Carboxyhemoglobin Formation Research Articles

The relationship between carbon monoxide breathing, tumour oxygenation and local tumour control in the C3H mammary carcinoma in vivo.

The effect of acute carbon monoxide (CO) breathing on blood oxygenation and tumour hypoxia was related to the radiation response of the C3H/Tif mammary carcinoma. Blood gas analysis showed that CO breathing caused a time- and dose-dependent formation of carboxyhaemoglobin (HbCO), a significant left shift of the oxygen dissociation curve and a reduction in tumour blood perfusion. These factors all contributed to a marked drop in tumour oxygen supply. In agreement with this, tumour hypoxia was found to be significantly increased: Microelectrode PO2 measurements showed a clear relationship between CO concentration and the proportion of low PO2 measurements (< or = 5 mmHg). The fraction of clonogenic hypoxic cells increased from 8% in air-breathing animals to 13%, 18% and 54% with 75,220 and 660 p.p.m. CO respectively. The tumour hypoxia resulted in significant radiation modification. The local tumour control after single-dose and fractionated irradiation gave TCD50 enhancement ratios (relative to air-breathing controls) of 0.90, 0.85 and 0.89 for single dose and five or ten fractions given in 5 days (P < 0.005 for all values). For 15 fractions in 5 days with 6- 6- and 12 h intervals, the TCD50 was similar in CO- and air-breathing mice, presumably as a consequence of insufficient reoxygenation during the short inter-fraction intervals. It is concluded that elevated HbCO levels to increased tumour hypoxia and that the induced hypoxia has a significant impact on the local tumour control also after fractionated irradiation.

Effect of methanol or modifications of the hepatic glutathione concentration on the metabolism of dichloromethane to carbon monoxide in rats.

1. The metabolism of dichloromethane (DCM) to carbon monoxide as measured by the carboxyhaemoglobin (COHb) level in the blood is stimulated by pretreatment with methanol (MET). After simultaneous administration of both DCM, 6.2 mmol kg-1 p.o., and MET, > 148 mmol kg-1 p.o., the COHb formation is inhibited. 2. MET ingestion results in a transient decrease of the glutathione (GSH) content of the liver. In rats treated with GSH-depleting chemicals such as diethylmaleate (DEM), phorone (PHO), or buthionine sulphoximine (BSO) there were no enhancements of the carboxyhaemoglobinaemia caused by DCM. The COHb formation was not influenced by an increase of the hepatic GSH concentration due to repeated administration of butylated hydroxyanisole (BHA). 3. It is concluded that cytochrome P450 IIE1 (CYP 2E1) is responsible for the metabolic interaction of both DCM and MET, and MET may be an inducer of CYP 2E1. The two pathways of DCM, the oxidative via CYP 2E1 and the metabolism via GSH/GSH-S-transferase seem to be independent.

Smoking, a cause of back trouble?

Epidemiological studies strongly imply that smoking may be a risk factor for back problems. It has been speculated that this is due to frequent coughing, unhealthy life style or osteoporosis in smokers. All of these hypotheses, however, do not accord with the experimental evidence. A new theory is therefore proposed. It suggests that smoking leads to malnutrition of the disc which in turn renders it more vulnerable to mechanical stress. Malnutrition can be brought about by carboxyhaemoglobin formation, nicotine-induced vasoconstriction, arteriosclerotic vessel wall changes, impairment of fibrinolytic activity and changes in the flow properties of blood. The evidence supporting these pathomechanisms is discussed. Future studies should test the above hypothesis experimentally.

Rate of formation of carboxyhemoglobin in exercising humans exposed to carbon monoxide.

The purpose of this study was to test the CFK equation for its prediction of the rate of formation of carboxyhemoglobin (HbCO) in exercising humans by use of measured values of the respiratory variables and to characterize the rate of appearance of HbCO with frequent blood sampling. Ten nonsmoking male subjects were exposed to carbon monoxide (CO) on two separate occasions distinguished by the level of activity. Steady-state exercise was conducted on a cycle ergometer at either a low (approximately 45 W) or moderate (approximately 90 W) power output. Each experiment began with an exposure of 3,000 ppm CO for 3 min during a rest period followed by three intermittent exposures ranging from 3,000 ppm CO for 1 min at low exercise to 667 ppm CO for 3 min at moderate exercise. Increases in HbCO were normalized against predicted values to account for individual differences in the variables that govern CO uptake. No difference in the normalized uptake of CO was found between the low- and moderate-exercise trials. However, the CFK equation underpredicted the increase in HbCO for the exposures at rest and the first exposure at exercise, whereas it overpredicted for the latter two exposures at exercise. The net increase in HbCO after all exposures (approximately 10% HbCO) deviated by less than 1% HbCO between the measured and predicted values. The rate of appearance of HbCO fits a sigmoidal shape with considerable overshoot at the end of exposure. This can be explained by delays in the delivery of CO to the blood sampling point (dorsal hand vein) and by a relatively small blood circulation time compared with other regions of the body. A simple circulation model is used to demonstrate the overshoot phenomenon.

Influence of aromatic hydrocarbons on the metabolism of dichloromethane to carbon monoxide in rats

The influence of prior or simultaneous oral administration of benzene, toluene, o-, m-, or p-xylene on the carboxyhemoglobin (COHb) level after a single dose of dichloromethane (DCM) was investigated in male rats. Six hours after administration of DCM, 6.2 mmol/kg, the mean maximum COHb level was 9.3 ± 1.9%. This level was significantly enhanced by prior administration of benzene (16.9 mmol/kg) at 12–24 h, of toluene (18.8 mmol/kg) at 20–28 h, of o- (16.6 mmol/kg) and m-xylene (16.3 mmol/kg) at 20–32 h, and of p-xylene (16.2 mmol/kg) at 24–32 h. The corresponding maximum COHb levels were 20.7 ± 1.3, 18.6 ± 1.1, 22.7 ± 1.2, and 13.2 ± 1.0%, respectively. After simultaneous administration of both DCM and the aromatic solvent, the COHb formation was inhibited: values of 1.3 ± 0.3, 1.7 ± 0.4, 3.6 ± 0.2, 1.9 ± 0.2, and 2.0 ± 0.2% COHb, respectively, were found. The inhibition was also evident when DCM was administered 12 h after toluene or m-xylene and 12, 16 or 20 h after p-xylene. The inhibition was dose-related as seen after combined gavage of o-, m-, or p-xylene and DCM. The o- and m-, but not the p-methylhippuric acid (MHA) excretion in the urine was significantly reduced after simultaneous administration of equimolar doses of DCM and the corresponding xylenes. In conclusion, it seems that the stimulation or inhibition of the COHb formation after DCM caused by pretreatment with or by simultaneous administration of the aromatic solvents is due to the induction of cytochrome P-450 IIE1 or to competition between DCM and the aromatic solvent on this isozyme of cytochrome P-450.

Sensitivity Analysis Applied to Coburn-Forster-Kane Models of Carboxyhemoglobin Formation

When mathematical model predictions disagree with the behavior of the physiological system modeled, blame is generally placed on the inadequacy of the model. It was shown using the Coburn-Forster-Kane (CFK) models of carboxyhemoglobin (COHb) formation as illustrations, that a sensitivity analysis of the model can provide estimates of the effects of data variability and inaccuracy on model predictions. Sensitivity functions were derived for each variable in the model, and families of them were plotted as functions of time with work level as a parameter. The sensitivity plots identify the variables which can contribute the most to disparities between model and system behavior and illustrate how the relative importance of the error in each variable changes with both time and work level. For example, with exposure to a constant concentration of carbon monoxide (CO) at a constant level of exercise, errors in blood volume determination, initial [COHb], and total hemoglobin concentration do not affect the calculated equilibrium value of blood [COHb]; neither inspired concentration of carbon monoxide nor endogenous production rate affect the rate at which equilibrium is achieved; and all other variables affect both the equilibrium value of blood [COHb] and the rate at which it is achieved. The sensitivity analysis provides a link between model output variability and input or data variability which can be used to assess the value of efforts to reduce data error and to estimate the overall uncertainty of model predictions.

Compensatory tracking in humans with elevated carboxyhemoglobin

A total of seventy-four men divided into five groups performed a compensatory tracking task for 4 hr with group mean carboxyhemoglobin (COHb) levels of 0.9, 5.6, 6.1, 11.4 or 16.6%. In all but one group, COHb was formed in approximately 5 min by having the subject breathe a high concentration of carbon monoxide (CO) from a Douglas bag. An appropriate low level of CO in the exposure/test chamber maintained the elevated COHb for the 4-hr duration of the experiment. A slow COHb formation group, not exposed to CO during bag breathing, which was only exposed to low-level CO in the exposure/testing chamber, served as a positive control. Even though mean tracking error scores increased in a nearly monotone manner as a function of COHb, the effects were not statistically significant. Even at the highest dose, the increase in tracking error was small. The increased mean error score due to rapid formation was virtually the same as that due to slow formation.

In vivo binding of carbon monoxide to cytochrome c oxidase in rat brain

The possibility of binding of CO to cytochrome c oxidase (cytochrome a,a3) in brain cortex has been examined in vivo by reflectance spectrophotometry. During ventilation with CO-containing gases, cytochrome a,a3 absorption at 605 nm increased in the parietal cortex of anesthetized rats during carboxyhemoglobin (HbCO) formation. HbCO levels, measured by changes in absorption at 569-586 nm in vivo, correlated positively with arterial HbCO by CO oximetry. Arterial blood pressure and calculated O2 content varied inversely with HbCO. During CO exposure, decreases in blood pressure, O2 content, and cytochrome a,a3 oxidation level could be reversed partly at constant HbCO by compression to 3 atmospheres absolute (ATA). After removing CO from inspired gas at 3 ATA, optical and physiological parameters recovered completely to control values except for minor persistent elevations of HbCO. Difference spectra from parallel experiments at constant HbCO revealed absorption minima at 588-592 nm and 600-605 nm as a result of hyperbaric exposure. Spectral analysis of these components was consistent with partial dissociation of a cytochrome a3-CO complex and cytochrome a reoxidation with increasing dissolved O2 in hyperbaric conditions.

Dichloromethane metabolism to carbon monoxide can be induced by isoniazid, acetone and fasting.

Pretreatment of rats with isoniazid (INH) produced an elevation of dichloromethane (DCM) metabolism to carbon monoxide (CO) as measured by carboxyhemoglobin (COHb) formation (Pankow 1988). INH induced an isozyme of cytochrome P-450 that is different from those induced by phenobarbital or 3-methylcholanthrene (Rice and Talcott 1979) and that is distinct from nine other rat hepatic microsomal cytochromes P-450 (P-45Oa-P-45Oi) and therefore designated as cytochrome P-450j (Ryan et al 1985). This isozyme can also be induced by acetone (Koop and Casazza 1985) or by fasting (Hong et al 1987). The results presented in this paper show that DCM metabolism to CO can be induced by INH, acetone, and fasting.KeywordsCarbon MonoxideOxygen InsertionBlood SampiesIndustrial ToxicologyIsoniazid TreatmentThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Carbon Monoxide (CO)-lnduced Hypoxia in Mice: Evaluation as an Experimental Model of Cerebral Ischemia for Drug Screening

An injection of 12.5 ml of carbon monoxide (CO) gas into an air-filled chamber (780 ml in volume) caused the death of the ICR or ddY mouse (6-8 weeks old) inside. The average survival time was 2.5 min for either sex of animals treated with nothing or saline and never exceeded 8 min. Pretreatment with pentobarbital Na (30 mg/kg, i.p.), hopantenate Ca (100 mg/kg, i.p.), vinpocetine (5 mg/kg, i.p. or 50 mg/kg, p.o.), flunarizine HCl (5 mg/kg, i.p.), glucose (6 g/kg, i.p.), phenobarbital (30 mg/kg, i.p.), Phenytoin (20 mg/kg, i.p.), arginine HCl (100 mg/kg, i.p. or 1 g/kg, p.o.) and alanine (100 mg/kg, i.p. or 1 g/kg, p.o.) prolonged the survival time of male mice. Insofar as tested, female mice responded rather poorly to these pretreatments. Survival for longer than 8 min occurred in some of the drug-pretreated animals of either sex. To be noted is the finding that most of the animals which survived 8 min once were able to survive the second 8 min on the following day without any drug-treatment. Monitoring of the time course of carboxyhemoglobin formation revealed that the carboxyhemoglobin level reached a plateau of 70% saturation within 2 min and then gradually increased. The lethal level was about 72%. Pentobarbital decreased the formation rate but did not elevate the lethal level. The results indicate that the CO-induced hypoxia model of mice is usable for screening of drug candidates which may be effective for treatment of human ischemic diseases.

Carbon monoxide (CO)-induced hypoxia in mice: evaluation as an experimental model of cerebral ischemia for drug screening.

An injection of 12.5 ml of carbon monoxide (CO) gas into an air-filled chamber (780 ml in volume) caused the death of the ICR or ddY mouse (6-8 weeks old) inside. The average survival time was 2.5 min for either sex of animals treated with nothing or saline and never exceeded 8 min. Pretreatment with pentobarbital Na (30 mg/kg, i.p.), hopantenate Ca (100 mg/kg, i.p.), vinpocetine (5 mg/kg, i.p. or 50 mg/kg, p.o.), flunarizine HCl (5 mg/kg, i.p.), glucose (6 g/kg, i.p.), phenobarbital (30 mg/kg, i.p.), phenytoin (20 mg/kg, i.p.), arginine HCl (100 mg/kg, i.p. or 1 g/kg, p.o.) and alanine (100 mg/kg, i.p. or 1 g/kg, p.o.) prolonged the survival time of male mice. Insofar as tested, female mice responded rather poorly to these pretreatments. Survival for longer than 8 min occurred in some of the drug-pretreated animals of either sex. To be noted is the finding that most of the animals which survived 8 min once were able to survive the second 8 min on the following day without any drug-treatment. Monitoring of the time course of carboxyhemoglobin formation revealed that the carboxyhemoglobin level reached a plateau of 70% saturation within 2 min and then gradually increased. The lethal level was about 72%. Pentobarbital decreased the formation rate but did not elevate the lethal level. The results indicate that the CO-induced hypoxia model of mice is usable for screening of drug candidates which may be effective for treatment of human ischemic diseases.

Toxicological interactions between carbon monoxide and carbon dioxide

Fischer 344 male rats were subjected to 30-min individual or combined exposures of carbon monoxide (CO) and carbon dioxide (CO 2). All deaths from CO occurred during the exposures, and the LC 50 values were 4600 and 5000 ppm, depending on experimental conditions. Animals exposed to CO 2 concentrations ranging from 1.3 to 14.7% for 30 min were neither incapacitated nor fatally injured. The addition of nonlethal concentrations of CO 2 (1.7 to 17.3%) to sublethal concentrations of CO (2500 to 4000 ppm) caused deaths of the exposed rats both during and following (up to 24 h) the 30-min exposures. The most toxic combination of these two gases (2500 ppm CO plus 5% CO 2) increased the rate of carboxyhemoglobin (COHb) formation 1.5 times that found in rats exposed to 2500 ppm of CO alone. The COHb equilibrium levels were the same. Exposure to both CO and CO 2 produced a greater degree of acidosis and a longer recovery time than that observed with either single gas. The results fit a mathematical model indicating a synergistic interaction. Combustion of 11 materials at their LC 50 values indicated that CO was probably the primary toxicant in one case and that the combined CO plus CO 2 was the cause of the deaths in three other cases. Additional fire gases need to be studied to explain deaths from the other materials.

Whole Body Oxygen Utilization During Acute Carbon Monoxide Poisoning and Isocapneic Nitrogen Hypoxia

Carbon monoxide (CO) poisoning occurs frequently in victims of enclosed space fires, resulting in the formation of carboxyhemoglobin (COHb). Based on in vitro studies it has been suggested that CO poisoning causes a left shift of the oxyhemoglobin dissociation curve, decreasing peripheral oxygen extraction and exacerbating hypoxic injury. Formation of carboxycytochrome oxidase has also been postulated to act as a toxin by blocking cellular oxygen utilization. The effects of in vitro CO poisoning were evaluated in studies of 12 anesthetized, paralyzed dogs ventilated at 150 cc/kg/min. Six were subjected to CO poisoning by ventilation with a 0.5% CO in air inspirate. Six were ventilated with a mixture of air and nitrogen (N2) to produce a similar decrement of arterial oxyhemoglobin (aO2Hb) saturation. Arterial and mixed venous blood gases, thermal dilution cardiac output, and spectrophotometric arterial and mixed venous O2Hb and COHb saturation were measured. Oxygen consumption (VO2) and extraction (EXT) were calculated from these measurements and the CO and N2 groups were compared by ANOVA and Wilcoxon sign rank test as oxyhemoglobin was progressively decreased. There were no significant differences in VO2 or O2 EXT in these two sets of animals subjected to equivalent reductions of arterial oxyhemoglobin despite the fact that CO poisoning was the mode of desaturation in one group. These findings suggest that CO poisoning is primarily a hypoxic lesion caused by replacement of O2Hb by COHb. Effects predicted from in vitro studies may not be manifest in vivo due to physiologic responses active in the whole organism. This may have implications for the resuscitation of CO-injured patients. Language: en

The effect of an unusual workshift on chemical toxicity: I. Studies on the exposure of rats and mice to dichloromethane

The 10- or 12-hr workday has become increasingly popular in industry. Current occupational exposure limits are designed to protect workers on the standard 8-hr/day workshift and are not intended for use for longer workshifts. Experiments were conducted to compare the effects of a 12-hr exposure schedule to those of an 8-hr schedule on the carboxyhemoglobin (COHb) formation resulting from dichloromethane (DCM) inhalation. Rats and mice were exposed to 200, 500, or 1000 ppm DCM for 8hr/day for 5 days or 12 hr/day for 4 days. The effect of the unusual exposure schedule on COHb levels was not significant. The metabolic pathway for the formation of COHb appeared to be saturated even at the lowest concentration of DCM. To examine the possible increase in the retention of inhaled DCM in the longer exposure schedule, single exposures for 8 and 12 hr were compared. The peak blood DCM level was dependent upon the DCM exposure concentration, but the half-life was independent of the duration of exposure and the concentration of DCM. The half-life of COHb in blood was prolonged by increasing the DCM concentration, but was not affected by the exposure period. Pyrazole treatment decreased COHb level and increased blood DCM level in rats exposed to DCM. These results suggest that the exposure limit for a chemical with a short biological half-life and readily reversible toxic effect may not need to be adjusted for a longer workshift which is in agreement with some of the mathematical models based upon the pharmacokinetics of a toxicant.

The mechanism of coronary artery spasm: Roles of oxygen, prostaglandins, sex hormones and smoking

A reduced oxygen supply to the heart causes coronary vasodilatation in the first instance. But if the hypoxia is severe or prolonged, the dilatation passes off and coronary vasospasm develops leading to a vicious circle with a further reduction of myocardial oxygenation. The spasm is associated with increased outflow of prostaglandin (PG)-like material and can be prevented or reversed by inhibitors of PG synthesis such as indomethacin or antagonists of PG action such as chloroquine. The spasm does not appear to be caused by thromboxane (TX) A2 since selective inhibitors of TXA2 synthesis enhance the hypoxic spasm and by themselves can cause spasm even in oxygenated hearts. The mechanism may be related to loss of negative feedback control of the PG pathway by TXA2. Oxygen may enhance TXA2 production and reduce formation of vasoconstrictor PGs, while smoking, because of the formation of carboxyhaemoglobin, may have the opposite effect. Oestradiol and testosterone do not influence the hypoxic spasm but progesterone at physiological concentrations blocks it completely. Progesterone may be the protective female hormone and the increased susceptibility to myocardial infarction in women on oral contraceptives may be related to reduced formation of endogenous progesterone.

Paint-Remover Hazard

The in-home use of paint removers containing methylene chloride results in the absorption of this solvent, which is metabolized to carbon monoxide. Exposure for two to three hours can result in the elevation of carboxyhemoglobin (COHb) to levels that stress the cardiovascular system. The metabolic formation of COHb continues following the paint-remover exposure, doubling the duration of the cardiovascular stress produced by a comparable COHb level after exposure to CO. Patients with diseased cardiovascular systems may not be able to tolerate this unexpected stress.

Alteration of carbon monoxide and hypoxic hypoxia-induced lethality following phenobarbital, chlorpromazine, or alcohol pretreatment

Mice were pretreated with phenobarbital, chlorpromazine, or alcohol prior to exposure to 1900 ppm carbon monoxide (CO) or 7.5% oxygen (O 2) environments. Pretreatment for 1 hr with chlorpromazine or ethanol increased the lethality of mice exposed to both CO and 7.5% O 2, while 1-hr phenobarbital pretreatment had no effect on CO lethality but increased 7.5% O 2 lethality. Changes in carboxyhemoglobin concentrations that were observed were inconsistent with the alteration in CO lethality. Studies of red blood cell 2,3-diphosphoglycerate concentrations and rate of carboxyhemoglobin formation in vitro showed that the apparent affinity of hemoglobin for oxygen and CO remained unchanged following drug or alcohol pretreatments. The different effects of the pretreatments on CO and 7.5% O 2 lethality and the lack of correlation of CO lethality with carboxyhemoglobin concentrations suggests that there are other factors besides extracellular events directly associated with oxygenation of tissues which are critical determinants of the lethal potential of CO or 7.5% O 2.

Acute carbon monoxide poisoning.

Acute carbon monoxide poisoning most commonly follows inhalation of coal gas but may also occur from internal combustion engines fumes and in burns victims. The condition must be treated with urgency. This paper describes the pathology of formation and dissociation of carboxyhaemoglobin and discusses the management including normobaric and hyperbaric oxygen. It is recommended that hyperbaric oxygenation be used where possible in acute carbon monoxide poisoning.

NERVOUS DISORDER IN ACUTE CARBON MONOXIDE POISONING

In acute carbon monoxide poisoning the action of carbon monoxide on living organism has not been recognized to be explained satisfactory on the basis of oxygen lack alone, and thus some factors which might explain the essential properties of carbon monoxide poisoning have been assumed and investigated. We have found a factor by examining animals exposed to carbon monoxide biochemically and pharma-cologically. The factor in acute carbon monoxide poisoning was the velocity of carboxy-hemoglobin formation, but not carboxyhemoglobin formation in itself. This factor may be named as the inner circumstance factor corresponding to the outer circum-stance factor. This factor may also be considered to have some important roles not only in carbon monoxide poisoning but also in other many poisonings.

Pulmonary gas transport time: larynx to alveolus.

The transport time of gas from the larynx to pulmonary alveolar capillary blood was directly measured by injecting a bolus of carbon monoxide into the inspired airstream of dogs and photoelectrically monitoring the formation of carboxyhemoglobin in the capillaries on the surface of the lung. The rapidity of transit (0.3 second) implies that gas transport during inspiration is facilitated by an interaction between bulk flow and diffusion.