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.' .; subject: IH~ER PHfLIP•MQRRIS U. S. A. -OFF I CE ' CORRES.FONOEMiCE RI CflHO~ID, Y!"R61N I A AT d , Dr. T. S. Osdene Date: December 16, 19'81 .. ~ , R, N Ferguson n ~. 4 , Nitrosamines "in Cigarette Smoke . ~ .. . i. . . - . , ,.:, .f - e . , ,_.,, .: :., . .:. .. , , ,. . . > . . . At your request, I-reviewed a table labeled "'Sources of NYtrosamines" ;.„ which•appeared in*the December 11, N.•Y. Times. The table lists human nitros- I :amine exposure from outside sources (exogenous) and those produced in the body ~' - . . . .. . _ . . . _ ._. . . / Y' (endogenous).-'This table is a grouping of a large number of different"nitros- amines. This is misleading since small chemical differences in nitrosamines r,yy y.y: translate into large-differences in activity and target organ in animal models `' and on recent literature on nitrosamines in smoke. :I will review this table based on a number of presentations made at an Interria= tional N-nitrosamine Conference I recently attended (Tokyo; September, 1981) It is first essential.to understand that chemical structure drastically .. ~~ ~ - .. .. . . ' ~ S affects the activity of nitrosamines. These studies, reviewed by Lijinsky, _M. make it inaccurate to group diverse nitrosamines into an aggregate "total, exposure." A nitrosamine has the general chemical structure and an change in R1 or R2 groupings will alter a multitude of the chemical and biological properties of the compound. The table in the Times is closely related to one presented by Fine2 at the Tokyo conference which is presented below. Concentrations are given in is a part per billion. either micrograms (pg) which is a part per million or in nanograms (ng) which r t K n i-- , .~; 4 ~: :

. . a f . 2• Human Exposure to.N-nitroso-Compounds`from Endogenous and Exogenous Sources All Exposures in pg/person/day Avera e ' • High -Exogenotis EMosure Cosmetics (volatile) - - , Car interiors (volatile) Dietary (volatile) Tobacco smoke (volatile and : 0.4 . . , - 0.2 16.0(20 cigts) . .. . , - 0.5 32.0(40 cigts) . - • non-volatile) .Endogenous Exposure (calculated) .. . . : ~ . .:-. ,. s ~ • Average U.S. diet 0.3-2.3 Average U.S. Diet plus 20 cigts/day 0.3-2.3 Vegetarian 2.3-16 High nitrate water 3.4-24 High meat diet 0.6-3.? Worker Exposure to Exogenous Sources Leather tanning (volatile) Tire•factory (volatile) UDMIi factory (volatile) 440 250 260 'The table clearly indicates that volatile-and nonvolatile nitrosamines (each a group of different compounds) are being considered for cigarette smoke. Fine as yet very confused.2 Exogenous exposure will be considered next, then I' will illustrate the problems with calculation of endogenous exposure. made a major point in his Tokyo talk that the field of endogenous exposure is exogenous industrial exposure at the Tokyo meeting.3 Significant nitrosamine exposure was found in each of the industries surveyed, which are listed below. Exogenous Exposure Fajen, et.al. presented the results of a multiyear study"of

The Fish Processaing Industry Manufacturers and Users of Synthetic Metalworking Fluids ,•;~,• Dye Manufacturing .The Leather Industry ' Industry The Iron and Steel Casting.Industry is-important the remember that a number of structurally different compounds -..were found.in this study. Another important point, is the authors conclusion: "It is conceivable, from the information that has been generated in this study, that nitrosamine exposure, as large as that in the tire and rubber in industry may be much more widespread than indicated in the Times. industry, may exist in other industries not yet surveyed." Exogenous exposure Exogenous exposure goes far beyond the limits of industry,-as pointed out .by Spiegelhalder and Preussmann at Tokyo. .-They found detectable vol., is inescapable that exogenous exposure sources have yet to be fully surveyed. _~ . . . ~ . and the possibility exists that there are many significant exogenous exposure nitrosamines in all rubber products, even pacifiers and balloons! The conclusion -'sources in addition to tobacco smoke. on a high nitrate diet. The data in the Times are thus low even corisidering only this one (supposedly inactive) nitrosoamino acid. Was this included in This area is evenless well understood. monitoring urinary nitrosoproline (NPro) to evaluate human exposure to endogenously formed N-nitroso compounds. * They find the minimum background excretion of NPRO in humans is 2.3 pg/day. This can go as high as 23.3 pg/day this tabulation or-not?.- diet. 1Qote that fish is not even included in the Times table. The conclusion of nitrosodimethylamine from fish under simulated gastric conditions. He suggests fish products are the major source of nitrosamines in the Western nitrosamine formation. He demonstrated the formation of "tens of pg per portion" A paper by Groenen et.al. is of particular interest in regard to endogenous . ~ . Endogenous Exposure is that endogenous formation is still a research area. All sources have not

The origin and levels of.nitrosamines in smoke have been extensively been evaluated, end endogenous.formation may be a major factor of exposure to a multitude of N-nitroso compounds, both volatile and nonvolatile. '' . ,.~~-. . . . . . The volatile'nitrosamines - nitrosodimethylamine (NDMA), nitrosomethyl- ethyl amine (NMEA), and nitrosopyrrolidine (NPyr) are all formed during smoking by reaction of NOX with amines. ;_Tso, et.al. studied fertilizer, cultivar, nitrosamines •in smoke. Nitrate in filler was the best predictor for volatile stalk position and post harvest handling effects on the level of volatile nitrosamines in smoke. Formation of nonvolatile or "tobacco specific" nitros- amines in smoke is more complex. This class of compounds is formed in tobacco .from nitrosation of alkaloids. The major compounds in this group are nitroso- nornicotine (NNN), nitrosoanatabine (NAtB), and NNK (a nicotine rearrangement 8 product). These compounds were studied by Hecht et.al and it was found that volatile nitrosamines 'in burley filler. Some of the nonvolatile.nitrosamines Again there is a nitrate effect-high nitrate fertilization gives higher non- they were not detected at harvest but were present in fully cured burley leaf. than.burley. The one other nitrosamine in cigarette smoke is nitrosodiethanol- amine. Hoffmann, et.al. showed this can be directly traced back to the amount of MH-30 used on tobacco.9 This problem has recently been solved by reformula- in smoke are also formed during smoking . Because of lower nitrate levels in filler, bright, RKS, and oriental are much lower in nonvolatile nitrosamines , tion of antisuckering agents (M1i-30) without diethanolamine. l0 -13 of the levels of N-nitrosamines in cigarette smoke. These papers were all from Hoffmann's group at the American Health Foundation. .Tobacco Smoke :` Four key references (1977-1981) were surveyed to give a current overview , ~ 12 10 The U. of Kentucky reference 1R1 cigarette can serve as a nonfiltered 4 , reference. ~ .N Volatiles (ng/cigt) Nonvolatiles(ng/cigt) NDMA NMEA NPyr NNN NAtB NNX 9.0 1.5 6.6 390 -- 160

This gives volatiles"=17.1 ng; nonvolatiles = 510 ng (per cigarette). This would produce a total• of 10,542 ng/pack or 10.5 pg ©f nitrosamines. -lhis' Zs . in significantly lower than 17.0 pg/day as in the Times, but does not include the recently discovered NAtB, which would probably place the total near that of nitrosamines are effectively iemoved by normal cellulose acetate filters. U.S. commercial cigarette will definitely deliver .less than 0.4 pg/day of volatile nitrosamines. The difficulty with commercial cigarette totals lies .with the nonvolatile nitrosamines, which show little selective filtration. 12 commercial Hecht showed-figures for a typical filtered U.Sl In a 1979 review, . , .. ~.._. _: .-.._ . : . . .. . '1R1 however is not a commercial cigarette. For one thing, volatile cigarette as NNN = 310, ng and NNK = 190 ng. Thus 10,000 ng or 10 pg per pack 13 would be provided to MS smoke. The numbers presented at the Tokyo meeting were significantly higher due to inclusion of NAtB. They claim13 that they studied a filtered, diluted cigarette (13 mg) which gave 907 ng of nonvolatile nitrosamines per cigarette, which would translate to about 18 pg/day for 20 In conclusion, the value of 17 pg total nitrosamines in the N.Y. Times is reasonably representative of commercial filtered cigarettes. This is however a composite of a number of structurally different compounds, of differing "nonvolatile" or tobacco specific class represents about 98%. origin. The volatile nitrosamines represent only about 2% of this total. The CONCLUSION qualification, is misleading. 1. The table as given in the Times, without significant explanation and 2. Total nitrosamines is an unjustified summation of different compounds (chemically and biologically) which happen to share the N-nitroso func- tionality. 3. Exogenous exposure is more widespread than indicated in this table. Also, almost everyone is exposed to products which could contain volatile nitrosamines.

included in endogenous exposure figures? This mnust be resolved. •r . -The tobacco smoke'numbers are realistic.but represent a very small amount research area. 6 The valties in the table They could be very low. Are nitrosoamino acids (NPro) -of volatiTe nitrosamines (2%) and a large amount of'nonvvlatile nitros- difficult to control since they do not show selective filtration. This 'Endogenous exposure is still a :are guesses. amines (98%). The volatile nitrosamines in smoke can be The nonvolatiles offer a tremendous potential, for reduction but are more ~ ~ N-nitrosation in rats and humans by monitoring urinary and faecal extrac- ~ tion.* Groenen, P. J.; Luten, J. B.; Dhont, J. H.; deCock-Bethbeder, Pi. W.; Prins, L. A.; Vreeken, J. W. Formation of volatile N-nitrosamines from food products, especially fish, under simulated gastric conditions.^ Fine, D. H.; Challis, B. C.; Hartman, P.; van Ryzin, J. Human exposure assessment of nitrosamines from endogenous and exogenous sources: model 1. Lijinsky, W. Chemical structural effects in carcinogenesis by nitrosamines.* . amines in the factory environment.* 3.. Fajen, J. M.; Rounbehler, D. P.; Fine, D. H. Summary report on N-nitros- calculations and risk assessment.* 7. Tso, T.X.; Sims, J. L.; Johnson, D. E. Some agronomic factors affecting N-dimethylnitrosamine content in cigarette smoke. Beitrage zur Tabakfor schung. 8: 34-38; 1975. C. Chemical'studies C-h.B.; Dong, M.; Ornaf, R. M.; Hoffmann, D.;.Tso, T. on tobacco smoke 51: Studies on non-volatile nitros- amines in tobacco. Beitrage zur Tabakforschung. 9 1-6; 1977. ~ Papers presented at: 7th International Meeting on N-nitroso Compounds. Tokyo, Japan: September 28-October 1, 1981. . . . . , ,: ~..,~ ._. .. . ,~, - . _ 8. Hecht, S. S.; Chen, problem is however under study in our research program for 1982. The nonvolatiles in cigarette smoke are a potential problem because they Spiegelhalder; B.; Preussmann, R. Nitrosamines and rubber.* ._ Ohshima, H.; Bereziat, J. C.; Bartsch, H. Measurement of endogenous Their only source is the alkaloids of tobacco:'

. Hoffmann, D,; Brunnemarin, K. D.; Rivenson, A.; Hecht, S: S. N-nitrosodi- ethanoZamine: )lnalysis, formation in tobacco products and carcinogenicity , in Syrian golden hamsters.~ ° ' 10 Brunnemann, K, Yu, L.; Hoffmann, D.. Assessment of carcinogenic volatile .: . . . y~ N-nitrosamines in tobacco and'in mainstream and sidestream smoke from _ cigarettes''- Cancer Research. 37: 3218-3'222; 1977. : ;11. 'Brunnemann,-'J. D.; Adams, J. D.; Ho, D. P. S.; Hoffmann, D. The influence of tobacco smoke on indoor atmospheres 11. ~ 1±: Volatile and tobacco specific nitrosamines in main- and sidestream smoke and their contribution to 0. indoor pollution. 4th Joint Conference on Sensing of Environmental f~ r 12 Pollutants. 87b-880; 1978_ Hecht S ; Chen C-h B ; Hoffmann S D s Tobacco-specific nitrosamines: . , . , . . . , . - . . ~ r. _ ,: .~ ti 1 Occurence, formation, carcinogenicity and 1 metabolism. Accounts of Chemical ~;~ Research. 12 92-98; 1979_. h 13. Hoffmann, D.; Adams, J. D.; Brunnemann, K.; Rivenson, A:; Hecht, S. S. Tobacco specific N-nitrosamines: Occurrence and bioassays.*- cc: ~ Mr. J. L. Charles Dr. R. A. Pages Mr. R. D. Carpenter 0 21s . J. John 0 w ~ Papers presented at: 7th International Meeting on N-nitroso Compounds. Tokyo, Japan: September 28-October 1, 1981. "i- ;~r ~11 ~ -i ~_:-~. ,... 0 RW j;; la_ W s: ;:yq x

Peopiowho• . ~ : drlr.k wa!er ricti . tn nitfate9 b i,-.--, lY~(hen nitrates and nixites are ing=s'ed in a Yrdtvarie:y o` Coods ct~amica1 r~. } -~: tior.stntlsebodycancreatenEtrbs?r:ines. ; •~• ,-;;, • r .~s~ .,;,.--~ • ~y i':: ~ • • ••• - ~!; r . •, . •~ Sourcea~la7iortal~leadeayotSel~f+eea~ ,_- . _. _. • s us ry ea, er, t- rocket tuM producls) raises poss:bfa expcsurA 10250 n:icroQra ~tr;• .- p+rsonperday.;. , .'~[:. • : . , • s~ ~y - ;•Expcsure to nitrosansines in so;-.e occupa~ons (n:h5 tnd i j •t+ ~ ~~ ~ ' • ~' j X :~. .r. <. ti- _ .. 7a*NewYxi7Lae/D.cll.W41

T031CCO STECIFIC D7-riE?P.QSA?!INES REDOCiI01 IS CIC'.dR:ITL S.`SOKr BY FILiRA7I0:{a (CCI) (IIO! (QS.) •Cg ) GO ' 50/85'. 50165 50!'Ss 50165 50J8i ` . 50165 50/85 501G5 .301100 S0/73 , 13.0 1.10 -40: • -40z 21.8 1.82 ls:~ -37Z. 22.«7 13.6 - 1.15 -4a. -30Z 22.5 1.66 12.9 1.05 -45Z -34Z 23.3 1.60 13.4 1.08 • -39-Z -34Z 21.8 - t.63 =Z Changa in anoke yield of tigarette vith aod vitboot filter. . ZSNA - Tobacco specifie P-n'stroaaninea. O'Ci_-acette E had a perforated filter tip. Colvrsa Sookad/ • . kngth of Cigarette '°=ar" Yicotine CO kKtt 15.6 458 • +4Z -44,: 15.0 816 18.5 3Z4 +9Z -39X ~ 16.9 __ ~333 ,: - 13.7 - 905 +13: a -3SZ 12.1 913 15.3 • - 342 +3-- -69: -14.9 •1110 12.0 313 -20Z -71Z 15.0 • 1760 - RNK ' lib2 . ISVA (ng) • Cnltj ~ - (r.e) ~ 360 ~ •570 - 139LT ` -50: . -,pZ - - -47Z 720 . 1080 c . ~- 2620 252 `. 390 966 =48Z- - . -R7Z .• - -45Z 481 735 - :- • 1750 399 ~ • ' 670 .. 1570 -45x ' . 39x ' . --40t 727 - •, 3080 ; • ' 2620 - ~ 213 - ' _ . '352 • .- . 907 ~ -73; a03: : - 1260 ~ •- -3170 249 - - • 593 • ~ . 1360 =71z : - -t9:- ` -7D: 868 e 1930 i Z45b0 .. J .. .~. V .. ~

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