Symposium: Prooxidant Effects of Antioxidant Vitamins

8/12/2019 Symposium: Prooxidant Effects of Antioxidant Vitamins

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Symposium : Prooxidant Effects of Antioxidant Vitam insIntroduction1

VICT OR H ERBE RT2Department of M edicine, The M ount Sinai School of M edicine and M ount Sinai M edical Center,Hew York City, NY 10029 and the Medical Service, and Hematology and Nutrition ResearchLaboratory of the Research Service, the Bronx Veterans Affairs M edical Center, Bronx, NY 10468

This sym posium , by five bench researchers who regularly add to existing knowledge rather than merelyregurgitating prior cla im s, illustrates the follow ing foura ph orism s in n utritio na l b io ch em istry :1. A ll vitam ins have pharm acological effects and actions, som e of which are either unrelated, or only indirectly related, to their vitam in action (Food and DrugAdministration 1993, Herbert et al. 1994, Herbert1994). The recent slang term nutraceuticals to describethose Pharm aceuticals that are also nutrients m isleadsby conveying they are separate from , rather than a subset o f, pha rmaceu ti ca ls .2. Every antioxidant, including vitam in antioxi-dants, is in fact a redox (reduction-oxidation) agent,protecting against free radicals in som e circumstances,prom oting free radical generation in others. E xcessiveantioxida nt action can adversely affect key physiological processes (Food and Drug Administration 1993,H erbert et al. 1994, O lson, this sym posium ).

W hen present in physiological [Recommended D ietary Allowance (RDA)] amounts, as part of the balanced biochem istry of > 150 redox and nonredox phyto-chem icals in each fruit or vegetable, they are always inboth the reduced and oxidized form s. In the pharm acological (above RDA) am ounts found in supplem ents,where they are only in the reduced form , they are unbalanced biochemistry not only lacking the over 150 balancing phytochem icals nature put in each fruit and vegetable but often p rom oting free rad ical generation. T heyalso have many chemical actions unrelated to eithervitam in or redox activity; these chem ical actions alsoare not counterbalanced by the other phytochem icalsin each fruit or vegetable (H erbert 1994, H erbert 1995).Harms reported from pharmacological amounts ofantioxidant vitam in supplem ents include prom otionof heart disease, cancer and liver and kidney disease(H erbert 1994, 1995).The answer to the question, If I drink orange juicefor vitam in C, why not take a vitam in C pill for thesame effect is that the effect is entirely different.

Antioxidant vitam ins as naturally present in food arebalanced biochem istry, i.e., part of a m ixture of redoxagents partly in oxidized form and partly in reducedform , plus numerous other ph ytochem ica ls.For truth in advertising, all supplements should bela be le d, P hy sio lo gic al (RDA) amo un ts o f su pp leme ntshelp some people, harm others, and have no effect onmost. Because of their potential for harm , pharmacological (above R DA) am ounts should not be taken without the advice of a licensed health professional.

People who ingest large am ounts of fruit and vegetables have high blood levels of a host of fruit and vegetable phytoc hem icals, in cluding a n um ber of a nticarcino-gens and a dozen redox agents, two of which are carotene and vitam in C. Ignoring all the confoundingvariables, careless epidem iologists decree that it is the/3-carotene and vitam in C, rather than the mix of over150 phytochem icals in each fruit and vegetable, that isprotective against cancer (H erbert 1992).3. The reduction of molecular oxygen to water bythe addition of four electrons is the major source ofenerg y fo r anim al life (F arber et al. 1990). F ree rad icals,the price we pay for breathing, are essential for

health and life in moderation and harmful to healthand life in excess.4. Moderation in all things is the essence of soundnutrition. Too little or too much of any nutrient isharmful. M ore is sometimes better, sometimes worsebut always more expensive. For every nutrient, everytheoretical (and actual) up side is balanced by a theoretical (and actual) d ow n sid e. T oo little pro vitam in' P re se nted as p art o f t he S ym po sium : P ro ox id ant E ffe cts o f A n tiox id an t V itam in s g ive n at th e E xp erim en tal B io lo gy '9 5 m eetin g,

A tlanta, G A, on A pril 13, 1995. This sym posium w as sponsored byth e Am erica n In stitu te o f N u tritio n. G ue st ed ito r fo r th e sympo siu mp ub lic ation w as V icto r H erb ert, th e Mou nt S ina i S ch oo l o fM e dic in e,N ew Y ork C ity , NY, a nd th e B ro nx V eteran s A ffa irs M ed ica l C enter,B ro nx , NY .2 T o w hom c orre sp on de nc e sh ou ld b e ad dres sed : B ro nx V ete ran sA ffairs M ed ica l C en ter, 1 30 W . K in gsb ridg e R oa d, B ron x, NY 1 04 68 .

0 02 2-3 166 /9 6 3 .0 0 19 96 Ame ric an In stitu te o f N utritio n. J. N utr. 1 26 : 1 19 7S -1 20 0S , 19 96 .1197S


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1198S SUPPLEMENTA ( / -caro tene ),itam in C , v i tam in E , i ron or s eleniump romo te s c an ce r; so doe s to o much (Herb ert & .Kasdan1994, Herb ert e t al. 1 995).The report (B l ot e t al. 1993)o f 29,584 vege tarian Ch inese w ith a high frequency of esophageal cancer hasbeen repre sented by supplement p romo te rs as ev idenceth at an tio xid an t su pplem e nts p ro tec t ag ain st c an cer.T his is hy pe, not fact. T he China study show ed thef ollow in g th re e th in gs, n on e o f wh ic h are n ew : )V egetarian ism d id n ot p ro tec t th e C hin ese ag ain st c an cer.2) N utrient def iciencies prom o te the dev elopm ent ofs ome cance rs . 3 ) Correct ing thos e nutrient def ic ienc ie sre du ce s th e f re qu en cy o f th ose c an ce rs (Herb ert 1 992).It has been k now n f or m any y ears that nutrient def ic ie nc ie s p romo te c an ce rs. T h e Plumme r-V in son sy nd rome, d ue to iro n d ef ic ie nc y , h as b een known f or mo rethan half a century to prom ote the dev elopm ent ofesophageal cancer (W y n der et al. 1957). T he Chinas tudy s ub jects were def ic ient ( i.e ., b elow min ima l dailyv itam i n re qu irem en ts to su stain n ormal m e tab olism )in so -c alle d an tio x id an t v itam i ns A , /0 -c aro te ne and E .S upp lemen ts c on tain in g /3 -c aro te ne and v itam i n E , b yraisin g in tak e s abov e th e m i nimum daily re qu iremen t,e lim i nate d th e d ef ic ie nc ie s th at p romo te d th e c an ce rs,th ere by re duc in g th e f req uen cy o f tho se c an ce rs (H erbert, 1992).In terestin gly , in th e C hin a stu dy , v itam in C sup plem e nts w e re w o rth le ss ag ain st can cer, ju st as th ey (an d/0-caro tene) proved worthles s agains t heart d is ease (Jia-lal and G ru nd y 1 99 3, S te in berg 1 99 3).O ur ow n g ro up (R an e t al. 1 993 )rep orted that, in th earea in C hina w ith the highest f requency of the trio off olie ac id d ef ic ie nc y (c au se d b y coo k in g th e nutrie ntso ut o f f ood ), v itam in B -1 2 d ef icien cy (cau sed by v eg etari an ism) and esophageal carc inoma , we cou ld revers etoward normal p re can ce rous e so phag eal d y sp lasia b ye ith er im p ro vin g th e d iets (b y less p ro lo ng ed c oo kin gof food plus adding a few ounces of anim al proteinth ree to f ou r tim e s a w e ek ), or k ee pin g th e b ad d iet an dadm inisterin g sup plem en ts o f v itam in B -12 an d f olieac id . T ho se p eo ple w h ose eso ph ag eal d ysp lasia c ellsw ere not y et m o rphologically comm itted to be cancerce lls re versed to n ormal; th ose w h ose c ells w e re comm itted did not.In th is symp osium , Marie tte G erb er p re sen ts w o rkf rom her INSERM-CRLC g roup in Mon tp ellie r, Fran ce .T h ey stu die d 2 69 h osp ital-b ase d c on tro ls an d 1 46 p at ien ts w i th prostat ic , ovarian , endometrial , co lorec tal orlung carc inomas. They f ound that v i tam in E p lasma concentrations increased and m alondialdehy de (MDA )plasma concent rat ions decreased in proport ion to growin g tumor siz e an d n od e inv asio n. T h is su gge ste d th at,alth ough v itam i n E may hav e d ec re ase d lip id p ero x id a-tio n (su gg este d by th e d rop in MDA le v els), it may simu ltaneous ly have i nc reas ed grow th and spread o f cance r.In th is sympo sium , Jame s A . O lso n, a past p re sid en tof A IN and one of the w orld's leading researchers onv itam in A an d th e man y caro te no id s, d isc usses th e bal

ance o f help f ul and harmfu l ac ti on s t he caro teno id s canhav e, depending on circum stances and on the m ix ofc aro te no id s in an y g iv e n f ood.O lso n's p ap er f ollow s th e N e th erlands stu dy (De V e te t al. 1 991), su gg estin g -c aro te nesupp lemen ts p rom o te cancer of the cerv ix , and the Finnish study , publis hed i n 1994 (The A lpha Tocophero l, /3 -caro tene Canc er Pre v en tio n S tu dy Group 1994), in dic atin g /3 -c arote ne su pp lem en ts are asso ciate d w ith 1 8 mo re lu ngc an ce r in smo k ers th an is a p lace bo .Th i s randomized , double -b lind , p lacebo-cont ro ll edprimary prevent ion t rial comparing dai ly supplementatio n w i th a-to coph ero l, /0 -c aro te ne , b oth o r p lac ebo in29,133 m ale sm o kers in Finland show ed that neitherv itam in prev ented lung cancer. In f act, lung cancerrate s w e re 1 8 h ig he r w ith /3-caro ten e th an w ith p lacebo, and there w ere m o re heart disease deaths. M e ntak ing v itam in E had m ore hem orrhagic strok es. A lthough they did hav e less prostate cancer, total (all-c au se ) mo rtality was 8 h ig he r among th ose who to ok/3 -caro tene than among thos e tak i ng p lacebo.O ne reason v itam in C supplem ents increase lungcancer and m o rtality in sm o kers m ay be because v itam in C su pp lem e nts d riv e n ico tin e ou t o f th e b lo od in toth e u rin e (H erb ert an d S ub ak -S harp e 1 99 5), c au sin gsmo k ers to re ach f or th e n ex t cig are tte (m o re c arcin ogens) that m u ch f aster to sustain their nicotine high.Pare nth etic ally , o ur lab is n ow in v estig atin g wheth er/3 -caro te ne su pp lem e nts also d riv e n ico tin e in to th eu rin e. V itam i n C supp lemen ts c an double c ard iac risk .W e (H erb ert) d iscu ss in th is symp osium th at th e majo rity o f f ree rad ic al d amag e is p ro du ce d b y c ataly ticiron, and that in ov er 10 of all A m e ricans w ho hav eh ig h bod y iro n due to h ete ro zy gou s h emochromato sis,supplem ents of v itam in C (tak en by 43 of A m ericans), b y d riv in g rep etitiv e f re e rad ical rele ase f romh ig h bo dy iro n, slow ly an d in sid io usly p romote h eartd ise ase , c an ce r and p rematu re ag in g. E lsewhe re (Herbert and Subak -Sharpe 1995, Herbert 1995a)we d is cu ssv itam in C , in its nonv itam in chem ical action, to beth e main so urce o f ox alate (an d o xalate k idn ey ston es)in the hum an body , as w ell as harm s from v itam in Ein its nonv itam in chem ical actions as an inhibitor ofblood clotting and as a prom oter of imm une activ ity(Herbert 1995 , Herbert 1995a) .In this sy m posium , Joel L . S chw artz discusses hisw ork at the N ational Institute of D ental R esearch ontumo r p romo tio n b y an tio x id an t v itam i ns.C ancer, the m ajor subject of the abov e f our sym posium p ap ers, sp rin gs f rom d eran ged c ell re plicatio n,large ly gene ti cal ly pred isposed , as are mos t chron ic d iso rd ers (S imopou lo s e t al. 1 993).W heth er a g en etic p redisposition is ex pressed as disease or suppressed islarg ely a f un ctio n o f e nv iro nmental f ac to rs, in clu din gw hat w e eat and w hat w e av oid eating (Herbert andSubak -S harp e 1995, S imopou lo s e t al. 1 993).In su n K im , in h er p ap er S up plem e nts d o n ot red uc eU .S . all-c au se mo rtality , wh ic h con clu ded th is S ym -


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INTRODUCTION 1199Sposium , updated and strengthened the w ork of her Centers for Disease Control group, published in 1993 (K imet al. 1993), indicating that m ortality am ong A m ericans w ho tak e supplem ents is identical to that of thosew ho nev er tak e them . T his suggests that supplem entshelp som e, harm others and hav e no ef f ect on m ost, sothe bottom line is a w ash. Caring for her new babyprecluded her m ak ing the deadline to publish her sy mposium paper in this issue of T HE JOUR NA L .T his S ym posium also illustrates the f ollow ing threenutrition science ax iom s, all detailed at length in thebook s T he V itam in Pushers (B arrett and Herbert 1994)and T otal N utrition (Herbert and S ubak -S harpe 1995):1} Wha t is true about nutr ition is not magic, a nd wha tis m agic about nutrition is not true. 2) S cience is notabout w hat one believ es, but about w hat the ev idencesay s. 3) N utrition is a science and not a religion.Finally , this S ym posium illustrates three therapyax iom s (Herbert 1986). T hese are as follow s: 1) N otherapy is e f fectiv e until it has been objectiv ely , repro-ducibly and reliably dem onstrated to be m ore ef fectiv ethan a suggestion, a placebo or doing nothing. 2) N otherapy is saf e until it has been objectiv ely , reproduci-bly and reliably dem onstrated to be as safe as doingnothing. 3) If there is any question w ith respect tosafety , before using a product, it m ust be objectiv ely ,reproducibly and reliably dem onstrated that the potential for benef it ex ceeds the potential for harm .T he ubiquitous H of fm ann L aR oche adv ertising blank eting the lay and prof essional literature claim ing thatT he safety of antiox idant v itam ins E, C and beta carotene is w ell established (v erbatim quote) is a deceptio n f or p ro fit.T he ads deceiv e by om ission of adv erse facts. T hisis the m ost pernicious of the tactics of v itam in pushersbecause it m ak es it im possible for the reader, ev en if ahealth prof essional, to recogniz e that he or she is beingdeceiv ed (B arrett and H erbert 1994, H erbert 1987, H erb ert 1 99 5).T he core of sound nutrition is three basic w ords(m oderation, v ariety and balance), f iv e basic foodgroups, sev en dietary guidelines (the new m oderatelyupdated U.S . gov ernm ent guidelines are due out at theend of 1995) and the m odif ications thereof for agegroup, sex , genetic v ariations and so forth. S ellingm egadoses of antiox idant v itam ins to f ight cancer, enhance the im m une sy stem and retard aging, w ith representations that the products hav e been dem onstratedto do so and also hav e been dem onstrated to be safeis y et another m ultibillion dollar alternativ e m edicinef raud (B arrett and H erbert 19 94). T he term alternativ em edicine cloak s m any frauds, because the term conceals that there are three k in ds of alternativ es: genuine,question able and f rau dulent (B arrett and H erbert 1994 ,H erb ert 1 98 6).A m erican diets av erage 120 of the R DA for v itam in A , /S -carotene and v itam in C (Herbert and S ubak -S harpe 1995). N onex perim entally produced dietary v i

tam in E def iciency has nev er been reported in theUnited S tates (Herbert and S ubak -S harpe 1995). T heresearch reported in this S y mposium conf irm s the logicof the 10th R ecom mended Dietary A llow ance Comm ittee authors (Hodges and Olson 1987, Olson 1987)in low ering the R DA for v itam ins A and C and rejectsthe logic of the 10th R DA Subcom mi tee editors (S ubcomm ittee 1989) to not only hav e a high v itam in CRDA of 60 m g but to raise it to 100 m g for sm ok ers.N ote a dded in p ro of O n J an ua ry 1 9 1 99 6 G in aKo la ta r ep or te d in Th e New Yo rk Times ( Stu die s fin db eta -c a ro te ne , u se d by millio ns, d oe sn 't fo re sta ll c a ncer or hea r t disea se, p. A16) tha t Dr . Richa rdKla usner , D ir ector of the Na tiona l C ancer Institute(NC I), c alled a p re ss c on fer en ce to a nn ou nce th at:1) The P hysicia ns' H ea lth Study, funded by NCI,involving 22,071 physicia ns who wer e r andomly a ssigned to ta ke 50 mg of -ca roteneor a dummy pillevery other da y, ha d ended on December 31, 1995,a fte r 12yea r s , w ith the conclu si on tha t -ca r o tenesupplements did not pr otect a ga inst ca ncer or hea rt dise a se . Th e d ir ec to r o f th e stu dy, D r . C ha r le s Hennekensof H a rva rd U niver sity, wa s quoted a s sa ying, Ther ei s absolutely no benefi t in -caro tenesupplements ,a nd tha t finding is the biggest disa ppointment of mycareer .2) The Beta -C ar otene a nd Retina l Effica cy Tr ia l(CARET) , funded by NCI, t es ted 30 mg -caro tenep lus25,000 I.U . vita min A da ily vs. pla cebo in 18,314smoker s or a sbestos wor ker s a t high r isk for lung ca ncer . The study wa s ha lted on Ja nua ry 10, 1996, 21months a hea d of schedule, when study director D r.G ilber t S. Omenn of the U niver sity of Wa shington inSe attle c on clu ded th at th e vitamin s mig ht b e h armfu lb eca use th e r a te o f lu ng ca nc er wa s 2 8 h ig her amo ngth e supp lement-ta ke rs th a n th e p la c ebo g roup , a n d th er ate of dea th fr om hea rt disea se wa s 17 higher .3) D r. Kla usner concluded tha t D r. Victor H er ber twa s r ight (H er ber t, 1986a ) tha t no ma tter how compelling a nd exciting a hypothesis is, we don't knowwh eth er it wo rks with ou t clin ica l tr ia ls.

LITER TURE ITEDB arrett, S . & Herbert, V . (1994) The V itam in Pushers: How theH ealth Food Industry is S elling A m erica A B ill of G oods. Pro

m etheus Press, A m herst, N Y .B lot, W . } ., L i, J.-Y ., T ay lor, P. R ., Guo, W ., Daw sey , S ., W ang,G .-Q ., Y ang, C . S ., Z heng, S .-F., G ail, M ., L i, G .-Y . , Y u , Y . , L iu,B -q., T angrea, J., S un, Y - h., L iu, F., Fraum eni, J. F., Jr., Z hang,Y .-H . & L i, B . (1993) N utrition interv ention trials in L inx ian,C hin a: su pp le m en tatio n w ith sp ec if ic v itam in /m in eral c om b in ati on s, c an ce r i nc id en ce , an d d is eas e-s pe ci fi c mo rt al it y in t he g eneral p op ulatio n. J. N ati. C an ce r In st. 85 : 14 83 -1 49 2.De V et, H. C. W ., K nopschild, P. G., Grol, M . E. C., S chouien,H . J. A . & S turm ans, F. (1991 ) T he role of /3-carotene and otherdietary f actors in the etiology of cerv ical dy splasia: results of ac as e-c on tro l s tu dy . I nt . J. E pid em i ol . 1 0: 6 03 -6 10 .Farber, J. L ., K yle, M . E. & C olem an, J. (1990) B iology of disease:


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1200S SUPPLEMENTme ch an ism s o f c ell in ju ry b y ac tiv ate d o x yg en s pe cie s. L ab . I nvest . 62 :670-679.Food and D rug A d m inistration (FD A | FD A C onf erence on A n tiox i-d an t V i tam in s an d C anc er an d C ard iov ascu lar D ise ase (N o vembe r 1 -3 , 1 99 3). C om p le te trans cript av ailab le f rom : E liz ab eth A .Y e tley , O ff ice of S pecial N utritionals, O SN HFS -450, FD A , 200C S treet S W , W ashington, D C 20204-0001.Herbert, V . (1986) Unprov en (questionable) dietary and nutritional m ethods in cancer prev ention and treatm ent. C ancer 58:1930-1941.H erbert, V . (1986a) V egetables, f ruits, and oncologists. S cience232:11.H erbert, V . (1987) H ealth claim s in f ood labeling and adv ertising:literal truths but false m essages; deceptions by om ission of adv erse f ac ts. N u tr. T od ay 2 2: 25 -3 0.H erbert, V . (1992) D iet and cancer prev ention. N C A HF (N ationalC ouncil A g ainst H ealth Fraud) N ew sletter 15: 1.H erbert, V . (1994) T he antiox idant supplem ent m y th. A m . J. C lin.Nu tr. 6 0: 1 57 -1 58 .

Herbert, V . (1995) Editorial: V itam in C supplem ents and dise as e c ou nt erp oin t. J. Am . Coll . Nu tr. 1 4: 1 12 -1 13 .Herbert, V . (1995a| A lfalfa, v itam in E, and autoim mune disordersreply to W h ittam , J., Jensen, C . & H udson, T . A m . J. C lin.N utr. 62: 1026.Herbert, V . & K asdan, T . S . (1994) M isleading nutrition claim sand their gurus. N utr. T oday 29: 28-35.H erbert, V ., S haw , S ., Jay atillek e, E ., R osm an, A . S ., G unter, E. W . ,B ow man, B ., Giardina, P. & Grady , R . W . (1995) Ev idence anew assay , saturation of f erritin, is the m ost reproducible andreliable m easure of the w hole range of body iron stores. B lood 86(suppl.): 584a.H erbert, V ., S haw , S ., lay atillek e, E. & S topler-K asdan, T . (1994)M ost f ree-radical injury is iron-related: it is prom oted by iron,he m in , h olof erritin and v itam in C , an d in hib ite d b y d es fero xam -in e an d ap of erritin . S te m C ells 1 2: 28 9-3 03.H erbert, V . & S ubak -S harpe, G . J., eds. (1995) T otal N utrition:

T he O nly G uide Y o u'll Ev er N eed: From the M ount S inai S chooof M edicine. S t. M artin's Press, N ew Y o rk , N Y .H odges, R . & Olson, J. A . (1987) R ecom m ended dietary intak es(R DI) of v itam in C in hum ans. A m . J. C lin. N utr. 45: 693-703.lialal, I. & G rundy , S . M . (1993) Ef fect of com bined supplem entatio n w ith a-toc op he ro l, asco rb ate, an d b eta caro ten e o n low -d ens it y l ip op ro te in o xi dat io n. C irc ul at io n 8 8: 2 78 0- 27 86 .K im , I., W i lliam son, D . F., B y ers, T . & K oplan, J. P . (1993) V itam inand m ineral supplem ent use and m ortality in a US cohort. A m

J. Pu bli c H eal th 8 3: 5 46 -5 50 .O lson, J. A . (1987) R ecomm ended dietary intak es (R DI) o f v itam inA in hum ans. A m . ]. C lin. N utr. 45: 704-716.R an, J. Y ., Dou, P., W ang, L . Y ., Q in, Y ., f in, S . Y ., L i, X . F., Y uanR . X . , Hao, J. M ., Z hang, H. & L i, P. (1993) Correlation of lows erum f ol at e an d t otal B 1 2w i th h ig h in cid en ce o f e so ph ag eal c arcn oma (EC ) i n S h an x i, Chi na. I n a h ig h- fre qu en cy e so ph ag eal c arcn oma (EC ) are a, f olate an d B ,2 d ef ic ie nt s ub je ct s w i th e so ph ag ead ysp lasia (E D) i m pro ve w ith ad ded f olate an d B ,.. B lo od 82 (su pp1) :532a (abs .) .S im opoulos, A ., H erbert, V . & Jacobson, B . (1993) G enetic N utrition: D esigning A D iet B ased on Y o ur Fam ily M edical H istoryM acm illan, N ew Y o rk , N Y . R eprinted D ecem ber 1995 as a paperback entitled T he H ealing D iet.S ubcom mittee on the 10th Edition of the RDA s (1989) R ecom

m ended D ietary A llow ances, 10th ed. N ational A c adem y PressW a sh ing to n, DC.S teinberg, D . (1993) A ntiox idant v itam ins and coronary heart dise ase . N . E ng l. J. M e d. 1 99 3 3 28 : 1 48 7-1 48 9.T he A lpha-T ocopherol, B eta C arotene C ancer Prev ention S tudGroup (1994) T he ef fect of v itam in E and beta carotene on thincidence of lung cancer and other cancers in m ale sm ok ers. NE ng l. I. M e d. 3 30 : 1 02 9- 10 35 .W y nd er, E . L ., Hu ltb erg , S ., J ac ob so n, F.&B ro ss , I . J. ( 19 57 ) E nv iro nm ental f actors in cancer of the upper alim entary tract; S w edishs tu dy w i th s pe ci al re fe re nc e t o Plummer-V in so n (Pat ers on -Ke lly )s yn drome. Can ce r 1 0: 4 70 -4 87 .

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Symposium: Prooxidant Effects of Antioxidant Vitamins