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0 Carbon Nionoaide' as a Contributor to the Heaitb Hazards of C'icarette Smoking _ POUL A'STRUP _ Department of'Clinical Chemistry CL Rigshospitalet DK-2100 Copenhagen. Denmark There is clear evidence that moderately elevated carboxyhemoglobin, (CGHb) levels are associated with various chan_es of the cardiovascular systzm: Those changes occur at COHIb levels of 5-20%, which are not uncommon in, inhaling smokers. A very significant chan.e is the increased vascular permeability. Carbon monoxide (CO) exposure (20-25% COHbI of men for 3 hours leads to a50(k' increase in disappearance rate from the blood of injected serum ""I-labeied albumin, (Parving 1972) and to an i increase in, capillary filtration rate measured plethysmo¢rsphically on the calf (Siicgaard~Andersen et al. 1967). Increased pcrmeabiiity where the lymph flow and the protein flux in the thoracic duct increased considerably during exposure to CO was also demon- strateti' in 11 do-s. It was of interest that the increase in protein tlux wa,s moree pronounced for the high-molt:culnr-weighr proteins than for the luw- molecufar weight proteins (Parving et al. 1972). CO1 exposure also leads to hypierlipemia as shown first by Astrup et al: ('I!967) and Kjeldsen (l'969). This was demonstrated in r.ibbits fed usual fodder with or without the addition of cholesterol snd, exposed to COHb level., betl+reen, 15' and, 25%. We have seen this effect of CO in al our experiments. 'I7fe CO-induced elevatinn of serum cholesterol has usually led to IS-2017'c higher lexels for the first 2-31 weeks in comparison to the groups not expo.rd to CO; after this period, the serum cholesterol levels were approximately the same in both groups. Many investigators have found somewhat hi~her serurn cholesterol levels ini smokers in comparison to nonsmokers (Schievelbein I!968), usually about 10-1IS'me%„which maybt:explainedlbyrai,ed COHb l'evels. AT}1EAtOGEM1C AND ARTERIAL WALL-INJURING EFFECTS OF CO The above mentioned effects of' CO on vascular permeability and cun serum cholesterol are clhtrly atherogenic and are related to our earty findings (see. for

I 0 . l 76/ P. Astnup example, Astrup et al. 1967)demonstrating that the moderately elevated COHb levels for 8-1'0 weeks were associated with an incrcased accumultition of' cholesterol in the arterial walls of cholesterol-fed rabbits. Since the aortic cholesterol accumulation was about 150% greater in the exposed animals in eomparison to the nonexposed~ we neglectatd' a possible effect of the slight hypercholesterolpmia during the first weeks of the exposure period. We were therefore surprised to learn when we repeated our experiments a couple of years ago (Stettder et al. 1977). this time keeping serum cholesterol concentrations on the same level in the two groups of'anirnals by individual cholesterol feedin:, that no enhancement of the cholest~-.ol accumulatiom in the arterial •wcills occurred under these circumstances. Furthermore. the cholesterol uptake rate in the arterial' intima of' CO-exposed' animals, measured by using a sophisticated double isotope technique, was not increased, either, except. in the aottic arch where a slight increase was dernonstrated. Perhaps the more important coronary arteries were not investigated here. Hoa'ever, others nSarma et al. 1I975) have found that human, coronary arteries petfused' with blood huvin_ W'c COHb increased their cholesterol uptake in compsrison, to coronary arteries perfused with normial blood: The lipids sy,nthesis inithie arterial wall did not change. Because the hypercholesterolemic effect of CO exposure is observed only in the frst' weeks of' exposure: the enhant:ement' of' arterial' accumulation of cholesterol has beenidifficult to observe in long-lastine experiments of 40-60 weeks or rnore, with serum cholesterol' levels hi;hly increased in both the exposed!and the nonexposed groups of animals (Armita_e et al. 1'976).. The pathologists in our group observed mit;roscmpically morphologicali changes in the arterial intima of noncholesterol-fed'rabbits exposed to f80'_200' ppm CO ('1-t-16no COHb) for a few weeks (Kjeldsen et, al'. 1'972). These injuries were characterized first of all by an increased subendothelial edema and& esti_ators. also by other lesions indistinguishable from what experienced' ins have described as early atherosclet rotiie intimal changes. A couple of years agoo we tried to repeat our findings of intirnal damage caused' by CO exposure. (Hugod et al. 1978). c. blind technique was applied, and the pathologists were unable to document injuring effects of CO on the intima of arteries. The experiments were repeated using CO cpncentrations of 200-4000 ppm, with the same lack of'c-•idence of a direct histotoxic effect of CO on the intima or subintima of coronary arteries and aortas. Therefore, our conclusions today are that moderate CO1 exposure does not lead to morphological chunges of the vascular wall. The atherogenic effects of experimental CO exposure must therefore be related' primarily to tiy,percholesterobcmic effects and not to arterial w.allg injuring effects. Tlie role of increased vascular permeability in certain vascular regions is unclear. The well-documentedihigher prevalence of'ztherosclerosis in smokers in comparison to nonsmokers is clearly correlated to their COHb levels„since it can be calculated thatsmokers with COHb levels o~f S% or more have a 21 tirncs higher prevalencc of atheroscierosis than smokers with a 1o0sas~099 ~>

0 4 taust' be explained primarily by the effect of CO on the lipid metaboli'sm: secondarily by a possible increase in endothelial petmeability in ccrrtain regions. and further by myocardial effects of CO. _: -_. . ' CO EXPOSURE AND tWYOCARDIAL EFFECTS ~ It has been reported by v_;uious: authors that prolonged miidi CO exposure inn experimental animaS leads to dt__enerstive myocardial chances (Campbell 1929-1'930; Christ 1'9:z5: Ehrich et al'. 1'9-1-t.: Lewey and' Drabkin 1944). The.e anatomical, changes clo:zl?v resembled those produced by hypoiiaand consisted of'edema. degeneration of the muscle fibers. multiple small perivascular ne- croses. and: hemorrhages. Microscopic scarification of the heart muscle was also reported. . Wltrastructural studies by the pathologists in our team (Thomsen. 1'974; Thomsen and Kjeldsen! 197-1), have demonstrated local areas off partial cnr, total necrosis of' myofibrils and de_enerati.ve changes ot' mitochondria in the myoeardiis of rabbits and Mtacaca iris monkeys exposedl to about 200 ppm CO for not more than 2 weeks. Those studies. however. were not pertormzd' by using a blind technique. and we are at present n:ptatinethe experiments. The results are now under e+alu•rtion. The reported effect of CO on, myocardial tissue is, similar to the effects caused' by hypoxia: therefore. the CO effects are probably explained by an impairment of the oxygen transport and oxygcn unloading functions. not only of hemo-lbbim (Hb) but also of myo=lobin tMbo. which has a still hieher affinity for CO than Hib. This impairment leads to decreased venous and tissue oxygen tensions in eontrast, to the quite normal oxygen tensions observed in moderate hypoxia. where compensating cardlorespinitory adjustment exists. To counteract de- creased myocardiaF ox;•_cn, tensions of elevated COiHb levels. a•:onsidzr.cble increase in coronary blood flow occurs: in man there is about a.25c increase at 9-10%COHb (Ayres et al. 1970) with oxygen tensions in the.coronary sinus about ?1~7c below normal. This is in accordance with the oliservation! of'a greater myocardial stress in individuals havine COHb levels of 5-9( in comparison: to non•CO'expos.:d individuals at compar.ible work lnvd. ('Knclson 1972). One-fourth ot the ex- posed individuals aged 411-60 years developcd abnormal elcctrocardiograrn,, with arrhythmia in some. Similarly, angina pectoris and intermittent clLud!icatim develop carfier att comparable workloads in patient+ with very moderatcly increased CO'Hb: levels (2%) than without CO (Aronow and I,bell 1'973'; Aronow et aJ. 1974). CO EXPOSURE AND FETAL DE1lELOPMENT' Fetal developtncnt in rabbits is grestly influcnced by 9-1dD~'r and 16'-1I3% .... . .. . . 1.1005053100

The tindinss ane a reduction in birth wei_ht and a hi;hly increased neonatali mortality. The same effects are found by exposure of pregnant 'rabbits to hypoxia ('l0`7c oxygen) (Astrup et al. 1975). Also. exposure to nicotine in11uL ences the fetal development in a similtu way probably caused by a neduced' oxygen supply due to vessei,contractions in the fiettus. CON6LUSIONS' The conclusions of studies reported in the literature and of our own studies of about 10 years on the physiological a:..l pathological effects of moderately elevated CO'Hb levels in man and animals are that they lead to: 1. increased vascular permeability; 2. ittcreased' serum cholesterol levels with subsequent enhancement of arterial cholesterol accumulation: 3. decreased work-load threshold for developing claudicatio. angina pectoris, etc: 4. changes in myocardial function and probably also in myocardial structure in CO-exposed men and animals; 5. effects on fetal development andneonatal motrtality. Therefore, a reduction in CIQ levels in tobacco smoke would undoubtedly lead to a~less hazardous cigarette. REFERENCES ArmitagF. A.K.. R:F. Davies, and D:W4. Turner. 1976. Threffects of carbon monoxide on the develbprnent of atherosclerosis in the white carneau pigeon. Arlrerosclcrosvs 23:333, Aronow, W.S. and M.W. Isbell. 1973. Carbon monoxide effect on exerciee•induced angina pectoris. Ann. Intrrn. ;Nrd: 79:392. ~ Aronow. W:S.. E.A. Sto-mmer: and M.W. Isbell. 1974. Effect of carbon monoxide exposure on intermittent claudi.:ation: Cerculutii,n 49:445: Astrup; P.,,K: Kjeldsen. and J. Wanstrup. 1'967. Enhancing influence of carbon monoxide on thedevelopment of atherornxtosis in cholesterol-ted rabbits. J. Atlirrosclar. Res. 7:343'. Astrup. P:, K. Kjcldsan. H:M. Olsen. and! D. Trolle. 1972. Effect of moderate carbon tnonoxide exposure on fetal development. L"nvcu I1:1?''0. Aserup, P.. D: Trolle, H1 M. Olsen. and K. Kjeldi;en. 1975L Etlfect of modcrate hypoxia expsoure on fetal dtvclopmcnt, Arch. Etmiron. HK•ulr/r 30: t5~ Ayres. S,M.. S. Gi:utelli~ and H. Mueller. 1'970: Myocardial and systemic responses to carboxyhemoglobin. Ann. Ns Y. Auud: 5ri: 174:268. Campbell. R'.F. 1929-30: Tis+ue oxygen tension and carbon monoxide poisoning. J. Pli~sitrl. ti8af.. Christ. C. 1935. Expezimcntelle Kuhlenoxydvergiftung. Hbrzmu+kclnekroaen und Elr:lc- troiwrdiogramm: Qritr: PurNul. rtrau. .tll,t:: Puthul: 9+3:I1!I. El+rich; W: E.. S. B;ctlct. and F. H: Lewey. P9". C:udicu changes t'rom CO puiwning. 10050101 ~~3

Carbon Mbno:idr 179 Hugod. C.. L.H. Hawkins. K. Kjcidi;en, H.K. Thomren: and P. Astrup. 197R. Effectof carbon monozidecxr-.1sure on aortic and coronary intimal morphology in the rzbbit. arhrrusclrrrnis 33:3. Kjeldsen. K. 1969'. "Smoking and. A'therosclerosis,° p. 143. Thesis. Uni.•ersity of' Copenhaeen. Munksgaard. Copenhagen. K/`Idsea. K.. P. A:ytrup: and J. Wan,uup. 1972. Uitraattvctural intimal changes in the rabbit aorta after a mWcrate carbon monoxide e.-posurt:.Adrrr,+xclcrrsis. 1i6:67: Knelsqn, J.H. 1972. UUnited States air quality criteria and ambienrst:rndards for carbon monoxide. l'Dl B~rrirhte. Nr. 180:99. Lewey. F.H. and D:L'. Dr.rbkin, 1944. Experimentalichronictarbonmonoxide poisoning of'db__s. .-Iwtrr.,J. Mrd: St•i: 2b8t50.. Parn•ing; H.-H. 1972. The effect of hypoxia andicarbon nonoRide on pla.ma volume and eapillary, permeability to albumin. Saand. J. Clin. Lab. lmrest. 30:49. Parving. H.-H!. K. Ghlsson. H.J: Buchvrdt-Hansen. and I4ti Rorth. 1'97'_. Effect of carbon monoxide exposure on capillar-v permeability to albumin and a;-macrogiob- ulin. Scand. J: Cliir: Lsrh. lvmcsr. 29:3S I. Sarma. J S':.M.. H. Tillmanns. S. Ideka. and R.J. Bing. 1975. The ef•fect of carbon monoxide on lipid metabolismot humancoronaty arteries. ArJtnrrrxclernsis 221:d93L Schievelbein. HL. ed: 1966. NNikorin. Phurmak-alogrt and' To:ciltologir des Tabuk- sraarhrs: Georg Thieme Verlag. Stuttgart. Sig;aard-AndersenJ:. K. Kjzldscm F. Bonde Petersen. and P. Astrup. 1967. A possible connectibn between carbon monoxide exposure. capiltary tiltration irate. aad athero• - sclerosis..tcta Mcd: Sourid: !ti_:397. Stender. S:. P: A'strup: and' K. Kjeldsen. 1977. The effect of carbon monoxide on eholesterol in the aortic wall of'rabbits. Adrrrusrl'rrosis 28.3'57'. Thomsem H.K. 1974. Carbon mconoxidt-induced aeheroscletosis in primates. An electron microscopic study on the coronary arteries of' macaca itis.monkes s. arlterusvlrrosis aD:_°33. Thomsen. H.K. and K. Kjcldsen. 1974. Threshold limit for carbon monoxude-induced! myocardial damaee..arrh. Envirnn. H~eultJi. 29:73. Wald. N.. S. Howard. P.G. Smith. and K. Kjeldsen. 1973. Association between atherosclerotic dise:,se-. and carboxyhaemoelbbin levels in tobacco smokers. Br: Mrd. J. 1:761. COMMENTS SiCHwAttTZ Dr. AstruF. I was very impressed with your lovely set of data. I would like to ask you a question about the pregnunv rabbits: Were they exposed during the e:uly part of the pregnancy? ASTRIUP: Diuring~the whole pregnancy: SCMWARTZ: Were there any fetal anomalies, were there any congenital anomalies? ASTttUP: There wetie about four or Piwe congenital anomalies.. SCHWAttTL•' It's particularly interesting becaune there have been an increasing number of reports suggesting that smokinu durinr nrr+onancv maw result 10050531102 S