanaaA hr f M l . lntamatlaaally faaanua w ar part. In aa --ante at hla cancer hwrftri ha. h a I -- nrtm U aa aaoelA haML tta Maria at -- u alM a habit t dann! Ca--w C-- pla la etriliaaA aa all m iav antha -- jrtoiBd aiaaaal tt^wartd. T rt m liM lIa a i rth ____^ S --Saa rtOh"--SSSrt S T a T ! --? I a h than thaee vtth aaaaMa aai a '^ f t n --llr, ft haa aal lacnaaaA S iiL w T a r t i a linttboaa m a l Afctricta ot tha 1 at A al t^cSisis irnaia nf lima raarg j ' Afc Suapods Fopor Naeacthaiaaa, ha Aa aat Aany Ujrt ar andthai ia aH| aa rr't5,c i "i r lt'S: Ana ta thh Jmm bPm n l Mac that Ao-- aa aan today i aaathraaet, --auch anA aUa! rta. M any Curaa V la a M J .-ilu 'S h a T ' T u " r it S -- -- im e w Z a a i--drtT th a t-- --th a t* baut an* tha M M h a n y ha hana> tat M n , fc apt---- h J w 1 Ihat, ha haUaraa (hatj a aafflhaeetafindaai w ar earn aa there ar p d t _ V11__ IU Aa aat halle than 3 , t a u aH-- tcaatM w a r ---------------- -* tha Aalk e-- i Weh -- p area he tha i tba Om athU S f 1 cue at Iba drufi In tha ha Ha la -- la tha future S which ha ehrt | tth it ln lauhe_______ . . . . , v aw at tha Hrat * V i w r t a t | w I ta an the hn-- rni, taaUroaaTk da that Opa at a n at hraaat cawar. Ha tat that ha am *Na tth tttr-- U M ta ia ti vbaa ha raanlta ol hu at U natt M t tha heia.* ha j atadlaa an pahdaMA In tha' i TlnhaA Putaa. Knew Rar Operation Ha ia aUa oa af tha ta | phyueaac in tba orlA <">llUr ' with the adrenal eparaoa. a , type at aurparr ineuaiad at tha I U airerettr at Chkapa Medical I School by Dr. C hart H u a -- - Aa pnaidant <*f tba luaraa- Ap* 06051 RQa o S TO U.4TH Cancer May Be U v0 *' Caused by Asphalt, [ 1Says Brazil Expert S I - i. r o r a l^ 'i 1 SAO PAULO, Brazfl--The upsurge in lung vancer may be due more to aiphalt and oil tfeanj to dgaret raoking. 1. 1 ~ . * That 1| tha theory i d t t n i by .Pml. Antonio frtttoM ? 5ra*0'i internUofuJly I Id ib sehishe'lmeiTliw at hit e 3 m L m tD tl ban. vr%* | cu t, who to d #anaar Id } t r matter aatf b o ra* t n t rant. n M t --rtil a* to __ _ Acoar fro totora Otman ^tQea? aw typa erf *!tot*tm ttAt DM nr-tof* that ttaa to the laaraaM S toay 1h IJiw w# ank * j i yam tt lira, U m the not Bw," at urys. j API 06052 r F S S0 R ESEA R CH AND EN G IN EER IN G COMPANY ,FORMERLY STASfiAi:. V/L DEVELOPMENT COMPANY! p . O Box 5i. L i n d e n . N . J i .EDlCAl RESEARCH d i v i s i o n [CKABDT. .MD o>tT 1 O IR C C TO . A C * 0 t " * " H0A o P T O X l 'c O L O O I S T *ND c I n m i i o n m d NlCAL * * C A * C H P H Y 1 I C I A N er CLI A p ril 1 1 , 1f$S i. L V. kmm L. 8 B a n * # Jp . A l i m X* D t o U y 7 . . Ou t L. X to n d ra C. ! H I I lia d ft. C. A ita li* X. X. t a i d f t I h m V. OAor* 7. J. Satan Z tta n A * M * f j n w O d t a 1b ttai A tari o f p n n to tat d A iv w id A * ' A tta I tta i \ p o rilM B l to m m m t t talr id tta i * total 4 A ttaA i i# REEtllk Att intoniti Ol i. i. w i t o r torto ft. A. Kiboo / J3. . Stroop / ft. X. SOXAXSV, X. 0. API 06053 t h e f a t e cr p o u u i c l i c a b o k a h c h o b o c a b b o b iv soot foUJMn o r a n b u s s x o v u t o t h e a t m o s p h e r e u d b t o s i t i o i iv t h e xsnos Hans L. Falk Paul Kotin (UniT> of Southern California School of Medicine, Los Angeles, Calif.) The aromatic hydrocarbon content of soot-polluted atmosphere vas found to differ u t atlrely and quantitatively fro* gasoline and diesel engine exhausts. One atmospheric ^drocarbon as traced to incinerator soot and robber tire dost. In Tlew of the high concentration of 3,U-banspyrsne and the absence of certain gogree hydrocarbons from t^e atmosphere, a study as undertaken to esternine the fate of yiese compounds. Aromatic hydrocarbons vere absorbed on filter peper to determine the effects of air and light and synthetic smog upon them. ' The destruction rate of these compounds varied from c o l l e t s to only 20 per cent folloving a U6-hour exposure to air. Synthetic smog similar to that detected in urtan atmosphere attacked the hydro* esrbons at varying ratea. Ho qualitative difference vas observed in the destruction of the exposed hydrocarbons either in their pure state or vhen adsorbed m toot. These ex periments resolved the qualitative and quantitative differences in the hydrocarbons at their source and in the atmosphere. An analysis of the lunge of the average city dueller reveals the presenoe of epproxinately 1 gm. of soot recoverable at autopsy. The soot thus obtained vas measured SraTimetrically. Spectrophotometrie analysis of the recovered soot failed to revesl the usual aromatic hydrocarbons. The presence of the less stable carotenoids pointed to the actual absence of aromatic hydrocarbons. The absence of aromatic hydrocarbons vaa further substantiated by adding up to of hydrocarbons to the extracted soot, folloved by quantitative recovery of these amounts. The rate of removal of aromatic hydrocarbons from soot deposited in the lungs of mice is now under study. JOPr/mak - U/ll/55 Proceedings of the American Association for Cancer Research I, April 1955 06054 A P06S3BI* CABCHOQZUC ASBR IV CIQABBTB J. M. Essehberg Aaron M. Leavitt Edward Gaffney (Introduced by Kurt Stern) (Dept, of Anatoay, Chicago Medical School Chicago ILL.) After collating our work on the production of lung tumors by exposure to cigarette smoke, we attempted next to discover the responsible carcinogenic agent In ^te cigarettes. Three possible sources were indicated) the cigarette paper, the nicotine of the tobacco, and the arsenic content of the cigarette. Our automatic smoking machine served In all these Investigations. Seventy- two l/Jax mice were used, half experimental and half controls for each experiment, with aax equally divided In each group. Each experiment lasted 1 year. Data on weight and reproductive capacity were recorded. At the end of the experiment the mice were killed, perfused, and serial sections prepared. Those that died during the experiment were similarly prepared. Paper.-- O f the 26 perfused miee exposed to the smoke from cigarettes* made of "-tne sheets of cigarette paper in each, thirteen had lung tumors) eleven of the 29 controls had tumors. Hyperplasia, pneumonia, and reproduction occurred in both groups, and the weight curve of both was practically the same. Nicotine.-- Of 28 experimental mice exposed to smoke from cigarettes low in nicotine content, eighteen had lung tumors. Among 30 controls, thirteen had lung tumors. Both groups suffered from pneumonia, but only the experimental mice showed reduction in weight and inhibited reproductive capacity. Arsenic.-^3.55 Mg* of arsenic was added to the cigarettes of low nicotine content used in the nicotine experiment. The effects an the experimental deviated only slightly from these exposed to nicotine alone. It is concluded that mice exposed to nicotine indicate positive results. COFl/aak - y n / 5 5 Proceedings of the American Association for Cancer Research i 5 ------------- ----------------------------- API 06055 CABCHOOEHC COAL TAB E ST M A IES William E. Pool Adolph 0. Kaauer Lloyd J. Sullivan Charles B. M U l i n g h a m with the technical assistance of Mary C. Stesoski (Introduced b y Robert E. Olson) (Graduate School of Public Health, Univ. of Pittsburg, and the Mellon Inst., Pittsburgh, Pa.) The recognition of 3,U*-benspyrene as a coal-distillation by-product led some investigators to assome that it is the most potent, if not the only, carcinogen in tar or pitch. This assumption is not supported b y findings published during the past decade ad data developed in our laboratory during the past 2 years. Comeercially available Co a l distillates containing no demonstrated amounts of benspyrene have been found to possess tumor-inducing potency ccuq>arable with that of our standard solutions of 3*Ubenspyrene. Retaliates were tested from by-product coke ovens of the type used to car bonise more than 90 per cent of the coal coked in the United States in normal times. Solutions ef the test materials in bensene or toluene were applied to the shaved, interscapular areas of C57/B1/6 mice 3 times weekly until a malignant papilloma de veloped or the animal died. Crude tar and the pitch residuum of the tar after fractional distillation were bioassayed in this manner and found to possess carcinogenic activity comparable with that reported in literature for tars and pitches distilled industrially under conditions not necessarily identical with those used b y our sources. Among the intermediate fractions tested and found to be actively carcinogenic were two grades of creosote oil, and a "crystal-free anthracene oil" widely used as a wood preservative. A technic of chromato graphic separation and spectroscopic analysis believed to be capable of identifying 3,1*benzpyrene in concentration of 0.005 par cent has thus far failed to reveal this substance in the oils tested. Creosote oil has been reported in the literature to possess co carcinogenic and anticarclnogenlc components, but the oil itself apparently has not pre viously bean reported as being carcinogenic. Preliminary data on the carcinogenic activity of the fractional distillates ranging from tar through pitch will be presented and discussed. The authors have had no opportunity to search for human case experiences re lated to the industrial use of the materials tested, and would discourage inferences from animal data alone that substances are carcinogenic for humans. COPT/mak - U/ll/55 Proceedings of the American Association for Cancer Research 2:1, April 1955 API 06056 _-r-rj 0f TEST LOW COHCnmUTIOIS QP CiBCnOQEHS H EPUBRHAL CARCHOODBSIS* fS* k COMPARISON WITH CO-CiRCHOQDB Philippe Shubik Umberto Saffiotti (fbe Chicago Medical School, Dir. of Oncology, 2755 V. l$th St., Chicago, 111.) A study of the action of very low concentrations of carcinogen on the skin Bade in order to analyze: (a) the production of tunors with a solution containtraces^ of carcinogen, con?)arable to inpurities in certain industrial products; the effect of the sane solution when used as a promoting agent. A grot?) of 30 Sviss female mice was painted once with a single application of 1.0 per cent 9,10-dimethy1-1,2-benzanthracene in mineral oil and then repeatedly with a 0.01 per cent solution of the same carcinogen. Another similar group received only repeated paintings with the 0.01 per cent solution. The yield and progression of the induced tumors were analyzed. The pretreatK ot with a single application of a 1.0 per cent solution, Insufficient to produce tumors unaided, shortened the latent period far the appearance of the tumors brought oat by the repeated applications of the 0.01 per cent solution; the pattern of tumor induction seemed similar in the two groups but differed substantially from that of mice treated with a single application of carcinogen followed b y the promoting agent croton oil. This again emphasises the specificity of action of croton oil and distinguishes it clearly from activity that might be attributable to weak carcinogenic action. COPl/mak - U/ll/55 Proceedings of the American Association for Cancer Research si, April 1955 API 06057 FRACTIONATION OF CIGARETTE TAR George F. Wright Ernest L. tender (Dept, of Chemistry, Univ. of Toronto, Torbhto, Canada, and ^ section of Epidemiology, Sloan-Kettering Inst, for Cancer Research, New Tork, N.T.) The present research program attempts to identify the agent or agents responsible for the established carcinogenic activity of cigarette tar to mouse epidermis. Tar has been examined from smoked whole cigarettes as well as those which have been extracted with chloroform prior to smoking. The cigarette tar is separated into 10- per cent bases, 12-18 per cent acids, and 50-60 per cent neutral material, all chloroform-soluble. The remainder is water-soluble. The narcotic part of the basic tar, comprising U7 per cent of the total bases, is removed in order that test animals can survive. The acidic part of the tar has yielded a highly fluorescent compound, C ^ H ^ O ^ . ' The neutral fraction, which still contains over 1 per cent of nitrogen, has been separated by molecular distillation as well as by bulk elution from silica gel with suc cessive solvents of increasing polarity. Fraction 1 (no N) principally contains saturated hydrocarbons. Fraction 2 (0.36 per cent N) contains highly fluorescent material, the ultraviolet spectrum of which resenbles that of compounds like 3,U-benzpyrene. This spectrum is enhanced by deliberately adding 3,U-benzpyrene prior to chromatography. It is estimated that not more than about 1 part per million of 3,U-benzpyrene can be present in the total tar. Fraction 3 (0.6 per cent N) and especially Fraction k (1.5 per cent N) yield a crytalline compound (m.p., 86* C.), comprising 0.01 per cent of the total tar. The greater part of the nitrogenous material is found in Fractions 5 and 6 (U-6 per cent N)< All the fractions are applied to CAF^ and Swiss mice. The chloroform-insoluble, the basic-free, the acidic, the basic (nicotine-free), and neutral tars are applied in 50 per cent concentration; and the molecular distillates and the chromatographic eluents of the neutral tar, in 10 per cent solution. Ve feel that as yet unestabliahed carcinogens or co-carcinogens are in tobacco tar, since the concentration in which benzpyrene seems to be in cigarette tar is insufficient to account for the observed carcinogenic activity to mouse epidermis. vOPT/mak - U/ll/55 Proceedings of the American Association for Cancer Research :1, April 1955 API 06058 FURTHER PRODUCTION OF CARCINOMA WITH CIGARETTE TAR Ernest L. Winder Evarts A* Graham Adele B. Croninger t of Surgery, Washington Univ. School of Medicine, St. Louis, Missouri, and Section of Epidemiology, Sloan-Kettering Inst, for Cancer Research, New Tork, N.T.) the Tests on different mouse strains.-- Swiss and C57 mice were painted with iearette tar in a manner similar to that reported for CAF^ mice, with the exception that the tar had been standing in acetone longer than in the previous experiment. Among Swiss mice 22 papillomas and twelve cancers were noted among 86 mice. The respective results for C57 mice were ten papillomas and two cancers among 89 mice, abereas those previously reported for CAF^ mice were U8 and 36 out of 81 mice. The data show Swiss mice to be a more susceptible strain to cigarette tar pg-jTvHnp than C57 mice. The possibility is advanced that the higher rate of lesions in CAF^ mice could --- be because this experiment was conducted with tar that was fresher than that used in the second experiment. Possible chemical alterations of the tar as a consequence of standing jl is acetone solution, which could lead to a decrease of carcinogenicity, are discussed. W The observed differences may also be due to differences in strain susceptibility. It is suggested that in experiments using cigarette tar as a possible carcinogen the tar be prepared freshly once a month, be refrigerated in brown bottles, and that the acetone solutions used for the applications be prepared at bi-weekly intervals. Tests with denicotlnized cigarette tar.--CAF^ mice were painted with a cigarette tar from which nicotine had been removed by washing the tar with a 2 per cent solution of HC1. Up to date the animals had been painted for 13 months. Papilloma and carcinoma formation is so far somewhat greater than observed with total tobacco tar. This may be due to the fact that the animals were able to tolerate denicotlnized tar better. These data suggest that there are mouse carcinogens in tobacco independent from any that might be present in the basic fraction. COPT/mak Proceedings of the American Association for Cancer Research 2:1, April 1955 API 06055 ESSO RESEARCH AND ENGINEERING (FORMERLY STANDARD OIL DEVELOPMENT COMPANY) P . O . B O X 51. LINDEN. N. J . COMPANY - eDical search d.v.s .on *~*N b,,n,,t ( !H N I O H . M -D. ^ C L .H .C *U P H T M tC IA N April 12, 1955 Dr. E. V. Adana Or. L. C. Beard, Jr. Mr. Allen E. Dooley Or. F. D. Oaaaaaay Or. C. H. Bine Or. E. K. Linder Dr. H. M. Merlale Ik*. R. C* MLthoff Or. M. I. Heequlst Or. Jainaa V. Oaborn O r . F. J. Sandera Gentlemen: Attached ia the agenda for the eeating of the Subeoenlttee an Carcinogenicity of the API Medical Adrieory Comdttee to be held on Saturday, April 23, 1955 at the Hotel Statler in Buffalo* Sincerely youra, )f . M t j d f R. I. ECXARBT, M. D. REE/mak Att. cc: Hr. D. 7. Stroop 'S Or. A* V. Horton Or. R. A. Kehoe Or. J. Pbair API 06060 A Q O m * FOR THE M E E T H Q OF THE SUBCOHKITTXE CM CABCIIOOM ICirr OF THE API HEXOSiL A W I S O R X COMMITTEE Saturday, April 23 1955 Detroit Roam, Hotel Sttier, Buffalo ^.30-10:30 a.a. - Executive Session - Subcoa-- lttee Meabers Only IO.3O i .k . ' - Subco-- ittee Meeting - Medical Advisory Ceaelttee Meabers and Quests Yslcoae I. Approval of Minutes of Previous Meeting H . Progress Report by Dr. A. V. Horton H I . Progress Report by It. J. Phalr 17. Counents, If any, by Dr. R. A. Kehoe V. Efficiency of Solvent Extrection In Reaovlng Carcinogens fro* Lubricating Oils VI. B n l s l o n Techniques V H . Possible Lung Carcinogenicity of Lubricating Oil Mists V U I . Any Other Hev Business H . Executive Session if necessary X. A d j e u m e n t API 06061 r 1 4 TH E STA N D A R D O IL CO M PANY I April 15, 1955 Dr. R. R. ~cVardt, tir*etor Vadical Raiisereh Division Paso Rps.rch A Pagins-rla* Co. 5.n. Do* *1 Lindsn, Jaraoy Pot OCCUPATI ''SAL C A K K K EAZA1D8 by V. C. Huopar, M.5. D*r Dr. Te^ardti . Ia rafrones to our ysooat oorrospoteonco rogar*tag tfe aber subject sad our tolopteno ooavorastlen of today, X aw **- closing tvo U ) dopi of this artielo by Dr. Suoyor dlftrStetod March 9, 1955 to aonbors of tte V A Tiro ad AeelMovt trovasti ra-rertr^nt by Z, H. Follia of tho lotioaol ?troloea Association in Vashinctoa. Tory truly voura, JVOtaad Ina, (2) CCi Dr, fioerf* M. Saunors Mr. D> V. Stroopc^ J. W, datera, M.d. A API 06062 T 1 OCCUPATIONAL CANCER HAZARDS W. C. Hueper, M.D., National Cancer Institute (The article reprinted herewith was prepared for the March-April, 1955 issue of "safety Standards" a publication of the U. S. Department of Labor.) The rapid development of m o d e m industrialism has been associated with the appear ance of many new occupational health hazards of which those causing cancers occupy an important position. The term "occupational cancer" is applied to malignant tumors originating in in dividuals during the course, and/or as the result of the regular and usually prolonged exercise of certain occupational activities entailing contact with some exogenous, physical, chemical or parasitic agent acting in proper intensity. Occupational can cers thus are caused by specific agents or etiologically related to well-defined occupational conditions which form an integral part of the ordinary working environ ment. They differ through these aspects from the accidental occupational cancers which result from or follow upon some extraordinary, unforeseen, accidental injury sustained at work and being of a nonspecific nature. Types and Nature of Occupational Carcinogens Occupational agents which are known or strongly suspected as having caused cancers of various organs in workers who became exposed to them are largely chemicals. Some of these chemicals are well defined (arsenicals, chromium compounds, nickel, asbestos, benzidine, beta-naphthylamine, 1-aminodiphenyl, benzol), others consist of variable mixtures of a large number of chemical compounds, a few of which possess carcinogenic properties and some of which have been identified (sc-ot, coal tar, pitch, bitumen, tar oils, creosote oil, anthracine oil, lamp black, lignite tar and crude paraffin oil; shale oil and various petroleum fractions (industrial fuel oils, diesel oils, lubricating oils, cutting oils, crude paraffin oils, petroleum tars, pitches, asphalt and coke), and crude isopropyl liquor produced in the manufacture of isopropyl alcohol). A second group of occupational carcinogens is composed of agents characterized by their ionizing and nonionizing radiation (x-radiation, radioactive substances, ultra violet radiation). The third group is represented by environmental agents and condi tions which sometimes have an occupational association, and which may be related to certain infections (schistosoma hematobium) or several specific climatic, geologic, dietary, and nutritional conditions, and which in part have a more or less indirect relation to carcinogenesis (malnutrition with protein and vitamin B-complex deficiency). In addition to these established occupational carcinogens there are a number of potential human carcinogens which have been shown to elicit cancers in experimental animals and to which workers become exposed 'during their regular occupational activi ties (synthetic estrogens, chlorinated aliphatic hydrocarbons, methylated naphtha lenes, diethylene glycol, p-thiourea, thio-acetamide, light green SF, brilliant blue FCF, fast green FCF, butter yellow, beryllium, selenium, cobalt, and various polymer ized plastics). These potential agents also must be considered in the adjudication of compensation claims. Evaluation of Evidence API 06063 For the establishment of casual relations between an exposure to these agents and the subsequent development of a cancer of an occupational cer.esis and therefore com pensable nature, tne following rrerecuisites must be f-lfilled. T NATIONAL PETROLEUM ASSOCIATION MUNSEY IU IL O IN W A S H I N G T O N 4, 0. C. M E T R O P O L I T A N I - ) T 11 FStS 55-3 P A T im A. o o v m iu C M M DORALO C. PRAIA AMOCUn C N M t RT. iFeArLaLcIRaL win I DORACI L.L0RRU ATI R. A.RDXU nnmMmR March 9, 1955 TO: MEMBERS NPA FIRE AND ACCIDENTrPREVENTION DEPARTMENT In comparatively recen^^ears, incer hazards in industry have been recognized as of increasing impcrtai e and magnitude. Several organizations are devoting considerable study ie problem and health authorities in mar large cities cure watching the sito Lon very closely in the areas of their Jurisdiction so that necessary yj.es id regulations may be enacted if, in their opinion, they become necessary fdlt. the safety of workers. Because certain petroJ^um products ^materials produced in the re fining of crude oil are among those listed ^occupational carcinogens, a recent article appearinjr in the Mardh-April^ ^ 9 5 5 issue of "Safety Standard a booklet published by tjre Bureau of Labor Standards of the United States Department of Labor,should be of particular interest to all those concerned with the protection a y safety of workers. The article referred to in "Safety Standards" ti/led, "Occupational Cancer Bazars" by Dr. W. C. Hueper, ( M.D. of the Nationals Cancer Institute, is, in our opinion,of sufficient importance for us tc reproduce it for your information (file. A copy of Dr. Hueper's article as it appeared in "Safety Standards" is, attached hereto. API 06064 T 2 - 1 Definite evidence oust be available indicating that the claiaant had occupational tact with any one of the various agents listed; that this contact was either of pro- ^ r e d nature extending as a rule over periods of at least 6 months; and was of adequate for eliciting a cancerous response, according to any previous experience vhlch ^ t b e available on this point. Single exposures may be considered to be effective if t*hhee causal agent consists of external ionizing radiation or the exposure mechanism favors production of a carcinogenic depot in the tissues from vhieh a prolonged exposure of the bost^oorrggaannism may ensue. r b. The route of exposure to or introduction of the carcinogenic agent in addition its specific chemical properties and metabolic peculiarities determine the site of "^e organ or tissues in vhlch a cancer is elicited. Therefore, not any cancer, but cancers of specific sites sure related to any particular carcinogenic agent. c. The type of exposure does not need to be continuous or extend up to the time of appearance of the cancer, but may be intermittent. In fact, any contact with the occu pational carcinogenic agent may have ceased many months to years, or occasionally, even ecades before the cancer becomes manifest. Effective carcinogenic exposures may be ' sustained not only by the ordinary operators employed in operations with occupational carcinogenic hazards, but also by workers entering such operations on a transitory basis, such as supervisors, maintenance personnel, repairmen, truckers, loaders, yardmen, and vorkers employed in rooms and buildings near the hazardous operations, if housekeeping god exhaust disposal methods are inadequate and environmental contaminations result. d. Occupational Medical Stigmata-- For the establishment of causal relations between occupational exposures to carcinogens and subsequently appearing cancers, it is of dis tinct value to analyze the medical history of affected persons for functional or anatomic disease manifestations characteristic of a pathogenic action of the particular carcinogen allegedly involved. Such noncancerous and often preparatory o r precancerous systems of etlologic specificity act as stigmata or biologic fingerprints supporting not only the actuality of a previously sustained specific exposure, but also its causal relationship to the cancer present. Symptomatic manifestations possessing such a significance are, far Instance, chronic radiodematltls, chronic tar dermatitis, arsenic dermatosis, chronic solar dermatitis, chronic radiation periostitis, asbestosls of the lung and leukeaoid reactions after exposure to benzol and ionizing radiation. Chemical analyses of tissues for the incriminated chemical also may sometimes help in establishing previous contact with any specific occupational carcinogens, such as arsenic, chromium, nickel, radioactive substances, and benzol. It is important, however, to note that these procedures are not applicable for all occupational cancers* Seme carcinogens do not produce any etlologlcally characteristic symptoms; in fact, they may not elicit any preliminary toxic or other disease phenomena despite a persistent and prolonged carcinogenic exposure. Thus, cancers of the bladder la dye and rubber workers may develop in the absence of any preliminary local or general wrning symptoms after more than one or two decades of continuous, intermittent, or discontinued exposure to certain carcinogenic aromatic amines. There also does not exist any parallelism between the toxic and/or irritative properties of any chemical and its potential carcinogenic qualities, nor, is there a relationship between the degree of toxicity of any particular carcinogen and its relative carcinogenic potency. e. Extensive experience with occupational cancers indicates that there usually elapses * latent period of years, if not decades, between the onset of exposures to a carcinogenic gent and the appearance of the resulting cancer. It is for this reason most unlikely tkmt occupational cancers became manifest within the first year following the inception of eon- **ct with a carcinogenic agent. In fact, all cancers which make their appearance during ^irst three years of occupation in a carcinogenic environment should he subjected to scrutiny for a more probable nonoccupational origin before they may be considered an occupational viewpoint. API 06065 L 4 4 - 3 - Compensation Lavs be in Workmen's compensation laws enacted in various countries and states reveal a remark- 1 th able lack of uniformity as to the types of occupational carcinogenic agents, industrial re operations with carcinogenic hazards, and occupational cancers covered. As of October A1 1 , 19 5 4 , full coverage laws applying to all kinds of occupational diseases including re cancers had been passed in 26 States in the United States and the District of Columbia; th schedule coverage laws not always covering occupational cancers, or all types, were in re force in 20 States and no occupational disease laws had been enacted at that time in 2 ur States (Mississippi and Wyoming). in While workmen's compensation laws based on the principle of schedule overage may provide some degree of compensation against disability and injuries 1 fl-- M 1 ml from occupational cancer hazards, such legal provisions designed for the protection of worken are tonally inadequate, if not obsolete, in an era of rapidly changing and Increasing rr occupational disease panorama. g' t> However, even the blanket or general coverage compensation law which is sufficiently a flexible to include not only the present but also any future occupational cancer hazards, usually has a statute of limitations which is inadequate for providing fair protection under certain and not too unusual circumstances met with in occupational cancers. Since 01 occupational cancers may become manifest many years after cessation of exposure to occupa an tional carcinogenic agents, a statutory time clause of from six months to six years may la be too short for occupational cancers which may appear after a longer period. Fit oc In the workmen's compensation laws existing in most States, certain groups of workers or employees, such as especially farm labor and domestic servants, are excluded from coverage by the law.- Since farming as well as housework have become and are increasingly sb becoming occupations having extensive contact with industrial products (pesticides, herbi tb cides, synthetic fertilizers, antisprouting agents, hormonal fattening agents of livestock sy lubricants and fuel of farm machinery, residual oils for smudge pots, soil Improvers, anti ca biotics, detergents, waxes, polishes, dry cleaning agents), there is no sound scientific si reason for excluding members of such occupations from coverage by the workmen's compensa du tion laws and from adequate protection against cancers arising from exposure to potential Pe and actual occupational carcinogens. Labor lodes and Standards oc ir Any attempt toward achieving an adequate compensation by financial means for a cancerd* tc condition acquired through contact with occupational agents not only presents considerabl g economic difficulties but i alsc of questionable humane merit. While such a procedure i* tt evidently the best that can be done after an occupational cancer has became an accomplish* fact, the wiser, more rational, and in the long run, more economical approach to a reason' able conTcl of occupational cancer hazard; lie; obviously in their prevention wherever ft this is possible. C( Ot The goal car be achieved to a large degree by the enforcement of proper work condition* in operations ir. which cancer hazards exist, so that either any contact of workers with | such agents is eliminated or reduced tc an ineffective level. As to the fundamental step 17 for accomplishing such a control cf C'_cupa*ional cancer hazards, it would be advisable tc | P3 have all factories, workshops, laboratories and ether establishments producing, handling) I cr using known or suspected r.arcinoeer.i : materia..? to register with the appropriate State I public agency, Tris information would provide *r.e basis for establishing the supervision^ cf plant; by healtn or labor agencies ana would create the proper machinery for familiar icing manager; cf such operations vi*r the pcte-tial carcinogenic properties of the sub stance; and device; usee ir. their establishments ar.c with the methods and procedures by whlcn they night t- irontrcllec cr avriced- API 06066 rje The relative effectiveness of any adopted can best be determined by . k - medical, sanitary and technologic control mearures to ascertaining the changes in the occupational cancer j incidence among the total population at risk occurring during some 10 to 30 years after their introduction. It is therefore desirable that provisions be made for routinely recording all cancer cases occurring among worker groups exposed to occupational carcinogen: All precancerous and cancerous lesions observed among members of such groups should for thi: reason be made notifiable with the State health agency. All persons having knowledge of these cancers should be held responsible for such reporting. The adoption of such measures represents an important step from a public-health viewpoint, because there is a growing urgency to determine the environmental causes responsible for significant changes in the incidence rates of several cancers. What, Then, Are the Conclusions? 1. The increasing rate at which occupational carcinogens have been discovered during recent decades suggests that only a fraction of the actually existing industrial carcino gens are known and that heretofore unknown and new occupational carcinogens may be added to the present industrial environment through the development and use of new chemicals and production methods. > 2. There is a great deal of evidence indicating that only a relatively small fraction of the cancers produced through contact with occupational carcinogens has been recognized >a. and/or placed on record. Because of the established widespread industrial contact of large worker groups with known occupational carcinogens, the potential scope of the occu- ptional cancer problem evidently is much larger than apparent from the reported number of occupational cancer cases and hazardous industrial operations. 3. Medicolegal decisions in compensation procedures of occupational cancer claims -T should be based on a competent and critical evaluation of the entire evidence related to A the exposure conditions of the claimant, the presence or absence and the type of any symptomatic manifestations observed during the latent and developmental periods of the rt; cancer and characteristic for a particular agent, the length of the latent period, the site of the cancer, any specific histologic and histochemical characteristics, the pro i duction of corresponding cancers in experimental animals by the incriminated agent and ii pertinent epidemiologic data. 1*. Schedule coverage laws are inadequate for providing proper protection against occupational cancer hazards because of the dynamic state of modern industry resulting in the constant addition of new chemicals and production methods which may entail here ru tofore unknown occupational cancer hazards. The statute of limitations contained in the general coverage laws represents its main defect in the fair and equitable application of this type of workmen's compensation law to occupational cancer hazards. see or- 5- Since the prevention of occupational cancer hazards and not financial compensation for established occupational cancers appears to be the more sensible and humane method of control, labor codes should be properly adjusted and enforced so as to eliminate or reas onably contain occupational cancer hazards in modern industries. ot 6. For ascertaining the actual scope of the occupational cancer problem and for the ei institution of adequate control measures, it is essential that occupational cancers and tc t-.ecancerous conditions are made notifiable with local and State health and labor authoritie,1 ze 1 A comprehensive study of occupational cancer hazards will provide a sound basis for equally urgent investigation of the apparent extension of industry-related cancer hazards large parts of the general population. API 06067 UNIVERSITY OF CINCINNATI )' m m it m o t o r N n u m n e m c im a m i i ^ m u i multm ^ i |(|X| l o r M W CIM -- CDCIN AVCNUS .ATI ir OHl*IwO / t w i * D M m c r r u io . c i ciimmti m i f W I l t CAflTW MM May 3, 1955 M r. D. V. Stroop D irector, Dept, of Technical S ervices A m erican Petroleum Institute 50 W est 50th S treet New York 20, New York Dear Dave: E nclosed is the original copy of m y report which 1 trust w ill perm it you to make a satisfactory sten cil. This is going to save us a great deal of work. A separate letter is going out to each M edical D irector, giving them their identifying number for their company so they can interpret the attached table. It w as very n ice to see you for a m om ent in B uffalo, and I hope we can get together for a longer period som etim e in the future. With very b e st p erson al reg a rd s, 1 am Sincerely yours, E n clo su re cc: Dr. Robert E. Eckardt Copy from ). V. Stroop for information of Member8 of Medical Advisory Caemlttee ^ fe- API 06068 k Subcom m ittee on C arcinogenicity API Mcdic.3l A dvisory C om m ittee Epidem iologic al Studies K ettering l-a'ooratory Buffalo. New York A p ril 3, 1955 J. C entral R e g istra tio n No tabulations of the newly reported c a se s have been prepared for review at this tim e. This does not im ply that p ro g ress has not been made during the past year, but is due rather to the exten sive changes in our m ethods of handling the rep o rts. As noted at the la st m eeting of this Subcom m ittee, use of the Key Sort C ards (hand tabulation) w as discontinued and IBM equipm ent (electro n ic tabulation) substituted. This action w as taken in order to obtain g rea ter flex ib ility and to perm it the study of m ore va ria b les w ith le s s effo rt. H ow ever, it did require the preparation of an en tirely new code since m ore item * in som e detail w ere included; c ler k s had to be trained to code and punch; and the n e c e ssa r y b asic equipm ent had to be a ssem b led . T hese a c tiv ities are still in p rogress. Although additional cler ic a l a ssista n ts were assign ed to this par ticular project, much m ore tim e w ill he n e c e ssa r y before the change over is c o m p leted . To date oniv some. 17% of the m o re than 1800 r e c o r d s now on file have been reco d ed . It is a n ticip a ted , h ow ever, that the staff en gaged in thus effo rt can be further augm ented th is su m m e r . During this period the number of c a se s reported to the Central R egistry a lso has in creased sign ificajitly. O ver 5uo new reco rd s have been r e c e iv e d sin c e Janu ary 1, 1954, the date of the la s t co m p lete rep o rt. Two m ore com pan ies have began to send in th eir r eco rd s, and the oth ers g en era lly are m aking e v e r y e flo r t to keep up w ith th eir cu rren t c a s e s . A table is appended giving the number of c a se s reported each year since the estab lish m en t of the r e g istr y . (The participating com pan ies have been given a code num ber, but each w ill be notified sep arately how to identify their record. ) G eographical (.overage of the industry is now alm ost com plete. E ffo rts in the :Y.ture w ill be d ir e cted to im p rove iho a ccu ra c y of the reporting and to .n d u ilc a la r g er uum oer of em p lo y e e s in the reporting b ase. Som e parf.cipatinu com pan ies are rep resen ted by a single r e fin ery. It can be anticipaied, h o w e v e r, if tins p r o g r e s s is m ain tain ed , that significan t fig u r e s soon w ill be fo rth co m in g . API 06065 s 2. 1 J. Spec ia l S tudies At the 1934 m e e tin g , it w a i pointed out that c en tr a l r e g is tr a tio n o cages, although very useful from many a sp e cts, could not be considered an epid em iological study. F rom the v ery beginning o f the p ro ject, a search has been underway to find other avenues to exp lore. T hese included health exam inations, insurance sta tistic s, and sim ila r record s. LaBt y e a r, two co m p a n ies w e r e found to have c e r ta in r e c o r d s d eem ed worthy of review with the thought of arranging for m ore detailed in v e s tigations. This has been done, and, unfortunately, it m ust be reported that for the tim e being th ese reco rd s arc not in such a form a s to p erm it valid or useful studies. However, this approach should not be abandoned, and it is proposed that the sea rch w ill continue for a fea sib le m ethod of employing routine m edical or insurance reco rd s in the solution of this problem . At this point it see m s d esira b le to ca ll attehtion to a proposed mortality study d evised for the coal tar industry. C entral reg istra tio n , patterned after the API m echanism , has already been esta b lish ed . However, due to en tirely differen t p erson n el p r a c tic es and production m ethods, it is b eliev ed that a valid study o f c a u ses of death as related to exposure to coal tar and fum es m ight be fe a sib le . An outline of the su g g e ste d ap p roach is a tta ch ed to th is rep o rt. It will be noted that the exp erien ce of high and low le v el exposure em ployee groups is to be com pared using not only company record s but a lso in fo r mation obtained from Social Security files and health departm ent record s. This is considered e sse n tia lly a pilot study, but, if su c c e ssfu l, th is technique could be adapted to other sim ila r situ a tio n s. E n clo su res API 06070 Total Number of C ases R eceived From API M ember Com panies A s of A pril 26, 1955 Comp*i ny Number ' 1 2 3 4 5 b 7 8 q 0 11 12 13 14 15 16 17 18 19 i 20 ! 21 22 23 24 25 Total per year 1i------------------------------J 1950 1951 - i i 5 1 .- - i ' ! * * - - - - - - .. - - 23 3 bu 88 * 1 - 7 6 - 64 : - 35 - - 36 - 12b 1952 1953 - - - - - 37 - - 22 fc - - - - - 26 - 9 11 - - 2U 12 4 3 - - lu 53 . 141 1 17 . _ - 53 - - 2 8 * : fc J 4C ____________________ ___________________ 314 1954 - * 16 - 73 1U - 14 26 12 - 29 59 12 44 - 25 320 1955 - - 7 . - 4 - 11 j 3 3 _ 30 20 4 1 102 19 204 Toiai num ber o: c a s e s rep orted r>; A p ril 26, 1955 - 1839 API 06071 A Kettering Laboratory nar^rtment of Preventive Medicine & Industrial Health u TM College of Medicine Cincinnati, Ohio Coal Tar Project Proposed Mortality Study I. n M active To compare mortality rates of certain groups of employees of the sponsoring companies for (1) cancer of various sites but with particular interest in pulmonary neoplasms and (2) other important causes of death including those usually considered degenerative. The comparisons will take into account the (1) occupation of the workers by broad categories determined essentially by degree of pulmonary exposure to tar fumes, (2) length of employment by the sponsoring companies and (J) other variables if they prove important. II. Population 3ample to be Studied . It will be necessary to have at least 2,500 essentially unselected employee records fur nishing approximately 25,000 person years of experience in the coke and tar distillation plants to test this approach. Even with a sample of this size, negative findings cannot be relied upon although positive results would be significant. The workers to be accepted for inclusion in the study sample will be: (1) All employees and pensioneers on the rolls of the coke or tar distillation plants of the participating companies in the year 1940 who had had at least five years service in such operations. (2) All employees of the coke or tar distil ia t: or. plants who co-iplete five years service in such operations during the subsequent decade ending January 1, 1951. API 06072 Poal Tar Pro1ect Pror^ossd M o r t a l i t y Study (Cont.) Page 2 III. Information to be Collected (D (2) (3) (4) (5) (6) (7) (8) (9) (10) (ID (12) # (13) *(14) *(1:5) Plant Identification Employees Initials Identifying Code Number Social Security Number Year of birth Race Veteran Status (if available) Army Serial Number (if available) Occupational History " Present Work Status Year employed by the reporting company Year of employment termination regardless of cause Year of death (if available) Cause of death (if available) Place of death (if available) If the starred items (numbers 13, 14, and 15) are unobtainable from company files, an attempt will be made to complete the record by a search of Social Security and Health Department files. It is hoped that this maneuver will reduce the error created by loss of individuals from the study universe due to changes in employment, residence, and other factors. IV. Methods ( 1 ) A standard form will be prepared to collect the desired information. (2) The participating companies will complete the record for such employees that fall into the categories described under II. The use of an identifying code number and initials of the indivi dual employee will protect his identity and take care of company liability. (3) The information 30 collected will be transferred to I' cards for electronic tabulation. ' (4) Tabulations and analyses will be in accordance with the objectives of the study for such occupational groups for which a reasonably large experience can be assembled. API 06073 UNIVERSITY OF CINCINNATI DEPARTMENT OF PREVENTIVE MEDICINE AND INDUSTRIAL HEALTH CABLE ADDRESS: KETLAR. CINCINNATI TELEPHONE C A riro i M U May 3, 1955 Mr. D. V. Stroop D irector, Dept, of Technical S ervices A m erican Petroleum Institute 50 W est 50th S treet New York 20, New York Dear Dave: Enclosed is the original copy of m y report which I trust w ill perm it you to make a satisfactory sten cil. This is going to save us a great deal of w ork. A separate letter is going out to each M edical D irector, giving them th eir identifying number for th eir com pany so they can interpret the attached table. It was very nice to see you for a m om ent in Buffalo, and 1 hope we can get together for a longer period som etim e in the future. With v ery b e st p erso n a l r eg a r d s, I am Sincerely yours, E n clo su re cc: Dr. Robert E . Eckardt Copy from I). Y. Stroop for information of Members of Medical Advisory Committee May . API 06074 Subcom m ittee on C arcinogenicity API M ed ica l A d v iso r y C o m m ittee E pidem iological Studies K ettering Laboratory Buffalo, New York A pril 23, 1955 I Central R egistration No tabulations of the new ly rep o rted c a s e s have b een p rep a red for r e v ie w at this tim e. This does not im ply that p ro g ress has not been ^ade during the past y ea r, but is due rather to the e x ten siv e changes our methods of handling the rep o rts. A s noted at the la s t m eeting of this Subcom m ittee, use of the Key Sort Cards (hand tabulation) w as discontinued and IBM equipm ent (electron ic tabulation) substituted. This action w as taken in order to obtain greater flex ib ility and to permit the study of m ore varia b les w ith le s s effort. H ow ever, it did require the preparation of an en tirely new code since m ore ite m s in some detail w ere included; clerk s had to be trained to code and punch; the n ecessa ry b a sic equipm ent had to be a ssem b led . T hese a c tiv ities are still in progress. Although additional c le r ic a l a ssista n ts w ere a ssig n ed to th is p a r ticular project, much m ore tim e w ill be n e c essa ry before the change over is com p leted . To date only so m e 17% o f the m o r e than 1800 r e c o r d s now on file have b e e n r e c o d e d . It is a n ticip a te d , h o w e v e r, that the staff engaged in this effort can be further augm ented this sum m er. During this period the num ber of c a s e s rep orted to the C entral Registry also has in creased significan tly. Over 50u new record s have been r e c e iv e d sin c e Janu ary 1, 1954, the date o f the la s t c o m p le te r ep o rt. Two m ore com p an ies have begun to sen d in th e ir r e c o r d s , and the o th er s generally are making every effort to keep up w ith their current c a se s . A table is appended giving the num ber of c a s e s rep orted each year sin ce the establishm ent of the r e g is tr y . (The participating com p an ies have been given a code num ber, but each w ill be notified sep arately how to identify their r e c o r d .) Geographical coverage of the industry is now alm ost com plete. Efforts in the future w ill be d irected to im prove the accu racy of the reporting and to include a la rg er number of em p lo y ees in the reporting base. Some participating com panies are represented by a single refin ery. It can be an ticip a ted , h o w ev er, if th is p r o g r e s s is m a in ta in ed , that significan t fig u r e s soon w ill be fo rth co m in g . API 06075 2. Ij S p e c ia l Studi e s At the 1954 m eeting, it w as pointed out that cen tral r e g istr a tio n of ca ses, although very useful from m any a sp e c ts, could not be considered an epidem iological study. F rom the very beginning of the project, a search has been underway to find other avenues to explore. T hese included health ex a m in a tio n s, in su ra n ce s t a t is t ic s , and s im ila r r e c o r d s . Last year, two com panies w ere found to have certain reco rd s deem ed worthy of review with the thought of arranging for m ore detailed in v e s tigations. This has been done, and, unfortunately, it m ust be reported that for the tim e being th ese r ec o r d s are not in such a fo rm a s to p erm it valid or useful studies. H ow ever, th is approach should not be abandoned, and it is proposed that the sea r c h w ill continue for a fe a sib le m ethod of employing routine m ed ical or insurance reco rd s in the solution of th is p rob lem . | At this point it see m s d esirab le to call attention to a proposed j m ortality study devised for the coal tar industry. Central registration , patterned after the API m echanism , has already been established. | However, due to en tirely different personnel p ractices and production l __ m ethods, it is b elieved that a valid study of ca u ses of death as related to exposure to coal tar and fu m es m ight be fe a sib le . An outline of the s u g g e ste d ap p roach i s atta ch ed to th is r e p o r t. It will be noted that the experience of high and low lev el exposure em ployee groups is to be com pared using not only com pany reco rd s but a lso in fo r mation obtained from S ocial Security file s and health departm ent reco rd s. This is considered e sse n tia lly a pilot study, but, if su ccessfu l, this technique could be adapted to other sim ila r situations. E n clo su res \ API 06076 Total Number oi C ases R eceived F rom API M em ber Com panies A s of A p ril 26, 1955 Company Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Total per year 1950 5 - - - - 5 1951 - 233 60 88 - - 1 - 7 6 - 64 - 35 - 236 - 126 856 1952 - 37 - 6 - 26 9 - 20 4 - 10 - 21 - 7 140 1953 - - 22 - 11 - 12 3 - 53 141 17 - 53 - 2 314 1954 - - 16 - 73 10 - 14 - 26 12 - 29 59 12 44 - 25 320 1955 - - 7 - 4 - 11 - 3 3 - 30 20 4 _ - 1 102 19 204 Total num ber of c a s e s reported by A p ril 26, 1955 - 1839 API 06077 Kettering Laboratory Department of Preventive Medicine & Industrial Health College of Medicine Cincinnati, Ohio Coal Tar Project Proposed Mortality Study I. pbiective To compare mortality rates of certain groups of employees of the sponsoring companies for (1) cancer of various sites but with particular interest in pulmonary neoplasms and (2) other important causes of death including those usually considered degenerative. The comparisons will take into account the (1) occupation of the workers by broad categories determined essentially by degree of pulmonary exposure to tar fumes, (2) length of employment by the sponsoring companies and (3) other variables if they prove important. II. Population Sample to be Studied It will be necessary to have at least 2,500 essentially unselected employee records fur nishing approximately 25,000 person years of experience in the coke and tar distillation plants to test this approach. Even with a sample of this size, negative findings cannot be relied upon although positive results would be significant. The workers to be accepted for inclusion in the study sample will be: (1) All employees and pensioneers on the rolls of the coke or tar distillation plants of the participating companies in the year 1940 who had had at least five years service in such operations. (2) All employees of the coke or tar distil lation plants who complete five years service in such operations during the subsequent decade ending January 1, 1951. API 06078 ity Study (Cont.) Page 2 jjl. Information to be Collected (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) *(13) *(14) *(15) Plant Identification Employees Initials Identifying Code Number Social Security Number Year of birth Race Veteran Status (if available) Army Serial Number (if available) Occupational History Present Work Status Year employed by the reporting company Year of employment termination regardless of cause Year of death (if available) Cause of death (if available) Place of death (if available) If the starred items (numbers 13, 14, and 15) are unobtainable from company files, an attempt will be made to complete the record by a search of Social Security and Health Department files. It is hoped that this maneuver will reduce the error created by loss of individuals from the study universe due to changes in employment, residence, and other factors. IV. Methods ( 1 ) A standard form will be prepared to collect the desired information. (2) The participating companies will complete the record for such employees that fall into the categories described under II. The use of an identifying code number and initials of the indivi dual employee will protect his identity and take care of company liability. (3) The information so collected will be transferred to IBM cards for electronic tabulation. (4) Tabulations and analyses will be in accordance with the objectives of the study for such occupational groups for which a reasonably large experience can be assembled. API 0607 THE ATLANTIC REFINING COMPANY IN C O R P O R A TE D l i t t PETROLEUM PRODUCTS 8 6 0 SOUTH BROAD STREET P H IL A D E L P H IA 1. P A . RELATIONS DEPAWTMENT i mi*" L 0 *,5ST,At-m f * - D D I M C T O M E D IC A L D IV IE IO N 13* 1955 I. P. 0. k a X I d bs 1 1 ths if if It w k . 1.1. i4Ma k . 1. V. M m r . B r K M T U M B . V. Bw API 06080 tn 'ase \ujxe: 1 Coluan 2 Col'^an 3 Hundreds Te ns Digets "J ' & W W b 1 - 1951 2 - 1952 ~ebruary . s i X> WV MfMl 7 - M a n n e Acrkers aews and "'emnal Employes) 1 - -ipe L m e C r e w and Pro d u c t i o n rforkers " - --tsiae 7SA API 06081 IBM Card Code API Project February 1, 1955 Case Number - Punch directly Column 1 - Hundreds 001 Column 2 - Tens Column 3 - Digets Year of Report X - Prior to 1950 Y - As a doubl punch - 1960 and over 0 - 1950 1 - 1951 2 - 1952 3 - 1953 4 - 1954 5 - 1955 6 - 1956 7 - 1957 8 - 1958 9 - 1959 I API 06082 Column 7 (Note double * punching) Page 2 Geographic Location (Residence or place of employment at time of report) 0 - Not Specified - Unknown 1 - North Eastern States: Connecticut Delaware Illinois Indiana Kentucky Maine Maryland Massachusetts Michigan New Hampshire New Jersey New York Ohio Pennsylvania Rhode Island Vermont Virginia West Virginia Wisconsin 2 - South Eastern States: Alabama Florida Georgia Mississippi North Carolina South Carolina Tennessee 3 - North Central States: Colorado Idaho Kansas Montana Nebraska North Dakota South Dakota Utah Wyoming North Eastern - Central States: Iowa Minnesota Missouri 4 - South Central States: Arizona New Mexico Oklahoma Texas ^ 4 - South Eastern - Central States : Arkansas Louisiana 5 - South Pacific States: California Nevada - North Pacific States: Oregon Washington 6 - Marine Workers (Crews and Terminal Employes) 7 - Pipe Line Crew and Production Workers 8 - Outside USA ' API 0608 Sex and Race 0 - Unknown or not given 1 - Male, white 2 - Male, colored 3 - Male, other races 4 - Male, race unknown 5 - Female, white 6 - Female, colored 7 - Female, other races 8 - Female, race unknown Work Status at Time of Report 0 - Unknown or not given 1 - Active 2 - Leave 3 - Retired 4 - Other Age on Date of Report X - Under 30 years Y - Dead 0 - Unknown or not 1 - 30-34 2 - 35-39 3 - 40-44 4 - 45-49 5 - 50-54 6 - 55-59 7 - 60-64 8 - 65-69 9 - 7 0 and over given Age at Onset (First definitive diagnosis of a neoplasm) Follow the code of Column 10, except for Y which can be disregarded. Survival Period (From onset to date of report or death) 0 - Unknown or not given 1 - 0-5 months 2 - 6-11 months 3 - 12-17 months 4 - 18-23 months 5 - 24-29 months . 6 - 30-35 months 7 - 36-47 months 8 - 48-59 months 9 - 6 0 and over months Page 4 Type of Tumor - Histocrenic Classification (American Cancer Society Cod e ) Column 13 - Tens Column 14 - Digits Tumors of Glandular Epithelium (00-09) 00 01 02 03 04,05 06,08 09 - Ductal tumor - Tumor of mucinous secreting epithelium - Papillary tumor, not elsewhere classified - Neoplastic cyst, not elsewhere classified - Functionally active tumors - Other specific glandular tumors - Unspecified tumors of glandular epithelial origin Tumors of Nonqlandular Epithelium (11-14) 11 - Tumor of transitional epithelium 12 - Tumor of basal epithelium 13 - Tumor of haso-squamous epithelium 14 - Tumor of squamous epithelium 1 5 , 1 6 ............................ Tumors of Melanin Forming Tissue (17) 17 - Tumor of melanoblast Tumors of Epithelium, not elsewhere classified ------------- e----------^ ---------------- r i B - i s r ' 18 - Specific tumors of epithelium, not elsewhere classified 19 - Unspecified tumors of epithelial origin Leukemias (20-29) 20 21 22 23,25 26 27 28 29 - Lymphocytic leukemia - Monocytic leukemia - Granulocytic leukemia ............................ - Compound leukemias - Leukemia and lymphoma - Other specific leukemias - Leukemia, type not specified Lymphomas (30-39) 30 - Lymphosarcoma 31 - Reticulum cell sarcoma 32 - Hodgkin's disease 33 - Plasma cell myeloma 34 - Giant follicular lymphoma 35 ............................ API 06085 Page 5 (Cont.) Type of Tumor - Hlstoqenic Classification Lymphomas (Cont.) 36 - Compound lymphomas 37 ................... ........ 38 - Other specific lymphomas 39 - Lymphoma, type not specified Tumors of Nervous Tissues and Associated Structures -------------------------------------------------------------------------------- 40 -Tumor of ganglion 41 -Tumor of sympathicoblast 42 - Tumor of neuroepithelium 43 - Tumor of paraganglion 44 - Argentaffinoma 45 - Tumor of peripheral nerve sheath 46 - Tumor of meninges 47 - Tumor of glia 48 - Other specific tumors of nervous tissue and structures 49 - Unspecified tumors of nervous tissue origin Tumors of Vascular Tissue (50-59) 50 51 52 53 54 55,57 58 59 - Tumor of blood vessel - Hemangiomatosis - Multiple hemorrhagic hemangioma of kaposi - Tumors of specialized vascular structures - Tumor of lymph vessel ............................ - Other specific tumors of vascular tissue - Unspecified tumors of vascular tissue origin Tumors of Muscle (66-69) 66 - Tumor of smooth muscle 67 - Tumor of striated muscle 68 - Other specific tumors of muscle 69 - Unspecified tumors of muscle origin Tumors of Connective Tissue (70-77) 70 - Tumor of fibrous tissue 71 - Tumor of mucinous connective tissue 72 - Tumor of lipoid tissue 73 - Tumor of cartilage 74 - Giant cell tumor 75 - Ewings sarcoma 76 - Tumors of osseous tissue, not elsewhere classified 77 - Tumors of serous and synovial surfaces api oeoee ( C o n t . ) Type of Tumor - Histogenic Classification Page 6 Tumors of Nonepithelial Tissues, not elsewhere classified (78-79) 78 - Specific tumors of nonepithelial tissue, not elsewhere classified 79 - Unspecified tumors of nonepithelial tissue origin Tumors of Embryonal and Mixed Tissues (80-89) 80 - Tumor of trophoblast 81 - Tumor of embryonal gonadal tissue 82 - Tumor of teratoid tissue 83 - Tumor of epithelial and mesodermal tissues 84 - Tumor of epithelial and lymphoid tissues 85 - Tumor of mixed tissues, salivary gland typ e 86 - Tumor of dental tissues 87 - Tumor of mesenchyme 88 - Other specific tumors of embryonal and mixed tissues 89 - Unspecified tumors of embryonal and mixed tissue origin Tumors, not elsewhere classified (97-99) 97 - Tumors of uncertain histologic type-no agreement as to classification 98 - Tumors of specific tissues, not elsewhere classified 99 - Timor, cancer, neoplasm, and other general and nonspecific terms Other Conditions (XX, X8 and X9) XX - No information X8 - Not a neoplasm X9 - Diagnosis not completed, possibly a neoplasm Type of Tumor - Degree of Malignancy General Malignancy Code (Used with all Histogenic Code Numbers except Code Numbers 20-39) X - Not a neoplasm, no premalignant significance 0 - Not a neoplasm, but having premalignant significance 1 - Benign neoplasm, no premalignant significance 2 - Benign neoplasm, but having premalignant significance API 06037 Column 5 (Cont.) 16-17 (Note double punching for melanomas 60-65) *t Page 7 Type of T^imor - Degree of Malignancy General Malignancy Code (Cont.) 3 - Diagnosis not completed, suspected malignancy 4 - Neoplasm, malignancy not determined 5 - Malignant neoplasm, non-infiltrating (including carcinoma in situ) 6 - Malignant neoplasm, differentiated 7 - Malignant neoplasm, undifferentiated (anaplastic) 8 - Malignant neoplasm, differentiation not determined 9 - Malignant neoplasm, metastatic site Leukemia Malignancy Code (Used with Histogenic Code Numbers 20-29) 5 - Aleukemic, not otherwise specified 6 - Chronic 7 - Acute 8 - Not determined Lymphoma Malignancy Code (Used with Histogenic Code Numbers 30-39) 1 - Specified as benign (except the term "benign lymphoma") 6 - Single 7 - Multiple 8 - Multiplicity not stated Primary Site (Based on Maryland State Cancer Program Code) Column 16 - Tens Column 17 - Digits Buccal Cavity and Pharynx International Classification Number 00 - Lip, upper 140A 01 - Lip, lower 140B 02 - Lip, unspecified 140C 03 - Tongue 141 04 - Floor of mouth 143 05 - Salivary Gland 142 06 - Other and unspecified parts of mouth 144 07 - Oral nasopharynx 145 08 - Nasopharynx 146 09 - Hypopharynx 147 OX - Pharynx, ether and unspecified parts 148 API 06088 golu j6-l7 (Cont.) Primary Site Digestive System and Peritoneum 10 - Esophagus 11 - Stomach 12 - Duodenum 13 - Small intestine 14 - Large intestine, except rectum 15 - Rectum 16 - Biliary passages 17 - Liver 18 - Pancreas 19 - Peritoneum IX - Unspecified digestive organs Respiratory System 20 21 22 23 24 25 2X -- >'30 - Nose, nasal cavities. and middle ear - Accessory sinuses - Larynx - Trachea - Bronchus and lung - Media stinum - Other and unspecified thoracic organs - Breast Genital Organs 40 - Cervix uteri 41 - Corpus uteri 42 - Other specified parts of uterus 43 - Uterus, unspecified parts 44 - Ovary and oviduct 45 - External and unspecified female genital organs 47 - Prostate 48 - Testis 49 - Penis 4X - Other and unspecified male genital organs (scrotum) Urinary System 50 - Kidney 51 - Bladder 55 - Other and unspecified parts of urinary system Page 8 International Classification Number 150 151 152A 152B 153 154 155A 155B 157 158 159 16 0A 160B 161 162A 162B 164 165 170 171 172 173 174 175A,175B 176 177 178 17 9A 179B 180 181A 181B API 06089 es 1 Page 9 Skin Melanoma Other Type8 Other Types 60 - Skin of lip 61 - Skin of face, head, 19 0A 190B 191A 191B neck 62 - S k in o f upper 19 0C 191C extremities 63 - Skin of trunk 190D 191D 64 - Skin of lower 190E 191E extremities t 65 - Skin, unqualified 190F 191F ^Soft Tissue 66 - Soft tissues of face, 197A head, neck 67 - Soft tissues of upper 197B extremities 68 - Soft tissues of trunk 197C 69 - Soft tissues of lower 197D extremities 6X - Other and unspecified 197E _ soft tissues r (Note: This group will include neoplasm of periph^al nerves which are coded to 193 of the International List.) % Bones 70 *, Jaw bone 71 - Bones of head and face 196A 196B * 72 - Bones of upper extremities 196C ^ 73 - Bones of trunk 196D 74 - Bones of lower extremities 196E 75 - Bones, unspecified sites 196F i > Brain and Other Parts of Central Nervous System - I 76 - Eye 192 77 - Brain 193A 78 - Othercentral nervous 193B system and intracranial i nerves ' Lymphatic and Hematopoietic System 80 - Reticulum cell sarcoma 81 - Lymphosarcoma 82 - Other malignant neoplasm of lymphoid tissue 200.0 200.1 200.2 API 06090 r ol m a n jg.17 (Cont.) 18 ^ Page 10 Prin^i-y Site International Classification Number Lymphatic and Hematopoietic System 83 - Hodgkin's disease 84 - Giant follicular lymphoma 85 - Other forms of lymphoma 86 - Multiple myeloma 87 - Lymphatic leukemia 88 - Myeloid leukemia 89 - Monocytic leukemia 8X - Other and unspecified leukemia 8Y - Mycosis fungoides 201 202.0 202.1 203 204.0 204.1 204.2 204.3,204.4 205 Malignant Neoplasm of Other Sites 90 - Thyroid 91 - Adrenal 92 - Pituitary 93 - Thymus 94 - Pineal 95 - Other and unspecified endocrine glands 96 - Other specified sites 9X - Unspecified sites or unknown 194 195A 195B 195C 195D 195E 199A 199B Stage of Disease 0 - Unknown, not given, or pre-cancerous 1 - Early local, confined to primary site with no evidence of mtastass and no extension 2 - Advanced local, no evidence of distant mtastass but extension to adjacent anatomical sites 3 - Regional nodes and/or extension to adjacent anatomical sites 4 - Distant mtastass, including extensive spread to adjacent anatomical sites 5 - Recurrence, original site 6 - Recurrence, metastatic site Metastatic Sites X - Regional nodes Y - Local extension 0 - Unknown, not given, or none 1 - Remote mtastass, bones upper extremities 2 - Remote mtastass, bones lower extremities 3 - Remote mtastass, bones spine 4 - Remote mtastass, bones skull API 0 6 0 9 1 Column i9 (Cont.) 20 21 22 23-24 Page 11 M e t astatic Sites 5 - Remote mtastass, 6 - Remote mtastass, 7 - Remote mtastass, 8 - Remote mtastass, 9 - Remote mtastass, mediastinum lungs liver brain generalized Original Diagnosis 0 - Unknown or not given 1 - Medical department of the company 2 - Private physician 3 - Public clinic 4 - Self or other Method of Diagnosis 0 - Unknown or not given 1 - Periodic examination 2 - Special study 3 - Symptoms 4 - Other Treatment X - Hormone Y - Chemotherapy 0 - No treatment or unknown 1 - Surgery 2 - Surgery with X-Ray 3 - Surgery with radium 4 - Surgery with radioactive isotope 5 - X-Ray only (Radiation) 6 - Radium only 7 - Radioactive isotope only 8 - X-Ray and radium or isotope Present or Last Occupation in Petroleum Industry Column 23 - tens Column 24 digits 00 - Unknown, not given, or none Production 01 - Rigger and driller 02 - Well puller 03 - 04 - 05 - Others with frequent exposure to crude petroleum 06 07 08 09 - Others with infrequent exposure to crude petroleum API 06052 1 Page 12 3-24 (Cont.) Present or Last Occupation in Petroleum Industry Refining 20 - Catalytic cracking (includes thermal cracking of catalytic feeds) - Operators 21 - Catalytic cracking (includes thermal cracking of catalytic feeds) - Laborers, still cleaners, etc. 22 - Thermal cracking - Operators 23 - Thermal cracking - Laborers, still cleaners, etc. 24 - Coking operations - Operators 25 - Coking operations - Laborers, still cleaners, etc. 26 - Blending of heavy fuel oils (#3-6) 27 - Blending of heating oil (#2) 28 - 29 - Others on cracking operations 30 - Refining and blending of lubricants - Operators 31 - Refining and blending of lubricants - Laborers, still cleaners, etc. 32 - Packaging of lubricants 33 - Manufacture and packaging of greases 34 - 35 - Others - lubricants and greases 36 - Refining and filtration (pressing or centrifugation) of paraffin - Operators 37 - Refining and filtration (pressing or centrifugation) of paraffin - Laborers, still cleaners, etc. 38 - Packaging of paraffin 39 - Others - paraffin 40 - Distillation of crude oil - Operators 41 - Distillation of crude oil - Laborers, still cleaners, etc. ' 42 - Production of asphalt - Operators 43 - Production of asphalt - Laborers, still cleaners, etc. 44 - 45 - 46 - 47 - 48 - 49 - Straight run distillations - Others 50 - White oil manufacturing - Operators 51 - White oil manufacturing - Laborers, still cleaners, etc. 52 - 53 - 54 55 - 56 - Ptro-chemical operations - Operators 57 - Petro-chemical operations - Laborers, still cleaners, etc. API 06OS2 =s gl222 24 (Cort.) Page 13 Present or Last Occupation in Petroleum Industry Refining (Cont.) 58 59 - Special products - Others 60 - Maintenance - Pipe Fitters 61 62 - Maintenance - Boilermakers 63 - Maintenance - Mechanics 64 - Maintenance - Tank Cleaners 65 66 67 68 69 - Maintenance - Others 70 71 - Loading department 72 73 74 75 76 - Control laboratory 77 - 78 - 79 - Others not otherwise specified General Refining Operations Transportation 80 81 82 83 84 85 - Pipe line workers 86 - Marine division - Transportation of light and medium distillates (end boiling point 6500) 87 - Marine division - Fuel oil carriers 88 - Fuel oil carriers - Others 89 - Transportation - Others Marketing and Executive 90 - Service stations 91 92 93 - 94 - Others - Distribution 95 - Others - Office workers, 96 97 98 - etc. 06094 IO slunjn 3.24 (C en t.) ;5 29-30 31 32 Page 14 Prosant or Last Occupation in Petroleum Industry Others (Not included in the four main divisions) 99 - Job to be described in detail on card Approximate Number of Years Employed in the Petroleum Industry Prior to Onset 0 - Unknown, not given, 1 - 0-1 year ? - 2-4 years 3 - 5-9 years 4 - 10-14 years 5 - 15-19 years 6 - 2 0 and over years or none Principal Occupational Assignments in the Petroleum Industry (2/3-3/47 Follow the code of Column 23-24 Approximate Number of Years so Engaged in Principal Assignments Follow the code of Column 25 Secondary Occupational Assignments in the Petroleum Industry Follow the code of Column 23-24 Approximate Number of Years so Engaged in Secondary Assignments Follow the code of Column 25 Principal Petroleum Product Contact The information will be punched as a secondary petroleum contact if only one product is listed and if the exposure is described as rare, infrequent, or light. 0 - No contact 1 - Not given or unspecified petroleum products 2 - Crude petroleum, reduced crude, asphalts 3 - Gasoline, light ends, and solvent naphthas ( 400 F. ) 4 - Medium distillates (400-650 F . ) 5 - Lube distillates and related uncracked intermediates (600-1000 F . ) 6 - Refined products 7 - Products derived from thermal cracking units in refineries before or without catalytic cracking (600-1000 F . ) . 06095 32 (Cont.) 33 31 35 -37 Page 15 Principal Petroleum Product Contact 8 - Products derived from coking operations ( 600 F . ) , . 9 - Products derived from catalytic cracking and reforming processes or from thermal rraekina units in refineries with catalytic crackers (600-1000 F . ) X - Chemical additives y - Petro-cheraicals Approximate Number of Years so Exposed X - No exposure 0 - Unknown or not 1 - 0-1 2 - 2-4 3 - 5-9 4 - 10-14 5 - 15-19 6 - 2 0 and over given Secondary Petroleum Contact Follow the code of Column 32 0 - No exposure in any degree Approximate Number of Years so Exposed Follow the code of Column 33 X - No exposure Principal Other Occupation - Punch as Coded Column 36 - Tens Column 37 - Digits 00 - Unknown, not given, or none Professional and Semi-Professional 01 - Doctors, lawyers, clergymen, dentists, pharmacists, chemists, chiropractors, veterinarians, optometrists 02 - Midwives 03 - Nurses 04 - Students 05 - Teachers 06 - Auditors, clerical workers, bookkeepers, secretaries, draftsmen, tellers, steno graphers, telephone and telegraph operators, cashiers, librarians, accountants, pay masters API 06096 Principal Other Occupation Professional and Semi-Professional (Cont.) 07 - Technicians, photographers, musicians, artists, assayers 08 - Other professional and semi-professional theatrical people, reporters, publishers, undertakers, opticians, managers of theaters, civil and mechanical engineers, dieticians 09 - Housewives Proprietors (10-19 inclusive apply only to people who own their own business) 10 - Store owners (sellers of merchandise, not food). jewelers, furriers, clothing stores, hardwood, art stores, florists, etc. 11 - Store owners (of food), grocers, stalls in market, produce dealers, bakers, oyster business, ice business, huckster 12 - Cafe and restaurant owners, saloon keepers 13 - Barbers, cleaners, laundry hairdressers 14 - Turners, plumbers, paper hangers, con tractors, cabinet makers, shoemakers, tailors, stone cutters, blacksmiths, sheet metal, printers, upholsterers, carpenters 15 - Painters 16 - Garages 17 - Manufacturers (small) (not food) (food under 11) 18 - Junk dealers 19 - Other business (owner), funeral directors, owner of business (business unknown), organ builder, taxi proprietor, farmer, hauling, pool room, coal and wood, real estate Skilled Labor 20 - Craftsmen (men with specific trades demand ing a certain amount of specialized skill). Wheelwright, millwright, glaziers, copper smiths, glass blowers, tool makers, car penters, plumbers, electricians, machinists, cabinet makers, pattern makers, surveyors, silver engravers, paper hangers, tinners, primers, wood-workers, mechanics, lineman, slaters 21 - Blacksmiths, pipe fitters, boiler makers, brass molders, riveters, welders, sheet metal workers 22 Stone masons, cement workers, bricklayers, plasterers, pottery makers, brickmakers Column ~ .37 (Cont.) Principal Other Occupation Page 17 Skilled Labor (Cont.) 23 - Marine and stationary engineers and firemen, railroad engineers and firemen 24 - Railway men (steam and street), dispatchers, motormen, conductors, signalmen, brakemen 25 - Painters 26 - Taxi drivers, truck drivers, chauffeurs 27 - Mechanics (garage) 28 - Tailors, dressmakers, shoemakers, milliners 29 - Others. Jockeys, ship fitters, crane operators, lumber inspectors, simplex operators, watchmakers, tiremakers, riggers, jewelers, car repairmen, tractor drivers, tar men (Trade apprentices are in their specific trades.) Sales and Service ` , 30 - Interior decorators, window dressers, sales men and clerks in stores (not food handlers) 31 - Workers in food trades, salesmen, hucksters, milkmen, brewers, millers in food stores, ice handlers, bakers, sugar testers, meat dealers, canning, pickling, oyster shuckers 32 - Workers in slaughter houses, meat packers 33 - Waiters, waitresses, stewards, bartenders, butlers, chefs 34 - Barbers, hair dressers, manicurists, matrons, masseurs 35 - Cleaners, laundry workers 36 - Commercial travelers, insurance agents, insurance collectors, tax collectors, real estate agents, insurance adjusters, credit investigators 37 - Policemen, firemen, mail carriers, city inspectors and guards 38 - 39 - Other miscellaneous sales and services, U. S. Army and Navy, Marine pilot, gas station attendants, manager of paper routes, weather bureau observer, manager hotel store room, foreman coal company, meter readers, carpet and linoleum layers, sea captains, salesmen (business unknown), paker (business unknown), bill-poster Factory Workers and General Laborers 40 - Factory workers, clothing, shoes 41 - Factory workers (others), machine operators, upholsterers, still men, furniture finishers, awning makers, bookbinders, cigar makers, nickel platers, brass polishers, brush makers, coopers, grain handlers API 06098 golj2 36-37 (Cont.) f Page 18 Principal Other Occupation Workers__and_General_JLaborer3 (Coni.) 42 - Janitors, watchmen, orderlies, porters, sextons, parlor car porters, elevator tenders, window washers, dish washers 43 - Domestics, cooks, housemaids, maids, laundresses, charwomen, housework by day, nursemaids 44 - Day laborers, street cleaners, stevedores, garbage collectors, farm hands, hostlers, (wood workers, if colored) 45 46 47 48 49 - Factory worker (factory unknown) "1 Miscellaneous 50 - Newsboy, messenger boys, errand boys, ushers, bootblacks, movie operators, bundle wrappers 51 - 52 - 53 - r 54 - 55 - 56 - 57 - Ragmen, light housekeepers, miscellaneous odd jobs, car parkers, lamp lighters, pin setters, pugilists, gardeners, attendants at public baths, grave diggers 58 - Invalids 59 - Mentally deficient 5X - Reform school 38 Approximate Number of Years Employed at Principal Otner Occupation - Punch as coded 0 - Unknown or not given 1 - 0-1 year 2 - 2 - 4 years 3 - 5-9 years 4 - 10-14 years 5 - 15-19 years 6 - 2 0 and over years J 39 Exposure to Irritants Other Than Petroleum - ^ * ruz. ^riiauipaA Physical Agents 1 - Trauma 2 - Radiant Heat 3 - Solar or Ultraviolet Rays 4 - Radioactive Substances or Roentgen Rays API 0^099 j9 (Cont. ) 40 Page 19 Exposure to Irritants Other Than Petroleum (Cont.) Inorganic Substances 5 - Arsenic 6 - Chromates Organic Substances 7 - Aromatic Amines 8 Tar, Pitch, Creosote and Anthracene Oils 9 - Soot ( X - Others (Specified in detail) Cj) - Unknown, hot given, or none Approximate Number of Years Exposed to Principal Irritants Other Than Petroleum 0 - Unknown, not given, or none 1 - 0-1 year 2 - 2-4 years 3 - 5-9 years 4 - 10-14 years 5 - 15-19 years 6 - 2 0 and over years Degree of Exposure to Principal Irritant Other fflian Petroleum 0 - Unknown, not given, or none 1 - Heavy and continuous 2 - Heavy and occassional 3 Heavy, amount not indicated 4 Light but continuous 5 - Light but occassional 6 - Light, amount not indicated Secondary Irritant Other Than Petroleum Products Follow the code of Column 39 Approximate Number of Years Exposed to Secondary irritant Other Than Petroleum Products Follow the code of Column 40 Degree of Exposure to Secondary Irritant Other Than Petroleum Products Follow the code of Column 41 API 06100 SOCONY MOBI L OIL COMPANY, 26 Broadway, New York 4, N . Y. INC. 31 August 1955 Mr. David V. Stroop African Petroleum Institute 50 W. 50th St. Hew York, N* Y. Dear Dave: Allan Dooley of the Tbxas Company alerted us to tbs two a tta c h e d articles on Cutting Oil Cancer which appeared in tbs B r i t i s h Journal of Industrial Medicine, 1955, 12, 2k0 and Dr. Saunders has reviewed these papers and we both think it would be an excellent idea to distribute copies of tbea to the Medical Advisory Constttee and also to members of the new API Interdlvlsional Coanlttee on labels. Very truly yours, A. C. Pabst Industrial fyglenist Medical Department ACP:jd attach. Copy Prom D. V. Stroop 7or Information of Members of Medical Advisory Committee 9/6/55 API 06101 % Bru j ,,utuur. \trtl.. 0 5 5 . 12. 244. CUTTING OIKS AND SQI'AIVIOl'S-CELL CARCINOMA PAKI II: \N KXPKRIMKNTAI. S l l l)Y OK TIIK. ( AKC INOGK.NICITY OK TWO TYPK.S OK (TTTING OII.S* ID J. P. W. (ill MAN and S. I).VhSShl.lNOVITCTI I t o w t h r l h \ n i K H I ' l H i l l i n g '. ( h i h m u I t h t i t m t ' ( i*//rwr, ( i u r l p h . O i i t a n u m i l I I U I I I ON 1*1 HI It \ l It IN M V I ' A M V 2 V I V " l That mineral oils and their derivatives would with vegetable and mineral oils in relatively small indue* squamous-cell carcinoma when punned on to amounts and various cutting compound additives, Ihe skin of mice was reported by Twort and Twori (Id.ll I. and in a series of other papers hy these authors which huve since been statistically analysed including emulsifying, wetting, and penetrating agents. Disinfectants are also frequently added. A preliminary rcporlTry (iilmun and Vessclino- by Irwin and Goodman (194b). More recent work such (1955) demonstrated that certain fractions of MJ demonstrated that both straight-run distillates soluble cutting oil were capable of inducing a high lWoodhouse and Irwin, 050) and high boiling incidence of tumours in the mouse. The fractions point fractions of catalytically cracked petroleum that proved carcinogenic were cut at h'O, mis (Smith. Sunderland, and Sugiura. 051) may KOO. and *>t() I under vacuum distillation to contain numerous carcinogenic hydrocarbons, al avoid cracking. though to date no pure carcinogens have been The present contribution is concerned with an isolated from such compounds. analysis of the tumour responses obtained m The literature which we have reviewed contains several experiments involving prolonged exposure surprisingly few references to occupational cancers of mice lo samples and dilutions of a soluble cutting directly uttrihuiuble to cutting oil exposure in the oil as well as preliminary results obtained from tests engineering industry. However, the relationship using a straight cutting oil. Hoth of these products between excessive exposure to such products and a were cutting oils in use al the metal working plant high incidence of other occupational skin diseases referred to in Part I. a ell documented <t ruickshank. I*>50 ; Shapiro. Cutting oils are generally sprayed in a continuous 1930). stream over the point of contact between the cutting Cruickshank and Squire (1950) have presented edge of the machine tool and the metal being evidence, from both clinical observations and processed. Al Ibis point, minute quantities of the tological tests on mice and rabbits, implicating coolant are subjected to extremely high temperatures exposure to cutting oils as an occupational cancer which might quite possibly cause cracking of the huard. A later publication by ( ruickshank and oils. The oil spray is collected under each machine Gourevitch (1952) supported this opinion. In the and generally tillered through a system of weirs litter puper the authors suggested that it was quite before returning to a sump for recirculation. Hence, possible that this cancer risk (exposure to cutting one lot of oil, subject to periodic replenishment, b in the engineering industry) had not been long frequently remains in use for several weeks. enough in existence for it to become apparent from nortality rate studies such as those of Henry (1947). It is interesting to note that in recent years the numbers and uses of the so<alled " cutting fluids " lave increased considerably. Such cutting fluids laterally consist of a ratetively stable aqueous anulsion of sulphurized petroleum oil distillates Materials Tested One of ihc cutting oils under investigation is marketed in the form of weter-soluhlc cmuluon and is used in dilutions of one pari lo eight or more of water. Asdilutmm of tha order might lend to obscure ihc presence of a weak carcinogen, teats were run using both the undiluted emulsion and various dilutions of ibis fluid. Sample* of *T^m orb tuftfwng^ m inn fryfrwN*m*Mtfawnth used culling oils were also tested because u has bean `i l ( iflctr Inattiui* d f ( M * hown ihai cracking may greatly enhance ihc cercino 244 API 06102 4 CUTTING OILS AN D S Q U A M O U S -C E LL C A R C IN O M A : P A R T II 245 jMuctty of petroleum oik (Smith and other*, 1931) md it teemed probable that the uaed oil might contain minute amount* of *udi cracked material*. The propertm of the tern type* of cutting oil and the Mveral sample* Mated may be lummeriaed a t follow* : Cattlag Oft A.--Tha ia a aoluble cutting fluid in the form of a stable oil-in-waier amulaion containing active additive*, about 431',, sulphuriaad mineral oil baae, and 40*s water when marketed. It is usually diluted with mght or more pens of water before use. Caning Off B.--This is a straight cutting oil, a uiphunaed mineral oil blended with fatty oik. It is usually cut back with a low vneoaity straight paraffin oil before use. Ta Soluble Oil A-1-51 Soluble Oil A-I-J3 Soluble Oil A-2 Soluble Oil A-3 Soluble Oil A-4 Straight Oil B-l Straight Oil B-2 Undiluted; unused (market product) As above--separate sample o ^ tamed over 12 months later Dilute I : 4 retar ; unused Dilute I : 8 water ; unused Dilute approx. I S rater; uaed* Dilute 6 :4 pern paraffin o i l ; unused Dilute 6 :4 p ara paraffin o il; used.t Samples of oil A were teased against CH. C*t Meek sadR.F.i nuce,whikoil Bwastestedagainst C*Hmice aety- Mela* end tamalea me uaed in about equal wnhan ia all trtak. Exposure consnted of painting theskin three timas weakly with frosn 30to 100mg. of the test matenek The oils sera applied rith a carnal hair brush to a clipped area at the base of the neck. Agm at the beginning of the kxperenenu varied dl0tly but all groupe tall within a reaps of from 90to 130day*. Anenak werehousedingiaasjan ingroupsof tve and tad a suusdard commerai ratioa of fox cubaa without developing tumour* befon the M.T.T. minus two times its standard deviation. (3) Percentagecancer - uC 100 Voff When C = total number of mice developing histologically confirmed squamous-cell carci noma. (4) Mean Non-tumour Survival Time (M.S.T.) = ..t, Nfll W hen * - - sum of survival times in days of all non-tumour mice, those still alive at the termina tion of the experiment being credited with survival times equal to the duration of the experiment in days. W hen Nai -- number of animah that failed to develop a tumour. The M.S.T. is accompanied by a statement of the number of non-tumour survivor* at the end of the experiment and its duration in day*. Table I summarizes the results obtained from two separatetests ofsampleA-1 begun 18months apart. In each of these trials a different batch of the soluble cutting oil A was used. Of the three strains of mice exposed, the C,H and C ,, black were inbred stock from our own colony while the R.F. mice, obtained commercially, wen not necessarily inbred. It will be readily noticed that then was. in both trials, an appreciable difference in response between the two inbred strains. This is expressed both in the percentage of tumours and to a less marked degree in the induction period (M.T.T.). Tabu I T uteoua k e s f o n s e o f m ic e t o s k in f a i n t i n o w it h A SOLUBLE CUTTINO OIL AND WITH COHN OIL (CONTKOL CKOUFl Timour response and ranrinopsnanty in this report tie rwaasmeil by meen* of the following simpte (I) Mean Tumour Time (M.T.T.) ^ Where t = sum of the tenas in days to tha appaerance of the Ant Honour on aneli tumour (2) Whan N = actual set up ter Tgrnogf N oiM iM ir SOT* A-I-SI A-I-SJ CSMfll Su m C.H C.,gL CC...HBL tt.F. C.M c.,et N Nrm 30 IS 40 n J** J0 J0 JO JO JO JO -- JI0 Ds*. EapoMN* u Tm MTT Cm - mr 01 10 JOS JM J so US If r JJ) J jj 0 1_04 1 0 0 --0 EaO o f E iS ihusi av vivati Dtps J 001 % 0 JM JO) 1 Otti 0 110 f 401 It 401 MST IOS*) JJJ JM JJ* J1M0 J4S m When N = M tan I M Mr * s a k s s a a s m ( 'IMIbrt<iUiaih . mos c a r. N .y, u x a . Oil A proved highly toxic to the R.F. mice tested, with the result that this group had a non-tumour mean survival time (M.S.T.) of only 109 33 days. Over 30% of the mice in this trial had died without API 06103 1 246 BRITISH J O U R N A L O F INDUSTRIAL MEDICINE bavins developed a tumour before reaching the M.T.T. for the group at a whole (144 days). All the R.F. mice were dead by 310 days, and for this rceaon length of exposure hat been choaen for the companion between templet and strains shown in Table I. The control groups of C,H and Cit black were exposed to the tame treatment at the test mice, except that they were painted with a domestic com oil. Regardless of the differences in response of the strains, it is quite evident that cutting oil A has, for a crude commercial product, quite a high tumour* inducing potency against mice and that this response shows a high level of repeatability. In an initial investigation, the used oil (sample A-4) had shown only a very slight carcinogenic potency (Gilman. 1930-31, unpublished data). Consequently the tests summarized in Table 2 ware undertaken, making use of similar dilutions of used (A-4) and unused (A-J) materials along with an unused intermediate dilution (A*2) of one part oil A to four parts of water. It was hoped that a comparison of the results obtained with these and with the undiluted product might help to clarify the role of dilution in reducing the tumour-producing activity of the used product. Tabu 2 EFFECT OF DILUTION ON TUMOUS RESPONSE OF C.H MICE TO SOLUBLE CUTTING OH. A Ta b u 3 RESPONSE OF C ,, BLACK MICE TO DILUTIONS OP SOLUBLE CUTTING OIL A 1 1 Dito Sanate' ne 1 Numkar N in* 343 te D ty t Tum our a M E4 of v n a t h rto o Tum our M T T ()!) C tft- mr DureIKMI lOejfB) : A -1 Horn 30 Al 1 : 4 30 30 A3 1 S 30 30 A -4 1 1 40 39 iMBtf) 41 49 233 9 30 401 0 0 -- 3 3 17 404 0 494 0 494 3 Jf9 It ie interesting to note that after 436 days the I :4 group showed 20% tumours, a figure only slightly in excess of the response registered by the C(H mice after 90 days less exposure time to the same treatment The results recorded in Table 4 for the straight cutting oil (samples B-l and B-2) are from a pilot lest involving too few animals and too short an exposure time to warrant the making of comparisons between these and the other cutting oil samples tasted. However, sample B-l was apparently re sponsible for skin tumours in two of the 10animals exposed. One of these developed into a typical squamous-cell carcinoma and eventually metasta sized to the lung. Tabu 4 TUMOUR RESPONSE OP C J t MICE TO STRAIGHT CUTT1NO OIL (BLENDED S : 4 WITH PARAFFIN OIL) 3*5 Dan' BaSaT N N n a t. es MTT Sar. (M en yuan O va JM A * l Naaa j p 13 11 U l M3 . 9M A -3 1 :4 ! 1*1 3 43* S 3 A -J 1 ; 1 s> -- t 4 M 333 A -4 1:S m m -- 13 411 Hm N 1 No*. 1 % Taaaar M TT (4a)) % 1 Oovbob Caaaw s -l IS I* 20 1*2 10 us 1 -1 1* 10 -- S3 Thus it would appear that this cutting oil is also carcinogenic, although confirmation of this and detailasto potencywill havetoawaitthecompletion of experiments in I m T as ti I. tow areni >!: era tllN S ss The percentage of C,H mice tumours from the 1 :4 solution is slightly Isss than a of that observed for the pure product, while the induction period (M.T.T.) had inenasad o p the about 70 days. Meither the used nor the 1:g dilutions hod elicited any after expaeune for a full year. Mice of the apparently Up aaeoopdbie CtT of the sohiMs otttapm used oo the C,H (Table 3). After -days' exposure the C ,, group show what less marked The oil base of the soluble cutting oil tasted is a 30-30 blend of sulphurised and Altered straight-run dlstillatss of a crude mineral oil. Thaae baas oil fractions are supposedly not cracked and contain no additives other than commercial flower of sulphur. Thus it might be expected that oil A would give a tumour response comparable to thoee reported for similar straight-run distillates. Howomr, it would appear to be considerably more potent to the mouse then the several mineral oils and fractions tested by Woodhouss (1931, 1932) and his colleague This discrepancy in intensity of response suggests the bility that one or more of the additives used in compounding the cutting fluid may be acting API 06104 \ O tLS AND SQUAMOUS-CELL CARCINOMA : PAKT It 247 oik. None of theee ia the literature re* g * laboratory. Th actual uaa o tiw o* net either marked^ Investigated at fluid A apparently or enhance its gwt a reduction in carrinogank activity might have psa assodated with oxidation of the cardnogntic wnqmtwnii *------ r* -- r ^ g |--eeilrTr fr m grotwhe contact with metal particles. That oxide* gen may inhibit the potency of carcinogenic shale afl and syntketlr tar hat bean shown by Twort and Twurt (1930k However, ir ail probability the W1hbk2kasanpts ftmctioa of tiw various levak d dM ion. This rnattnHna k supported by eridmee obtained front wsi asiag C ../C .H hybrids. times reported bySmithandothers(1931),conoem- in the affect of dilution with an inactive irwwrial on the caranoganidty of active fractions of catalytically cracked oik. Theee dau seemingly influenced the interim recommendation by Holt. Hendricks, Eckardt, Stanton, and Pap (1931) that blends of oil containing more than 10% of catalytically cracked oil boiling above 700 F. be considered CTOUIOfMCa Smith and Sunderland (1931) have reported diflbrances in the raaponae of various strains of mice to the same carcinogen. The evidence presented in this communication dearly supports their obser vations (Table Ik It appears advisable, therefore, to teat againat more than ons strain of mica whan attempting to dtermina whether or not a substance k carcinogenic. This would seem to be particularly important if the rabbit k not avallabia for duplicata tasting. Ht accordance with the tiiggaeiiiin of Hkger and Woodhouae (1932k The inclusion of the mean survival time of thoee animais that Ceiled to develop tumours along with the number of non-tumour survivors end the duration of each trial gives some indication of the reliability of the results in terms of the toxicity of the substances tested and response of the treated mica (other than tumour development) to the condhiona of the particular experiment. A soluble cutting fluid (oil-in-water emulsion) used in industry has been shown to be carcinogenic to three dMhrem strains of mice. The response of test groups to a standard skin painting technique varied with the strain umd font) 19 to 41% tumours after 310 days' exposure. Results proved reproducesbh and comparatively y-- m w in two trials repeated altar an interval of 1 months. The teapotmee in mice to I : 4 and I : I aqueous dilutiona of this soluble oil were compared with the undiluted product and with a I : g used dilution altar 363 days' exposure. A marked reduction in kwrosm k *S uction periods accompanied dilution. chief e fe t of dSuticeTk the kfRhSg of the induction period. Thus when duration of traetment whk a dilute oil wae lengthened suffleiantiy the aheohne rumour response approeched that of mice axpoeed to the more concentrated emuhmaa. Reaoks of tasas using a straight cutting o il (bland) am reportad and suggest that this type may aho be API 06105 i 248 BRITISH JOURNAL OF INDUSTRIAL MEDICINE Hut-. Tha cuv* Manat in thaao imp utation diaptayad r. N. D.. an* Sqwra. J. a. 11*90). MS., 7. |. to Or. J. O. Cunningham (Dtractor. Division of Ilmaa. J. a. W.. na Varna! Caaaar Ree. Coni. Aca " S. D (1*99). Rraa. CanM. !*m Iat., Na* V on. la Urn Industrial Hygiana, Ontario Daparimant of HaaJth), iluuuHt whoaa division tbs original oil aamptaa worn Haanr. Miepar, SI... a '. aa 11*47). a Woo d h * o -u im t .mOrd..LS.M11*..9421. .9S*S.r t l . y Cmmtr, 4.2*2. oMainsd. i*ffaatly apprariaiad bythaauthon. HoH. J a . Handncke, N V . Echar*. R. E.. Sam oa. . L., and Wa alaa wah to oxpraaa our approbation to Dr. J. D. Rape. R. C. 11*91). Syaipoaiaai aa a Cerner Caairel On for Hiph-Buliap Caulytkally C raft4 Oik. Aaiar. Scfcrodar of tha DopartmaM of Pathology, Ontario Vstarinary CoMaga, Gnalph. who otamtnad htito- Irm a. Amo*.. Ctucaoa. Illmoia. J. O . aa4 Goodman. N (d1*rr4**1.foWJ.urHr.r*.. 4. 229. Cam*.. 44, 2*1 Shapiro. H. (1*90). M W r a. Or>. ladbarr. Hr.. H. F.. 2*. 9. paihotogacaNy all mouae tumour malarial diacuaaad in amah. W. E.. cad Sunderland. O. A. (1*91). Cmmrrr | | , 2SI. thhiaport. ----- .----- . aad Samira. K. (1*91) 4rr*. Icdurr. H r , 4. 2**. T oon. C. C.. aad T oon. J. M. (1*20). J . H rt.. (cafo.. 2*. 272. R eferences -------. ------- (1*21). J. m rw H rt . 12. 204. Wnodhnme. O. L. 11*911. Rni. Empire Cancar C a a u a p i. Tam ay* I math Annual Report, a. 170. Cndctaaank. C. N. O. I 1*901. J rmy. m a . h a . , IS . 4S0. ----- (1*92). Bra. Eaton* Caaaar Campana. Thmimk ____ an o u m i t t . A. 11*921. Saw at n f JadUcrrM Rapon. p. 222. kHktm .% . 74. ------ . and Irm a. J O. (1*90). J. H rt.. (am * . 4S. 121. t I I J I j API 06106 E sso R esea r c h a n d E n g in e e r in g (FORMERLY STANDARD OIL DEVELOPMENT COMPANY) P. O. Box 51, L i n d e n , N. J. Co m p a n y MEDICAL r e s e a r c h d i v i s i o n moBtnr E C C K A R D T . R M .O . M .D . DIRECTOR HATHAN v H EN D R IC KS. CH E HEAD IND USTRIAL H YG IENIST h0*ACE W G ER A R O t. RH D , M D H EAD TO XICO LOG IST p c r t h a n d E S E N N IS O N . M.O. CHIMP c l i n i c a l r e s e a r c h p h y s i c i a n October 18, 1955 Mr. 0. V. Stroop Anariean Petroleum Institute $0 West 50th Street New Tork 20, Hew lork Dear Mr. Stroop: If the attached two articles hare not bean brought to the attention of the nanbers of the Medical Advisory Cownittee of the API, it would probably be advantageous to see that they are circulated at least to the nodical nsabers of the rsawittee. Sincerely youra, R. E. ECKARST, M.D REE task Encs. - Cancer of tho Respiratory TractRecant Trends in Mortality, Edward A. Low, J. of the International College of Surgeons, Yol. 2li, Wo.l, * JBiy, g g . " -- Accident Prevention in Childhood-- The Kerosene Hasard, H. A. Carithers, J.A.M.A.. Yol. 159, Mo. 2, Sept. 10, 1955. Copy From D. V. Stroop f*or information Of Members Of Medical Advisory Committee 10/28/55 API 06107 |Reprinted from the Journal of the International College of Surgeons Voi. X X I V , No. 1, July, 1955] Cancer of the Respiratory Tract Recent Trends in Mortality E D W A R D A. LEW* I NEW YORK CITY, NEW YORK THIS paper presents data on death rates from cancer of the respiratory tract in the general population of the United States and among Industrial and doubtedly represents a real rise in the incidence of respiratory cancer. While a number of factors have been suggested as being implicated in this increase, data are Ordinary policyholders of the Metropoli not available to show how much of the tan Life Insurance Company. rise can reasonably be attributed to the Broadly speaking, these data indicate effect of specific factors. the following conclusions: 7. The highest respiratory cancer death 1. About half the increase in the num rates in the white male population of the ber of deaths from respiratory cancer United States are found in the highly ur over the past twenty-five years reflects banized and industrialized states, and the X merely the growth of population and the greater proportion of persons at the older ages. 2. Respiratory cancer affects predomi lowest in the agricultural and mountain states. 8. Among white male Industrial policy holders, who are predominantly urban nantly males past the age of 45 and fe residents and employed for the most part males past the age of 55, the death rates in industry, respiratory cancer death among males being from four to six times rates have averaged from 30 to 50 per those among females. cent higher than among white males in 3. Respiratory cancer death rates past midlife are likely to continue rising. 4. In general, the magnitude of the respiratory cancer death rates reported from different parts of the United States appears to be associated with the Quantity and quality of medical facilities available for accurate diagnosis of the disease. 5. Part of the increase in the reported incidence of respiratory cancer reflects im proved diagnosis, more complete case find ing, and more accurate reporting. 6. Part of the increase, however, un- the general population of the United States; however, the death rates among white female Industrial policyholders have been about the same as for white females in the general population. 9. Among male Ordinary policyholders, most of whom are drawn from the middle and better-to-do classes of the population engaged in nonhazardous occupations, respiratory cancer death rates have on the whole been somewhat lower than among white males in the general population. The statistics in this paper relate to the broad category of respiratory cancer. In 1950, some 85 per cent of the deaths in Actuary and Statistician. Metropolitan Life Insurance Company. this category were accounted for by can \ Read at the Nineteenth Annual Conrreaa of the United States and Canadian Sections, International Collere of Sur* cer of the lung trachea and bronchus, as eeons. Chicago, Sept. 6-10, 1954. Submitted for publication Sept. `4. 1954. shown in Table 1; Printed tn U-S.A i API 06108 4 VOL. XXIV. NO. 1 T A B L E 1.-- D e a t h s i r o , n R e s p u ' f t t r , , tj C a i n e , i,, t h e U n i t e d S t a t e s , 1 '>50 D'twl*<l Stt' Xlimb*ro.r Deaths Ptrrrntagr of AU Deaths from Respiratory Canrrr Trachea, Bronchus, and Lung Specified as Primary... .. 7,618 35 Lung and Bronchus Unspecified as to Primary or Secondary.......10.695 50 Larynx ............... ... 1,852 9 v ose. Nasal Cavities, Middle Ear, Sinuses.. ... 645 3 Mediastinum .......... .. 409 2 Thoracic Organs Secondary 284 1 Total ............ ...21,503 1 o o Increase in Deaths From Respiratory Cancer.-- During the past twenty-five years, mortality from respiratory cancer has risen so sharply in the United States that this once rare disease has now be come an important cause of death, partic ularly among white males. In 1950, only diseases of the heart, vascular lesions of the central nervous system, cancer of the digestive system, hypertension and ar teriosclerosis, and accidents (all forms) outranked respiratory cancer as a cause of death among white males at ages 55 and over. The total number of deaths reported in the United States as due to respiratory cancer rose from 3,900 in 1930 to almost 27.000 in 1953, or about sixfold. If the toll from this disease continues to mount as it has in recent years, there will be about 40.000 such deaths reported in 1960. LEW: CANCER OF RESPIRATORY TRACT As is brought out in Chart 1, approxi mately half the increase in the number of deaths from respiratory cancer reflects merely the growth of our population and a greater proportion of persons at the older ages, who are subject to higher death rates from this disease than younger per sons. Hence, about half the increase in the number of such deaths represents a higher reported incidence of respiratory cancer. This is indicated in Table 2. Among white males the number of deaths reported as due to respiratory cancer rose about sevenfold between 1930 and 1953. Among white females the cor responding increase was somewhat less than threefold. The relative increase in respiratory cancer deaths was even great er for nonwhite persons. However, the rather small number of such deaths re ported among nonwhite persons in 1930 suggests that proportionately very many more cases of respiratory cancer were then being missed in the nonwhite than in the white population. In each race and sex group with the ex ception of white females, somewhat less than half the increase in the number of respiratory cancer deaths reported be tween 1930 and 1953 was accounted for by the growth and aging of the population; among white females the corresponding proportion was about sixty per cent. Increase in Deaths from Cancer of Other Sites.--Between 1930 and 1953 the T a b l e 2.-- I n c r e a s e in X u m b e r o f D e a t h s f r o m R e s p i r a t o r y C a n c e r in t h e U n i t e d S t a t e s , 1930 to 1953 Xumber of Deaths ISJJ* 1910 Total Increase Increase m Deaths Due to Higher Incidence Growth and Aging of Population Total persons .................. 26.920 White males .................. 20,930 White females ................ 3.990 N'onwhite males ............. 1,670 N'onwhite females-........... 330 3,900 2,650 1,100 100 50 23,020 18,280 2,890 1,570 280 11,900 9,800 1,100 850 150 11.120 8.480 1.790 720 130 Based on 107c sample of 1953 deaths in U. S. population. Adjusted to include Texas. 13 API 06109 *RNAL OF THE INTERNATIONAL COLLEGE OF SURGEONS JULY. 1955 Chart 1.-- Number of deaths from cancer of the respiratory tract in the United States in 1930, 1940, ^ 1950 and 1953. U M B E R OF D E A T H S ( T H O U S A N D S ) C h a r t 2.-- Number of deaths from cancer of other sites m the United States in 1930, 1940, 1950 and 1953. 14 API 06110 VOL. XXIV NO i LEW. CANCER OF RESPIRATORY TRACT Table 3.-- c r e a s e 1 X i ' m b r y r,i H e a t h s f r o m C a n c e r O t h e r T h a n R e s p i r a t o r y in th e V n ite d Spates. 1930 to 1953 ,\umher of Deaths 1930** Total Increate Inerente m Death* Due to Htgher l ncifienee Growth and A gmg of Population Total person? ...... ... White males . . White females ..... . . Xonwhite males . .. . ... Xonwhite females ..... ...... 192.U20 83.780 2.28A 7.690 8.270 113.850 47.720 59,100 2,400 4,630 78.170 36.060 33.180 5.290 3,640 -- 3.730 1.175 -- 7.280 2,050 325 81.900 34.8So 40.460 3.240 3.315 Based on lO'-e sample of 1953 deaths in U. S. population. 'Adjusted to include Texas number of deaths reported in the United States as due to cancer other than of the respiratory system, rose from 114,000 to 192,000. (Here and elsewhere in this paper, the term "cancer" excludes the leukemias and Hodgkin's disease.) As is brought out in Chart 2, the entire increase in reported deaths from such cancers can be accounted for by the growth and aging of the population. This is indicated in Table 3. The table also shows that when adjust ment is made for the increase in deaths clue to the growth and aging of the popu lation, the number of deaths from cancer, other than of the respiratory system, has since 1930: (a) increased slightly for white males, (b) decreased about 12 per cent for white females, (c) nearly doubled for nonwhite males, and (d) in creased about 7 per cent for nonwhite females. The relatively much greater reported increase among nonwhite males than among white males, as well as the increase of such cancers among nonwhite females in contrast to a decrease in the age-ad justed incidence among white females, may be attributed to the substantial prog ress made in raising the standards of T a b l e 4 .-- R esp ira to ry Cancer D eath R a te s per 100,000 U nited S ta te s P opulation, 1930, 19O, and 1950 White Malet 2930 1920 1950 White Femaiet 2930 1920 25-34 . . ............ 8 35-44 ... ......... 3.4 45-54 ... ......... 10.7 55-64 ... ......... 20.1 65-74 .. .........26.4 75-84 ... ......... 21.8 85 & over.. ......... 19.6 1.3 6.0 23.8 47.4 53.8 51.7 32.6 1.2 7.9 39.1 95.9 119.4 109.1 102.7 .6 1.7 3.7 9.5 11.7 9.7 7.4 .5 1.7 6.3 12.8 18.4 18.3 14.1 Ages 25-34 .. 35-44 . 45-54 55-64 65-74 75-84 . 85 & over 1930 ........ l.i ...... 2.0 .. .. 3.0 ... 6.8 . .4,5 . 6.7 . -- Xonwhite Males 1920 1.5 4.8 16.7 21.3 26.6 15.0 6.3 1950 2.1 9.4 40.6 79.0 67.8 48.6 10.7 15 Xonwhite Fem aiet 1930 1920 ,i .5 1.3 1.8 3.1 4.7 1.7 9.4 3.4 10.6 -- 2.8 6.7 -- 1950 .5 2.2 6.5 15.5 27.2 40.0 44.0 1930 l.i 2.6 8.7 15.5 17.8 19.5 19.1 Ap i 06111 JOURNAL >K THE INTERNATIONAL ..u LLEi .E Ol .-URoEON' JULY. 1"V, diagnosis, case rinding, and reporting of cancer in the nonwhite population closer to the level of those in the white popula tion. Part of this may reflect the increas ing exposure of the nonwhite population to modern medicine, as a result of large scale migration from the rural South to northern cities. The same developments have, of course, also been responsible for much of the increase in the reported in cidence of respiratory cancer among non whites. Renpiratory Cancer Death Rates by Age. Sex and Race in the General Popu lation.--The effect of population changes on the trend of respiratory cancer mortal ity can be eliminated by using death rates for specific age groups. Such death rates for each sex and race make it possible to investigate further the nature of the rise in respiratory cancer mortality. Table 4 and Charts 3 and 4 show such death rates for 1930, 1940, and 1950 in the general population of the United States. The most striking feature of these trends is that the death rates have risen very much more rapidly for males than for females, even though as far back as 1930 respiratory cancer mortality was al ready much higher among males than among females. Between 1930 and 1950, the white male death rate from this dis ease increased by 130 per cent at ages 35-44, by 260 per cent in the age range 45-54, and from 350 per cent to 400 per cent at ages 55 and over. For white females, the increases were only 30 per cent at ages 35-44, about 70 per cent in the age range 45-64, 130 per cent at ages 65-V4, and 340 per cent at ages 75 and over. As a result of these sex differences in trend, the overall death rate from re spiratory cancer for white males had by C h a r t 3.-- Age pattern of male death rates from cancer of the respiratory tract in the United States in 1930, 1940 and 1950. ` 16 API 06112 VOL. NXtV. NO. I T aBLE 5.-- Statistics mi Calim i Lasts U hile Male Cohort Born In Respiratory Cftn'rr Zrralh Rat' per jon.imn .if .\ftn>nrri Agtj s-s* 35-61 1855-1805 1865-1875 1615-i88o 1885-1895 1895-1905 . . . 0.4 ... ....6.0 10.7 23.8 39.1 20.1 47.4 95.9 26.4 53.8 119.4 51.7 109.1 1950 increased to about 4 \ '> times that among white females, whereas in 1930 the corresponding difference had been only about 2Vi times. The disparity was great est in the age range from 45 to 64, in which the 1950 death rates among white males were approximately six times those among white females; in the age range from 65 to 74 the male death rates were about four times the female rates. In 1950, the deaths from respiratory cancer among white males at ages 55 to 64 accounted for 4.2 per cent of the total LEW: CANCER OF RESPIRATORY TRACT mortality in this age group; the corre sponding figures at ages 45 to 54 and 65 to 74 were 4.0 per cent and 2.5 per cent, respectively. Among white females, the deaths from respiratory cancer accounted for only about 1.2 per cent of the total mortality in the broad age range 45-64. Among nonwhite lives the ratio of male to female death rates from respiratory cancer has been about the same as among white lives. However, between 1930 and 1950 the respiratory cancer death rates increased more than tenfold for nonwhite males at ages 45 and over, and very appreciably, although not as rapidly, for nonwhite females. The age-specific death rates from re spiratory cancer have thus risen much faster in the nonwhite than in the white population. Consequently, by 1950 the nonwhite death rates from respiratory cancer had come to exceed the correspond- -- WHITE O EA Th RATE p e r 100,000 -- -- NC)N WHI l ' I950y ^X l940 ^ 19 3 0 1950 9 4 0 ___ ^ 1930 _ UNDER ( hart 4.-- 35 TO 44 Age 5 55 TO TO 5* 64 pattern of female 65 75 U N D E R 35 TO TO 74 over ss 44 death rates from cancer of the in 1930, 1940 and 1950. 45 TO 54 respiratory 55 65 TO TO 64 74 tract in the United 7 ft OVER States 17 API 06113 1 J o i n s \ I . I l l THL INTKHN ITIONAL <<H I.F-i.E OF S-IRC.EONS Jl'I.Y. I '-.I ing white death rates at ages under 55. While the reported death rates in 1950 1'or nonwhites at ages over 55 were still below the corresponding rates for whites, it is necessary to keep in mind that the reporting of deaths among older non whites is known to be somewhat deficient as to numbers and inaccurate both as to age and causes of death. If allowance could be made for the lower standards of diagnosis, case finding, and reporting of respiratory cancer in tnis segment of the nonwhite population, it is likely that the current death rates from this disease among nonwhites at these ages would turn out to be close to if not higher than the corresponding death rates among white lives. It is quite clear that among both whites and nonwhites respiratory cancer takes its heaviest toll past midlife. For males under 45 and females under 55 death rates from this disease were all below 10 per 100,000 in 1950. At ages over 45 the death rates rise rapidly with advance in age. Among white males the death rates increase to a maximum at ages 65-74 (120 per 100,000 in 1950) and then decline somewhat. Among white females the death rates con tinue to rise to the oldest ages, the maxi mum being recorded at ages 85 and over (44 per 100,000 in 1950). Respiratory cancer death rates in England, Canada and other countries show the same charac teristic earlier peak for males. It has been suggested that one possible explanation of the earlier peak in the male death rates is that some new carcinogenic factor, to which a larger proportion of males than females are exposed, may have been operating on an increasing scale over the past three or four decades. If this factor also affected younger males to a greater degree than older males, then the cohorts of younger males who have been exposed to the increasing operation of this factor from an earlier age would be ex pected to show higher death rates than the cohorts of older men. The actual ex perience (in 1930, 1940, and 1950) of several cohorts of white males in the United States presented in Table 5, does show that the older cohorts have been subject to lower respiratory cancer death rates than the more recent cohorts. If the hypothesis just mentioned is true, then the peak of the respiratory cancer death rates probably will shift to the more advanced ages, when the more recent co horts attain the older ages. The trend of the age-specific death rates from respiratory cancer indicates that the percentage increases in death rates from 1940 to 1950 were generally smaller than those from 1930 to 1940 for both whites and nonwhites in each sex; how ever, the absolute increases in death rates from 1940 to 1950 were greater than those from 1930 to 1940 in most of the age groups over 45. It appears, therefore, that the increase in respiratory cancer death rates is slowing down at the younger ages only. Judging by recent trends in the general population, further increases in Agee 25-34 35-44 45-54 55-64 65-74 T able 6.--R e s p i r a t o r y C a n c e r D e a t h R a t e s p e r 100,000 Industrial Policyholders-- M etropolitan L ife Insurance Com pany 19S0-3S, lU O - ii a n d 1950-52 }030-3! . ... i .i .. ............ 4.9 . . 17.0 . . . ............34.2 . 42.9 White Male 1950-it 1.2 7.5 34.5 75.1 81.6 1950-5! 1.3 10.3 53.7 134.2 184.7 1910-3! .7 1.7 4.3 8.5 10.8 White Female .4 2.4 6.2 13.5 20.0 18 1950-52 .5 2.2 6.2 14.1 29.5 API 06114 VOL w : \ . .Ml ; respiratory cancer death rates past mid life are to be expected. /?'.'7tivotunj Cnuci r Deoth Rides by Aye (nifl Si x aiH'iny 1iidnstriol Policyholders.-- Industrial policyholders represent for the most part urban wage earners and their families. They are generally persons in the lower income brackets and include a high proportion of men engaged in manu facturing and mechanical industries, in mining, in transportation, and in per sonal service. The age-specific death rates from respiratory cancer among these in sured lives thus shed light on the incidence of this disease in urban areas and among workmen in industry. Table 6 shows the age-specific death rates among white male and female Industrial policyholders of the Metropolitan Life Insurance Company in the periods 1930-1932, 1940-1942 and 1950-1952. A notable feature of the death rates from respiratory cancer among Industrial policyholders is that they have been sub stantially higher than the rates in the gen eral population for white males at ages 35 to 74, where as for white females they have been remarkably close to those in the general population at all ages. Over the years, the disparity in respiratory cancer death rates between white male Industrial policyholders and white males in the general population has been di minishing. In recent years, death rates from respiratory cancer among white male Industrial policyholders have ex ceeded those among white males in the LEW- CAXCER uF RESPIRATORY TRACT general population by nearly a third in the age group from 35 to 44. by about two-fifths in the age range from 45 to G4. and by more than a half at ages 65 to 74. The death rates from cancer other than of the respiratory system have also been higher among white male Industrial policyholders than among white males in the general population, but the differen tials have been much narrower, ranging from 5 per cent in the age group 35-44 to 20 per cent at ages 65-74. The death rates from nonrespiratorv cancers among white female Industrial policyholders have been about the same as for white females in the general population. The trend of the age-specific death rates from respiratory cancer among white In dustrial policyholders indicates that for males at ages 45 and over the absolute increases in death rates from 1940-1942 to 1950-1952 were significantly greater than those from 1930-1932 to 1940-1942: for males at ages under 45, the absolute increases were about the same in both periods. For females the absolute in creases from 1940-1942 to 1950-1952 were generally smaller than from 1930-1932 to 1940-1942. It seems, therefore, that the increase in respiratory cancer death rates is slowing down only among females or at best possibly also among males at the younger ages. Judging by recent trends among Industrial policyholders, respira tory cancer death rates may be expected to continue rising among males past mid life. Age 25-34 ..... 35-44 . 45-54 ..... 55-64 .... 65-74 .... 75 & over . TABLE7.--Respiratory Cancer Death Rates per 100.000 Ordinary Policyholders--Metropolitan Life Insurance Company. 19-10-32.1939-iO and 1950-12 J9?0.J2 .. 1.5 .... 4.2 .. 11.8 ...25.6 .. 31.4 .. . 27.1 White Male 0.9 5.2 oo o 49.2 62.4 49.6 J9S0-5S i .i 7.2 34.5 87.5 145.1 100.6 J910.St 0.7 2.1 5.3 9.0 9.6 _ Wh\te Female 0.8 2.9 777 17.5 35.9 -- 19 J9SO.S? 0.6 2.3 5.8 19.8 39.8 82.0 API 06115 journal of the international college of surgeons JULY. 1955 Respiratory Cancer Death Rates by Aye mtd S'.' "iii'niy Ordinary Policyholders.-- Ordinary policyholders are drawn chiefly from the middle and the w ell-to -d o classes of the population engaged in non hazardous occupations. The age-specific death rates from respiratory cancer among them, therefore, give some indication of the incidence of this disease among per sons in the higher socio-economic groups of the population. Table 7 shows the agespecific death rates among male and fe male Ordinary policyholders of the Metro politan Life Insurance Company during the periods 1930-1932, 1939-1940. and 1950-1952. In the most recent period respiratory cancer death rates among males insured under Ordinary policies were on the whole lower than in the general population; by some 10 per cent lower in the age range from 35 to 64 and at ages 75 and over. However, in the age group from 65 to 74, respiratory cancer death rates among male Ordinary policyholders were about 20 per cent higher than in the general population. The generally lower death rates among Ordinary policyholders are in line with the recent findings on social class mortality in England and Wales,* which showed that in 1950 lung cancer mortality among men aged 20 to 64 in the two highest social classes (professional, managerial, etc., and intermediate occupa tions) was only about 80 per cent of that for all occupied and retired men. The respiratory cancer death rates among female Ordinary policyholders at the ages of 55 and over have been some what higher than in the general popula tion. This too is in line with the recent findings on social class mortality in England and Wales, which showed that in 1950 the lung cancer mortality of married women aged 20 to 64 in the three highest "The R eg istrar G eneral's D ecennial S u p p lem en t io r E n g . land an d W ales. 1951. O c c u p a tio n a l M o rta lity . P a r t 1. social classes was somewhat higher than the average for all married women. The trend of the age-specific death rates from respiratory cancer among Ordinary policyholders indicates that for males aged 55 and over the absolute increases in death rates were significantly greater in the 1940's than in the 1930's; for males aged under 55 the absolute increases were about the same in both periods. For fe males aged 55 and over the absolute in creases in death rates were very much smaller in the 1940's than in the 1930's; for females aged under 55 the death rates actually decreased during the more recent period. It appears, therefore, that the in crease in respiratory cancer death rates is slowing i nvn for females and perhaps also for males at the younger ages. Judg ing by recent trends among Ordinary policyholders, further increases in respira tory cancer death rates are to be expected for males past midlife. Geographic Variations in Respiratory Cancer Death Rates.--Geographic varia tions in respiratory cancer death rates offer some clues as to the factors which may be implicated in the increased in cidence of this disease. In considering such variations, it is necessary, however, to keep in mind that differences in death rates reported from various regions may be attributable to differences in the ac curacy of diagnosis, case finding, and re porting as well as to the effect of specific factors. Table 8 shows the age-specific death rates from respiratory cancer for white males in different regions of the United States in 1950. In general, the highest age-specific death rates were recorded in the Middle Atlantic and New England regions and the lowest in the East South Central, the West North Central, and the Mountain regions. The corresponding agespecific death rates from respiratory can cer for white females show no such clear 20 API 06116 \\.L. \ \ ; v Nu. cut pattern and do not vary as much from .me part of the country to another. Table 9 and Chart 5 present age-adlusted death rates from respiratory cancer for white males in individual states. The highest death rates were recorded in Louisiana. New Jersey, District of Co lumbia. New York, Maryland, and Dela ware (all in excess of 30 per 100.000). The lowest death rates prevailed in North Dakota. Arkansas, Idaho, New Mexico, North Carolina, and Utah (all below 15 per 100.000). Broadly speaking, the highly urbanized and industrialized states had high rates while the predominantly agri cultural and mountain states had low rates. Contrary to this general observa tion, Louisiana had the highest age-ad LEW CANCER OF RESPIRATORY TRACT justed death rate of all states (34.8 per 100.000), and high rates were also re corded in Florida (27.8 per 100.000) and Nevada (27.7 per 100.000). For white females, the highest death rates from re spiratory cancer were also most often found in the highly urbanized and indus trialized states (as well as in Louisiana, Florida, and Nevada). The 1940 respira tory cancer death rates by state presented much the same picture. If in 1950 white males in the United States as a whole had shown the relatively high age-specific death rates from respira tory cancer observed in the Middle At lantic States, the number of deaths from this disease among them would have been increased by about 25 per cent. If these Age Adjusted Death Rates per 100,000, Vhlte Male Population Under 17 E X v H 17-20 W///A 21-22, H H 25 4 7er Chart 5.-- Age distribution of cancer of the respiratory tract in the white male population of the United States in 1950. 21 AFI 06117 JOURNAL o f THE INTERNATIONAL COLLEGE OF SURGEONS JULY l Table 8.-- G e o g r a p h i c V a r i a t i o n s m R e s p i r a t o r y C a n c e r D e a t h R a t e s o f W h i t e M a l e s by B road Regions of the U nited S ta tes-- 1950 25:2^ Date Rate per 10o, .* . 70.J C5 Tft 'j & nrrr N e w England ... . 1.1 8.8 40.3 97.2 140.3 111.2 Middle Atlantic . .. 1.3 8.8 47.8 121.4 165.6 139.9 East N'oith Central 1.3 7 2 40.4 97.0 111.3 100.6 West North Central . 1.1 6.5 26.8 69.5 85.2 90.2 South Atlantic .. . . . 1.1 8.9 39.7 98.3 112.8 106.9 East South Central . .. 1.1 9.1 32.3 65.9 70.7 81.1 West South Central . . 1.1 8.4 35.3 91.5 92.1 111.6 Mountain . ...... ......1.6 4.2 29.7 61.8 109.7 92.2 Pacific .. . . .. 1.1 7.5 37.6 90.2 121.2 103.4 United States..... .... 1.2 7.9 39.1 95.9 119.4 108.3 Canada (1950-51 ) ..- ......0.7 4.5 27.5 72.7 101.4 82.6 men had experienced the age-specific death rates from respiratory cancer found in 1950 in England and Wales, the number of deaths among them from this disease would have been doubled. For white males in the general popula tion of Canada, the age-specific death rates from respiratory cancer were almost as low as those in the three regions of the United States mentioned above as having the lowest rates. In the Province of Ontario, the death rates were moder ately higher, but still somewhat below the average for the United States as a whole. In the Metropolitan Life Insurance Com pany's experience among Industrial policy holders in Canada, white males also showed much lower death rates from re spiratory cancer than white male policy holders in the United States, but white females showed about the same death rates in both countries. Table 10 shows for each state the 1940 and 1950 crude (not age-adjusted) death rates from respiratory cancer for all per sons combined, as well as the number (in 1940) of physicians per 100,000 popula tion in the state. This latter ratio pro vides a rough measure of the medical fa cilities available for diagnosis and case finding. The comparison of the 1940 and 1950 crude death rates indicates that the incidence of respiratory cancer rose dur ing the 1940's in every state. However, the smallest percentile increases occurred in the states with relatively high death rates in 1940 and the largest increases were reported from states that had low rates in 1940. This is consistent with the hypothesis that, in the past, geographic differences in respiratory cancer mortality reflected largely differences in the pro portion of such cases detected and re ported. With improvements in diagnosis and more complete case findings, the dis parity between the states has diminished. It is not surprising to find that the states with relatively high numbers of physi cians per 100,000 population reported high death rates from respiratory cancer. The magnitude of the reported death rates from respiratory cancer is clearly associ ated with the quantity and quality of the medical facilities available for accurate diagnosis of the disease. Improved Diagnosis and More Complete Case Finding of Respiratory Cancer.-- There is considerable evidence that de velopments leading to more careful and more frequent diagnostic study of patients as well as improvements in diagnostic techniques have played a very important part in the recorded rise of respiratory cancer death rates. This evidence cannot, API 06118 1 VOL. XXIV. NO. I LEW: CANCER OF RESPIRATORY TRACT however, be translated into estimates of the proportions of deaths currently re ported as due to respiratory cancer which twenty-five years ago would have been reported under cancer of other sites or as due to other diseases. The more significant pieces of evidence are: 1. As a result of more and better in struction in diagnosis at both the under graduate and graduate levels, there has been a great increase in the number of physicians with good training in diag nosis. The number of specialists in radi ology and bronchoscopy has also increased markedly. Furthermore, the publicity given in the medical and lay press to the sharp rise in respiratory cancer has of itself led to greater awareness of this dis ease and thus to more frequent search for it. 2. The facilities available for diagnosis of respiratory cancer and their use have likewise multiplied. The growth and utili zation of hospital facilities have been par ticularly marked since World War II. Impetus to the use of roentgen was given by the mass roentgen campaigns for tu berculosis detection even before World War II, and later by the large scale roentgen examinations for military serv ice and in the armed forces. Industrial medical services have been expanded steadily and there, too, roentgen examina tions have become almost routine. Of spe cial importance has been the increase in accessibility of modern medical facilities to persons living in agricultural and out lying regions. 3. The development of better diagnostic methods (such as roentgen rays, bron choscopy, cytologic examinations and diag- T able Region 9.-- Geographic Variations in Respiratory Cancer Death Rates of W hite B y States, 1950 A g e A d j u s t e d D ea th R a te per 100.000 Low (Under 7) 'f*dium Low '17-tll Medium High (;i-7i) M ales High <75end Over) N e w England ............ Me. 20.2 Vt. N. H. 21.6 23.0 Mass. R. I. Conn. 25.3 27.0 29.3 Middle Atlantic .......... Pa. 24.5 X.Y. X. J. 33.5 34.2 East North Central........ W:s. Ind. 17.8 20.7 Ohio Mich. 22.7 24.8 111. 26.1 West North Central....... N. D. Neb. Iowa S. D. 11.8 15.2 16.0 16.4 Kans. Minn. Mo. 17.1 17.2 20.6 South Atlantic ........... N. C. 14.0 W. Va. 20.0 Ga. Va. S. C. 23.0 23.5 23.8 Fla. Del. Md. D. C. 27.8 30.9 32.0 34.0 East South Central........ Ky. 15.2 Tenn. Ala. Miss. 17.3 17.8 20.2 West South Central...... Ark. 13.5 Okla. Texas 19.9 20.9 La. 34.8 Mountain ................ Idaho 13.6 N. Mex. 13.7 Utah 14.9 Colo. Mont. 18.2 20.1 Ariz. Wyo. 23.6 23.8 Nev. Pacific.................. Wash. Ore. 18.2 19.8 Calif. 24.8 23 API 06119 JnURNAL OF THE INTERNATIONAL COLLEGE OF SURGEONS JULY. IMS Table 10.-- Death R a t e s f r o m R e s p i r a t o r y Cance, ami P h y s i c i a n p e r 100,000 P o p u l a t i o n Increase m Death R a t e f r o m 1910 to 1950 A m o n g All Persons B y States R, i}'rnioryj Cancer Death Rate per lQO.'lO1' Phytxcians ~ per $*ntr 19+C 950 Incrcaee 200.000* South Carolina 1.9 Arkansas . ) > Mississippi . .. 2.4 North Carolina 2.7 Georgia . . ,2.8 Alabama . .. 2.9 Tennessee .... 3.3 Oklahoma .. ....3.3 N e w Mexico . ....3.6 Kentucky .... ..3.6 W y o m i n g ..... ..3.6 West Virginia .....3.7 North Dakota . ...4.1 Texas ........ ..4.1 Idaho ....... ..4.2 Delaware.... ...4.5 Virginia ... 4.7 I o w a .... .... 4.7 Arizona . . 5.2 Indiana .. 5.3 Kansas . . .5.6 Colorado . 5.6 Nebraska . 5.7 Vermont . . .5.8 Utah ....... 6.0 South Dakota .. 6.2 Nevada ..... 6.3 Montana .. .6.4 Maine . . .....6.4 Wisconsin . ..6.5 Florida 6.6 Michigan . ......6.6 Minnesota ......6.6 Missouri . . 7.0 Oregon . .... 7.2 Ohio ......... 7.2 Louisiana .. 7.6 Washington . ... 7.8 Pennsylvania ......8.0 Maryland .... ..9.3 Illinois ....... 9.5 N e w Hampshire .9.8 California ... 10.0 Rhode Island . .10.1 Massachusetts ...10.5 Connecticut .. .10.7 N e w Jersev ... 11.5 N e w York .. .13.5 8.5 8.3 8.1 6.0 9.3 8.7 9.4 11.5 7.0 9.4 12.0 10.9 8.2 10.7 8.0 18.2 10.9 12.2 11.1 13.5 13.0 11.5 11.8 15.4 7.0 11.0 18.7 13.9 12.6 12.0 15.5 14.5 12.3 14.7 13.9 14.7 15.0 12.3 15.8 16.5 17.0 13.9 15.0 16.3 16.4 18.3 21.0 20.9 347 74 277 94 238 69 122 1 i 232 90 200 73 185 100 248 101 94 83 161 97 233 109 195 96 100 81 161 108 90 81 304 127 132 108 160 122 113 119 155 121 132 115 105 175 107 124 166 146 17 104 1 1 79 197 151 117 96 97 117 85 112 135 120 120 121 86 126 110 140 93 134 104 135 97 104 58 127 98 137 77 164 79 154 42 133 50 172 61 135 56 183 71 152 83 140 55 203 'In 1940. nostic thoracotomy) and the more fre quent use of radical surgery have uncovered many cases of respiratory can cer which would have been missed in earlier years. The growing tendency to obtain microscopic confirmation in sus pected cases has had the same effect. The special morbidity studies conducted by the National Cancer Institute in ten large metropolitan areas showed that in 1938 some 66 per cent of the respiratory cancer cases diagnosed had been confirmed by biopsy or autopsy whereas by 1948 this proportion had risen to 75 per cent. Since the ten large metropolitan areas were well above the average as regards medical practice in 1938, it is likely that for the country as a whole the relative increase in biopsy and autopsy has been even greater. 4. The fact that the magnitude of the respiratory cancer death rates is clearly associated with the quantity and quality of medical facilities, and that during the 1940's respiratory cancer death rates in creased most in states with low death rates and relatively low ratios of physicians to population, also supports the view that much of the increase in respiratory cancer was the result of improved diagnosis and more complete case finding. 5. The marked increase during the 1940's in the reported death rates from respiratory cancer among nonwhite lives can also be attributed largely to improved detection and better reporting of the dis ease in this segment of the population, particularly at the older ages. At these ages, some of the increase probably repre sents the reporting of respiratory cancer as the cause of death in cases in which the past would have been reported as due to senility or ill-defined causes. 6. The sharp declines in the mortality from tuberculosis, pneumonia, and other respiratory diseases, such as chronic bronchitis, have probably resulted in the detection of respiratory cancer cases which formerly would have been reported as deaths from these diseases. Since tu berculosis death rates have decreased least at the older ages, where respiratory cancer death rates have risen most, it is not likely that sizable numbers of deaths once reported as due to tuberculosis have come more recently to be reported as due API 06120 VOL. XXIV, NO. I LEW- CANCER OF RESPIRATORY TRACT to respiratory cancer. It is likely, how 2. Among white females, mortality from ever. that the high death rates from pneu respiratory cancer, adjusted for changes monia which prevailed before this disease in age distribution, has only about doubled came under control included many cases in the past twenty-five years. If all this of respiratory cancer. increase were due to better detection and 7. An increase in the proportion of cases where the respiratory system is reported as the sole or primary site rather than as the secondary site may be another factor in the recorded rise in respiratory cancer death rates. In this connection, it may be noted that in 1940 the number of deaths in the United States in which respiratory cancer was reported as an as reporting, it would still be much smaller than the increase in white male mortality. This suggests that a considerable part of the increase in white male mortality from this disease cannot be accounted for in this manner, since it is difficult to see why physicians should be able to diagnose re spiratory cancer more readily in one sex than in the other. sociated cause (7,375) was not much less 3. The magnitude of the increase in than the number in which it was reported respiratory cancer death rates over the as the primary cause of death (9,543). past twenty-five years has varied by age, Other Factors in the Increase in Re spiratory Cancer.--While it has been sug gested that improved diagnosis, more complete case finding, and more accurate reporting of respiratory cancer have been responsible for most, if not all, of the in crease in the reported incidence of the disease, many considerations do not sup port so extreme a view. On the whole, the evidence points to a real rise in the mor being smallest at ages under 45, and great est at the most advanced ages. If the in crease at the younger ages were all due to better detection and reporting, it would still leave most of the increase at the older ages unaccounted for. since it is difficult to see why physicians should be able to diagnose respiratory cancer very much better at the older ages than at the younger ages. tality from respiratory cancer. 4. The markedly higher death rates The more significant of these considera tions are: 1. During the past twenty-five years the white male mortality from respiratory cancer, adjusted for changes in age distri bution, increased five times. An increase of this magnitude and rapidity appears greater than can be accounted for solely by better diagnosis, case finding, and re porting, especially as no other site of cancer has shown as large a proportionate increase. If all the increase in respiratory cancer were due to better detection, and from respiratory cancer among white male Industrial policyholders as compared with those for white males in the general population cannot be explained in terms of the better diagnostic facilities in urban areas, since white female Industrial policy holders residing in the same areas show respiratory cancer death rates substantial ly the same as those for white females in the general population. The reasons for the higher death rates of white male In dustrial policyholders must rather be sought in some environmental factors. reporting, it would mean that physicians 5. The lower death rates from respira practicing twenty-five years ago were able tory cancer among white male Ordinary to identify at most only one out of five policyholders, who presumably have ac cases existing at that time--the increase cess to even better diagnostic facilities is continuing despite the fact that the dis than Industrial policyholders or white ease is now more generally recognized. males in the general population, also sug- 25 API 06121 Ju l RN \L n t' T!;F INTERN \TI"NVL iJl. LE< IE OF lROEONs JVL. 1S3 pest factors related to environment, occu pation. and social class. The recent find ings on the incidence of respiratory can cer in the two highest social classes in England and Wales point to the same con clusion. In this connection, it may be noted that several life insurance studies have indicated somewhat higher than aver age mortality from respiratory cancer in such numerically important occupations as painters, roofers and slaters, carpen ters and cabinet makers, coppersmiths and tinsmiths, and electricians. 6. The geographic variations in respir atory cancer mortality in the general pop ulation likewise indicate that some envi ronmental factors may be contributing to produce the higher death rates found in the most urbanized and industrial states. The high age-adjusted death rates in states such as Louisiana, Florida, and Nevada also appear to require explanation in terms of special factors. 7. There is reasonably convincing sta tistical evidence that a number of differ ent factors may be implicated in the rise in the incidence of respiratory cancer. Adequate data are not available to show how much of the rise can be attributed to the effect of specific factors. SUMMARY ZUSAMMENFASSUNG Der Verfasser legt an Hand von Kurven und Tabellen statistische Angaben ber die Sterblichkeitsziffern des Krebses der Atmungsorgane innerhalb der allgemeinen Bevlkerung der Vereinigten Staaten und unter den Industriellen und Sonstigen Ver sicherten der Metropolitan Life Insurance Company vor, vergleicht die Zahlen mit den Sterblichkeitsziffern bei anderen Ar ten des Krebses und betrachtet ihre Be ziehungen zum Alter, Geschlecht und zur Rasse des Patienten, zur Gegend des Wohnsitzes usw. Die Kaktoren, die beim heutigen Anstieg der Hufigkeit des Krebses der Atmungsorgane eine Rolle spielen, werden angefhrt. RSUM L'auteur prsente des dates statistiques, illustres par cartes et courbes, sur la mortalit par les cancers des voies respi ratoires parmi la population entire des tats Unis et parmi la population, Indus trielle et Ordinaire, assure par la Mtropolitan Life Insurance Comp, Il compare ces chiffres avec la mortalit par des autres formes de cancer, corrlativement d'aprs l'ge, sexe, rgion d'habitation etc. Des facteurs concernants l'augmentation pr sente des cas de cancer respiratoir sont rgistrs. The author presents statistical data, il lustrated with charts and tables, on the death rates from cancer of the respiratory tract in the general population of the United States and among Industrial and Ordinary policyholders of the Metropoli tan Life Insurance Company, comparing these rates with the death rates from other forms of cancer and correlating the evi dence from the points of view of age, sex, race, region of residence, etc. Factors in the current increase of cancer of the re spiratory tract are listed. RESUMEN El autor presenta una estadstica ilus trada con cuadros, sobre el grado de mor talidad del cncer del aparato respiratorio en la poblacin general de los Estados Unidos de Amrica y entre los asegurados Industriales y Comunes de la Metropolitan Life Insurance Company, comparando este grado, con el grado de mortalidad de otros cnceres y relacionando la edad, sexo, raza, residencia, etc. Se ponen en unalista los factores que aumentan el cncer del apa rato respiratorio. 26 API 06122 vol.xxiv. n o . ; SUMARIO O autor apresenta dados estatsticos, ilustrados com grficos e quadros, sobre a mortalidade por cncer do tracto respi ratorio na populado geral dos Estados Unidos e entre assegurados Industriis e Comn da Metropolitan Life Insurance Company, comparando essas taxas com as devidas a outras formas de cncer e cor relacionando os dados sob os aspectos idade, sexo, ra?a, regio de residencia, etc. Sao apresentados os fatores do au mento atual do cncer do tracto respira torio. LEW: CAXCER OF RESPIRATORY TRACT RIASSUNTO L'utore presenta e documenta con gra fici e tavole i dati statistici relativi alla mortalit per cancro del polmone sulla popolazione generale degli Stati Uniti e fra assicurati della Metropolitan Life In surance Company, nel departimento In dustriale ed Ordinario li paragona con quelli relativi alla mortalit per cancri di altre sedi, in rapporto all'et, al sesso, alla razza, alla provenienza ecc. Elenca, poi, i fattori responsabili dell'aumento dei carcinomi polmonari. 27 API 06123 I i *4 S . . I I V I \< < III! M I' n f N I- N I l u s -- ( S K I I Ml- H* t 0*4 . f . ` . ' 'w N ' ' 1>W d k w' ^ ' . . . ) v * n . i ' n t k . . " v s. L . . K . :*. v . 1 ,;nd V.ui :ent pi''de> ^ s. ' V . . V . - ' 1. ii'n-mp t-1t'' c late: t >s. ' w " nw ' ' ' I ' d * w` * ' ' . w c in that i n * " ; -.uMiidn f i ' .v .. . l ' c v .Mim i '! blood prc-salire did 1 .p - s. " c. r's-'tt.i'ts.c' and it least :A K ' u ! ' O l . VI V . I)- ACCIDENT PRKXKNTION IN CHILDHOOD-- THE KEROSENE HAZARD I I , , . I ( m, < M l > J ,, -----. / /,, \..-dc'it' h.-.'.L iv.ouv tiv leading ..ui'c i<i death monc .hiklun ovei .'ivye.u >'lage Itv piomincn*i. ,.|aident *11>ii,t1it\1due inp.iittothe widespread U'C ,.| .'vnit'itv-iapetui agent' and imimmi/.ttu'n poveduri.'' "kji have helped .ontrol onimunvablc di- j.i'C .irvi ;n.in', .'tlvi mlc-tions in childhood Pneumonia durihea and vntviit-- ,n one time the ^'inni.'iV't .au'C ol eie.ith among >'line: .hildren-- h.A.' been g:.mlyingly ontrolled In la.t. pneumonia. Ji.irrlie.i. me.t'le- Jiphtlieita. whooping cough. scarlet lever meningitis and poliomyelitis. all combined. do net kill a many Amciv.in ehildien a' do accidents One*-third oi all death' in ehildien at the prC'ent time* ic'tilt lr'in .ueident' while in IWdti a.eident' caused only one-twentieth oi the death' occurring ineluldhood There ha been in reeent years ante reduetion in death iii'in aeeident' among ehildren. but to a niueh le" extent than tront disease' i'ee tieare i Since Iv.tt) death Mom eotntnumeable dieae have been re duced y ~ ' , . from gastroenteritis .from appendiei- n 'O'. .trom tuhereulo'i SW'. .and Irani pneumonia and intluen/a sn' .but trom accidentonly Tin reduetion in aeeident doe not neeearil\ mean. how ever that children are being injured le frequently lodav physician are saving more who have been burned, poisoned, crushed, or mangled Over one-halt ot all fatal aeeident in childhood occur among children under 5 year ol age Dietrich emphasized that the creates! etlort at accident prevention should be made in thi ace group not only because these children have nioreaccident but because education toratety 1more tiuitlul when directed toward young children. Acci dent in the I to 4 vear age group have rien in promi nence aac.iueoldeath. In I*430-1^51pneumonia, in- iluenza. and the common communicable disease of childhood ranked above accident with the eatroin- te'tinal die.ic not tar behind. In 1V5I-1*452 acci dent were in first place, almost doubling in number the death trom pneumonia and inilucnza. the next ranking ei.uip Ihi, however, inot the whole picture It ha been estimated by authorities on the accident problem that i.t averv latal accident among children there arc at lea! Mm nonlatal accidents. 4 oi which reuh in some peitn.inent disability Tiletablehow thedi'tnbunon ottheprincipaltvpcs ol accident among children aged 1to 4 vear Although motor vehicle' burn diowning, and tall all precede poi'omng a c u u e ot death, thi cause neverthele give ric to an extremely import.mt aspect ol the prob lem and illu'iiate' it' magnitude Poisonings are moi likely to occur in children ot age I through 2 iee table i Thi ithe age ol inquisitivene when ome chil dren will eat or drink almost anything k tR O S IN t POISONING One ol the commonest, though not moi fatal, type ot poisoning among young children is caused bv the consumption ot petroleum oils, principally keroene Bain in her study ot accidental poisonings m children under 5 year ot age m the United States found that petroleum product accounted for 25c> of accidental poisoning in this age group The Florida Children's 1951-1952 1930-1931 lcaJtfic . juhv 'r death in shiljren jg u 1 ) to ^ \<jt\ Death rate* p c ' t>> u j n s t f iric.aw*.' leufccm u j h J H o d g k in dicac Commission in cooperation with the Florida chapter ot the American Academy of Pediatrics and the Florida Pediatric Society recently sent a questionnaire to 156 hospital in Florida in an effort to determine the inci dence ot poisoning within the state caused by ingestion ol volatile oil Ot *40 hospitals returning the question naire. accepted children who might be poisoned. In Ivy?. 22v children, all under 6 years of age. were admitted to 45 hospitals fortreatment because of poison ing bv volatile oils. Nearlv all of these children were R u J h i V ' i 6 C E u . h i h i i m u a l M e e u n * '| t h f A m c r u J l t M r J u . i 11 A>s. ,* . *n M ir*i f a I )ck 1 T h e ' . I * r t h e f i g u r e j n d : j M c j r e h j c J 'n e \ p e n e n k <> o l t h e Ms ' . ' p .n l *i l n j r j n ke C , ' m p j n v ln du * -i ru l D e r a n m e n i I Affr.!'. i) H .<nd i , ' . t NN o u n l hi j A ^ i d c m * Be Prc i - c . i n N , ' v, i u " ^ n u r t t t v , Am J P j h H e j l i h 3 B . *** ' M j t pi l W h i ,, ' e* A M P-- . * . j M u I O Aw* i d em Pre* emi**n j n o th e o e n e t j , P - j . t t --* . N v , W M Du, ' h H F P*e e n 'i. * t .! U hildh.sj A*, d e n ts \V h j i Arc kk . . F - 1 J A M A 4 t . 'rOIC* IJhd - N>* h- .*<* * H i " k l ' k j ! h vl ) u e t* A * t d e n tj ; P.'nin^ m N c u n i ' c h i l d '" J Pe, . . I l m m ; : J -e 1 API 06124 * no U t l l l F M m x F M I O N -- CtKIlHl-Kb poisoned b> dnnWmi: kerosene In addition. "S children were treated a' outpatients in IS hospitals, and itwas estimated by 24 hospitals that 2SS others probably were treated Thus a total of oxer 5(JO Florida children were treated in that one year tor volatile oil poisoning, caused in neurlx all cases b> ingestion of kerosene There was onlx one death among this group \n examination ot data from the bureau ot xital statistics ot the Florida State Board of Health, however, showed that tour other children met death in the state in 195? from drinking petroleum products. They were not treated in the re portin'.: hospitals. These fatalities indicate, in all proba bility a much larger incidence of this type of poisoning than was discovered as a result of the questionnaire. A detailed study was made of all cases of poisoning trom petroleum oil products recorded at one ot the re porting hospitals, the Duval Medical Center. Jackson ville During 1953. 7b patients were treated on the charity childrensservice,one ofwhom died. The mean Pcnintaitt Distribution, b\ Print tpal Tspvs. o f Deaths A n u l e i u s A n i o n e C hi u t>ue to t o u r Y , , , ' s o t Age ' M W from Vo lr~ l * l u U l fiu J- i**i -.Up j - r ! !* ' %% ! \ ` ! a* ft vi t . . ir- tnt.il Rito . v. - . - h i * ' v. h vle 1 : 4. : 4. ' i: : . m j : Burs* i ani *< ** * : t: :i--f..J:i! >**v is-.J : < u * ftaK' t ? 'it* *. * `.'4 . 14 4 1 : n * 1 : I" 1 7 ` .* L ? ..... L . !. h<l 's ' ' rtUv1' i*U` 4 J > oZ ' 7 i.: l ''-' Fa. I - 4 i . . i : . u ? , ]* l ... : 4 * i 4 l 'u - -i :.f t , * .* S . ' - t If 1.7 Tuk fit ' v * *..! 4 i : : : U' .U 's -' r p l d L- p s ( j- i - 1 . ; i \t . i.: . , . 1 -a i j \ll v t rv r .irt - i *> u ? : 4 it* l V 5 v jv j;#) hospital stay of these children was 4.53 days. The per diem cost of patient care in this hospital in 1953 was S12.36. If. on the basis of this per diem cost and this average hospital stay, one computes the cost of hos pitalizing the known 229 patients treated in Florida hospitals in 1953, he finds that hospitalization cost approximately S12.S00. The cost in terms of psycho logical trauma to the young child and his parents, of course cannot be measured. Kerosene ingestion isnot a type ot poisoning confined to the South, although it is probably commoner in this area than inother sections of the country. In June. 1953, the committee on accident prevention of the American Academy of Pediatrics reported a syrvey of 507 cases ot accidental poisoningthatoccurred throughout the United States In ihis series kerosene was ihe second com monest toxic agent, comprising I6rr of the total.' A 6 The Near Book of B e d u i n o Sene-" edited bv O r ' S b L'his.apo ihc ^ td T B . v k P u N i - h e r s I n , 1**4 p * V . v n i n u Uv'fttfoi C o m m i t t e e ll!ino<* ol A fretu an AvaJemv of P e O u t r u ' P c r w r t j l . o m m j n u a t i o o to the author B o i o p / u N A . n d W o o d * ** U' k e r o x n c P o i t o n m p S e w Otraflv V A i J l O I DCs > 1*4* i.V .V I.V .. Sep. 10. 1055 review 'I 3 5 cases ot poisoning recorded in six Chicaco hospitals during a recent nine month period, made bv'the poisoning control committee of the Illinois chap ter of the American Academy A Pediatries, disclosed thatin4b cases,or 12r:.thecauseotthepoisoning was the inge'tion ot petroleum distillates, principally kero- bene * In the Jacksonville area kerosene is widely used tor heating homes as well as for cooking Consequently, a decided rise in cases of poisoning during the winter months would be expected, but tor many years there have been numerous cases in the wards during the sum mer. Throughout 1953. tor example, the distribution ol kerosene-poisoning cases at the Duval Medical Center was tairlv equal, as shown in the following tabulation Jau .s:\ a * r . r \ Muri b Al-r.l 11j t Jl.: r .1. i \ 4 \ . t - *1 ;i* *..* t f 7 u t 1" N*u **r o Ivxft ' Although there may be more kerosene in the child s en vironment in the winter, it isduring the summer that he willbe more likelytodrink itbecause ofthirst. Thisob servation emphasizes an important principle in the pre vention among young children of poisoning from all toxic liquids, active youngsters should be given fluids between meals, especially in hot weather, so that thirst will not be the stimulus to the consumption ot liquid poison. It is not the purpose of this paper to present a com plete discussion ot kerosene poisoning. Certain contro versial features of the disease, however, are reviewed here because they may have a bearing on survival Deaths from kerosene poisoning may be due to two causes, i1i aspiration with pneumonitis, subsequent pulmonary edema, and secondary infection of the lungs, and (2) toxic effects on one or more organs or systems of the body, in particular the liver, stomach, and in testinal tract, and especially the brain. The lungs are almost invariably involved in severe cases, and it is now believed that aspiration is far more important than is absorption in causing damage to the lungs. In ex perimental animals pulmonary damage can be produced by the injection of kerosene intravenously Some ex perimenters believe italso can be produced by injection of the oil into the gastrointestinal tract when the pos sibility of aspiration is removed.' Practically speaking, blood levels in r.un probably never would reach those produced in experimental animals when kerosene is in jected intravenously If there s pulmonary irritation trom absorption alone, it is probably not great. Chil dren who have consumed more than several ounces ot kerosene quickly show signs of toxicity with drowsiness and later coma Kerosene contains hydrocarbons com monly used in some anesthetics, but varies considerably m coma-producine ability because ot variability in r e fining processes. TREVTMEST The immediate problem facing all physicians treating childrenwho have consumed kerosene .swhether ornot to aspirate the stomach The condition of the child, and to alessextent the history,willserve as a practical guide API 06125 l,,l. t-*g J jne.uii individual ^.i-c !f .'nccan he 'lireor.lv .1 -raT jnn'iint w.is"ijlluwcd. n vomiting has i\kur'.'J .md ,1 jt^reate no 'igns ot tovisitv w.t.h drew-ine" a .'M ,, probably bc't Icti alone On re other hard ! s.c e'pcwi.illy with di/zmc". Ji.-vi'inc". 01 ko:-o.a. arepresent,or it'someone .ictu.illv >,m hintdrink akon- Miler.ihle quantity, eaietul l.oagc oi the 'tom.iJi a h ilie head and chest lowered. is indicated Pimhing oil (,fthetube,quuk vvithdiawal.and. itpo"iMc. aviMd-iitC 0fvomiting jLinne lavage aie important point' in tech nique. vcvtnr\r i*rtvistin\ Tho brief repoit on poisoning trom petroleum dotillatc' in one state 'erics not only to illu'ii.ite the magnitude oi the problem of pot'oning among children but to >tre" particularly the impoitanee ot accident', of alltvpcs. as a cause of morbidity and mortality amone the young. No attempt has been made to docu" nuny important taeets of the accident piohlem, 'Uch as ac cident pronencss. lor example. The tact that 2')' ot the accident victims, in some roups studied, sustained over 50r< of the accidents is important to physicians. Accident repeaters should have a physical appraisal with special emphasis on vision, hearing. orthopedic status, and neurological inteeiity. Detailed psychologi cal investigation may be necessary lor those having no physical basts for repeated accidents. All physicians vvho give medical care to children have an opportunity, indeed a responsibility, to promote accident prevention among them. General practitioners, who provide most ot the medical care children receive, have especially good opportunities to promote satety. Becoming safety-minded and teaching safety to parents and children should entail little, if any. additional bur den to the busy physician. Some specific suggestions ot proved value in accident prevention that doctors can make a part of their routine practice are given below. 1. Education of parents in accident prevention should begin before the child learns to walk. Mention the common home accidents at well-child check-ups. whether in private office or clinic. Distribute pamphlets on accident prevention; they are available for the ask ing from several leading insurance companies and the National Safety Council. When such literature is left on waiting room tables, it does little good, but when given to a parent with firm instructions. 'Read this." itcan be ofvalue. 2.On callsinthe homes otchildren, observe unsafe conditions and suggest corrective meas ures. 3. When treating a patient for any accidental in jury, inquire into the eau'e ot the accident and tactfully point out how a recurrence can be prevented in the future. There is no better time than while treating an accidentally injured child to nuke the parents and the child himself aware that safety measures are ot value 4. In prescribing drugs, stress the dangers of .nmdicious use and carcle" storage Tho isalso a good tune toinquire about the handling ot hjrnitul cleaning ager insecticides, and fuel in the home 5 When a child h.o repeated accidents, make a complete appraisal ot the patient and his environnien. in an jttempt to rind the cause Public health nurses may be ot value in such a PtRORvl.FMhwMPV--vUIKR 11 't.idy .i c.i.irdiun ot pu*',;k `-c.iiiti .ind .ic!l-hcine. be ' Icadc: in community p u n c o - dacw'.wd u n sa id aictv a"J aw'.dcnt picveneon. ' ; " l'.is ' _ ' v s I , v. p . r . s v . i vi,j I*.'*.* *' ' 1 \ \.k ". \ v - I .V *s >, i)k >i \i \ : v* v . CLINICAL NOTES NEW ME IHOD FOR I.OCVL WESNIESIV IN I'EROR VI. ENDOSCOPY I'R H IX IIW R Y R H 'ORT H i / l'i i r J . AtiU-r. M . D . . r i h - c i u \ A>:: Current methods ot local anc'thc'ia lor pcroi.il en doscopy arc uM'uti'tactory because ot iI)the tovis re sults oi the cifccttve surtace jnc'thctie'. i2> the di'comiort-- to put it mildly-- to the patient c.ai'cd by peroralendoscopies under local anc'ihc'ia. and i3ithe lack ot rclavation ot the structure' underlying the mueo'j ot the pharynx and larynx A 'urlace ane'thctie doe' not relax Ihe deeper structures 'iich ,i'the b.i'e ot the tongue and the cneopluryngeu' nui'cle (the "pinshcock ot the C'ophagU'" i The upper tront teeth aid their guni' remain sen'itive to the unavoidable pre"iirc ot the endoscope The patient with long upper teeth and or a short, muscular neck is a dreaded prospect for peroral endoscopies. I have devised a method whereby the conventional surtace anesthetics can be avoided almost completely. The usual preoperative medication (barbiturates, nar cotics. and atropine) isgiven. The area to be described below isanesthetized by injecting a procaine-hyaiuromda>e mixture ti50 turbidity-reducing units to 30 cc. ot Ir r procaine)ora2H lidocaine (Xylocatne) hydro chloride solution and by instilling a 5rr hexyleaine (Cyelainei hydrochloride-- 2G trtpelennamine (Pynbenzamtne) mixture (ratio of 3.1) into the tracheobron chial tree. The superior laryngeal nerve is injected first. If one preters the external approach, the space between the cranialborder ofthethyroidcartilageand thehyoid bone ts palpated A I1: in. 23 gauge needle is inserted per pendicularly to the skin 0.5 cm. anteriorly to the supe riorcornu ofthethyroidcartilage untila resistance itrie thyrohyoid membrane) can be felt isee table, injection 1). Then the greater palatine canjl is injected The oral opening ot this canal lies about I cm medially to the second molar and lcm. anteriorly to the border be tween the hard and sott palate It suffices to enter the greater palatine canal for a depth ot ,5 cm This reaches the anterior, middle, jnd posterior palatine ne -es. resulting in anesthesia ot the hard and sott paljte. uvula, and anterior pillars (see table, injection 2a) An alternate method is to imect the mucosa over- Ffsjm the W ftjn* Admmixrjiton API 06126 V >/> % \\\ %S\ V* % API 06127 REPORT OF THE SUBCOMMITTEE ON CARCINOGENICITY to the API MEDICAL ADVISORY COMMITTEE On Tuesday, October 25tn, the Subcommittee on Carcinogenicity net in Dr. Eckardt's room in the Terrace Plaza Hotel in Cincinnati. The meeting got under way about 9:00 with the following members in attendance: Dr. M. N. Newquist, Dr. E. K. Linder, Dr. R. C. Mithoff, Dr. E. W. Adams, Dr. M. M. Marisic, and Dr. R. E. Eckardt. The reports by Dr. Horton and Dr. Phair were discussed. At about 10:30 the group moved to the Kettering Laboratory and conducted their meeting in the presence of Dr. Kehoe, Dr. Horton, Dr. Phair, and Dr. Heyroth of the Kettering Laboratory. In addition, Dr. B. E. Bennison of the Medical Research Division of Esso Research and Engineering Company sat in as a guest. Distributed to all members of the Medical Advisory Committee orior to the San Francisco meeting are reports by Dr. Horton and Dr. Phair dated October 1955 and- summarizing all the work which has been done on this project to date. In addition data tables of Dr. Horton's work will have Deen distributed to the members of the Medical Advisory Committee by the tijae. of the San Francisco meeting. In Table 1 of these summary tables, which is seventeen pages long, the data on various fractions from the refining of petroleum have been collected. Included in the Table besides the relative carcinogenic potency is a column listing the benzpyrene content of the oil sample as determined by the method Dr. Horton had published in the scientific literature. In general it can be 'said that particularly for severely cracked materials the relative carcinogenic potency at least roughly follows the benzpyrene content of the oil. There are however certain samples, in particular lubricants and uncracked stocks, which show a much greater carcinogenic potency for che mouse than would be anticipated from the benzpyrene content. It was -his observation which led the Kettering Laboratory to the theory that certain materials serve as accelerators to the carcinogenic action of polycyclic aromatic hydrocarbons. As a result of this theory the laboratory is now tentatively expressing its concept of carcinogenic potency in the following formula: PMC * Wa (C1 + C2 + 0 3) In this summary the various terms are defined as below: PMC is equal to the carcinogenic potency for mice exhibited by an eel, expressed in terms of the concentration of methyicnoianthrene in benzene -nat produces tumors in the skin of mice at the same rate and under comparable experimental conditions as that produced by,the oil. M& equals tne contribution to potency due to accelerators. o e ii: - 2 - j- -:cuals the benzpyrene type polycyclic carcinogens expressed m nethylcholantnrene equivalents. C p equals the carcinogenic substances extractable by maleic anhvcride (probably derivatives of benzanthracene) expressed in methylcholanthrene equivalents. C3 equals carcinogenic substances insoluble in concentrated sulfuric acid expressed in methylcholanthrene equivalents. Chromatography will presumably separate a given oil into two components, the first of which will represent the Ma in the above equation and the remainder of which will represent the (Cq + C2 + C3). Thus by chromatographing a series of oils in which the Pm c is known (as shown in Table 1, last column) it should be possible to solve the above equation for 14a since the (Cl + C2 + C3) portion of the equation will be retained on the chromatograph column and can be elutriated as a group free of the Ma component. This work naturally will be principally devoted to a study of the differences between uncracked stocks since it is in these uncracked stocks that the Ma appears to have the greatest significance. In fact, the laboratory has developed some evidence, as indicated in Table 6 of their most recent tabulation summary, that the Ma factor may vary from one to six or possibly even more. The laboratory has begun to use benzpyrene as a reference carcinogen since it has been the feeling of the Subcommittee and the laboratory that benzpyrene might be a more representative carcinogen for petroleum products than methylcholanthrene. The data collected by the laboratory and summarized in Table 4 suggest that benzpyrene at a given concentration has only about 50^ of the activity that the same concentration of methylcholanthrene has. This fact should be kept in mind in attempting to interpret any experimental work which the laboratory is doing in which the benzpyrene is used as a carcinogen. The laboratory has undertaken some work on the possible inhibiting effect Df one carcinogen upon another and believes that all published data claiming to show inhibition of one carcinogen by another are subject to the error of poor health of the animals due to high concentrations of mixtures of the two carcinogens. The experimental data in support of this concept are presented in Table 5. In Table 7 data are presented by the laboratory on solutions of benzpyrene in various solvents which suggest that many of the solvents have a significant accelerating action of benzpyrene much as they did upon methylcholanthrene. For instance, this accelerating effect seems to have made itself evident in paraffins, olefins, cycioparaffins, alxyl benzenes, ana aj_tyl naphthalenes, particularly when these materials exceeded a certain cnaan length. ^ Otner experiments which have been conducted by the laboratory _are summanzea m Tables 6, 9, 10, and 11 and the washing experiments are ctnarized in Table 12, whicn contains tnree pages. API 06132 - 3 - Tue laboratory is nov collecting evidence which suggests that the aromatics of oils of tne nature of API-3 contain about 15-20* of non-hydrocarbons. These non-hydrocarbons seem to be of the carbazole type. For Instance, the lab orator:/' has isolated from API-o (Table 1 page 13) and other higher fractions of this series the components carbazole which has the formula below. /\ In addition to this type compound the laboratory has isolated compounds of the 1,2-benzfluorine class and of the 2,3-benzfluorine class. V /cA /v 2,3-benzfluorine It is important to emphasize that though structurally these two classes of compounds appear quite similar, nonetheless chemically they are quite different. In addition to this chemical work the laboratory is pursuing its attempt to isolate what it calls a low boiling carcinogen which presumably boils in the range of 720-750F* It does not believe that carbazole or the benzfluorines are this carcinogen but it does believe that evidence has accumulated to suggest that there must be such a carcinogen so that isolating it may be of help in solving some of the problems now facing the laboratory in its solution of the problems of the carcinogenicity of this type oil. It is the belief of the laboratory that when they have obtained an ultimate solution to the equation PMC = Ma ( - 1 + - 2 + C3 ) tr.at it will then be possible to present to the petroleum industry an analytical tool which will permit the evaluation of the potential relative -2---no^enicitj o. any petroueum materiax. It should be recognized however w..a^ i-n_s i-ietnod wnlj. proDab^-y De --o.tg anc. tedious and require tne deter..mnaznon 01 at _easz four components anc. therefore may r.cz be tarticularly API 06133 xracxijal :or use in refinery operations. However, this bridge presumably cs-r. only be crossed when we coma to in. At the present tine the laboratory estimates that it will take six generations of nice at a minimum to obtain tne necessary answers to the above equation. With a minimum life of nine months for each generation and assuming that each step proceeds without any hitcn, this represents a minimum of fifty-four months of additional work by the laboratory in tne solution of this problem. The report by Dr. Fhair shows encouraging results in attempts at making statistical evaluations of cancer in the various participating companies. It is, however, discouraging to realize that only sixteen of twenty-five companies have participated in this effort and that in the last few years the number of participants may have diminished even more than this. For instance, in 195U only twelve companies participated in the epidemiological studies. It should be quite apparent to the medical members of the Medical Advisory Committee that if there is any hope of accomplishing anything with these epidemiological studies this hope resides in the full cooperation of all of the participating companies. This would then provide a large enough sample so that significant statistical analysis could be made and leads shown which might permit more detailed studies by individual companies or by the group as a whole. Nonetheless it must be recognized that if participation does not continue in this project it is doomed to failure ^through no fault of Dr. Fhair, but strictly due to the failure of cooperation xhe part of the participating companies and their medical directors on m e Medical Advisory Committee. Since the Subcommittee has been emphasizing xhe epidemiological aspects on this problem so long and intends to push the epidemiological studies, even at the expense of the experimental studies, it therefore seems apparent that if we are unable to obtain cooperation the epidemiological studies might just as well be terminated. The Subcommittee is in no position to do anything but make suggestions to the individual medical directors who sit in on the Medical Advisory Committee, but it is the suggestion of this Subcommittee that the experimental work in and of ixself has no real value since it has no direct tie in with the hm.n experience. The whole meat of all of the work which has been sponsored by xhe Subcommittee on Carcinogenicity lies in an attempt to develop an understanding of things that may be of importance to man and if the studies on man, namely the epidemiological studies, are not successful then all of xne work of the Subcommittee will have been in vain. The Subcommittee simply wisnes to re-emphasize that for the past five or six years it has seen stressing and encouraging all medical directors to participate in the epidemiological studies. 3 E E /jb m C ctober 1, l? 5 p API 06134  E sso Research and Engineering fPO EM EhLY STANDARD OIL DEV ELO PM EN T COMPANY) V. O. BOX S I. LIM DK N. N. J . Co m pa n y <4DICAl S C S E A R ' i , DIVISION c ICRaMCT. > c md O UttCTO II V H C N O M lC K I CM | HKAO IN JU IT R IA L HVOIBMIVT moaacc m ahanot. o .m d H E At> T O l l C O L O O t t T CffTftAM O C B K M N itO N . M O C H ltr CLINICAW flC M A U C M PH YS IC IA N Kavember 2, 1955 Mr. D. V. Stroop American Petroleum Industry 50 . 50th Street New York 20, H. Y. Dear Mr. Stroop: I am attaching sene information recently received from Dr. Hewquist who received it from our British associates in the field of petroleum cancer studies. I believe that the members of the Medical Advisory Ccosittee as well as those at the Kettering Laboratory would be interested in reviewing the Progress Report by Dr. Carruthers and Dr. Cook, and also Progress Report by Dr. Woodhouse and Dr. Squire. I would appreciate it if you would have these reports duplicated for these individuals. I do not believe that the rest of the attached information would be worth while duplicating since it concerns only the agenda and minor changes in the nomenclature. Very truly yours, RSE:evn Encs. MRC.55/830 MRC.55/815 MRC.55/8lk MRC.55/80U J . . R. E. BCKARDT, M. D. Copy From D. V. Stroop For Information of Members of Medic<il Advisory Committee li/1*; 55 API 06135 4 MEDICAL RESEARCH CO U N CIL 4 ici.-. u i f l c " c- 3p ,0.11*1o Circula`ion .bers al* Ca.inittee) iC.55/ 830 C.LX). ag.1 9 C crinittgo on the Carcinogenic Action of Minorai Oils r-zMA for tho ilinetco ;tn ..outing to be- 'void at 26, Old Quean Stn=ot, V'estninc-c-v, L-;.:ovi, 3.W.1., on Tuesday, 25th October, "1955 a.- *'.15 a.m. Minutes of the provious msoting (HP.C.55/ 510, C 1M). tiin.1 8 - already circulated) Amendments to nomenclaturu of oil fractions. A memorandum (1210.5^015, CtUiO.55/8) fEnclosure JL) Bxponsus grunt to Dr. William 2 . Smith for testing oil fractions (Minute 155) Progress Reports (i) Chemical - ty If, Carruthers and J .J. C o c k (MRC.55/81 if, CL.MO.55/9 (Enclosure B) (ii) Biological - by D.L. ffoodhouse and J.R. Squire. . Progress Report No. XV* (MBS.55/802*.* C1M0 .5 5 /7 UEnolosure_c) Future Plans Any other business Date of noxt mooting API 06136 MEDICAL RESEARCH COUNCIL '1i n:;.L1.rsi;'idd" :;oi- fir'. c i ^ i o ; Circulation (Mu. ,,r :i o' Connittco) IRC .55/815 `JuvIO. 55/ 8 Cofiunittoo on the Caroia t o n i c Action of Minorai Oils >1ornane 1 ,,t u r o f O i l P r v o t i ons It will be rocalled that, at tuo Sixteenth Meeting of the Canmitteo, the standardisation of t;;o :oinencl.tura of the various oil fractions m s discussed (Minuto 152) and it \r s agrood that Professor Squire and Professor Morten should considor this in the light of coding symbols alroady agreed (Minuto 1j56). Professor Squire and Professor Morton now propose tho following anondmont to liinuto 136. paragraph if, lino ? DBIafTB ...... -.Turo split into arcriatic (L) and raffinato (R) portions " SUBSTITUTE n *....... were split into aromatic (A; and paraffin raffinato (P) portions." This amendment and the nrovious confusion of synbols call for amendments in tho following documents as 3hovn: &M0.55/2 and CMMO 5 5 / & for R road P CAMO. 5^/16; CMO.55/3 and G j B.55/4j for M , P and R road m, p and r. API 06137 MEDICAL RESEARCH COUNCIL MRC.55/814 GUIO. 5 ^ 9 Coc-.ittoa on tho Carcinogenic l etton of M ineral O tis P rogress Raiiort by u'. Carrutners and J.T.', Cook Tho 1955-56 s e r ie s o f ar.ir.C ul e x p e r im e n ts v.-itt. tr.o ..ir.v a it f n o t io n s are to bo c a rrie d out vrith f a c t i o n s o b t a i n e d iron tho a c t i v e i.en -picrato-iorain g m aterial by chrunatography and fra c tio n a l d is t i l l a t i o n . r'or th is purpose, tho fiv e nenplcrato-form ing fr a c tio n s ^SgWLr, K^S^air, K ^ h J r , K^3ga 4 r, and K^Sghlr have beon soparated in to three main fra c tio n s by chromatography on alvciina by the general method outlined in tho l a s t R eport. The o i l fra c tio n s, in batohoa o f about 200 g . , were adsorbed on 2 Kg. of fresh ly a ctiv a te d alunina and su ccessively elutod with pecrolour. eth er, bonsene and methanol. Elution with aach solvent was continued un til no noru m aterial was recovered, and three f a i r l y w ell dofined fra c tio n s obtainod. Corresponding e lu ate s fran a l l the chrot.iatograns were combined, and tho three composito fra c tio n s sent to P ro fesso r Morton f o r fra o tio n a l d is t i ll a t io n . The to t a l q u a n titie s of theso fra c tio n s obtained vrero a s fo llo w s:- ( i ) potroluix: other oluato; 1977 g . ( 7?/->) yellow o i l , ( i i ) b e n s e n o e l u a t o j 349 g . ( 13.50 o r a n g o - y o llo w o i l , ( i i i ) mothanol elu ato ; 244 g. ( 9. 5-0 blaoc viscou s gun with a strong unpleasant ar.oll. The u l t r a - v i o le t a b s o rp tio n sp e c tra o f th o chrcrantogram f r a c tio n s K^S^aUr i , i i and i i i , and L, i i and i l l , in d icato tn a t fra c tio n s i and i i are s t i l l cunplex m ix tu res of d if f e r e n t rin g system s. In each case th e re i s g e n -l a b so rp tio n w ith a f a l l of in te n s ity tow ard tnu lo n g .m vclongth. The sp e c tra o f t .o p u t r o l o u n o t h e r o l u a t e a ( i ) h o w e v e r, show tw o n o i l d e f i n o d moxLan a t 234 a n d .'2is ss- vjhicn p o s - i b l y i n d i c a t o t h o p r e s e n c e o f c o n s i d e r a b l e a m o u n ts o f d i b e n r o t h i o p h a n --.r-i v a tiv -jK i n th .'.-c f r a c t i o n s . E x p e r im e n ts a r e i n p r o g r o s s w h ic h may l e a d t o a c a s a u n on t h i s - o in t. I-. c o n t r a s t t o th o s e , th e s p e c tr a o f th e m eth a n o l o l u a t j s i i i ) - .x h i b i t e d o i l d o f in o d 's a x io a a t 243, 292 a n d 3^ 8-355 4. 9 -.5: 1 5, and 5 . c , ..5 4 , 7 a ttrib u ta b le to the presence of carb&zale d e riv a tiv e s. .o ise in ;eo( i : . ; w it!. f . a i f f i o . l l y o f ro ro v in g t n i s m a te r ia l f r e r . th e c n rn i.ia t-'gra..'.. I t i s o f i r . r . r c n t ir. t n i s .(.riecai-n t n a t o t l o a s t one c a r b a z o l e API 06138 ,.11' l `i li. n i, L -ifeoci l i <m a corre spending fm .cti.uu in fchn plum in-fon-ninfr "'Li' a'i r nfeinulii ' our -votr.. ..'tin the plcmt'-*-!'orv.lng fmotions (jd) r'.Kura u.i/'i a ! r'c Loon .nibtivi nod oy .Vii'^-c.r.'Alo chrcuuutofn'iphy, and vw tm>ro iro.tu.`a<d two - *X`x- t/.iiidn fru th-oi. imo -liosio, 'am i) had m.p, bii-li nud **ib `.town liy +*n v.lamentary V'nb -\r i<i ultra "-viol..--': i.'ovation spectra to bo a trli,vj':!\yl ' `.2ntl\top'n--u C* ,i,, : -L 5in pii' ,'tempts to desulphurise thin oornuund 'nth t'.'U.'-Y vj. i, iioillnj.-. "Yini"'i <-tu unnuuoaRaful* In l,'t.stihyi1r,ifurfui7/l alo h l-i.*.< ;ri nation -van on.iii>.v.-. but vms accimpnuiad hy hydrin 'nun felon wltli 5mv.ts.lii.n cf a moru or Ion.; ru-ii lately hydrogenated diphenyl .iorivntivw m i d i h m not you Iy -o .v .nauti find, "h.i second compound, Isolated from it^S^aApl l) iui-l mp. 1oV> \uu shown to bo a derivative of phenanthrane by Its ultm-violot `.ti'orpfeon npncti-um, 'lamenta ry njin.iyacn of fio substance and Its -trini trnlw.issano complex. (if.p. 2t.Vi*-2o6) Indicatoti fcho mo locular formula ^1^0 for th parent hydr<.<on.rboti.. The molting points of those two compounds, however, do not n.jrrospoud l;o those reevudeni for any known C <eH phonunthreno hydroanrbon or IQ i t s t r i n i t rob utvsono comp lux In raspon oc to a requeet by the CamrAttue tho following Table has boon drawn up d e liu j f it in r the compounds fh ich have so f a r b-on is o la t e d from tho Kuwait o i l . API 06139 Compound isolated Eutootio of 2 :6 - and 2 : 1 - din thylanthraoono 2 :6 -Dime thylanthracene 2 :7-DirnethyJ anlhrr. oi.no 1 :8-Dimethylphenunthrone Unknown trirao thvldiben*thii (or equivalent) (m p Qi*.--i)Unknown tetrr- or pcntawothyl- flurrcnc (or equivalent) (i..p. 190-15)9; 2 :3 ;6 ~Trin^ thyl j nt hr..Cv-iva Uritmn tri- or tctramethylanthraoene (o. p, 108-110). Unknown tri- or totmraethylanthraoono (n. p. 224~225) Unknown tri- or totramothylnnthraoono (nup. 169-^70/ Molecular Formula. 1 iRU. c 1 6H ii, C16",4 0>5V 3 or C'A a Se 1716 or ' * t % ,8 1716 or ciaPi8 or 1#l16 r 1 # | 8 API 06140 Molecu]ar 206 206 206 2C6 226 222 or 2 J 220 220 or 234 220 or 234 220 2% ) Structural _ Formula 3 C e c o "} OE 3 O q H ai3 C I O O ,TM3 GFI3 OOif3 g-^3 C X , > ' - p /3 -CI3 f'raetion l'roro ohi eh 31.li-tod 4siw , n. K|^ SgCiA n* K, S bAp. 4 2 K^iJjbAp. or 5 - e ,* . -- TM3 CH3 ^ _ K S V>t>. I* 2 K.SS_a4ni, Ki3,nAra, ...S^bftn, KVbf.ni. JSgbAn, K^s|bi. n. coo 3 or 4 - TM3 K4 ^ ><icu r 1 3 or 4 L r C C ^ O en, W.in, K. S bAm. * 5 4 6 i 3 o r If bA -i >- m 3  -- Contenni,, ire-Tatad Molecular Frrela 1:2:3-Trine thylphcnanthrc no S/it Unknm.-n trinethyl6:7-bcnzcthicnaphthon C,5Hu S 1:3:5: 7-Tot r a TM thylr.wthmcono 1:3:6:7-Tetrancthyl '.nthrnoone ciaPi8 2:3;6 7-^0 Irarx;thj'lan thrr.eenc Unknown t^tn.ncthyl: nthif cure (n.p. 6 7 "69c) Unknr T . n te tranc thvlphenanthr .no (n.p. 103) Sa",a 31 ^ 3 1 -.'lethylpyrena S/ia Unknown to tra- or penta - noth/loarhazolo (n.p. 1Si#.--1051'' or CO O API 06141 I0tb Octobor, 1955* Molecular Vei 'h t. 220 226 234 234 234 234 234 216 225 or 237 Structural Crh 5 CK* V 0% ^ 1 3-^ 3 H3 0 13. ^ ^ CH 5C^^V^H 3 C O S7 'C \-CK 3 CX;' i 4 ;-c h 5 ( ^ '\} - ^ 3 Froetit n fVo 1 d l 2Lwl2 i W ** Vi^ K^S^uAci, K, S,hfo. 4 7 K, ShAi. 4 t \ S3 ^ n K^SybAn. K^SW-n, K^S^;iAn* K^S?,J .p . K^SyiAp. ;. i} 4 or 5 K4 S7*^P- -CH, MEDICAL "t:r.clB32ificd" ,'-r ro ed fled C ircult! ; c:rl. rs of Corrttce ) RESEARCH COUNCIL c o :? i r s E on z r ~ r ( r _ - : Z `: act: ? - o f cns Pr-rrcr.' V-.XV (S<r-t. :?55) From B.L. Tf-ndl.rurc -.r.d J.T.. -yolre, .v. or Research lab o ra to ries, and Deumnont o f Pst/.oii.y, ensversity of Diiminghar, " ca u .'- d ik e d . Testa ca rrie d eut b_, l i , t . Wesdhetau: (1754-55) The fraction s have been applied tc the rabb its fo r 45 "seeks and to the nice fo r 40 weeks. The rabbit tunoura arc given in Table I . Fraction KaVSa W* VV \w V /S a Wn tabu: i Rnbbit tumours at 45 weeks tunoura Fraction tumours Fraction (j) 0 (n) 0 w* Wp (t) 1 (d) 2 Wr K4 'V r (f) .0 W a * (g) 3 w (m) 1 V sV (c) 1 K4S 6;*br ( 0) 1 (a) 0 K4S/ p 00 2 K.^. S,AP u > -) Wr V PAr Total 2 (1) 8 3(2) 18 (u) 15 3(4) tunours (p) 4 (r) 2 (b) 5 (c) 7 (k) 4 (a) 3 25 (i) 7 Kouso tumours have appeared in the following mineral o i l fra c tio n s, b ( 1 ) ; o ( 1 )} k ( 1 ) ; 1 ( 2) ; in ( 1 ) ; p ( l ) : Loo treatod with tin; weaker standard D (j) had 100# incidence of `- incurs by the 28th week. The stronger standard 0(2) nad produoed 100# of tu..ours at the end of 15 week3 . A complete return of a l l tu.icurs vith 3it e s v/ill bo given on CC..^)letior. of the e3cpori:nor.t^, 1 . 2. 2 ttccHs , API 06142 4 Esso Research and Engineering 'FORMERLY STANDARD OIL DEVELOPMENT COMPANY1 P O Box 51. Li n d e s , N. J . Co m p a n y medical r esea r ch division 0*^*7 E ECKAROT. PH D . D D IR E C TO * *THAN V H END RICKS. CH E HEAD IN D USTRIAL H YG IEN IST HORACE W GCRAROE. PH D , M O H EAD TO XICO LOG IST , C R T K . n o e B E N N I S O N M O. Villi' C L I N I C A L R E R E A R C H R H Y E I C I A N November 2, 1955 Mr. D. V. Stroop American Petroleum Industry 50 W. 50th Street New York 20, N. Y. Dear Mr. Stroop: I am attaching some information recently received from Dr. Nevquist who received it from our British associates in the field of petroleum cancer studies. I believe that th members of the Medical Advisory Committee as well as those at the Kettering Laboratory would be interested in reviewing the Progress Report by Dr. Carruthers and Dr. Cook, and also Progress Report by Dr. Woodhouse and Dr. Squire. I would appreciate it if you would have these reports duplicated for these individuals. I do not believe that the rest of the attached information would be worth while duplicating since it concerns only the agenda and minor changes in the nomenclature. Very truly yours REE:evn Enes. MRC.55/83O MRC.55/815 MRC.5 5 / 8 1 U MRC.55/80I R. E. ECKARDT, M. D Copy From D. V. Stroop For Information of Members of Medical Advisory Committee 11/4/55 API 06143 API 06144 Compound 1solatod Eutaotlo of 2:6- and 2:7" dimo thylanthraoeno 2:6-Dimethylanthraoeno 2: 7-Dime thylanthraoeno 1:8-Dimethylphenanthrene Unknown trimethyldibonzthiophen (or equivalent' (m.p. 84-860). Unknown tetra- or pentnmothylfluorcnc (or equivalent) (m.p. 198-199; 2:3:6-Trimothylanthraocne Urirmn tri- or tctmmethylanthnioene (m.p. 108-110). Unkramm tri- or totramethylunthr.- n<no (nup. 224-225) Unknovm tri- or totrnmcthyl anthraoeno (m.p. 169-170) Moleoular ..Fonnulft.. ci6H^ C1614 C16,4 C15H14S or 17"i8 ci8Hao ci7l6 or C1716 Sshi8 or C17% ciePi8 or C1^l6 C1*18 Moleoular Weight 206 206 206 206 226 222 or 236 220 220 or 234 220 or 23k 2 20 2% Structural Formula *5 " ' o a S ch3 O O o " 3 3 1 > > g P '3 s& "> < X ^ ) 0 ^3-C3l3 Frootlon from which is o la te d K^S^bAm, K^SgoA-m. Kj^S^aAtn. K(jS2tAm. K. S hAp. k 2 K^hAp. cm35 K S bAp. k 2 K, S aAm, K j. S. uAin, ICS5bAm, K b V m , I^S^nAm, K ^ S g h A m . K<^t>An. < s x x ? 5' v Kk. S5b/.m*, K U, S6bAm. bAo < T J 0 3 > !- ` Compound ipc 'lp.tgd Molecular Formula 1 :2' 3-Trinethylphonanthrono Unkno\,m trinothyl6 :7 -honzothionaphthen 017"l6 w 1 :3:5:7-Tetranothylanthraoene 1 :3:6 :7 -Tetramo thy]anthracene 2 :3 :6 *7-Totramo thylanthrecenc linkTM>mi totranc thylanthraccnc ('1.p. 67-60) Ihiktu \vn to tramo thyl phcnnnthrc no (n. p . 1 0 0 ') C 1 3 H1 8 C1818 C18H18 C1 3 1-Methylp.yrone C1 7 1 2 Unknown tetra- or penta - 16 *117" nothylonrbazolo (r.i.p. 18 4 -1 8 5 ) or ' i t 11 " API 06145 10th October, 1955* Molecular W eight. 220 226 234 234 234 234 234 216 223 or 237 Structural Formula O S J , ; / 1 3 -CH3 13H , -J * 5 c% j ch < C ^ S 3 0 Hj CH3 CH5 3Cg ? 'rr5 i^ 4 - ^ t-C H 3 1^3 Fraction from r/hich isolated. K. S bitp. 4 6 K. S b A p . 4 6 K^S^nAm, K^S^bAm. K S aAm. K S bAm. 48 ' 48 K^SgoAm, K^SgbAn. K S bAm, K, S aAm. 4 7 ' 48 K^S-^oAp. \ S7Ap* ) ij. or 5 KAS 7 ^ p * "C H3 * MEDICAL "U n classified " ?cr Specified Circulation ['..'.sabers of C orrittee} RESEARCH COUNCIL :.3C.55/60V c2.-o. 5 5 / 7 COMTHEE CN THE CARCTL'CSNi: ACTIO*' OF ;5KERAL OILS Progress Report Nc.XV (Sept. 1955) From D.L. Woodhouse and J.R . Squire, Cancer Research la b o ra to rie s, and Department of Pathology, University of Birmingham, Medical School. T ests ca rrie d out by D.L. Woodhouse (1954-55) The fractio n s have been applied to the rab b its fo r 45 weeks and to the mice fo r 40 weeks. The rabbit tumours are given in Table I . Fraction W* w. W a ffi K4S6 V W* W TABLE I Rabbit tumours at L5 weeks tumours Fraction tumours Fraction - tumours U) 0 (n) 0 (f) 0 Wp (t) 1 Wp (d) 2 W a p (g) 8 Wr (p) 4 W *r (r) 2 W a r (b) 5 (m) 1 (e) 1 WV (o) 7 (o) 1 Wp (h) 2 Wr 00 4 (a) 0 Wp (q) 2 Wr (s) 3 Total 2 K4S9 (1) 8 D(2) 16 (u) 15 K t) 25 (i) 7 Mouse tumours have appeared in the following mineral o il fra c tio n s, b (1 ); c (1 ); k (1 ); 1 ( 2); m (1 ); p (l): Mioe treated with the weaker standard D(-j) had 100?? incidence of tumours by the 28th week. The stronger standard D(2) had produced 100f - of tumours at the end of 15 weeks. A complete return of a l l tumours wit.o s it e s w ill be given or. completion of the experiments, i . e . a fte r 52 weeks. I I API 0614 MEDICAL RESEARCH COUNCIL nclassified" Specified Circulation ecbcrs of Committee) tac.55/8U G&H0.55/9 Ccranittee on the Carcinogenic Action of Mineral O ils Progress Report by ' W. Carrothers and J.7, Cook The 1955-56 se r ie s of animal experiments with the Kuwait fra ctio n s are to to carried out with fra c tio n s obtained from the active non-picr&te-foming m aterial by chromatography and fra c tio n a l d is t i ll a t io n . For th is purpose, the fiv e ncn- separnted into three main fra ctio n s by chromatography on alumina by the general method outlined in the l a s t Report. The o i l fra c tio n s, in batches of about 200 g . , were adsorbed on 2 Kg, of fresh ly activ ate d alumina and successively eluted with petroleum ether, benzene and methanol. E lation with each solvent was continued until no more m aterial was recovered, and three f a i r l y w ell defined fra c tio n s obtained. Corresponding elu ates from U the chromatograms were combined, and the three composite fra ctio n s sent to P rofessor Morton fo r fra c tio n a l d is t illa t io n . The to ta l q u an tities of these fra ctio n s obtained were a s fo llo w s:- (i) potroleira other eluate; 1977 g. (77/0 yellow o il, ( i i ) benzene e lu ate; 349 g. ( 1 3 .5 0 orange-yellow o i l , ( l i i ) methanol e lu ate; 244 g. ( 9 .5 0 black viscous gum with a strong unpleasant smell. The u ltra -v io le t absorption spectra of the chromatogram fra c tio n s K iS-a4r i , i i and i i i , and K^S^blr i , i i and l i i , in dicate th at fra c tio n s i and l i are s t i l l complex mixtures of d iffere n t ring systems. In each case there i s g e n - l absorption with a f a l l of in ten sity toward the long wavelength. The spectra of tr.o petroleum ether elu ates ( i) however, show two well defined maxima a t 234 and 325 ai` which possibly indicate the presence o f considerable amounts of dibenzotniophen derivatives in these fr a c tio n s. Experiments are in progress which may lead to a 'o cisio n an th is -.oint. In contrast to those, tr.c spectra of the nstnanol siu ato s ( i i i ) exhibited well defined -laxira a t 243, 292 and 318-355 ,"103 4. 9 , 4.5.- and 5.C, 4 .5 , 4 .^ 7 attrib u tab le to the presence of carbazole d eriv ativ e s. This i s quite in .ceeping wit:, tr.e d iffic u lty of removing tr.is n a te n a l from tne cr.rcnatogram. I t i s of ir.torcst m th is connection tnat at le a st one carbazole -1 - API 06147 We are continuing our work with the picrute-foming fractions (2). These have also been subdivided by large-scale chromatography, and we have isolated other compounds from then. One of these, from K^S2alp(i) nup 84-86 and ^ shown by its elementary analysis and ultra-violet absorption spectrun to be a trimsthyldibenzothiophen C^jU j^S or its equivalent. Attempts to desulphurise this compound with Raney nideel in boiling ethanol were unsuccessful. In \ / teti&hydrofurfuzyl alcohol desulphurisation was achieved but was accompanied by hydrogenation with formation of a more or less completely hydrogenated diphenyl derivative which has not yet been identified. The second compound, isolated f K^SyaApC i) had m.p. 100 and was shown to be a derivative of phenanthrene by its ultra-violet absorption spectrum. Elementary analyses of the substance and its s-trinitrobenzene complex (m.p. 205-206) indicated the molecular formula CjgEijg for tha parent hydrocarbon. The melting points of these two compounds, however, fe not correspond to those recorded for any known C^gH^g phenanthrene hydrocarbon or its trinitrobenzene complex. In response to a request by the Committee the following Table has been dr* ' up delineating the compounds which have so far been isolated from the Kuwait oil, API 06148 MEDICAL RESEARCH COUNCIL "Unclassified" Per Specified Circulation (Members of Committee) iEC.55/ 830 GtLi'iO 9 Committee on the Carcinogenic Action of Mineral Oils AGENDA for the Nineteenth Meeting to be held at 26, Old Queen Street, Westminster, London, S.W.1., on Tuesday, 25th October, 1955 at 11.15 a*m. 1. Minutes of the previous meeting (MRC,55/510, CM0, Min.18 - already ' ri rriiilntwfl^ 2. Amendments to nomenclature of oil fractions. A memorandum (MRC.5f/8l5, QUID.55/8) (Enclosure A) 3. Expenses grant to Dr. William E. Smith for testing oil fractions (Minute 155) 4. Progress Reports (i) Chemical - by W. Carruthers and J . J . Cook (MRC.55/814, G1M0.55/9 (Enclosure B) (ii) Biological - by D.L. V7oodhouse and J.R. Squire. . Progress Report No. XV (MRC.55/804? CiMO.55/7 -(^ L 3UT e C) 5. Puture Plans . Any other business 7. Date of next meeting vo API 06149 MEDICAL RESEARCH COUNCIL "Unclassified" For Specified Circulation (Members of Committee) MRC.5 5 / 8I 5 CAMO.5 5 / 8 Committeo on the Carcinogenic .ction of Mineral Oils Nomenclature of Oil Fractions It will be recalled that, at the Bighteenth Meeting -of the Committeo, the standardisation of the nomenclature of the various oil fractions m s discussed (Minute 152) and it m s agreed that Professor Squire and Professor Morton should considor this in the light of coding symbols already agreed (Minute 136). Professor Squire and Professor Morton now propose tho following amendment to Minuto 136. paragraph 4, line "iRT.kffb " SUBSTITUTE " wero split into aromatic wore split into aromatic (P) portions." and raffinate (R) portions, aanndd ppaarraaffffiinn rraaffffiinnaattee This amendment and the previous confusion of symbols call for amendments in the following documents as shown: m, p and r. API 06150 -s E sso Research and Engineering IPOKNLKLY STANOAAO t/IL D tV SLO PN SN T COUPAN YI I' O BOX S I . L lM U K N . N. J . Co m pa n y eoical aesearch o iv u io n wow*t %. BCKAner. r*.o., .e. omtcroe ,,TMAM V MBNO*CM, CH B MgAO fMCKITIAL tuAACB ABHAMOB. PH D , H O MffAO T O I l C O M A t r pgATHAIi K M N A I fO N . M.O cN icr a i m e A i m n a i c m om yo icia m Noveabor 151 1955 Mr. 0 Y. Stroop Ansrican Petroleun Institute 50 Vest 50th Street Rev York 20, Rev York Dear Br. Stroop t Enclosed is copy of the Minstes of the Meeting of Research lo. 2 CoaHttee of the Institute of Petrols, end oopy of the Progress Report of the Coasclttee on the Csrcinofsnic lotion of Mineral Oils of the Medicai Research Council. Please have these duplicated for distribution to aeafcers of the Subooadttee on Csrolnogonioity of the API, and to the interested individuals at the Kettering Laboratory Very truly yours, i R. X. BKARDf, M. 0. fees. 2 i ropy Fraoe D. V. Stroop For Information Of Members Of Medical Advisory Committee l 11/17/55 . J API 06151 T 1 ! ' MEDICAL RESEARCH COUNCIL "Unclassified" Par Specified Circulation (Members of Comnlttoe) jac.55/aifO CiMO.55/10 Caamittaa on the Carcinogenic Action of Mineral Pile Progress Report HN. Green and M.J. Rsdcliffe 1 Dopartoant of experimental Pathology and Canoer Research School of Medioins, Leeds. Mouse experiment. Fractions usedt- Lj^Sjl a LjSgl b Lj'Sfd a o O.Ot>iDJt.B. a d(VlO) * * 0.0&<D.1UB. a d(i) a f I^SR a g ' LJ*S1** " h [ W -t l w "* } W k [ The e^erlasnt aas begin on 76*55> Tunours have been produced as follows: - | b (L^Sg) 3 tusowrs, at 9, 13 and 18 weeks. | o (l ^ A ) 2 twours, at 13 and <1* weeks d(Vlo) (00l;jDJI.B.) 1 tumour at 11* weeks f (0,0&jOJi.B.) 9 tiriours, 1 at 11 wsdcs, 2 at 11* weeks, 2 at 16 weeks and A at 18 msdcs 1 (LjSy) 3 tusours, 1 at 17 weeks and 2 at 16 weeks k (Ljj3gl) 1 tunour at 18 weeks. Survivors at 18 weeks are as follows: - a 1*5 g 29 b 32 h 29 o 39 1 21 d 35 3 19 e 20 k 17 f 1*1* API 06152 Rabbit Hxparlmant This was begun on 23b.55* The beginning of the experiment m s delayed owing to an epidemic of pneumonia amongst the rabbits Five rabbits have died since the experiment began. So far no tumours have boon produced. (The dilutions af DJf.fi. for rabbits are 03-i nnd 0.05-i). INSTITUTS OP PETROLEUV RSS-2-1S RESEARCH NO 2 COrSilTTES Minutes of Meotlng No . 15 held at 26 Portland Place ___________________On T u e s d a y .20-9-55 . . .. . ATTENDANCE IN THE CHAIR: QUEST: MEMBERS: APOLOGIES FOR ABSENCE: SECRETARY: F . M o r t on. P.h.3. Trasler ;.s, Ault J.N. Haresnapo R.B. Killingsworth . Pohl H.W. Stevenson E.J. Boorman X.W. Cook E.J. Dunsten A. Me Loan E. Herbert 1 MINUTES OF MEETING NO.12 These were signed aslcorrect, subject to the addit i o n of "Shell Petrolcrun,]po.," at the b e g i n n i n g of line 3 of t he last p a r a g r a p h of Minute 3 - 1 (Page 2) 2. MEMBERSHIP The m e t i n g aocepted the rosign'.tion of Mr. W. Pohl w i t h regret and desired t o reoord its thciiks t o h i m for his valuable services. The nomination of Mr. H.VJ. Stovenaon was approved b y the Committee, who were glad t o w e l c o m e fair. b a c k as a Member. 3. W O R K AT BIRKIUGiiA:: U N I V E R S I T Y The Chairman reported on the progrees of work at Birmingham U n i v e r s i t y and drew attention to the paper "The Constitution cf Petroleum Fractions} Structural Croup Analysis of o Kuwait Heavy Oaa Oil" whloh woe presented at the recent World Petroleum Congress, and to various documents circulated b y the URC, in particular MRC 55/510 CAMO Mlnuto 18 and CAMO 65/5 The Chairman distributed tables (dated September 20t h 1955) of Analytical Data on Kuwait, Lagunillae and O k l a h o m a Crude Oils and mentioned that w o r k in c o n n e c t i o n w i t h Tab l e 5, S u b - f r a o t i o n s f r o m aromatic e xtracts, was now being oarried out at Glasgow. The results indicated a v e r y considerable potency concentrated in residues. There were small quantities of Kuwait Crude left over} it w a s proposed to blend f r a c t i o n s K43ZAa / K 4 S S A b and K436Aa/K4S8Ab and tnen redistil the blends for further teet. API 06154 Tliere would siso be available 9one samples prepared from a Comercial Extract supplied by the Isle Grain Refinery, The Chairman mentioned that the Langunillas tests were a year behind owing to the with drawal of the Chester Beatty Initute. This work was being carried on by Professor Green of Sheffield/Leods University, but no medical school had been found to take an interest in the Oklahoma Crudes, which were therefore, being stored in their fractionated state. Professor Morton added that he would prepare for publication in the IP journal a further paper in continuation of that presented at the World Petroleum Congress. 4.DIESEL GASES FUMES The Chairman thanked Dr. Killingsworth for the material whioh he had provided for the report to the MRC and referred to a letter dated the 14th December 1954 from v Mr. A. Fogg of MIRA in which,on behalf of the Diesel Engine Manufacturers, the IP were asked to draw attention of the major petroleum companies to the necessity to carry out investigations with the objeot of eliminating any exhaust smoke which night be attributable to fuel variations. It was agreed that a general Interest in the problem, which was separate from the medioal aspect of smoke, was indicated but that it was a matter more for the Research Committee. Mr* Ault who promised to raise the subject at the meeting of MIRA whioh he was attending the next day was invited by Professor Morten to the next meeting of the Research Committee* 5 . ANY OTHER BUSINESS The Chairman intimated -that he vould shortly provide for circulation a copy of Mr. A.W.E. Poll's Thesis. 6 . DATE OF NEXT MEETING T o be arranged by the Chairman. prn w w m R E P O R T T O C O N S U M E R S By WILLIAM TERRELL Th e r e i s a t i c k i n g b o m b on the very d oontep of the Ameri can automobile industry and no one, including the scientists who dis covered it, seems to know what to do about it T he explosive discovery, which poses a greater potential threat to the motoring public, and to the American economy in general than any nuclear device, was brought to light last fall by D r. P aul Kotin, one of the w orld's top cancer researchers. He told a group of distinguished colleagues that automo biles, trucks and buses are a primary cause of lung cancer! Dr. Kotin, assistant professor of pathology at the University of South ern California M edical School in Los Angeles, stunned fellow scientists at the eighth annual lung cancer sym posium of the Detroit Institute for Cancer Research with this flat, unquali fied statem ent: "Vehicular exhausta represent the most common, universal and probably greatest source ol emitting known can cer-producing materials into the atmos phere in certain areas." If Dr. Kotin and others are correct, this means that unless and until some thing drastic is done, th e m illions of cars, trucks and buses on the highways today and those yet tc be produced along present engine design will con tinue to pour out enormous amounts of noxious gasas daily, helping to swell the alarming lung-cancer death rata among city dwellers. W hat is the autom obile industry do ing about this menace at present? Ap parently all it can. The problem of autom otive exhaust is not a new one-- although until very recently it was re garded as m erely a smelly, eye-smart ing nuisance rather than a potential mass killer. M anufacturers, singly and as a group, for some tim e have been funneling money into research and field tests, trying to come up with a positive answer. The road has been rough and the climb steep. In the first place, the sci entists to whom the car manufacturers first turned were far from agreed on the role of auto exhausts in the rising lung-cancer incidence. T he ground was virtually unbroken when the Automo bile M anufacturers Association Ve hicle Combustion Products Subcom m ittee pitched in to help Los Angeles rid itself of choking smog. New testing and evaluation techniques had to be developed and proved; new analytical methods had to be devised. At the tim e, few among the topdrawer scientists exploring air pollu tion, and no one in the industry, even suspected what Dr. Kotin and others, equally em inent in the field, were to API 06156 Slinckinti rhni firs Imre been tinnir about the effect of nulo exhaust fumes on Ainerir s health. For the first time, here is the complete truth about your car atul Ian a cancer. conclude: that exhaust fumes defini tely can cause cancer. --^H owever, when Dr. K otin uncov 'd the bomb, few people outside of .entific circles heard the news. News paper readers in New York found a four-paragraph Associated Press dis patch in the Daily Mirror, and nothing elsewhere. A check revealed that a national newspaper clipping service found only one other newspaper in the country that carried the dispatch at a ll: the Los Angeles Times. Coincidence? Perhaps. It certainly wasn't because Dr. Kotin was vague. Dr. Kotin told the D etroit sympo sium that mice used in tests have de veloped lung tumors after breathing compounds present in gasoline and diesel engine exhausts. Known cancerproducing chemicals have been found in exhaust products, he said. Dr. E. Cuyler Hammond, chief of the A m encan Cancer Society's statisti cal and research section, points out: "The number of motor vehicles now registered in the United States is near ly three times as great as the base period (1924-26) and motor fuel con sumption is more than five times as great. Although no exact measure is available, traffic congestion in cities and on highways near cities has probly risen to an even greater degree, erefore, the increase in fumes irom this source, particularly near cities and highways near cities is really tremen dous." T rem endous indeed! All this, cou pled with the dust from bituminous roads, which have increased six-fold in the same period, and others surfaced with asphalt and oil products, which have increased many times more, pre sents a formidable picture. RESEA RCH into air pollution gener ally was dramatized and probably stim ulated to its present degree by a series of tragic episodes in Belgium, Donora, Pa., Mexico and London, be tween 1930 and 1952. Since then an army of researchers has been studying air pollution generally and, more re cently, by the combustion of fuels, with emphasis on hydrocarbons, the known cancer producers. Their studies have revealed th at sig nificant, even alarming, am ounts of carcinogenic (cancer-producing) sub stances are poured into the air we must breathe by the machines of our indus trial age--especially autom otive m a chines. W riting in The Scientific Monthly, Dr. L auren B. Hitchcock, president and managing director of the Air Pollution Foundation in Los Angeles and one of the giants in th e field, observed in part: "As our cities expand, more public and private transportation is needed in the form of motor vehicles and in creased power requirements. This is the age of mechanisation, and virtually alt machines require power produced by a combustion process. Our present combustion processes are all very im perfect and contribute by far the major part of man-made pollution. Improve ment of combustion processes should be the first major goal of science and technology. "Vehicle combustion products are a major source of air pollution. Total motor-fuel consumption in the United States today is about 150 million tons per year; although the actual amount of automobiles never has been accu rately determined, it is calculated that one gallon of gasoline produces 1,000 feet of exhaust gas on the dry basis." T hat residual hydrocarbons are re sponsible for much of the increase in urban lung cancer and for much of the difference between the urban and rural incidence of the disease is accepted now by virtually every recognized authority, many of whom have been saying so in medical and other scien tific journals for some time. T o just what extent these fumes are respon sible has not and may never be deter mined. But the experts have a num ber of good clues. ( Continued on page 6 3 ) API 0615 API 06 15 9 CANCER (Continued itotn pagel! ) A S T H E American Cancer Society's Dr. Cuyler Hamm ond shows, the death rates from cancer in all parts of the body have been increasing steadily for a great many years. However, can cer death rates rise with age. and most of the increase is attributable to the aging of our population. W ith one notable exception. Dr. Hammond says, death rates by ages for cancer in vari ous locations have nni changed greatly during the past several decades. The exception is lung cancer, for which the age-standardized death rate among males has risen from about 0.7 per 100.000 in 1914 to 3.6 in 1930 to 19.5 in 1950. And among females it has risen from about 0.6 per 100.000 in 1914 to 4.3 in 1950. T hat means that about 17.400 males and 3,500 females died of lung cancer in 1952, the most recent year for which estim ates are available. To get at some of the questions arising from these statistics. Dr. Ham mond has adopted as a working hypo thesis (1 ) that human beings vary in their susceptibility to lung cancer; (2) th at some, if not most, cases of lung cancers are produced by a substance or combination of substances inhaled into the lungs, and (3 ) that the lungs must be exposed to the substance or sub stances for varying periods of time, up to 30 or more years, depending upon the cancer-producing potency and con centration of the substance, as well as the susceptibility of the individual. "fu m es from burning petroleum do contain measurable quantities oi known carcinogenic agents, and human beings do inhale those lumes," he says, as strongly as a scientist of his stature is likely to perm it himself. "It has been shown that an idling automobile en gine gives oft about one milligram of benzpyrene per minute. No small quan tity of this known carcinogen must be present at nose level in the air of a heavily congested city street." In sum, it may be said th at the po tency of hydrocarbon waste in the air is known and accepted. And while its exact place in pollution of the air we breathe has not been fully established, our knowledge is too meager to per mit complacency. Who, then, besides Dr. Kotin are en gaged in this vital area of research? There are many, among whom Dr. Kotin seems merely to have been the most vocal. T hese men, working away ir. their laboratories, receive 90 per cent of their funds from the four m a jor agencies sponsoring cancer research in this country: T he Notional Cancer Institute, the American Cancer Society, the Damon Runvon Memorial Fund and the Atomic Energy Commission. Private funds, such as those of the To bacco Industry Research Council and th e Automobile M anufacturers Asso ciation, to nam e but two, make up the other 10 per cent. All of these funds are given without strings for basic re search in a given area and the donors have no control over the direction which such research might take. Thus, it is possible that Dr. Kotin, working with a grant from Chrysler, among others, might come up with data relat ing car exhaust to lung cancer. Of course, each investigator, being human, is influenced to some degree by the direction of his own research. Thus, some may stress or discount the impor tance of this agent or th at in producing human lung cancer. M any reputable scientists, for instance, feel that Dr. K otin is too brash and should have gathered more evidence before he spoke out. Then, of course, there is a widely held belief, espoused by Drs. Cuyler Hammond and Daniel Horn, of the American Cancer Society, that cigarets account for at least 70 per cent of the difference in the urban and rural lung cancer death rates. Then again, a spokesman for the Damon Runyon Fund, admitting the contribution of cigarets, car exhaust and other factors to the general picture, offered the following excerpt from a W alter Winched radiobroadcast as a statem en t of his organization's stand at the moment: "The real threat in lung cancer . . . is the atomic fallout. By 1957 there will be twenty-five atomic reactors operat ing in the United States and as many abroad. . . fifty in all. The fallouts front these reactors, plus atomic dust from test explosions, constitute the real haz ard--to everything you eat, smell or breathe. The points of concentration of this radioactive material are the lung and thyroid glands. The Runyon Cancer Fund, incidentally, has invest ed more than a half million dollars of your donations in air pollution re search studies." The auto industry keeps hitting the problem hard in its own quiet, effective way. Both the American Petroleum In stitute and the Automobile Manufac turers Association are sponsors of a Coordinating Research Council. To at tack the present problem, the CRC has established a group to study exhaust gases, and under it four special panels to develop instruments and procedures needed for accurate sampling and analysis of exhaust gases: to find out how fuels, engine designs and operat ing conditions affect exhaust; and to make actual tests on cars in the field. Meanwhile, the AMA'i Vehicle Combustion Products subcommittee has also established four working pan els. The Induction System panel is concentrating on devices to improve operation at the fuel intake end of the engine. T he Exhaust System panel is concerned with means of cleaning up the exhaust after it leaves the engine but before it reaches the air. The T raf fic Survey panel is studying actual driving conditions and driver habits, and the N ew Devices panel is routing all devices they regard as promising from the outside to the proper indus try group. The AM Aboard of directors has ordered a patents cross-licensing agreement and it has been joined by all participating companies. WHERE dustry DOES the stand now automotive in in its "million dollar search" to eliminate the menace of car exhaust? John M. Campbell, chairman of the AMA's Vehicle Com bustion Products Subcommittee and administrative director of General Mo tors' research laboratories, said after Dr. Kotin's stunning announcement: "I know that many of you (attend ing the Southern California Conference on Elimination of Air Pollution in Los Angeles) have been waiting to hear what my industry has to report, since the scientific consensus is that, as of today, automotive exhaust gases con tribute the largest share of chemical materials to the reaction that gives you `smog.' "I am not going to quibble over the exact proportions of the automotive contribution. That will be established on a much firmer footing in the near future. Suffice it to say that I think, and so does my industry, that it has been clearly enough established that our contribution is significant, and so must be reduced as much as possible, as fast as possible. "W e are promising no miracles. Our first goal is an absolute minimum re duction of 50 per cent in the emission of unburned hydrocarbons from cars and trucks. I believe that we will ac tually give you considerably greater reduction with our first devices, and we'll keep on working tor further in* provement. But let's suppose we come up with 100 per cent reduction. What then? "When automotive'devices are avail able, it will still be up to local citizens in the final analysts to see that they are used to the best effect. I can prom ise you that these devices will be as (Continued on page 71) CANCER ( Continued from page 63) efficient and inexpensive as we know how to make them, but their proper installation, maintenance and use will be a problem of local regulation. It's going to be costly, not only in original investment, but in keeping inspection and enforcement at a high peak of effi ciency. You may also have to sacrifice something in the performance of your vehicles." There are at present several ap proaches to the problem. Since the noxious fumes result from incomplete burning of the fuel, especially at idle and deceleration, the trick has been to eliminate excess fuel either before or after it leaves the cylinders. This can be accomplished by an afterburner, which involves the addi tional hazard of an open spark or flame: by a so-called catalytic muffler, which depends on oxidation of the ex haust gas as it passes over a chemical; or by devices which limit manifold vacuum or cut off the flow of fuel to the cylinders in the deceleration cycle. There are several companies experi menting with all of these devices, but ^experts question whether they are el ective and for how long. Top industry spokesmen fear that a panicky public may demand legisla tion which could force motorists to in vest a sizable am ount of money--per haps S50 per car--for som ething th a t may not even be a palliative. Apropos of this, Jam es C. Zeder, vice president and director of engineering and research of the Chrysler Corpora tion, told a symposium on air pollu tion not long ago: "How good are these devices? Frankly, I don't know. One device, rep resentative of those under industry study, is on the Chrysler Corporation car which I have been using. It hat given promise of reducing hydrocar bons in exhaust fumes by as much as 90 per cent during deceleration. It has performed reasonably well so tar, but that doesn't satisfy us. "Before we in the automobile indus try consider a device promising it has to operate for hundreds of thousands of miles in good weather and bad, in broiling heat and bittei cold. It must be shaken over rough roads and, in the case of carburetion, must gasp for air on mountain peaks. Bitter experience has taught us ;hat this testing cannot be by-passed. Even with every test which we can devise, some drivers wilt manage to get into situations we did not foresee." The best estim ate on the time this search for an effective rem edy will take is several y ea rs-p e rh a p s five. Again, all vou can do is wait. If it does turn out that devices costing around $50 are needed, it will present a very attractive one-shot market represent ing an expenditure of som e $100 m il lion by the public. But. as Mr. Zeder, said: "It amazes me to see how much headway this un dertaking has picked up. After a tittle more than a year on the job. our people do know which way they are going even though all the answers arenff un covered. But we have reached a point where we can compare devices, ex change ideas and start the serious test work on the best of them." That, then, is the picture. Not only the independent research scientists, but combustion engineers of the several AMA members are working in their company laboratories. They meet regularly for free exchange of findings and ideas. M ost of all, however, the problem needs airing. By pressure, design or co incidence--or a com bination of each --th e press has alm ost entirely ignored the possible relationship between auto motive exhaust and the rising incidence of lung cancer. W hat can the public do until proven devices arrive to alleviate the menace? Laws might be passed banning cars from the highways. Ridiculous? Per haps. But rem em ber th at in w artim e automotive travel was cut to a neces sary minimum and an aroused public could bring about even stricter en forcement. However, it is doubtful that such a drastic step will need to be taken. Perhaps new and revolutionary en gine design could elim inate the prob lem entirely in new cars. But that would take more tim e and we would still have the question of what to do with the cars, trucks and buses already on the road. SO M EW H ER E there lies an answer. But whether it rests in stepped up medical research, in revolutionary new engines, in preventative devices or in curtailm ent of car use, one fact above all is certain. T he answer does not lie in secrecy or suppression. All the facts must be published for every American to read and under stand. It is only in this way th at the answ er will be found--through public awareness and determination to do something about it ' Exhau.it fumes must be reduced "as much as possible as fast as possible," stated G M 's John M. Campbell. Americans can only hope it won't also be too little and too late. API 06160 C A l 11 71