Tobacco Documents Online

_ - ; !EZ~~ __. _ H. SCHIEVELBEIN Ihas been often suggested that heavy smoking is merely a symptom of a particular type of personality or neurosis, anxiety, or psychosocial stress and that it is the linked association that is being measured in the epidemiological studies. Argu- ments of this kind are hard to substantiate and even more difficult to refute. Perhaps it is best to consider whether there is any reasonable mechanism evident whereby cigarette smoking could be casually responsible for the enormous load of excess mortality that is being attributed to it. ~ DEVELOPMENT OF CVD The mechanism by which a coronary artery can become completely closed is quite well understood. In general, the sequence of events is that the vessels become progressively narrowed by the developing arteriosclerosis and then.a - more sudden even( occurs that has the effect of blocking completely the residual lumen. Very often, angina pectoris, due to an oxygen deficiency of the myocar- dium, precedes such an event. The processes that may contribute to the infarction and sudden death include thrombosis, embolism, plaque rupture, and intimal hemorrhages. There is the question as to what extent cigarette smoke may be the direct cause of such an acute event. In the investigations, described as follows, it was presumed that the cause of CVD in general can be attributed to a disturbed fat metabolism. Recent investigations, which apparently show a correlation between CVD and a decreased serum level of high-density lipoproteins (HDL) due to . smoking, seem to substantiate the presumption (21. 23):- Whether cigarette smoke increases the permeability of the arterial endothelium as stated by Doyle (19) in this symposium, whether it influences the thrombus formation by aggregation of the thrombocytes. or whether some other mechanism plays a role are open questions. Tobacco smoke exposure in animals has never produced an arteriosclerotiZ condition similar to the human desease. In spite of this, two components of tobacco smoke assumed to be of major importance have been studied intensively. Below, I will discuss the acute and chronic effects of CO and nicotine on the development of CVD from the beginning to the possible catastrophic event of heart infarction or sudden death. This meeting has brought to light the importance of the necessity to review the available data, inasmuch as very recent Hndings could not be considered by all participants, i.e., the contribution of Astrup and Kjeldsen (8). CHRONIC EFFECTS OF NICOTINE ~ A presupposition for a possible chronic effect of nicotine in humans is a mea- surable concentration in the blood of smokers. This condition has been estab- lished by several authors, as can be seen in Table I. Nicotine has a special affinity forcertain_or_gans, i._e., the brain and the adrenals, as has been seen in animals and, therefore, it can be assumed that this distribution holds true for humans too. ' With regard to this fact, several studies have dealt with the possible effects of nicotine administration on the development of arterial wall injuries in animals, especially in rabbits which are predisposed to develop arteriosclerosis spontane- . ously. The main results are that nicotine, when administered alone, has no injuring effect on the intima. It is remarkable, however, that the daily dose of nicotine used in these animal studies, in general, was several times higher per kilogram body _ i i 1~.~ ~------ ' --- ----- -----------'. - opyrf96r I

WORKSHOP: CARBON MO`OxJUE AND CVD TABLE I BLO00 LEVELS OF NICVTINE IV C(OARET?E SNOKERS Aulhors Nicotine content Ing/mll Remarks MUhod Schievelbein and 25 Whofe venous blood. Gas-liquid Gru_ndke. 1968 - mean of 6 smokers chromalogcrphy Isaac and Rand. 1972 25 Plasma of venous blood. mean of 5 smokers Gas-liquid chromalography Langone. Gjika. and e73 btanimal value in Radioimmunoasiay van Vunakis, 1973 - scraof about 240 smukers Armitage ct a1L. 1974 30-40 Arterial w•hole bloud. hteasuremenr or Hill, 1975 4 smokers 39 Sera. mean of 6 smokers -'C-labeled niculine Radioimmunoassav weight than the daily amount of nicotine absorbed by heavy smokers. This is summarized in Table 2. By assuming that I mg of nicotine is absorbed into humans for every cigarette smoked, up to L?00 cigarettes have to be smoked and inhaled per day by an individual to absorb amounts of nicotine similar to those adminis- tered to the animals in the above-mentioned experiments where no arterial wall- injuring effects of nicotine were observed. When nicotine was administered-to hypercholeslerolemic animals. no, or only very-limited, additive effects of nicotine on the arterial wall injuries Were observed. Therefore, since very large doses of nicotine are unable to produce arteriosclerosis in rabbits, it is very unlikely that nicotine is lhe agent in tobacco smoke responsible for the increased incidence of arteriosclerosis in smokers. This may be valid in spite of the fact that nicotine exerts some influence on carbohvdrate-and fat metabolism. CHRONIC EFFECTS OF CARBON MONOXIDE - Several investigations have studied the possible relation between ambient CO or COHb levels and CVD. Kuller and co-workers (35) found no evidence for a correlation betnceen myocardial infarction or sudden death with ambient CO levels. Postmortem. TABLE 2 AMDIINTS or NICOTIYE USED IN EYPERIME?rAL SrCOIrs P' RA9BIrs' _ Authors Nicotine (per kg'day9 Corresponding no. of - eigatenes - - pcr day - Alherogenic effect Fisher et af.. 1973 0.3 ng 35 - None Schievelbein et al., 1970 2.3 ng - 160 None Grosgogeat rr al-. 1965 10 mg 700 None Scott et aL. 1973 6-18 ng 41A1-1:00 None • Compilation by Astrup (1976). p

H. SCHIEVELBEIN . . ; _ ACUTE EFFECTS OF NICOTINE Nicotine acts by release of catecholamines, as is summarized in Fig. 1. The outstanding effects of these hormones are an augmentation of the contractile force of the myocardium, an increase of heart frequence, and an elevation of blood pressure,-but at the same time a dilation of the coronary arteries. . Under normal conditions coronary flow is greatly enhanced during O. consump- tion, but in the case of coronary arteries changed by sclerosis, coronary blood flow cannot be elevated. In this situation a coronary insufficiency during intake of nicotine may occur and onset of angina pectoris becomes possible. These acute effects of nicotine may also play a part in observations in patients with angina pectoris «'ho showed a decrease in the mean duration of exercise before the onset of pain after smoking cigarettes with different nicotine content (5). In summarizing the evidence presented, we can conclude that nicotine may act as an additional factor in acute cardiac ischemia and its consequences. Ho%eever, more evidence is needed, especially with respect to the action of nicotine in humans. ACUTE EFFECTS OF CARBON MONOXIDE Angina pectoris is aggravated by exposure to CO %.hich results in COlib levels of 3-47e, as has been shown by Aronow (5), and seems to increase the alveolar to arterial difference in states of chronic hypoxemia (13). Patients with CVD obvi- ously cannot supply enough oxygen to the myocardium to prevent angina pectoris in the presence of even low levels of COHb, but this is not valid for healthy- - people. An oxygen deficiency ih patients with CVD is also suegested by studies of niLotine aympcthet¢ nerve gnngba.adrenal medutla, peripheral nerve endings r releose o htart pos chronutrop pas inotrap coronary perfusion mueased cardiac output increased rascutarbed may act; pOS.chronolrop pas inotrap rascutar bed vcsadilaLOn muscle 1 rosocanstncLan ( skin7 systolic blood pressurr elevated rasocansu,ctmn eoronary perfusicn increasrng - cardicc outputmaybe systolic and dmsto:,c diastolic bload - decreased ar un - blood pressure elevated pressure may fcll changed / automaticity ./ increased arrythnias may - appear ___ - 67 Fto. t. Cardiorascular actions of nicotine.

IF04rn-. II. SCIIIISVLLBBIN . normal blood flow by increasing oxygen extraction. This second option would subject tissue to lowered oxygen tensions, which does not seem feasible for the heart. - Another option revealed by chronically exposed monkeys is a decrease in oxy- gen consumption. While possible for the systemic circulation, it is probably not feasible for the myocardium. A funher attempt at adaptation must be seen in the increase in red blood cell volume and red blood cell count. Several authors observed polycythemia, eleva- tion of hematocrit, and in consequence decrease of plasma volume in smokers (2, 37, 44). In contrast to this finding no changes could be observed by us in healthy volunteer smokers. Our results are in agreement with those of Ayres and co- workers (9) who found no difference in the hemoglobin concentration-between smokers and nonsmokers. Maybe this difference in our findings is due to differ- ent ages of examined persons. - An elevation of the concentration of 2,3-diphosphoglycer,Lte (2,3-DPG) seems to be a further compensation mechanism for the influence of CO. This compound facilitates the delivery of oxygen to the tissues and is a specific metabolic product of the glycolytic pathway of the erythrocytes. An elevation of this compound was observed by Astrup (6) in persons at high altitude and by Dinman and co-workers (18) in humans and rats exposed to CO. This compensation mechanism seems to work in smokers too. Table 4 indicates some of the results.of our investigations (41). Healthy male and female volunteers smoked different brands of cigarettes. In aIL smoking periods, the concentration of 2,3-DPG was elevated in smokers in contrast to nonsmokers. For further information formation on adaptive changes see Ayres and co-workers (9). Finally, as the last option, the opening or the development of collateral blood vessels must be discussed. - All of these adaptive responses would probably serve admirably for healthy men. The development of coronary arteriosclerosis, however, might be predicted to render any of these adaptive responses ineffective or even dangerous and expose the myocardium to potentially lethal hypoxia. The results of Aronow and TABLE 4 CONCENrRATION OF 2.3-DIPHOSPHOOLVCERATE IV RED BLOOD CELLS' T) pe of ciga.ete garameter _ E F - B C K:15 K:14 K19 K:9 N:0.8- N:0.7 N:1 _' N:0.4 CO 4.4 C03 i CO-.3.6 . COHb (%) 4.2 ~ 1.47° 5.26 x 1.49 4-47 _ 1.73 5.56 _ 2.11 - 3.72±0.64 273-0.5'_ 2.51-0.56 2,3-DPG (mmoVliter 4.16 i 0 70 4.29 i 0.53 4.14 e 0-73 4.24 x 0.68 erythrocytcs) 3.32 c 0.40 3.87 x 0 49 9 3.94 - 0.4'- 3.69 a 0.34 • Condensate tK) and nlcotine IN): mg cigareHe: CO: volume ~r. . r Upper Gne, smokers; lowerline, nonsmokers..C ± S. opya9hr :k

rnsVCSTtvE MEDICINE 8, D00-1%]0 (1979) Evaluation of the Role of Carbon b"lonoxl-Se an Nicotine in the Pathogenesis of Arteriosclerosis and Cardiovascular Disease' H.SCHIEVELBEIN"- fns(imre of Clinical Chemitln., German Henrt Center, }frmi<h, West GrrnmmThe evidence for the role of smoking, carbon monoxide (CO1, and nicotine in the etiology of cardiovascular diseases ICVDI is evaluated critically. Positive statistical correlations betsceen smoking and CVD obtained in several epidemiological studies demonstrntn the need to investigate possible causative biological mechanisms. Ambient .^oncentrationc of CO influence COHb levels in humans. Correlations aro reported between the COHb lecel and CVD. but we are far from having ciearcut evidence of a public hcalth risk from ambient CO concentrations. Assuming that a major pan in the etiology of CV D is the development of arteriosclerosis. investications in this direction have been performed with CO and nicotine fn animal experiments. Neither substance has any influence, comparable to human ar- teriosclerosis, on the development of CVD. . INTRODUCTION The accompanying papers represent contributions to a conference on the role of carbon monoxide (CO) on the pathogenesis of cardiovascular diseases (CVD). In spite of this major subject, the inclusion of nicotine actions seems to be necessary Wfth regard to the general opinion that nicotine is the most aclive component of cigarette smoke. - The extensive epidemiological studies of smoking in relation to health by Doli and Hill and others, published in the first comprehensive report to the Surgeon - General (Terry Report) in 1964, that followed the growing realization of the as- sociation of cigarette smoking With lung cancer delivered statistically convincing evidence of a similar association with CVD. This association has been confirmed many times and, particularly impressively, in the Framingham Study by Da«ber, Kannel and co-workers in 1955 (17). It should be noted that this correlation is much stronger with cigarette smoking than ailh other forms of tobacco consump-n tion and that it is strongest in the lower aee group, becoming quite minor in degree by the age of 65- Furthermore, cigarette smoking is much more strongly related to the most catastrophic manifestations of ischemic heart disease-sudden death and myocardial infarction-than to the more or less dramatic manifestations including angina pectoris. The problem of the meaning of the association between smoking and CVD is a . - difficult one: Is it a direct causative relationship or merely a linked association:' It _ _ ~ I Presented at a Workshop on Carbon ]tonoxide and Cardiovascular Discase. sponsorcd by the ~ I American Health Foundauon and the Federal Health Office, Federal Republic of Germany, Berlin. October 10-C. 1978- . 'To sshom requests for reprims should be addressed: Institute of Clinical Chemistry, Germany ' HeaY, Center Munich. t-othstrasse 11, D-8000 Munich 2-FGR. West Germany. - 0091-7775179r0083-000t$02 -Q60 . Cop,M1[bi j 19ri by Academs Re.,. I- An rilbn of rtpmluclun in any (orm a.errrd. el- - ~oo.~ - 1 -

WORKSHOP: CARBON MONOXIDE AND CVD Ayres and co-Workers (10) who demonstrated that CO inhalation causes a shift in the lactate/pyruvate ratio tossard lactate, meaning a nearly complete conversion of myocardial metabolism to the glycolytic_pathtvay. Furthermore, hypoxia of the myocardium due to the diminished delivery of - oxygen in the presence of COHb may induce cardiac arrhythmia which may be responsible for sudden-death found more frequently in smokers than in non- smokers. . _ It is well established that COHb as low as 5% can result in a decrease in maximal oxygen uptake during exercise in normal young male subjects. It is an interesting phenomenon that the oxygen uptake is significantly less diminished in smokers (22). This leads to the question whether adaptive changes may occur in response to chronic carboxyhemoglobinemia as it is knoun to occur in subjects living in high altitudes. These studies and others show a large variability of responses of the organism to different concentrations of CO. This variability of reactions-to acute and chronic exposure in studies of men and primates suggest that the mammalian cardiopul- monary system may exercise one of several options when exposed to car- boxyhemoglobin hypoxia. _ Increased blood flow could restore tissue oxygen to normal and apparently this is the solution chosen by the myocardium but not by the systemic circulation. In Fig. 2, results of Ayres and co-workers (10) in the interpretation of Goldsmith and Aronow (24) are presented. It can be seen that in fact the myocardium does not increase oxygen extraction during exercise. - Another option would be to maintain oxygen consumption without increasing o Reatiny syetemi< Coronary L-L_IJ oxY9en Conrumption / I 2t6xt1 d Evercbe r_l 129 279 L8 10.8 ml/mm ml/min/100 9 Blood Flow a I I 1 1 66 90 -3.0 4.7 Umin mUm'n/f009 Ory9en Estrsctlon from Bbad I !.3 5.9 118 120 0 mutoo mm minoon+ Fre. 2. The effect of exercise on osygen consumplian, blood flow, ar.d ocygen ealraction from blood in the systemic and coronary circul;nion in healthy individuals [a0er Ayres and ao-workcrs ( IB)]. Reprinted with permission from Ref. Q4). - n

, ii , . ., WORKSHOP: CARBON AfONOX1DE AND CVD knowledge of these facts. only recent investigations have been included in Table 3. The "rnean of the mean" of all nine values for smokers in Table 3 is 6.3Sc COHb. This should be a realistic value and is far below the concentration which is expected to cause acute-effects on psychomotor or vigilance performance. (For investigation of CO yield from cigarettes see Robinson and Forbes, 38-) In light of the findings by Astrupand co-workers in 1967 in experiments carried out on rabbits, it was thought that CO in cigarette smoke may have contributed essentially to the observed effect of smoking upon the alterations of coronary vessels in men and in animals. Due largely to the study by Astrup and co-workers. CO has been assigned the role of a major arteriogenic agent in tobacco smoke [for review see Astrup. (7)1. - As a result, until 1976 there was little doubt that CO in cigarette smoke is the principal agent responsible for the development of this disease. in that year Davies and co-workers (16) presented a study where both coronary artery ar- teriosclerosis and the-accumulation of cholesterol and lipids in the aorta of rabbits were measured. In spite of the fact that the experimental design used to test the hypothesis was that which has been reported to produce the greatest accumulation of cholesterol in the aortic wall, the obtained-results conflicted with those of Astrup and co-workers. Davies and co-workers have been unable to confirm that an exposure to CO results in any significant accumulation of cholesterol in the aorta of rabbits. But they observed an increase in coronary artery arteriosclerosis in the animals as measured by the number of internal lesions. In contrast to the increased number of lesions, the percentage stenosis of affected arteries was rather higher in the animal group which was not exposed to CO. Also in 1976, another study was published by Armitage and co-workers (3) investigating the effects of CO on the development of arteriosclerosis in the white Carneau pigeon. CO had no enhancing effect in normocholesterolemic birds- In birds with hypercholesterolemia induced by adding 1% cholesterol to the diet, the severity of coronary artery arteriosclerosis was significantly higher in birds ex- posed to CO than in nonexposed birds. But this was only valid after an exposure time of 52 weeks: it was not detectable after an exposure time of 84 wecks. The severity of arteriosclerosis was related to the degree of hypercholesterolemia. In view of these reports demonstrating only negligible effects of CO exposure on the aortic accumulation of cholesterol, Astrup and co-workers repeated their previous experimenis. As was shown by Astrup and Kjeldsen (8), a different and improved assay method showed no influence of CO exposure on the development of arteriosclerosis in rabbits. _ To summarize the chronic effects of CO on the development of arteriosclerosis one can say that in numerous experiments, CO had no effect in normocholes- terolemic animals. Though the epidemiological data suggest an acceptable role for tobacco smoke in CVD, especially in coronary sclerosis, evidence linking CO as the causative agent has not been established. Naturally studies in man with single components of tobacco smoke are not feasible- The statistical corrclation between CO exposure in tobacco smoke and arteriogenesis may only reflect the fact that CO and the following COHb levels may be a marker for the intake of other substances in tobacco smoke.

WORKSHOP: CARBON MONOXIDE AND C\'D 33. lones. 1. G., and Sinclair, A. Arlerial disease amongsl blast furnace rnrlcrs. Amr. lJ, rnp. ll:e. 18, 15-20t197c1. 34. Kannel. W. B.. McGee. D., and Gcudon, T. A gen<r2l cardiosascvlar risk profile: The Framirgham studv. Ar,irc J. CnrJinl. 38, 16-51 f1976). . 35. Kullcr. L. H.. Radford. E. P-, Sa ift, D.. Pcrper. J. A., and Fisher. R. Carbon monoxide and hean attacks. Arch. Emwnn. fferrlrh 30, 477-48? (1975). - - - - 36. Langone.l. 1.. Gjika. H. B., and van Vunakis. H. Nicotine and os mctabolijes. Radioimmunoas- says for nicotine and-colinine. Blnrhrmisln- 12, 50?5-5030 11 9')1. 37.-Okuno, T. Smoking and blood changes. J.41fd 225. 1387-1?88 t I973). ' 39. Robinson,J.C..andForbes.F.Theroleofcaibonmonoxideincicueoesmoking.Arrh.Enriron. Nenlrh 30, 4?5-431 (1975). 39. Scheidemandel, V., and Daum, S. Carboxyhemogiobin concemraiions of the Munich populaiion- h6irnrhrrr. Sfed. Wnrhrmrhr. 115, 109-11? (1977)- 40. Schievelbein. H.. and Grundke, K. Gas-chromatographische ?iethode zur Oeslimmung von \ico- tin in Hlut und Gtueben. Z. AnnC. Chrni. 237, 1-8 (l9h8). 41. Schiavelbein. H.. Heinemann, O-, Loeschenkohl. K.. Troll. Clr.. and Schlegel. 1. V<iabolie aspects of smoking behaviour, in "Smoking Behaviour IR. E. Thurntyn, Ed.l. pp 371-379- Churchill Livingstont. Edinburgh-Landon-Vew.York, 198- 4_'. Schievclbein. H., Londong. V., Londong. \V., Grumbach, H.. Rreplik. V.. Schauer, A.. and Immich. H. Nicotire and ateriosclerosis. An expmimental coniribution to the influence of nicotine on fat metabolism. Z. Klin. Chrm. K(in. Biorhrm. 8. 190-196 ( 1970)- 43. Scott, R. A., Henson. D. E., Lesak, A.. Tumer, R. 1.. Nalikova. S.. and Hass. G. M. Rulaiions between metabolic increase in plasma free fauy acids and ihc occurrence of arterioscleroiic thrumhoancritis in.rabbits. Anrrr. J. PrtthnL 70, 209-213(1973). 44. Smith, J. R., and Landa., S. A. Smokers' pol.cy:hcmia..\'. En,l. J. 1/rJ. 298, 6-10119781. 45. Stewart. R- D. Baretla. E. D.. Plaue, L. R., Stewart, E- B.. KalTfkisch. J. H.. van Tserfoo, B., and Rimm, A. A. Carboxyhemoclobin levels in American blocd docors.l.l sf.i 229, 1187- 1195 (1974). 46. Turner, D. V., and Topping. D. L. The effect of tobacco smoke and some of its con+timems on triglyceride secretion in the squirrel munkey. Rex. Canrn:v_n. Clrrm. Pndiol. Pherun:uJ. 12, 85 - 100 (1975).

WORKSHOP: CARBON MONOXIDE AND CVD co-workers and Anderson and co-workers (I, 5) obtained in patients with CVD provide some evidence that these conclusion; may be-valid. With regard to the action of CO, conclusions can be drawn in accordance tcith the "The Committee on Medical and Biological Effects of Environmental Pollu- tants, Subcommittee on Carbon lfonoxide of 1977" (14) and in contrast to the different opinion of AronoW (5) that there is no evidence suegesting a higher incidence, prevalence, or prognosis of heart disease among industrial lsarkers who are exposed to high CO concentrations. Further, it has been shown that nicotine and CO are not components of major importance for the development of arteriosclerosis and CVD. but in my opinion. on the basis of damaged coronary_arteries, they may well support the occurrence of an acute event such as angina pectoris. myocardial infarction, and-sudden death. With regard to CO the effect may depend on the COHb level in the blood and on the extent of CVD, but a COHb_level as it is normally found in smokers may not harm healthy persons. In my opinion, there is no doubt as to the association of cigarette smoking and the increased risk for CVD. On the other hand, the interpolation of data from animal studies With a single smoke component seems to be very hazardous and may lead to incorrect interpretations, In this connection the experiments of Turner and Topper (46) should be mentioned. They found that the hepatic lipid secretion was very different when different amounts of total smoke xvere applied while maintaining quantitatively similar-CO and nicotine levels. Finally, it should be borne in mind that we are far from having evaluated all the causes for CVD. As has been-shown by Kannel and co-uorkers (3-3) the risk factors investigated in the Framingham Study which are the risk factors known so far by us, accounted for only one-fifth of the 8-year incidence of coronary heart disease. REFERENCES I. Anderson, E. W., Andelman. R. 1.. Strauch.l. \L. Formin, N. 1., and Knelson. 1. H. Effect of low•level carbon monoxide exposure on onset and duration of angina pecloris. A study in Ien patients v,ith ischemic heart disease. Ann. Jnrern. Aled. 79, 46-SO t 1973/. 2. Andrus. L. H., Miller, D. C., Stallones. R. A., Ehrlich. S. P-. and Jones. 1. P. Epidemiological study of coronary disease risk factors. Anrer. J. Epidenrinf. 87, 73-86 f 19581 . 3. Armitage. A. K.. Davies. R. F., and Turner. D. ll. The effects of carbon monoxide on the development of atherosclerosis in white Carneau pigeon..4rhrrosrleruoii 23, 3'3-334 119761. 4. Armitage. A. K., Dollery, C. T.. George, C. F., Houseman. T. H.- Lewis, P. 1.. and Turner, D. M. Absorption and metabolism of nicotine by man during cigarette smokieg. Br:r. L Clin. PGnnnacnl. 1, 18U-181 (1974). 5. Aronow, W. S. Effect of carbon monoxide on eardiocascular diseae. Prer. S/eJ. 8. (%3<7-rXq (1979). 6. Astrup, P. Intraerythrocytic 2.3-diphosphoglycerate and carbon monoxide exposure..lnn. N.Y. Acnd. Sci. 174, 252-'-54 (1970). 7. Astrup, P. Studies on carbon mononide and nicotine, in "Smoking and Health. I. Slodif)ing the Risk for the Smoker " (E. L. wynder. D. HofTmann. and G. B. Gori. Eds.). pp. 371--3J1. U.S. Department of Hcalth, Education, and Welfare. 1976. 8. Astrup, P., and Kjaldsen, IC Model studies linking carbon monoxide and"or nicotine to ar- teriosclerosis and cardiovascular diseasa Prn-. )fed. 8, Wr)-000 ( 19791. 9. Ayres, S. M., Evans, R. G., and Beohler, M. L. The prevalence of carboxyhemegJobinemia in I i,.l~ ~

.'251o H.SCHIEVEL6EIN - - New Yorkers and its effects on the coronary and systemic circulation. Prr.t 3fed. 8, 000-000 (1979). 10. Ayres. S. M., Giannelli. S.. Jr., and Mueller, H. Effects of low concentretions of carbon monoxide. Parl IV..P.tyocardial and systemic responses to carboxyhembglobin Ann. N.Y. Acad. Sri. 174. ?68-293 ( 1970). - 11. Barnard. R. J., and Duncan. H. W. Heart rate and ECG responscs of frrc 5ghlers.l. Orcup. 31rd. 17, '_47 (1975). - - 12. Bamard. R. J., Gardner, F. W.; Diaco, N. V., and Katlus, A. A- Near-masimal $CG stress testing and coronary artery disease risk factor analysis in Los Angeles city fire Gghters.J. Ocrup. Afrd. 17, 693-694 (1975). - 13. Brody. J. S.. and Coburn, R. _F. Effects of elevated carboxyhcmoglobin on gas exchange in the lung. Ann. N. )'. Arnd. Sri. 174, 256-260 (1970). - 14. Carbon monoxide. M1ledical and Biologic Effects of Environmental Pollutants. National Acadcm,v of Sciences. Washington. D.C.. t977. - 15. Cole. P. V. Comparative effects of atmospheric pollution and cigarette smoking on car- box)haemcglobin levels in man. Nnturr rLondnn) 255, 699-701 (19751. 16. Davies. R. F., Topping, D. L, and Turner. D. \I. The effect of intermittent carbon monoxide exposure on experimental atherosclerosis in the rabbil. Arhernsrlerusis 24. 5'-7-536 (1976). 17. Dauber, T. R.. Kannel. W. B.. Revotskic. N.. Slokes, J., Kagan. A., and Gordon, T. Some factors associated a¢h.the development ofcoronary heart disease. Six }'ears's foilowup experi- ence in the Framingham Study.Anier, J. PArh. Henlrh ,Vat. Health 49, 1349-1356 (1959). I8. Dinman. B. D., Eaton, I. W-, and Brewer, G. J. Effects of carbon monoxide on DGP concenrra- tions in the erythrocyte. Anrr. ;V.Y. Acnd .S6. 174, 246-251 (19701. 19. Do,vle. J. T. Risk factors in arteriosclerosis and cardiovas<ular discasc, with special emphasis on cigarette smoking. Prec. M1fed 8, 000-000 (-19791. 20. Fisher. E. R.. Rothstein. R.. Wholey. M. A.. and Nelson. R. Influence of nicoline on experimental atherosclerosis and its determinants. Arch.. Pnthril 96, .98 (1973). 21 Garrnson, R. J.. Kannel, W. B., Feinleib, \1. Cutelli, W. P. 61cNamara. P. V., and Padgett. S. 1. Cigarette smoking and HDL-chofesterol. Arherosderosis 30, 17-'_5 (1978). 22. Gliner. 1. A.. Raven. P. B-, Horvath, S. Af.. Drinkwater. B. L., and Sutton. J. C. Atads physiologic response lo long-term xork during thermal and pollutanl stress. J. Appl. Phrsiol. 39, 628-632 11975). 23. Goldbourl, U., and lledalie, 1. H. Characteristics of smokers, non-smokers and exsmokers among 10.000 adult malcs in Israel. Anrer. J. Epidrmiol. 105, 77 11977). 24- Goldsmirh, 1. R., and Aronow, W. S. Carbon monoxide and coronary hean disease: A Review. Emirun. Rrs. 10, 236-248 (1975). - 25. Goldsmith- 1. R.. and Landaw, S. A. Carbon monoxide and human health. Srirnrr 162, 135'-I359119581. 26. Grosgogeat. Y.. Anguaca, G., Lellouch, 1.. Jacoto. B., and Beaumont. 1.-L. L-intnxication ehronique par la nicotine chtz le lapin nourri au chnleslero. J. Atherusclrr. Aea- 5, ?91-301 (19651. 27. Hasskins. L- L. Blood carbon monoxide levels as a function of daily cigarette consumption and phyiical activity. Brit. J. brJ. Aled. 33, 123-129 (1976). 28. Heinemann, G., Loeschenkohl, K., and Schievelbein,.H. Evaluation o_f a suitable method for the photometric determination cf small amounts ofcarboxyhemoglobin- Xth Intemat. Congress for Clinical Chemistry, ltexico, February 27-March 3, 1978. 29. Heldxaara, Sf., Karvonen, M. 1., Vilhunen, R., and Punsar. S. Smoking. carbon monoxide, and atherosclerotic diseases. Brit. ,ifed. J. (, 268-270 (1978) . 30. Hernberg. S-, Karava, R., Koskela. R.-S., and Luoma, K. Angina pectoris. ECG findings and blood pressure of foundry workers in relation to carbon monoxide exposure Srand. 1 Wurl, Emiron. Heulth 2, (Suppl. 1), 54-63 (1976). . 31- Hill. P. Nicotine: An etiological factor for coronary heart disease. in "Smokir.g and Heahh. I. Modify ing (he Risk for the Smoker" (E. L. Wynder. D. Hoffmann. and G. B. Gori. Eds.). pp. 313-319. U.S. Department of Health, Education. and Welfare. 1976- - 32. Issac, P. F.. and Rand, M. 1. Cigarette smoking and plasma levels of nicotine. .%anrrr iLnndnrq 236, 308 (197'_). l~