PREVENTIVE
MEDICINE
8,
404-406 (1979)
Summary of the Workshop on Carbon Monoxide and Cardiovascular Disease, Berlin, October 10-12, 1978 GIO B. GORI Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014
A primary interest of this conference has been to identify, if possible, methods for prevention of disease and premature mortality that may result from exposure to carbon monoxide (CO). In this respect, there has been a resounding consensus that exposure to CO should be limited in all situations where feasible, whether the exposure is voluntary or not, habitual or casual. Clearly, prevention can be achieved without a detailed understanding of the pathogenic action of a given hazard, simply by controlling exposure and intake. The occupational health guidelines and methods presently available seem to offer a reasonable hope for prevention, even though questions of standard definition still await those refinements that any regulatory effort must undergo as knowledge progresses. Cigarette smoking is a major source of exposure to CO, although it appears that manufacturing methods of some modern cigarettes have been successful in reducing emission of about one order of magnitude when compared with traditional cigarettes. It would seem desirable that continuing research should be directed at devising methods for further reduction of the CO emission in cigarettes, to control exposure in occupational settings and in the general environment, to determine no-effect threshold levels and their range of values in healthy individuals and in those with histories of CVD or other predisposing diseases such as emphysema. The conference comes to the conclusion that exposure to CO leading to abnormal COHb levels may be without chronic consequences in normal individuals who appear able to compensate for whatever acute effects are present, at least up to certain ceilings of exposure. On the other hand, it leaves no doubt that abnormal COHb levels may aggravate cardiovascular disease in all its manifestations. However, these effects may be specifically apparent in individuals with pre-existing cardiovascular impairment. The most obvious acute effect is the hypoxia created by a decreased oxygencarrying capacity of the blood, even though such an effect may be compensated by the apparent higher hematocrit levels in individuals chronically exposed, such as smokers. Binding of CO to myoglobin also could effect oxygen transport in skeletal and cardiac muscles alike. However, in certain experiments, dogs supplied intravenously with high concentrations of COHb did not show the toxic effects of dogs that achieved the same COHb levels by direct inhalation of CO, indicating that the toxic effects may not be mediated by COHb, but rather by the dissolved plasma CO and its effects on cellular receptors. 404 0091-7435/79/030404-03$02.00/O Copyright @ 1979 by Academic Press. Inc. All rights of reproduction in any form reserved.
WORKSHOP:
CARBON
MONOXIDE
AND
CVD
405
Indeed, other preliminary and yet unconfirmed findings suggest that CO may bind to cytochrome oxidase in the reduced state, inhibiting respiratory functions in mitochondria. This could cause a decrease in total O2 utilization at the cellular level, a possibility also suggested by the finding of the virtually constant PO2 concentrations at tissue level, in spite of increase in circulating COHb. However, it must be said that mitochondrial cytochrome blockade as an explanation for acute myocardial failure still awaits confirmation. Its probability should be viewed critically also because of the known normal endogenous CO production during iron reclamation in the metabolism of heme molecules, although endogenously derived concentrations of CO are probably much lower than those encountered through environmental exposures. In general, it is agreed that a high COHb level decreases oxygen extraction by the myocardium and may be a factor in the attending cardiovascular sequelae. Current views on the pathogenesis of atherosclerosis point to the role of serum lipids, lipoproteins, and cholesterol. These molecules normally percolate through the intact arterial endothelium and, under certain conditions, do not interfere with normal processes of endothelial wear and tear and repair. When the relative concentrations of VLDL, LDL, and HDL are shifted toward VLDL and cholesterol levels are in excess of 150 mg per 100 ml of plasma, the situation is believed to aggravate endothelial injury and repair, and to result in atheromas and occlusive plaque formation. Genetics may play a significant role in individual susceptibility, and factors that modulate these events are many, diet being the most obvious one, while hypertension is also known to accelerate percolation of lipids, cholesterol, and lipoproteins through arterial endothelium. Smoking also may depress the concentration of HDL and is known to increase serum lipids and cholesterol levels, with an apparent aggravating effect on the risk of atherosclerosis. Whether this is due to direct CO effects is not known, but some experiments indicate that CO may inhibit lysosomal lipase activity in animals. In general, however, the conference indicates that the possible role of CO in the pathogenesis of CVD is still obscure; in other words, it is not yet clear whether the respiratory, enzymatic, and circulatory disturbances that have been associated with increased COHb levels have a direct or even indirect causative role in the pathogenesis of CVD. Investigations find it difficult to differentiate CO effects from those of other environmental disturbances or from those individual variations imposed by genetic factors. With cigarette smokers in particular, the relative contributions of CO, nicotine, allergenic fractions, and other yet unsuspected smoke components are very difficult to separate. The conference suggests that further research into the possible contributions of CO may have to concentrate on the utilization of better animal models-dogs or higher primates-for chronic studies, and on human volunteers for acute effects. In vitro studies should utilize organ and tissue cultures of specific target cells, where possible models of cellular transformation to myomas could be identified and modulated experimentally through a variety of risk factors. These models could also offer opportunities for studies of endothelial structure and function, and for biochemical and physiologic studies of myocardial function, cholesterol and lipoprotein transport and deposition, respiration, and attending enzymatic studies.
406
GIO
B. GORI
Recent interests in the possible role of allergic reactions in inflammation, thrombosis, and atherosclerosis also could be explored profitably. Continuing emphasis should be given to acute and chronic laboratory and epidemiologic studies in man, with better awareness of confounding variables in the choice of subjects and experimental design. The epidemiology of high-risk occupations and special groups of smokers should provide additional clues on the possible actions of CO in cardiovascular disease, particularly if conducted in populations that lack concomitant risk factors, such as the Japanese, or that experience particular conditions such as highaltitude living. The conference indicates that no beneficial effects are apparent as a result of abnormal CO exposure. While different individuals may be exposed without apparent harm to different concentrations of CO, the actual outcome could depend on predisposing disease, genetic makeup, and environmental and other conditions. With current knowledge, it may be difficult to establish no-effect thresholds of general validity, even though these may be suggested by available large epidemiologic studies in smokers. For the present time, the prudent course would seem to suggest control of human exposure to CO, specifically in the workplace. The cigarette industry should make use of the methodology available to lower the CO emission but, at the same time, continue to reduce the concentration of other undesirable components which are likely to prove more significant than CO in the development of less harmful cigarettes.
MEDICINE
8,
404-406 (1979)
Summary of the Workshop on Carbon Monoxide and Cardiovascular Disease, Berlin, October 10-12, 1978 GIO B. GORI Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014
A primary interest of this conference has been to identify, if possible, methods for prevention of disease and premature mortality that may result from exposure to carbon monoxide (CO). In this respect, there has been a resounding consensus that exposure to CO should be limited in all situations where feasible, whether the exposure is voluntary or not, habitual or casual. Clearly, prevention can be achieved without a detailed understanding of the pathogenic action of a given hazard, simply by controlling exposure and intake. The occupational health guidelines and methods presently available seem to offer a reasonable hope for prevention, even though questions of standard definition still await those refinements that any regulatory effort must undergo as knowledge progresses. Cigarette smoking is a major source of exposure to CO, although it appears that manufacturing methods of some modern cigarettes have been successful in reducing emission of about one order of magnitude when compared with traditional cigarettes. It would seem desirable that continuing research should be directed at devising methods for further reduction of the CO emission in cigarettes, to control exposure in occupational settings and in the general environment, to determine no-effect threshold levels and their range of values in healthy individuals and in those with histories of CVD or other predisposing diseases such as emphysema. The conference comes to the conclusion that exposure to CO leading to abnormal COHb levels may be without chronic consequences in normal individuals who appear able to compensate for whatever acute effects are present, at least up to certain ceilings of exposure. On the other hand, it leaves no doubt that abnormal COHb levels may aggravate cardiovascular disease in all its manifestations. However, these effects may be specifically apparent in individuals with pre-existing cardiovascular impairment. The most obvious acute effect is the hypoxia created by a decreased oxygencarrying capacity of the blood, even though such an effect may be compensated by the apparent higher hematocrit levels in individuals chronically exposed, such as smokers. Binding of CO to myoglobin also could effect oxygen transport in skeletal and cardiac muscles alike. However, in certain experiments, dogs supplied intravenously with high concentrations of COHb did not show the toxic effects of dogs that achieved the same COHb levels by direct inhalation of CO, indicating that the toxic effects may not be mediated by COHb, but rather by the dissolved plasma CO and its effects on cellular receptors. 404 0091-7435/79/030404-03$02.00/O Copyright @ 1979 by Academic Press. Inc. All rights of reproduction in any form reserved.
WORKSHOP:
CARBON
MONOXIDE
AND
CVD
405
Indeed, other preliminary and yet unconfirmed findings suggest that CO may bind to cytochrome oxidase in the reduced state, inhibiting respiratory functions in mitochondria. This could cause a decrease in total O2 utilization at the cellular level, a possibility also suggested by the finding of the virtually constant PO2 concentrations at tissue level, in spite of increase in circulating COHb. However, it must be said that mitochondrial cytochrome blockade as an explanation for acute myocardial failure still awaits confirmation. Its probability should be viewed critically also because of the known normal endogenous CO production during iron reclamation in the metabolism of heme molecules, although endogenously derived concentrations of CO are probably much lower than those encountered through environmental exposures. In general, it is agreed that a high COHb level decreases oxygen extraction by the myocardium and may be a factor in the attending cardiovascular sequelae. Current views on the pathogenesis of atherosclerosis point to the role of serum lipids, lipoproteins, and cholesterol. These molecules normally percolate through the intact arterial endothelium and, under certain conditions, do not interfere with normal processes of endothelial wear and tear and repair. When the relative concentrations of VLDL, LDL, and HDL are shifted toward VLDL and cholesterol levels are in excess of 150 mg per 100 ml of plasma, the situation is believed to aggravate endothelial injury and repair, and to result in atheromas and occlusive plaque formation. Genetics may play a significant role in individual susceptibility, and factors that modulate these events are many, diet being the most obvious one, while hypertension is also known to accelerate percolation of lipids, cholesterol, and lipoproteins through arterial endothelium. Smoking also may depress the concentration of HDL and is known to increase serum lipids and cholesterol levels, with an apparent aggravating effect on the risk of atherosclerosis. Whether this is due to direct CO effects is not known, but some experiments indicate that CO may inhibit lysosomal lipase activity in animals. In general, however, the conference indicates that the possible role of CO in the pathogenesis of CVD is still obscure; in other words, it is not yet clear whether the respiratory, enzymatic, and circulatory disturbances that have been associated with increased COHb levels have a direct or even indirect causative role in the pathogenesis of CVD. Investigations find it difficult to differentiate CO effects from those of other environmental disturbances or from those individual variations imposed by genetic factors. With cigarette smokers in particular, the relative contributions of CO, nicotine, allergenic fractions, and other yet unsuspected smoke components are very difficult to separate. The conference suggests that further research into the possible contributions of CO may have to concentrate on the utilization of better animal models-dogs or higher primates-for chronic studies, and on human volunteers for acute effects. In vitro studies should utilize organ and tissue cultures of specific target cells, where possible models of cellular transformation to myomas could be identified and modulated experimentally through a variety of risk factors. These models could also offer opportunities for studies of endothelial structure and function, and for biochemical and physiologic studies of myocardial function, cholesterol and lipoprotein transport and deposition, respiration, and attending enzymatic studies.
406
GIO
B. GORI
Recent interests in the possible role of allergic reactions in inflammation, thrombosis, and atherosclerosis also could be explored profitably. Continuing emphasis should be given to acute and chronic laboratory and epidemiologic studies in man, with better awareness of confounding variables in the choice of subjects and experimental design. The epidemiology of high-risk occupations and special groups of smokers should provide additional clues on the possible actions of CO in cardiovascular disease, particularly if conducted in populations that lack concomitant risk factors, such as the Japanese, or that experience particular conditions such as highaltitude living. The conference indicates that no beneficial effects are apparent as a result of abnormal CO exposure. While different individuals may be exposed without apparent harm to different concentrations of CO, the actual outcome could depend on predisposing disease, genetic makeup, and environmental and other conditions. With current knowledge, it may be difficult to establish no-effect thresholds of general validity, even though these may be suggested by available large epidemiologic studies in smokers. For the present time, the prudent course would seem to suggest control of human exposure to CO, specifically in the workplace. The cigarette industry should make use of the methodology available to lower the CO emission but, at the same time, continue to reduce the concentration of other undesirable components which are likely to prove more significant than CO in the development of less harmful cigarettes.
