Tobacco Documents Online

Polonium - 210

February 17, 1982 ECEIVED I-E8 M~MORANDUM TO: TI/TTC Legislative Counsel and Field Staff FROM: John D. Kelly You may get questions about the report last week claiming that polonium-Zl0, a radioactive substance reportedly found in tobacco smoke, causes lung cancer in smokers. Attached is cleared text which can be used to respond to any questions about the report. Additional background material on this subject is also attached. Please retain this material as this will be a recurring issue. Should any further details or clarification be necessary, please call Bill Toohey in TI's Public Relations Division at .[800)-424-9876. Attachment CC: Bill Cannell Mike Kerrigan Roger Mozingo Tobacco Tax Council TI03691200

RESPONSE TO WINTBRS/DiFRANZA NEJM LETTER In a recent letter published in the New England Journal of Medicine on February II, 1982, Drs. T.H. Winters and J.R. DiFranza claim that polonium-210, a radioactive substance reportedly found in tobacco smoke, smokers. According to the letter, in tobacco smoke is a result of the causes lung cancer in the presence of polonium-210 use of phosphate fertilizer in the cultivation of tobacco. Phosphate fertilizer, it should be noted, is normally applied by farmers to veEetables and other food crops and by homeowners to lawns and house- plants. Coal-burning electric power plants are a major source of polonium-210 in the air. This hyothesis was first proposed about 18 years ago and is still just that, a hypothesis. In fact, the authors unaccountably fail to mention recent research reports which cast serious doubt about the validity of the hypothesis. One such study published in a 1980 issue of Archives of Environmental Health examined this question. The investigators wrote that their results did not support the hypothesis that radioactivity in cigarette smoke contributes to the association between smoking and lung cancer. Another study, conducted here in the United States, was cited in the 1981 Surgeon General's Report on Smoking and Health. According to the Surgeon General: "In the case of polonium-Z10 a recent indepth study raises doubts on the significance of polonium-210 as a factor contrib- uting to lung cancer in smokers." T103691201

|. Schifi'rin A, ~rnontc M. Combined coot /~ infusion and multiple subculancous inj~'tions in Ty~ I diab~tlc patienls. Diabetes Care. 1981; 4:395-600. 9. LouBhc=d WD, Wou]fc-Ranag~o H, Clcmcnt JR, Albisser AM. ]nsu. lin aggregation in artificial delive~ systems. Diabetologia. ! 980;. 19:1-9. I0. In~dfingcr FJ. Dcbat~s on dlabeles. N Engl J Med. 1977; 296:122~.30. Joseph H. N~chalson, M.D., of Lawrence, died an August 7, 1981. He was in his 75th year. Dr. Nicholson received his de~ree from Tufts Collie Medical School in 1933. He was a member of the American Medical Associ- orlon, the American Heart Association, the American College of Physicians, the American College of Chest Physicians, and the American College of Cardiology'. MASSACHUSETTS MEDICAL SOCIETY PEARSON ~ Carl Maxwell Pearson, M.D., formerly of Dorches- ter, died on May 31, 1981. He was in his 63d year. Dr. Pearson received his degree from Boston University School of Medicine in 1946. He was a member of the American College of Physicians, the American Rheumatism Association, the Associa- tlon of American Physicians, and the American Medical Assad- atlon. DEATHS BtaoN -- Pierre Edouard Biron, M.D., of Beverly, died on Octo- b¢~ I2. He was in his 50th year. Dr. Bimn received his degree from the University of Ottawa School of Medicine in 1957. He was a member of the American Medical Association and the American Academy of Orthopedic He is survived by his wife, two daughters and a son, his parents, and a sister. RANOn^WA -- Khalld Mahmud Randhawa, M.D., of WesttqeId, died on December 12. He was in his 40th. year. Dr. Randhawa received his degree from Liaquat Medical Col- le~e in 1967. He was a member of the American Medical Associa- tion, the American Academy of Ophthalmolo~/and Otolaryngol- ogy, thc Royal Society of Medicine, the American Council of Otolaryngology, the Islamic Medical Association of the United States and Canada, and the Pakistan Medical Council. D~.~m~o -- Walter Stephen Denning, M.D., or Brookllne, died on December 23. He was in his 79th year. Dr. Denning received his degree from the University of Vermont ~.ollese of Medicine in 1929. He was a S0-year member of the Mas- sachusetts Medical Society. He is survived by a..d.aughter, seven grandchildren, and a great.. grandchild. H~.- Orrin Wayne Hall, Jr., M.D., formerly of New Bedford, died on March 19, 1981. He was in his 58th year.. Dr. Hall received his degree from Tufts College School of Medi- cine in 1947. He was a member of the American Medical Associa- tion and the American Society of Anesthesiologists, Jonssor~ ~ Elwood Gordon Johnson, M.D., of Newburyport, died on October 14. He was in his 68th year. Dr. Johnson received his degree from Tufts College Medical School in 1940. Fie was a member of the American Medical Associ- ation, the American Academy of F~mily Physicians, and the Royal Society of Medicine in London. lie is survived by his wife, a daughter, three sons, and a sister. LEL**.~D -- Harold Lea.haler Leland, M.D., df Lowell, died on No- vember I. lie was in his 89th year. . • I~-. Leland received his degree from Boston University School of Medicine in 1917. He was a member of the American Medical As- snclation, the American College of Surgeons, the American Uro- logical Assoriation, and a 50-year member of the Massachusetts Medical Society. lie is ~urvivcd by his daughter, two grandchildren, and one great- grandchild. _. ~ ~omcx -- James .Joseph .'~foher, .~'I.D., of l :larfford, died on Jan- uary 12, 1981. tic was in his 69th year. Dr. 3.Ioher received his degree from Yale Uni*x'rshy School of .Medicine in 1937. lie was a member oflhe American Society of In- ternal .Xh dh'ine_ Russo -- Edward Attilio Russo, M.D., of Gloucester, died on November 11. He was in his 69th year. . Dr. Russo received his degree from Tufts College Medical School in 1940. He was a member of the American Medical Association and the American Occupational Medical Association. He is survived by his wife, a daughter and three sons, four grand- children, and a sister. Sa^sns -- Harley Cecil Shands, M.D., formerly of Cambridge, died on December 4. He was in his 66th year. Dr. Shands received his degree from Tulane University School of Medicine in 1939. Fie was a member of the American Medical As- sociation and the American Psychi.atric Association. He was a Clinical Professor of Psychiatry at Columbia University College of Physicians and Surgeons. CORRESPONDENCE Letters to the editor are considered for l~ubl;catlon (subjec~ to editing and abridgment), provided that they arc submitted in duplkate~ signed by all authors, typewritten in double spac- ing, and do not exceed 1½ pages of text. They should not duplicate similar material being submitted or published else- where. Letters referring to a recent Journal article should be received within six weeks of the article's publication. We are unable to provide pre-publkatlon proofs, and unpublished malerlal will not he returned to authors unless a stamped, self- addressed envelope is enclosed. ~t~RAD|OACTIVIT'~; IN CIGARETTE SM?KE ¢ Editor: During the 17 )'ears since the Surgeon General's port on smoldng, intense re.-carch activity has been focused on the carcinogenic pmentiai of the tar component of cigarette ".,x*ke. OnlF one definite cbemi,.d c.~rc inogen -- bez~opyrene ~ -1-103691202

CORRESPONDENCE 365 Worcester, MA 01605 has b~en found. Conspicuous because arlts absence is research into the role of the radioactive component or cigarette smoke. The alpha cmillers Polonium-210 and lead-210 arc highly con° contented on tobacco Irichomes and insoluble particles in cigarette smoke,j The major source of the polonium is phosphate ferdllzer, which is used in growing tobacco. The trichomes of the leaves con- ccntrate the polonium, which persists when tobacco is dried and processed. L~vels of mPo wcre measured in cigarette smoke by Radioed ahd Hunts and in the bronchial epithelium oirsmokers and nonsmokca's by Little et al? After inhalation, ciliary action causes the insoluble radioactive particles to accumulate at the bifurcation of segmental bronchi, a common site of origin of bronehogenlc carcinomas. In a person smoking 1 ½ packs of clgaretts per day, the radia- tion dos~ to the bronchial epitheiiunt in areas of blfurcation is 8000 mrem per year -- the equivalent of the dose to the skin from 300 x-ray films of the chest per year. This/igure is comparable to total- body exposure to natural background radiation containing 80 mrem per year in someone living in the Boston area. It is a common practice to assume that the exposure received from a radiation source is distributed throughout a tissue. In this way, a high level of exposure in a localized region -- e.g., bronchial epithelium -- is averaged out over the entire tissue mass, suggest- ing a low level of exposure. However, alpha particles have a range of only 40/~nt in the body. A cell nucleus o1"5 to 6,am that is traversed by a single alpha particle receives a dose of 1000 reins. Thus, al- though the total tissue dose might be considered negligible, cells dose to an alpha source receive high doses. The mPo alpha activity of cigarette smoke may be a very effective carcinogen if a multiple mutation mechanism is involved. Radford and Hunt have determined that 75 per cent of the alpha activity of cigarette smoke enters the ambient air and is unab- sorhed by the smoker,~ making it available for deposit in the lungs d others. Little et aL have measured levels of mPo in the lungs of nonsmokers that may not be accounted for on the basis of natural exposure to this isotope. The dote/mental effects of tobacco smoke have been considerably underestimated, making it less likely that chemical carcinogens alone are responsible for the observed incidence of tobacco-related carcinoma. Alpha emitters in cigarette smoke result in appreciable radiation exposure to the bronchial epithellunt of smokers and probably secondhand smokers. Alpha radiation is a possible ctlo- logic hctor in tobacco.related carcinoma, and it deserves further study. TnoaAs H. Wt~r~as, M.D. Jos~a R. D~ Fa^nz~, M.D. University of Massachusetts Medical Center 1. Martell hA. Radioactivity of tobacco trichomes and insoluble clgarott," smoke panicles. Nature. 1974; 249:215-7. 2. Radioed EP Jr, Hunt VP,. Polonlum-210: a volatile radlo:lcment in arctics. Science. 196~; 143:247-9. 3. Lillle ~B. Radioed EP Jr, McCombs HL. Hunt VR. Dislribution Ioniurnn* in pulmonar~ tissues of ¢igaretto smoke~a. N Engl 196~; 273:1343-~1. THE SYNDROME OF NONTHROMBOCYTOPENIC PURPURA WITH EOSINOPHILIA: AN ACQUIRED PLATELET DYSFUNCTION Ta l,~e Editor: A 19-year-old man in the National Service was re- cently admitted to Singapore General Hospital for recurrent spon- tan~'ous bruising, epistaxes, and gingival bleeding of two weeks" daration. Inquiry revealed a healthy childhood with no similar symptoms; there was no antecedent febrile illness, no drug ingeso tlon, and a ncgatiue hmily history for bleeding disorders. On examination the /~ndings were unrcmarkable, apart from multiple ecchymoses O to 8 cm) on all four limbs. The liver, spleen, and lymph nodes were not enlarged. The hemoglobin was 14.2 g per deciliter, the total leukocyte count was 8600, with an absolute eosinophil count of 2320, and the platelet count was 170,000; the prmhrombin time, parthl lhromboplastin time, and erythrocyte sedimentation rate were normal Blood films v.ere negative for mb croft/aria. A chest film was normal. Stool sampling revealed the ova of Ar~loaoma duodmol~. Serum immunoglobulin levels were normal; lupus erythematosus.<ell preparations and tests fur anti- nuclear hctor were negative. Bone-marrow aspiration showed a normocdlular marrow with moderate eosinophilla, normal mega- karyocytes, and normal erythrold and granulopoletie ntaturadoa. The iv,/bleeding time was normal. Platdcts aggregated subnor- mally to adenosine diphosphate and did not agg~gate zo collagen, and lacked a secondary phase to epinephrine- Because of the ancyiostomai ova; the patient received a single oral dose of bephenlum. Three days later, the total leukocyte count was 5400, and the eosinophil count dropped to 750. The patient's stools were negative for ova two weeks after the anthdmintie therapy. There were no new outbreaks of ecchymoses. Platelets aggregated normally to adenosine diphosphate and epinephrine but subnor- mally to collagen. On review two months later, ~he ecchymoses had all resolved, the absolute eosinophil count was 240, and the plate- lets aggregated normally to all three agents. In Southeast Asia the syndrome of nonthrombocytopenic pur- Pora with cosinophilla is an acquired, ~ransicnt platelet dysfunc- tion seen primarily in children and rarely in young adults. The syn- drome is characterized, as it was in this patient, by spontaneous cutaneous or mucnsai bleeding of varying degrees of severity, last- ing a few weeks to several months. The prognosis is invariably good. Its precise cause is not known. Intestinal parasitism has been docu- mented in only half the affected children.~ The most consistent platelet abnormality is impaired aggregation to collagen.~ This syn- drome probably reflects an unusual immunologic response to an in- flammatory or infective process peculiar to Asian countries, and more research is needed to determine its pathophyslotogy. Singapore Republic of Singapore Y. K. Ku~a, M.D. Singapore General Hospital I. Suvad¢ V, Mahasandana C, Tunphaichi~" V. Tuchinda $. Acquired platdet dysfunction with eosinophilla: study of platclet function in 62 cases, Southeast Asian J Trop Mcd Public Hcallh. 1979; 10:35g-67. 2. Mitrakul C. Transien¢ sponlancous bruising with long bleeding timeand no~mal plat©let count. Am J CIIn PathoL 1975; 63:81-6. AZATHIOPRINE DECREASES SUPPRESSOR T CELLS IN PATIENTS WITH MULTIPLE SCLEROSIS 7"0 t~e s~ditor: ~zathloprine is an antimetabolite and immunosup. pressive agent primarily used to treat transplant recipients and pa- tients with autoimmune diseases. It has been reported to induce a variety of perturbations of the immune sys~emJ.~ Our interest in azathloprine is the possible usefulness of this drug in the treatment of patients with multiple sclerosls,s a disease suspected to have an immune pathogenesis.~ We gave seven patients with m. uhiple sclerosis enough azathio- prine to induce leukopenia (35~0 white cells per cubic millimeter), using the schedule suggested by Rosen? Not enough time has elapsed to allow us to evaluate the clinical effects of the drug in these patients. However, we have studied its effect on a subpopula- tlon of cin:ulatlng T lymphocytes. These T lymphoc~es are idemi- lied with use of the monoclonal antibody OKTg? Functionally, the}" act as supprcssor/cytotoxic cells. Circulating T cells recog- nized by OKT8 and a similar antibody are reported to decrease during the active stage of multiple sclerosis.~.~ The disorder had progressed in these patients (treated or con- trols) during the year before therapy, but no obvious changes had occurred one month before treatment. The control group consisted of I! patients with multiple sclerosis; two had relapses and remis- sions, and nine had chronic progressive disease. In the treated group one patient had a relapse and remission and six had chronic progressive disease. A phlebotomy was performed in each patient after azathioprine had been administered for at least two months. Circulating T cel/s were enriched from peripheral blood with the technique or sheep-erythrocTte rosettlng (95 per cent T cells). Indi- rect immunofluoresceoce was applied to identify ¢.'ells positive foc The percentage of OKT~-positbe T cells was 33.1:E3.! per cent in 16 normal healthy controls, 31.3:t:3.3 per cent in control T103691203

~|

Whether the cocarcinogenic effects of nicotine are important for man is a matter of speculatlor~ Tumor-promoting activity of croton oil exhibits a threshold both for frequency of application and for the quantity of agent present with any given treatment (~6). The animal studies in wl~ch nicotine acts as a cocarcinogen employ nearly lethal levels of nicotine administered once or twice a day. In contrast, smokers are exposed to a large number of low doses of nicotine daily. If a threshold amount of n~cotine per dose is requh~] for cocarcinogenJe activity, human smokers may not be affected in a manner similar to that of the mouse skin system- Polonium 210 There have been repeated suggestions that =0Po might contribute to o the carcinoge.nic activity of cigarette smoke in man (137). Polonium levels in tobacco result primarily from the use of phosphate fertilizers that are contaminated with radium decay products, particularly =opb, a precursor of mOPo (162, 168)'.~,~.~ little .~oPo is found in tobacco leaf, but some is transferred to the ~e-. Y~lds of 10 to 15 fCi of alpTm " emitters were recently reported for experimental cigarettes and 490 fCi/gm for commercial cigarette smoke condensate (86). Most of the radioactivity was due to insoluble forms of mPo. Cancer may arise from a single affected cell. It has been suggested that small amounts of insoluble =OPo concentrated in small areas might deliver an effective carcinogenic dose to a target cell (I]~). Harley et al. (71), however, found very few "hot spots" in the lungs of deceased smokers. Based on human experience with radon daughters, they assumed a lifetime risk ~ -. of lung cancer of 1 x 10~ for a dose of one tad/year. At most, the radioactivity they detected was estimated to explain only 10 percent of the lunl~ cancers suffered by cigarette smokers. They consider polonium 210 a questionable risk factor in human carcinogenesis. Polonium 210 contamination of tobacco can be effectively reduced by selection o.f plant types and sources of phosphate fertilizer, and by i.I Volat,le N-N|trosamln. as • • Tobacco smoke contains a number of secondary and tertzary amines. These amines, together with nitrogen oxides, may give rise to the in ~" ~o formation of nitrosamines, formation of most Although the nitrosamines is favored at low pH (110), a small amount of volatile nitrosamines is found in cigarette smoke and may be formed in the lungs under normal conditions (80, 8~, I70). The volatile N-nitrosa- mines are organ-specific carcinogens, which in mice give rise to tumors of the liver and kidney. At present, there is no reason to assume that volatile nitrosamines cause lung cancer in smokers. Nevertheless, it is prudent to limit the presence of any carcinogen in cigarette smoke. Volatile r. and by li~ Bladder ( The in~ ., intensive~ particular] liver and produce bl The prese~ strated yield was contrJbute¢ The uri: Yamasaki ~ converted • mutagens ~ nonsmoker. cancer~ individuals cigarette sz prevention. collected fr~ promutage~ smoke. Laryngeal ( Hamsters diluted dga~ b.een u.sed ~ mlnes ~.nduc~ of part~culm larynx (8~)... that are actz ~ induction, t=ssue direct]; Other Cance Cigarette : pancreas~ ora cancers has l quantitative 0 and esophage carcinogens. ] cancer of th~ T103691205

TABLE 2.--Known carcinogenic agents in the gas phase of cigarette smoke* as complete carcinogens. These PAH, however, are active as tumor initiators and thus contribute to the induction of tumors by tobacco "tar," which contains an abundance of eocarcinogens (20, ~8). Tables 3 and 4 list the tumor initiators and cocarcinogens in cigarette smoke known at this time. Large-scale model studies on mouse skin and inhalation studies with Syrian golden hamsters have shown that a significant reduction of "tar" and a selective reduction of tumor initiators and cocarcinogens will lead to a significant reduction of the carcinogenic potential of cigarette smoke (13, 23, 2L, 29, 30, 31, 32, ~8). Recently, a study has indicated that nicotine (and possibly other tobacco alkaloids) may be active as a cocarcinogen (1L), while another study did not show acrolein to have cocarcinogenic properties (~7). Further detailed investigations are required. Organ-Specific Carcinogens This approach toward.the less hazardous cigarette has been criticized by several groups as one-sided because it has been concerned only with ".tar," nicotine, and tumor initiators such as PAH and with cocarcino- gens, rather than with organ-specific carcinogens (85, 88,.I. 02). .. Table 5 lists the known organ-specific carcinogens. "In the case of polonium-210, a recent indepth study, raises doubts on the significance of n0po as a factorcontributing'to lung cancer in smokers. Neverthe- less, it may be prudent to reduce the ~oPo content of tobacco produet~ Among the aromatic amines, certain individual compounds are known human bladder carcinogens (e.g., 2r. naphthylarnine, 4-biphenylao 94 SOURCE: mine, and be as likely con bladder canc~ thesized frorr of a process toward the r~ reported. A major g~ the N-nitros~ nitrate are pr tobacco-speeL during tobac~ nicotine (NNK), and compounds a (NNN and concentration pg/cigarette and Syrian the respirato: T!03691206

(~0) HAWKSWORTH, G., HILL, MJ. The in v~vo formation of N-nitrosamlnes in the rat blmlder and theh' subsequent al~orpfion. B~ J~ of 29(5): ~53-358, May 1974. (~) IIECHT, S.S., ORNAF, I~M., HOFFMANN, D. Chemical studies on tobaem smoke. XXXIII. N:nitrosonorr~cotine in tobacco: Analysis of Rossible contrib- uting factors and biologic implicat~on~ Journc/ of t~ Nat~on~ In~tit~ 64(5): 1237-1244, May 19"~J. (~) HECHT, S.S., YOUNG, R., CHEN, C.B. Metabolism in the F-344 rat of 4=(N- methyl-N-nitro~amine)-l-(3-pyridyl)-1-butanone, a tobacco specific carcinogen. Car.~er Re~earck 40(11): 4144-4150, November 1980. (~) HENSCHLER, D, BONSE, G. Ad~oes ~z 2~armacok~ and 27wr~peu~/cs 9: L?3-130, 19/9. (/~) HILL, P., MARQUARDT, H. Plasma and urlne changes after smoking different brands of cigaretto~ CKn/c~t P~ar~no~o/c0y mul Tk~rapeut/~s 27(5): May (~') HILL, D.L., SHIH, T.W., JOHNSTON, T.P., STRUCK, P~F. Macromolecular binding and metabolism of the carcinogen 1,P,-dibromoethane. C~ncer 38(8): 24~8-2442, August 19~8. (~) HOFFMANN, D., ADAMS, J.D., BRUNNEMA.NN, ICD., HECHT, ~S. merit of tobaeco-spedfic N-n|troearnines in tobacco products. Cancer 39ff}: 2Sa~-2~9, I9~J. (~F) HOFFMANN, D., CHHN, C.B., HECHT, ~ The role of volatile and nonvolatile N-nitrosam~nes in tobacco eardnogenes~ In: Gori, G.B~ Zk~k, F.G. (Editors). Ban/n,ry Re~x~t #--A ~afe C/~aret~? Cold Sprin~ Harbor, New York, Cold Spring. Harbor Laboratory, 1980, pp. 113-127. (~) HOFFMANN, D., SCHMELTZ, I~ HECHT, S.S, WYNDER, E.L, Toby:co ¢ardnogene~is. In: Ge]boin, H.V., Tso, P.O. (Editors). Fb/yc~[~ end Can~er. New York, Aeademlc Press, 19/8, pp. 8~-11"L 105 T!03691207