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Management Information Library Clipping R.J- Reynolds Induslrlet, Inc. Hladquadera Bldg., Room B4102 E,t. 2855 Publication: WINSTON-SALEM SENTINEL Date: 3/13/81 5 Page: W.R.Bauer RoBennett P. J. Bott M,H,Cr~an . R.G. Dyer R. A. Eaten D.B.Fishe] N.S.Gaines G.A,Hoots D.K, Isbister J.C.Kennedy G.H.Long W,JoLovett J.BoMartin H.R,Martin E.F.McCarthy "[oSacco institute Nornes • New preslclen Ctlairman WESTMORELAND The Tobacco Institute. the IobbyinB and trade ass~iation of the tobacco industry, ha~ a new president. SamUel D, Chflcote Horace R. Kornegay, a ~ormer Norlh Carol~nu congreS~ma~ wh~ has bee~ the ~nstitute's president since 1969, ha~ mo~ed up to chairman ot the association. Chilcote. 4~. has been pres,- dent o[ the Distilled Splints Council of the United States. an ass~iation ~ich repre- al~ is bas~ in Washington. Among his responsibilities with the Tobacco Institute be the coordination of its public communications ellorts, in late 1979. those lofts included a magazine campaign which urged smokers and non-smokers to respect each other's rights rather than to be subjected to government regulations smoking in public, and {otlow" u~ campaigns are anticipated. Kornegay, 57, is a graduate ol Wake Forest University and its la~ sch~l. He se~ed in the U.S. House ol from 1961 until 1969. hsheville ~ative. he li~d Greens~ro ~f~re moving c0 Institute . r.',c G r~ th . P, cLa whorn J.R.M5 lla~ . Moz-s e ,Myers R,G,Page . Roomer A.J. Scb~nd2 er . Sidman , Tucker . Upchurch G. Vimon& J.W.West R. K. k~nit ing J.T,Wilson . Yena C. Huuhes TI04231"

Manufacturers secretive on additives - l~'t]~r~ =TO can~.r-c~usln~ ~ddl- they ~ o~ ~c~ ~e d~ ~ ~d like Io ~ee an ~I~ ot " ~[en[ whl~ ~ibi~ ~eJrin~ ot .~v~ ~ yo~ dta~t~ It'~ a tr~ that ~/ormatlom "It'~ prlvat~" wMt ~aDy ~ I~ For ~me~y parildm from ~e lua~ a~olel~ ~r~ ~'~n the [~er~ go~ Ci~ar~ ~an~a~e~ da vo1~ to ~y we don't put mu~ ~ bow an ~l~g irri~n~ and o~er ~ d~ ~ the ~ t~ ~rily k~p ~e ~dian gove~ mu~ bmuch~" dehyd~t~ung ird~n~}. Amon~lhe --~ed~youmay~get- meat in/orm~ ~ Mdi~vm a~ Ko~awski ~id ~ Can~a "It ~ manyo~erco~itlt~areaxid~ lint, nor ~ right ~ ~ow w~r ~o~ ~ legi~on r~m ~ ve~ ]lkel~' ~t t~ addiUves are ot nitrogen, which have ~n impli- ~diUv~are~vol~ ~do~id. ~e~t~iagbrands~ cat~ in ~e development at ~ intorma~ cigaret~ ~n~ . Mc~naJd ~id ~ ~ddiflve sit~ ~ Rothma~ Crav~ A ~ ~ phy~m~, but ihe level ot ~ f~ct~er~ do dirge ~ [Jr lad fion ~ ~i//e~al from ~t ~ ~ A.'~al ~z ~ ~ ~dltioa a~ • ~nsdlanclg~rel~i~no/~o~ nl~Uneyieldk ~lnt~ on ~cka[~ U~ "~'~ On~laa ciga~t~ ~ ~Jll likely ~ ~ ~ c~. But for Rlcke~ said ~r~n monoxide ~verage ~oker may.get' if, ~d ~i~ Ogar~ b ~aigh[~ ~tr= l[gh~ =~ ~ o~ I =m ]~ opt~ yhemoglob~. ~ $moke~ ~ l~eb" ~lt,~ or~e~ok~ e~y~ , Virgln~ ~ ~ ~ m~ ml~c ~ ~ d~ have ~db of ~r~hemoglobin range ~ro~" way b~ra~ ~okln~hln~ w~ ~. flu~.=aa flv~~ " "" " ~ a~ut3~r~tto~r~'~ do. =l~ * -. .t " . ~. ~d ~to~ vho works/ ~t~t o[ ~=t b sim~ar ~ l~n~ T~do~for~yS~r .,., ~~. 3. "- ~ ~ tob~=iffi r~ =~ [rom3tol2~r~ntolyo~ and re~rt~ In tod=y'l Price meal area for ~ heal~prot~iion} ~pply, or =~ut one pin~ tot ~e~ Watch i0dicHe ~e num~ ~ai- . ~O~blend~ciE~ar~ bra~ ~id It ~ dirtiest tar ~i =ver~ge~r~'~id.. ~ on ciEarelte ~ag~ ~y ~g- m~e or aromaUc toba~ whl~ g~'e~m~t to ~ine lt~g-] n~canUy ~der~mate ~e~t~ =~ mu~ ~onger ~ ~vor ~ ~ bw ~ and ni~t~e c[g=rett=I " " ~X ~ - ~. ~ ~ient~ and m~/o] ~ ~d Peter W. ~n~ ~ red.on ~ ~dffiv~ ~n do regal ~ cigarette is ~ ve~ ~mptex e~ co~t~ by ~ S~r, ~ ~e ~or of ~r=te ~talrs br~c,K~t~ ~ pr~uct, but ~ically it b a ~r ~d nicot~e num~ on ci~ for Ro~ ~ P~ ~ ~a Uae deli~w~em,'" ~cke~ ~id. by ~n~mers ~ ~ measure o[ ~a~ ~ ~fly ~ a "~'e ~ve not done ~e rind "o~ ~e~ to lower tar and ~icot~ potentJaJd~ r~. ~num~s new~paper ~ promotln¢ it= hippy work ~st would ~ r~ toba~ and =lot or ~e work can ~ re~ard~ on~ M a me~ of ~=v~ A ~= ~Eht d~a~¢~ ~ quJ~ to ~e( ~me i~lcation of ~ Jn¢ to It h~ ~n.done at ~ ranking c=ga~t~ [romlowtohi~ ~io¢ ~g~r ~ ~ ~ ~ot ot ~ ~ ~ ~ }~¢ht clK~ r~ar~ ceotre ~ ~u~w~ Urand~ey~eid.. =]] ~=~t~" The =d, which ~t~=n~more~i~c=gy,~e~. ~tario. . Can=do b ~oudN ~ ~, ~ ~ to nat~ ~vor ~" =idln l ~honeint~i~. co, ~re are eIr~tive way~ or ci~=rette man~act~e~ =~ ad~ ~chm~ new ~=v~ A Ullra .. Nor b ~ ~ve~ment planning r~ucing ~e leveb even mant ~at ~ ~tenUa]~r~e ~ht offe~you ~v~ tar ~ ~ do iL ~ ~ld. =We don't really RJckert =ld.~i= is done no~Jn~ li~e the d~uat[o~ ~ ~ O~ ~alt~" . .. J :" ~ow ~ a ~=r ~ and ~ any ~ by a]r dgutio~ =in¢ ve~ yew Unh~ 5Qt= where ~e ~eom ~=k~w~w=~cigp dgail w~¢ additlv~ ~e ~" It ~ro~l~2rettepa~rand ~ecoP [ General repor~ ~ many ~ ~ ret~ to ~ve ~a ~v~ ~ne would involve ~ "enormou= tributJonof~etflter." addldv~ ~e ~in~ ~ ~ incl.. ~id It w= not ~ ~itlve but "= amount ot work" to =~l~ cig~ X~ut 92 ~r ~nt of =11 ciga- in~ ~ell~ and =nfi-tr~ ~m~ ~e~t blend . . . ~ Virginia " ~tt~ ~out ~n{ wh=t to rett~=old la Canada ~ay are GI* l ~w~ t~r ; ' " Uvm ~ ~r~ ~ ~id It b "a' ~ ~o~em ~ ~t Canna hM "~ [i]~r ~i~ in r~ucing ~r ~ ~ ~ ~" " hi~y ¢om~fitlve ~ ~d I don~ ~o legi~tJo~ ~ ~a r~ting and nicotine ~1~ to ~ smoker, It . ~ [~t: U.~: .~rg~n~eral ~=~ an~, man~ wo~ ~ ~ man~ ~ dgarel~ or ~s ~Iriuagy no ett~ oa ~e ~ud~ tuc~mono ~wa~ ~t ~ou~y,w~heb~ng,* ~pr~ • '.. in cilaret~ ~ek~" R~ke~ ~i~ ~wer ~r and ~c~Ine ~a~t~Dr, ~d ~ay or'the ~I~ ~i]er~rcber~ow~it.l ~£ac~not~mmerci=~ly may ~,= grea~r heal~ risk thou i pr~lon ~n~ ~ Heal~ ~d lie ~ clga~ addi~v~ ~ ~ =v=i~ble/liter which can ~ m=nu. ~ron~eraran~~tenl We~are Cla~= ~ ~ ¢~e~ do~ow~td~l=~whati~[ t~tur~ into clg=~t~ which wig ¢on~m larger quaatitim ot ~n~ ~ m~t ~ =~me ~o~=~on from ~ dE.retie ~oke. ~. W~ Rick- [ til~r out carla ~oaoxide. he ~id._ ca~ingadditiv~ i ~me m~n~e~ ~ ~ ~t ~ o( ~t ~ ~ ~l~hener -- J ~vloral =iudim ~dlcate ~at . ~ ~d~ ~aba~ ~anut~ ~ ~dl~lv~ ~ arcing. ~e i~o~ =n' inherit ~rato~ that ~p~e who ~itch to low ~r and ~u(mg co~c~¢ m mo~tro~ uys m= I matron w~ r~u~ ~= coup,e or ~ og=ret~ smoke t~ ~ t~er- n~otlne ~garett= ~nge their is ~t not.~ ¢a~}n ~a~da. "~ ~Tear~ aEo". =~d ~an~= al g~e~ment -- uy= ~ =re smoking hib ~ to com~ ~he ~=n~act~e or c~aret~ In {~e~n,~=~ =~n l~a u~ =bout 4,000 c~po~s ~ the the lower yie~ ~ey smoke more canada, ~re are ve~lew, u any, ~g=te,~a. ' ~ ~oke prMu~ by the =vet=go ~nte~ivelv, inhaling d~r. ~king aOditiv~ ~," ex~utive d~or ~ ~, L~ Kol~L = ~archer ( cigarette, of whi~ ~ alone corn more p~[~ smoking ta shorter butt .Norm M~na~d told The ~ar in a ~ t~ Addition ~ar~ Foun- ~ rains =bout 40 c=~r~i~i lengt~ a~ ncre~ing ~e humor telephone interview. "I don't ~ant dation. ~d he ha= en~unter~ ~e ~ agen~ • ot cigarett~ok~ in a day. ynu to a~ume the~ are ~lutely ~me "s~rd r~ly" ttom man~ ~ The~ =re t~o pha~ ot c~garette none...out~ad~tw~are t~turers w~n qu~io~ =~ut ~oke--pa~l~atepha~andg~ ~ . ~c~na~ ~at~f~diti'~a "~.. ~,n ;¢lr~ ar~ pa-t;':=~ates carbon " ~id man~a~urersdonotle~e~th ~a. =It may ~ t~e. but ~ ~rnonox~de L~ z £as. A~se in ~ ga~ ~~~ other w~at ~ey are ~ng ~or do w~d like ~ ~ ~ ~zdeo~ [ {pha~ a~ Eydrogen ~3'ani~ ~ ~~,~~ w ~ ~ ~ ~ ~ ~ ~, , ....7 ~. ~ Jo] ~J~d ":au:nq ~oeq ~3 uo ~d pJ~4o.~ .~n o) ~u!~eJj~=a s.U., '" .... :" q t, ....... 9 9 lu [1V T104231103

Adve~is~ng Age, March 30, 1981 I=hampagne i c gs cause headache By CAROLYN PFAFF PAves--An exotic experiment n international marketing has )fought together thc state-con- roiled tobacco monopolies of 'ire countries--Japan, France, taly, Portugal and Austria--to aunc h a king-size cigaret called ~hampagne. But the project mw looks like an embarrass- nent to the French government .hat will end up in the interna- .ional law courts. In mid-March, all five coun- :ries except France separately aunched the Champagne cig- ~ret, in the same red and white packet. Addressing a news con- ference here, officials described 3hampagne as a "prestige" cig- ~ret, designed to compete with leading U,S. and British brands m Western Europe and Japan-- ~ market whose annual sales volume is estimated at $11 bil- lion. The venture called for each monopoly to manufacture the brand simultaneously and mar- ket it under the common name. But only France, originator of the whole ambitious scheme, knows about the potential blow-up. • The thorny problem is that SEITA, the French tobacco group, never bothered to check the use of the name with the country's champagne pro- ducers. Legally, they were able to register the name because it is protected only in the cate- gory of wines and beverages; "champagne" had never before been listed for cigarets. The champagne producers are in a state of fury. To add in- sult to injury, it turns out that SEITA also listed the name "co- gnac" for another future cig- aret. Said Joseph Dargent, press attache for the Committee (Continued on Page 80) Champagne woes (Continued from Page 2) terprofessional du Vin de Cham- pagne (CIVC): "We intend to go to the President of France, failing this, to the international courts. To put the name champagne on cig- arets is deplorable, and the con- nection with health hazards may permanently damage our image. Champagne and cognac are part of the great heritage of France. The President himself must protect US." However, President Oiscard d'Estaing, who is currently run- ning for reelcction, has shown no haste to involve himself in the problem. And curiously, the cig- aret is not on sale yet in France, even though a joint international press conference on the launch was held here March 6. The champagne growers' protest is currcntly blocked in the Minis- try of Agriculture. Moreover, the press has not yet had wind of the story because the champagne pro- ducers are courteously waiting for the Ministry to help them. • But one thing seems sure: The case is likely to cause the French government the kind of headache that traditionally results from overindulgence in champagne. On the one hand, it must answer to an international group of govern- ment-owned tobacco companies which see the Champagne intro- duction as a constructive and dar- ing innovation after years of diminishing returns. In Europe, the traditional state monopolies have been under- mined by Common Market regula- tions opening the doors to interna- tional brands. Thus, while Japan and Portugal still operate almost total monopolies, the other state companies are down to hn 80% market share. All make only small profits or none at all, even though their turnovers are impressive. Japan's JTS sells 10.9 billion cig- arets, Italy's Monital sells 70 bil- lion, Austria's ATW, 16 billion, and Portugal'sTabaqueira, 12.3 billion. France's SEITA sells 85.6 billion, but still managed to lose.FF236,135 ($47,440) last year. One industry analyst points out that govern- ments are getting impatient with the losses and that the Champagne venture is the first sign of a real will to change. • The other participating national tobacco companies, including Japan's powerful Tobacco & Salt Public Corp., presumed that France's SEITA had the right to parcel out the names of France's luxury products to promote cig- arets, or else why "embark on the projcct in the first place? In Austria, where consumers are having trouble pronouncing the new brand name. the Trademark & Design Protection Assn. had no objection to "Champagne" as a name for cigarets--or shoes. The official position at SEITA is "no comment." A spokesman pointed out, however, that the cig- aret had been registered legally and that if it was necessary to de- fend the namc in thc courts, SEITA was prepared to do it. # 18290 TI04231104

%. ooG1 Cigaret tobacco set to roll NEw Yo~K--U.S. Tobacco Co. and Douwe Egberts Co. this spring will begin testing Drum roll-your- own cigaret tobacco in selected LT.S. markets. Though Americans have never favored rolling their own cigarets, recently completed research indi- cates that the rising price of cig- arets and tightening of domestic purse strings have created a mar- ket for the product. Douwe Egberts will distribute Drum through U.S. Tobacco. Currently the Utrect, Holland-based tobacco marketer's Amphora pipe tobacco and other products are distributed through U.S. Tobacco. Drum will be featured in news- paper and regional magazine ads sporting the theme, "Break away from the puck." North Castle Pa~t- hers, Greenwich, Conn., also has created headlines such as "Auto- matic vs. Manual," "Quickie vs. Satisfied," and "Machine vs. Man." Though the price of domestic cigarets in the U.S. has not in- creased to the level of European brands, industry analysts feel that as manufactured cigaret prices crease, the roll-your-own market will grow. R. J. Reynolds Tobacco Co. and Brown & Williamson Tobacco Co. both make cigaret smoking bacco. However, neither has spent heavily to market brands. # T!04-231105

Pulmonary emphysema associated with the FZ a l-antitrypsin phenotype DO,~-xt.D W. C_OCKCRoF'r, MD, t:nCPIc]; ROZANNE K. TENNENT, }3 SC; SANDR.A L. [-[ORNE. PH U In one famdy three brothers were found to have a moderate deficiency of ,,,-antitrypsin associated with the unusual Pi fprotease inhibitor} phenotype FZ. The Pi phenotypes of their six living siblings were found to be FM [in three}. M [in two} and MZ [in one}. The three FZ brothers all had mod- erate to severe obstructive airways disease, and two had at least moderately severe pulmonary emphysema. Addi- tional risk factors included moderate cigarette smoking in two and prolonged exposure to grain dust in all three. The same risk factors applied to the six non.FZ siblings. but they had only mild symptoms and pulmonary dysfunction or no lung problems at all: one, a female smoker with the MZ phenotype, had probable early emphysema demonstrated radiologicaily. The three FZ men may have had reduced fertility, as they produced only 1 child among them, as compared with 39 among the other eight siblings. This faro- ily study thus suggests that individuals with the FZ phone- type are at risk for pulmonary emphysema and chronic obstructive airways disease, particularly in the presence of other risk factors, such as cigarette smoking and grain dust exposure. Au sein d'une famille, trois tr~res ont manffest~ un d~ficit mod~rd en ~-antitrypsine reiid ~ |'inhibiteur de protdase du ph~notype rare FZ. Chez leurs six fr~res et soeurs encore vivants, los uhdnotypes des inhlbffeurs des protdases se sent r~v(}h}s fitre FM (dans trois cas}, M (dans deux cas} et MZ (dans un cas}, Los trois fr&res de phdnotype FZ souf- fraient de troubles ventilatoires obstructifs mod~rds ou v6res, et deux avaient pour le moins un emphys6me pulmo- naire moddr6ment severe. Une exposition prolong6e ~ poussi~re de grain chez los trois sujets et le tabagisme mod~r~ chez deux representatent des facteurs de risque ditionneis. Cos m(~mes facteurs s'appliquaient aussi aux six fr6res et soeurs qui n'~talent pas de ph~notype FZ, mats ceux-ci n'avaient pas de probl~me pulmonaire ou seulement des sympt6mes de troubles ventilatoires bdnins; une fu- meuse de phdnotype MZ montrait :~ la radiographic un d~but probable d'emphys&me. Los trois hommes de phdnotype FZ ~taient possiblement de fertilit6 rdduite, n'ayant eu. & eux trois, qu'un enfant, alors que los 8 autres |r~res et soeurs en ont eu 39. L'~tude de cette famille indique donc que los individus de ph~notype FZ sent exposds & I'emphys6me pulmonaire et aux trnubles venti|atoires obstructifs chro- niques, particuli~rement Iorsqu'il y a prdsence d'autres fac- tears de risque tels que le tabagisme et I'exposition & la poussit~re de grain. In 1963 Laurell and Erik.sson' described the association between pulmonary emphysema and severe deficiency of the ~x,-globulin <x,-antitr.vpsin. In 1965 Fagerhol and From the division of pulmonary medicine, department of medicine. :,rid the ~ecnoo O1 medical gen¢l~cs, department of pedi:~r~c~. Uni~er~,l~ [Io~pil:d. Univcrsffy of Saska(chew;m. Saskatoon Reprint rcque~ to: Dr. Donald W. Cockerels. Divixion of pulmona~ medicine. Umvc~iW Ho~pilal, Sa~kamon. Braend= fractionated this plasma protein into F (fast). M (medium) and S (slow} variants on t!~e baals of their clcctrophorctic mobility on starch gel. and they po~- tu}ated the occurrence of (hr¢e codom[nan~ alleles a~ what has bccom¢ known as the pretense inhibitor (Pii locus. Persons wkh a scvcrc deficiency of ~,-antitrypsin w~r¢ subsequently found to haw very low secure levels o[ anod~er variant, which was designated Z because i[ had very slow ~lcctrophorctic mobility." Since then more ~han 20 additional Pi alleles have been described, including ~h¢ rare Pi null allele, which is responsible for complete deficiency of ~,-antitrypsin. These have been assigned letters of the alphabet based on the electrophoretic mobility of the corresponding ~,-autitrypsin variants on starch gel relative to the mobility of the F, M, S and Z variants2 The gene fre- quencies for these codominant alleles are about 0.94 for M (including recently described subtypesL 0.04 for S, 0.015 for Z and less than 0.0[ for each of the re- maining Pi alleles? The normal serum a,-antitrvpsin [evcl in ~tndividuals with the M phenotype is between 180 and ~80 mg/dl." Depressed levels are found in persons homozygous for the S allele (40% to 50% of normal) and the Z allele (10% to 15% of normal'), and none is detectable in those homozy-ous for the null allele;~ near-normal levels are associated with most of the less common Pi alleles, including F. Severe early-onset emphysema is clearly related to severe deficiency of ~,-antitrypsin in the serum (less than 40% of the normal level), as is seen with phenotypes Z, SZ, Z null and null.' .... How- ever, there is considerable controversy about the risk for emphysema or chronic obstructive airways disease of persons with intermediate levels (40% to 60% of normal) ~ those with phe~otypes MZ, M null, S and We recently assessed a patient with moderate tu severe pulmonary e~physcma and an intermediate serum level of e,-antitrypsin with an FZ phenotype. Since there was little published on the clinical features of this unusual Pi phenotype, and since the patient had a large cooperative family (8 living siblings, plus 40 nieces and nephews), a detailed family study was un- dertaken. Case report A 58-year~ld grain farmer and smoker of half a package of cigarettes per day l~r 42 years (the pro- positus in Table 1) was referred to the respiratory clinic at our hospital for the management of a recurrent spontaneous right pneumothorax. He had a 30-year history of variable dyspnea with wheezing and chest tighmess on exposure to dusts of oats and barley. These symptom~ were prevented if he wore a illaSk, For 7 T104231106

nmnths before referral he had had mild cxertional dyspnea but nu tough, sputum or chest pain, and only rare wheezing. After 4 months the dyspnea had creas,'d, without pain. over a 3-day period. A spon- taneous right pneumothorax was noted: it resolved with chest-tube drainage. One month later a small right pncumothorax ~ccnrred. and it failed to resolve over a 2-momb period of observation. His past medical his- tory and the results of a functional inquiry were non- contributor.,.'. Of his eight siblings who were still alive, many suffered from dyspnea or wheezing. Percussion of the chest elicited generalized hyper- resonance. The hemidiaphragms were inferiorly dis- placed and moved poorly, the breath sounds were slightly reduced in amplitnde and there were no ad vcntitious sounds. A chest roentgenogram revealed established vascular deficiency emph.vsema and a small right apical pneu- mothorax eFig. 1~. Pulmonary function testing showed moderate to severe fixed airflow obstruction (Table IlL Prick skin tests for allergy, were positive with extracts of oats. rye, barley, mixed grass pollen and mixed tree pollen. The hemoglobin level,, leukocyte count and dif- ferential, serum electrolyte levels, results of biochemical analysis of the blood and an electrocardiogram were normal. The serum level of (~,-antitrypsin was moder- ately reduced, at 120 mg/dl, and phenotyping showed the FZ pattern. The diagnoses made were: established moderate to severe pulmonary emphysema related to smoking and possibly to ~t,-antitrypsin deficiency, and mild asthma caused by allergy to grain dust and pollen. The pneumothorax resolved following repeated chest- tube .drainage accompanied by instillation of tetracy- cline into the pleural space on two occasions, Inhalation of salbutamoi and beclomethasone was prescribed for treating the bronchospasm, and smoking was prohi- bited. Family study Methods The patient's parents were first cousins of Austrian origin. His two oldest brothers had died, one many years earlier from trauma and the other recently, from a myocardial infarction at age 60. The 9 living siblings, their spouses and 38 of the 40 offspring of the il siblings were studied and a detailed pedigree was con- structed. A standardized questionnaire on respiratory symp- toms and exposure to cigarette smoke and grain dust was administered to the nine siblings. Each underwent chest roentgenography and standard pulmonary func- tion tests, including measurement of lung volumes and expiratory flow rates with a Godart 9-1 water spiro- meter (Expirograph, model 16000, Bilthoven, the Netherlands) before and after inhalation of a broncho- dilator (salbutamol, 200 /.tg), measurement of func- tional residual capacity with a constant-volume, vari--. able-pressure body plethysmograph (model 2000, Car- did-Pulmonary Instruments, Houston, Texas) and meas- urement of the lungs' diffusing capacity for carbon monoxide by the steady-state technique,r Values were compared with expected normal values for~.lung vol- umes,~ flow rates~ and diffusing capacity,' and were expressed as percentages of those predicted. Airflow obstruction was graded as severe if the forced expired volume in 1 second (FEV,) was less than 50% of that predicted or if the FEV,:[orced vital capacity (FVC) ratio was less than 60% of that predicted, as moderate Table I--Clinical features and laboratory data in the propositus and all 10 siblings Subject's ~t-antitrypsin Pack-years Years of Serum phenoty~e and Age of cigarette grain Features of chest czt-antitrypsin pedigree no. (yr)/sex smoking farming Clinical features - roentgenogram level (mg/dl)" FZ I1-~ 58/M 21 42 Moderate pulmonary emphysema, Vascular deficiency, 120 (propositus) spontaneous pneumothorax, hyperinflation, mild allergic asthma/rhinitis pneumothorax 11-4 60JM 3 32 Moderate pulmonary emphysema Vascular deficiency, 180 hyperinflatlon 11-7 54/M 14 38 Cough with sputum for 2 yr, Normal 130 exertional dyspnea for 1 yr FMI 11-8 52JM /8 0 Cough with sputum for 5 yr, Normal 230 mild dyspnea for 3 yr I1-10 48JM 10 32 Very mild dyspnea for 2 yr Normal 205 I1-11 46/M 0 30 No pulmonary symptoms Normal 190 MI 11-3 62JM 9 35 Grain-dust-induced wheezing Normal 270 11-6 56iF 23 0 Mild dyspnea for 5 yr, Normal 205 nocturnal cough for 3 yr MlZ 11-9 50/F 16 0 Mild dyspnea for 5 yr, Early vascular deliciency 150 nocturnal cough for 3 yr Unknown I1-1 Oead/M "Asthma"; died of myocardial Normal at age 60 infarction at age 60 11-2 Dead/M Died of trauma "Normal: 180 to 280 mffldl. 738 C.MA IOURNAI.;MARCH 15. lt~811VOI.. 124 T!04231107

if thL~e two walue.s wcrc less than 65% and 7.5% re- .pcctively of those predicted, as mild if they were less than 80% and 90% respecti~,cly of those predicted. and as very mild if the nmximum mide×piratory flow rate alone was less than 80% of that predicted. Serum oc,-antitr.vpsin levels and phenotype were de- termined in all the subjects, the former by radial munodiffusion'° with Partigen plates (Behring Diag- nostics, American Hoechst Corporation. Somerville, New Jersey) and the latter by both acid-starch gel elee- Irophoresis~ and isoelectrufocusing on polyacrylamide gel plates as described by Kueppers?'- The t-test'~ and the chi-square test" were used in analysing relationships for statistical significance. R esu Its The family pedigree is shown in Fig. 2, with the II siblings as geqeration 1I. their 40 offspring as gener- Table II--Results of pulmonary function tests in the propositus and his eight living siblings" Subject's Bronchodilator response =wantitrypsin ~o of predicted value phenotype and .°2"oo increase ~o increase pedigree no. TLC VC FRC RV DLo~ FEVt FVC FEV~/FVC MMFR in FEV~ in MMFR Interpretation FZ 11-5 124 106 171 203 89 58 ~05 54 17 0 25 11.4 114 106 154 I74 94 54 8B 60 22 2 0 11-7 103 115 123 12i 108 66 96 69 54 37 52 11-8 111 113 173 149 108 98 105 92 94 5 6 I1-10 98 11Z 103 I0~ 111 97 102 95 68 6 86 II-tl 102 114 104 113 136 102 99 102 114 4 26 M1 11-3 97 111 131 116 103 -" 77 82 95 64 15 0 11-6 115 98 127 150 92 72 89 80 55 8 0 M1Z 11-9 123 118 ~46 13Z 91 101 113 90 46 5 28 Moderate to severe fixed airflow obstruction Moderate to severe fixed airflow obstruction Moderately severe reversible airflow obstruction Normal Very mild reversible airllow obstruction Normal Mild reversible airflow obstruction Mild fixed aiHio~-= obstruction Very mild reversible airflow obstruction 'Abbreviations: TLC = total lung capacity; VC = vital capacity; FRC = functional residual capacity; RV = residual volume; DLco = steady-state diffusing capacity ol the lungs for carbon monoxide; FEVt = forced expired volume in 1 second; FVC = forced vital capacity; MMRF = maximum mid-expiratory flow rate. FIG. l--Vascular deficiency, h_~perinflation and small right apical pneumothorax (arrowhead indicates edge) in propositus, CMA JOURNAL/MARCH 15. 19gilVOL. 124 739 TI0423I 108

alton Ill and their parents as generation I. The ,v,-anti- trypsin phenot.vping revealed that the eight living sib- lings of the propositus included two with the FZ phe- notype, three with the FMI phenotype, two with the MI phenotype and one with lhe MIZ phenotype. [t is therefore probable that the parents were types FMI and MIZ. The 38 studied members of generation lIl had the following phenotypes: 14 M (5 MI and 9 MIM2). 9 MIS. 6 FM (2 FMI and 4 FM2), 6 M? (the variant being unidentified) and 3 MZ (I M1Z and _M~.ZI. The clinical features and puhnonary function of the living members of generation lI are summarized in Tables I and tl respectively. All but one of these sib- lings admitted to some respiratory symptoms, which in some may have been attributable to cigarette smoking or allergy or both. The propositus and one FZ brother had clinical and radiologic evidence of moderate to severe pulmonary emphysema, the MZ sister had radiologic evidence of early pulmonary emphysema and the remainder had mild respiratory symptoms with normal chest roentgenograms. The pulmonary function studies showed moderate to severe airflow obstruction in all three FZ brothers, and mild or very mild obstruc- tion or normal function in two each of the six non-l:'Z siblings. The serum levels of a,-antitrypsin were moderately reduced in two of the three FZ siblings and in the MZ sibling, and were normal in the remaining siblings (Table I). The mean levels for the six ot~-antitrypsin phenotypes in nine siblings and 38 offspring are shown in Table Iii. Compared with the mean level for the M phenotype. 245 "- 59 mg/dl, the mean level was 20% lower. 196 = 59 mg/dl ( P = 0.05). for the FM pheno- type, 31% lower (P < 0.02) for the MS phenotype, 36% lower (P < 0.001) for the MZ phenotype and 42% lower (P < 0.001) for the FZ phenotype. The unidentified variant was associated with normal serum levels of ~x,-antitrypsin. Although all the siblings attempted to have families, there was only I natural offspring among the three FZ brothers, while there were 39 offspring among the eight non-FZ siblings, a highly significant.difference (P < 0.001). in addition, the only reported miscarriages oc- curred among the wives of the FZ men {1I-4 and 11-7), whose wives had the M phenotype. The third FZ brother (11-5) and his wife. of phenotype MS, had no offspring. Discussion We have identified three brothers with the uuusual c¢,-antitr3.,psin phenotype FZ. All three had moderate to severe obstructive airways disease, and two had at least moderately advanced vascular deficiency pul- monary emphysema. Their six living siblings had at worst only mild abnormalities in pulmonary function. and only one Iwith the MZ phenotype) had radiologic evidence of early pulmonary emphysema. The three FZ brothers had an unusually small number of offspring when compared with their eight siblings ~1 v. 39). The nine family members with the FM phenotype had a mean serum ~,-antitr.~.psin level about 20% lower lhan 740 C.MA JOI.'RN,'tL; MARCH 15. 19SI/VOL 124 that of the 16 family members with the M phenotype. Despite early identification of the FZ variant of antitrypsin with starch gel electrophoresis~° and more recently with isoelectric focusing,~ the FZ phenotype is very uncommon. In population surveys reviewed by Cook" up to 1975 and in those published since then only I individual with the FZ phenotype has been iden- tified out of 19 899 persons studied. The F allele was one of the first three Pi alleles identified,~ and estimates of its frequency have varied widely ~ to as high a~ 0.1 !.'~ However, in early studies there was a tendency to overestimate the frequency, as poorly stored M serum can be falsely typed as FM.'~ More recent studies in the Dutch" and in white populations in the United States~ have suggested an F allele frequency of 0.002. The frequency of the Pi Z allele is between 0.01 and 0.02 in populations of western European origin.' Thus. the expected frequency of the FZ phenotype may be Table Ill-Mean serum :=,-antitrypsin levels for the six PI pheno- types in nine siblings and 38 ~ffspring Mean serum level ~ Significance of Pi phenotype standard difference from level (and no. of subjects) deviation (mg/dl) with Pi M phenotype M (16) 245 ~ 59 FM (9) 196 ~ 59 P = 0.05 MS (9) 169 ~ 73 P < 0.02 M? (6) 284 ~ 9! Notsignificanl MZ (4) 156 -,..-" 17 P < ~1 FZ (3) 143 -,- 32 P < 0.001 FIG. 2~Pedigree of family members, showing a~-anti- trypsin phenotypes. Males are indicated hy squat'es, fe- males by circles, abortions by dots. adopted children in brackets and dead individuals by oblique lioe through synlboL Propositus ~II-5~ is indicated by an arrow. TI04231109

calculated from the Hardy-Weinbe~ equilibrium as follows: 2 x F frequency x Z frequency = 2 x 0.002 x 0.015 = O.OQO06 or ! in about 17 000. This is in agreement wixh the results of the population studies that found this phenotype only once in 19 899 individuals, and points out the rarity of this phenotype: it has about one quarter of the frequency of homozy- gosity for the Z allele. Studies of F or FM individuals have shown near- normal Levels of ~,-antitrypsin in the serum.''."..'° Fagcrhol,-'* however, documented that the F allele produced about 43% of the a,-antitrypsin present in two samples of serum from FM individuals and sug- gested that the F allele may contribute less protein than the M allele. He further suggested that hetero- geneity may exist among the genes called F. Interpre- tations of the early findings must be cautious because of the problem of the incorrect identification of M serum as FM." The F allele in our family appeared to produce less protein than the M allele(s), as the serum levels were 20% lower in the FM individuals than in the M individuals. This suggests that the F allele in our family may only have contributed about 40% of the ~x,-antitrypsin present in the serum of FM individuals and that the serum levels in FZ individuals should be lower than those in MZ individuals, as was observed. The mean ,-,,-antitrypsin levels in serum from MS and MZ individuals in our family were reduced, in keeping with the observations of others." We are aware of only two previous reports of the association of the FZ phenotype with disease. Among 196 patients with obstructive airways disease Fagerhol" found an excess of phenotype FZ (detecting it in I patient, as opposed to the expected 0,08). In a similar study of 124 patients with obstructive airways disease Mittman and Lieberman'2 also found an excess of this phenotype (detecting it in ! patient, as opposed to the expected 0.05). No details are given of clinical status or lung function for either FZ patient. The pathogenesis of pulmonary emphysema in gen- eral and of pulmonary emphysema related to a,-anti- trypsin deficiency is incompletely understood. It has been hypothesized that emphysema has a multifactorial basis and results from destruction of lung tissue brought about by the interaction of genetic and environmental factors. Factors with a genetic component may include the activities of proteolytic enzymes (such as elastase and trypsin) that arc released from polymorphonuclear Icukocytes in the lung' and of ~x,-antitrypsin in serum or m secretions; ~x,-antitrypsin is thought to protect the lung by antagonizing these proteolytic enzymes. However. the protective role of m-antitrypsin may be overcome by excessive exposure to environmental sti- muli that might repeatedly result in leukocyte enzyme release. Such stimuli include cigarette smoke,~= grain dust:' and certain gases found in polluted air.~ In sup- port of this hypothesis is the recent demonstration that topical (but not systemic} administration of human ,~,,-andtrypsin prevented the emphysema induced in hamsters by the inhalation of papain, a proteolytie en- zyme with elastase activity.~ As yet unidentified host factors, such as the availability of Ieukocytes and the local availability of c~,-antitrypsin, may also be im- portant. Sex also plays a role, since emphysema de- velops less rapidly in females than in males with ~- antitrypsin deficiency due to homozygosity of the Z allele.~ While the association of severe ~,-antitrypsin defi- ciency (as in persons of Pi type Z) with emphysema is clearly established, the role of intermediate o~,-antitryp- sin deficiency (as in persons of Pi type MZ) remains controversial. Several studies have shown the frequency of the MZ phenotype among patients with emphysema or chronic obstructive airways disease to be greater than (generally around three times) that in control populations.~-'~' On the other hand, some investigators have found no significant differences in puhnonary func- tion in randomly selected (nondiseased or "nonrefer- red") MZ subjects compared with M subjects. Greater sensitivity in the detection of increased risk would b~ obtained by determining the frequency of the MZ phenotype in diseased subiects rather than the prevalence of disease in MZ subjects. To demonstrate increased risk in MZ individuals by the latter type of study a large number of MZ subjects are required. Al- ternatively, concentration on a group of MZ subjects with additional risk factors (,e.g., older male smokers) might improve the chance of demonstrating i~reased risk. The results of both types of studies are consistent with a modest increase in the risk for emphysema in subjects with intermediate et,-antitrypsin levels and with a multifactorial basis for its development. Intermediate deficiency of a,-antitrypsin may pre- dispose to emphysema or obstructive airways disease principally in persons exposed to additional risk factors, such as cigarette smoke or grain dust. The con- tribution of o~,-antitrypsin deficiency to the develop- ment of emphysema should depend on its activity (level) in the serum, and the risk for emphysema may be slightly greater in individuals with the FZ phenotype than in those with the MZ phenotype. Additional risk factors were present in our three FZ brothers: two were moderately heavy cigarette smokers and all three had over 30 years' exposure to grain dust. In addition, tile propositus was moderately atopie and had allergic asthma related to grain dust and pollen exposure. How- ever, the role of asthma in the development of fixed obstructive airways disease or emphysema is not clear. There was a suggestion, from the histories, that other members of this family might also have had atopic allergic pulmonary symptoms, but this possibility wits not explored further. There is some evidence that the Pi phenotype may be associated with fertility, It has been suggested that the MZ female may have increased fertility related to re- duced viscosity of the cervical mucus.' The possibility that our FZ men had reduced fertility is intriguing, but there is no obvious explanation. In summary, we have presented a family in which three brothers had the unusual ~,-antitrypsin phenotype CMA JOURNAL/MARCH 15. 19~tI/VOL 124 7-I! T!04231110

FZ. All three had moderate to severe obstructive air- ways disease, and two had obuious pulmonary emphy- sema. The F allele in this family appears to have pro- duced about 40% tff the ~,-antitrypsin found in FM individuals. A combination of this allele and the Z allele, which is responsible for severe deficiency o[ c<,-antitrypsin, resulted in moderate deficiency of this plasma protein, perhaps slightly worse than in MZ in- dividuals. A multifactorial hypothesis for the develop- ment of obstructive airways disease in these individuals is suggested, the factors including intermediate ~z,-anti- trypsin activity, ctgarette smoking, grain dust exposure and, possibly, atopic allergic asthma. We thank Dr. F.M.W. AI-Katib for reterring the propo- situs and for his help in studying this family, Dr. D.W. C~x for confirming the FZ and FM phenotypes, Mrs. B.A. Berscheitl for technical assistance, and Miss K.A. Storey and Mr. A. Campbell (or help in preparing the manu- script. This study was supported in part by the Medical Re- search Council or' Canada Igrant MA-7051). the Saskat- chewan Anti-Tuberculosis League and the Department of National Health and Welfare (grant 608-1084-40). References I. L.',UltELL C-B, ERIKSSON S: The electrophoretic <st-globulin pattern of serum in t~l-antitrypsin deficiency. So'and .t Clht Lab l~tvest 1963: 15:132-140 2. FAGERI-IOL MK. BRAENO M: Serum prealbumin: p01y- morphism in man. Sc[¢trce 1965; 149:986-987 3. F^GEaHOL MK: Serum Pi types in Norwegians. Actu Patho! Mtcrobiol ScRod 1967; 70:421-428 4. MoRsE JO: Alphat-antilrypsin deficiency. N Engl J Med 1978: 299: 1045-1048. 1099-1105 5. KUEPr'E~,S F. CItrt~STOP~.RSON MJ: Alpha~-antitrypsin: further genetic heterogeneity revealed by isoclectric fo- cusing. Am J Hum Gener 1978; 30:359-365 6. KUEeeEaS F, Brxc~: LF: ~z~oantitrypsin and its deficiency. Am Rev Respir Dis 1974; I I0:176-194 7. B~.TI.~S [')V. Mat-KI.EM PT. CIIRISTIE RV: The normal lung: physiology and methods o'f study. In Respiratory Funcdon in Disease: an Introductiott to the Integrated Study o] the Ltme. 2nd ed. Saunders. Philadelphia, 1971: t0-95 8. GOLDMAN Ill. BECKI.AKE ME: Respiratory function tests: nOrmal values at median altitudes and the prediction of normal resulls. Am Rev Tuberc 1959: 79:457-467 9. Moaats JF. KosKt A. JOIINSON L~: Spirometric standards for healthy nonsmoking adolts. Anl Rev Respir Dis 1971: 103:57.~67 10. ~lraNCtNI G. CAI4B(INaRA AOo HEREM,~NS JF: Immuno- chemical quantitation of anligens by .,,ingle radial im- munodiffu.,,ion, htt ] I//tmut~oche/rff.~try 1965; 2:235-254 II. LIEFIERMAIV J. GAInIII.IS L. GAROtJI"TE B, ~IITTM,~N C: Identification and ch;tracteri.~tics of the common alphal- antitrypsin phenotypes. Chest 1972; 62:557-564 12. Kul~PPr.as F: Determination of ,,~-antitrypsin phenotyi',es hy isoelectric focusing in 151 polyacrylamide gels. J Lab C/in Med 1976: 88:15t-155 13. SrI:EL R(JD. ]'~)~tRIE JIl: l~ru~t'iph'.~ ¢lltd Procedures oJ Stati.~tic~ with Spechd R~./¢'rcnce tt, the Bioloeical Sciences. McGraw, New York. 1960:43 14. Ibid: 41 15. F.x(,vaHot. MK: The serum alpha,-antitrypsin polymorph- ism. in Dr: GRoL'CIIy J, EBLIN(; FJG. Ht'NOERSON IW (edsl: F~urth i~H~'rt~attotml (.'o~l,jr~.x.~" t~] /-J'tlmatl G~'neth'.t. Ex- cerpta Medica. Amsterdam. 1912:277-285 7-11 C.MA J(.)URNAI.:'MARCH 15. 19811VOL. 124 16. Cook PJL: The genetics of at-antitWpsin: a family study in England and Scotland. Aim Hum Goner 1975: 38: 275-287 17. BI.UNDELL G, FRATEK A, COLE ~B, NEVIN NC: Alpha~- antitrypsin phenotypes in Northern Ireland. [bid: 289- 294 18. HOFFMANN JJML. VaN DEN BROEK WGM: Distribution of alpha-l-antilrypsin phenotypes in two Dutch population groups. Hum Genet 1976; 32:43--48 19. GhNZ T. MARTIN J-P. CLEVP.: H: Classification of antitrypsin (Pil phenotypcs by isoelectrie focusing. Distinc- tion of six subtypes of the Pi M phenotype. Hum Genet 1977: 38:325-332 20. FXGERHOt MK: Quantitative studies on the inherited vari- ants of serum ~r~-antitrypsin. ScRod J Clh~ Lab htvest 1969: 23:97-103 21. Idem: Le syst;=me des Pi. sa g~n,:tlque et ses rapports avec les maladies. Poumo~ Coettr 1971; 27:41-51 22. M~TTr,~aN C. LtEBERM~N J: Protease inhibitor phenotypes in patients with chronic hmg disease (abstrL Cli, Res 1972; 20:242 23. AUEanaCH O, HAMMOND EC. GARFINKEL L. BENaNTE C: Relation of smoking age to emphysema. Whole-lung sec- tion study. N En.el J 3,led 1972; 286:853--857 24. DOSMaN JA. COTTON DJ (eds}: Occttptttio/wl Pulmottury Disease: Foctts on Grain Dust and HeMth, Acad Pr. New York, 1980 25. SMrrH TJ, PETERS JM. READING JC, CASTLE CH: Pul- monary impairment from chronic exposure to sulfur di- oxide in a smelter. Am Rev Re.rpir Dis 1977; 116:31-39 26. MX~TOn,~Na PA. S~aRE NN: Effect of human alpha~- antilrypsin on papain-induced emphysema in the hamster. Am Re~" Respir Oh" 1976; 113:607-612 27. MI'I'TMAN C, BARBELA T, LIEBERMAN l: Antitrypsin defi- ciency and abnormal protease inhibitor phenoty,pes. Arch Environ Health 1973: 27:201-206 28. Banr, re'rr TB. GoT'roy, D. JOHNSON AM: Protease inhibi- tots in chronic obstrt~ctive pulmonary disease. Am Rev Resph" Dis 1975:. 111:587-593 29. COOPER DM, HO~-PPNEn V, Cox D, ZAMEL N. BRYAN LEVISON H: Lung function in alphat-antitrypsin hetero- zygotes (Pi type MZ). Am Rev Respir Dis 1974; II0: 708 -715 311. Cox DW, HOF.PPN~a VH, Lr.v~soN H: Protease inhibitors in patients with chronic obstructive pulmonary disease: the alphat-antitrypsin heterozygote controversy. Am Rev Respir D& 1976: 113:601-606 31. SHI(;EOt~;~ JW. Hal.l. WJ, HYDE RW, ScHw,~a'rz RH. Mun- HOLKAR G$0 SPEERS DM. LtN C-C: The prevalence of at-antitrypsln heterozygotes (Pi MZ) in patients with ob- structive pulmonary disease, lbid: 1077-1084 32. WEnB DR, HVDF. RW. SCttWaRTZ RH. Hat.t, WJ. CON- D~Mt J J. TOWNES PL: Serum a~-antitrypsin variants. Pre- valence and clinical spirometry. Am Rev Respir Dis 1973: 108:918-925 33. COL~- RB, NEVtN NC. BLUNDELL G, Mkaak'l'T JD, Mc- DON^LD JR. JOHNSTON WP: Relation of alpha-l-antitryp- sin phenotype to the performance of pulmonary function tests and to the prevalence of respiratory illness in a working population. Thorax 1976; 31:149-157 34. MoRsE JO. Lt:sowt'rz MD, KNUDSON RJ. Bul~aows B: Relation of proteasc inhibitor phenotypes to obstructive lung disea.~s in a community. N E,gl I Med 1977: 296: ! 190--I 194 35. CH^N-YkUNG ~vl, ASHLEY M J, CUREY P, I~,|ALEDY H: Pi phenotypes and the prevalence of chest symptoms :rod lung function abnormalities in workers employed in dusty industries. Am Rev Respir Di.r 1978; 117:239-245 36. Buts'r AS, S~-.x'roN GJ. AZZ.aM A-MH. AD~.HS BE: Pul- monary functton in heterozygotes for alpha~-antitrypsin deficiency: a case--conlrol study. Am Rer Respir Di~ 1979: 12t): 759-766 T104231111