Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 8 (2010) / Chapter Skim
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2 Carbon Monoxide
2 Carbon Monoxide
Pages 49-143
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From page 49... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
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Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing odor, taste, and sensory irritation, or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL.
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At this exposure level, patients with coronary artery disease may experience a reduced time until onset of angina (chest pain) during physical exertion (Allred et al.
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Exposure to the derived AEGL-3 concentrations will result in COHb values of about 14-17% in adults, which, based on case reports, were considered protective of heart patients against CO-induced myocardial infarction. It should be noted, however, that a clear threshold for this end point cannot be defined because myocardial infarction might be triggered at lower COHb in hypersusceptible individuals.
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(31 mg/m3) coronary artery disease (Allred et al.
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. Environmental exposure to CO can occur while traveling in motor vehicles, working, visiting urban locations associated with combustion sources, or cooking and heating with domestic gas, charcoal or wood fires, as well as by environmental tobacco smoke.
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For nonlethal effects of CO, subjects with coronary artery disease (increased frequency of arrhythmias and reduced time to onset of angina and to changes in the electrocardiogram) and children (syncopes and long-lasting neurotoxic effects)
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Symptoms .1 Physiologic background 2 During physical exertion reduced concentration time to onset of angina and electrocardiogram signs of myocardial ischemia in subjects with coronary artery disease 3-8 Background concentration 5-6 Increase in cardiac arrhythmias in in smokers subjects with coronary artery disease 7 Headache, nausea in children 10 No appreciable effect, except 13 Cognitive development deficits in shortness of breath on vigorous children exertion, possible tightness across 15 Myocardial infarction in subjects the forehead, dilation of cutaneous with coronary artery disease blood vessels 20 Shortness of breath on moderate 25 Syncopes in children exertion, occasional headache with 25 Stillbirths throbbing in temples 30 Decided headache, irritable, easily fatigued, judgment disturbed, possible dizziness, dimness of vision 40-50 Headache, confusion, collapse, fainting on exertion 60-70 Unconsciousness, intermittent convulsion, respiratory failure, death if exposure is long continued 80 Rapidly fatal Source: Adapted from WHO 1999a. The susceptible subpopulations for lethal effects are subjects with coronary artery disease and the unborn fetus (see Section 2.3)
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. Over 80% of the survivors had COHb levels below 40%.
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Mean COHb values for Groups A and B were 62% ± 10% and 28% ± 14%, respectively. In Group A, the percentages of subjects with COHb levels of 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, and 80-90% were 2%, 6%, 26%, 44%, 21%, and 2%, respectively, and 3%, 25%, 32%, 24%, 12%, 3%, 0.6%, and 0.6% of the patients in the corrected Group B had COHb values of 0-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 6070%, and 70-80%, respectively.
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Autopsy revealed three-vessel coronary artery disease and global subendocardial ischemia. Two blood samples showed COHb of 24.1% and 21.5%.
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The patient's medical profile was negative for coronary heart disease risk factors, such as smoking, hypertension, diabetes mellitus, and coronary artery disease. A coronary angiogram performed 1 week later failed to reveal evidence of coronary obstructive lesions.
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. TABLE 2-4 Incidence of Atherosclerotic Coronary Artery Disease and COHb in Fatalities That Involved CO Exposure Number of Cases Group 1 Group 2 Group 3 Total 28 10 100 Age (years)
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Further evidence that these subjects had coronary artery disease was provided by the presence of at least one of the following criteria: angiographic evidence of narrowing (~70%) of at least one coronary artery, documented prior myocardial infarction, or a positive stress thallium test demonstrating an unequivocal perfusion defect.
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Forty-one subjects with established coronary artery disease (36 men and 5 women) with a mean age of 62.8 ± 1.1 years were analyzed.
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(1993) studied 28 men and 5 women with documented coronary artery disease and a minimum of 30 ventricular ectopic beats per hour over a 20 h period.
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. The following COHb values were measured at the end of exposure: 0, 31, 32, 32, 33, 39, 41, 42, 43, 45 and 52% in subject H.C., 0, 27, 35, 41, 43 and 48% in subject F.C.
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From page 66... ...
to investigate the effect of physical exertion at different COHb levels. The COHb was determined colorimetrically by measuring the amounts of carmine solution that had to be added to the diluted blood sample or to an equal dilution of normal, oxygenated blood to adopt the color of a CO-saturated blood dilution.
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TABLE 2-5 Effects of Acute Carbon Monoxide Exposure in a Human Subject Exposure Total Concentration, Exposure At Time (min) / Volume % (ppm)
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68 TABLE 2-5 Continued Exposure Total At Time (min) / Concentration, Exposure Number Volume % (ppm)
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Subject JHB reached COHb concentrations of 25% (mean of eight experiments) and 33% (four experiments)
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analyzed 28 patients with CO poisoning that were 14 years old or younger; 25 of the 28 CO exposures were secondary to faulty venting or faulty combustion of gas furnaces, 2 of 28 were secondary to faulty combustion of a gas stove, and 1 of 28 was secondary to motor-vehicle exhaust. Twelve patients had COHb concentrations of less than 15% and were completely asymptomatic.
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Symptoms and COHb concentrations are presented in Table 2-6. All patients were successfully treated with hyperbaric oxygen.
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, violent anger, and nervosity were observed. In eight children 4 to 9 years old, the intoxication did not alter the intellectual capacities, but in six cases (reported COHb concentrations of 4%, 6%, 25%, and 27%; missing data for two children)
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COHb levels were measured on 66 persons and showed a mean of 18.2 ± 6.4%, with almost half falling between 21% and 25%. Persons in whom COHb levels were drawn had a mean exposure time of 107 ± 33 min.
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Results presented in Table 2-8 show that mean COHb in severe and very severe poisonings were only slightly higher (not statistically significant) than those in the mild and moderate group.
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TABLE 2-8 COHb, Exposure Duration, and Lactate Concentrations in Relation to Severity of Carbon Monoxide Poisoning Mild and Moderate Severe and Very Very Severe Parameter Poisonings (no.) Severe Poisonings (no.)
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In conclusion, the three cases of stillbirths were associated with maternal COHb concentrations of 22% or higher.
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1991. TABLE 2-10 Overview of Clinical Scoring, COHb and Fetal Outcome Time of COHb Exam After Treatmenta Grade (%)
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discharged 36 h later in good health and delivered a term healthy male infant weighing 2920 g. week 16 3 39 not stated 100% oxygen by face mask for Poisoning was caused by a malfunctioning heater; after 18 h 19-year-old, 8 h; after 5 h COHb had reduced exposure she complained of severe headache and nausea; she pregnancy to 4% was discharged after 8 h of oxygen therapy and delivered a week 30 healthy 3940-g male infant.
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2.8 5 h with oxygen 100% oxygen by face mask The woman was found unconscious together with case 5; fetal 6 heart rate was 136 per min at the scene and 190-200 per min 5 18-year-old, treatment during ambulance and helicopter h after the exposure; after 5 h, she was somnolent but oriented pregnancy transport to the hospital and regained full mental alertness during the next 2 h; fetal week 13 heart rate decreased to 150-160 per min the next day and the woman was discharged; she delivered a nonviable 1210-g fetus at 33 weeks of gestation; autopsy revealed brachycephaly, craniosynostosis, multiple organ cavity anomalies, multiple contractures of extremities, hypoplastic lungs and a small brain with hydrocephalus. Source: Adapted from Caravati et al.
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indicated that most lethal poisoning cases occurred at COHb levels higher than 40% and that survival of CO-exposed humans were likely to be seen at levels below 40%. Persons with coronary artery disease constitute a subpopulation that is much more susceptible to the effects of CO.
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irreversible neurotoxic effects resulting in defects in the cognitive development and in behavioral alterations were observed in a long-term followup study, especially in young children (mean COHb 21%) (Klees et al.
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82 TABLE 2-12 Summary of LC50 Data in Laboratory Animals Concentration Exposure Species Remark Reference (ppm)
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log log time (min) FIGURE 2-1 LC50 values for CO in different species.
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The COHb values were 60% or higher in rats that had died after unrestrained exposure and 50% or higher in rats that had died after restrained exposure. Darmer et al.
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3.2. Nonlethal Toxicity A large number of studies investigated nonlethal effects of single and repeated CO exposures in animals (see WHO [1999a]
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, the animals were removed from the chamber 5 min after the exposure period so that venous blood samples could be taken for COHb analysis. During the four preliminary exposures to CO at 1,000 ppm, there was generally no visible effect on the animals until 18-20 min of exposure had elapsed, at which time they generally became less active, occasionally sitting down for short periods.
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increased the severity and extent of ischemic injury and the magnitude of STsegment elevation, which was induced in anaesthetized dogs more by coronary artery ligation than by ligation alone.
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for 12 min daily from gestational days 6-18. The COHb level reached at the end of each exposure was 16%.
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Besides a dosedependent increase in embryo lethality, fetus weights were significantly reduced at exposure levels of 125 ppm or higher. No fetal malformations were detected.
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. A COHb of 13-15% increased the severity and extent of ischemic injury and the magnitude of STsegment elevation in a myocardial infarction model in dogs (Sekiya et al.
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CO not only occupies oxygen-binding sites, molecule for molecule, thus reducing the amount of available oxygen, but also alters the characteristic relationship between oxyhemoglobin and the partial pressure of oxygen, which in normal blood is S shaped. The difference in the partial pressure of oxygen between freshly oxygenated arterial blood (P(O2)
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In an individual with diminished coronary circulation because of coronary heart disease, however, this situation may result in a decrease in the venous oxygen partial pressure of the myocardium precipitated by an inability to maintain the normal arterio-venous gradient. Studies in dogs suggest that exercise plus an increased COHb, in addition to the global myocardial hypoxia, leads especially to areas of relative hypoxia in the left ventricle secondary to redistributive changes in subendocardial blood flow (Einzig et al.
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, in turn explaining the sublethal COHb levels in blood samples from deceased people exposed to CO. CO shifts from the blood into the muscle tissue have been reported in the literature (Luomanmaki and Coburn 1969; Bruce and Bruce 2006)
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Statistical analysis showed no statistically significant differences in COHb levels between heart and peripheral blood samples (Levine et al.
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. Differences among COHb levels in the heart blood when compared with those found in the periphery (e.g., femoral vein)
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Species Variability With regard to lethal effects, COHb concentrations of 50-80% have been reported as lethal in rats and guinea pigs (Rose et al.
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1985) or even to contribute to death from myocardial infarction in individuals with coronary artery disease (Grace and Platt 1981; Balraj 1984)
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. Due to physiologic adaptation in these subpopulations, they are not considered more susceptible than patients with coronary artery disease.
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Because it is generally not advisable for patients with severe coronary artery disease to travel to places at high altitude, it is not considered necessary to especially take that part of the identified susceptible subpopulation (that is, patients with coronary artery disease; see below) into account when deriving AEGL values.
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From page 100... ...
. Because rats have a higher ventilation rate per kilogram of body weight than humans, their COHb concentrations reach the steady state faster, and, therefore, for the same exposure time, the slope for rats is smaller than the corresponding slope for humans, that is, the COHb concentration depends strongly on the ventilation rate in humans compared with rats.
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From page 101... ...
They used the following integrated form of the CFK equation and parameters: where A = PO2/M OHb B = 1/DL + PL/VA M = Ratio of affinity of blood for CO to that for O2; M = 218 OHb = mL of O2 per mL blood; OHb = 0.2 COHbt = mL of CO per mL blood at time COHb0 = mL of CO per mL blood at beginning of the exposure PO2 = average partial pressure of oxygen in the lung capillaries; PO2 = 100 mm Hg VCO = rate of endogenous CO production; VCO = 0.007 mL/min DL = diffusivity of the lung for CO; DL = 30 mL/min mm Hg PL = the vapor pressure of water at body temperature, PL = 713 mm Hg Vb = blood volume; Vb = 5,500 mL PCO = partial pressure of CO in the air inhaled (mm Hg) VA = alveolar ventilation rate; VA = 6,000 mL/min (awake)
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The CFK model predicted COHb for both men and women as well as for resting and exercising subjects within a standard error of about 2%. In contrast to the original model, which assumes all variables to be constant except t, PL, COHbt, and PCO, the following parameter alterations were introduced: PO2: When the partial pressure of oxygen in inspired air (PiO2)
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The arterial-venous difference ranged from 2.3% to 12.1% COHb. The CFK equation overestimated venous blood COHb, whereas arterial blood levels were significantly and consistently underestimated.
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. In patients with coronary artery disease, which constitute the most susceptible subpopulation, effects, such as significant electrocardiogram changes, reduced time to the onset of angina, and increased cardiac arrhythmia, start occurring at exposure concentrations little higher than current ambient air quality guidelines (e.g., the U.S.
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FIGURE 2-2 COHb for different exposure concentration–time combinations. Source: Peterson and Stewart 1975.
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DATA ANALYSIS FOR AEGL-2 6.1. Human Data Relevant to AEGL-2 In patients with coronary artery disease, COHb of 2 or 4% significantly reduced the time to angina and the time to 1-mm change in the ST segment of the electrocardiogram during physical exercise; at 4% the total exercise time and the heart-rate-blood-pressure product were also significantly reduced (Allred et al.
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6.3. Derivation of AEGL-2 The derivation of AEGL-2 values was based on effects in patients with coronary artery disease.
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For the derivation of AEGL-2 values a level of 4% COHb was chosen. At this exposure level, patients with coronary artery disease may experience a reduced time until onset of angina (chest pain)
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In contrast to the anecdotal case reports on myocardial infarction discussed in the derivation of AEGL-3, the studies investigating electrocardiogram changes and angina symptoms in patients with coronary artery disease, used here for the derivation of AEGL-2 values, are high-quality, well-conducted experimental studies with well-characterized exposure conditions and information on interindividual variability. An exposure concentration of 4% COHb is unlikely to cause a significant increase in the frequency of exercise-induced arrhythmias.
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No study is available that compared the effects on the cardiovascular system of a 4% elevation of the background COHb level in nonsmoking and smoking patients with coronary artery disease. However, a single exposure to COHb levels of 6.2-11.5% over a smoking background of 3-8%
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A level of 4% COHb was the NOEL for AEGL-2 effects in patients with coronary artery disease; the LOEL was estimated at 6-9%. In comparison, the LOEL was about 10-15% in children and 22-25% in pregnant women.
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From page 112... ...
However, the Polish study considered 321 lethal CO poisonings from 1975 to 1976 and provided COHb levels for 220 survivors and 101 fatal cases. The survivors had a mean COHb level of 28.1% (SD = 14.1)
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In these cases, the COHb measured in the maternal blood were higher than 22-25%. Persons with coronary artery disease constitute another susceptible subpopulation (Balraj 1984)
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However, the Polish study considered 321 lethal CO poisonings from 1975 to 1976 and provided COHb levels for 220 survivors and 101 fatal cases. The survivors had a mean COHb level of 28.1% (SD = 14.1)
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that reported headache as the only symptom when subjects were exposed to 20-33% COHb. Several case reports indicate that in patients with coronary artery disease, CO exposure can contribute to myocardial infarction.
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At slightly higher COHb levels (5-6%) , there may be an increase in cardiac activity in subjects with coronary artery disease (WHO 1999a)
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Therefore, heavy smokers with coronary artery disease, which have a higher risk for myocardial infarction already from smoking (American Heart Association 2002) , may be at somewhat higher risk compared with nonsmoking patients.
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The category severity definitions are no effect, discomfort, disabling, some lethality, lethal, and AEGL. In the figure depicting the COHb levels, the AEGL lines are drawn at the COHb levels for adults.
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FIGURE 2-3 Categorical representation of all CO inhalation data.
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The ERPG-1 value is based on a COHb of 5-6%, which, based on the original CFK model using a ventilation rate at rest, is considered to be produced by 1 h CO exposure to 200 ppm. This exposure level is not expected to produce any effects during a 1 h exposure period.
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The committee cautions that sensitive individuals, such as persons with angina or heart disease, should not be exposed to concentrations approaching the EEGL as they may incur serious adverse health effects (Comment: The EEGL derivation excludes patients with coronary artery disease. Moreover, model calculation for deriving EEGL values assumed a resting ventilation rate, while for derivation of AEGL values a ventilation rate corresponding to light to moderate activity was assumed)
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From page 122... ...
1989b. Acute Ef fects of Carbon Monoxide Exposure on Individuals with Coronary Artery Disease.
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1985. Exacerbation of coronary artery disease by occupa tional carbon monoxide exposure: A report of two fatalities and a review of the lit erature.
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1986. Myocardial infarction after acute carbon monoxide poisoning: Case report.
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1981. Subacute carbon monoxide poisoning.
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1989. Effects of low-level carbon monoxide exposure on resting and exercise-induced ventricular arrhythmias in patients with coronary artery disease and no baseline ec topy.
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1989. Effects of short-term exposure to carbon monoxide in subjects with coronary artery disease.
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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Koch, 1991. Effects of 4 Percent and 6 Percent Carboxyhemoglobin on Arrhythmia Production in Patients with Coronary Artery Disease.
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2000. Pediatric carbon monoxide poisoning.
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(1990, 1991) Toxicity end point: In an experimental study in 63 subjects with coronary artery disease, a significantly reduced time to ST-segment depression in the electrocardiogram and a significantly reduced time to onset of angina pectoris during physical exercise were found at 2 or 4% COHb (Allred et al.
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From page 132... ...
4 h AEGL-3 8 h AEGL-3 = 403 ppm/3 = 130 ppm (150 mg/m3) 8 hAEGL-3 The COHb levels corresponding to the AEGL-3 values are given in Table B-4 in Appendix B
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From page 133... ...
The alveolar ventilation rate was calculated as VA = VE − fVD (Peterson and Stewart 1975) with VE = total rate of ventilation (mL/min)
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Results are shown in Table B-1. For children, newborns, and adult smokers, the end-of-exposure COHb values for exposure to the concentrations calculated in Table B-1 were computed using the CFK model in Table B-2.
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Data are shown for CO exposure concentrations indicated (70-kg man)
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136 Acute Exposure Guideline Levels FIGURE B-2 Calculation of 60-min exposure concentration that would result in 40% COHb in a healthy adult.
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Concentration (ppm) , Rounded 10 5,120 5,100 30 1,810 1,800 60 998 1,000 240 439 440 480 403 400 For children, newborns, healthy nonsmoking adults, and smokers, the end-ofexposure COHb values for exposure to the AEGL-3 exposure concentration–time combinations were computed using the CFK model.
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138 Acute Exposure Guideline Levels TABLE B-5 Continued Experiment Concentration Time COHb COHb Number (ppm)
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From page 139... ...
. In patients with coronary artery disease, which constitutes the most susceptible subpopulation, effects, such as significant electrocardiogram changes, reduced time to the onset and increased cardiac arrhythmia, start occurring at exposure concentrations little higher than current ambient air quality guidelines, e.g., the U.S.
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From page 140... ...
1989b. Acute Effects of Carbon Monoxide Exposure on Individuals with Coronary Artery Disease.
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From page 141... ...
At this exposure level, patients with coronary artery disease may experience a reduced time until onset of angina (chest pain) during physical exertion (Allred et al.
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From page 142... ...
was used to calculate exposure concentrations in air resulting in a COHb of 4% at the end of exposure periods of 10 and 30 min and 1, 4 and 8 h. Data Adequacy: AEGL-2 values were based on cardiac effects in subjects with coronary artery disease, which constitute the most susceptible subpopulation.
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From page 143... ...
Lethal effects from myocardial infarction in hypersusceptible patients with coronary artery disease at even lower CO concentrations, which could be at the upper end of the range of CO concentrations found inside buildings and in ambient air outside, cannot be excluded.
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